THE MECHANISM OF LEWIS ACID CATALYSED EpOXIDE REARRANGEMENT TO ALDEHYDE
A Thesis Submitted in Partial Fulfilment of the Requirements for the Degree of Doctor of Philosophy in Chemistry at the University of Canterbury
by
Shayne G. C. Nam
February 2005
;CENCES
""JAARY
;zD 305
f\I 17+
ii
WORK IN THIS THESIS HAS APPEARED IN THE FOLLOWING PUBLICATIONS "NMR Separation of ~-Prochiral Protons to the Ether Oxygen of Chiral Esters with Lanthanide Shift Reagents.", Coxon, James M.; Cambridge, James R. A.; Nam, Shayne G. C. Org. Lett. 2001, 3, 4225.
"Identification of
~-Prochiral
Protons to the Ether Oxygen of Chiral Esters of 2-
Arylethan-1-o1s with d-Yb(hfc)3 Shift Reagents.", Coxon, James M.; Cambridge, James R. A.; Nam, Shayne G. C. Synlett. 2004, 8, 1422.
111
Acknowledgements I would like to thank Professor Jim Coxon for his supervision and guidance throughout this project. He not only gave me the opportunity to undertake this degree, but maintained good humour and support despite the number of years it has taken me to finally complete this thesis. I finally hope that he now believes he has made a real chemist out of me!
Thanks also must be extended to Professor Michael Hartshorn for taking an interest, coming out of retirement and acting as an unofficial associate supervisor over the last few years. Without your regular Wednesday morning meetings for help, encouragement and weekly deadlines, this thesis would still be an unobtainable dream. I am also grateful for the hours he has spent proof-reading this thesis.
The technical staff in the Chemistry Department have been most friendly and helpful. In particular, I would like to thank Rewi Thompson for providing me with assistance with NMR and especially when I was unable to obtain a sufficient 'lock' during a number of chiral shift analyses.
The Marsden Government Fund are gratefully acknowledged for financial assistance with their postgraduate scholarship.
The staff of College House who have provided me with food and close accommodation to the university laboratory. A special mention must be made to the principal of the College, Dr Andrew Stockley, for not only employing me, but imparting his advice and wisdom throughout my time as a resident tutor. I also met a number of great students who entertained me and left me with fond memories during this time.
Thanks to my parents George and Mary and sister Gynelle for their encouragement throughout my PhD. You have always been there for me in a number of ways during my ongoing education.
To all my Canterbury friends, thanks for all the good times - especially Hitch for being a good mate, Cam and Jo, and Mark for letting me stay in your homes over the last year while writing up my 'life's work'.
Mostly, thank you Tiffany for your love and support over the last 5 years. Your continual commitment and interest in what I have been doing has meant a lot and thanks for lasting the distance living in separate islands and not seeing much of me.
IV
Abstract This thesis describes investigations centred on the mechanistic pathway of the Lewis acid-promoted conversion of epoxides into aldehydes. Such studies were directed to gain new information about this important, fundamental rearrangement which contributes to our knowledge and understanding of how and why chemical reactions occur. The research undertaken involved the use of deuterium labelling studies working with enantio-enrlched epoxides.
Chapter One reviews previous literature and the results of previous mechanistic
studies into the Lewis acid catalysed rearrangements of epoxides.
Chapter Two describes the development of new methodology for the measurement of
the relative amounts of hydrogen and deuterium in each position of the aldehyde produced by hydride or deuteride migration in the rearrangement of styrene oxide. The method consisted of reduction of the aldehyde to an alcohol and subsequent reaction of the alcohol with a chiral acid chloride in the presence of a chiral shift reagent [Yb(hfc)3 or Eu(hfch] to measure the diastereomericlenantiomeric excess in the aldehyde product mixture. The diastereomeric/enantiomeric excess thus determined, can be correlated back to determine the full stereochemical course of the initial epoxide rearrangement. De-convolution of overlapping peaks by mathematical modelling was sometimes necessary.
Chapter Three describes the enantiose1ective synthesis of several undeuterated and
deuterated styrene oxides that were then used as substrates to study their BF3.0Etz and LiCI04 rearrangement to give aldehydes.
In Chapter Four the BF3.OEt2 catalysed rearrangement of enantioenriched deuterated analogues of styrene oxide are investigated.
Chapter Five describes the difficulties encountered when attempting to rearrange both
racemic and optically active styrene oxides with LiCI04 in refluxing benzene. Dr D.Q. McDonald's reactions are reproduced to substantiate the claim that his previously
v reported results were compromised by traces of acid present in the samples of epoxide starting material.
The LiCIOJether catalysed rearrangement of enantio-enriched deuterated analogues of styrene oxide are investigated in Chapter Six with evidence of some racemisation occurring during the rearrangement process.
An overall discussion is presented in Chapter Seven with results of the
rearrangements of styrene oxide. The results are interpreted using both the Blackett and Fujimoto models and comparisons are made with previous mechanistic studies. Explanations and final conclusions are drawn with future studies outlined. The experimental details that substantiate the claims made in the previous chapters are included in Chapter Eight.
vi
TABLE OF CONTENTS
Chapter One
Introduction
1.1
INTRODUCTION ............................................................................................................................ 2
1.2
EPOXIDE STRUCTURE ............................................................................................................... 2
1.3
OCCURRENCES OF EPOXIDES ................................................................................................. 3 1.3.1 Industry ......................................................................................................................................... 3 1.3.2 BiologicaL ..................................................................................................................................... 3
1.4
REARRANGEMENT OF EPOXIDES .......................................................................................... 4
1.5
CATALYSTS FOR EPOXIDEREARRANGEMENTS .............................................................. 6 1.5.1 BF3 as a catalyst ............................................................................................................................ 7 1.5.2 LiCI04 as a catalyst ....................................................................................................................... 8
1.6
DEUTERIUM ISOTOPE EFFECTS ............................................................................................. 8
1.7
PREVIOUS REARRANGEMENT RESULTS ........................................................................... 12 1.7.1 BF3 gas catalysed rearrangement of symmetrically 1,1-disubstituted epoxide ........................... 12 1.7.2 BF3 gas catalysed rearrangement of2,3,3-trimethyl-l-butene .................................................... 14 1.7.3 BF3.OEh catalysed rearrangement of l-octene oxide ................................................................. 16 1.7.4 LiCI04 and BF3.OEt2 catalysed rearrangement of styrene oxide ................................................ 18 1.7.5 NaCI04 rearrangement ofp-methoxystyrene oxide .................................................................... 20 1.7.6 BF3. OEtl catalysed rearrangement of optically active 1, 1-disubstituted epoxide ....................... 21 1.7.6.1
Comparing the Fujimoto study to the Blackett Mechanism .......................................................... 23
1.7.7 BF3.OEt2 and LiCI04 catalysed rearrangement of optically active p-methyl and mmethoxystyrene oxide ................................................................................................................. 24
1.8
WORK DESCRIBED IN THIS THESIS ..................................................................................... 27
vii
Chapter Two
2.1
NMR Determination of Prochiral and Deuterium Populations
INTRODUCTION ......................................................................................................................... 31 2.1.1 Chiral derivatising agents ........................................................................................................... 31 2.1.1.1
Search for methods to reduce the aldehyde product to alcohol ..................................................... 32
2.1.2 Chira1 shift reagents .................................................................................................................... 33 2.1.3 Chiral solvents ............................................................................................................................ 35
2.2
NMRSEPARATION OF THE PROCHIRAL PROTONS jl- TO AN ESTER OXYGEN ..... 35
2.2.1 NMR resolution of esters derived from 2-pheny1ethanol.. .......................................................... 36
2.3
IDENTIFICATION OF jl-PROCHIRAL PROTONS TO THE ETHER OXYGEN OF CHIRAL ESTERS OF 2-PHENYLETHANOL WITH d-Yb(hfc)3 SHIFT REAGENT ......... 43 2.3.1 Assigning the prochiral protons [3- to the ester oxygen in the lH NMR of ester derived from 2pheny1ethanol .............................................................................................................................. 43
2.4
RELATIONSHIP BETWEEN THE RELATIVE INTEGRALS OF THE PROCHIRAL PROTONS AND THE DETERMINATION OF APPROPRIATE DELAY BETWEEN PULSES IN THE lH NMR ........................................................................................................... 46
2.5
INTEGRA TION OF THE lH NMR SPECTRUM BY MANUAL INTEGRATION .............. 48
2.6
INTEGRA TION OF THE IH NMR SPECTRUM USING MATLAB ..................................... 49 2.6.1 '2 Peak versus 3 peak integration' .............................................................................................. 51
2.7
AN ATTEMPT TO IMPROVE THE ANALYSIS BY ENDEAVOURING TO SEPARATE THE PROCHIRAL PROTONS
13- TO A DIOXOLANE LINKAGE ....................................... 52
2.7.1 Preparation of 1,3-dioxolane acetals ........................................................................................... 53 2.7.2 NMR shift studies of 1,3-dioxolane acetals ................................................................................ 54 2.7.3 An attempt to enhance the difference in proton signals with (R,R)-( +)-1 ,2-diphenyl-l ,2ethanediol. ................................................................................................................................... 55 2.7.4 An attempt to separate the prochiral protons [3- of2-octyl-(4R,)5R)-dimethyl-l,3-dioxolane ... 55
2.8
CONCLUSION ....••....•.......•..............................................•.•..•..•..•..•.•.•.•...•.•.•.•.•.•...•.••.•.....•........... 56
viii
Chapter Three
Synthesis of Optically Active Styrene Oxides
3.1
INTRODUCTION ......................................................................................................................... 59
3.2
SYNTHESIS OF OPTICALLY ACTWE STYRENE OXIDE ................................................. 60 3.2.1 Synthesis of undeuterated (S)-styrene oxide ............................................................................... 62 3.2.2 Synthesis of (S)-styrene oxide-a-dJ............................................................................................ 64 3.2.3 Synthesis of (R)-styrene oxide-a-dJ............................................................................................ 67 3.2.4 Synthesis of (lS),(2R)-styrene 3.2.4.1
Chapter Four
oxide-~-dJ
cis) ................................................................ 71
.......................................................................................
71
(AD-a trans) ............................................................ 72
Isomers of (lS),(2S)-styrene oxide-p-dj ........................................................................................ 73
3.2.7 Synthesis of (lR),(2R)-styrene 3.2.7.1
oxide-~-dJ (AD-~
Isomers of (lR),(2S)-styrene oxide-p-dj
3.2.6 Synthesis of (lS),(2S)-styrene 3.2.6.1
(AD-a cis) ................................................................ 68
Isomers of (1S),(2R)-styrene oxide-p-dJ ....................................................................................... 70
3.2.5 Synthesis of (lR),(2S)-styrene 3.2.5.1
oxide-~-dJ
oxide-~-dJ (AD-~
Isomers of (lR),(2R)-styrene oxide-p-dj
trans) ............................................................ 74
.......................................................................................
75
BF3.OEt2 Catalysed Rearrangement of Styrene Oxide
4.1
REARRANGEMENT OF UNDEUTERATED STYRENE OXIDE WITHBF3.OEt2 ............ 78
4.2
REARRANGEMENT OF a-DEUTERATED EPOXIDE .......................................................... 79 4.2.1 Rearrangement of (S)-styrene oxide-a-dJ................................................................................... 79 4.2.2 Rearrangement of (R)-styrene oxide-a-dJ................................................................................... 81
4.3
REARRANGEMENT OF
~-
DEUTERATED EPOXIDE ......................................................... 82
4.3.1 Rearrangement of (1S),(2R)-styrene
oxide-~-dJ
4.3.2 Rearrangement of (lR),(2S)-styrene
oxide-~-dJ (AD-~
(AD-a cis) ....................................................... 83
cis) ....................................................... 85
4.3.3 Rearrangement of (lS),(2S)-styrene oxide-~-dJ (AD-a trans) ................................................... 86 4.3.4 Rearrangement of (lR),(2R)-styrene
oxide-~-dJ (AD-~
trans) ................................................... 87
4.4
DISCUSSION OF ERRORS ......................................................................................................... 88
4.5
DISCUSSION ................................................................................................................................. 89
4.5.1 The rearrangement of cis- and trans-d epoxide (4.14 and 4.16) ................................................. 89
ix
4.5.1.1
The rearrangement of cis-~-deuterated epoxide (4.14) ................................................................ 90
4.5.1.2
The rearrangement oftrans-~-deuterated epoxide (4.16) .............................................................. 91
4.5.2 Fujimoto method to calculate the facial selectivity for hydride migration in the BF3.OEh rearrangement of undeuterated epoxide ...................................................................................... 93 4.5.3 Results for the rearrangement of a-deuterated epoxide (4.6) ..................................................... 95
Chapter Five
Lithium Perchlorate in Benzene Rearrangement of Styrene Oxide
5.1
INTRODUCTION ......................................................................................................................... 97
5.2
REARRANGEMENT OF (S)-STYRENE OXIDE ..................................................................... 99
5.3
THE PURITY AND DRYING OF LITHIUM PERCHLORATE ........................................... 100
5.4
REARRANGEMENT OF (S)-STYRENE OXIDE WITH DRIED LITHIUM PERCHLORA TE ........................................................................................................................ 100 5.4.1 Rearrangement of (R)-styrene oxide ......................................................................................... 101 5.4.2 Rearrangement of 1:1 mixture of (S) and (R)-styrene oxide ..................................................... 102 5.4.3 Rearrangement of (+)-styrene oxide (Lancaster) ...................................................................... 104
5.5
SYNTHESIS OF (+) STYRENE OXIDE FROM META-CHLOROBENZOIC ACID (MCPBA) ...................................................................................................................................... 104 5.5.1 Rearrangement of(+) styrene oxide (MCPBA) ........................................................................ 105 5.5.2 Rearrangement of (+) styrene oxide (MCPBA) purified on an alumina column ...................... 106
REARRANGEMENT OF (+) STYRENE OXIDE (LANCASTER~- CATALYTIC
5.6
AMOUNT OF MCPBA OR MCBA ........................................................................................... I06 5.7
SUMMARY TABLE OF STYRENE OXIDE RESULTS ........................................................ 107
5.8
SYNTHESIS, REARRANGEMENT AND REPRODUCTION OF QUENTIN MCDONALD'S DEUTERATED STYRENE OXIDE RESULTS .......................................... 108 5.8.1 Rearrangement of(+) styrene
oxide-cis-~-dl
and (+) styrene
oxide-trans-~-dl
oxide-cis-~-dl
and (+) styrene oxide-trans-~-dl (purification with
(no purification)
109 5.8.2 Rearrangement of(+) styrene
alumina column) ....................................................................................................................... 110
x
5.8.3 Rearrangement of (+) styrene oxide-cis-~-dl and (+) styrene
oxide-trans-~-dl
(purification with
alumina column and catalytic amount of MCPBA or MCBA) ................................................. III 5.8.4 Rearrangement of (+) styrene
oxide-cis-~-d1 and
(+) styrene
oxide-trans-~-d1
(purification with
alumina column, No LiCI04 only a catalytic amount of MCPBA or MCBA) .......................... 112
5.9
SUMMARY TABLE OF (+) STYRENE OXIDE-CIS-(3-d1 AND (+) STYRENE OXIDETRANS-(3-dl RESUI. TS ............................................................................................................... 113
5.10
CONCLUSION ............................................................................................................................ 114
Chapter Six
Lithium Perchlorate in Ether Rearrangement of Styrene Oxide
6.1
INTRODUCTION ....................................................................................................................... 116
6.2
REARRANGEMENT OF UNDEUTERATED STYRENE OXIDE WITH LiCI04 IN ETHER .1', ............................................................................................................ , ••••••••••••••••••••••••••••••••••••••••
6.3
116
REARRANGEMENT OF a-DEUTERATED EPOXIDE ........................................................ 118 6.3.1 Rearrangement of (S)-styrene oxide-a-d1 ................................................................................. 119 6.3.2 Rearrangement of (R)-styrene oxide-a-d1 ................................................................................. 121
REARRANGEMENT OF (3- DEUTERATED EPOXIDE ....................................................... 122
6.4
6.4.1 Rearrangement of (1S),(2R)-styrene oxide-~-dl (AD-a cis) ..................................................... 122 6.4.2 Rearrangement of (IR),(2S)-styrene oxide-~-dl (AD-~ cis) ..................................................... 124 6.4.3 Rearrangement of (1S),(2S)-styrene oxide-~-dl (AD-a trans) ................................................. 125 6.4.4 Rearrangement of (lR),(2R)-styrene
oxide-~-dl (AD-~
trans) ................................................. 126
6.5
DISCUSSION OF ERRORS ....................................................................................................... 127
6.6
DISCUSSION ............................................................................................................................... 128
6.6.1 The rearrangement of cis- and trans-d epoxide (6.14 and 6.16) ............................................... 128 6.6.1.1
The rearrangement of cis-J3-deuterated epoxide (6.14) ............................................................... 129
6.6.1.2
The rearrangement of trans-J3-deuterated epoxide (6.16) ............................................................ 131
6.6.2 Fujimoto method to calculate the facial selectivity for hydride migration in the BF 3.OEt2 rearrangement of undeuterated epoxide .................................................................................... 132 6.6.3 Results for the rearrangement of a-deuterated epoxide (6.6) ................................................... 134
xi
Chapter Seven
Mechanistic Implications of Optically Active Styrene Oxide Rearranged with BF3.0Et2 and LiCIOJether and Comparisons with other Systems and Models
7.1
THE BLACKETT MECHANISTIC MODEL FOR THE LEWIS ACID CATALYSED REARRANGEMENT OF EPOXIDES ...................................................................................... 136 7.1.1 Surface plots of kDH, kIP, k and MHII'<1niMHcis as a function of the aldehyde ratios derived from either the cis or trans deuterated epoxide ................................................................................. 142
7.2
COMPARISONS OF THE FUJIMOTO MECHANISTIC MODEL WITH THE BLACKETT MECHANISTIC MODEL ................................................................................... 145
7.2.1 A further comparison of the Fujimoto mechanistic model and the Blackett mathematical model with styrene oxide and its derivatives ....................................................................................... 152 7.2.2 A direct comparison of the BF3.OEh and LiCl04 catalysed rearrangement of styrene oxide with p-methyl and m-methoxystyr~ne oxide using only the Fujimoto model. .................................. 153 7.2.3 Mechanistic implications ........................................................................................................... 157
7.3
CONCLUSION ............................................................................................................................ 159
7.4
FUTURE STUDIES ..................................................................................................................... 162
Chapter Eight
Experimental
8.1
GENE~
8.2
EXPER.IMENTAL WORK DESCRIBED IN CHAPTER TWO ............................................ 168
8.3
EXPERIMENTAL WORK DESCRIBED IN CHAPTER THREE ........................................ 179
8.4
EXPER.IMENTAL WORK DESCRIBED IN CHAPTER FOUR .......................................... 196
8.5
EXPER.IMENTAL WORK DESCRIBED IN CHAPTER FIVE ............................................ 201
8.6
EXPER.IMENTAL WORK DESCRIBED IN CHAPTER SIX ............................................... 205
EXPER.IMENTAL .................................................................................................. 166
APPENDIX A .......................................................................................................................................... 212 APPENDIX B "........................... ".................. "......"............................................. ".................................. ".. 219
xii
Abbreviations AD-mix-a
Sharpless asymmetric dihydroxylation a-mix
AD-mix-p
Sharpless asymmetric dihydroxylation p-mix
Ar
aryl, aromatic
br
broad
Bu
butyl
c.
approximately
cj
compare with
d
doublet
o
chemical shift in parts per million
DIDAL
diisobutylaluminium hydride
DMSO
dimethyl sulfoxide
DNA
Deoxyribose Nucleic Acid
ee
enantiomeric excess
EI
electron impact
equiv
equivalent(s)
ES
electro spray
Et
ethyl
Eu(dcm)3
tris-(d,d-dicampholylmethanato) europium (III)
Eu(dpm)3
(dipivalomethanato) europium (III)
Eu(bfc)3
europium tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorate]
g
gram(s)
HMPA
hexamethylphosphoramide
hr
hour(s)
Hz
hertz
IR
infrared
J
coupling constant
L
litre(s)
Il
micro
m
milli, multiplet
M
molar
MCBA
meta-chlorobenzoic acid
xiii
MCPBA
meta-chloroperbenzoic acid
Me
methyl
min
minute(s)
mol
mole(s)
mp
melting point
MS
mass spectrometry
NMR
nuclear magnetic resonance spectroscopy
p-
para-
PBLG
poly-y-benzyl-L-glutamate
ppm
parts per million
PPTS
pyridinium p-toluene sulfonate
Pr(tmhd)3
praseodymium tris(2,2,6,6-tetramethyl-3,5-heptanedionato)
s
singlet
t
triplet
t-
tertiary
THF
tetrahydrofuran
TLC
thin layer chromatography
VS.
versus
CHAPTER ONE
Introduction
Chapter One Introduction
1.1
2
INTRODUCTION
At the heart of the synthesis of new chemical materials is the requirement to understand bond formation and cleavage. The objective of this thesis is to address selected problems introduced into rational synthesis of complex organic molecules by regiochemistry and stereochemistry. Specifically, ring opening reactions of epoxides are frequently used to initiate intramolecular ring closure including chiral synthesis. The most fundamental aspect of our research program is the physical organic investigation of epoxide chemistry important in organic synthesis. Experimental studies were conducted to determine the barriers to internal rotation of intermediate carbocations and measure regiochemistry and facial selectivity to establish a detailed understanding of epoxide rearrangement.
1.2
EPOXIDE STRUCTURE
Epoxides owe their importance to their high reactivity, which is due to the ease of opening of the highly strained three-membered ring. The bond angles of the ring, which average 60°, are considerably less than the normal tetrahedral carbon angle of 109.5°, or the divalent oxygen angle of 110° for open chain ethers. Since the atoms cannot be located to permit maximum overlap of the orbitals, the bonds are weaker than in an ordinary ether and the molecule is less stable. It is well documented that the protonation of an epoxide oxygen weakens the c-o bonds and facilitates ring opening. 1
However, recent work has shown that the rate acceleration of epoxide opening reactions is greater than can be attributed to relief of ring strain. Explanations include a stabilising interaction at the transition state from the symmetry of through bond orbitals2 and stabilisation ofthe positive charge at the reaction centre by the oxygen leaving groUp. 3
Chapter One - Introduction
1.3
3
OCCURRENCES OF EPOXIDES
Many compounds which were formerly of theoretical interest have found ever increasing industrial applications. This is the case of ethylene oxide, which was first prepared by Wurtz in 1859 by the reaction of alkali hydroxide and ethylene chlorohydrin. 4 Many years later, ethylene oxide and its homologues were carefully investigated by Kraususkii. 5 These studies showed the high reactivity of ethylene oxide and other known epoxides, which may serve as starting materials for the syntheses of a series of compounds.
1.3.1
Industry
Epoxides are useful building blocks for an increasing variety of chemical products because a large number of compounds can be obtained from them by simple chemistry. For example, when ethylene oxide is mixed with alcohols in the presence of small amounts of H2S04, monoethers of ethylene glycol are formed. These compounds, when dissolved in
most organic solvents or sometimes in water, are good solvents for many synthetic and natural resins and oils. In the presence of sulphuric, phosphoric, and other acids ethylene oxide is readily hydrated to ethylene glycol. This is widely employed as an anti-freeze in car radiators, as a solvent, preservative, substitute for glycerine and for absorbing methylamine in refrigerator systems. Therefore many epoxide derived products in tum serve to obtain solvents, emulsifiers, synthetic fibres, plastics, pharmaceuticals, insecticides, perfumes, plant protective substances and in the manufacture of explosives. 6 It is now difficult to imagine any branch of industry that has not made use in some way of the progress in epoxide chemistry.
1.3.2 Biological Reactive epoxides are implicated in reactions with DNA and are important carcinogenic materials. 7 The carcinogenic action of halogenated olefins is believed to involve the interaction oftheir metabolically-produced epoxides with cellular nucleophiles, these being a site on DNA. 8 This presumably occurs through the opening of an epoxide c-o bond. For
4
Chapter One - Introduction
example, chlorooxirane is known to alkyl ate various nucleic acid bases, DNA, RNA and protein residues. 9
1.4
REARRANGEMENT OF EPOXIDES
It is well known that epoxide opening reactions can be facilitated by protic or Lewis acids
and can be accompanied by either attack by an external nucleophile, or rearrangement to give aldehydes and ketones by way of a hydride 1,2 shift. lO Work in this thesis will concentrate on the Lewis acid catalysed rearrangement of styrene oxides. A general mechanism of epoxide rearrangement catalysed by BF 3 is shown in Scheme 1.1.
... (b)
_ R
2
7----\-0~BF3
Rl
1.1
HH
1.3
1.2
~
~====l!-!!!=.
tBF' Rl0.H R2
H
1A
Scheme 1.1. Rearrangement of epoxide with BF3.
Co-ordination of the BF3 to either of the electron lone pairs of the epoxide provides electrophilic assistance for opening of the epoxide ring. Breaking of the epoxide c-o bond can occur either (a) with participation of the migrating hydrogen in a concerted process, or (b) without participation of the migrating group to give a short lived carbocation intermediate, where either of the two terminal hydrogens can migrate to give aldehyde.
Analysis of the selectivity for hydride migration can provide information about which of the two pathways is occurring. Rearrangement via pathway (a), where the bond making of
5
Chapter One - Introduction
the hydrogen to the migration terminus is involved in the breaking of the epoxide
c-o
bond, should result only in hydride migration with inversion of configuration at the migration terminus. Hydride migration with retention of configuration will only occur in the two step process (b), where free rotation about the C1-C2 bond of the carbo cation positions a hydrogen to migrate with retention of configuration.
For many years, epoxide rearrangements were considered to be concerted. However, rearrangement of exocyclic epoxide gave epimeric mixtures of aldehydes, which can only occur when the reaction proceeds via a carbocation intermediate: II
~tBU 0
;FtBu H" ..
...
-H+ ...
OH H
OH
1.6
H~IBU
CHO
1.10
1.8
plBU
1.12
1f ~tBu
HO ~tBU.... H H
1.7
....
;F'BU OW'
-H+ .. CHO--.£:::::/ tau
H 1.9
1.11
1.13
Scheme 1.2. Schematic representation of epoxide rearrangement, where configuration of the ring is defined by a 4-tert-Bu group, or fusion to a second ring.
For rearrangement of each of the epoxides 1.6 and 1.7, an epimeric mixture of aldehydes 1.12 and 1.13 was obtained. In each case there was a marginal preference for aldehyde formed from hydride migration with inversion of configuration, i.e. 1.12 from 1.6 and 1.13 from 1.7. In a concerted process, the product of inversion would be formed exclusively. The observation that some aldehyde is formed from hydride migration with retention of configuration, is consistent with the reaction proceeding at least in part via a carbocation intermediate, especially when the concerted product would be the thermodynamically more stable equatorial aldehyde.
Chapter One - Introduction
6
The marginal preference for aldehyde formation from hydride migration with inversion of configuration is explained by epoxide 1.6 initially opening to carbo cation conformer 1.8. A 60° rotation about the CI-C2 bond will give conformer 1.10, where a hydrogen is aligned with the carbo cation p-orbital and can migrate with inversion of configuration. A further 60° rotation gives conformer 1.11, where the other hydrogen is aligned to migrate with retention of configuration. If the rate of rotation were fast relative to the rate of migration, an identical ratio of epimeric aldehydes would be observed. The observed preference for the product formed from hydride migration with inversion of configuration results from the rate of rotation of the cation being comparable to the rate of hydride migration.
1.5
CATALYSTS FOR EPOXIDE REARRANGEMENTS
Many types of catalyst exist for promoting epoxide opening reactions. Protic acids have been used, but the conjugate base of a protic acid is often nucleophilic enough to prevent rearrangement of an opened epoxide. More usually, Lewis acids are used, where coordination of the Lewis acid to either of the epoxide lone pairs provides the electrophilic assistance necessary for epoxide opening.
Thorpe et al. have investigated computationally the co-ordination of BF3 and H+ to epoxide. 12 Co-ordination to the least hindered face is marginally preferred. Co-ordination of a proton to the less hindered face of propene oxide was calculated to be favoured by 0.2 kcallmol over protonation to the more hindered face. The barrier for concerted conversion between the two protonated structures was calculated to be 16.9 kcallmol at the MP2/6-
31G*//MP2/6-31G* level of theory however interconversion is thought to be more likely by equilibrium between the coordinated forms and uncoordinated epoxide. Studies have been conducted investigating the structure of BF/3 and other Lewis acids 14 co-ordinated to carbonyl compounds which show that BF 3 co-ordinates to the lone pairs of the oxygen, while the interaction of a lithium ion is electrostatic. Examples also exist where both lone pairs on the oxygen are co-ordinated to a Lewis acid. 15
Chapter One Introduction
1.5.1
7
BF3 as a catalyst
There is ambiguity in the general literature as to the relative behaviour of the boron trihalides as Lewis acids. BF3 often is named as the strongest Lewis acid of the series with the relative acceptor ability following the stated order BF3 > BCl3 > BBr3 > BI3. This is the order that would be expected from considerations of differences in the inductive effect with the changing electronegativity of the halide. Thus, with fluorine being the most electronegative one could predict, assuming this effect to be the prevailing one, that greater positive charge would reside on the boron atom in BF3 than on the boron atom in BCh and so forth to produce the order in Lewis acidity cited. Apparently the only experimental evidence that would support this order of acidity is the relative chemical stability of the various donor-acceptor complexes of BF 3 compared with the same kind of stability of the analogous BCb and BBr3 complexes. When, for example, a saturated solution of boron trihalide in ethanol is distilled, boron trihalide ethyl etherate is formed. I6 Thus, boron trifluoride-diethyletherate can be distilled without decomposition, while the boron trichloride-diethyletherate cannot be distilled, but decomposes into ethyl chloride and complex mixtures of ethoxy boron chlorides and boron oxychlorides. I7
A study has also been completed investigating the equilibrium constants between BF3.0Eh and carbonyl compounds. IS It was found that for the equilibrium:
o (yl(H
V
...
K
...
Scheme 1.17. Equilibrium between BF3.0Eh and BF3 co-ordinated benzaldehyde.
the equilibrium constant, K
0.208 in CH2Clz.
There are no experimental studies in the literature investigating the co-ordination ofBF 3 to epoxides. The electronic structures of BF3 co-ordinated to carbonyl compounds has been extensively studied by ab initio molecular orbital calculations 19 and recently an x-ray
Chapter One Introduction
8
crystal structure of BF 3 co-ordinated to benzaldehyde has been published. 20 The crystal structure shows that the BF 3 co-ordinates to the oxygen in a trans conformation.
1.5.2
LiCI04 as a catalyst
It has been reported that epoxides undergo facile lithium salt catalysed rearrangement to
carbonyl compounds in benzene solution?} Lithium perchlorate is completely insoluble in refluxing benzene at 80°C, but a small amount of LiCI04 is carried into solution by added epoxide, sufficient to cause rearrangement with reactive systems. There were problems encountered with LiCI04 in benzene as a catalyst and this is outlined in more detail in chapter five.
We required a more successful method involving LiCI04 as the catalyst and a recent report in the literature suggested that highly concentrated solutions of LiCI04 in diethyl ether can induce highly selective transformations. 22 In contrast to the Lewis acid BF3, where coordination is expected to the lone pairs of an ether oxygen, LiCI04 has been shown to interact in an electrostatic fashion with oxygen containing substrates.
1.6
DEUTERIUM ISOTOPE EFFECTS
The replacement of one or more atoms in a reacting system by others of their respective isotopes is one of the most subtle structural perturbations which may be made. Changes in reaction rate which are brought about by isotopic substitution are known as kinetic isotope effects and carry mechanistic information. 23
Isotopic substitution does not affect the potential energy surface of the molecule nor does it perturb the electronic energy levels. It is only those properties that are dependent upon atomic masses which are affected; for chemical purposes, the perturbation can be considered to be limited to vibrational frequencies,z4 Each vibrational frequency, and
Chapter One - Introduction
9
therefore energy, depends on the masses of the atoms vibrating and will vary with the isotopic species.
Vibrational energy will usually change during the course of a reaction or between reagent and transition state since some bonds are in the course of being broken or made and their associated frequencies will be affected. Isotopic substitution should therefore affect reaction rates. The extent to which this occurs depends greatly upon the relative masses of the isotopes.
Our studies focus on hydrogen eH) and deuterium eH) isotope effects, rates being denoted kH and kD respectively.
If kIf'#:- kD a kinetic isotope effect (KIE) exists, expressed as the ratio kHlkD; it is described as "normal" when kHikD > 1 and "inverse" when kHlkD < 1.
A primary isotope effect (PKIE) arises when the bond to an isotopic atom is broken in the rate-determining step; a secondary isotope effect (SKIE) results when the isotopic atom(s) is at the reaction centre, but the bond remains intact throughout the reaction.
A large proportion of observed isotope effects concern C-H bond breaking. The vibrational energy associated with the stretching of a covalent bond (C-H, C-D) is quantised so that
By hcy
(V + 1/2) hv; V
0, 1,2....
where V is the vibrational quantum number, v the frequency of the transition from one level to the next and y the corresponding wavenumber (= 1IA). Values of v for C-H and C-D stretching modes (from lR spectra) are around 3000 and 2100 cm1, respectively, and the corresponding frequencies, v, are 9 and 6.3 (1013 s-I).
Chapter One Introduction
10
In either case, transitions are associated with energy considerably greater than thermal energies at room temperature so that almost all molecules will be populating the ground vibrational level at around 2SoC.
The potential functions (i.e. length-energy relationships) for C-H and C-D bond stretching are essentially identical, but the distribution of rotational energy levels in each bond differs.
Those of the C-D bond lie at a lower energy than those of the C-H bond for a given value of V because the vibrational frequency of deuterium is lower due to its greater mass.
Figure 1.1. Potential energy curves for C-H and C-D bonds showing the different dispositions of vibrational levels and the origins of their different bond dissociation energies. Ez = Ev at V = 0
zero point energy.
11
Chapter One - Introduction
The ground vibrational state is defined by V = 0 so that Ev = Yz hv; this is known as the zero-point energy (vibrational energy remaining even at 0 K) and, as explained, lies lower for the C-D bond.
However, the isotopic difference in the energies of corresponding vibrational levels diminishes as the value of V increases until at the dissociation limit it is zero. It is clear, then, that more energy is expended in breaking a C-D bond than a C-H bond since it was originally at the lower potentiaL
In general, the dissociation energy of a bond to a heavy isotope is greater than that to a
light isotope of the same element and is associated with a slower rate- a normal PKIE.
Relative vibrational frequencies of C-H and C-D stretching modes are approximately in the ratio: 1
(fH/I-lH) _ _ _ 21 (frJI-lD) 2
The force constants, fH = fD' are equal and the relative masses, I-lH, J.lD, can be replaced by the masses ofH, D if the remainder of the molecule is relatively massive. Then
1
2
2
= 1,41
It has been predicted that at room temperature C-H cleavage should be about seven times
faster than C-D cleavage, other conditions being equa1. 25
Calculation of the kinetic isotope effect can be achieved by application of statistical thermodynamics26 and it emerges that the kinetic isotope effect diminishes with
12
Chapter One - Introduction
temperature. For example, the kinetic isotope effects calculated can range from 1620 (-100°C) to 16 (200°C)?7
1.7
PREVIOUS REARRANGEMENT RESULTS
For many years, the focus of the Coxon Research Group at the University of Canterbury has been to understand organic reactions particularly those involving strained small ring opening and molecular rearrangement. Outlined below is a brief historical overview of this group's results and comparison with some international research groups' results relevant to this thesis.
1.7.1
BF3 gas catalysed rearrangement of symmetrically 1,I-disubstituted epoxide
In order to obtain an estimate for the deuterium isotope effect for a 1,2 hydrogen migration, Blackett and co-workers28 rearranged the symmetrical epoxide 1,2-epoxy methylpropane 1.14 with BF3 in CCl4 (Scheme 1.3).
BF3Qas o
+
...
1.15
MeXMe
coo
H
1.16
Scheme 1.3. BF3 catalysed rearrangement of 1,2-epoxymethylpropane-l-d1.
The aldehyde reacted further with epoxide to give dioxolane and a small correction was necessary to account for an isotope effect in this process. The ratio of hydrogen to deuterium migration (MH/Mo) was 1.92. The primary isotope effect for the hydride shift can be obtained by adjusting the value of MHIMO by the small secondary deuterium isotope effect. It was assumed that the secondary isotope effect was in the range of 1.0-1.2 and the true primary isotope effect, kHlkD == C. 2.
13
Chapter One - Introduction
The rearrangement was considered to occur by the following mechanism: -
OBFa
Me~Me H D
aldehyde
aldehyde
...
...
/
kH
F~O~D e Me
...
k'
~
....
k'
-
0BFa MeH-W, Me
H
D
1.19
D
Me~Me H
F3BO
1.20
.l - k' k'
kp
]Iloo
aldehyde
I
1.18
4·
ko
1.17
k
H Me:::®:Me D OBF3
~--)Ioo-
aldehyde
1.21
Scheme 1.4. Migration of hydrogen and deuterium in the rearrangement of 1,2-epoxy methylpropane-1-d1.
It was assumed that there were six minimum energy conformations of cation that need to
be considered. Four have a hydrogen or. deuterium aligned for migration with the carbo cation p-orbital (1.18, 1.19, 1.20 and 1.21). The other two structures (1.17 and its mirror image) have the OBF3 group at 90 degrees to the cation plane.
kH (kD) is the rate constant for the 1,2 migration of hydrogen (deuterium) from a carbon
bearing a deuterium (hydrogen). The ratio lfH/!IlD is the ratio of the rate of hydride migration from a carbon carrying a deuterium I the rate of deuteride migration from a carbon carrying a hydrogen and hence the ratio contains both primary and secondary isotope effects. Calculations have been carried out by Aaron Thorpe12 to separate these effects.
14
Chapter One - Introduction
1.7.2
BF3 gas catalysed rearrangement of 2,3,3-trimethyl-1-butene
As part of an attempt to identify the factors which influence the rearrangement of the intermediate carbocation, Blackett et al. 29 further investigated the selectivity for hydride migration in the rearrangement of a,a-disubstituted epoxide. They rearranged the two deutero isomers of 2,3,3-trimethyl-1-butene oxide 1.22 and 1.25. In this system the symmetry present in the methylpropene oxide system is removed and more information can be obtained. Namely, whether or not the selection of the migrating hydrogen atom depends upon the stereochemical origin of the proton relative to the bulky tertiary butyl group and the smaller methyl group.
The reaction was again complicated by the aldehyde products reacting with epoxide to form dioxolane. Small corrections were therefore made to compensate for the secondary deuterium isotope effect for this reaction. The final, corrected ratios of deuterium labelled aldehydes are shown in Schemes 1.5 and 1.6.
BF3gas
° ,..
t-BuxMe
o
+
CHO
t-BuxMe
coo H
1.23
1.24
1
2.65
Scheme 1.5. Rearrangement of 1.22.
BF3 gas,. CCI4. OoC
t-BuxMe 0
CHO
+
1.23
1.24
1
0.89
Scheme 1.6. Rearrangement of 1.25.
More deuterium relative to hydride migration is observed in the rearrangement of epoxide 1.25 than in the rearrangement of epoxide 1.22. Assuming that the deuterium isotope effect is the same or similar in both reactions, migration of the hydrogen trans to the bulky tertiary butyl group is preferred 1.93 : 1 (MHtraniMHcis) in the rearrangement of nondeuterium labelled material.
Chapter One - Introduction
15
Blackett's results were interpreted using the following mechanistic scheme:
Hb~gBF3 Me "-( Bu
Ha 1.26
1.27
1.30
~ 1.31
aldehyde
aldehyde
Scheme 1.7. Blackett's mechanistic scheme for the rearrangement of 2,3,3-trimethylbut-leneoxide.
Co-ordination of BF3 to epoxide facilitates ring opening to give cation conformer 1.27. It was assumed that the OBF3 group rotates in the direction to relieve the steric interaction between the bulky tertiary butyl group and the OBF3. A 60° rotation about the CI-C2 bond will give conformer 1.28, where Hb is aligned with the cation p-orbital and can migrate. A further 60° rotation would give conformer 1.29, where Ha is aligned with the adjacent porbital and can migrate. It was assumed that there is a barrier to rotation between the two essentially mirror image conformers, caused by the eclipsing of the methyl and OBF3 groups.
Conformations 1.30 and 1.31 were assumed by Blackett to be too high in energy due to the steric interaction between the gauche arrangement of the OBF3 and tertiary butyl groups. Blackett used racemic epoxides and so in his experiment aldehyde formed from conformer 1.28 is indistinguishable from aldehyde from conformer 1.31. Likewise, it was not possible to determine the contribution of conformer 1.29 relative to 1.30.
16
Chapter One - Introduction
The studies reported in this thesis use optically active epoxide so that measurement of the full stereochemical course of hydride (deuteride) migration can be made.
For the Blackett system the relative values for the rate constants for deuteride (kD compared to hydride (kH
=
=
1.0)
1.71) migration and the rate constant for interconversion of
conformers 1.28 and 1.29 (krot
1.84) (Table 1.1) can be evaluated using the expressions:
1.23/1.24 = 1/0.89 = (kD / kH )[1 + (kH / k)] 1.24/1.23 = 2.65 = (kH / k D)[l + (kD / k)]
12,3,3-trimethYI-1-butene oxide (BFs gas)
kHD
kDH
!
MH/ranJMHcis
1.0
1.71
1.84
1.93
Table 1.1. Results of the relative rate for H-migration versus D-migration, rate constant for interconversion and diastereotopic selection for 2,3,3-trimethylbut-l-ene oxide.
1.7.3
BF3.0Et2 catalysed rearrangement of l-octene oxide
Lim et al. 30 investigated the rearrangement of I-deuterated and 1,2-dideuterated 1,2epoxyoctane (1.32 and 1.35, Schemes 1.8 and 1.9), where a secondary carbo cation intennediate could be formed in contrast to the tertiary cation in the system investigated by Blackett. Experiments also showed that an ether solvent (dioxane) was required to effect clean rearrangement of the less substituted epoxide. This was rationalised in tenns of the extra stabilisation required for cleavage of a secondary as opposed to tertiary carbonoxygen bond.
17
Chapter One - Introduction
1.33 1
1.34 4.78
1.36 1
1.37 3.03
Scheme 1.8. Rearrangement of octene oxide.
Scheme 1.9. Rearrangement of octene oxide.
The results were considered consistent with the Blackett model; where more deuterium migrates on rearrangement of 1.35 than 1.32; showing that migration of the hydrogen trans to the bulky substituent is preferred over migration of the cis hydrogen 1.40 : 1
(MHtran/MHcis).
The larger deuterium isotope effect calculated for the rearrangement of octene oxide
(J?HIJtiD
=
4.3) than for the rearrangement of 2,3,3-trimethyl-l-butene oxide (J?HIkflD =
1.71) was considered consistent with the migrating hydrogen being more symmetrically bonded between C 1 and C2 in the transition state for the rearrangement of octene oxide (Table 1.2).
1-octene oxide (BF 3.OEt2 • dioxane)
kHD
kDH
krot
MHtranslMHcis
1.0
4.3
10.0
1.40
Table 1.2. Results of the relative rate for H-migration versus D-migration, rate constant for interconversion and diastereotopic selection for l-octene oxide.
Chapter One - Introduction
1.7.4
18
LiCI04 and BF3.0Et2 catalysed rearrangement of styrene oxide
McDonald et al. 31 investigated the rearrangement of racemic deuterated styrene oxide with LiCI04 in refluxing benzene * and with BF3.0Eh in dioxane at room temperature (Schemes 1.10 and 1.11). It was expected that the aromatic substituent would stabilise a carbo cation intennediate more than in the rearrangement of alkyl substituted epoxide, making it less likely that the reaction will occur via a concerted process.
Ph)2~ H
+
0
1.38
Lewis acid I solvent
1.39
1.40
LiC104 I benzene, t. BF3.0Et2 I dioxane
1.42:t 0.03 1.48:t 0.04
Scheme 1.10. McDonald's rearrangement of styrene oxide-~-dl'
Ph)2~ o
Lewis acid,...
H
1.41
Lewis acid I solvent
Ph H oXCHO
1.39
LiCI04 I benzene, t. BF3.OEt2 I dioxane
+
Ph
H
COOXH
1.40
2.41 ± 0.07 1.83±O.O5
Scheme 1.11. McDonald's rearrangement of styrene oxide-~-dl.
For the rearrangement of styrene oxide with both LiCI04 and BF3.0Et2, more deuterium migration is observed from rearrangement of trans, rather than cis deuterated epoxide 1,41 : 1 and 1.14 : 1 (MHtransIMHcis) respectively (Table 1.3). This is similar to the selectivity observed from rearrangement of2,3,3-trimethylbut-l-ene oxide and l-octene oxide.
• A further investigation in this thesis into the rearrangement of styrene oxide with LiCI04 in benzene has found that the results of D.Q. McDonald have been compromised by traces of acid present in the samples of epoxide starting material. This is detailed in cbapter five.
Chapter One - Introduction
19
kHO
kOH
krot
MHtranJMHc/s
styrene oxide (UCI04. benzene)
1.0
2.0
4.85
1.41
styrene oxide (BFa.OEtz. dioxane)
1.0
1.68
Table 1.3. Results of the relative rate for H-migration versus D-migration, rate constant for interconversion and diastereotopic selection for styrene oxide.
The results from all three of the above studies have been explained with reference to the Blackett model (Scheme 1.12) where rotation of the cation intermediate occurs in the direction to relieve the 1,4 steric interaction between the bulky substituent and the O-BF3 group. Conformation 1.44 is formed first, allowing hydrogen Hb to migrate with inversion of configuration, before rotation t.o form conformer l.4S, where Ha can migrate with retention of configuration at the migration terminus. These two experiments used nonoptically active epoxide and so the assumption that migration from only these two conformations could therefore not be tested or confirmed.
S
..
X+ L
0- -BFa
H
D
OBFa
S~LHa
Hb
1.42
Ha
~~LHb
FaBO
1.43
-
k
...
~
F3BO~Ha S
L
Hb
1.45
~~" aldehyde
1.44
~~. aldehyde
Scheme 1.12. General mechanism of a,a-disubstituted epoxide rearrangement.
20
Chapter One - Introduction
1.7.5 NaCI04 rearrangement of p-methoxystyrene oxide Whalen et aI. 32 examined the rearrangement of p-methoxystyrene oxide in an aqueous solution of 0.1 M NaCI04 (Scheme 1.13). The ratio of hydrogen migration to deuterium migration was determined to be c. 3:1. This ratio is similar to the kinetic isotope effect observed previously for a 1,2-hydride migration33 and it was therefore suggested that the cation intermediate is long-lived and that both terminal hydrogens have equal migratory aptitudes. aldehyde
o
0-
1
H
,H
OMe~",
~I ~H, '" "'~ ~:==!~ ~I ~H: "~ 'H"D "".....==d!!--"'" .~~o~ """"'..==~ ~ _ __ ~ I 'T c OMe
/'/' 1.46
OMe
/'/
1.47
OMe~
T
1.48
~~~ 1.49 0
IH20
t
diol
Scheme 1.13. Reaction ofp-methoxystyrene oxide in basic solution.
Examination of unreacted epoxide starting material' after one half-life of the reaction revealed that scrambling of the deuterium label between the cis and trans positions had occurred. This was attributed to epoxide opening to the stabilised carbo cation, which has a long enough lifetime so that bond rotation and ring closure to the enantiomeric epoxide can occur before hydride migrates to form aldehyde (Scheme 1.13). Opening of the epoxide under these "spontaneous" or pH> 7.5 reaction conditions is therefore reversible.
Coxon et aI.34 later challenged Whalen's conclusions. Since isomerisation of the epoxide is not complete after one half-life of the reaction, suggesting that the rate of hydride migration is comparable with the rate of rotation for conversion between the cation conformers. Based on the observed preference for migration of the HR terminal, proehiral proton (trans to the bulky substituent) in the rearrangement of l-oetene oxide and 2,3,3trimethyl-1-butene oxide, it was argued that a similar bias for migration in the
Chapter One Introduction
21
rearrangement of p-methoxystyrene oxide should exist when the rate of hydride migration is similar or greater than the rate of rotation of the carbo cation.
A solution to this issue required that the rate constants for conversion of epoxide isomers
vs. hydride migration be determined. Whalen et ai. 35 showed that the two prochiral hydrogens did indeed migrate to an equal extent. The rate of conversion of 1.46 in an equilibrium mixture of 1.46 and 1.49 in 1 : 9 dioxane (dfl)-water (PH 9.1) was determined by IH NMR spectroscopy to be 2.4
± 0.1
x 10-3 s·l. The rate constant for epoxide
conversion to aldehyde in the same solvent system was determined to be 7.1 x 10-4 S·I. The rate of equilibration of epoxide deuteroisomers therefore exceeds the rate of epoxide conversion to aldehyde by a factor of3.4.
Whalen also measured the amount of hydrogen compared to deuterium migration that had occurred during aldehyde fon;nation at various stages during the reaction. It was determined that the ratio of hydride/deuteride migration during aldehyde formation remained constant as the ratio of epoxides 1.46 : 1.49 changed. This showed that cis and trans deuterium have equal migratory aptitudes, within the experimental error. Further
evidence for the equal migratory aptitudes of the cis and trans hydrogen (deuterium) comes from rate data, which shows that the rate of aldehyde formation from the rearrangement ofp-methoxystyrene oxide adheres strictly to first order kinetics.
There were two important results from Whalen's study on the reaction of pmethoxystyrene oxide: (1) Epoxide opening to cation is reversible under the basic conditions. (2) There is no stereoselection in that both methylene hydrogens appear to have an equal propensity to migrate.
1.7.6 BF3.0Etz catalysed rearrangement of optically active
l~l-disubstituted
epoxide
Fujimoto recently published an important paper,36 investigating the stereo selectivity of hydride migration in the rearrangement of optically active epoxides 1.50 and 1.55
Chapter One - Introduction
22
(Schemes 1.14 and 1.15). The two a-substituents on this epoxide have a similar steric requirement to the epoxide system studied by Blackett and so should exhibit parallel stereo selectivity of hydride migration.
The two deutero isomers were synthesised optically active using the Sharpless asymmetric dihydroxylation and epoxidation. The epoxides were rearranged with BF3.0Etz in CH2Ch to give aldehyde, but in low yield (21 %). The ratio of aldehydes 1.51-1.54 produced was analysed by reduction with LiAIH4 or LiAID4 and reaction of the resulting alcohol with (S)-MPTACI to give the (R)-MPTA ester. The signals for the S and R protons at C2 of the aldehyde were separated in their lH NMR spectrum, allowing integration and determination of the relative aldehyde populations. The results are shown in Schemes 1.14 and 1.15 .
~
.. Ph(CH2)4
o
BFa·OEtz .. CH2CI2
1.50
H
0
H
~D'~~' 1.51 11
0 D ~~D ,,,,H ~;;C~ +
1.52 17
1.53 50
1.54 22
1.52 14
1.53 22
1.54 33
Scheme 1.14. Fujimoto's rearrangement of 1.50. H
D
Ph(CH2){~~ 1.55
1.51 31
Scheme 1.15. Fujimoto's rearrangement of 1.55.
A deuterium isotope parameter z, was determined from the equation 31z : 14z : 22 : 33 = 50 : 22 : 11z : 17z to be 1.77. This is the ratio by which hydrogen migration is faster relative to deuterium migration. i.e.
Ii?H/kfID.
The value of z was used to estimate the
relative amounts of aldehydes 1.51-1.54 that would be formed from undeuterated epoxide
23
Chapter One - Introduction
(41:18:16:25). This is the ratio of the four transition conformers for hydride migration shown in Scheme 1.16.
F BO
Ha
t;e~CMe2.R
Hb
Hb
OBF 3
Me~CMe2R
1.58
Hb 1.57
Ha 1.59
25
41
16
----),.. ....
Me~CJlllezR Ha
OBF 3
1.60 18
Scheme 1.16. Transition conformers in the rearrangement of undeuterated epoxide.
Fujimoto determined that in undeuterated epoxide, the hydrogen trans to the bulky substituent is 1.44-fold more likely to migrate than the cis hydrogen. This is similar to the result of Blackett et al. 25 , who determined that the trans hydrogen prefers to migrate by a ratio of c. 1.9 : 1. Fujimoto was also able to measure the facial selectivity of the epoxide rearrangement. Blackett et al. 25 only considered that conformers 1.57 and 1.58 were present in the rearrangement process because the system studied did not give sufficient experimental information to include in the analysis the possibility that on opening of the epoxide rotation might occur in both directions. The results from the rearrangement of optically active epoxide show that a significant amount (c. 34%) of the reaction goes through conformations 1.59 and 1.60, where the bulky substituent and OBF3- groups are in a gauche orientation. The results also confirm that 'the hydrogen anti to the bulky substituent prefers to migrate with inversion of configuration at the migrating terminus, whereas the hydrogen syn to the bulky substituent prefers to migrate with retention of configuration. '
1.7.6.1 Comparing the Fujimoto study to the Blackett Mechanism
24
Chapter One Introduction
If the model developed by Blackett25 to calculate rate constants for conversion between cation conformers relative to hydride (deuteride) migration is valid, we should be able to separately apply his mathematics to each side of the Fujimoto Scheme32 and gain interesting results. Calculations are presented later in this thesis by utilising the experimental results obtained by Blackett and Fujimoto to test whether or not Blackett's assumptions are valid.
1.7.7 BF3.0Et2 and LiCI04 catalysed rearrangement of optically active p-methyl and m-methoxystyrene oxide Dr J.R.A. Cambridge recently completed in this laboratory, and in conjunction with my own studies, a study on the BF3.OEt2 and LiCI04 catalysed rearrangement of optically active p-methyl and m-methoxystyrene oxide. 37 This study was directed to further test the assumption that rotation occurs preferentially to relieve the oxygen interaction with the larger substituent on the cation and establish if there is facial selectivity of hydride migration in an epoxide rearrangement. Using the method developed by Fujimot0 32, he determined the course of rearrangement of undeuterated p-methyl and m-methoxystyrene oxide using the data obtained for the deuterated analogues 1.61 and 1.62 (Figure 1.2).
1.61
1.62
Ha = DorHb= D
Figure 1.2. Deuterated analogues of p-methyl and m-methoxystyrene oxide.
Deuterium migration is retarded relative to hydrogen (isotope effect) for each of the four possible transition conformers for hydrogen / deuterium migration. A deuterium isotope
Chapter One Introduction
parameter,
Z =
25
kIflkDH, i.e. (hydrogen migration from a carbon bearing deuterium relative
to deuteride migration from a carbon bearing a hydrogen) was calculated to be 2.5 for pmethyl and 2.3 for m-methoxystyrene oxide. This value allows the relative contribution of each of the four transition conformers in undeuterated material to be established as percentages as B : A : C : D (Scheme 1.17). Ar=m-methoxyphenyl. A=BF3 : 36 Ar=m-methoxyphenyl, A=U+ : 45 Ar=p-methylphenyl. A=BF3 Ar=p-methylphenyl, A=U+
Ar=m-methoxyphenyl. A=BF3 : 16
o
Hc'A'Hb Ar Ha
Ar=m-methoxyphenyl, A=U+ : 0
f
: 32 : 28
Ar=p-methylphenyl, A=BF3 Ar=p-methylphenyl. A=U+
A=BF30rLt
t
t
retention syn
O"A
1°r~'mc ~~aQ)~
anti
c
r A
inversion
o
f
Ar=m-methoxyphenyl, A=BF3 : 33
Ar=m-methoxyphenyl, A=BF3 : 15
Ar=m-methoxyphenyl, A=Lt : 48
Ar=m-methoxyphenyl, A=U+ : 7
Ar=p-methylphenyl, A=BF3 Ar=p-methylphenyl, A=U+
Ar=p-methylphenyl, A=BF3 Ar=p-methylphenyl, A=U+
: 34 : 29
: 17 : 4
: 17 : 38
Scheme 1.17. Estimation of the hydride migration for undeuterated p-methyl and mmethoxystyrene oxide in the BF3.0Et2 and LiCI04 catalysed rearrangement to aldehyde.
The study showed that the rearrangements must proceed at least in part via a carbocation intermediate.
Quite unexpectedly the study also shows that for the p-methylstyrene oxide in the BF3.0Et2 and LiCI04 catalysed reactions, the majority of the reaction occurs by epoxide opening with rotation of the oxygen towards the aromatic group. In the BF 3.0Et2 catalysed reaction, hydride/deuteride migration occurs to an equal extent with inversion or retention of configuration. In the LiCI04 reaction, when epoxide opening occurs with rotation of the
Chapter One - Introduction
26
oxygen away from the aromatic group, hydride/deuteride migration occurs almost exclusively with inversion of configuration. In the case of the deactivated m-methoxystyrene oxide, more of the reaction goes by epoxide opening with rotation towards the aryl group compared with the p-methylstyrene oxide. These were unexpected results as it has been previously assumed that the interaction of the aromatic group and oxygen would be disfavoured.
However, ab initio molecular orbital density functional calculations have been investigated by Cambridge at the B3LYP/6-31+G*//B3LYP/6-31+G* level of theory and for the corresponding carbocation intermediates, the sy n cation (Figure 1.3) has been found to be lower in energy than the anti conformation (Figure 1A) by 3.75 kcallmol. This goes in some way to confirm the preference for rotation towards the aryl group.
Figure 1.3. The syn carbocation mInImUm with equal probability of either hydrogen migrating. 0 kcal/mol.
Figure 1A. The anti carbocation minimum with hydrogen in hyperconjugation with the cation p-orbital. 3.75 kcallmol.
Chapter One - Introduction
1.8
27
WORK DESCRIBED IN THIS THESIS
The objective of the work in this thesis is to further investigate the mechanism of epoxide rearrangement. Specifically, whether the rearrangement of styrene oxide proceeds via a concerted or carbocation pathway and what factors influence the selectivity in the rearrangement process. Of the mechanistic studies described above only that of Fujimoto et al. 32 and Cambridge33 used optically active epoxides, other studies used racemic epoxides and assumptions were made about the stereo selectivity of the rearrangement process. In this investigation optically active styrene oxide is used and these assumptions can be tested. The results of these studies will be interpreted utilising both Blackett and Fujimoto models and compared with the previous mechanistic studies in the literature.
Chapter two describes the development of new methodology for the measurement of the relative amounts of hydrogen and deuterium in each position of the aldehyde produced by hydride or deuteride migration in the rearrangement of styrene oxide. The method consisted of reduction of the aldehyde to an alcohol and subsequent reaction of the alcohol with a chiral acid chloride in the presence of a chiral shift reagent [Yb(hfc)3 or Eu(hfc)3J to measure the diastereomeric/enantiomeric excess in the aldehyde product mixture. The diastereomeric/enantiomeric excess thus determined, can be correlated back to determine the full stereochemical course of the initial epoxide rearrangement. De-convolution of overlapping peaks by mathematical modelling was sometimes necessary. This work was carried out in collaboration with J.R.A. Cambridge and the results of some of this work have been published in Organic Letters38 and Synlett. 39
Chapter three describes the enantioselective synthesis of several undeuterated and deuterated styrene oxides that were then used as substrates to study their BF3.0Eh and LiCI04 rearrangement to give aldehydes.
Chapter One - Introduction
28
In chapter four the BF3.0Eh catalysed rearrangement of enantio-enriched deuterated
analogues of styrene oxide are investigated.
Chapter five describes the difficulties encountered when attempting to rearrange both racemic and optically active styrene oxides with LiCI04 in refluxing benzene. Dr D.Q. McDonald's reactions are reproduced to substantiate the claim that his previously reported results27 were compromised by traces of acid present in the samples of epoxide starting material.
The LiCI04/ether catalysed rearrangement of enantio-enriched deuterated analogues of styrene oxide are investigated in chapter six with evidence of some racemisation occurring during the rearrangement process.
An overall discussion is presented in chapter seven with results of the rearrangements of
styrene oxide. The results are interpreted using both the Blackett and Fujimoto models and comparisons are made with previous mechanistic studies. Explanations and final conclusions are drawn with future studies outlined. The experimental details that substantiate the claims made in the previous chapters are included in chapter eight.
Morrison, R. T.; Boyd, R. N. Organic Chemistry 5th ed. Allyn and Bacon Publishing 1987. 2 Sawicka, D.; Wilsey, S.; Houk, K. N. J. Am. Chern. Soc. 1999, 121, 864. 3 Banks, H. D. J. Org. Chern. 2003,68,2639. 4 WUrtz, A. Ann. Chim. Phys., 1859, 55,400. 5 Krasuskii, K. A. J. Russ. Phys. Soc. 1902,34, 537. 6 Malinovskii, M. S. Epoxides and their Derivatives. Sivan Press Binding 1965. 7 Politzer, P.; Martin, F. J. Chemical Carcinogens 1988, 5, 624. 8 Banerjee, S.; Van Duuren, B. L. Cancer Res. 1978,38,776. 9 Green, T.; Hathway, D. E. Chem.-Biol. Interact. 1978, 22, 211. ni 10 Nonnan, R. O. C; Coxon, J. M. Principles of Organic Synthesis 3 ed. Blackie Academic and Professional 1993,590. II Blackett, B. N.; Coxon, J. M.; Hartshorn, M. P.; Jackson, B. L. J.; Muir, C. N. Tetrahedron 1969, 25, 1479. 12 Coxon, J. M.; Thorpe, A. 1.; Smith, W.B. J. Org. Chern., 1999, 64, 9575. 13 Gung, B. W.; Wolf, M. A. J. Org. Chern. 1992,57, 1370. 14 Wiberg, K. B.; Marquez, M.; Castejon, H. J. Org. Chern. 1994,59,6817. 15 Lewinski, J.; Zachara, J; Horeglad, P.; Glinka, D.; Lipkowski, J, Justyniak, I. Inorg. Chern. 2001,40,6086. 16 Wiberg, E.; Schuster, K. Ber. Dtsch. Chern. Ges. 1934,67, 1807. 17 Muetterties, E. L. The Chemistry ofBoron and its Compounds. John Wiley & Sons, Inc 1967. I
Chapter One Introduction
29
Gajewski, J. J.; Ngernmeersri, P. Org. Lett. 2000,2,2813. Gung, B. W.; Wolf, M. A J. Org. Chem. 1992,57,1370. 20 Reetz, M. T.; Hullmann, M.; Massa, W.; Berger, S.; Rademacher, P.; Heymanns, P. J. Am. Chem. Soc. 1986, 108, 2405. 21 Rickborn., B.; Gerkin, R. M. J. Am. Chem. Soc. 1968,90,4193. 22 Sankararaman, S.; Nesakumar, J. E. Eur. J .Org. Chem. 2000,2003. 23 (a) Melander, L.Isotope E./.fi!cts on Reaction Rates, Ronald Press, New York, 1960. (b) Wiberg, K. B. The Deuterium Isotope Effect, Chem. Rev. 1955,55,713. (c) Melander, L.; Saunders, W. H. Reaction Rates of Isotopic Molecules, Wiley, New York, 1980. (d) Collins, C. J.; Bowman, N. S.Isotope Effects in Chemical Reactions, ACS Monograph, New York, 1970. (e) Westheimer, F. H. Chem. Rev. 1961,61,265. 24 Issacs, N. S. Physical Organic Chemistry, Wiley, New York, 1987. th 25 Atkins, P. W. Physical Chemistry, 5 ed. Oxford University Press, 1994,945. 26 Issacs, N. S. Physical Organic Chemistry, Wiley, New York, 1987. 27 Ibid. Note these values are derived from a highly simplified model and are greatly exaggerated, but illustrate the temperature effect. 28 Blackett, B. N.; Coxon, J. M.; Hartshom, M. P.; Richards, K. E. Aust. J. Chem. 1970,23,839. 29 Blackett, B. N.; Coxon, J. M.; Hartshorn, M. P.; Richards, K. E. J. Am. Chem. Soc. 1970,92,2574. 30 Coxon, J. M.; Lim, C. Aust. J. Chem. 1977,30, 1137. 31 Coxon, J. M.; McDonald, D. Q. Tetrahedron Lett. 1988,29,2575. 32 Ukachukwa, V. C.; Blumenstein, J. J.; Whalen, D. L. J. Am. Chem. Soc. 1986,108,5039. 33 (a) Collins, C. 1.; Rainey, W. T.; Smith, W. B.; Kaye, 1. A J. Am. Chem. Soc. 1959,81,460. (b) Winstein, S.; Takahashi, J. Tetrahedron 1958,2,316. 34 Coxon, J. M.; Hartshorn, M. P. Tetrahedron Lett. 1987,28,1333. 35 Ukachukwu, V. C.; Whalen, D. L. Tetrahedron Lett. 1988,29,293. 36 Hara, N.; Mochizuki, A; Tatara, A; Fujimoto, Y. Tetrahedron Asymm. 2000, 11, 1859. 37 Cambridge, J. R. A PhD Thesis, University of Canterbury, 2004. 38 Coxon, J. M.; Cambridge, J. R. A; Nam, S. G. C. Org. Lett. 26,2001,4225. 39 Coxon, J. M.; Cambridge, 1. R. A; Nam, S. G. C. Synlett. 8,2004, 1422. 18
19
CHAPTER Two
NMR Determination of Prochiral and Deuterium Populations
Chapter Two - NMR Determination ofProchiral Hydrogen and Deuterium Populations
2.1
31
INTRODUCTION
During the course of our investigations on acid-catalysed rearrangement of unsymmetrical optically active deuterated epoxides to aldehydes, we required a method to distinguish the prochiral protons (deuteron) p- to the oxygen functionality. We needed to do this in the aldehyde product{s) 2.1 or the corresponding alcohol 2.2 or a derivative thereof (Figure 2.1).
2.1
2.2
Figure 2.1. Rearrangement product of styrene oxide and corresponding alcohol.
The work reported in this thesis is directed to measuring the extent or otherwise of prochiral proton selection for migration from Cl to C2.1 A determination of such retention/inversion in the rearrangement requires a measure of the relative population of hydrogen and deuterium at each of the prochiral p-positions.
Since the C2 hydrogens are prochiral and indistinguishable in a normal NMR spectrum, asymmetry must be induced to make the prochiral protons magnetically non-equivalent and hence resolvable in an NMR spectrum: Furthermore the signals must be able to be fully resolved in order to obtain accurate integration measurements.
2.1.1
Chiral derivatising agents
Methods already exist for distinguishing the prochiral protons
a,-
to the alcohol 2.2. For
example camphanic chloride has been used as a chiral auxiliary for NMR resolution of prochiral protons adjacent to the alcohol functionality.2 For a primary alcohol reaction with (lS)-(-)-camphanic chloride gives a chiral ester. 3 The ester on its own did not provide
Chapter Two - NMR Determination ofProchiral Hydrogen and Deuterium Populations
32
sufficient asymmetry to resolve the prochiral protons, so further resolution was achieved by the addition of a europium shift reagent (either Eu(dpm)3 or Eu(dcm)3) to the NMR solution, allowing resolution and integration of the prochiral protons a- to the ester oxygen. 3
+
JQ~CI
~o
o 2.3
2.4
2.5
Scheme 2.1. Resolution of prochiral hydrogens/deuteriums by reaction with a chiral derivatising reagent.
In contrast to the previous work above, where resolution of the prochiral protons a- to an ester oxygen has been achieved, we required a system which would allow NMR separation of the protons
~-
to the ester ether oxygen. To date, NMR resolution of prochiral
~-protons
to oxygen has not been reported.
2.1.1.1 Search for methods to reduce the aldehyde product to alcohol It was envisaged that a chiral acid chloride derivatising agent might be useable in the
analysis of the products from epoxide rearrangement if the aldehyde 2.1 was first reduced to alcohol 2.2.
Problems were initially encountered attempting to reduce the aldehyde and many methods of reduction were performed.4 Sodium borohydride (NaBH4) and lithium borohydride (LiBH4) were first investigated with tetrahydrofuran (THF) as the solvent. Reaction time (4 hours to 24 hours) and temperature (O°C to refluxing) were varied with limited success as these reactions gave either low yields or polymeric mixtures.
Chapter Two - NMR Determination ofProchiral Hydrogen and Deuterium Populations
33
In our hands the most effective reducing conditions for reduction of phenylethanal 2.1 to
give 2-phenylethanol 2.2 was established as 2 mol. equivalents of lithium aluminium hydride (LiAIH4) in ether, allowing the mixture to be stirred at room temperature for 3 hours (Scheme 2.2).
------Jl ....
ether, R.T
2.1
OH
V I
....:;:;
2.2
Scheme 2.2. Reduction of phenylethanaI
2.1.2
Chiral shift reagents
To increase resolution in an NMR spectrum, addition of a lanthanide shift reagent to an organic compound can result in the shift of signals to higher (or lower) frequency, the magnitude of the shift determined primarily by the distance of the proton from the coordinated shift reagent. The six-coordinate lanthanide complex forms a weak addition complex in fast exchange on the NMR time scale with the unbound organic substrate with a large variety of organic compounds. The induced shifts are caused by a large difference in the interaction between the paramagnetic metal and the NMR nucleus. The McConnell equation (.6.0
k(l
3 cos2e)r-3) qualitatively defines the relationship between the induced
shift .6.0, where r is the distance from the metal centre from the proton and e is the number . of degrees that the proton nucleus lies away from the axial axis of symmetry of the organic compound.
Lanthanide-shift reagents are in general less useful at high fields. Since under the fast exchange conditions that typically prevail, line-broadening is proportional to Bo2. For substrates which show large induced shifts (e.g. alcohols) it is preferable to acquire spectra on a 100 MHz IH NMR instrument, rather than a 500 MHz instrument where linebroadening will be 25 times more severe. For many metal ions, line-broadening of the IH NMR signals is significantly large rendering them ineffectual as shift reagents. However,
Chapter Two - NMR Determination ofProchiral Hydrogen and Deuterium Populations
34
for lanthanides line broadening of the proton signals is small relative to the magnitude of the downfie1d shift.
Following the early work of Whitesides with the camphor-based chiral shift reagent EU(PVC)2,s several other chiral shift reagents were introduced by research groups,6 many of which are now available commercially. Several early reviews have compiled details of the application of chiral lanthanide shift reagents. 7 Most applications involve analysis, but
Be, 19F,
IH
NMR
and 3l p are commonly used. Within the limitations imposed by the
requirement that the substrate coordinate with the metal, the application of chiral shift reagents in determining resolution of complexes is broad. Almost every organic complex which has been examined seems to give some separation of resonances with some shift reagent, provided that the chiral centre is reasonably close to the site that coordinates to the metal ion. In this connection, it has been noted that it may be necessary to try several shift reagents to achieve a useful valu.e of 86 for an intractable substrate. It is difficult to predict which shift reagent will yield the best shift differences for a given substrate. The shift reagent which we have found most satisfactory in our investigations is ytterbium tris[3(heptafluoropropylhydroxymethylene)-(+)-camphorate] (Yb(hfc)3) 2.6 (Figure 2.2).
2.6
Figure 2.2. d-Yb(hfc)3 shift reagent. It remains unclear why Eu(hfch is used almost exclusively in the literature. 8 In the
following study both europium and ytterbium chiral shift reagents are used. It is important to dry the europium shift reagent prior to use (as hydrolysis leads to formation of EU203 and severe line-broadening), although sublimation (200°C, 0.05 mmHg) is preferred. We found there were distinct advantages in using Yb(hfc)3 in our work.
Chapter Two
2.1.3
NMR Determination ofProchiral Hydrogen and Deuterium Populations
35
Chiral solvents
NMR spectroscopy in liquid crystalline solvents has recently become a method of choice for the resolution of enantiomers. 9 Chiral agents form diastereoisomeric solvation complexes with solute enantiomers. These complexes are in rapid reversible equilibria with solvent complexes. The best results in the literature have been obtained with poly-ybenzyl-L-glutamate (PBLG). The pro-S and pro-R protons in a sample would become distinguishable because of differing quadrupolar couplings of the enantiomers. Integration of the spectrum can thereby give an accurate measure of the amount of deuterium in each prochiral position. In order to obtain the smallest possible line width in the proton decoupled deuterium NMR, it is important that a completely homogenous sample is obtained. This was maximised by centrifuging the sample in the NMR tube repeatedly. However despite repeated attempts to use deuterium NMR in the presence of PBLG, replication of the literature procedure lO was unsuccessful. One reason for the lack of success could be a failure to obtain a sufficiently homogeneous sample. It is also possible that the NMR probe was not sensitive enough or the decoupler did not work effectively on our 300 MHz machine. Attempts were made to purify and re-use the poly-y-benzyl-Lglutamate liquid crystal by dissolving in methylene chloride, followed by the addition of ethanol to induce crystallisation of the polymer. Due to the expense of the PBLG, no further attempts were made to solve these problems.
2.2
NMR SEPARATION OF THE PROCHIRAL PROTONS (3- TO AN ESTER OXYGEN
The following work was performed in collaboration with Dr James Cambridge where I concentrated on 2-phenylethanol and he focused on the octyl, p-methyl, and m-methoxy alcohol derivatives of 2-phenylethanol. ll This work parallels the previous examples where camphanic acid chloride has been used to introduce asymmetry in an ester derivative and further chiral resolution has been obtained by the use of lanthanide shift reagents. In the
Chapter Two
NMR Determination ofProchiral Hydrogen and Deuterium Populations
literature only protons
(l-
36
to the ester linkage were resolved. Our task is more demanding
since we require resolution of the prochiral protons on the p. carbon. We achieved this by reduction of the aldehyde product(s) of the rearrangements to give alcohols which were derivatised with chiral acid chloride. Reduction of the aldehyde to an alcohol limits the likelihood of enolisation of the aldehyde and loss of the deuterium label at C2. The alcohol, phenylethanol, formed from reduction of the rearrangement product of styrene oxide was reacted separately with four chiral acid chlorides: (lS)-(-)-camphanic chloride
2.7,
N-(l-naphthalenesulfonyl)-S-phenylalanyl
chloride
2.8,
N-(p-
toluenesulfonyl)-S-phenylalanyl chloride 2.9 and N-( 4-nitrophenylsulfonyl)-S-phenylalanyl chloride 2.10 (Scheme 2.3).
2.2.1
NMR resolution of esters derived from 2-phenylethanol
It was hoped that at least one of the chiral esters might be such that a sufficiently
asymmetric environment was produced that the prochiral hydrogens both ester oxygen would be resolved in a IH NMR spectrum (Scheme 2.3).
r I
OH +
~
:#7
pyridine
...
CI
2.2
r
2.7
2.11
OH
I·
+
~
2.2
2.8
2.12
(l-
and
p. to the
Chapter Two
NMR Determination ofProchiral Hydrogen and Deuterium Populations
~OH
pyridine
V
2.2
.....
2.13
2.9
pyridine
2.2
37
...
2.10
Scheme 2.3. Esterification of 2~phenylethanol. For each of these four esters, the p~prochiral hydrogens were not distinguishable in the IH NMR spectra, and although the a-prochiral protons showed some non-equivalence, incomplete resolution made population analysis difficult and of insufficient accuracy for our purposes.
In an attempt to enhance the magnetic asymmetry of the P-hydrogens, we investigated the NMR spectrum (300 MHz) of the diastereomeric complexes formed by addition of the lanthanide chiral shift reagents- ytterbium d-3-heptafluorobutyrylcamphorate (d-Yb(hfc)3) and the 1- and d-forms of europium heptafluorobutyrylcamphorate (Eu(hfc)3).
Addition of 1- or d-Eu(hfc)3 shift reagents to the esters of 2-phenylethanol 2.11, 2.12, 2.13 resulted in differentiation of the a-prochiral protons with sufficient clarity to allow accurate NMR integration. However, no separation of the p-prochiral protons was observed.
38
Chapter Two - NMR Determination ofProch ira I Hydrogen and Deuterium Populations
It is interesting that the shift of the prochiral
(l-
(and
~-)
protons is the same whether 1- or
d-Eu(hfc)3 shift reagent is used, showing the asymmetry of the ligand for the diastereomeric complexes was not transmitted to these protons.
The downfield shifts on addition of d-Yb(hfc)3 shift reagent to 2.11, 2.12, 2.13 show that the prochiral protons (l- to the ester linkage, are differentiated but the
~-protons
are not.
Complexation of the nitro ester 2-phenylethyl N-(4-nitrophenylsulfonyl)-(S)-2-amino-3phenylpropanoate 2.14 with d-Yb(hfch or 1- or d-Eu(hfc)3 shift reagents in all cases resulted in NMR differentiation of both the
(l-
and the
~-prochiral
concentration of 1- or d-Eu(hfc)3 necessary to separate the
protons. However at the ~-prochiral
protons, an
interfering peak occurred (-Sppm) due to the europium shift reagent in the region of the
~
prochiral protons of 2.14 which made integration inaccurate. Fortunately, even though broadening does occur with d-Yb(hfc)3, there is no interference of the proton signals from the ytterbium shift reagent and integration is more accurate. d-Yb(hfc)3 is also less moisture sensitive than 1- or d-Eu(hfch and for these reasons, further studies were conducted using d-Yb(hfc)3 as the chiral shift reagent.
Figure 2.3 shows the signals for the
~-
prochiral protons being resolved into two separate
peaks on incremental addition of d-Yb(hfc)3 to the ester 2.14
Chapter Two - NMR Determination ofProchiral Hydrogen and Deuterium Populations
~'--------------~~----- ~U~ ~ __
__
____
39
JI,u.u~ ,p.
pp.
A
1\
I
J~ ...
3.0 ppM
40
Chapter Two - NMR Determination ofProchiral Hydrogen and Deuterium Populations
\ \
~LL
l ,po
f\/ \ -,.....,. 8.~
" j Il.a
1.5
1,1f
Ii.$
~.O
~~",-
5.5
Figure 2.3. Incremental addition of d-Yb(hfc)3 to 2.14.
...,.......----..------.-----.
!i.1f
4.S
~----.-
'-
,.-1·-·----,--.-.. . . . . 11.0 pp.
41
Chapter Two - NMR Determination ofProchiral Hydrogen and Deuterium Populations
Quantitative titrations were conducted by incremental addition of d-Yb(hfc)3 to 2phenyl ethyl N-(4-methylphenylsulfonyl)-(S)-2-amino-3-phenylpropanoate 2.13 and 2phenylethyl N-(4-nitrophenylsulfonyl)-(S)-2-amino-3-phenylpropanoate 2.14 (Figure 2.4). The downfie1d shift of the proton signals from the esters on increasing addition of dYb(hfc)3 are shown in Figures 2.5 and 2.6. For 2.13 the proton signals for H3
and~,
u- to
the ester linkage are separated by addition of sufficient Yb(hfc)3, however the signals for protons HI and H2 remain indistinguishable. Similar results are observed for the other two esters 2-phenylethyl (lS)-(-)-camphanate and 2-phenylethyl N-(l-naphthalenesulfonyl)(S)-2-amino-3-phenlypropanoate.
Figure 2.4. Protons of 2.13 and 2.14.
11 10
i
9
8 !§ 7 1/1
j: 4
0.00
5,00
10.00 15.00 20.00 25.00
Equivalents d .Yblhfcl.lihlft reagent added
Figure 2.5. The downfield shift of the proton resonances of 2.13 with added d-Yb(hfc)3 shift reagent. HI x, H2 x, H3 .,
~
., Hs .6., H6
III,
H7
Hs -. (Symbol x is used for both
HI and H2 in this particular graph as they are not differentiated).
Chapter Two - NMR Determination ofProchiral Hydrogen and Deuterium Populations
42
Complexation of 2.14 with d-Yb(hfc)3 results in complete resolution of both the a (H3 and
lit) and !3 (HI and H2) protons (Figure 2.6). 11 10
s:
.!!;
9
8
~ 7 1/1
1i
E
6
!IJ 5 4
3
2+-----~------~----~ 1.00 3.00 0.00 2.00 Equlvalentli d .Yblhl'c), "hlft 1'CIa1l1l:"' addlld
Figure 2.6. The downfield shift. of the proton resonances of 2.14 with added d-Yb(hfc)3 shift reagent. HI
H2 x, H3 ., lit ., Hs A, H6
II,
H7
0,
Hs -.
The extra asymmetry provided by the shift reagent to the ester 2.14 compared with the other similar esters 2.12 and 2.13 may reflect that 2.14 contains the Lewis basic nitro group. The p-nitro group in 2.14 is a hard Lewis base and so will co-ordinate to the lanthanide shift reagent. This is in contrast to 2.12 and 2.13, where the naphthalene and tolyl groups will not co-ordinate to the shift reagent. Co-ordination of the p-nitro group will affect the position of equilibrium for formation of the ester-shift reagent complex and this could explain the greater downfield shift per equivalent of shift reagent for all proton resonances in 2.14 compared to 2.12 and 2.13. The geometry of the shift reagent-ester complex will also be affected by the presence of the Lewis basic nitro group.
J ames Cambridge found for the corresponding esters of l-octanol no differentiation of the
!3-prochiral protons was achieved on addition of d-Yb(hfc)3 and d-Eu(hfc)3, although in all cases the a-prochiral protons were differentiated. He did find that resolution of the a- and !3-prochiral protons occurred for the corresponding ester 2-p-methyl-phenylethyl N-( 4-
43
Chapter Two - NMR Determination ofProchiral Hydrogen and Deuterium Populations
nitrophenylsulfonyl)-(S)-2-amino-3-phenylpropanoate
on
addition
of
d-Yb(hfc)3,
indicating that an aromatic substituent p. to the ether oxygen is a necessary structural feature for differentiation of the p-prochiral protons. ll This aryl substituent may be involved in intra-molecular n-stacking and impose the necessary asymmetry to the pproton environment for differentiation.
2.3
IDENTIFICATION OF P-PROCHIRAL PROTONS TO THE ETHER OXYGEN OF CHIRAL ESTERS OF 2-PHENYLETHANOL WITH dYb(hfc)3 SHIFT REAGENT
Having shown we can resolve the signals for the two prochiral protons p- to the ester oxygen, it was necessary to assign each signal as Hs or HR. In order to do this, esters were made from derivatives of 2-phenylethanol, synthesised stereoselectively deuterated in the 2-position. If the two deuterated epimers are present in unequal, known amounts, the two signals obtained for the p-prochiral protons can be assigned as arising from R or S deuterated ester, based on their relative integral. This work was again performed in collaboration with Dr James Cambridge where he focused on the p-methyl, and m-methoxy alcohol derivatives of 2-phenyl ethano I while my work concerned the unsubstituted case. 12
2.3.1
Assigning the prochiral protons p- to the ester oxygen in the iH NMR of ester derived from 2-phenylethanol
The synthesis started with the Sharpless asymmetric dihydroxylation of styrene-a-d1 with AD-mix p and AD-mix a to give (lR)-1-phenyl-l,2-ethanediol-l-dl and (lS)-l-phenyl1,2-ethanediol-l-d1 respectively (Scheme 2.4).
Chapter Two - NMR Determination ofProchiral Hydrogen and Deuterium Populations
0
d
OH
AD-mix
~
lID
44
OH
~~ 2.16
2.15 D
d
AD-mix a
2.17
lID
~f1i OH OH 2.18
Scheme 2.4. Synthesis of(l8)- and (lR)-1-phenyl-1,2-ethanediol-1-dl.
A 2: 1 mixture of the Sand R diols was subjected to the reaction sequence outlined in Scheme 2.9. Addition of trimethyl orthoacetate and chlorotrimethylsilane gave chloroacetates 2.37 and 2.38. Reduction with LiAIH4 gave a 2:1 mixture of (28)- and (2R)phenylethan-l-01-2-d). It has been shown previously for the reduction of the phenyl substituted compound that hydride displaces the chlorine in an SN2 reaction, with inversion of configuration at the reaction centre. 13 Previously, Mosher et al. 13 has completed the same series of reactions to give selectively deuterated 2-phenylethanol. For this phenyl substituted compound, a 96:4 mixture of the secondary and primary chloro compounds were formed. Mosher et al. 13 showed that reduction of this mixture with LiAID4 afforded the same ratio of primary to secondary alcohol, implying that styrene oxide is not an intermediate in the reduction reaction. This is in accord with the results of Eliel. l4
Chapter Two
NMR Determination ofProchiral Hydrogen and Deuterium Populations
2.16 + 2.18 CH3 C(OMe:., 1 : 2
H
Me3SiCI
~"H CI
H
.~
2.19
2.20
1
2
OH
~~
V
O=
0~-
45
2.21 1
+
00, "t"/.i ~H 2.22 2
2.24 2
Scheme 2.4. Assigning the NMR spectra of the prochiral
p protons of 2.23 and 2.24.
Esterification of the 2: 1 mixture of alcohols was achieved by the method outlined earlier and a 2:1 mixture of Sand R esters deuterium labelled
p- to the ester oxygen was obtained
(Scheme 2.4). The esters were analysed by IH NMR. When sufficient d-Yb(hfc)3 was added to the ester mixture in CDCh, the signal for the protons
p-
to the ester oxygen
resolved into two separate signals, where the downfield peak was twice the size of the upfield peak. This showed that the downfie1d peak is from the R ester; the upfield peak is from the S ester (Figure 2.7).
46
Chapter Two - NMR Determination ofProchiral Hydrogen and Deuterium Populations
i
i
I
I
Ester 2.24
I
)
Hs
\I
(
2 ; 1
9.0
:~G"HH".!IHO lit ..
L!lSi
8.S
I ...
~~
ct
~
•
~
U
l.~U
Jl
~
8.0
~(>r
~:'ff
1.5
•
: 2~"
,
1,0
"
tl!",p
_3Uu
6.5
6,0
S,S
5.0
0,5
4.0
ppm
la-HHr M1Itb " .. 1
Stp
""3
lolvtnt t&CB
J~
lOtl
OI'OUh
Figure 2.7. NMR spectra of the prochiral p. protons of2.23 and 2.24.
Therefore in undeuterated ester, the Hs prochiral hydrogen
p-
to the ester oxygen will
resonate downfield from the HR prochiral hydro gen.
2.4
RELATIONSIDP BETWEEN THE RELATIVE INTEGRALS OF THE PROCHIRAL PROTONS AND THE DETERMINATION OF APPROPRIATE DELAY BETWEEN PULSES IN THE IH NMR
The downfield (Hs) signal of the separated
p- prochiral protons is a broader peak in the IH
NMR spectrum of the ester-shift reagent complex than the upfield peak, indicating a faster relaxation time due to its closer proximity to the paramagnetic field of the Yb(hfc)3 shift reagent. An experiment was conducted to determine whether the difference in relaxation time would affect the relative integrals of the two proton signals by varying the delay time between pulses when running the NMR spectrum.
d-Yb(hfc)3 was added to undeuterated 2-phenethyl (N-4-nitrophenylsulfonyl)-(S)-2-amino3-phenylpropanoate in CDCh in an NMR tube. Sufficient d-Yb(hfc)3 was added that the prochiral protons
p- to the ester linkage were resolved in the NMR spectrum. Five spectra
47
Chapter Two - NMR Determination ofProchiral Hydrogen and Deuterium Populations
were recorded over a period of time where the value of db the delay between pulses was varied between 0.5 and ten seconds. If the differing relaxation times of the two prochiral hydrogens did alter their relative integrals, the integral would systematically vary with changing d 1.
I
•
d l (s)
Downfield : Up field proton integral
0.5
1.0040: 1
0.5
1.0173 : 1
1
1.0482 : 1
5
1.0211 : 1
10
1.0061 : 1
Table 2.1. Integral of the prochiral protons
~-
to oxygen in 2.14, with varying delay
between NMR pulses.
It can be seen that in all cases the downfield peak is slightly larger than the upfie1d peak.
This is thought to be due to a small overlapping peak from an impurity which was present in the sample (Figure 2.8).
I
.. , T·'
4 ••
5.0
H~: Ith:~~u
~r
: i:a~"
~"'f
•
3;.... :
~~n
in
..
t~~e/)nt
Jun
n:ll
...
Figure 2.8. Impurity in the downfield peak of prochira1 protons
•• B
~-
3 ••
ppo
to oxygen in 2.14.
Chapter Two - NMR Determination ofProch ira I Hydrogen and Deuterium Populations
48
The exact position of the impurity peak changed in each spectrum as the equilibrium with the chiral shift reagent changed slightly over time and this it thought to be responsible for the small variation in the relative integral for the two prochiral proton peaks in the different NMR spectra.
There is no trend in the integral for one proton increasing relative to the other, with increasing d i . If a difference in relaxation time were responsible for a consistent under- or over-estimation of the integral, there would be a consistent trend as the delay between NMR pulses was increased, allowing both proton nuclei to relax before the next pulse is
applied. If the two protons in the ester-shift reagent complex do have different relaxation times, it does not significantly affect the relative integrals of the two signals and is therefore considered to be fast on the time-scale used for accumulation of the spectra.
In the NMR analyses in this thesis 'all integrals are taken from NMR spectra with a delay between pulses of one second. Consistent with what has been noted previously for the integration of proton NMR signals in the presence of chiral shift reagent, a variation of approximately 5% was observed in the relative integrals from spectra taken at different conc~ntrations
2.5
of shift reagent.
INTEGRATION OF THE lH NMR SPECTRUM BY MANUAL INTEGRATION
The signals of the prochiral proton signals
f3-
to the oxygen of ester 2.14 were not fully
resolved and a measurement of the relative integral of the two peaks was required.
The major resonances correlating to the Hs and HR peaks in the IH NMR spectrum were enlarged and then carefully "cut out and weighed". This process was repeated several times and an average taken (Table 2.2).
Chapter Two - NMR Determination ofProchiral Hydrogen and Deuterium Populations
AV Weight (g) d-Eu(hfc)3 Addition EuCSR 5 EuCSR6 EuCSR 7 EuCSR8 EuCSR9 EuCSR 12 EuCSR 13
49
Ratio
Hs:HR 0.3417 : 0.2733 0.2865 : 0.2621 0.2616 : 0.2~ 0.2225 : 0.2070 0.1619: 0.1579 0.2755 : 0.2163 0.2691 : 0.2272 x
Hs :HR 1.25 : 1 1.09: 1 1.05: 1 1.07 : 1 1.03 : 1 1.27: 1 1.18: 1 1.13 : 1 (average)
Table 2.2. An example of the average ratio of HS : HR peaks obtained from manual integration on addition of d- Eu(hfc)3 chiral shift reagent.
2.6
INTEGRATION OF THE IH NMR SPECTRUM USING MATLAB
A more accurate method was investigated to determine the relative integral of the two signals in the lH NMR spectrum. This was achieved by the de-convolution of the peaks into two separate, overlapping curves using the mathematical modelling package MATLAB. The area under each of the separate curves could then be calculated.
First the data is acquired and processed by applying a ''weighting function" to the free induction decay (FID). The digitised output from the NMR is then converted into a 'hpgl' file giving the x-y coordinates of the NMR spectrum. This information is then exported from the NMR spectrometer to a PC computer and edited as a text file.
After performing a few trial simulations and integrations, the data output from the NMR machine is best modelled in the form of a Lorentzian function rather than a Gaussian one. (Figure 2.9.)15
Chapter Two - NMR Determination ofProchiral Hydrogen and Deuterium PojJUlations
50
0.5()
~
.r;:
(lAO
]
';: ~;
c
!l.ll)
c:: .~ v.
;;l
C'"
">
lUll
c::
'~
.,"
j
().l II
G.OD
-5
-J
-2
'-1
o
2
3
4
Figure 2.9. Comparison of a Gaussian curve vs. Lorentzian curve.
A Lorentzian curve (Figure 2.7.) is given by the function:
f(x : p,r) = 1.. 7!
_--!..~2 --::: .....
(x
pi + (Iz'j
where r is the halfwidth.
The MATLAB script* iteratively found the least squares fit to the lorentzian distribution peaks and calculated the area of each peak, even when the two peaks were overlapping. When two peaks overlap, the program calculates each peak to give the additive effect of the observed line. It was also necessary for the analysis to take into consideration the sloping baseline for some of the spectra.
An example of the integration of overlapping peaks is shown in Figure 2.10.
• The MATLAB script was written in collaboration with Dr Alan Wilms, Maths Department, University of Canterbury.
Chapter Two - NMR Determination of Prochiral Hydrogen and Deuterium Populations
51
1800 •
f
1600
, I
data
Indl\1duaJ distributions best fit sum
,
'\ ' - - - - - - - -
f\ ~' \ i ', V, \
1400 1200
I
1000
..
I,\ !
I
'y
BOO 600 400 1500
2000
2500
3000
3500
4000
Figure 2.10. Integration of overlapping peaks in MATLAB for 2.23. The relative integral of the peaks is 3.9112 : 4.6673.
Integration of the NMR spectra by using the MATLAB integration script is of course more sophisticated but is more accurate than manually measuring the integrals.
2.6.1
'2 Peak versus 3 peak integration'
A series of simulations were perfonned to detennine whether a more accurate integration of the Hs and HR peaks could be obtained by including the chiral shift reagent peak in the MA TLAB computation. This had the effect of decreasing the gradient to give a flat baseline and therefore improving the accuracy of integration (Figure 2.11).
Chapter Two - NMR Determination of Prochiral Hydrogen and Deuterium Populations
52
2000
1800
•
data individual distributions best fit sum
1600 1400 1200 1000 800
~---------~-
600 L----L----~---~----L---~
1500
2000
2500
3000
3500
4000
Figure 2.11. Integration of the two Hs and HR peaks of2.14 including the larger chiral shift reagent peak in the MA TLAB computation to give a flat baseline.
2.7
AN ATTEMPT TO IMPROVE THE ANALYSIS BY ENDEAVOURING TO SEPARA TE THE PROCHIRAL PROTONS [3- TO A DIOXOLANE LINKAGE.
As outlined earlier, the use of chiral ester derivatives of 2-phenylethanol in conjunction with chiral lanthanide shift reagents allows separation of the [3-prochiral protons to the ester linkage. However, by converting the aldehyde into a chiral cyclic acetal there is also the possibility of differentiation of the prochiral protons on the aldehyde. The cyclic nature of the acetal reduces its conformational freedom compared with the corresponding ester and this may result in separation of the prochiral protons in the NMR spectrum after addition of chiral shift reagent. Also forming the cyclic acetal would eliminate the need to reduce the aldehyde to the primary alcohol simplifying the synthetic pathway for analysis, but also poses the problem of proton exchange under the acidic conditions in the preparation of the cyclic acetal. 16
Chapter Two - NMR Determination ofProchiral Hydrogen and Deuterium Populations
2.7.1
53
Preparation of 1,3-dioxolane acetals
The literature method for preparing the required acetals while reducing the likelihood of enolisation was exploredY Pyridinium p-toluenesulfonate (PPTS) is reported to be an excellent catalyst for the preparation of 1,3-dioxolane acetals and ethanediol (90-95%).17 PPTS is a weakly acidic salt and this characteristic makes it ideal for acid-sensitive compounds. PPTS was prepared in a 90% yield by the addition ofp-toluenesulfonic acid to pyridine at 22_24°C. 18 After stirring for 20 minutes, the excess of pyridine was removed with a rotary evaporator on a water bath c. 60°C to afford a quantitative yield of PPTS as slightly hygroscopic colourless crystals. Recrystallisation gave the pure salt (90%, m.p 120°C).
The 1,3-dioxolane acetals were prepared using a solution of phenylethanal (1 mmol) in benzene, 2,3-butanediol (2 mmol) and PPTS (10 mol%) was added and the mixture refluxed with water separation by a Dean-stark trap until the starting aldehyde had been completely reacted. Excess solvent was then removed in vacuo, ether was added, and the mixture washed with sodium hydrogen carbonate solution and saturated sodium chloride solution. The organic phase was dried with sodium sulphate and the solvent removed under reduced pressure to give the cyclic acetal 2-benzyl-4,5-dimethyl-l,3-dioxolane 2.25 (85% yield) (Scheme 2.5).
benzene
2.1
2.25
Scheme 2.5. Synthesis of2-benzyl-4,5-dimethyl-l,3-dioxolane 2.25
Having successfully synthesised the racemlC mixture of the cyclic acetal 2.25, for subsequent reactions 2,3-butanediol was substituted with (2R,3R)-( -)-2,3-butanediol to give the chiral cyclic acetaI2-benzyl-(4R,5R)-dimethyl-l,3-dioxolane 2.26 (Scheme 2.6).
Chapter Two - NMR Determination ofProchiral Hydrogen and Deuterium PojlUlations
54
benzene
2.26
2.1
Scheme 2.6. Synthesis of2-benzyl-(4R,5R)-dimethyl-l,3-dioxolane 2.26
2.7.2
NMR shift studies of 1,3-dioxolane acetals
Initial NMR shift studies were carried out using the following chiral shift reagents: d- and 1- 'Eu(hfc)3, d- and I-Yb(hfc)3 and Eu(fod)3. For none of these reagents was there sufficient resolution of the prochiral protons (HsIHR) initially centred at 0 2.92 ppm in the 1H NMR to' allow differentiation. However, the addition of d-Eu(hfc)3 shift reagent shifted the (HsIHR) resonances downfield. The upfield proton was deshielded by the incremental addition of shift reagent more rapidly than the downfield proton to give a signal looking like an overlapping triplet. Further additions caused the two peaks to "split" into a doublet but not with sufficient resolution to allow differentiation. Subsequent additions only served to move the proton resonances into a broad singlet.
Europium compounds generally induce downfield shifts in substrate resonances, while praseodymium analogues generally cause upfie1d shifts. Since praseodymium cause upfield shifts, it was envisaged that this magnetic interaction may allow us to differentiate the prochiral
protons
(HsIHR)
using
praseodymium
tris
(2,2,6,6-tetramethyl-3,5-
heptanedionato) (Pr(tmhd)3)' However, experiments with this shift reagent only served to move the proton resonances into a broad singlet not allowing any differentiation.
55
Chapter Two - NMR Determination ofProchiral Hydrogen and Deuterium Populations
2.7.3
An attempt to enhance the difference in proton signals with (R,R)-(+)-1,2diphenyl-l,2-ethanediol
The chiral cyclic acetal 2-benzyl-(4R,SR)-diphenyl-l,3-dioxolane 2.28 was prepared from (R,R)-(+)-1,2-diphenyl-l,2-ethanediol 2.27 thereby introducing two aromatic substituents (Scheme 2.7).
I: ° &Y" 2.1
';/
HO "H +
~
"
..?-
H
"'"
OH
W N~
MeC6H4S03'
H
Ha
"Hb
~
... crt~~~ ~ H .1
H
benzene
2.28
2.27
Scheme 2.7. Synthesis of 2-benzyl-(4R,SR)-diphenyl-l ,3-dioxolane 2.28
It had been hoped that the two aromatic substituents may n-stack with the phenyl group of
the aldehyde and build greater NMR differentiation of the prochiral protons.
However, the NlvIR results were similar to the 2-benzyl-(4R,SR)-dimethyl-I,3-dioxolane
2.26 system using the same shift reagents. No differentiation was possible and the results were no better or worse than the 2-benzyl-(4R,SR)-dimethyl-l,3-dioxolane system.
2.7.4
An attempt to separate the prochiral protons 1,3-dioxolane
~-
of 2-octyl-(4R,)SR)-dimethyl-
The rearrangement products of the alkyl substituted epoxides have proved difficult by the chiral ester route. Dr James Cambridge was unable to differentiate the
~-prochiral
protons
for the corresponding esters of l-octano!. 11 Therefore we also used this method to investigate the rearrangement product of 1,2-epoxyoctane (Scheme 2.8).
Chapter Two - NMR Determination ofProchiral Hydrogen and Deuterium Populations
56
+~ H
OH
benzene
2.29
2.30
Scheme 2.8. Synthesis of 2-octyl-(4R,)5R)-dimethyl-l ,3-dioxolane 2.30
However, the NMR results were agam similar to the 2-benzyl-(4R,5R)-dimethyl-l,3dioxolane 2.26 system using the same shift reagents. No differentiation was possible and no further time was spent exploring this method.
2.8
CONCLUSION
Even though we were unable to improve on our own analysis using 1,3-dioxolane derivatives, we have made the observation that it is possible to separate the
~-prochira1
protons in the NMR spectrum of ester derivatives of 2-phenylethanoL This makes possible analysis of the stereos elective deuteration of alcohols and hydride migration using selectively deuterated starting materials.
J. M.; Thorpe, A J. J. Org. Chem. 2000, 65, 8421. (a) Schwab, J. M. J. Am. Chem. Soc. 1981,103, 1876. (b) Schwab, J. M.; Li, W.; Thomas, L. P. J. Am. Chem. Soc. 1983,105,4800. (c) Shapiro, S.; Arunachalam, T.; Caspi, E. J. Am. Chem. Soc. 1983, 105, 1642. (d) Schwab, J. M.; Ray, T.; Ho C. J. Am. Chem. Soc. 1989,111, 1057. 3 Gerlach, H.; Zagalak, B. J. Chem. Soc., Chem. Commun. 1973,274. nd 4 Hudlicky, M. Reductions in Organic Chemistry 2 ed. ACS Monograph 1996. 5W hitesides, G. M.; Lewis, D. W. J. Am. Chem. Soc. 1970,92,6979. 6 a) Goering, H. L.; Eikenberry, J. N.; Koermer, G. S. J. Am. Chem. Soc. 1971,93,5913. b) Fraser, R. R.; Petit, M. A; Saunders, J. K. J. Am. Chem. Soc.Chem. Commun. 1971,1450. c) McCreary, M. D.; Lewis, D. W.; Wernick, D. L.; Whitesides, G. M. J. Am. Chem. Soc. 1974, 96, 1038. 7 a) Fraser, R. R. Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: New York, 1983. b) Sullivan, G. R. Top. Stereochem. 1976, 10,287. sa) Guanti, G.; Banfi, L.; Narisano, E. Tetrahedron: Asymmetry. 1990,1,721. b) Baldenius, K. U.; Kagan, H. B. Tetrahedron: Asymmetry. 1990,1,597. c) Deshmulch, M.; Dunach, E.; Juge, S.; Kagan, H. B. Tetrahedron Lett. 1984,25,3467. 9 Meddour, A; Canlet, C.; Blanco, L.; Courtieu, J. Angew. Chem. Int. Ed. 1999,38,2391. 10 Meddour, A.; Canet, 1.; Loewenstein, A; Pechine, J. M.; Courtieu, J. J. Am. Chem. Soc. 1994, 116,9652. 11 a) Cambridge, J. R. A. PhD Thesis, University of Canterbury, 2004. b) Coxon, J. M.; Cambridge, J. R. A; Nam, S. G. C. Org. Lett. 26, 2001, 4225. 1 Coxon,
2
Chapter Two - NMR Determination ofProchiral Hydrogen and Deuterium PojJulations
57
12 a) Cambridge, J. R. A PhD Thesis, University of Canterbury, 2004. b) Coxon, J. M.; Cambridge, J. R. A; Nam, S. G. C. Synlett. 8, 2004, 1422. 13 Elsenbaumer, R. L.; Mosher, H. S. J. Org. Chern. 1979, 44, 600. 14 Eliel, E. L.; Delmonte, D. W. J. Am. Chern. Soc. 1958,80, 1744; Eliel, E. L.; Rerick, M. H. ibid. 1960,82, 1362. 15 Varian NMR System Operation Manual, Version 5.3 Software, 1996,367. th 16 Solomans, T. W. G. Organic Chemistry 5 ed. Wiley, New York 1992, 726. I? Sterzycki, R. S. Synthesis. 1979, 724. 18 Miyashita, M.; Yoshikoshi, A; Grieco, P. A. J. Org. Chern. 1977,42,3772.
CHAPTER THREE
Synthesis of Optically Active Styrene Oxides
Chapter Three - Synthesis of Optically Active Styrene Oxides
3.1
59
INTRODUCTION
The Lewis acid catalysed rearrangement of mono-substituted epoxide has been shown to involve a 1,2-hydride shift to give aldehyde. The purpose of my studies was directed to establish the detailed stereochemical course of this reaction. The stereochemical course of hydride migration can be determined by the rearrangement of specifically deuterium labelled epoxides which are optically active. In particular we wish to analyse the regio- and stereochemical distribution of the deuterium label in the aldehyde products by the methods outlined in the previous chapter.
The investigation extends the previous studies of the rearrangement of mono-substituted and l,l-disubstituted epoxide by using optically active labelled epoxide. Previous studies measured only the relative migratory of the two terminal epoxide hydrogens by rearrangement of the racemic analogues of 3.1, 3.2, 3.4 and 3.5. Rearrangement of optically active epoxides allows the full stereochemical course of the hydride or deuteride migration to be measured. The work has been carried out in parallel with Dr James Cambridge l who has conducted studies on substituted styrene oxides and the results of both studies are compared.
Six regioselectively deuterated, optically active isomers of styrene oxide were synthesised (Figure 3.1).
~'D I~ 0 H ---::3.1
3.4
cr~~
3.2
3.3
0
0
3.5
3.6
Chapter Three - Synthesis of Optically Active Styrene Oxides
60
Figure 3.1. Deuteroisomers of styrene oxide. In addition to the cis and trans p-mono-deuterated epoxides 3.1, 3.2, 3.4 and 3.5, we report
the rearrangement of the a-mono-deuterated epoxides 3.3 and 3.6, where the overall facial selectivity for hydride migration can be measured.
The synthesis of epoxides 3.1, 3.2, 3.4 and 3.5 results in an enriched mixture of epoxide deuteroisomers, the minor components of which have either no deuterium label, or have the deuterium label non selectively positioned in the molecule. The ratio of the various deuterated and undeuterated epoxides in each mixture was determined by IH NMR and 2H NMR so the results of each rearrangement can be adjusted to establish the products from rearrangement of each pure epoxide.
3.2
SYNTHESIS OF OPTICALLY ACTIVE STYRENE OXIDE
For the mechanistic studies, we required epoxides that were as pure enantiomerically as possible. Formation of epoxides directly from terminal alkenes, for example using Jacobson's epoxidation catalyst, does not give high enough ee values? These catalysts bearing chiral salen ligands have been developed for the epoxidation of conjugated cisdisubstituted and trisubstituted ole fins with> 90% ee,3 but styrene undergoes epoxidation with only 50-70% ee using these and related oxo-transfer catalysts4 a difference attributed to two separate factors: first, terminal olefins such as styrene may simply undergo addition by chiral epoxidation catalysts with lower enantiofacial selectivity than cis-disubstituted and trisubstituted olefins; second, asymmetric epoxidation of terminal olefins is subject to a special type of enantiomeric "leakage" pathway. 5
Methods exist however, for conversion of 1,2-diols into epoxides with retention of the stereochemical integrity and the 1,2-diols can be made highly enantioselectively by the Sharpless osmium-catalysed asymmetric dihydroxylation procedure. Sharpless has
Chapter Three - Synthesis of Optically Active Styrene Oxides
61
continued to improve this methodology and with the recent discovery of the phthalazine ligands has led to a wide range of olefinic substrates. The AD-mix formulations namely, AD-mix-a and AD-mix-p are available commercially premixed from Aldrich reagents which simplify performing the reaction on a millimole scale, where only trace amounts of the ligand and the osmium salt are required. AD-mix-a and AD-mix-p give opposite diol enantiomers for the asymmetric dihydroxylation reaction. (Scheme 3.1).
AO-mix-p
Bottom, a attack
Scheme 3.1. Stereochemistry of the Sharpless dihydroxylation.
It has been shown that the Sharpless dihydroxylation reaction gives a 97% ee for the
dihydroxylation of styrene. 6 The stereospecific conversion of the 1,2-diol to epoxide can be achieved by a number of methods, the most convenient is the one pot procedure of Kolb et al. 7 This process is based on the acetoxonium ion mediated formation of acetate esters of halohydrins and proceeds with inversion at the halide receiving stereocentre. Subsequent base mediated ester saponification and cyclisation with a second inversion at the halide centre gives the epoxide. Thus, the transformation results in overall retention of configuration. The regioselectivity of the initial acetoxyhalide formation is therefore inconsequential. This method is known to give styrene oxide with an enantiomeric excess identical to the starting diol (Scheme 3.2):
62
Chapter Three - Synthesis of Optically Active Styrene Oxides
OH
OH
<~~"
AD-mix-p.
3.5
MeC(OMels.,. MesSiCI
3.6
0;
OAe
("H H
CI
K2C03 MeOH
..
0
3.7
3.8
Scheme 3.2. Dihydroxylation and epoxidation of styrene.
The six deuterated epoxides (3.1 - 3.6) can therefore be made from the corresponding alkene by Sharpless asymmetric dihydroxylation, followed by conversion of the diol to epoxide.
The synthetic targets are the three deuteroisomers of styrene shown in Figure 3.2: H
d~ ~
~
H D
;)
3.9
H
D
D
H
~---;)
H
0" 0 3.10
3.11
Figure 3.2. Deutero isomers of styrene.
3.2.1
Synthesis of undeuterated (S)-styrene oxide
The Sharpless asymmetric dihydroxylation and epoxidation methodology was first tested on undeuterated material to develop techniques and an understanding of how to handle these volatile materials before attempting the synthesis of the deuterated epoxide. 1Phenylethanol 3.13 was prepared by reduction of acetophenone with sodium borohydride. Dehydration of the alcohol involved passing the vapours over alumina. 8 A purpose built Pyrex tube drawn out at one end was packed with 100-200 mesh alumina (grade H) and inserted in an electric furnace and the tube kept at a temperature of 420-470oC. The alcohol
63
Chapter Three - Synthesis of Optically Active Styrene Oxides
was heated and the vapour passed through the column under reduced pressure (0.3 mmHg). The styrene was collected at liquid nitrogen temperature. Sharpless asymmetric dihydroxylation then gave the diol and epoxide was fonned using trimethyl orthoacetate and trimethylsilyl chloride, followed by ring closing saponification with K2C03 in MeOH (Scheme 3.3).
U 3.12
OH I
3.13
----~~~H OH
OH
3.5
1. MeC(OMeb, Me3SiCI .. 2. KZC03, MeOH
3.14
3.15
Scheme 3.3. Synthesis of undeuterated (S)-styrene oxide.
Experiments showed that the effective yield of the Sharpless asymmetric dihydroxylation reaction could be increased by extraction of the diol with ethyl acetate. The literature procedure called for extraction of the diol from the aqueous layer with CH2Ch. Difficulties were encountered with emulsion fonnation and this was avoided by using ethyl acetate.
Purification of the epoxide by flash chromatography on either silica gel or alumina was possible with the solvent 10% ether/pentane. The epoxide was initially left on both columns for 3 hours to test the stability of the epoxide. Neither acidic silica gel nor basic alumina catalysed the rearrangement or decomposition of styrene oxide. Storage of styrene oxide was also possible for a short time (4 weeks) in the freezer (-26°C).
d-Yb(hfc)3 chiral shift reagent was added incrementally to 3.8. At a concentration of dYb(hfc)3 sufficient to resolve the a-protons of racemic 3.8, only one peak was obtained for the a-hydrogen in the IH NMR spectrum, showing that 3.8 was fonned with> 95% ee.
Chapter Three - Synthesis of Optically Active Styrene Oxides
64
The successful synthesis of styrene oxide showed that the Sharpless asymmetric dihydroxylation and epoxidation via the ortho ester is a viable route to optically active epoxide. The synthesis of the deuterated styrene oxides is reported below.
3.2.2
Synthesis of (S)-styrene oxide-a-d1
For the synthesis of the deuterated epoxide, the deuterium atom was introduced by sodium borodeuteride reduction of acetophenone to give 1-phenylethanol-1-d1 3.16 > 98% deuterated at C1 by 1H NMR.
What seemed a simple and effective procedure for the dehydration of 1-phenylethanol involved passing vapours over alumina, but proved to have hidden problems with 1phenylethanol-1-d1 3.16. Dehydration of alcohols under these conditions is thought to take place in pores or crevices in the alumina surface with the alcohol molecules situated within an acidic site. 9 The interesting feature of this reaction was that the dehydration of 1phenylethanol-l-d1 gave not only styrene-a-d1 3.11 with 78% deuteration, but styrene showing that isotopic exchange reactions occurred between deuterium or hydrogen in the active sites on the alumina (Scheme 3.4).
crx
78%D
3.16
3.11
D
OH
I~
~
3.5
Scheme 3.4. Dehydration of I-phenylethanol-1-d/ to give styrene-a-d1 with 78% deuteration. A series of experiments were initiated to see if the amount of deuterium incorporated in 1phenylethanol-l-d1 could be retained by altering the conditions of the alumina support. The above reaction was carried out on alumina that had not been specially dried. We repeated the reaction, but using alumina which had been dried in an electric furnace under vacuum
65
Chapter Three - Synthesis ofOptically Active Styrene Oxides
for 5 hours and this again resulted in deuterium loss and the formation of both styrene-a-dj with only 60% deuteration and styrene (Scheme 3.5).
0
OX' I"" OH
dry AI 20 a o Ll 420-470 C
~
,..
C
+
60%0
3.16
3.5
3.11
Scheme 3.5. Dehydration of I-phenylethanol-l-dl with dry Ah03 to give styrene-a-dj with only 60% deuteration.
In another reaction, alumina was saturated with 98% deuterium oxide (D20). This was effected by first drying the alumina by heating in an electric furnace under vacuum for 5 hours. The alumina was cooled and D20 (5 mL) added and the mixture agitated for 24 hours. This process was repeated a second time to ensure deuteration of all the active sites in the alumina. This gave styrene-di _8 deuterated variously in all eight positions (Scheme 3.6).
o
I"" ~ ~
OH
1. dry A1 20 3, Ll 420-470 oC x 2
_ _ _ _ _ mmmmmm
2. Sat. D20x2
3.16
0)=)=<0
,..
O~_OD o
0 3.18
Scheme 3.6. Dehydration of I-phenylethanol-l-dj with Ah03 saturated with D20 to give styrene-di _8 •
The deuterium content of the required styrene-a-dj obtained from the aluminium oxide pyrolysis was too low and non-regiospecific for our purposes. However, the thermolysis may have synthetic value and could be explored further in the future. Therefore several alternative dehydrations methods were investigated. 10
Chapter Three - Synthesis of Optically Active Styrene Oxides
66
The first of these methods was the reaction with thionyl chloride in pyridine (SOCh, py).ll I-Phenylethanol and SOCh in pyridine were frozen into two separate layers with dry ice I acetone (-78°C) and were allowed to slowly thaw at room temperature. The product was isolated in pentane and washed with aqueous acid (H2 S04)' This method failed to dehydrate the alcohol and instead the aryl chloride was isolated. We have since learnt that alcohols which possess an aromatic substituent react with thionyl chloride via a SNi (substitution, nucleophillic, internal) reaction mechanism to give the corresponding chlorides with retention of the configuration of the hydroxyl bearing carbon atom. Reaction occurs through the chlorosulfite which collapses, with the elimination of sulphur dioxide, to give an ion-pair and then the chloride. The role of the aromatic substituent is thought to stabilise the cationic part of the ion-pair by delocalising positive charge. In the presence of pyridine, however, inversion of configuration occurs, probably because the pyridine removes a proton from the hydrogen chloride generated in the first step and the resulting chloride then reacts with the chlorosulfite in the SN2 manner. 12
We next investigated dehydration of I-phenylethanol by reaction with dimethyl sulfoxide (DMSO).13 However, the product styrene polymerised under the reaction conditions. This involved heating the alcohol in DMSO in an oil bath at 160°C under a reflux condenser for 16 hours, pouring into 5% hydrochloric acid, and extracting with benzene. When pure styrene and DMSO were reacted under these same conditions, polystyrene formed in 90% yield; however, when the experiment was repeated in the presence of 20% by weight mdinitrobenzene, the yield of polystyrene was reduced to 5% and 65% pure styrene was recovered by distillation. Thus the addition of 20% m-dinitrobenzene to the 1phenylethanol dehydration afforded pure styrene but only in 39% yield. Therefore, in application of this method to the preparation of sensitive alkenes, polymerisation inhibitors were necessary.
The most effective dehydrating agent for the transformation of 1-phenylethanol to give styrene was determined to be potassium bisulfate (KHS04).14 Fusing the aryl alcohol with KHS04 at 200°C in the presence of a catalytic amount of p-methoxyphenol and under partial vacuum afforded the alkene which distilled as it was formed. The yield was 78%.
Chapter Three - Synthesis of Optically Active Styrene Oxides
67
This method is suitable for the dehydration of I-phenylethanol-l-d1 and the deuterium incorporation of the a-deuterated styrene 3.11 was> 98% at the a-carbon by IH NMR (Scheme 3.7):
/-
3.12
cat. p-Methoxyphenol
3.16
3.11
Scheme 3.7. Synthesis of styrene-a-dl.
The epoxide was prepared using the methodology outlined above. The Sharpless asymmetric dihydroxylation with AD-mix-a gave (lS)-1-phenylethane-l,2-diol-l-d1 3.14 which was converted to epoxide by reaction with trimethylorthoacetate and trimethylsilyl chloride to give chlorohydrin ester. Ring closure was effected by saponification with potassium carbonate in methanol. (S)-Styrene oxide-a-d) 3.3 was formed > 98% regioselectively deuterated in the a-position (Scheme 3.8).
AD-mix a
3.11
.
~H OH
OH
1. MeC(OMeh, Me3SiCI ... 2, K2C03, MeOH
3.14
3.3
Scheme 3.8. Formation of (S)-styrene oxide-a-dl from styrene-a-d}.
3.2.3 Synthesis of (R)-styrene oxide-a-dl (R)-Styrene oxide-a-d] was prepared using the methodology outlined above. The Sharpless asymmetric dihydroxylation with AD-mix -~ gave (lR)-l-phenylethane-l ,2-diol-l-dl 3.17 epoxidation with trimethylorthoacetate / trimethylsilyl chloride followed by K2 C03
/
Chapter Three - Synthesis of Optically Active Styrene Oxides
68
MeOH to give (R)-styrene oxide-a.-d) 3.6 > 98% regioselectively deuterated in the a.position (Scheme 3.9).
OH
0
OX I
3.12
""
h'
KHSO"
...
cat. p-Methoxyphenol
3.15
3.11
o 1. MeC(OMeh, Me3SiCI.
2. K2 C0 3• MeOH 3.17
3.6
Scheme 3.9. Synthesis of (R)-Styrene oxide-a.-d).
3.2.4 Synthesis of (1S),(2R)-styrene oxide-Jl-d1 (AD-a. cis) Styrene-cis-D-d1 (greater than 95% stereospecifically labelled by lH NMR) 3.9 was synthesised by the method outlined in Scheme 3.10. It was obtained from phenyl acetyleneI-d], prepared by replacement of the hydrogen of phenyl acetylene by reaction with ethyl
magnesium bromide and decomposition with D20. Phenylacetylene-l-d1 was also purchased from Aldrich® and showed greater than 98% deuterium incorporation as determined by IH NMR spectroscopy.
H(Z) H
1. EtMgBr... 2.02 0
3.19
1_ '\ = D-==3.20
1. [CP2ZrCI(I;}]x. toluene
0 - - - - - - - - - : 1........ 2 H0 .
2
O _
~
0
II
3.9
Scheme 3.10. Synthesis ofstyrene-cis-~-d}.
J. Cambridge successfully reduced an analogous alkyne under a hydrogen atmosphere over a palladium catalyst. l Quinoline was added to modify the reactivity of the palladium
69
Chapter Three - Synthesis ofOptically Active Styrene Oxides
surface to allow alkyne co-ordination to the surface, while the coordinatively less reactive alkene is blocked. A tenninal alkene, conjugated to an aromatic group is very reactive and competes efficiently with quinoline for sites on the palladium catalyst. The palladium catalyst can then catalyse cis-trans isomerisation or hydrogen exchange reactions of the alkene.
However, C ambridge I found some scrambling of the deuterium label had occurred between the three vinylic positions in the reduction of p-methylphenyl acetylene-l-d1 to pmethylstyrene-cis-~-dl.
This problem was ameliorated by stopping the reaction short of
full reduction to minimise the cis-trans isomerisation of the alkene.
Another method was found in the literature which further reduced the cis-trans isomerisation of the alkene and eliminated the scrambling of the deuterium label in the aH vinylic position namely using zirconium chemistry. IS Therefore, styrene-cis-~-dl 3.9 was synthesised with Schwartz's reagent by the hydrozirconation of phenylacetylene-l-dI followed by hydrolysis with H20 under an Argon atmosphere.
Epoxide 3.1 was then made by the Sharpless asymmetric dihydroxylation with AD-mix-a and epoxidation with trimethylorthoacetate / trimethylsilyl chloride followed by K2C0 3 MeOH (Scheme 3.11). H
H
On 3.9
AD-mix-a
... ~D OH OH 3.21
Scheme 3.11. Fonnation of (1 S),(2R)-styrene oxide-~-dJ 3.1 from
3.1
styrene-cis-~-d1 3.9.
/
Chapter Three
Synthesis ofOptically Active Styrene Oxides
70
3.2.4.1 Isomers of (1S),(2R)-styrene oxide-l3-dl A similar ratio of epoxide deuteroisomers were present in the final epoxide mixture, as formed in the hydrozirconation of deuterated alkyne described above. Table 3.1 shows the
IH and 2H NMR integrals of the a- and l3-positions of (1S),(2R)-styrene oxide-l3-dl 3.1.
I
trans integral
cis integral
a integral
184.95
14.65
195.90
14.59
381.81
0
I
.
I
Table 3.1. 1H and 2H NMR integrals for the a- and l3-hydrogen / deuterium signals of 3.1.
The ratio of epoxides can then be determined by solving the four simultaneous equations using Microsoft Excel Solver ®:
.
alHNMR
Equation- 1
A+B+C
195.90
cis IHNMR
Equation- 2
A+B
14.65
trans IHNMR
Equation- 3
2HNMR
A+C C Equation- 4 B
184.95 381.81
---
14.59
After minimisation of the residual squared values of A, B and C, the following is the ratio of epoxides obtained:
H,,(S) (R)"H
~'H ,"'" 0 H
~o
I~
3.15 (A) 4.0%
O',,(S) ",H H
Vo
3.2 (8)
3.1 (C)
3.3 (0)
3.5%
92.5%
0%
Figure 3.3. Isomers of (1S),(2R)-styrene oxide--l3-d1•
71
Chapter Three - Synthesis of Optically Active Styrene Oxides
3.2.5
Synthesis of (lR),(2S)-styrene oxide-l3-dl (AD-13 cis)
Styrene-cis-l3-dl was synthesised as described previously with Schwartz's reagent by the
hydrozirconation of phenylacetylene-1-dl followed by hydrolysis with H20 under an Argon atmosphere (Scheme 3.10).
Epoxide 3.4 was then made by the Sharpless asymmetric dihydroxylation with AD-mix-13 and epoxidation with trimethylorthoacetate / trimethylsilyl chloride followed by K2C03
/
MeOH (Scheme 3.12).
AD-mix-p,..
cr ~~
__
(R)(S)
~HH D
~ /;
3.9
1. MeC(OMeh. MesSICI ,.. 2. K2COs• MeOH
3.4
3.22
Scheme 3.12. Formation of (lR),(2S)-styrene oxide-l3-dI 3.4 from styrene-cis-p-dl 3.9.
3.2.5.1 Isomers of (lR),(2S)-styrene oxide-l3-d1
As calculated using the methodology above, a similar ratio of epoxide deuteroisomers was present in the final epoxide mixture, as formed in the hydrozirconation of deuterated alkyne described above. Table 3.2 shows the IH and 2H NMR integrals of the a- and
P-
positions of (lR),(2S)-styrene oxide-p-d1 3.4.
trans integral
cis integral
a integral
lHNMR
186.45
16.15
197.40
2HNMR
15.79
384.21
0
Table 3.2. IH and 2H NMR integrals for the a- and l3-hydrogen / deuterium signals of3.4.
Chapter Three - Synthesis of Optically Active Styrene Oxides
72
After solving the four simultaneous equations using Microsoft Excel Solver
®
and
minimisation of the residual squared values of A, B and C, the following is the ratio of epoxides obtained:
a,lHNMR
Equation- 1
cis lHNMR
Equation- 2
trans lHNMR
Equation-3
2HNMR
Equation-4
o
"I"'H IRl H
~ I ""
~
A+B+C A+B A+C C B
H·" ""
197.40 16.15 186.45 384.21
---
15.79
o
",0
{RJ {R)
H
~
3.8 (A)
3.5 (8)
3.4 (C)
3.6(0)
4.7%
3.5%
91.8%
0%
Figure 3.3. Isomers of (1R),(2S)-styrene oxide-~-dl.
3.2.6 Synthesis of (1S),(2S)-styrene oxide-~-dl (AD-a trans) Styrene-trans-~-dl
3.10 was prepared from partial hydrogenation of phenyl acetylene by
diisobutylaluminium hydride (DIBAL) and quenching of the reaction with D20 (Scheme 3.13). The IH and 2H NMR spectra of the resultant alkene showed it to be greater than 95% stereospecifically labelled as the required (E) isomer. The yield of this reaction was 68%, with 87% deuterium incorporation in the trans
~-position.
The remaining 13% of the
material was predominantly undeuterated styrene approximately 6% and styrene (7%).
~H
1. OIBAL-H ,.. 2.02 0
3.19
Scheme 3.13. Synthesis of styrene-trans-~-dl.
3.10
cis-~-deuterated
Chapter Three - Synthesis of Optically Active Styrene Oxides
(1S),(2S)-Styrene
oxide-~-dl
73
3.2 was prepared by sharpless asymmetric dihydroxylation
with AD-mix-a as per the method described above for undeuterated styrene oxide 3.15:
~H OH
3.10
OH
3.23
3.2
Scheme 3.14. Synthesis of (1S),(2S)-styrene oxide-~-dl from
styrene-trans-~-dl.
3.2.6.1 Isomers of (1S),(2S)-styrene oxide-~-dl A similar ratio of epoxide deuteroisomers was present in the final epoxide mixture, as formed in from partial hydrogenation of phenylacetylene by diisobutylaluminium hydride (DIBAL) described above. Table 3.3 shows the IH and 2H NMR integrals of the a- and ~ positions of (lS),(2S)-styrene oxide-~-dl 3.2.
trans integral
cis integral
a integral
IHNMR
3.72
39.82
40.88
2HNMR
358.18
15.37
0
Table 3.3. IH and 2H NMR integrals for the a- and ~-hydrogen / deuterium signals of3.2.
After solving the four simultaneous equations using Microsoft Excel Solver
®
and
minimisation of the residual squared values of A, B and C, the following is the ratio of epoxides obtained:
Chapter Three - Synthesis ojOptically Active Styrene Oxides
(lIHNMR
Equation- 1
A+B+C
40.88
cis IHNMR
Equation- 2
A+B
39.82
trans IHNMR
Equation- 3
2HNMR
A+C C Equation- 4 B
H,,(S) ,,,,H
va
H
3.72 15.37
---
358.18
H,,(S) (fI)"H
H ,,(S) ("1",0
~o
~H
V
3.15 (A)
3.2 (B)
5.1%
74
91.0%
11,,(S) ,.,H
(Jd'H
3.1 (e)
3.3 (D)
3.9%
0%
Figure 3.3. Isomers of (lS),(2S)-styrene oxide-J3-d).
3.2.7 Synthesis of (lR),(2R)-styrene oxide-J3-dl (AD-J3 trans)
Styrene-trans-J3-dz3.10 was made by the diisobutyl aluminium hydride reduction of phenyl acetylene as described previously in Scheme 3.13.
(IR),(2R)-Styrene oxide-J3-d1 3.5 was prepared by the method described above for undeuterated styrene oxide 3.8:
H
0
~H 3.10
AD·mlx·~
OH
OH 1. MeC(OMeh, Me3SiCI,..
2. KZC03, MeOH
3.24
3.5
Scheme 3.15. Synthesis of (IR),(2R)-styrene oxide-J3-d1 from styrene-trans-J3-d1•
Chapter Three - Synthesis of Optically Active Styrene Oxides
75
3.2.7.1 Isomers of (IR),(2R)-styrene oxide-(3-d1 The ratio of epoxide deuteroisomers was calculated using the results in Table 304 which shows the IH and 2H NMR integrals of the
and (3-positions of (lR),(2R)-styreneoxide-
(X-
~-dr3.5.
trans integral
cis integral
IHNMR
3.81
43.35
43.84
LHNMR
379.77
20.23
0
(X
integral
Table 3.4. IH and 2H NMR integrals for the (X- and ~-hydrogen / deuterium signals of3.5.
After solving the four simultaneous equations using Microsoft Excel Solver
®
and
minimisation of the residual squared values of A, Band C, the following is the ratio of epoxides obtained:
a IHNMR
Equation- 1
A+B+C
cis1HNMR
Equation- 2
A+B
trans IHNMR
Equation- 3
2HNMR
~'~ 3.8 (A)
3.7%
3.81 -
~
20.23
----
379.77
~ I
43.84 43.35
A+C C Equation- 4 B
o
=
"O",o (R)(R)
H
'4
3.5 (8)
91.5%
H" 0 "H
~o 3.4 (C)
4.9%
Q, O"H
~H 3.6 (0) 0%
Figure 3.4. Isomers formed in the synthesis of (lR),(2R)-styrene oxide-(3-dl
These mixtures of epoxides were used in the studies reported in the following chapters.
Chapter Three - Synthesis of Optically Active Styrene Oxides
76
Cambridge, 1 R A PhD Thesis, University of Canterbury, 2004. Palucki, M.; Pospisil, P. J.; Zhang, W.; Jacobsen, E. N. J. Am. Chem. Soc. 1994, 116, 9333. 3 a) Jacobsen, E. N.; Zhang, W.; Muci, A R.; Ecker, J. R; Deng, L. J. Am. Chem. Soc. 1991, 113, 7063; ~~ Lee, N. H.; Zhang, W.; Muci, A R; Jacobsen, E. N. Tetrahedron Lett. 1991,32, 5055. c) Chang, S.; Lee,N. H.; Jacobsen, E. N. J. Org. Chem. 1993,58, 6839. d) Brandes, B. D.; Jacobsen, E. N. J. Org. Chem. 1994, 59,4378. e) Hosoya, N.; Hatayama, A; Irie, R.; Sasaki, H.; Katsuki, T. Tetrahedron. 1994, 50,4311. 4 a) Zhang, W.; Loebach, J. L.; Wilson, S. R; Jacobsen, E. N. J. Am. Chem. Soc. 1990,112,2801. b) Halterman, R. L.; Jan, S. T. J. Org. Chem. 1991,56,5253. c) Collman, J. P.; Lee, V. 1; Zhang, X.; !bers, J. A; Brauman, J. L J. Am. Chem. Soc. 1993,115,3834. d) Naruta, Y.; Ishihara, N.; Tani, F.; Maruyama, K. Bull. Chem. Soc. Jpn. 1993, 66, 158. 5 Groves, J. T.; Stern, M. K J. Am. Chem. Soc. 1987,66,158. 6 Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A; Hartung, J.; Jeong, K; Kwong, H.; Morikawa, K.; Wang, Z.; Xu, D.; Zhang, X. J. Org. Chem. 1992,57,2768. 7 Kolb, H. C.; Sharpless, K. B. Tetrahedron 1992, 48,10515. 8 Newton, L. W.; Coburn, E. R Organic Synthesis Collective 1964, 3, 312. 9 Blanc, E. J.; Pines, H. J. Org. Chem. 1968, 33, 2035. 10 Larock, R C. Comprehensive Organic Transformations, VCH Publishers, Inc, 1989, 151. II Schwartz, A.; Madan, P. J. Org. Chem. 1986,51,5463. 12 Coxon, 1 M.; Norman, R. O. C. Principles of Organic Synthesis, Blackie Chapman and Hall, London, 1
2
1993,109. Traynelis, V. J.; Hergenrother, W. L.; Livingston, J. R.; Valicenti, J. A J. Org. Chem. 1962,27,2377. Parinello, G.; Stille, J. K J. Am. Chem. Soc. 1987,109, 7122. 15 Nelson, 1 E.; Parkin, G.; Bescaw, 1 E. Organometallics, 1992, 11,2181. 13
14
CHAPTER FOUR
BF3.0Et2 Catalysed Rearrangement of Styrene Oxide
Chapter Four-BF3.0Et2 Catalysed Rearrangement ofStyrene Oxide
4.1
78
REARRANGEMENT OF UNDEUTERATED STYRENE OXIDE WITH BF3.0Et2
Suitable conditions for the BF3.0Eh catalysed rearrangement were established first for undeuterated epoxide 4.1. Reaction of the epoxide using a catalytic amount ofBF3.0Eh in dioxane for 20 minutes at room temperature resulted in a high yield (85%) of aldehyde with little intermolecular reaction. The reaction was carried out first using 100 ,..,L of epoxide, then on a smaller scale (35 ,..,L) and a similar yield and ratio of products was obtained in both experiments.
To allow for analysis and integration of the prochiral protons
p- to oxygen in the product
aldehyde, the aldehyde was reduced with LiAIH4 and the resulting alcohol was reacted with N-(4-nitrophenylsulfonyl)-S-phenylalanyl chloride (Scheme 4.1). The prochiral protons of the ester, are distinguished in the IH NMR spectra by addition of d-Yb(hfc)3 chiral shift reagent. 1
o
'" (R)
~ """
1
A
4.1
,.,H
H
SF .OEt 3 2,.. dioxane
(?iH. ."H """
1
0
h
H
~H ",H OH
LiAIH4 ,..
1 """
A
R*CI,..
H ",HOR*
I""" ~ h
4.2
4.3
85%
99%
4.4
94%
Scheme 4.1. Rearrangement, reduction and esterification of undeuterated (R)-styrene
oxide-a-dl.
Chapter Four
4.2
79
BF3.OEt2 Catalysed Rearrangement ofStyrene Oxide
REARRANGEMENT OF a-DEUTERATED EPOXIDE
In order to establish the overall facial stereo selectivity for hydride migration (S)-styrene
oxide-a-d z 4.5 and (R)-styrene oxide-a-d1 4.6 were rearranged separately and the results of the two experiments compared. The rearrangements of these two optically active adeuterium labelled epoxides give two possible enantiomeric aldehydes, 4.7 (resulting from hydride migration with inversion for the (S)-epoxide or retention of configuration for the (R)-epoxide) and 4.8 (resulting from hydride migration with retention for the (S)-epoxide or inversion of configuration for the (R)-epoxide) at the migration terminus (Scheme 4.2).
~~ 4.5 or
BF3.0Et2,.. dioxane
o
~ I ""
",,"H (R) H
~ H
I ""
"DH
(S)
0
h
+
4.7
o
~H (R)O
4.8
~
4.6
Scheme 4.2. Rearrangement of (S)- and (R)-styrene oxide-a-d1•
4.2.1
Rearrangement of (S)-styrene oxide-a-d1
(S)-Styrene oxide-a-d1 4.5 was synthesised with> 95% ee, (established by d-Yb(hfc)3 chiral shift reagent) and approximately 98% D incorporation as measured by IH NMR at the a-position. Three separate rearrangement reactions were conducted with BF3.0Et2 using the established conditions.
For the analysis, the aldehyde products were reduced to alcohols 4.9 and 4.10 which were esterified
with
N-(4-nitrophenylsulfonyl)-S-phenylalanyl
chloride
to
gIve
the
diastereomeric esters 4.11 and 4.12; these are different due to the chirality at the carbon to the ester linkage.
p-
80
Chapter Four - BF3.OEt2 Catalysed Rearrangement ofStyrene Oxide
4.7 + 4.8
LiAIH4
....
H ",D OH "" ()
~ I
s
+
~D "H "" (') OH I
~
R
R*CI ....
~
4.9
~OR* ~ ~ (s) +~ (~) OR* 4~1
4.10
4~2
"\
R*-
-0- " ~ _
N02
II
~
(S)~
0
~-N
0
o
Scheme 4.3. Reduction and esterification of 4.7 and 4.8.
The ratio of the diastereomeric esters 4.11 and 4.12 was determined for each experiment by IH NMR of the ester in the presence of d-Yb(hfc)3 chiral shift reagent (Scheme 4.3). The
average ratio of esters 4.11 and 4.12 and hence the corresponding aldehydes 4.7 and 4.8 are shown (Table 4.1).
(H R)
(Hs)
I
I
~
D"HH
dioxane
I
'::::
~
(R)
0
+
4.8 (1)
H I '::::
~ ~
"DH
(S)
0
4.7 (2)
H migration with retention of
H migration with inversion
configuration (1)
of configuration (2)
1.
54.5
45.5
2.
53.9
46.1
3.
53.5
46.5
Average
53.9
46.1
Reaction
Table 4.1. Inversion I retention of configuration in the rearrangement of (S)-styrene oxide-
a-dl:
* The results in the table have an estimated error of ±4% and these errors are discussed further in 4.4 of this chapter.
Chapter Four - BF3.OEt2 Catalysed Rearrangement ofStyrene Oxide
81
The results reported above using the (S)-styrene oxide-a-dl enantiomer are considered unreliable due to an unidentified impurity in the 1H NMR spectrum of esters 4.11 and 4.12 which occurred in the region of the
13-
Hs integral thereby artificially increasing the
integral of the hydrogen migration with retention of configuration. The ratio is therefore invalid
4.2.2
Rearrangement of (H)-styrene oxide-a-d1
The overall facial stereo selectivity of hydride migration from the terminal prochiral methylene protons was established with (R)-styrene oxide-a-d1 4.6. This compound was synthesised with > 95% ee (established by d-Yb(hfc)3 chiral shift reagent), and approximately 98% D incorporation as measured by IH NMR at the a-position and rearranged with BF 3.OEh using established conditions above. The ratio of the aldehydes 4.7 and 4.8 was established (from three separate experiments) as 48.2 : 51.8 by reduction of the mixture to alcohols 4.9 and 4.10, esterification followed by measurement of the integrals of the
13-
Hs and HR resonances in the IH NMR spectrum
after the addition of chiral shift reagent to the diastereomeric esters 4.11 and 4.12.
Table 4.2 shows that migration of the methylene protons in the formation of aldehyde therefore occurs, within experimental error, equally with retention and inversion or alternatively that racemisation of the aldehyde is occurring under the reaction conditions but without loss of deuterium.
Chapter Four BF3.OEt2 Catalysed Rearrangement ofStyrene Oxide
82
(HRl
(Hsl
I dioxane
~ ./
(S)
0
4.7 (1)
I ~ D
H,"DH
, ~
+
I
"HH
~. (R)
./
0
4.8 (2)
H migration with retention
H migration with inversion
of configuration (l)
of configuration (2)
1.
47.8
52.2
2.
47.4
52.6
3.
49.5
50.5
Average
48.2
51.8
Reaction
Table 4.2. Inversion / retention of configuration in the rearrangement of (R)-styrene oxidea-dl.*
The unequal mixture of enantiomeric aldehydes in subsequent experiments under the same reaction conditions demonstrate that racemisation is not occurring to any significant amount.
4.3
REARRANGEMENT OF (}- DEUTERATED EPOXIDE
To establish the facial selectivity of each of the methylene protons it is necessary to study the reactions 4.13, 4.14, 4.15 and 4.16 where the terminal protons are separately labelled as deuterium (Figure 4.1).
• The results in the table have an estimated error of ±4 % and these errors are discussed further in 4.4 of this chapter.
Chapter Four - BF3.OEt) Catalysed Rearrangement ofStyrene Oxide
4.13
4.15
4.14
4.16
83
Figure 4.1. Deuteroisomers of styrene oxide
4.3.1
Rearrangement of (1S),(2R)-styrene oxide-~-dl (AD-a. cis)
(1S),(2R)-Styrene oxide-~-dl, 4.13 (enriched 92.5%, and containing 4.153.5%,4.174.0%) on reaction with BF3.0Et2 gives four aldehydes, the ratio of which was established by NMR after reduction (LiAIH4 ) and esterification with N-( 4-nitrophenylsulfonyl)-Sphenyl alanyl chloride (Scheme 4.4). The integrals of the ~- Hs and HR resonances in the IH NMR spectrum were determined after the addition of chiral shift reagent to the diastereomeric esters (Table 4.3).1
Chapter Four BF3.OEt2 Catalysed Rearrangement a/Styrene Oxide
~'H I~ b D ~
~'D I~. 0 H
+
+
~
84
~'~
4.13
4.15
4.17
92.5%
3.5%
4.0%
~D
V
0
4.2
4.18
4.3
4.19
H
+
D
"DH
61 I ~i
(S)
(
+
0
'~'
~ I ~
"HH
(R)
4.7
4.8
4.9
4.10 (Hs)
(HR)
H
~ I
~
4.4
I
I
H OR'
~
H ",DOR'
cr>
I
~
~
H
4.20
D
+
~ i ~i i
(
0
-9
(S)
hi
4.11
+
~ I
D ",.HOR'
~
(R)
~
4.12
Scheme 4.4. Rearrangement, reduction and esterification of (lS),(2R)-styrene oxide-p-dl.
Ester 4.20 is responsible for the 2H NMR signal a,- to the ester oxygen, while 4.11 and 4.12 give rise to a 2H NMR signal at the p- position. The amount of 4.20 relative to 4.11 and 4.12 can therefore be obtained by comparison of the 2H NMR integral for the
a,-
and p-
positions. This can be converted into the percentage of total ester, by multiplying by the fraction of deuterated ester.
Esters 4.4, 4.20 and 4.12 give rise to the Hs p- IH NMR signal, while 4.4, 4.20 and 4.11 all contribute to the HR p- proton signal. See Appendix A for a detailed calculation analysis.
85
Chapter Four - BF3.OEt2 Catalysed Rearrangement o/Styrene Oxide
BF 3·OEt2 dioxane
4.13
Reaction
,..
me I
~
I
0
(Hs)
(HR)
I +
I
c0i I "-::::
H ",0 H
H
(R) I
~
0
"-::::
+
~
(S)
0
4.18(1)
4.8 (2)
4.7 (3)
H migration
migration (inv) Hs(retn)
migration (retn) HR (inv)
o
o
a HNMR
P HNMR
PHs1HNMR
PHR1HNMR
integral (1)
integral (2+3)
integral (2)
integral (3)
70.9
29.1
70.7
29.3
distinguish
1
1.05
Table 4.3. 2H and IH NMR integral of aldehyde/ester from rearrangement of 4.13.
However, the results of the two experiments reported above using the (lS),(2R)-styrene
oxide-p-d1 4.13 enantiomer are somewhat problematic. In the first experiment we failed to distinguish the P- Hs and HR resonances in the IH NMR spectrum as it was determined that the pure sample was not in a concentrated enough solution. In the second experiment, due to an unidentified impurity in the IH NMR spectrum of esters 4.11 and 4.12 that occurred in the region of the P- HR integral thereby artificially increasing the integral of the hydrogen migration with inversion of configuration.
4.3.2
Rearrangement of (1R),(2S)-styrene oxide-p-di (AD-P cis)
We were able to successfully determine the facial selectivity separately with the (lR),(2S)styrene oxide-p-dj isomer, 4.14 (enriched 91.8% and containing 4.16 3.5%, 4.1 4.7%).
(lR),(2S)-Styrene oxide-p-dl isomer 4.14 was reacted with BF3.0Eh to give aldehydes the ratio of which was determined in the usual way outlined above. The results of three duplicate rearrangements are shown below (Table 4.4).
86
Chapter Four- BF3.OEt2 Catalysed Rearrangement ofStyrene Oxide
(Hs)
0
BF3 •OEt2 dioxane
,.. cr~D 10 0 4.18 (1)
4.14
H migration
(H R)
I
+
il~HH '-'::: (R) (
.
0
I
H ".D H '-':::
+
0
4.8 (2) D migration (retn) Hs (inv)
(S)
0
0
4.7 (3) D migration (inv) HR (retn)
a 2HNMR
p 2HNMR
PHs1HNMR
PHR1HNMR
integral (1)
integral (2+3)
integral (2)
integral (3)
1.
76.2
23.8
1
1.03
2.
73.2
26.8
1
1.08
-'.
74.8
25.2
1
1.07
Average
74.7±3
25.3±3
1
1.06±0.02
Reaction
I
Table 4.4. 2H and IH NMR integt-als of aldehyde/ester from rearrangement of 4.14.*
4.3.3
Rearrangement of (1S),(2S)-styrene oxide-p-dl (AD-a trans)
(1S),(2S)-Styrene oxide-p-dl isomer, 4.15 (enriched 91.0% and containing 4.13 3.9%,4.17 5.1 %) was reacted with BF3 .OEt2 to give aldehydes the ratio of which was determined in the usual way (Table 4.5).
• The error for each experimentally derived parameter is estimated from a combination of the sensitivity of the lH and 2H instruments and the average standard deviation of three separate experiments.
Chapter Four BF3,OEt2 Catalysed Rearrangement of Styrene Oxide
87
(Hs)
BF 3 ,OEI2 dioxane
)10
c?~D I ~ 0
I
+
4.18(1)
4.15
H migration
Reaction
I + ~H 0 ~
(R)
~
I
&i I
~ ~
H
(S)
0
4.7 (3)
4.8 (2) D migration (inv) Hs(retn)
(H R)
D migration (rein) HR (inv)
a 2HNMR
(32HNMR
(3 Hs IHNMR
(3 HRIHNMR
integral (1)
integral (2+3)
integral (2)
integral (3)
60.9
39.1
1
1.35*
1.
Table 4.5. 2H and IH NMR integrals of aldehyde/ester from rearrangement of 4.15.
This result was considered unreliable as experienced previously with the other epoxides derived from the AD-a mix', due to an unidentified impurity in the IH NMR spectrum of esters 4.11 and 4.12 that occurred in the region of the (3- HR integral thereby artificially increasing the integral of the hydrogen migration with inversion of configuration.
4.3.4
Rearrangement of (IR),(2R)-styrene oxide-(3-d1 (AD-(3 trans)
However, we were able to determine successfully the facial selectivity separately with the (lR),(2R)-styrene oxide-(3-d1 isomer, 4.16 (enriched 91.5% and containing 4.144.9%, 4.1 3.7%). 4.16 was reacted with BF3.0Et2 to give aldehydes the ratio of which was determined in the usual way. The results of three duplicate rearrangements are shown below (Table 4.6).
• Some epoxides in particular 4.5, 4.13 and 4.15 derived from the Sharpless asymmetric dihydroxylation AD-
mix-a contained an unidentified impurity in the IH NMR spectrum of the derived ester which sometimes affected accurate integration of the
p- Hs and HR integrals.
Chapter Four
88
BF3.OEt2 Catalysed Rearrangement of Styrene Oxide
(Hs)
BF3•OEt2
en"
dioxane
~
~
(
• ~
0
I
)II>
4.16
I
0
+
I ~ (~) (H ~H ~
0
+
4.18 (1)
4.8 (2)
H migration
D migration (reIn) Hs (inv)
(HR)
I
~ I '< (;)
(H
0
~
4.7 (3) D migration (inv) HR (retn)
a 2HNMR
13 2HNMR
13 HSIHNMR
I3H/HNMR
integral (1)
integral (2+3)
integral (2)
integral (3)
64.5
35.5
1.14
1
2.
64.5
35.5
1.07
1
3.
65.6
34.4
1.09
1
Average
64.9±3
35.1±3
1.10±0.03
1
Reaction
Table 4.6. 2H and IH NMR integrals of aldehyde/ester from rearrangement of 4.16.*
4.4
DISCUSSION OF ERRORS
The largest cause of error in the above experiments is associated with the measurement of the relative amount of hydrogen and deuterium in each of the prochiral positions from the rearrangement of l3-deuterated epoxide. Variations between 5 and 10% were obtained in the relative IH NMR integral at different concentrations of chira! shift reagent. Facial selectivity measurements of the products from rearrangement of epoxide deuterated in the a-position are the most accurate due to the fact that only hydrogen migration is being measured in the IH NMR spectrum. In the products from rearrangement of 13deuterated epoxide, only some 30% of the material contains a migrated deuterium label so a small difference in the IH NMR integral represents a much larger relative difference in
• The error for each experimentally derived parameter is estimated from a combination of the sensitivity of the IH and 2H instruments and the average standard deviation of three separate experiments.
Chapter Four - BF3. OEtl Catalysed Rearrangement ofStyrene Oxide
89
the amount of deuterium in each prochiral position. The measurements are however accurate and reproducible enough to show the preference for migration with inversion or retention of configuration of the two terminal epoxide hydrogens.
In the BF3.0Et2 catalysed rearrangements the measured preference for hydrogen migration with inversion of configuration measured from the rearrangement of a-deuterated epoxide is really 50 : 50 within the experimental error.
The error for each experimentally derived parameter is estimated from a combination of the sensitivity of the IH and 2H NMR instruments (~ ±2%) and the average standard deviation of three separate experiments. The estimated errors are included in the tables and schemes below.
4.5
DISCUSSION
4.5.1
The rearrangement of cis- and trans-d epoxide (4.14 and 4.16)
To evaluate the nature of the rearrangement process, the experimental data from each of the two epoxides 4.14 and 4.16 must be used. After adjusting for the isomers in the mixture of epoxide 4.14 and 4.16 and then performing a calculation outlined in Appendix A, the results of three duplicate rearrangements are shown below (Scheme 4.5).
90
Chapter Four-BF3.0Et2 Catalysed Rearrangement ofStyrene Oxide
c:(1D I~
0
+
4.18
,~
1~
0
'~
c(1H
I~
4.7
6
4.8
H migration
D migration with inversion
D migration with retention
dioxane
75±3%
15±4%
10±4%
BFa,QEt 2 ... dioxane
64±3%
12±4%
24±4%
0
~'H0
I ~( i H + c
BFa.OE!~
4.14
Q
~.~ 4.16
Scheme 4.5. Rearrangement results of 4.14 and 4.16.
The schematic of discrete carbo cations graphically representing the structural requirement for the stereochemistry of hydride migration leading to aldehyde for the rearrangements of (lR),(2S)-styrene oxide-p-d1 4.14 and (lR),(2R)-styrene oxide-p-dl 4.16 are shown in Schemes 4.6 and 4.7.
4.5.1.1 The rearrangement of cis-l3-deuterated epoxide (4.14) The rearrangement of (lR),(2S)-styrene oxide-p-d1 is shown in Scheme 4.6. Hydride migration from conformers Band C gives aldehyde 4.18 (75%), deuterium migration with inversion of configuration from conformer A, gives aldehyde 4.7 (15%), and deuterium migration with retention of configuration from conformer D, gives aldehyde 4.8 (10%).
The ratio of product 4.18 from B and C respectively is established from the results of the rearrangement of 4.16 which shows the ratio of 4.8/(4.8 + 4.7)
24/36.
Conformations A and B with the OBF3 and aromatic group in a gauche orientation with the aryl group were expected to be sterically more congested than C and D. A surprising result of this experiment questions this.
Chapter Four
91
BF3.OEt2 Catalysed Rearrangement o/Styrene Oxide
Retention
H
o
HO
0
b
4.18 4.18 from C + B
24/36 ·75
~H ~b
~'~
I"": ( (ii
4.8
4.14
= 75±3%
10±4%
t
A 65±7%
=50±8%
-
F3BO~H
syn
35+7%
OBF IT\ 3
anti
-
O~BF3
Ar \J.J H =='"'" ArKYiH ~ Ar \j}+f o D H H
o
c
A
, I
~H
H
12/36· 75 = 25±8%
HO
(ii( I"":
Vb
b
0
4.18
4.7
4.18 from C + B
15±4%
75±3%
Inversion
Scheme 4.6. Carbocation confonnations in the rearrangement of 4.14.
However, ab initio calculations perfonned by Dr James Cambridge on styrene oxide show that the OBF3 group prefers to be syn to the aryl group (see Chapter 7).2 Confonners Band D could be expected to interconvert, but Cambridge's calculations indicate that they do not as the intennediate or transition state between them collapses to Lewis acid coordinated epoxide as the oxygen approaches the plane of the p-orbital. 4.5.1.2 The rearrangement of trans-l3-deuterated epoxide (4.16) The four confonnations of carbo cation leading to hydride or deuteride migration for the rearrangement of 4.16 are shown in Scheme 4.7.
92
Chapter Four - BF3.OEt2 Catalysed Rearrangement a/Styrene Oxide
Retention
rV«D Vb
r:~H
Va
4.18
4.8 24.:t4%
4.18 from A+D
38+7%
,. .
t
10/25 * 64 = 26.:t8%
15/25 * 64 =38.:t8% ,
=64.:t3%
t
I
N<;(D
~
(yo
:
I
H,"DH :
"'b "
0
4.7
4.18
12±4%
4.18 from A+D = 64±3% Inversion
Scheme 4.7. Carbocation confOlmations in the rearrangement of 4.16.
For 4.16 hydride migration occurs from conformers A and D to give aldehyde 4.18 (64%), and deuterium migration with inversion of configuration occurs from conformer C to give aldehyde 4.7 (12%) and deuterium migration with retention of configuration from conformer B gives aldehyde 4.8 (24%). Aldehyde 4.18 is formed in 64% yield from A and D and therefore the results from the reaction of the isomeric deuterated epoxide 4.14 allows the partition of hydride migration from A as 38 % and from D as 26% to be established.
A most significant and unexpected result of these two experiments is that in the opening of the epoxide, the reaction partitions in favour of rotation of the OBF3 group towards the aryl group and this is consistent with computational studies and this is graphically summarised in Chapter 7. For both 4.14 and 4.16 this is 1.9 : 1 and 1.6 : 1 respectively.
Chapter Four
4.5.2
BF3.OEt2 Catalysed Rearrangement ofStyrene Oxide
93
Fujimoto method to calculate the facial selectivity for hydride migration in the BF3.0Et2 rearrangement of undeuterated epoxide
An analysis developed by Fujimot0 3 in a study of boron trifluoride etherate-catalysed
rearrangement of 1,1-disubstituted epoxides can be used to determine the course of rearrangement of undeuterated epoxide using the above data for 4.14 and 4.16 and to estimate the relative contribution of each pathway (A-D) see Appendix B for this detailed calculation and analysis.
Hydrogen migration is faster relative to deuterium (isotope effect) for each of the four possible transition conformers for hydrogen/deuterium migration. A deuterium isotope parameter, z
IfH/l[ID, (i.e. hydrogen migration from a carbon bearing deuterium relative
to deuteride migration from a carbon bearing a hydrogen) is calculated to satisfy the relation: 50: 15z : 25 : lOz = 24z : 40: 12z: 25. From this data the value ofz (lfHIlfID) 2.3 and this value allows the relative contribution of each of the four transition conformers in undeuterated material to be established and expressed as percentages as B : A : C : D 38±5% : 26±5% : 19±5% : 17±5%. The analysis shows that in the rearrangement, retention is marginally favoured 55% to inversion 45% but the experimental accuracy is such that this ratio must be regarded as c. 1: 1 (Scheme 4.8).
94
Chapter Four - BF3.OEt2 Catalysed Rearrangement ofStyrene Oxide
Retention
~H V 0 17±5%
38±5%
t
64%
syn
t
36%
OBF 3
anti
~ Ali-Q)-t:( ~ Ar~~F3 H C
26±5%
H ArQ)-H H OBF3 D
19±5% Inversion
Scheme 4.8. Fujimoto analysis of optically active styrene oxide rearranged with BF3.OEh. The analysis shows that rotation of the OBF 3 group towards the aryl group is favoured 64% to 36% (1.8:1) over rotation away from aryl group and this preference is well within
the accuracy of the experiments. This is an unexpected and surprising result since we have previously assumed that the interaction of the aryl and OBF3 group would be disfavoured.*
For the products of reaction, where rotation occurs towards the aryl group, inversion and retention are of equal importance. This suggests either that there is a symmetrical cation intennediate where both protons are equally disposed to migrate or that interconversion between the mirror images conformers B and A of the cation is fast relative to hydride transfer. Rotation away from the aryl group results in products resulting from inversion
• See Chapter 7 to compare with calculations of James Cambridge.
Chapter Four
BFj.OEt2 Catalysed Rearrangement o/Styrene Oxide
95
19% and retention 17%. With the inherent experimental error it can not be inferred that there is any marked preference between inversion and retention and the cation intermediate may be symmetrical or interconversion between the mirror image forms of the cation C and D is rapid relative to hydride transfer.
4.5.3
Results for the rearrangement of a-deuterated epoxide (4.6)
The rearrangement of a-deuterated epoxide gives a measure of the overall facial selectivity for hydride migration. The selectivity observed for the BF3.0Eh catalysed rearrangement of (R)-styrene oxide-a-d1 4.6 can be compared to the selectivity calculated above, based on the rearrangement of (lR),(2S)-styrene
oxide-~-dl
4.14 and (IR),(2R)-styrene
oxide-~-dl
4.16.
The result for 4.14 and 4.16 of 45% inversion: 55% retention is similar to that measured for reaction of 4.6 (52% inversion: 48% retention). Since these ratios can be regarded as c. 1: 1, within experimental error, the similarity in these ratios demonstrates remarkable consistency considering the complex nature of the experiments. Within experimental error, hydride migration occurs equally between retention and inversion.
1 a) Coxon, J. M.; Cambridge, J. R. A.; Nam, S. G. C. Org. Lett. 2001, 26, 4225. b) Coxon, J. M.; Cambridge, J. R. A.; Nam, S. G. C. Synlett. 2004, 8,1422. 2 Cambridge, J. R. A. PhD Thesis, University of Canterbury, 2004. 3 Hara, N.; Mochizuki, A.; Tatara, A.; Fujimoto, Y. Tetrahedron Asymm. 2000,11, 1859.
CHAPTER FIVE
Lithium Perchlorate in Benzene Rearrangement of Styrene Oxide
Chapter Five - Lithium Perchlorate in Benzene Rearrangement of Styrene Oxide
5.1
97
INTRODUCTION
It has been reported that epoxides undergo facile lithium salt-catalysed rearrangement to
carbonyl compounds in benzene solution. I Lithium perchlorate is completely insoluble in retluxing benzene at 80°C, but a small amount of LiCI04 is carried into solution by added epoxide, sufficient to effect rearrangement with reactive systems. When the epoxide is added to a boiling mixture of LiCI04 and benzene, the salt disappears from the bottom and forms a ring at the surface of the retluxing liquid. In fact, if hexamethylphosphoramide (HMP A) or other phosphine oxide is added to enhance salt solubility, diminished and irreproducible rates of reaction are obtained. 2 The HMPA-LiCI04 complex, even though present in much greater concentration, is less effective catalytically than the epoxidesolubilised salt. Using only LiCI04, reproducible first-order (in epoxide) kinetics are observed. Since only a small amount of LiCI04 is carried into solution (the bulk remaining undissolved), the effective species in the reaction are the free epoxide and insoluble salt. This fact allows kinetic arguments to be based on epoxide structural features, unencumbered by an unknown but presumably variable epoxide-LiCI04 complex concentration. Rickborn et a11,2 found that all tertiary epoxides react rapidly with LiCI04, and this fact and the observed products were best explained by a carbocation mechanism. For the nontertiary epoxides they studied, in particular styrene oxide, they expected this epoxide to react faster than observed. Rickborn et al l ,2 also found phenylethanal to be reasonably stable to these reaction conditions.
In the light of continuing interese,4 in the rearrangement of substituted styrene oxides D.Q. McDonald et al5 investigated the rearrangement of racemic and isomeric (E)- and (Z)styrene oxides-~-dl with LiCI04 in retluxing benzene (Scheme 5.1).
98
Chapter Five - Lithium Perchlorate in Benzene Rearrangement of Styrene Oxide
er" er
D
~
\
,1-
LiCI04
...
benzene, Do 80°C
cYi° c»
5.1
D
H
-....c:
\
,1-
5.2
D
+
I
~
5.3 2.41
LiCI04
...
benzene, A 80°C
0
5A
± 0.07
crr H H
~
D H D
+
OXrH
0
5.3
~
0
5.4
1.42 ± 0.03
Scheme 5.1. McDonald's rearrangement of styrene oxide-~-dI.
The results of this investigation show that the rearrangement of these styrene oxides occurs with diastereotopic selection6 of the ~-hydrogen trans to the phenyl group, rather than the ~-hydrogen cis
to phenyl group. The ratio of aldehydes 5.3 and 5.4, as determined from the
integrals of the 2H NMR spectrum at Cl (9.78 ppm) and at C2 (3.65 ppm), was dependent on the structure of the starting epoxide. For epoxide 5.1 the ratio of hydrogen: deuterium migration was 2.41±O.07 while for epoxide 5.2 the ratio was 1.42±O.03. The reaction was complete in 4 hours and no isomerisation of the starting epoxides was observed in this period
eH and 2H NMR analysis of reaction aliquots withdrawn over the course of the
reaction).
The results of the above study have been explained previously by the Blackett model (Scheme 5.2) where rotation of the cation intermediate occurs in the direction to relieve the 1A-steric interaction between the bulky substituent and the O-Li+ groUp. 7 Conformation 5.7 is formed first, allowing hydrogen Hb to migrate with inversion of configuration, before rotation to form conformer 5.8, where Ha can migrate with retention of configuration at the migration terminus.
Chapter Five - Lithium Perchlorate in Benzene Rearrangement o/Styrene Oxide
S
o-u+
Xo---u+ L
H
99
I
S~L
)Boo
Hb
0
5.5
Ha
5.6
/;ia
S~L Hb
k
...
~
Li+O-~Ha
Lro+
S
L
Hb 5.8
5.7
~~.
~ ~"
aldehyde
aldehyde
Scheme 5.2. General mechanism of a,a-disubstituted epoxide rearrangement.
These two experiments used non-optically active epoxide and so the assumption that migration occurred from only these two conformations could not be tested. We wished to establish the full stereochemical course of this reaction in detaiL The stereochemical course of the hydride migration can be determined by the rearrangement of specifically deuterated labelled epoxides that are optically active.
5.2
REARRANGEMENT OF (Sj-STYRENE OXIDE
We first studied the reaction of optically active (S)-styrene oxide 5.9 with LiCI04 to develop techniques and an understanding of how to handle the optically active material before attempting to rearrange the deuterated chiral epoxide. The reaction mixture of (S)styrene oxide and LiCI04 was refluxed in benzene for 4 hours at 80°C (Scheme 5.3), as described by McDonald 5 a method adapted from Rickborn et al. 8 A IH NMR was recorded and the product found to consist largely of the starting material (c. 90%) and phenylaldehyde 5.10. The slow reaction rate compared with McDonald was at first thought to be due to the hydration of the LiCI04 and that our batch of LiCI04 may have lost some of its catalytic activity.
THE LIBRARY UNIVER~)IW OF CANTERBURY
NL
Chapter Five
Lithium Perchlorate in Benzene Rearrangement ofStyrene Oxide
H,,/S) ",H H
Vo
LiC104, t=4 hrs )10
benzene, A aooc
5.9
H,,,(S) ",H H
Vo 5.9
+
100
en"" I
(90%)
~
(
~
0
5.10
(10%)
Scheme 5.3. LiCI04 rearrangement of (S)-styrene oxide.
5.3
THE PURITY AND DRYING OF LITHIUM PERCHLORATE
At that time it was thought that the LiCI04 was required to be extremely pure and dryas hydrated LiCI04 is known to have a lower solubility in benzene than anhydrous material and has been reported to diminish its catalytic activity.9 A new batch of LiCI04 was purchased from Aldrich® and opened in a glove box under Argon and one third was transferred to a Schlenk flask. Nitrogen gas was flushed through upon transferral of the LiCI04 solid to a Gallenkamp heating apparatus. For all subsequent experiments, anhydrous LiCI04 was prepared by heating the commercially available anhydrous material under high vacuum (P20S trap) at 160°C for 48 hours. The dried LiCI04 was then used immediately. This method would reduce the likelihood that hydration of LiCI04 was the cause of the observed slow reaction rate compared with McDonald.
5.4
REARRANGEMENT OF (S)-STYRENE OXIDE WITH DRIED LITHIUM PERCHLORATE
The reaction mixture of (S)-styrene oxide and freshly dried LiCI04 was refluxed in benzene for 24 hours (Scheme 5.4).
Chapter Five - Lithium Perchlorate in Benzene Rearrangement of Styrene Oxide
~H
LiCI04 , t=19 hrs
,...
V8
benzene, 1l. aooc
+
101
polymer
5.10
Scheme 5.4. LiCI04 rearrangement of (S)-styrene oxide.
Aliquots were withdrawn at regular intervals throughout the reaction and the sample examined by IH NMR. The reduction in starting epoxide and formation of phenylaldehyde were measured using the integrals of the Ph-Cfu- and -CHO peaks in the spectrum. (S)Styrene oxide was found to rearrange to phenylethanal only after 19 hours under reflux conditions. However, the aldehyde was relatively unstable to the prolonged reflux and the reaction mixture contained material considered to be polymerised aldehyde. The polymerised material has not been identified, but the potential aldol product (E)-2,4diphenyl-2-butenal 5.11 (Figure 5.1) has been eliminated as the likely by product. The 1H NMR of the reaction mixture shows no corresponding aldol addition or condensation peaks in the spectrum.
5.11 IHNMR (270 MHz, CDCh): 3 9.66 (s, lH), 7.44 -7.15 (m, lOH), 6.87 (t, J = 7.3 Hz, 1H), 3.70 (d, J = 7.3 Hz,2H).
Figure 5.1. Potential aldol product (E)-2,4-diphenyl-2-butenal
5.4.1 Rearrangement of (R)-styrene oxide From the results of the above experiment and having taken all the necessary precautions with the LiCI04 solid, it was now clear that the slow reaction rate compared with McDonald's experiments 5 could not be attributed to the catalytic activity of LiCI04 • It
102
Chapter Five - Lithium Perchlorate in Benzene Rearrangement of Styrene Oxide
appeared then that chiral (optically active) styrene oxides did not rearrange as effectively as the non-optically active styrene oxides. It was thought that impurities present in the optically active styrene oxides from synthesis (i.e. compounds in the AD-mix)* may inhibit the reaction. In order to confirm this hypothesis, (R)-styrene oxide 5.12 was synthesised, purified by column chromatography and rearranged under identical conditions (Scheme 5.5) to compare the reaction rate with that of (S)-styrene oxide. The results for (S)-styrene oxide and (R)-styrene oxide were similar, i.e. 20 hours under reflux conditions.
The
reaction mixture also contained some unidentified polymerised material. Purification of the chiral starting epoxide had no overall effect on the rate of reaction.
...
LiCI04 • t==20 hrs
5.12
di
H +
polymer
5.10
Scheme 5.5. LiCI04 rearrangement of (R)-styrene oxide.
5.4.2
Rearrangement of 1:1 mixture of (S) and (R)-styrene oxide
The experiments to date suggested that the optically active styrene oxides complex differently with LiCI04 than the racemic epoxide and that this results in differing reactivities of LiCI04 with optically active and racemic epoxides. It has been known for some time that mixtures ofenantiomers can exhibit unusual physical and chemical properties attributable to the formation of diastereomeric species in solutions. 1o For example, the NMR spectrum of a racemic mixture of enantiomeric compounds may differ from that of the pure enantiomer,l1 or the rate of an organic reaction involving a racemic mixture of chiral compounds maybe different from that using the corresponding enantiomerically pure compound. 12 When the enantiomeric excess obtained in the products
'Reagent for Sharpless Asymmetric Dihydroxylation. Contains cbiralligand (DHQ)2PHAL, K3Fe(CN)6, K 2C03, and KZOs0 4 .2H20. Sharpless, K B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J.; Jeong, K; Kwong, H.; Morikawa, K.; Wang, Z.; Xu, D.; Zhang, X. J. Org. Chem. 1992,57,2768.
Chapter Five - Lithium Perchlorate in Benzene Rearrangement o/Styrene Oxide
103
of an asymmetric reaction is not linearly proportional to the optical purity of the chiral catalyst used, this has been tenned either a positive ("asymmetric amplification") or a negative non-linear effect, depending on the direction of deviation from that expected when an enantiopure catalyst is used. Kagan and co-workers 13 first described non-linear effects of the enantiopurity of a catalyst on the product enantiomeric excess in asymmetric reactions, and developed mathematical models of this behaviour which help elucidate mechanistic infonnation about the reaction.
In order to confinn whether our optically active styrene oxides complex differently with LiCI04 than the racemic epoxide resulting in differing reactivities, we rearranged a 1: 1 mixture of both (8)- and (R)-styrene oxide (Scheme 5.6). This reacted under identical reaction conditions to give a 50% yield of S.10 together with some unidentified polymer after 21 hours.
..
LiCI04 , t=21 hrs benzene, 880°C
5.9 1 : 1 mixture
5.12
~H+
Vb
polymer
5.10 (50%)
Scheme 5.6. LiCI04 rearrangement of 1:1 mixture (8)- and (R)-styrene oxide.
The kinetics of this epoxide reaction were not studied in detail, but the observed rate suggested kinetically complex behaviour as it was not first order. Further LiCI04 rearrangements were planned with the (8)- and (R)-styrene oxide varying the ratio of enantiomers to establish the relationship between reaction rate and enantiomeric excess. These experiments would have tested whether amplification in product chirality of the epoxide may come at the cost of a suppressed rate of aldehyde fonnation.
However, given the differences in observed rates of the 1: 1 (8)- and (R)-styrene oxide mixture compared with the McDonald's results5 for racemic styrene oxide, we determined
Chapter Five - Lithium Perchlorate in Benzene Rearrangement of Styrene Oxide
104
the best strategy was to investigate the conditions for rearrangement further using racemic (±) styrene oxide.
5.4.3
Rearrangement of (±)-styrene oxide (Lancaster)
A control experiment was performed on (±) styrene oxide 5.13 purchased from Lancaster®. (±) Styrene oxide was rearranged with LiCI04 as described previously and interestingly for
this styrene oxide, the reaction took 23.5 hours to give a total mixture containing phenylethanal5.10 with some polymer (Scheme 5.7).
The meaning of these results remained unclear for quite sometime as it was envisaged at the very least, the racemic Lancaster® styrene oxide would rearrange completely after 4 hours in accord with McDonald's results. 5
...
LiCI0 4 , t=23.5 hrs benzene, 6 BOoc
+ polymer
5.13
Scheme 5.7. LiCI04 rearrangement of(±) styrene oxide purchased from Lancaster®.
5.5
SYNTHESIS OF (±) STYRENE OXIDE FROM META-CHLOROBENZOIC ACID (MCPBA)
(±) Styrene oxide 5.13 was
synthesi~ed
by adding styrene 5.14 to a solution of meta-
chloroperbenzoic acid (MCPBA) in chloroform to see if we could reproduce McDonald's results (Scheme 5.8). This method was used by McDonald 5 to synthesise his epoxides 5.1 and 5.2 and would determine whether the synthetic technique of preparing his epoxides had any affect on the rate of LiCI04 rearrangement.
Chapter Five - Lithium Perchlorate in Benzene Rearrangement o/Styrene Oxide
H 0
MCPBA chloroform, OoC
105
H
~H 5.13
5.14
Scheme 5.8. Synthesis of (±) styrene oxide from MCPBA. 5.5.1
Rearrangement of (±) styrene oxide (MCPBA)
(±) Styrene oxide synthesised from MCPBA was used without further purification (as per
McDonald5) and rearranged with LiCI04 in the usual way. This epoxide 5.13 rearranged exclusively to phenylethanal5.10 after 4 hours and the result is reproducible (Scheme 5.9).
H
0
H
~H
,..
LiCI04 , t=4 hrs
benzene, ilSOOC
~(H
Vo 5.10
5.13
Scheme 5.9. LiCI04 rearrangement of (±) styrene oxide synthesised from MCPBA.
This result can be explained by looking at the general epoxidation reaction mechanism (Scheme 5.10).
o
I
o'-"'''c (II
~\
H
R'
0
o~
R'
\
p H
Scheme 5.10. General epoxidation mechanism.
In this reaction the peroxy acid transfers an oxygen atom to the alkene. The addition of oxygen to the double bond occurs via syn-addition. The epoxide may have acidic impurities from the synthesis, namely excess meta-chloroperbenzoic (MCPBA) or metachlorobenzoic acid (MCBA) residues. These acid residues may serve as an acid catalyst in the LiCI04 rearrangement which may explain the observed increase in reaction rate conversion to aldehyde.
106
Chapter Five - Lithium Perchlorate in Benzene Rearrangement of Styrene Oxide
5.5.2
Rearrangement of (±) styrene oxide (MCPBA) purified on an alumina column.
In order to test this hypothesis, (±) styrene oxide synthesised from MCPBA was purified on an alumina (grade-H) column to remove any trace amounts of acid. Flash chromatography was used and the epoxide eluted with 10% ether/pentane. The purified (±) styrene oxide was rearranged as previously described to give 51 % phenylethanal after 4 hours and 87% phenylethanal together with some polymeric material after 23 hours (Scheme 5.11).
H
~H I"'" ~
,.. a~HH I"'" (
LiCI04 , 1=4 hrs
benzene, 6. 80°C
~
5.13 Purified on alumina
0
,..
LiCI04 , 1=23 hrs benzene, 6. 80°C
OiHH I"'" ~
(
+ polymer
0
5.10
5.10
51%
87%
Scheme 5.11. LiCI04 rearrangement of (±) styrene oxide synthesised from MCPBA and purified on an alumina column.
5.6
REARRANGEMENT OF (±) STYRENE OXIDE (LANCASTER~ CATALYTIC AMOUNT OF MCPBA OR MCBA
Another senes of rearrangement reactions were performed with (±) styrene oxide purchased from Lancaster® to serve as a double check and confirm that the acid residues were serving as an acid catalyst in the LiCI04 rearrangement. Namely, (±) styrene oxide with a catalytic amount of either MCPBA or MCBA was rearranged with LiCI04 to give exclusively phenylethanal after 4 hours (Scheme 5.12).
o
H~H
1'-':: ()
H
//
5.13
..
LiC104, t=4 hrs
cat. MCPBA or MCBA
benzene, 11 aooc
5.10
Scheme 5.12. LiCI04 rearrangement of (±) styrene oxide from Lancaster® with a catalytic amount of either MCPBA or MCBA.
Chapter Five - Lithium Perchlorate in Benzene Rearrangement ofStyrene Oxide
5.7
107
SUMMARY TABLE OF STYRENE OXIDE RESULTS Experiment
Time (hrs)
No epoxide present. Phenylethanal with some polymer.
19
No epoxide present. Phenylethanal with some polymer.
20
50% epoxide with 50% phenylethanal with some polymer.
21
tH tH
No epoxide present. Phenylethanal with some polymer.
23.5
tH
49% epoxide and 51 % phenylethanal
4
13% epoxide. 87% phenylethanal with some polymer.
23
ti
1. (2S) styrene oxide
CfH (fH 0':1
2.
(2R) styrene oxide
3.
Rearrangement Product (yield%)
Reactant(s)
o:
1:1 mixture of (2S) and (2R) styrene oxide
(±) styrene oxidepurchased from Lancaster
5.
(±) styrene oxidesynthesised from MCPBA
6.
tt) styrene oxidesynthesised from MCPBA (Alumina column to remove trace amounts of acid) 7.
tt) styrene oxidepurchased from Lancaster (catalytic amount of MCPBA or MCBA)
LiCI04 in benzene @80oC
ti
CfHH (fH
4.
Catalyst
~
I.
~
~
4
l
I.
tH ~
100% phenylethanal.
I.
100% phenylethanal.
4
Chapter Five - Lithium Perchlorate in Benzene Rearrangement of Styrene Oxide
5.8
108
SYNTHESIS, REARRANGEMENT AND REPRODUCTION OF QUENTIN MCDONALD'S DEUTERATED STYRENE OXIDE RESULTS
Having investigated the LiCI04 catalysed rearrangement with benzene in detail, we were now in a position to determine whether the removal of the acid catalyst present in McDonald's experiments affected the diastereotopic selection of C2 hydrogens in the rearrangement of C1-substituted epoxides. 5 This first required the synthesis of (±) styrene oxide-cis-~-dl
and (±) styrene
oxide-trans-~-d],
where the C1 hydrogens are replaced
separately and stereospecifically by deuterium. The synthesis of these two compounds is shown below (Scheme 5.13). D
H
~H
1. DIBAL-H 2. D2 0
,..
0"
MCPBA
,..
chloroform, OOC
0 (»D
I"': //
5.16
5.15
5.17
1"
2. EIMgB, D2 0 H
H
~D 5.18
1. DIBAL-H 2. H2O
,..
0
5.19
0
MCPBA chloroform,OoC
...
0
(»~H I"': D //
5.20
Scheme 5.13. Synthesis of(±) styrene oxide-cis-~-dl and (±) styrene oxide-trans-~-dl'
Styrene-trans-~-dl
was prepared from partial hydrogenation of phenyl acetylene by
diisobutylaluminium hydride (DIBAL) and quenching of the reaction with D20. This reaction had to be repeated several times as initially there were problems with low yields and deuterium incorporation at the C 1 position. The yield and deuterium incorporation were increased from 33 - 90% and 54 - 80% respectively by using a new cylinder of DIBAL, sealed ampules of D20 and longer reaction times. The IH and 2H NMR spectra of the resultant alkene showed it to be greater than 95% stereospecifically labelled as the required (E) isomer.
109
Chapter Five - Lithium Perchlorate in Benzene Rearrangement of Styrene Oxide
Styrene-cis-p-dj (greater than 95% stereospecifically labelled) was obtained from
phenylacetylene-l-dl, prepared by replacement of the hydrogen of phenylacetylene by reaction with ethyl magnesium bromide and decomposition with D20 (greater than 98% deuteration) followed by partial reduction with DIBAL.
Careful oxidation of the alkenes with m-chloroperbenzoic acid (MCPBA) in chloroform gave (±) styrene oxide-cis-p-dj and (±) styrene oxide-trans-p-dj and were stereospecific with no detectable isomerisation. It was discovered that low yields and complex mixtures could result during epoxidation if the reaction mixture was not kept cold or in the dark. 5.8.1
Rearrangement of (±) styrene oxide-cis-p-dj and (±) styrene oxide-trans-p-dj (no purification)
(±) Styrene oxide-cis-p-dj and (±) styrene oxide-trans-p-dj used without further
purification (cf McDonalds) were separately rearranged with LiCI04. These two epoxides 5.17 and 5.20 rearranged exclusively to give aldehydes 5.3 and 5.4 after 4 hours (Scheme 5.14).
cr\(Hb 0
I
~
Ha
~
.
LiCI0 4 , t=4 hrs
benzene, Li BOoC
~D ~
Vo
5.3
5.4
Ha = D
2.41 2.31
1 1
(D.O. McDonald 5 ) (present work)
Hb = D
1.42 1.37
1 1
(D.O. McDonald 5 ) (present work)
5.20 Ha = D 5.17 Hb = D
0
I
D"'-yH
+
Scheme 5.14. LiCI04 rearrangement of (±) styrene oxide-cis-p-dj and (±) styrene oxidetrans-p-dj (no purification)
The ratio of aldehydes 5.3 and 5.4, as determined from the integrals of the 2H NMR spectrum for deuterium at Cl (9.78 ppm) and at C2 (3.65 ppm), was dependent on the structure of the starting epoxide. For (±) styrene oxide-cis-p-dj the ratio of hydrogen:
Chapter Five - Lithium Perchlorate in Benzene Rearrangement of Styrene Oxide
110
deuterium migration was 2.31 : 1 while for (±) styrene oxide-trans-p-dj.the ratio was 1.37 : 1. These results correspond well within experimental error with McDonald's reported results of2.41
5.8.2
± 0.07 for 5.1 and 1.42 : 1 for 5.2 respectively.s
Rearrangement of (±) styrene oxide-cis-p-d1 and (±) styrene oxide-trans-p-d1 (purification with alumina column)
(±) Styrene oxide-cis-p-dj and (±) styrene oxide-trans-p-dj were purified on an alumina
column to remove any acidic impurities present and then separately rearranged with LiCI04 in refluxing benzene. The reactions were monitored by 2H NMR and aliquots withdrawn at intervals of t
=
2, 4, 8 and 16 hours. It was envisaged that the 2H NMRs
recorded would be used to plot a graph of apparent ratios of aldehydes versus time. A line would be drawn on the graphs and extrapolated back to zero time to reduce the effect of polymer side reactions when estimating the ratio of aldehydes in the rearrangement reactions. This method was determined to give the best ratio of aldehydes 5.3 and 5.4 and would be compared with McDonald's results.
However, the results showed that the removal of the acidic impurities of the epoxides affect the rate of rearrangement to such an extent that very little of the epoxides were converted into aldehyde. Any aldehyde that does form is unstable to the reaction conditions of refluxing benzene and polymer side reactions predominate. This is evidenced by the multiple peaks in the 2H NMR and consistent with the results of the undeuterated epoxides.
111
Chapter Five - Lithium Perchlorate in Benzene Rearrangement of Styrene Oxide
5.8.3
Rearrangement of (±) styrene oxide-cis-p-dl and (±) styrene oxide-trans-p-dl (purification with alumina column and catalytic amount of MCPBA or MCBA)
(±) Styrene oxide-cis-p-d1 and (±) styrene oxide-trans-p-dl were purified on an alumina
column to remove any acidic impurities present. A catalytic amount of either MCPBA or MCBA (0.018 g) was added to the epoxides to mimic trace acid residues. The epoxides were separately rearranged with LiCI04 in refluxing benzene. These two epoxides 5.17 and 5.20 rearranged exclusively to give aldehydes 5.3 and 5.4 after 4 hours (Scheme 5.15).
LiCI04 , t=4 hrs
,..
cat. MCPBA or MCBA 0
benzene, II 80 C
5.3
5.20 Ha = D 5.17 Hb
=D
Ha = D
5
2.41
(D.O. McDonald )
2.48
2.37
(present work- MCPBA) (present work- MCBA)
1.42
(D.O. McDonald )
1.46
(present work- MCPBA) (present work- MCBA)
1.39
5
Scheme 5.15. LiCI04 rearrangement of (±) styrene oxide-cis-p-d1 and (±) styrene oxidetrans-p-d1 (purification with alumina column and catalytic amount ofMCPBA or MCBA)
The ratio of aldehydes 5.3 and 5.4, as determined from the integrals of the 2H NMR spectrum for deuterium at CI (9.78 ppm) and at C2 (3.65 ppm), was dependent on the structure of the starting epoxide. For (±) Styrene oxide-cis-p-d1 the ratio of Hydrogen : Deuterium migration was 2.48 : I (MCPBA) and 2.37 : I (MCBA) while for (±) styrene oxide-trans-p-dl.the ratio was 1.46 : I (MCPBA) and 1.39 : I (MCBA). These results
compare within experimental error with McDonald's reported results 5 of 2.41
± 0.07 for
5.1 and 1.42 : I for 5.2 which confirm that both acid residues and LiCI04 catalysed the rearrangement of (±) styrene oxide-cis-p-dl and (±) styrene oxide-trans-p-d1.
Chapter Five
5.8.4
Lithium Perchlorate in Benzene Rearrangement of Styrene Oxide
112
Rearrangement of (±) styrene oxide-cis-~-dl and (±) styrene oxide-trans-~-dl (purification with alumina column, No LiCI0 4 only a catalytic amount of MCPBA or MCBA)
(±) Styrene
oxide-cis-~-dl
and (±) styrene
oxide-trans-~-dl
were purified on an alumina
column to remove any acidic impurities present. For these rearrangement reactions, no LiCI04 was used, only a catalytic amount of either MCPBA or MCBA (0.018 g) was added to the epoxides to mimic trace acid residues. This was to detennine whether the acid residues were acting solely as a catalyst or were responsible for the total rearrangement reaction. The epoxides were rearranged separately in refluxing benzene. These two epoxides 5.17 and 5.20 gave c. < 5% aldehydes 5.3 and 5.4 after 4 hours. This confinns that the acid residues serve only as a catalyst in the LiCIOJbenzene rearrangement of epoxides.
113
Chapter Five - Lithium Perchlorate in Benzene Rearrangement of Styrene Oxide
5.9
SUMMARY TABLE OF (±) STYRENE OXIDE-TRANS-~-dl RESULTS
Experiment
Catalyst in benzene @ 80°C
Reactant( s)
to
1. (±) styrene oxide-cls-P-dt
(unpunfied)
OXIDE-CIS-~-dl
Time (hrs)
2.
,6" 60OH 6"
LiCI04
4
LiCI04
4
LiCI04
~
5. (±) styrene oxide-cis-p-dl (purified On alumina column)
tH'
~o
~-
I±l""oo"',~"'·p-',
(purified on alumina column)
I
0--
I±l "'''"' "d."..., (purified On alumina column)
0--
~ /,
8.
0
W_·'''·_p-', (purified on alumina column)
0--
~ /,
°+
0Xi0
4
1.--::;
2.48
1
4
~\O+ 1.46 1.39
d)/H 1.--::;
: :
HH
~I
7.
:
2,4,6, 8& 16
0
LiC104& MCPBAor MCBA
1
° + a~H 1.--::; °
2.37
6" 60OH 6" 0
LiC104& MCPBAor MCBA
h
Very little of the epoxide actually converted to aldehyde. Any aldehyde that formed was unstable to the prolonged refluxing in benzene and polymer side reactions predominated.
!
~ /, 6.
LiCI04
cnr°
2,4,6, 8& 16
0
0--
HH
Very little of the epoxide actually converted to aldehyde. Any aldehyde that formed was unstable to the prolonged refluxing in benzene and polymer side reactions predominated.
~I
I±l_--P-', (purified on alumina column)
1.--::;
1.37
.
:
o
0Xi0
I.
(purified on alumina column) :c- I
4.
+
2.31
0--
~
I±l_.m"......,
cfi° '.--::; °
0
I±l_ ......... (unpur1fied) 3.
Rearrangement Products (ratio)
HH
~ /,
AND (±) STYRENE
: :
6
1 (MCPBA) 1 (MCBA)
OXiH ° 1.--::;
1 (MCPBA) 1 (MCBA)
No LiCI04 only MCPBA or MCBA
4
less than 5% aldehyde
No LiCI04 only MCPBA or MCBA
4
less than 5% aldehyde
0
Chapter Five - Lithium Perchlorate in Benzene Rearrangement ofStyrene Oxide
5.10
114
CONCLUSION
In conclusion, we can now detennine with confidence that the acidic impurities present in McDonald's epoxides affect the stereoselection of hydrogen migration when styrene oxide is rearranged with LiCIOJbenzene and question the validity of his reported results. McDonald's results are more consistent with LiCI04ibenzene catalysed rearrangement assisted with an H+ acid catalyst.
The slow reaction rate observed in the LiCI04ibenzene rearrangement of all racemic and optically active styrene oxides for conversion into aldehyde is a consequence of having no H+ acid catalyst present or if it is removed from the reaction by alumina column. Furthermore, we can now eliminate the slow conversion rate being attributed to the catalytic activity of our LiCI04 or the chirality of the epoxides as initially thought. The aldehyde that fonns at a slower rate is unstable to the prolonged reflux conditions (greater than 4 hours) and complex unidentified polymer reactions predominate. It has been determined that the polymer fonned is not the potential aldol product (E)-2,4-diphenyl-2butenal.
B.; Gerkin, R. M. J. Am. Chem. Soc. 1968,90,4193. Rickborn, B.; Gerkin, R. M. J. Am. Chem. Soc. 1971,93, 1693. 3 Coxon, J. M.; Hartshorn, M. P. Tetrahedron Lett. 1987,28,1333. 4 Ukachukwu, V.C.; Blumenstein, J.J; Whalen, D. L. J. Am. Chem. Soc. 1986, 108,5039. 5 a) McDonald, D. Q. Honours Thesis, University of Canterbury, 1987. b) Coxon, J. M.; McDonald, D. Q. Tetrahedron Lett. 1988,29, 2575. 6 (a) Coxon, J. M.; Lim, C. E. Aust.J. Chem. 1970,30,1117. (b) Blunt, J.W.; Coxon, J. M.; Lim, C. E.; Schuyt, H. A Aust.J. Chem. 1983,36,97. (c) Blackett, B. N.; Coxon, 1. M.; Hartshorn, M. P.; Richards, K. E. J. Am. Chem. Soc. 1970,92,2574. 7 Coxon, J. M.; Blackett, B. N. J. Am. Chem. Soc. 1970, 92, 2574. 8 Rickborn, B.; Gerkin, R. M. J. Am. Chem. Soc. 1971,93, 1693. 9 Pocker, Y.; Buchholz, R. F. J. Am. Chem. Soc. 1970,92,2075. 10 Horeau, A; Guette, J. P. Tetrahedron 1974, 30, 1923. II Harger, M. 1. P. Chem. Commun. 1976,555. 12 Wynberg, H.; Feringa, B. L. Tetrahedron 1976, 32, 2831. 13 Guillaneux, D.; Zhao, S. H; Samuel, 0.; Rainford, D.; Kagan, H. B. J. Am. Chem. Soc. 1994,116,9430. 1 Rickborn,
2
CHAPTER SIX
Lithium Perchlorate in Ether Rearrangement of Styrene Oxide
Chapter Six - Lithium Perchlorate in Ether Catalysed Rearrangement ojStyrene Oxide
6.1
116
INTRODUCTION
Coxon and McDonald 1 have reported previously that rearrangement of styrene oxide to aldehyde occurs in high yield with a catalytic amount of LiCI04 in refluxing benzene. Attempts to reproduce this result with commercially available racemic styrene oxide however have been unsuccessful, and even after reaction times of several hours, little of the epoxide was converted into aldehyde. Any aldehyde that does form is unstable to the reaction conditions of refluxing benzene and polymers become the dominant product(s). In separate studies (Chapter five) we determined that the styrene oxide studied earlier by McDonald l contained traces of meta-chloroperbenzoic acid. Sankararaman et al. 2 has shown that a lithium ion in concentrated solutions of lithium perchlorate in diethylether can result in more selective transformations of styrene oxide than other more traditionally used Lewis acids such as BF3. They found that styrene oxide gave only phenyl ethanal , which was stable to the reaction conditions. Based on the observed chemo- and regio-selectivities and the products of rearrangement, they inferred that the rearrangement of epoxides in the lithium perchlorate/ether medium proceeds by coordination of the lithium ion to the epoxide oxygen. This is followed by the cleavage of a C-O bond to give the most stable carbocation and subsequent hydride migration to give the observed product. They attributed the observed chemo- and regio-selectivities to the mild Lewis acidity of the lithium ion in ether. 3
6.2
REARRANGEMENT OF UNDEUTERATED STYRENE OXIDE WITH LiCI04 IN ETHER
We have found that styrene oxide 6.1 rearranges with 5M lithium perchlorate in ether, to give aldehyde 6.2 in high yield (95% as measured by lH NMR) when the lithium perchlorate used is freshly dried at 160°C for 48 hours over P20S in vacuum (Scheme 6.1).
Chapter Six - Lithium Perchlorate in Ether Catalysed Rearrangement of Styrene Oxide
° crr.j";;~ 6.1
117
5M LiC104,.. ether
6.2 95%
Scheme 6.1. Rearrangement of undeuterated styrene oxide with 5M LiCI04 in diethylether
We have found however that even when great care is taken to attempt to reproduce exactly all reaction conditions, reaction times are not reproducible. Depending on the batch of LiCI04, styrene oxide can rearrange fully to give phenyl aldehyde in times ranging from 2 to 24 hours.
It was thought that the inconsistent reaction times might be attributed to styrene oxide reacting on the solid surface of the lithium ion in the saturated ether solution. An experiment was performed to test this hypothesis by filtering off the excess LiCI04 solid in the saturated ether solution. Styrene oxide was stirred at room temperature in LiCI04/ether and aliquots withdrawn at regular intervals (t = 2,6, 12 and 24 hours). However, the results for the extent of rearrangement were the same whether or not solid LiCI04 was present in the saturated ether solution.
Over the course of our rearrangement reactions, three batches of LiCI04 were purchased on separate occasions from Aldrich.® Since the rate of the rearrangement reactions can vary depending on which batch of LiCI04 was used, each experiment is identified as using batch 1,2 or 3.
To allow for analysis and integration of the prochiral protons
~-
to oxygen in the product
aldehyde, the aldehyde was reduced with LiAIH4 and the resulting alcohol was reacted with N-(4-nitrophenylsulfonyl)-S-phenylalanyl chloride (Scheme 6.2), The prochiral protons of the ester, are distinguished in the IH NMR spectra by addition of d-Yb(hfc)3 chiral shift reagent. 4
Chapter Six Lithium Perchlorate in Ether Catalysed Rearrangement of Styrene Oxide
o
'"
~
'I "" i
(R)
~
",H 5M LiCIO H ether
4,..
LiAIH4 ,..
~H ",H OH
I"" ---:;
6.1
118
~
H ",HOR.
R*CI,..
I"" ---:;
6.4
6.3
Scheme 6.2. Rearrangement, reduction and esterification of undeuterated (R)-styrene oxide-a-dl.
6.3
REARRANGEMENT OF a-DEUTERATED EPOXIDE
In order to establish the overall facial stereoselectivity for hydride migration (S)-styrene oxide-a-dl 6.5 and (R)-styrene oxide-a-dl 6.6 were rearranged separately and the results of the two experiments compared. The rearrangements of these two optically active adeuterium labelled epoxides give two possible enantiomeric aldehydes, 6.7 (resulting from hydride migration with inversion for the (S)-epoxide or retention of configuration for the (R)-epoxide) and 6.S (resulting from hydride migration with retention for the (S)-epoxide or inversion of configuration for the (R)-epoxide) at the migration terminus (Scheme 6.3). "(S,"H
~° I"" ~
H
6.5
LiCI04 ,..
or
ether
o
~
",,"H
I "" :/:/
(R)
~ H
""
1
---:;'
0
~
D,"HH
"DH
(S) i
+
6.7
H
6.6
Scheme 6.3. Rearrangement of(S)- and (R)-styrene oxide-a-dl.
1 ""
(R)
0
~
6.8
Chapter Six - Lithium Perchlorate in Ether Catalysed Rearrangement of Styrene Oxide
6.3.1
119
Rearrangement of (S)-styrene oxide-a.-d1
(S)-Styrene oxide-a-dl 6.5 was synthesised with> 95% ee (established by d-Yb(hfc)3 chiral shift reagent) and approximately 98% D incorporation as measured by IH NMR at the a-position. Eight separate rearrangements were conducted with two different batches of LiCI04 using the established conditions.
For the analysis, the normal procedure was adopted: the aldehyde products were reduced to alcohols 6.9 and 6.10 which were esterified with N-( 4-nitrophenylsulfonyl)-S-phenylalanyl chloride to give the diastereomeric esters 6.11 and 6.12; these are different due to the chirality at the carbon
~-
to the ester linkage.
7
°.
",HOH
I """ {R}
6.7 + 6.8
~
6.9
ow H
R'CI ,..
",0 OR'
I "-':: (s) h
6.10
6.11
+
7°
",H OR'
I """ {R} h
6.12
~
R'=
_
o~
N02~#-N o
0
Scheme 6.4. Reduction and esterification of6.7 and 6.8.
The relative amounts of esters 6.11 and 6.12 were determined for each experiment by IH NMR of the ester in the presence of d-Yb(hfc)3 chiral shift reagent (Scheme 6.4). The ratio of esters 6.11 and 6.12 are of course identical to the ratio of aldehydes 6.7 and 6.8 (Table 6.1).
Chapter Six - Lithium Perchlorate in Ether Catalysed Rearrangement of Styrene Oxide
(H R)
(Hs)
I
I
o",(S)
",H H
Uo
LiCI0 4
ether
Reaction 1. t=2hr (61 % rearranged) 2. t=24hr (100% rearranged) 3. t=24hr (100% rearranged) 4. t=48hr (100% rearranged) 5. t=48hr (100% rearranged) Reaction 5M (BATCH 2) LiClO4/ether
1. t=0.5hr (65% rearranged) 2. t=2hr (100% rearranged) 3. t=24hr (100% rearranged)
~" I '-':::: /-
(R)
0
6.8 (1)
6.5
5M (BATCH 1) LiClO 4/ether
,.,..
120
+
c0i" I '-':::: /-
(S)
0
6.7 (2)
H migration with retention of configuration (1) 40.3 46.7 47.6 47.6 49.8
H migration with inversion of configuration (2) 59.7 53.3 52.4 52.4 50.2
H migration with retention of configuration (1) 43.1 48.5 50.0
H migration with inversion of configuration (2) 56.9 51.5 50.0
Table 6.1. Inversion I retention of configuration in the rearrangement of (S)-styrene oxide-
a-dl .*
Table 6.1 shows that migration of the methylene protons in the formation of aldehyde occurs therefore, within experimental error, with slight preference for inversion over retention (59.7: 40.3) when the epoxide 6.S is 61% rearranged and (56.9: 43.1) when 65% rearranged. However, it can be seen from the results that when the epoxide is 100% rearranged, formation of aldehyde is observed to occur equally with retention and inversion indicating that that some racemisation of aldehyde is occurring under the reaction conditions, but without loss of deuterium. Any kinetic preference for dioxolane (or polymer) formation from reaction of 6.7 with 6.S compared with 6.8 with 6.S is expected to be so small as to be insignificant.
• The results in the table have an estimated error of ±4% and these errors are discussed further in 6.5 of this chapter.
121
Chapter Six - Lithium Perchlorate in Ether Catalysed Rearrangement ofStyrene Oxide
6.3.2
Rearrangement of (R)-styrene oxide-a-dl
The overall facial stereoselectivity of hydride migration from the terminal prochiral methylene protons was also established with (R)-styrene oxide-a-d1 6.6 to compare the results with the (S)-styrene oxide-a-d1 6.S enantiomer. (R)-Styrene oxide-a-d1 6.6 was synthesised with > 95% ee, (established by d-Yb(hfc)3 chiral shift reagent) and approximately 98% D-incorporation as measured by IH NMR at the a-position and rearranged with LiCI04 (batch 2) using the established conditions. The relative amounts of aldehydes 6.7 and 6.S were determined for each experiment by IH NMR of the ester in the presence of d-Yb(hfc)3 chiral shift reagent in the usual way (Table 6.2). (H R)
~" I
~
(R)
H
~
6.6
Reaction 5M (BATCH 2) LiClOJether
1. t=0.5hr (20% rearranged) 2. t=2hr (50% rearranged) 3. t=4hr (100% rearranged)
LiCI04 ether
,..
(Hs)
I
cfsi"° I '-'::::
(S)
~
6.7 (1)
H migration with retention of configuration (1) 36.4 42.2 46.7
I
+
cr"" I ~
~
(Rl'(
°
6.S (2)
H migration with inversion of configuration (2) 63.6 57.8 53.3
Table 6.2. Inversion / retention of configuration in the rearrangement of (R)-styrene oxidea-d1.*
Table/ 6.2 shows that migration of the methylene protons in the formation of aldehyde occurs with preference for inversion over retention (63.6 : 36.4) when the epoxide 6.S is 20% rearranged. From the results, as the epoxide rearranges to form more aldehyde (from 50-100% yield) over time, there is a decrease in the inversion: retention ratio and this supports the earlier results obtained for (S)-styrene oxide-a-d1 6.S, namely that
• The results in the table have an estimated error of ±4% and these errors are discussed further in 6.5 of this chapter.
Chapter Six - Lithium Perchlorate in Ether Catalysed Rearrangement ofStyrene Oxide
122
racemisation of the aldehyde is occurring in competition with the rearrangement reaction. The epimerisation occurs without loss of deuterium under the reaction conditions.
6.4
REARRANGEMENT OF
~-
DEUTERATED EPOXIDE
To establish the facial selectivity of each of the methylene protons it is necessary to study the reactions of 6.13, 6.14, 6.15 and 6.16 where the terminal protons are separately labelled as deuterium (Figure 6.1).
crbD crbH H',(S) (R)'"H
H,(S)(S),,,D
·6.13
6.15
6.14
6.16
Figure 6.1. Deuteroisomers of styrene oxide
6.4.1
Rearrangement of (1S),(2R)-styrene
oxide-~-dl
(AD-a cis)
(1S),(2R)-Styrene oxide-~-dl, 6.13 (enriched 92.4%, and containing 6.153.5%,6.174.0%) on reaction with LiCI04 gives four aldehydes, the ratio of which was established by NMR after reduction (LiAIH4) and esterification with N-(4-nitrophenylsulfonyl)-S-phenylalanyl chloride (Scheme 6.5).
Chapter Six Lithium Perchlorate in Ether Catalysed Rearrangement o/Styrene Oxide
~'D 1 ""'= 0 H
+
...
~'~
6.15 3.5%
6.13 92.4%
1. LiCI04 ether
+
h
~H V 0
6.17 4.0% H
+
H
h
~
0
6.18
HOH
~
HD
()i 1 ""'= •
6.2
:1
+
h
123
Q ? HHOH • ~ H
6.7
6.8
+
h
6.3
6.19
6.10
6.9
(Hs)
(HR)
3. R'CI
~OR' I~ h
+
~OR' I~ H D h
6.4
I
+
~,"DOR' I""'=(~
+
~ ~R' (R)
1
h
h
6.20
I
6.11
6.12
Scheme 6.5. Rearrangement, reduction and esterification of (1S),(2R)-styrene oxide-~-dl.
We were unable to determine the integrals of the ~- Hs and HR resonances in the 1H NMR spectrum after the addition of chiral shift reagent to the diastereomeric esters (6.4, 6.11, 6.12 and 6.20) obtained from the (1S),(2R)-styrene
oxide-~-dl
6.13. It was determined that
the solution of the pure sample was not adequately concentrated (Table 6.3).*
'We had experienced similar problems with the (lS),(2R)-styrene oxide-~-dl 6.13 enantiomer during the BF3.OEt2 rearrangement analysis so, no further LiCIOJether rearrangements were performed with this enantiomer.
Chapter Six - Lithium Perchlorate in Ether Catalysed Rearrangement ofStyrene Oxide
124
(Hs)
(H R)
I LiCI0 4
,.
ether
6.13
Reaction
5M(BATCH2)
cri &i D
I
~
0
+
I
I "" (R)
//
H.... ",D H
H +
0
rys>r ~
0
6.18 (1)
6.8 (2)
6.7 (3)
H migration
o migration (inv)
o migration (retn)
Hs(retn)
HR (inv)
a 2HNMR
p2HNMR
PHS1HNMR
pHR1HNMR
integral (1)
integral (2+3)
integral (2)
integral (3)
72.7
27.3
failed to distinguish·
failed to distinguish·
LiCIOJether
1. t=24hr (100% rearranged)
Table 6.3. 2H and IH NMR integral of aldehyde/ester from rearrangement of 6.13.
Ester 6.20 is responsible for the 2H NMR signal a- to the ester oxygen, while 6.11 and 6.12 give rise to a 2H NMR signal at the p- position. The amount of 6.20 relative to 6.11 and 6.12 can therefore be obtained by comparison of the 2H NMR integral for. the a- and ppositions.
Esters 6.4, 6.20 and 6.12 give rise to the Hs p- IH NMR signal, while 6.4,6.20 and 6.11 all contribute to the HR p- proton signal. See Appendix A for a more detailed calculation analysis.
6.4.2
Rearrangement of (IR),(2S)-styrene oxide-p-d1 (AD-P cis)
We determined successfully the facial selectivity separately with the (lR),(2S)-styrene oxide-p-dj isomer, 6.14 (enriched 91.8% and containing 6.16 3.5%, 6.1 4.7%). (lR),(2S)Styrene oxide-p-dj 6.14 was reacted with LiCl04 (batch 3) using the established conditions to give aldehydes the ratio of which was determined in the usual way outlined above. The results of three duplicate rearrangements are shown below (Table 6.4) and are explained in 6.6.1.1 of this chapter.
125
Chapter Six - Lithium Perchlorate in Ether Catalysed Rearrangement ofStyrene Oxide
(Hs)
0 LlCI04 ether
..
c(<(D ~
0
+
~H I ~
H migration
(R)
~
6.18(1)
6.14
(H R)
I
0
I
H ",D H
+
~
(S) i
~
0
6.7 (3)
6.8(2) D migration (retn)
D migration (inv)
Hs (inv)
HR (retn)
Reaction
a HNMR
13 2HNMR
13 HSIHNMR
13 HR IHNMR
5M (BATCH 3) LiCI04/ether
integral (1)
integral (2+3)
integral (2)
integral(3)
l.t=24hr(100~rerurranged
72.7
27.3
1
1.20
2. t=24hr (lOO~ rearranged
76.6
23.3
1
1.15
3. t=24hr (lOO~ rerurranged)
73.1
26.9
1
1.19
Average
74.1±5%
1
1.18±0.03
2
?':9±5%l
Table 6.4. 2H and IH NMR integrals of aldehyde/ester from rearrangement of 6.14.*
6.4.3
Rearrangement of (1S),(2S)-styrene oxide-l3-dl (AD-a trans)
(lS),(2S)-Styrene oxide-l3-dl isomer, 6.15 (enriched 91.0% and containing 6.133.9%,6.17 5.1%) was reacted with LiCI04/ether to give aldehydes the ratio of which was determined in the usual way (Table 6.5).
• The error for each experimentally derived parameter is estimated from a combination of the sensitivity of the IH and 2H instruments and the average standard deviation of three separate experiments.
Chapter Six- Lithium Perchlorate in Ether Catalysed Rearrangement ojStyrene Oxide
(Hs)
H,,(S) (S),,,D crb'H
..
LiCI04 ether
I"'"~ ( ~D 0
!
H migration
Reaction 5M (BATCH 2)
2
I ~DH I "'" (S) (
I "'" + ~H (R)
~
6.18 (1)
6.15
(HR)
I
+
126
~
0
6.8 (2)
0
6.7 (3)
D migration (inv) Hs{retn)
D migration (retn) HR (inv)
a HNMR
~2HNMR
~HsIHNMR
~HRIHNMR
integral (1)
integral (2+3)
integral (2)
integral (3)
64.7
35.5
1.19*
1
LiCIO,Jether 1. t=24hr (100% rearranged)
Table 6.5. 2H and IH NMR integrals of aldehyde/ester from rearrangement of 6.15.
This result was considered unreliable for the same reason as we experienced previously with the other epoxide 6.13 derived from the AD-a mix *, an unidentified impurity in the IH NMR spectrum of esters 6.11 and 6.12 occurred in the region of the ~- Hs integral thereby artificially increasing the integral of the hydrogen migration with retention of configuration. Despite the unreliable result with epoxide 6.15, we subsequently determined the facial selectivity with (lR),(2R)-styrene
6.4.4
oxide-~-dl
(see below).
Rearrangement of (IR),(2R)-styrene oxide-~-dl
(AD-~
trans)
Six separate rearrangements were conducted on (lR),(2R)-styrene
oxide-~-dl
isomer, 6.16
(enriched 91.5% and containing 6.14 4.9%, 6.1 3.7%) with LiCI04 (batch 3) using the established conditions. The results of the rearrangements are shown below (Table 6.6).
* Some epoxides in particular 6.13 and 6.15 derived from the Sharpless asymmetric dihydroxylation ADmix-a contained an unidentified impurity in the lH NMR spectrum of the derived ester which sometimes affected accurate integration of the
~-
Hs and HR integrals.
Chapter Six - Lithium Perchlorate in Ether Catalysed Rearrangement o!Styrene Oxide
127
(Hs)
LICI04
,..
ether
6.16
Reaction ATCH 3) LiCI04/ether
ged) ged) • 3. t=6hr (12% rearranged)
y"o I ~
(
/-
0
(H R)
I
+
1'-'.:: ~"" (R) (
/-
0
I
+
6.18(1)
6.8 (2)
H migration
D migration (retn) Hs (inv)
a 2HNMR integral (1) 72.2* 49.9* 86.2*
f32 HNMR inte al (2+3) 27.8* 50.1 * 13.8*
65.9 67.6 67.1 66.9±5%
34.1 32.3 32.9 33.1±5%
I '-'.:: ~H (5) (
/-
0
6.7 (3)
o migration (inv) HR (retn)
f3 HSIHNMR inte al (2)
f3H R IHNMR inte al(3)
failed to distinguish
failed to distinguish
failed to distinguish
failed to distinguish
failed to distinguish
failed to distinguish
1.23 1.20 1.23 1.22±0.02
1 1 1
1
Table 6.6. 2H and IH NIVIR integrals of aldehyde/ester from rearrangement of 6.16.
6.5
DISCUSSION OF ERRORS
Facial selectivity measurements of the products from rearrangement of epoxide deuterated in the a-position are the most accurate because only hydrogen migration is being measured in the 1H NMR spectrum.
The largest cause of error in the above experiments is associated with the measurement of the relative amount of hydrogen and deuterium in each of the prochiral positions from the
• Experiments 1, 2, and 3 were initially conducted to determine what affect or extent racemisation of the aldehyde (if any) may have on the IH and 2H NMR results. However, all three experiments gave unreliable IH and 2H NMR results. The percentage conversion of aldehyde was too low giving a low signal to noise ratio in the 2H NMR spectra and also making it impossible to distinguish the Hs and HR protons in the IH NMR spectra.
Chapter Six - Lithium Perchlorate in Ether Catalysed Rearrangement ofStyrene Oxide
rearrangement of
~-deuterated
128
epoxide. Variations between 5 and 10% were obtained in
the relative 1H NMR integral at different concentrations of chiral shift reagent. This variation is more pronounced for the rearrangement of the
~-deuterated
epoxide. Only c.
30% of the material contains a migrated deuterium label so a small difference in the IH NMR integral at C2 represents a larger relative difference in the amount of deuterium in each prochiral position.
The measurements for all the epoxide rearrangements are however sufficiently accurate and reproducible to show the preference for migration with inversion or retention of configuration of the two terminal epoxide hydrogens.
The error for each experimentally derived parameter is estimated from a combination of the sensitivity of the IH and 2H NMR instruments (~ ±2%) and the average standard deviation of three separate experiments. The estimated errors are included in the tables and schemes below.
6.6
DISCUSSION
6.6.1
The rearrangement of cis- and trans-d epoxide (6.14 and 6.16)
To evaluate the nature of the rearrangement process, the experimental data from each of the two epoxides 6.14 and 6.16 must be used. After adjusting for the isomers in the mixture of epoxide 6.14 and 6.16 and then performing a calculation outlined in Appendix A, the results ofthree duplicate rearrangements are shown below (Scheme 6.6).
Chapter Six - Lithium Perchlorate in Ether Catalysed Rearrangement ojStyrene Oxide
c?1 1/
D
0
m
H
+
1/
6.18
LiCI04 ether
0
+
c(1H 0
1/
6.7
6.8
H migration
D migration with inversion
D migration with retention
II>'
74±5%
21±4%
5±4%
II>'
67±5%
7±4%
26±4%
0
~'~
129
6.14
0
~'~
LiCI04 ether
6.16
Scheme 6.6. Rearrangement results of 6.14 and 6.16*.
The conformations for hydride migration leading to aldehyde for the rearrangements of (1R),(2S}styrene
oxide-~-dl
6.14 and (lR),(2R)-styrene
oxide-~-dl
6.16 are shown m
Schemes 6.7 and 6.8 and discussed below.
6.6.1.1 The rearrangement of cis-~-deuterated epoxide (6.14) The rearrangement of (1R),(2S)-styrene
oxide-~-dl
is shown in Scheme 6.7. Hydride
migration from conformers Band C gives aldehyde 6.18 (74%), deuterium migration with inversion of configuration from conformer A, gives aldehyde 6.7 (21 %), and deuterium migration with retention of configuration from conformer D, gives aldehyde 6.8 (5%).
Conformations A and B with the O-Li+ and aromatic group in a gauche orientation were expected to be sterically more congested than C and D.
• The results of the a-deuterated epoxides 6.5 and 6.6 suggested that racernisation of the aldehyde was occurring under the reaction conditions. Racemisation was presumed to be occurring at a slower rate than the rate of epoxide rearrangement as there is a measurable difference between deuterium migration with inversion or retention.
130
Chapter Six - Lithium Perchlorate in Ether Catalysed Rearrangement ofStyrene Oxide
Retention
H
o
H D
~'~
()l I
~
(
//
0
6.14
6.1B
6.B 5±4%
6.18fromC+B= 74±5% 26/33 * 74 = 58±7%
t B
I
79±9%
LiCI0 4
i
t
21±9%
o
c
A
~
7/33 * 74 = 16±4%
~H
V8 6.7
6.18fromC+B= 74±5%
21±4%
Inversion
Scheme 6.7. Carbocation conformations in the rearrangement of6.14.
However, ab initio calculations performed by Dr James Cambridge on styrene oxide show that the O-Li+ group prefers to be syn to the aryl group (see Chapter 7).5 Conformers Band D could be expected to interconvert, but Cambridge's calculations indicate that they do not as the intermediate or transition state between them collapses to Lewis acid coordinated epoxide as the oxygen approaches the plane of the p-orbital.
The relative importance of pathway Band C, which give the same product for 6.14, follows by simple arithmetic from the reaction of the isomeric deuterated epoxide 6.16.
131
Chapter Six - Lithium Perchlorate in Ether Catalysed Rearrangement of Styrene Oxide
6.6.1.2 The rearrangement of trans-~-deuterated epoxide (6.16) The four confonnations of carbocation leading to hydride or deuteride migration for the rearrangement of 6.16 are shown in Scheme 6.8. 0
~'~
cn
rH
//
Retention
c?Y
t
I //
6.16
0
6.8
t
20+9%
80+9%
0lIl'
0
6.18
LiCI0 4
26.±4%
D
6.18 from A+O
~
5/26 * 67
=13.±3%
t
=67.±5%
I
21/26 * 67
= 54.±7%
,
m H
I ~ //
~H
HO (
Uo
0
6.7
6.18
6.18 from A+O
=67.±5%
7.±4%
Inversion
Scheme 6.8. Carbocation confonnations in the rearrangement of 6.16.
For 6.16 hydride migration occurs from confonners A and D to give aldehyde 6.18 (67%), and deuterium migration with inversion of configuration occurs from confonner C to give aldehyde 6.7 (7%) and deuterium migration with retention of configuration from confonner B gives aldehyde 6.8 (26%). Aldehyde 6.18 is fonned in 67% yield from A and D and therefore the results from the reaction of the isomeric deuterated epoxide 6.14 allows the partition of hydride migration from A as 54 % and from D as 13% to be established.
Chapter Six - Lithium Perchlorate in Ether Catalysed Rearrangement of Styrene Oxide
l32
A most significant conclusion from these two experiments is that in the opening of the epoxide, the reaction partitions in favour of rotation of the O-Li+ group towards the aryl group 4 : 1 for both 6.14 and 6.16. This is consistent with computational studies and is graphically summarised in Chapter 7.
6.6.2
Fujimoto method to calculate the facial selectivity for hydride migration in the BF3.0Et2 rearrangement of undeuterated epoxide
A method developed by Fujimoto 6 can be used to determine the course of rearrangement of undeuterated epoxide using the above data for 6.14 and 6.16 and to estimate the relative contribution of each pathway (A-D) see Appendix B for this detailed calculation and analysis.
Hydrogen migration is faster relative to deuterium (isotope effect) for each of the four possible transition conformers for hydrogen/deuterium migration. A deuterium isotope parameter, z
=
kDHIJliD, (i.e. hydrogen migration from a carbon bearing deuterium relative
to deuteride migration from a carbon bearing a hydrogen) is calculated to satisfy the relation: 58: 21z: 16: 5z = 26z: 55 : 7z: 12. From this data the value ofz (lfH/kHD ) = 2.4 and this value allows the relative contribution of each of the four transition conformers in undeuterated material to be established and expressed as percentages as B : A : C : D 43±5% : 37±5% : 12±5% : 8±5%. The analysis show that in the rearrangement retention is slightly favoured, 51 % over inversion 49%. However, within experimental error and given the evidence that racemisation of the aldehyde is occurring, this ratio must be regarded as a lower limit to the value which is considered to be more likely inversion being favoured over retention c. 1.5:1 (Scheme 6.9). This ratio has been estimated from the results of the a-deuterated epoxides 6.5 and 6.6.
Chapter Six - Lithium Perchlorate in Ether Catalysed Rearrangement of Styrene Oxide
133
Retention
B.±5%
43.±5%
LiCI0 4
t
BO.±10%
t
20.±7%
anti
~H
Va 37.±5%
12.±5% Inversion
Scheme 6.9. Fujimoto analysis of optically active styrene oxide rearranged with LiCI04.
The analysis shows that rotation of the o-Li+ group towards the aryl group is favoured 80% to 20% (4:1) over rotation away from aryl group and this preference is well within the accuracy of the experiments. This is unexpected and a surprising result since we have previously assumed that the interaction of the aryl and O-Li+ group would be disfavoured. *
For the products of reaction, where rotation occurs towards the aryl group, inversion and retention are of equal importance (although the results of the a-deuterated epoxides 6.S and 6.6 suggest slightly more inversion would be occurring without racemisation of the aldehyde). This suggests either that there is a symmetrical cation intermediate where both protons are equally disposed to migrate or that interconversion between the mirror images
• See Chapter 7 to compare with calculations of James Cambridge.
Chapter Six - Lithium Perchlorate in Ether Catalysed Rearrangement ofStyrene Oxide
134
confonners B and A of the cation is fast relative to hydride transfer. Rotation away from the aryl group results in products resulting from inversion 12% and retention 8%. With the inherent experimental error it can not be inferred that there is any marked preference between inversion and retention and the cation intennediate may be symmetrical or interconversion between the mirror image fonns of the cation C and D is rapid relative to hydride transfer.
6.6.3
Results for the rearrangement of a-deuterated epoxide (6.6)
The rearrangement of a-deuterated epoxide gives a measure of the overall facial selectivity for hydride migration. The selectivity observed for the LiCI04/ether catalysed rearrangement of (R)-styrene oxide-a-dj 6.6 can be compared to the selectivity calculated above, based on the rearrangement of (IR),(2S)-styrene oxide-p-dj 6.14 and (IR),(2R)styrene oxide-p-dj 6.16.
The result for 6.14 and 6.16 of 49% inversion: 51% retention is within the range of that measured for reaction of 6.5 and 6.6 (50%-63% inversion: 50%-36% retention) taking into account experimental error, the extent of rearrangement and possible racemisation of the aldehyde. Having taken these factors into account, the similarity in these ratios demonstrates remarkable consistency considering the complex nature of the experiments. We can conclude that hydride migration with inversion is slightly preferred over retention in the LiCIOJether catalysed rearrangement of styrene oxide.
1 Coxon,
J. M.; McDonald, D. Q. Tetrahedron Lett. 1988,29,2575. Sudha, R.; Malola Narasimhan, K.; Geetha Saraswathy, V.; Sankararaman, S. J. Org. Chem. 1996, 61, 1877. 3Geetha Saraswathy, V.; Sankararaman, S. J. Org. Chem. 1994,59, 4665. 4 a) Coxon, J. M.; Cambridge, J. R. A; Nam, S. G. C. Org. Lett. 2001,26,4225. b) Coxon, J. M.; Cambridge, J. R. A; Nam, S. G. C. Synlett. 2004, 8, 1422. 5 Cambridge, J. R. A PhD Thesis, University of Canterbury, 2004. 6 Hara, N.; Mochizuki, A; Tatara, A; Fujimoto, Y. Tetrahedron Asymm. 2000, 11, 1859. 2
CHAPTER SEV N
Mechanistic Implications of Optically Active Styrene Oxide Rearranged with BF3.OEt2 and LiCI0 4/ether and Comparisons with other Systenls and Models
Chapter Seven - Mechanistic Implications of Optically Active Styrene Oxide Rearranged with BFJ.OEt2 136 and LiCIO/ether and Comparisons with other Systems and Models
7.1
THE BLACKETT MECHANISTIC MODEL FOR THE LEWIS ACID CATALYSED REARRANGEMENT OF EPOXIDES
The results from previous studies of the rearrangement of non-optically active epoxides have been analysed in terms of the mechanism first put forward by Blackett et al. 1 In his study, the two deutero isomers of 2,3,3-trimethyl-l-butene oxide 7.1 and 7.2 were rearranged with BF3 in CC14 and the final, resultant ratios of deuterium labelled aldehydes from each epoxide are shown in Scheme 7.1. t-Bux~e D
H
BF3 gas CCI4 • oOc
...
t-BuxMe D
7.1
7.3 1
t-Bux~e H
CHO
D
BF3 gas CCI 4. OoC
....
7.2
+
t-BuxMe CDO
H
7.4 2.65
t-BuxMe D
CHO
7.3 1
7.4 0.89
Scheme 7.1. Rearrangement of7.1 and 7.2.
Deuteride is favoured over hydride for migration in the rearrangement of epoxide 7.2 while for 7.1, hydride migration is favoured. Remembering that there is an inherent kinetic preference for hydride migration (a kinetic isotope effect which is expected to be similar in both reactions), the experiments establish that for undeuterated epoxide, migration of the hydrogen trans to the bulky tertiary butyl group is preferred 1.93 : 1 (MHtranslMHcis) in the rearrangement of non-deuterium labelled material. Blackett's results were interpreted by the following mechanistic scheme:
Chapter Seven - Mechanistic Implications of Optically Active Styrene Oxide Rearranged with BF3.OEt2 137 and LiCIO/ether and Comparisons with other Systems and Models
X+ -
Me
OBF 3
IBu 0- -BF 3 He
Hb
"..
Hb
Hb~~BF3 Bu
Me
He
Ha
7.5
7.6
He
~e~IBu F3BO
Me~IBu
Hb
7.8
k
~
F3BO~~a Me Bu Hb
7.9
Hb
Me~IB~ He
7.7
~.".
~~"
aldehyde
aldehyde
OBF 3
7.10
Scheme 7.2. Blackett's mechanistic scheme for the rearrangement of 2,3,3-trimethylbut-lene oxide.
Co-ordination of BF3 to epoxide facilitates ring opening to give cation conformer 7.6. It was assumed that the OBF 3 group would rotate in a direction to relieve the steric interaction between the bulky tertiary butyl and the OBF3 groups. A 60° rotation about the CI-C2 bond will give conformer 7.7, where Hb is aligned with the cationp-orbital and can migrate. A further 60° rotation would give conformer 7.8, where Ha is aligned with the adjacent p-orbital and can migrate. It was assumed that there would be a barrier to rotation between the two essentially "mirror image" conformers, a barrier resulting from eclipsing of the methyl and OBF3 groups. The experiments allow an estimation of the relative rate constant for the interconversion "mirror image" conformers.
Conformations 7.9 and 7.10 were assumed by Blackett to be high in energy due to the steric interaction between the gauche arrangement of the OBF 3 and tertiary butyl groups and these conformers were not included in his mathematics. Blackett used racemIC epoxides and so in his experiment aldehyde formed from conformer 7.7, is indistinguishable from aldehyde from conformer 7.10. Likewise, it was not possible for him to determine the contribution of conformer 7.8 relative to 7.9. Blackett did however recognise the limitations of his model when making this assumption and was aware that he
Chapter Seven - Mechanistic Implications o/Optically Active Styrene Oxide Rearranged with BF3.OEt2 138 and LiCIO/ether and Comparisons with other Systems and Models
needed one further parameter (that could be obtained from optically active deuterated epoxide studies) ifhe was to include this possibility.
For the Blackett model, the relative values for the rate constants for hydride (kPH = 1.71) relative to deuteride (kHD = 1.0) along with the rate constant for interconversion of conformers 7.7 and 7.8 (krot = 1.84) were established as shown in Table 7.1.
\2,3,3-trimeth YI-1-butene oxide (BF, gas)
kHD
kDH
1.0
1.71
k rel
1.84
MHtranJMHds
1.93
Table 7.1. Results of the relative rate for H-migration versus D-migration, rate constant for interconversion and diastereotopic selection for 2,3,3-trimethylbut-l-ene oxide,
The values in Table 7.1 were evaluated by the following methodology:
Chapter Seven -Mechanistic Implications o/Optically Active Styrene Oxide Rearranged with BF3.OEt2 139 and LiCIO/ether and Comparisons with other Systems and Models
Me~D(Hb) tSu 0 H (Ha)
Me/\:7
D (Ha)
0
7.2
7.1 \
D- migration
H-
mig"tiO"/
Hb migration
[
1 + k Ha
]
k,.ot
For epoxide 1.22
For epoxide (2)
Ha =D andHb=H
Ha =H andHb=D
Hb migration
wherekD = 1
Ha migration
Hb migration
[
D migration
1 + _1_ ] k rot
From Eq 1 and solving for k rot
2.65 kH
[1+_1 k rot
kH kH + k rot
______ Eq 1
D migration
1+ [
H migration
0.89
kH
[1 +
~_~~, c~~~:
k rot
~
* krot
~k-'rot:- ~
I
'- - - "
2.65 - kH
2.65 - kH
kH = (2.65 - k H)
2.65 - kH
]
kH
[, +
1.12 kH
=
kH ] __ - - - - Eq 2 k rot
From Eq 2 and substituting in Eq 1 for k rot
kH
=>
wherekD = 1
Ha migration
Hmigration
2.65
D- migration
0.89
2.65 : 1
Ha migration
\
1.12 kH
1.12 kH
2.l2
3.65 kH
=> kH
= 1.71
[ 1 + 2.65 - kH 2.65 + -kH
1
-1
~
Chapter Seven - Mechanistic Implications of Optically Active Styrene Oxide Rearranged with BFJ.OEt2 140 and LiClOlether and Comparisons with other Systems and Models
From previous equation
krot-
=
1.71 2.65 - 1.71 1.84
Hb migration
Ha migration
rates are equal as no deuterium isotope effect Hb migration
Ha migration
=
=
[l+~ 1.84
]
1.93
For the analysis above, only rotation away from the bulky group was considered although it was recognised this was an assumption. A correction calculated by Aaron Thorpe2 can be applied to the experimental value of kHlkD since this measured value is actually the ratio of the rate constant for hydrogen migration from a carbon bonded to deuterium versus deuterium migration from a carbon bonded to hydrogen. 3 The secondary isotope effect was calculated for the lowest energy pathway for hydride migration of2,3,3-trimethylbut-l-ene oxide to be 0.92 (Scheme 7.3).
Chapter Seven - Mechanistic Implications of Optically Active Styrene Oxide Rearranged with BFJ.OEt2 141 and LiCIO/ether and Comparisons with other Systems and Models
roLYP,'!).31O* I J .. R3L"I'P/6.31G"'/SCI.!'CM
Scheme 7.3. The potential energy surface for the rearrangement of2,3,3-trimethylbutenel-ene oxide with BF3. All stationary points are optimised at the B3LYP/6-31 G* level.
Even though the limitations of experiments on the deuterated racemic epoxides did not allow for an additional parameter to be established, the rotation away from the large alkyl group was considered a reasonable and necessary assumption and the model has been applied to other epoxide systems studied in the group.· The results for all racemic systems studied using the model are shown in Table 7.2.
• (Y.F) Fujimoto, Y. F. studied 7.11 and 7.16.; (B.B) Blackett, B. studied 2,3,3-trimethyl-l-butene oxide.; (C.L) Lim, C. Y. studied octene oxide.; (Q.M) McDonald, D. Q. studied styrene oxide, a) Q.M's deuterium spectra for these results are not as accurate as S.N. b) These results are affected by trace amounts of acid.; (A. B) Butterfield, A.B. studied p-methyl styrene oxide.; (S.N) Nam, S. G. C (present work) studying styrene
oxide.; (J.C) Cambridge, J. R. A. studied p-methyl and m-methoxy styrene oxide c) gives an odd result.
Chapter Seven -Mechanistic Implications of Optically Active Styrene Oxide Rearranged with BF3.OEt2 142 and LiCIO/ether and Comparisons with other Systems and Models
kUH/kHD
k rot
MHtranslMHcis
1.22 : 1
1.96
3.24
1.61
2.65: 1
0.89: 1
1.71
1.84
1.93
4.78: 1
3.10:1
4.37
10.65
1.41
1.83 : 1
1.48 : 1
1.69
11.94
1.14
(S.N) styrene oxide BF 3.OEt2
3.00: 1
1.78 : 1
2.56
5.82
1.44
(Q.M) styrene oxide LiC10./bz b)
2.41 : 1
1.42 : 1
2.00
4.89
1.41
(S.N) styrene oxide LiCIOJEt
2.85: 1
2.03: 1
2.58
9.57
1.27
(AB) p-methy1 LiCIO./bz
2.29: 1
1.31:1
1.87
4.40
1.42
(I.e) p-methyl LiCIOJEt
5.67: 1
1.50: 1
4.00
2.40
2.67
(I.e) p-methy1 BF 3.OEt2
2.33: 1
2.70: 1
2.43
-24.33 CJ
0.90
(J.e) m-methoxy BF 3.OEh
2.33: 1
2.23 : 1
2.30
69.00
1.03
(J.e) m-methoxy BF 3.OEt2
2.70: 1
2.23: 1
2.56
17.25
1.15
Cis epoxide
Trans epoxide
Hmign:D mign
Hmign:D mign
(Y.F) tbu1k epoxide BF 3.OEt2
2.57: 1
(B.B) tbu epoxide BF3 gas (C.L) octane oxide BF 3.OEt2 (Q.M) styrene oxide
BF 3.OEt2 a)
Table 7.2. Results of kDHI kHD, krot and MHtrans/MHcis for the above epoxide rearrangements.
Using this model a negative value is obtained for Cambridge's p-methyl styrene oxide (-24.33 for k rot) which confirms that the model is invalid or that the experimental results
for this system are in error.
7.1.1
Surface plots of kDH, kHD, k and MHtranslMHcis as a function of the aldehyde ratios derived from either the cis or trans deuterated epoxide
The relationship of the relative rate constants for hydride (~H) relative to deuteride
(JliD =
1) migration and the rate constant for interconversion of cation conformers (krot) are shown in Table 7.2. These values are used to calculate hydrogen selectivity, namely the preference or otherwise of the hydrogen trans versus hydrogen cis to the bulky substituent (MHtransIMHcis) to migrate.
Chapter Seven - Mechanistic Implications ojOptical/y Active Styrene Oxide Rearranged with BF3.OEt2 143 and UClO/ether and Comparisons with other Systems and Models
The experimental ratios of the deuterium labelled aldehydes are used to calculate the relative values of If H, I!'D, kro' and MH'ransIMHcL5 where I!'D = 1. The relationship of these parameters are shown graphically in the following surface diagrams (see below) plotted as a function of the aldehyde ratios which are derived by experiment. The surfaces provide a visual representation of the relationship of the parameters for the model showing how the values of If H, I!'D, kro, and MH,ranslMHcis change with the varying ratios of aldehyde.
For example, using Blackett's experimental aldehyde ratios of 2.65 (from the cis epoxide 7.1) and 0.89 (from the trans epoxide 7.2) the figure allows a value for
If HII!'D of 1.71
to
be read from the surface (Graph 7.1 ):*
O
Graph of k Hlk
Graph 7.l.
If HII!'D
H
O with
varying cis to trans ratios
as a function of the aldehyde ratios derived from the cis or trans
epoxide .
• The graphs are generated using Microsoft® Excel and these calculations are coded into an Excel spreadsheet. A copy is enclosed on CD ROM with this thesis.
Chapter Seven - Mechanistic Implications of Optically Active Styrene Oxide Rearranged with SF3.OEt2 144 and LiCIO/ ether and Comparisons with other Systems and Models
Similarly, surfaces can be constructed of k rot and MHtrans/MHcis as a function of the ratio of aldehyde and are shown in Graphs 7.2 and 7.3 below: k,ot with varying cis to trans ratios
_ __ __
_
- t 200.000
k...
100.000
Graph 7.2. krot as a function of the aldehyde ratios derived from the cis or trans epoxide.
MH""n./MHc/. with varying cis to trans ratios [J 5.ooo-
Graph 7.3. MHtranslMHcis as a function of the aldehyde ratios derived from the cis or trans epoxide.
Chapter Seven - Mechanistic Implications of Optically Active Styrene Oxide Rearranged with BFJ.OEt2 145 and LiCIO/ether and Comparisons with other Systems and Models
The graph of lfH/JIlD as a function of the aldehyde ratios (Graph 7.1) shows a smooth continuous surface with only positive values. The general shape of the graph is convex and it appears that kDH/kHD is upper bounded as the trans ratio increases. This implies that the first derivative of kDH/kHD decreases with respect to the trans ratio. Similarly the MHtranslMHcis graph as a function of the aldehydes ratios (Graph 7.3) shows a smooth
continuous surface with no sharp discontinuities. It appears that the values of MHtranslMHcis increase linearly with the increase ofthe cis ratio and decrease exponentially
with the increase of the trans ratio. The graph of krot as a function of the aldehydes ratios (Graph 7.2) is in the form of a hyperbolic function. This contrasts to graphs 7.1 and 7.3 as there is a sharp discontinuity from positive to negative krot values when the cis and trans ratio approach the same value; The value of krot = 0 when the cis and trans ratio are equal and positive when cis/trans> 1 and negative when cis/trans < 1.
7.2
COMPARISONS OF THE FUJIMOTO MECHANISTIC MODEL WITH THE BLACKETT MECHANISTIC MODEL
The studies reported in this thesis are for optically active styrene epoxide so that a measurement of the facial stereochemical course of hydride (deuteride) migration can be established. The results of styrene oxide in Chapters 4 and 6 and that of Fujimoto et al. 4 show migration of Hb with retention of configuration and Ha are significant and actually invalidates the assumption Blackett had to make namely, that the carbo cation rotates in only one direction to minimise the large group/OBF3 interaction. Hydride migration from all four possible hydride migration conformers must be considered and the experiments reported herein provide a measure of this. Fujimoto et al. 4 investigated the stereo selectivity of hydride migration in the rearrangement of 7.11 and 7.16 (Schemes 7.4 and 7.5). The two a-substituents on this epoxide have a similar steric requirement to the epoxide 7.5 studied by Blackett and so should exhibit a similar partition between rotation of the OBF 3 group towards and away from the bulky substituent in the BF3.OEtz catalysed rearrangement.
Chapter Seven - Mechanistic Implications o/Optically Active Styrene Oxide Rearranged with BF3.OEt2 146 and LiCIO/ether and Comparisons with other Systems and Models
D
H
Ph(CH2)4~~
BF3·OEt2 CH 2CI2
1;C~ · 1~: · 1;C~ 1~~
)Iio
+
7.11
7.12
7.13
7.14
7.15
11
17
50
22
Scheme 7.4. Fujimoto's rearrangement of7.11.
H
D
Ph(CH2)4~
BF3·OEt2 CH 2CI 2
.
1;C~ 1~: .1;C~ +
7.16
7.12 31
7.13 14
7.14
22
+
1~~ 7.15 33
Scheme 7.5. Fujimoto's rearrangement of7.16.
Fujimoto's experiments give a deuterium isotope parameter z, as determined from the equation 31z : 14z : 22 : 33
=
50 : 22 : lIz : 17z to be 1.77. This is the ratio by which
hydrogen is faster relative to deuterium migration i.e.
H
kDH/k D.
This value of z was then
used to estimate the relative amounts of aldehydes 7.12-7.15 that would be formed from undeuterated epoxide as 41:18:16:25 reflecting the four conformers for hydride migration shown in Scheme 7.6.
/
Hb
RMe3C~Me F3BO
Ha 7.21 (8) 18
7.17
~
RMe2C
T
Me
RMe2C~M~
Ha~OBF3
RMe2C
T
Me
Ha 7.20 (e)
Hb 7.18 (A)
16
41
Scheme 7.6. Important conformers and Fujimoto's results undeuterated epoxide 7.17.
Ha
-
F3BO~Hb
Hb
OBF 3
7.19 (D)
25
III
the rearrangement of
Chapter Seven
Mechanistic Implications o/Optically Active Styrene Oxide Rearranged with BF3.OEt2 147
and LiCIO/ether and Comparisons with other Systems and Models
Fujimoto detennined that in undeuterated epoxide 7.17, the hydrogen trans to the bulky substituent is 1.44-fold more likely to migrate than the cis hydrogen. This is similar to the result reported by Blackett et al.I, who detennined for 7.5 that the trans hydrogen prefers to migrate by a ratio of c. 1.9 : 1. Fujimoto was also able to measure the facial selectivity of the epoxide rearrangement. He found that inversion (from confonners A + C) is favoured over retention (from confonners B + D) 57 : 43.
The experimental results from the rearrangement of optically active epoxide 7.17 show that; (i) a significant amount (c. 34%) of the reaction goes through confonnations 7.20 and 7.21, where the bulky substituent and OBF3groups are in a gauche orientation with each other (Scheme 7.7). (ii) for products of reaction where rotation occurs towards the bulky substituent (left hand side) inversion and retention are of equal importance. This suggests either that there is a symmetrical cation intennediate where both protons are equally disposed to migrate or that interconversion between the mirror image confonners Band C of the cation is fast relative to hydride transfer. (iii) rotation away from the bulky substituent (right hand side) gives 41 % with inversion and 25% retention and (iv) either interconversion between the mirror image cations A and D is slow relative to hydride transfer or that the cation is not symmetrical with a preference for an arrangement to the cation A. (v) 'the hydrogen anti to the bulky substituent prefers to migrate with inversion of configuration at the migrating terminus, whereas the hydrogen syn to the bulky substituent prefers to migrate with retention of configuration. '
If the model developed by Blackett! to calculate the relative rate constants for conversion between cation confonners relative to hydride (deuteride) migration is valid, we should be
Mechanistic Implications of Optically Active Styrene Oxide Rearranged with BF3• OEt2 148
Chapter Seven
and LiCIOlether and Comparisons with other Systems and Models
able to apply separately his mathematics to each side of the Fujimoto Scheme2 and obtain some comparative relative rate constants.
There is an assumption in all these studies that interconversion of 7.19 and 7.21 does not occur. Conformers 7.19 and 7.21 could interconvert, but Cambridge's calculations (see 7.2.3 of this chapter) indicate that they do not as the intermediate or transition state between them collapses to Lewis acid coordinated epoxide as the oxygen approaches the plane of the p-orbital.
The results of the calculations are presented below (Scheme 7.7): -
OBF 3
RMe2c~Me Ha Hb 34%~
)I'
Ha
Hb
RMe~C~Me FgBO
7.17 ~ 66% 1: 1.94
RMe2C
Ha
y
7.21 (8)
Ha 7.20 (C)
18%
16%
Fujimoto resutts (left hand side) MHt/MH.= 1.13
RMe~~w~:3 ----~
F3BO~b
Me
RMe2c~~e Hb
Hb
7.18 (A)
7.19 (D)
41% Fujimoto resutts overall H
'Z. (kHD/ko )" 1.77
MHt/MHa = 1.44
OBF3
25% Fujimoto resutts (right hand side) MHt/MHa " 1.64 Blackett analysis (r1g1lt hand side) 'Z. (kHO/koH) = 2.03
krot = 2.24 MHt/MH a " 1.91
Scheme 7.7. Important conformers in the rearrangement of Fujimoto's undeuterated epoxide with Blackett's calculated rate constants.
An analysis of the left hand side of Scheme 7.7 (rotation towards the bulky substituent)
gives the relative rate of change of the two conformers Band C to be 11.00 (krot). This shows that interconversion between the mirror image conformers Band C is fast relative to
Chapter Seven - Mechanistic Implications 'of Optically Active Styrene Oxide Rearranged with BF3.OEt2 149 and LiCIO/ether and Comparisons with other Systems and Models
hydride transfer. This suggests that the aldehydes fonned will be comparable C (16%) and B (18%) and therefore MHJMHa will be approximately equal to one for the left hand side. Fujimoto calculates MHJMHa to be 1.13 and from the Blackett model we calculate 1.17. This contrasts with the right hand side of Scheme 7.7 when rotation occurs away from the bulky substituent, where the interconversion of confonners A and D (krot = 2.24) is slower than hydride migration. Hence the aldehyde products A and D are in the ratio 43.6% : 22.3% [MHbIMHa = 1.64 (Fujimoto) and 1.91 (Blackett)] with product from confonner A being more favoured over confonner D.
Blackett's model also produces reasonable values for the deuterium isotope parameters z D
I0D ) when analysing separately each side of Scheme 7.7 to that obtained by Fujimoto. The values obtained for z (kDH I0D ) = 1.83 (left hand side) and z (kDH I0D ) = 2.03 (right (k
H
hand side) are both> 1 as expected. A Fujimoto analysis necessarily only gives a z (kDHlkHD ) value for the overall hydrogen/deuterium migration process (left and right hand side of Scheme 7.7) and he calculated this to be 1.77. It is interesting that when the Blackett analysis is applied separately to each side of the Fujimoto scheme, the values for
J!HI0D , krot and MHJMHaare within range of Fujimoto's values given the complexity and nature of the work and analysis.
The two a-substituents on Fujimoto's epoxide 7.17 have a similar steric requirement to the epoxide 7.5 studied by Blackett and so should exhibit parallel stereo selectivity for hydride migration. If we take the partition between rotation towards and away from the bulky substituent from Fujimoto's epoxide 7.17 and assume that the same partition would occur in Blackett's epoxide 7.5, we can establish a measure of facial selectivity for Blackett's epoxide for both rotation towards and away from the bulky substituent. The results of this analysis are shown below (Scheme 7.8):
Chapter Seven - Mechanistic Implications of Optically Active Styrene Oxide Rearranged with BF3.OEt2 150 and LiCIO/ether and Comparisons with other Systems and Models
34%~ 1 7.5
)I'
: 1.94
~ 66% Ha
Hb
t~u~Me F3BO
Ha
tBu~~e
tHa~OBF3 Bu "-y Me
F~BO~Hb Bu "-y Me
Hb
Hb
Ha
OBF 3
7.10 (8)
7.9 (C)
7.7 (A)
7.8 (D)
19.7%
14.5%
43.6%
22.3%
Fujimoto analysis (left hand side) MH;,IMHa = 1.36 Blackett analysis (left hand side)
Fujimoto analysis overall with Blackett epoxide
z (kHO/koH) = 1.54 MH;,IMH a =1.72
Fujimoto analysis (right hand side) MH;,IMHa =1.96 Blackett analysis (Right hand side)
z (kHO/koH) = 1.64
z (kHO/koH) =1.76
krot =3.61
krot = 1.41
MH;,IMH a = 1.45
MH;,IMHa = 2.25
Scheme 7.8. Important confonners in the rearrangement ofundeuterated 2,3,3-trimethyl-1butene oxide 7.5 along with Blackett's calculated rate constants and a Fujimoto analysis.
The values of MHbI'MHa calculated by the Blackett mathematics are similar to the values obtained from the Fujimoto analysis for each side of Scheme 7.8. Blackett et al. 1 reported that Hb (the hydrogen anti to the bulky substituent) is more susceptible to the migration (by c. 1.91 fold) than Ha by considering only confonnations A and D. This reported value has now been confinned in the Fujimoto analysis by utilising the partition between the two rotation modes. We have detennined from the Fujimoto analysis of the Blackett system (assuming the same partition away from and towards the bulky alkyl group) that Hb migrates more readily [1.96 ( = 43.6/22.3)] than Ha. Applying the Blackett analysis for the right hand side (only rotation away from the bulky substituent) gives a new calculated value of MHbI'MHa to be 2.25 compared to Blackett's original value of 1.91. Rotation towards the bulky substituent (left hand side) gives a value ofMHbI'MHa = 1.45 (Blackett) and 1.36 (Fujimoto).
Chapter Seven - Mechanistic Implications of Optically Active Styrene Oxide Rearranged with BF3.OEt2 151 and LiClOlether and Comparisons with other Systems and Models
Blackett's model produces similar results for z (If HlkfiD) to Fujimoto and applicable values for krot when separately analysing each side of Scheme 7.8. The values obtained for the deuterium isotope parameters z (lfHlkfiD)
=
1.64 (left hand side) and z (lfHlkfiD)
=
1.76
(right hand side) are both> 1 as expected for each of the four possible conformers for hydrogen Ideuterium migration. Fujimoto analysis only gives a z (kDHlkHD) value for the overall hydrogen/deuterium migration process (left and right hand side of Scheme 7.8) and this was calculated and reported to be 1.54.
Analysing the left hand side of Scheme 7.8 (rotation towards the bulky substituent) gives the relative rate of change of the two conformers B and C to be 3.61 (krot). This shows that interconversion between the mirror image conformers Band C is fast relative to hydride transfer. This suggests that the aldehydes formed will be comparable C (19.7%) and B (14.5%). This contrasts with the right hand side of Scheme 7.6 when rotation occurs away from the bulky substituent, where the interconversion of conformers A and D (krot
=
1.41)
is slower than hydride migration. Hence the aldehyde products A and D are in the ratio 43.6% : 22.3% with product from conformer A being more favoured over conformer D.
We know that hydride migration from all four conformers A, B, C and D has to be incorporated into the model. * This leads to the conclusion that the hydrogen anti to the bulky substituent prefers to migrate with inversion of configuration for 7.5 as for 7.17.
We have assumed that reaction conditions for Blackett's epoxide with BF3 in CCl4 will emulate the reaction conditions for Fujimoto's epoxide with BF3 as the etherate in CH2Ch. We have shown the value of applying Blackett's model to each side of the Fujimoto Scheme2 and compared the results of the two models .
• Blackett assumed the sterle interaction between the gauche arrangement of the OBF 3 and tertiary butyl groups to be too high in energy, thus allowing only rotation away from the bulky substituent to be considered.
Chapter Seven -Mechanistic Implications o/Optically Active Styrene Oxide Rearranged with BFJ.OEt2 152 and LiCIO/ether and Comparisons with other Systems and Models
7.2.1
A further comparison of the Fujimoto mechanistic model and the Blackett mathematical model with styrene oxide and its derivatives
The mathematics applied to styrene oxide and its p-methyl and m-methoxy derivatives establish the value of Blackett 1 model (although limited) applied separately to each side of Scheme 7.9 in calculating the values for the relative rate constants for hydride (IfH) cf deuteride
(J!iD
=
1.0) migration, the rate constant for interconversion between cation
conformers (krot) and overall hydrogen migration (MHbIMHa). The results of the calculations are presented below (Scheme 7.9):
Ar=phenyl, A=BF3 Ar=phenyl, A=U+
:38% :43%
o
Ar=p-methylphenyl, A=BF3 Ar=p-melhylphenyl, A=U+
: 45% : 32%
i A=BFlO' Li'
: 28%
, ,:
t
:17% : 8%
Ar=m-melhoxyphenyl, A=BF3 : 16%
Hc'/--\'Hb Ar Ha
Ar=m-melhoxyphenyl, A=BF3 : 36% Ar=m-melhoxyphenyl, A=U+
Ar=phenyl, A=BF3 Ar=phenyl, A=U+
Ar=m-methoxyphenyl, A=U+
: 0%
Ar=p-melhylphenyl, A=BF3
: 17%
Ar=p-melhylphenyl, A=U+
: 4%
t
retention
syn
anti
D
B inversion
Ar=phenyl, A=BF3
:26% : 37%
Ar=phenyl, A=U+
Ar=phenyl, A=BF3
: 19% :12%
Ar=phenyl, A=U+
Ar=m-melhoxyphenyl, A=BF3 : 33%
Ar=m-methoxyphenyl, A=BF3 : 15%
Ar=m-melhoxyphenyl, A=U+ : 48%
Ar=m-methoxyphenyl, A=U+
: 7%
Ar=p-methylphenyl, A=BF3 Ar=p-melhylphenyl, A=U+
Ar=p-melhylphenyl, A=BF3
: 17%
Ar=p-melhylphenyl, A=U+
: 38%
: 34% : 29%
Blackett analysis (left hand side)
Blackett analysis (right hand side)
(kHo/koH)
krel
MHt/MHa
(S.N) styrene oxide BF3. OEI2
2.66
3.92
1.68
(J.C) p-melhyl BF3.0E12
2.59
23.55
1.11
(J.C) m-methoxy BF3.0E12
2.37
17.89
(kHOIkOH)
krel
MHt/MHa
(S.N) styrene oxide BF3.0E12
2.39
22.75
1.11
(J.C) p-melhyl BF3.0E12
2.08
-4.33
0.52
1.13
(J.C) m-melhoxy BF3.0E12
2.16
-13.80
0.84 1.47
(S.N) styrene oxide UCI04
2.54
11.41
1.22
(S.N) styrene oxide UCI04
2.73
5.81
(J.C) p-melhyl UCI04
3.03
22.22
1.14
(J.C) p-melhyl UCI04
5.88
0.60
10.78
(J.C) m-melhoxy LiCI04
2.42
-46.51
0.95
(J.C) m-melhoxy UCI04
2.25
0.00
8998.75
Chapter Seven - Mechanistic Implications of Optically Active Styrene Oxide Rearranged with BFj.OEt2 153 and LiClOlether and Comparisons with other Systems and Models
Scheme 7.9. Conformers in the rearrangement of styrene oxide (present work), p-methyl and m-methoxystyrene oxide derivatives (work of James Cambridge) with Blackett mathematical analysis.
It should be noted that for the Blackett epoxide 7.5 and the Fujimoto epoxide 7.17 there is
similarity between the two substrates and the two different analysis models. The results calculated above, establish that the Blackett model does not fit styrene oxide and its derivatives. Since for these substrates the reaction favours rotation towards the aryl group while for the other substrates rotation away from the large alkyl group dominates. For example in some styrene oxide systems, there are krot values of 0, -4.33, -13.80 and -46.51. Negative krot values are invalid and a krot value of 0 leads to an illogical value for MHtranslMHcis of 8999. This clearly shows that the Blackett model can not be applied to the
styrene oxide systems where rotation is dominantly towards the aryl group.·
7.2.2
A direct comparison of the BF3.OEt2 and LiCl04 catalysed rearrangement of styrene oxide with p-methyl and m-methoxystyrene oxide using only the Fujimoto model.
Dr James RA. Cambridge recently completed in this laboratory, and in conjunction with my own work, a study on the BF3.0Et2 and LiCI04 catalysed rearrangement of optically active p-methyl and m-methoxystyrene oxide. 5 His study was directed to further test the assumption that rotation occurs preferentially to relieve the oxygen interaction with the larger substituent on the cation and establish the degree or otherwise of facial selectivity of hydride migration in an epoxide rearrangement.
Using the method developed by Fujimoto\ he determined the course of rearrangement of undeuterated p-methyl and m-methoxystyrene oxide using the data obtained for the
• Ratios of rotation towards aryl: away from aryl for each epoxide system. p-methy1 styrene oxide 66 : 34 (BF 3.OEt2), 57 : 42 (LiC10 4); styrene oxide 64 : 36 (BF 3.OEt2), 80 : 20 (LiC10 4); m-methoxystyrene oxide 69 : 31 (BF 3.OEt2 ), 93: 7 (LiC104).
Chapter Seven - Mechanistic Implications o/Optically Active Styrene Oxide Rearranged with BF3.OEt2 154 and LiCIO/ether and Comparisons with other Systems and Models
deuterated analogues 7.22 and 7.23 (Figure 7.1). Also incorporated are the results of this thesis for styrene oxide (Scheme 7.10).
7.22
7.23
Ha = D or Hb = D
Figure 7.1. Deuterated analogues ofp-methyl and m-methoxystyrene oxide.
A deuterium isotope parameter,
Z = kDH/kHD ,
i.e. (hydrogen migration from a carbon
bearing deuterium relative to deuteride migration from a carbon bearing a hydrogen) was calculated to be 2.5 for p-methyl and 2.3 for m-methoxystyrene oxide. This is the ratio by which hydrogen is faster relative to deuterium migration and this allows the relative contribution of each of the four pathways in undeuterated material to be established with the partition between B : A: C : D (Scheme 7.10):
Chapter Seven
Mechanistic Implications a/Optically Active Styrene Oxide Rearranged with BF3.OEt2 155
and LiClOlether and Comparisons with other Systems and Models
Ar=phenyl, A=8F3 Ar=phenyl, A=Li+
:38% :43%
Ar=phenyl, A=8F3 Ar=phenyl, A=Li+
o
Ar=m-methoxyphenyl, A=8F3 : 36% Ar=m-methoxyphenyl, A=Li+ : 45%
Hc)L-\,Hb Ar Ha
Ar=p-methylphenyl, A=8Fg
: 32%
Ar=p·melhylphenyl, A=LI+
: 28%
A=BF~ or Lt
t
Ar=m-methoxyphenyl, A=8F3 : 16% Ar=m-methoxyphenyl, A=LI+
: 0%
Ar=p-melhylphenyl, A=8F3
: 17%
Ar=p-methylphenyl, A=LI+
: 4%
t
retention
syn
:17% : 8%
anti
~ .t!r-GJ
D
inversion
Ar=phenyl, A=8F3 Ar=phenyl, A=Lr"
:26% :37%
Ar=m-methoxyphenyl, A=8Fg : 33% Ar=m-methoxyphenyl, A=LI+ : 48% Ar=p-methylphenyl, A=8F3 : 34% Ar=p-methylphenyl, A=Li+ . : 29%
+
Ar=phenyl. A=8F3 Ar=phenyl, A=Li+
:19% : 12%
Ar=m-methoxyphenyl, A=8F3 : 15% Ar=m-methoxyphenyl, A=Ll+
: 7%
Ar=p-methylphenyl. A=8F3
: 17%
Ar=p-melhylphenyl. A=Ll+
: 38%
Scheme 7.10. Estimation of the hydride migration for undeuterated styrene oxide, pmethyl styrene oxide and m-methoxystyrene oxide in the BF3.0Et2 and LiCI04 catalysed rearrangement to aldehyde.
In all six of the systems investigated in the BF3.0Eh and LiCI04 catalysed rearrangement of styrene oxide and its derivatives, opening of epoxide with rotation of the Lewis acid coordinated oxygen towards the aromatic group is preferred to epoxide opening with rotation away from the aromatic group (Table 7.3).
Epoxide
Lewis Acid
Rotation towards aryl: away from aryl
p-methyl styrene oxide
BF3.0Et2
66
34
p-methyl styrene oxide
LiCI04
57
42
styrene oxide
BF3.OEh
styrene oxide
LiCI04
80
20
BF 3.OEh
69
31
m-methoxystyrene oxide
m-methoxystyrene ox~ LiCI04
64: 36
93 : 7
Chapter Seven - Mechanistic Implications of Optically Active Styrene Oxide Rearranged with BFJ.OEt2 156 and DClO/ether and Comparisons with other Systems and Models
Table 7.3. Epoxide opening with rotation towards and away from the aromatic group.
The LiCI04 rearrangement of epoxide, opening with rotation towards the aromatic group is more favoured for the electron withdrawing m-methoxy substituted styrene oxide than for styrene oxide and this is followed by the p-methyl substituent. Within experimental error the same trend is observed for the BF 3 rearrangement.
In all the BF3.0Etz catalysed reactions of styrene oxide and its derivatives, hydride/deuteride migration occurs to an equal extent with inversion or retention of configuration (Table 7.4). In the LiCI04 reactions of p-methyl and m-methoxystyrene oxide, when epoxide opening occurs with rotation of the oxygen away from the aromatic group, hydride/deuteride migration occurs almost exclusively with inversion of configuration. This is in contrast to styrene oxide which shows an equal extent of inversion or retention of configuration. In all other cases (BF3 catalysed rearrangements and LiCI04 catalysed rearrangements with rotation towards the aromatic group); there is little or no preference for hydride (deuteride) migration with inversion or retention of configuration (Table 7.4).
Epoxide
Lewis
Rotation towards aryl
Rotation away from aryl
Acid
(inversion: retention)
(inversion : retention)
p-methyl styrene oxide
BF 3.OEtz
34
32
17 : 17
p-methyl styrene oxide
LiCI04
29
28
38 : 4
styrene oxide
BF3.OEtz
26
38
19 : 17
styrene oxide
LiCI04
37
43
12 : 8
m-methoxystyrene oxide
BF3.0Etz
33
36
15
m-methoxystyrene oxide
LiCI04
48
45
7
16 0
Table 7.4. Facial selectivity for hydride migration.
The results are consistent with the rearrangements proceeding via a carbo cation intennediate pathway.
Chapter Seven
Mechanistic Implications of Optically Active Styrene Oxide Rearranged with BF3.0Et2157
and LiCIO/ether and Comparisons with other Systems and Models
7.2.3
Mechanistic implications
Calculations perfonned by Aaron Thorpe et al. 6 on the acid catalysed rearrangemen~'4of propene oxide show that hydride migration for this substrate is concerted with ring opening of the epoxide. In this instance a discrete carbocation intennediate is not fonned during the reaction. Only hydride migration with inversion of configuration will occur in a concerted rearrangement. For reactions of tertiary substituted epoxide carbo cation intennediates have been implicated by experiment and calculations. 7 In both the LiCI04 and BF3.0Et2 catalysed rearrangements of styrene oxide, p-methyl- and m-methoxystyrene oxide, a significant amount of hydride (deuteride) migration with retention of configuration is observed, requiring that most if not all of the reaction proceeds via a carbocation pathway (Table 7.4 above).
The results reported above were unexpected. In the previously published results for the rearrangement of styrene oxide, 8 it was assumed that the interaction of the aromatic group and oxygen would be disfavoured and only anti cation rotation could occur. These experiments show that not only rotation in the syn direction occurs for styrene oxide, pmethyl and m-methoxy styrene oxides, but it is in fact the favoured pathway for both the BF3.0Et2 and LiCI04 catalysed reactions. Ab initio molecular orbital density functional calculations of stationary points on the
potential energy surface for the rearrangement of styrene oxide with
Lt have been
investigated by Cambridge at the B3LYP/6-31+G*//B3LYP/6-31+G* level of theory. 5 No account was taken of solvent or the counter CI04- ion. 9 The Lt ion co-ordinates with the lone pair on the epoxide oxygen syn to the aryl ring and in the gas phase also interacts with the ring. lO The two transition states were detennined for opening to carbo cation showing the dihedral aryl-C+ -C-O angle showing that rotation about the C l-C2 bond occurs with ring opening of the epoxide (Figure 7.2).
Chapter Seven - Mechanistic implications of Optically Active Styrene Oxide Rearranged with BF3.OEt2 158 and LiCIO/ether and Comparisons with other Systems and Models
7.25
+15.19
7.26
+11.24
,
,
, \
7.29
--,, ,- , --
7.28
+10.42 +10.26
,
,
7.30
,
,, ,
, ,,
-------" ~
+8.83 \
7.27
"
"" " "" 'I
+6.51
"
"
I,
"
7.24
•"
" " " " " " "
• I 'I
I,
' I
" "
"'I "I,
"II I.
"I, II
"" "" ""
··· ·
"
I
Figure 7.2 Reaction surface for the Li+ catalysed rearrangement of styrene oxide. Structures are optimised at the B3LYP/6-31 G* level of theory. Relative energies are in kcallmol.
The carbocation (i.e. transition state 7.25) with the lithium coordinated oxygen cis to the phenyl ring (rotation towards the aromatic ring) is calculated to be higher in energy than the conformation (transition state 7.26) with the lithium coordinated oxygen trans to the phenyl ring (rotation away from the phenyl ring) by 3.95 kcallmol.
Chapter Seven - Mechanistic Implications of Optically Active Styrene Oxide Rearranged with BFJ.OEt2 159 and LiCIO/ ether and Comparisons with other Systems and Models
The calculations perfonned by Dr. James Cambridge of the stationary points for gas phase rearrangement of styrene oxide coordinated to a lithium ion indicate that rotation of the epoxide oxygen away from the phenyl ring would be kinetically favoured.
However, our experimental results rule this out. Presumably solvent plays a major role in lowering the transition state energy leading to the more stable cis carbocation confonnation. This goes in some way to explain the experimental observation that rotation of the epoxide oxygen towards the phenyl ring is energetically favoured.
Figure 7.3. The syn carbocation 7.27 minimum with equal probability of either hydrogen migrating. 0 kcal/mol.
Figure 7.4. The anti carbocation 7.28 minimum with hydrogen in hyperconjugation with the cation p-orbital. 3.75 kcallmol.
7.3
CONCLUSION
Chapter Seven - Mechanistic Implications of Optically Active Styrene Oxide Rearranged with BFJ.OEt2 160 and LiCIO/ether and Comparisons with other Systems and Models
The Blackett mechanistic model for the Lewis acid catalysed rearrangement of epoxides is useful but limited. The experimental data available to Blackett required him to assume the steric interaction between the gauche arrangement of the OBF 3 and tertiary butyl groups to be sufficiently high in energy that rotation towards the bulky substituent would not occur.
The results reported in Chapters 4 and 6 of the BF3 and LiCI04 catalysed rearrangement of styrene oxide and the work of Cambridge3 and Fujimoto et al. 2 show that rotation towards the bulky substituent can contribute significantly to such reaction and it is necessary to consider hydride migration from four conformers. However, the method developed by Blackett l to calculate the relative values for the relative rate constants for hydride (IfH) cf deuteride (f(ln
=
1.0) migration, the rate
constant for interconversion between cation conformers (krot ) and overall hydrogen migration (MHt/MHa) are valid for Blackett's epoxide 7.5 when three assumptions are made: (i) partitioning between rotation towards (34%) or away (66%) from the bulky substituent are the same as determined for Fujimoto's epoxide 7.17, (ii) the reaction conditions for Blackett's epoxide, namely BF3 in CCI4, emulate the reaction conditions for Fujimoto's epoxide with (BF3-etherate in CH2Clz) and (iii) interconversion of7.8 and 7.10 does not occur.
Where rotation occurs towards the bulky substituent (left hand side of the Schemes) for Blackett's epoxide 7.5 and Fujimoto's epoxide 7.17, inversion and retention of the hydride migration are of equal importance. We conclude therefore that a symmetrical cation intermediate with both protons equally disposed to migrate is important or alternatively interconversion between the "mirror image" conformers Band C of the cation is fast relative to hydride transfer.
Rotation away from the bulky substituent (right hand side) for Blackett's epoxide 7.5 and Fujimoto's epoxide 7.17 gives predominately product from A with inversion and less favoured is migration from D with retention of configuration. This requires either that
Chapter Seven -Mechanistic Implications o/Optically Active Styrene Oxide Rearranged with BFJ.OEt2 161 and LiCIO/ether and Comparisons with other Systems and Models
interconversion between the mirror image cations A and D is slow relative to hydride transfer or that the cation is not symmetrical.
We have measured successfully the facial selectivity of each of the terminal hydrogens in the BF3 and LiCI04rearrangement of styrene oxide. Where rotation occurs towards the aryl substituent (left hand side of the schemes), inversion and retention of the hydride migration are of equal importance. This result parallels with that of Cambridge's p-methyl and mmethoxystyrene oxide analogues. We can conclude again that a symmetrical cation intermediate with both protons equally disposed to migrate is important or alternatively interconversion between the "mirror image" conformers Band C of the cation is fast relative to hydride transfer.
In the BF3 and LiCI04rearrangement of styrene oxide where rotation occurs away from the
aryl substituent (right hand side and the minor pathway), inversion and retention of the hydride migration are of equal importance. We conclude as above that a symmetrical cation intermediate with both protons equally disposed to migrate is important or alternatively interconversion between the "mirror image" conformers Band C of the cation is fast relative to hydride transfer. This result parallels that of Cambridge's p-methyl and m-methoxystyrene oxide analogues with BF 3, but contrasts with his LiCI04 results where he found that product formation occurs predominately with inversion via A and less favoured is migration via D with retention of configuration. This requires either that interconversion between the mirror image cations A and D is slow relative to hydride transfer or that the cation is not symmetrical.
The Blackett model does not account for the results of the rearrangement of optically active deuterated styrene oxide and its p-methyl and m-methoxy analogues, but is consistent with the results obtained by Blackett and Fujimoto for epoxides 7.5 and 7.17. Blackett's limited model proposed for epoxide systems removed the possibility of rotation towards the bulky alkyl substituent would occur. For the rearrangement reaction(s) involving the Blackett / Fujimoto epoxides, the majority of rotation is away from the bulky alkyl substituent and this is preferred c. 66 : 34. However, for styrene oxide and its p-
Chapter Seven - Mechanistic Implications of Optically Active Styrene Oxide Rearranged with BF3.0Et'j 162 and LiClOlether and Comparisons with other Systems and Models
methyl and m-methoxy analogues, rotation occurs via a carbocation with significant preference towards
the bulky
aromatic
substituent
in both BF3
and
LiCI04
rearrangements. *
Therefore the limitations of Blackett's model become more evident when analysing the rearrangement reactions of styrene oxide and its derivatives. The preference for products arising by ring opening and rotation towards the aryl group is supported by ab initio density functional molecular orbital calculations.
7.4
FUTURE STUDIES
There has been difficulty monitoririg the kinetics of epoxide rearrangements with LiCI04. We have found that even when great care is taken to attempt to reproduce exactly all reaction conditions, reaction times are not reproducible. Depending on the batch of LiCI04, styrene oxide can rearrange fully to give phenyl aldehyde in times ranging from 2 to 24 hours. For this reason, a separate study determining the general reaction surface for rearrangement would be valuable.
Blackett's epoxide 2,3,3-trimethyl-1-butene oxide could now be synthesised with optical activity by the following methodology (Scheme 7.11):
• Ratios of rotation towards aryl: away from aryl for each epoxide system. p-methyl styrene oxide 66 : 34 (BF3.OEt2), 57 : 42 (LiCI0 4); styrene oxide 64 : 36 (BF3.OEt2), 80 : 20 (LiCI0 4); m-methoxystyrene oxide 69: 31 (BF3.OEt2), 93: 7 (LiCI0 4).
Chapter Seven - Mechanistic Implications of Optically Active Styrene Oxide Rearranged with BFJ.OEt2 163 and LiCIO/ether and Comparisons with other Systems and Models
)
-
H
1. Me3A1, CI 2ZrCP2
,..
->-<:
2. D20
7.29
AD-mix-p
,..
7.30
OH
OH
T~
MeC(OMeb
,..
cat. PPTS
7.31
Me OMe
oXo
r~D
Me3SiCI
.
~OAC H 'D
)
7.35
MeOH
..
7.33
7.32
-
K2C0 3
H
,..
)
7.36
~'~ 7.34
as above -
0
D
----)Iloo-
----)Iloo-
0
~'~ 7.37
Scheme 7.11. Synthesis of optically active deuterated 2,3,3-trimethyl-l-butene oxide. The real challenge is to develop an NMR method to analyse the facial selectivity for hydride and deuteride migration in the rearrangement of this alkyl substituted epoxide 7.34 and 7.37.
The methodology of Fujimoto should be first attempted where his epoxides are rearranged with BF3.0Etz in CH2Ch. The ratio of aldehydes produced are then analysed by reduction with LiAIH4 or LiAID4 and reaction of the resulting alcohol with (S)-MPTACI to give the (R)-MPTA ester. This allows integration and determination of the relative aldehyde populations.
The Lewis acid catalysed rearrangement of optically active 2,3,3-trimethyl-l-butene oxide could be studied using the methodology of Fujimoto. Experimentally, we could determine a measure of facial selectivity in the rearrangement and test our assumption that rotation towards and away from the bulky substituent is the same as for Fujimoto's epoxide 7.17.
I
2
Blackett, B. N.; Coxon, J. M.; Hartshorn, M. P.; Richards, K. E. J. Am. Chem. Soc. 1970,92,2574. Coxon, J. M.; Thorpe, A. J. J. Org. Chem. 2000, 64, 8421.
Chapter Seven - Mechanistic Implications of Optically Active Styrene Oxide Rearranged with BF3.OEt2 164 and LiCIO/ether and Comparisons with other Systems and Models
3
1.71
The true expression for the primary isotope effect is defined as: kHadj
H mig
The experimentally measured ratio needs to be multiplied by an expression for an appropriate secondary isotope effect:
SKIE
to give the required isotope effect:
x SKIE
The secondary isotope effect was calculated for the lowest energy pathway for hydride migration of 2,3,3trimethylbut-1-ene oxide to be 0.92. With this correction to the experimental determined isotope effect (1.71) the required isotope effect is calculated as:
1.71 x SKIE
N.; Mochizuki, A; Tatara, A; Fujimoto, Y. Tetrahedron Asymm. 2000,11,1859. Cambridge, J. R. A PhD Thesis, University of Canterbury, 2004. 6 Coxon, J. M.; Maclagan, R. G. A R.; Rauk, A; Thorpe, A J.; Whalen, D. J. Am. Chem. Soc. 1997,119, 4712. 7 Blackett, B. N.; Coxon, J. M.; Hartshorn, M. P.; Richards, K. E. Aust. J. Chem. 1970,23,839. 8 Coxon, J. M.; McDonald, D. Q. Tetrahedron Lett. 1988,29,2575. 9 a) Maruoka, K.; Murase, N.; Bureau, R.; Ooi, T.; Yamamoto, H. Tetrahedron. 1994,50,3663. a) Coxon, J. M.; Hartshorn, M. P.; Lawrey, M. G. Chem. and. Ind. 1969, 1558. Optimisations with BF3 were more difficult since the structures often converge by fluoride transfer to a cation intermediate and examples of fluorohydrin formation are known. 10 No stationary point could be found where the Lt co-ordinated anti to the aryl ring. 4 Hara,
5
CHAPTER EIGHT
Experimental
166
Chapter Eight - Experimental
8.1
GENERAL EXPERIMENTAL"
Physical and Spectroscopic Techniques
Melting points were obtained on either an electrothermal heating block or a Reichert microscope hot-stage and are uncorrected.
iH NMR spectra were obtained on either a Varian Unity 300 or Varian Inova 500 spectrometer, operating at 300 and 500 MHz respectively.
13 C
NMR were obtained on
either a Varian Unity 300 or a Varian XL 300 instruments at 75 MHz. Chemical shifts are reported in parts per million (ppm) on the 0 scale, and were referenced to residual protonated solvent peaks: deuteriochloroform spectra were referenced to CHCb at OR 7.26 and CDCb at Oc 77.0. 2H NMR were obtained on either a Varian Unity 300 or Varian XL 300 instruments at 46 MHz with capacitor B inserted and a 30-60 MHz cable installed.
IR spectra were obtained on a Shimadzu FTIR-8201 PC spectrophotometer. Spectra of solids were obtained from KBr pellets. Oils were run neat on KBr plates. Values are reported in wavenumbers (cm- i).
Electron impact mass spectrometry was carried out on a Kratos MS80RF A at 70 eV and 4 kV accelerating potential. Electrospray mass spectrometry was carried out on a Micromass LCT at 3.2 kV and 150°C (probe temperature), with nitrogen nebulisation at 150 Lih and desolvation at 500 Lih.
Chromatography
Analytical thin layer chromatography (TLC) was conducted on aluminum-backed Merck Kieselgel KG60F254 silica plates or aluminum-backed alumina type H plates. Plates were
• I Shayne Nam declare that to the best of my knowledge, all the data in this Experimental Section are accurately reported.
Chapter Eight - Experimental
167
visualised by both short- and long-wave UV light. Flash chromatography was routinely carried out using Merck Silica 60 (40-63)l) following the procedure of Still and coworkers. l Where stated, alumina flash chromatography employed Laporte Alumina, Grade H (100-200 mesh). Solvents used for chromatography were either purified by simple distillation (ether) or from calcium hydride (ethyl acetate, dichloromethane and hexanes).
Reagents and Solvents
Reagents and solvents used in reactions were purified according to well-established procedures. 2 Diethyl ether and benzene were distilled from sodium benzophenone ketyl immediately prior to use. Toluene and dichloromethane were distilled from calcium hydride. Methanol was distilled from Mg(OMeh and stored under nitrogen over 4 A molecular sieves. Dioxane was refluxed with conc. Hel and water for 12 hr with slow passage of nitrogen to remove acetaldehyde. After cooling the solution KOH pellets were added slowly and with shaking until no more would dissolve and a second layer had separated. The dioxane was decanted, treated with fresh KOH pellets to remove any aqueous phase, and then transferred to a clean flask where it was refluxed for 12 hr with sodium, then distilled from it.
Unless otherwise stated, all reactions were performed in oven- or flame-dried glassware under an atmosphere of dry argon or nitrogen. Reaction temperatures refer to the actual reaction temperature and not the external bath temperature. Aqueous phases were extracted with at least three portions of the required solvent. The organic extracts were washed with water and dried over MgS04 or Na2S04. Drying agents were filtered off, prior to concentration of solvents on a Biichi rotary evaporator. A high vacuum pump was used to remove any remaining solvent.
Chapter Eight - Experimental
8.2
168
EXPERIMENTAL WORK DESCRIBED IN CHAPTER TWO
2-Phenylethyl (1S)-(-)-camphanate3
V I
·
OH +
~
:#?
pyridine
,..
CI
2.2
2.7
2.11
2-Phenylethanol (0.055 mL, 0.46 mmol) and dry pyridine (0.056 mL, 0.69 mmol) were added to a solution of (1S)-(-)-camphanic chloride (100 mg, 0.46 mmol) in dry CH2Ch (5 mL) under N2. After three hours the solution was washed with HCI (5 mL, 1M), saturated Na2C03 (5 mL), dried over anhydrous Na2S04 and the solvent removed on a rotary evaporator. The product was recrystallised from petroleum ether as needles (121 mg, 87%). mp 71 - 72°C. IH NMR (300 MHz, CDCb) 87.20- 7.35 (m, 5H), 4.46 (t, J= 7 Hz, 2H), 3.01 (t, J= 7 Hz, 2H), 1.6-2.4 (m, 4H), 1.09 (s, 3H), 0.95 (s, 3H), 0.84 (s, 3H). HRMS (ES) 303.1594 (MH+). ClsH2304 requires 303.15963.
2- Phenylethyl (N-l-naphthalenesulfonyl)-(S)-2-amino-3-phenylpropanoate
~OH
pyridine
V
2.2
2.8
2-Phenylethanol (0.097 mL, 0.82 mmol) and dry pyridine (0.100 mL, 1.29 mmol) were added to a solution of N-(l-naphthalenesulfonyl)-I-phenylalanyl chloride (306 mg, 0.82
169
Chapter Eight - Experimental
mmol) in dry CH2Clz (5 mL) under N2. After three hours the solution was washed with HCI (5 mL, 1M), saturated Na2C03 (5 mL), dried over anhydrous Na2S04 and the solvent removed on a rotary evaporator. The product was recrystallised from methanol-H20 to give a white solid (323 mg, 93%). mp 84 - 90°C. iH NMR (300 MHz, CDCh) 86.80-8.55 (m, 17H), 5.29 (d,J= 10 Hz, 1H), 4.16 (m, 1H), 3.84-3.96 (m, 2H), 2.87 (d,J= 6 Hz, 2H), 2.58 (t, J= 7Hz, 2H). HRMS (BS) 460.1580 (MH+). C27H26N04S requires 460.15825.
2-Phenylethyl (N-4-methylphenylsulfonyl)-(S)-2-amino-3-phenylpropanoate
~OH
pyridine
V
2.2
2.9
,..
2.13
2-Phenylethanol (0.106 mL, 0.89 mmol) and dry pyridine (0.1 08 mL, 1.34 mmol) were added to a solution of N-(p-toluenesulfonyl)-l-phenylalanyl chloride (301 mg, 0.89 mmol) in dry CH2Clz (5 mL) under N2. After three hours the solution was washed with HCI (5 mL, 1M), saturated Na2C03 (5 mL), dried over anhydrous Na2S04 and the solvent removed on a rotary evaporator. The product was recrystallised from methanol as needles (360 mg, 88%). mp 134-135°C. IR (KBr, cm- i) 3416, 3290, 1737, 1330, 1163, 1090. iH NMR (300 MHz, CDCh) 87.60-6.95 (m, 14H), 5.01 (d, J
=
9 Hz, 1H), 4.17 (m, 1H), 4.03 (m,2H),
2.97 (d, J= 6 Hz, 2H), 2.71 (t, J= 7 Hz, 2H), 2.38 (s, 3H). HRMS (BS) 424.1582 (MH+). C24H26N04S requires 424.15825.
170
Chapter Eight - Experimental
2-Phenylethyl (N-4-nitrophenylsulfonyl)-(S)-2-amino-3-phenylpropanoate
pyridine
2.2
)100
2.10
2-Phenylethanol (0.103 mL, 0.84 mmol) and dry pyridine (0.103 mL, 1.33 mmol) were added to a solution of N-(4-nitrophenylsulfonyl)-1-phenylalanyl chloride (310 mg, 0.84 mmol) in dry CH2Clz (5 mL) under N 2. After three hours the solution was washed with HCI (5 mL, 1M), saturated Na2C03 (5 mL), dried over anhydrous Na2S04 and the solvent removed on a rotary evaporator. The product was recrystallised from methanol as needles (366 mg, 96%). mp 100-102°C. IR (KBr, cm- I) 3414, 3277, 1730, 1522, 1350, 1171, 1087. IH NMR (300 MHz, CDCb) () 8.16-6.94 (m, 14H), 5.23 (d, J= 10 Hz, 1H), 4.22 (m, 1H), 4.15 (t, J = 7 Hz, 2H), 2.89-3.07 (m, 2H), 2.82(t, J = 7 Hz, 2H). HRMS (BS) 455.1283 (MH+). C23H20N206S requires 455.12768.
Pyridiniump-toluenesulfonate4
Pyridinium p-toluenesulfonate (PPTS) was prepared as follows; p-toluenesulfonic acid monohydrate (5.70 g, 30 mmol) was added to pyridine (12.1 mL, 150 mmol) with stirring at room temperature (slightly exothermic). After stirring for 20 minutes, the excess of pyridine was removed with a rotary evaporator on a water bath at ca. 60°C to afford a quantitative yield of PPTS as slightly hygroscopic colourless crystals. Recrystallisation from acetone gave the pure salt (6.8 g, 90%), C12H13N03S, mp 120°C.
171
Chapter Eight - Experimental
2-benzyl-4,5-dimethyl-l,3-dioxolane5
benzene 2.25
2.1
To a solution of phenylethanal (0.12 g, 1.0 mmol) in benzene (10 mL), 2,3 butanediol (0.18 g, 2.0 mmol) and pyridinium tosylate (0.025 g, 0.1 mmol) were added and the mixture refluxed with water separation by a Dean-stark trap until the starting aldehyde had been completely used (5 hours). Excess solvent was then removed in vacuo, ether (40 mL) was added, and the mixture was washed with sodium hydrogen carbonate and saturated sodium chloride solution. The organic phase was dried over anhydrous Na2S04 and the solvent removed under reduced pressure to give the impure acetal. The product was purified by flash chromatography on silica gel (petroleum ether: 70/ethyl acetate: 30) which gave (0.16 g, 85 %). IH NMR (300 MHz, CDCh) 8 7.31-7.20 (m, 5H), 5.23 (t, J= 4.8 Hz, IH), 3.60-3.47 (m, 2H), 2.92 (d, J= 4.4 Hz, 2H), 1.23 (d, J= 6.3 Hz, 3H), 1.18 (d, J = 5.9 Hz, 3H). HRMS (ES): (MH+) 193.1230. C12H1602 requires 193.1229.
2-benzyl-(4R,5R)-dimethyl-l,3-dioxolane
benzene 2.1
2.26
To a solution of phenylethanal (0.12 g, 1.0 mmol) in benzene (10 mL), (2R,3R)-(-)-2,3butanediol (0.18 g, 2.0 mmol) and pyridinium tosylate (0.025 g, 0.1 mmol) were added and the mixture refluxed with water separation by a Dean-stark trap until the starting aldehyde had been completely used (5 hours). Excess solvent was then removed in vacuo, ether (40
Chapter Eight Experimental
172
mL) was added, and the mixture was washed with sodium hydrogen carbonate and saturated sodium chloride solution. The organic phase was dried over anhydrous Na2S04 and the solvent removed under reduced pressure to give the impure acetal. The product was purified by flash chromatography on silica gel (petroleum ether: 70/ethyl acetate: 30) which gave (0.1865 g, 97 %). IH NMR (300 MHz, CDCh) =
4.8 Hz, IH), 3.62-3.49 (m, 2H), 2.92 (d, J
=
(5
7.32-7.22 (m, 5H), 5.25 (t, J
4.9 Hz, 2H), 1.24 (d, J
5.9 Hz, 3H), 1.19
(d, J= 6.3 Hz, 3H). HRMS (ES):(MH+) 193.1230. C12H1602 requires 193.1229.
2-benzyl-(4R,5R)-diphenyl-l,3-dioxolane
OX? ~
10
,
·0
2.1
,H
HO
H
+
~
0
"
",
H
-;/'
W
~
H
N
OH
MeC6 H4S03'
benzene
He
,.Hb
~
,.. cfi~::(!~~ o
H
2.28
2.27
To a solution of phenylethanal (0.06 g, 0.5 mmol) in benzene (5 mL), (R,R)-(+)hydrobenzoin (0.214 g, 1.0 mmol) and pyrldinium tosylate (0.0125 g, 0.05 mmol) were added and the mixture refluxed with water separation by a Dean-stark trap until the starting aldehyde had been completely used (24 hours). Excess solvent was then removed in vacuo, ether (40 mL) was added, and the mixture was washed with sodium hydrogen carbonate and saturated sodium chloride solution. The organic phase was dried over anhydrous Na2S04 and the solvent removed under reduced pressure to give a white crystalline solid. (0.012 g, 78 %). IH NMR (300 MHz, CDCh) 1H), 4.73 (d, J
(5
7.42-7.12 (m, 15H), 5.74 (t, J= 4.4 Hz,
7.8 Hz, IH), 4.60 (d, J = 8.3 Hz, IH), 3.22 (d, J = 4.4 Hz, 2H).
173
Chapter Eight - Experimental
2-0ctyl-(4R,5R)-dimethyl-l,3-dioxolane
+~ H
OH
benzene
2.30
2.29
To a solution of octanal (0.12 g, 1.0 mmol) in benzene (10 mL), (2R,3R)-(-)-2,3butanediol (0.18 g, 2.0 mmol) and pyridinium tosylate (0.025 g, 0.1 mmol) were added and the mixture refluxed with water separation by a Dean-stark trap until the starting aldehyde had been completely used (5 hours). Excess solvent was then removed in vacuo, ether (40 mL) was added, and the mixture was washed with sodium hydrogen carbonate and saturated sodium chloride solution. The organic phase was dried over anhydrous Na2S04 and the solvent removed under reduced pressure to give the impure acetal. The product was purified by flash chromatography on silica gel (petroleum ether: 70/ethyl acetate: 30) which gave (0.1863 g, 93 %). IH NMR (500 MHz, CDCh) 8 5.03 (t, J= 4.9 Hz, 1H), 3.613.59 (m, 2H), 1.65-1.60 (m, 2H), 1.43-140 (m, 2H), 1.38-131 (m,8H), 1.28 (d, J= 5.4 Hz, 3H), 1.22 (d, J= 5.9 Hz, 3H), 0.87 (t, J= 4.4 Hz, 3H).
2-Phenylethanol6
()! I
~
0
2.1
H
LiAIH4 -------'------Jl,... ....
ether, R.T
~OH
o
2.2
Phenylethanal (0.16 g, 1.31 mmol) was dissolved in dry purified ether (5 mL) and injected into a round bottom flask containing LiAIH4 (0.10 g, 262 mmol, 2 mol eq.) in ether (20 mL). This reaction mixture was allowed to stir overnight at room temperature. The reaction was then quenched with saturated NH4CI solution pH=3 and extracted with ether and dried
174
Chapter Eight - Experimental
over MgS04 to give 2-phenylethanol (O.13g, 82%). IH NMR (300 MHz, CDCh) 0 7.357.22 (m, 5H), 3.86 (t, J
=
4.8 Hz, 2H), 2.82 (t, J = 4.8 Hz, 2H), 1.69 (bs, 1H).
(lR)-1-phenyl-l,2-ethanediol-l-d17
OH
AD-mix
p )Il1o
OH
~~ 2.16
2.15
Styrene-a-dl (0.5 g, 4.75 mmol) was added to a vigorously stirring solution of AD-mix-~ (5.88 g) in tertiary butyl alcohol (21 mL) and water (21 mL) at O°C. The solution was stirred for 48 hours at O°C. Sodiummetabisulphite (3.72 g, 19.6 mmol) was added and the reaction mixture was stirred for two hours, and allowed to wann to room temperature. The reaction mixture was diluted with CH2Clz, the organic layer separated and the aqueous layer extracted with ethyl acetate. The solvent was removed under reduced pressure and flash chromatography on silica gel (ethyl acetate / petroleum ether) gave (lR)-l-phenyl1,2-ethanediol-1-dj as white crystals (0.41 g, 62 %). mp 72 - 74°C. [lit. 8 [a]2oD -67 (c 0.90, CHCh, ee> 97%) for undeuterated material]. IH NMR (300 MHz, CDCh) 0 7.38-7.28 (m, 5H), 3.77 (d, J
=
11.0 Hz, 1H), 3.67 (d, J
=
11.0 Hz, 1H), 2.57 (bs, 1H), 2.14 (bs, 1H). 13 C
NMR (75 MHz, CDCh) 0 137.4, 129.0, 126.0, 74.0 (t, JeD = 21.3 Hz), 67.8. 2H NMR (46MHz, CHCh) 0 4.80 (s).
175
Chapter Eight - Experimental
(1S)-1-phenyl-l,2-ethanediol-l-d1
AD-mix a
,.. ~~ OH
2.17
OH
2.18
Styrene-a-d j (1.0 g, 9.5 mmol) was added to a vigorously stirring solution of AD-mix-a (11.76 g) in tertiary butyl alcohol (42 mL) and water (42 mL) at O°C. The solution was stirred for 48 hours at O°C. Sodium metabisulphite (7.45 g, 39 mmol) was added and the reaction mixture was stirred for two hours, warming to room temperature. The reaction mixture was diluted with CH2 Ch, the organic layer separated and the aqueous layer extracted with ethyl acetate. The solvent was removed under reduced pressure and flash chromatography on silica gel (ethyl acetate / petroleum ether) gave (1S)-I-phenyl-l,2ethanediol-l-dj as white crystals (0.92 g, 69 %). IH NMR (300 MHz, CDCb) 8 7.37-7.27 (m, 5H), 3.71 (d, J = 12.0 Hz, IH), 3.62 (d, J = 11.7 Hz, IH), 3.29 (bs, IH), 2.90 (bs, IH).
Mixture of (2R)- and (2S)-2-chloro-2-phenyl-ethyl acetate-2-d1
~~ + OH
approx.
OH
OH
OH
~~
Me3SiCI
,..
d:f D"
2.16
0
-....c
\~O=\
approx.
2 2.18
CH 3C(OMeh
o=(
+~oII'H ~
CI
H
2 2.20
2.19
(1S)-I-Phenyl-l,2-ethanediol-l-dj (0.3474 g, 2.5 mmol) and (IR)-I-phenyl-l,2-ethanediol-
I-dj (0.7575 g, 5.4 mmol) were dissolved in dry CH2 Ch (19.5 mL) and the solution cooled to o°c. Trimethyl orthoacetate was added (1.08 mL, 8.46 mmol) , followed by trimethylsilyl chloride (1.10 mL, 8.67 mmol). The solution was stirred for three hours, slowly warming to room temperature. The solvent was removed by evaporation under reduced pressure to give 2-chloro-2-phenyl-ethylacetate-2-dj as a colorless liquid (1.03 g,
Chapter Eight - Experimental
176
99%). IH NMR (500 MHz, CDCh) 8 7.43-7.26 (m, 5H), 4.44 (m, 2H), 2.07 (s, 3H). HRMS (ES) 199.6629 (MH+). ClOHl1DCI02 requires 200.05886.
Mixture of (2R)- and (2S)-2-phenylethanol-2-dl
cP~0 0"
---0
~
,1
0=\
approx.
o={
+~o :::--.. lItH CI
...
+ ~~ H OH
H approx.
2
2.20
LiAIH 4
2.19
H
OH
~~
2
2.22
2.21
The mixture of (2R)- and (2S)-2-chloro-2-phenyl-ethylacetate-2-dj (144 mg, 2.4 mmol) from above was dissolved in ether (10 mL) and LiAIH4 was added (91 mg, 2.4 mmol). The solution was stirred at room temperature for two hours. Saturated NH4CI was added dropwise until the LiAIH4 residues formed a paste on the bottom of the flask. The solution was dried by the addition of anhydrous MgS04, filtered and the solvent evaporated under reduced pressure to give a clear liquid. IH NMR (500 MHz, CDCh) 87.43-7.23 (m, 5H), 3.85 (d, J= 6.3 Hz, 2H), 2.85 (m, IH), 1.59 (bs, IH).
Chapter Eight - Experimental
177
2-Phenylethyl (N-4-nitrophenylsulfonyl)-(S)-2-ammo-3-phenylpropanoate
~°tb~'SH
O~O ~ 'N
0(
N No 2
H OH
~fI< approx.
pyridine
2.21
R
~
I '-':::: ~
2.24
)10
2.13
0(
N
No2
I
~O.h;~'SH
O~O ~ 'N
2 2.22
D
approx. 2
I
H
R
: approx.1
D
I ""
~
2.23
A 2:1 mixture of (28)- and (2R)-2-phenyl-ethanol (0.09 g, 0.647 mmol) and dry pyridine (0.087 mL, 1.08 mmol) were added to a solution of N-(4-nitrophenylsulfonyl)-Iphenylalanyl chloride (227 mg, 0.734 mmol) in dry CH2Ch (7 mL) under dry N2. After three hours the solution was washed with HCI (7 mL, 1M), saturated Na2C03 (7 mL), dried over anhydrous Na2S04 and the solvent removed under reduced pressure. The product was purified by flash chromatography on silica gel (ethyl acetate / petroleum ether) and gave 2phenyl ethyl (N-4-nitrophenylsulfonyl)-(8)-2-amino-3-phenylpropanoate as a white solid (254 mg, 84%). IHNMR (500 MHz, CDCh) 8 8.14 (dd, J= 2.4,6.8 Hz, 2H), 7.77 (dd, J= 2.0,6.8 Hz, 2H), 7.22-7.19 (m, 5H), 7.13 (d, J= 7.8 Hz, 2H), 7.02-6.96 (m, 5H), 5.25 (d, J
= 9.8 Hz, IH), 4.25-4.22 (m, IH), 4.12 (t, J= 6.8 Hz, 2H), 3.04 (dd, J= 5.4,13.7 Hz, IH), 2.93 (dd, J = 6.8, 13.7 Hz, IH), 2.77 (t, J = 6.8 Hz, 2H). HRMS (ES) 456.1340 (MH+). C23H22DN206S requires 456.13396.
178
Chapter Eight - Experimental
NMR
investigation
of
2-phenylethyl
(N-4-nitrophenylsulfonyl)-(S)-2-arnino-3-
phenylpropanoate by the addition ofYb(hfc)3 chiral shift reagent
Aliquots
of d-Yb(hfc)3
were
added
to
a
solution
of
2-phenylethyl
(N-4-
nitrophenylsulfonyl)-(S)-2-amino-3-phenylpropanoate in CDCb in a 3 mL NMR tube until the prochiral protons
~
to the ester linkage were resolved in an NMR spectrum (approx. 10
eq. shift reagent added). The integral of the downfield peak was twice the integral of the upfield peak. It was therefore concluded that in undeuterated material the downfield peak is Hs; the up field peak is HR.
lH
NMR
integral· of
2-phenylethyl
(N-4-nitrophenylsulfonyl)-(S)-2-arnino-3-
phenylpropanoate with varying dl
IH NMR of 2-phenylethyl (N-4-nitrophenylsulfonyl)-(S)-2-amino-3-phenylpropanoate with sufficient Yb(hfc)3 chiral shift reagent to separate the prochiral protons
~_
to the ester
oxygen. The integral of the two signals was measured from NMR spectra taken with a varying the delay time between pulses.
d 1 (s)
Downfield : Upfield proton integral
0.5
1.0040: 1
0.5
1.0173:1
1
1.0482: 1
5
1.0211 : 1
10
1.0061 : 1
Chapter Eight - Experimental
8.3
179
EXPERIMENTAL WORK DESCRIBED IN CHAPTER THREE
I-phenylethanol9
riY Sr
V
_1,-,---,M----"9'-----------}.....
2,
0
AH 3.13
Bromobenzene (6.74 g, 42.9 mmol) in dry ether (40 mL) was added to magnesium turnings (lg, 41.5 mmol) in dry ether (30 mL), when no reaction occurred 1,2-dibromoethylene (2 drops) was added. After stirring for one hour with no evidence of reaction, a small crystal of iodine was added. The reaction proceeded slowly. After stirring for one hour at room temperature, acetaldehyde (2.41 mL, 43.1 mmol) in dry ether (30 mL) was added dropwise. The solution was stirred for sixteen hours at room temperature. Water was added dropwise (30 mL) and the solution was filtered. The organic layer was separated and dried (Na2S04)' The product was purified by flash column chromatography on silica gel (pentane / ethyl acetate) to give 1-phenylethanol as a colourless liquid (3.88 g, 74%). IH NMR (300 MHz, CDCb) () 7.40-7.27 (m, 5H), 4.81 (q, J= 5.9,11.3 Hz, 1H), 1.48 (d, J= 7.3 Hz, 3H).
Acetophenone
3.13
3.12
A solution of Jones' reagent (H2S04 (0.9 mL) and Cr03 (1.06 g) in H20 (3 mL)) was added dropwise to 1-phenylethanol (1.0 g) in acetone (3 mL). When the colour of the solution changed from green to brown, sufficient sodium metabisulphite was added to return the solution to a green colour. The aqueous solution was extracted with ether. The organic layer was dried (Na2S04) and solvent was removed by rotary evaporation to give
Chapter Eight - Experimental
180
acetophenone as a yellowish liquid (0.66 g, 68%). IH NMR (CDCh) 8 7.84-7.25 (m, 5H), 7.26 (d, J = 7.8 Hz, 2H), 2.41 (s, 3H).
I-phenylethanol10
3.12
3.13
Acetophenone (48.06 g, 0.4 mol) was added dropwise to a stirring solution of sodium borohydride (7.57 g, 0.2 mol) in H20 (50 mL) and ethanol (50 mL) at O°C. After 2 hours stirring at room temperature the solution was saturated with NaCl, the organic layer was separated and the aqueous layer extracted with EhO. After drying over K2C03 the solvent was removed under reduced pressure to give 1-phenylethanol as a clear liquid (46.13g, 94%). IH NMR (300 MHz, CDCh) 8 7.41-7.28 (m, 5H), 4.82 (q, J
=
6.1, 11.7 Hz, 1H),
1.49 (q, J = 7.3 Hz, 3H).
Styrene ll
3.13
3.5
1-Phenylethanol (4.18 g, 34.2 mmol) was placed in a round bottom flask connected to a purpose built Pyrex tube drawn out at one end and packed with alumina. The tube was inserted in an electric furnace capable of maintaining a temperature of 420-470°C and monitored by an electric probe placed inside the furnace. The drawn out end of the tube was connected to a receiver immersed in liquid nitrogen. The exit tube of the receiver was connected to a vacuum pump. The alcohol was distilled under reduced pressure through the
181
Chapter Eight - Experimental
Pyrex tube while maintaining a temperature of 420-470°C. This afforded styrene as a colourless liquid (2.95 g, 83 %). IH NMR (300 MHz, CDC h) 0 7.42 - 7.22 (m, 5H), 6.72 (dd, J= 10.7, 17.6 Hz, 1H) 5.75 (d, J = 17.6 Hz, 1H), 5.24 (d, J= 10.7 Hz, 1H).
(1S)-1-phenyl-l,2-ethanediol-1 7
AD-mix a )100
~~ OH
OH
3.14
3.5
Styrene (1.5 g, 14.26 minol) was added to a vigorously stirring solution of AD-mix-a (20.0 g) in tertiary butyl alcohol (70 mL) and water (70 mL) at O°C. The solution was stirred for 48 hours at O°C. Sodium metabisulphite (11.12 g, 58.5 mmol) was added and the reaction mixture was stirred for two hours, warming to room temperature. The reaction mixture was diluted with CH2Ch, the organic layer separated and the aqueous layer extracted with ethyl acetate. The solvent was removed under reduced pressure and flash chromatography on silica gel (ethyl acetate I petroleum ether) gave (1S)-1-phenyl-1,2-ethanediol as white crystals (1.36 g, 69 %). IHNMR (300 MHz, CDCh) 0 7.38-7.27 (m, 5H), 4.83 (dd, J= 3.4, 7.8 Hz, 1H), 3.67 (dd, J= 3.9, 11.2 Hz, 2H), 2.58 (bs, 1H), 2.20 (bs, 1H).
(S)-Styrene oxide 12
~~ OH
OH
3.14
1. MeC(MeOh Me3SiCI )100 2. K2C0 3 1 MeOH
3.15
Trimethylsilyl chloride (0.457 mL, 3.62 mmol) was added to a stirring solution of trimethylorthoacetate (0.461 mL, 3.62 mmol) and (1S)-phenylethan-1,2-diol (0.5 g, 3.62 mmol) in CH2Ch (10 mL) at O°C. After one hour, the solvent was removed under reduced
Chapter Eight - Experimental
182
pressure and the residue dissolved in methanol (10 mL). K2C03 (1.21 g) was added, the mixture was stirred for 2 hours and the solvent was removed under reduced pressure. The residue was partitioned between H20 and CH2Ch. The organic layer was separated and dried over NaS04, filtered and the solvent evaporated under reduced pressure to give a yellow liquid. The product was purified by flash chromatography on silica gel (10% ether: pentane) to obtain (S)-styrene oxide as a colourless liquid (0.347 g, 80%). [a]22D +24.1 (c 1.67, CHCh) [lit. 13 [a]22D +24.6 (c 1.37, CHCI3, ee 96%)]. IH NMR (300 MHz, CDCh) 8 7.38-7.27 (m, 5H), 3.86 (dd, J
2.9,4.4 Hz, IH), 3.14 (dd, J
3.9,5.4 Hz, 1H), 2.80 (dd,
J= 2.9,5.9 Hz, IH).
I-Phenylethanol-l-d/O D
NaBD4 ,..
~ ,~
OH
Ir:;;
3~2
3~6
Acetophenone (8.65 g, 72 mmol) was added dropwise to a stirring solution of sodium borodeuteride (1.5 g, 36 mmol) in H 20 (10 mL) and ethanol (10 mL) at O°c. After 2 hours stirring at room temperature the solution was saturated with NaCI, the organic layer was separated and the aqueous layer extracted with Et20. After drying over K2C03 the solvent was removed under reduced pressure to give I-phenylethanol-l-dz as a clear liquid, greater than 98% deuterated at C1 by IH NMR and mass spectrometry (7.77 g, 88%) IH NMR (300 MHz, CDCh) 8 7.38-7.25 (m, 5H), 1.97 (s, IH), 1.48 (s, 3H). 2H NMR (46MHz, CHCh) 84.85 (s).
Chapter Eight ~ Experimental
183
ox D
1
OH
~I ~
3.16
3.11
I-Phenylethanol-l-dJ (6.01 g, 48.8 mmol) was placed in a round bottom flask connected to a purpose built Pyrex tube drawn out at one end and packed with alumina. The tube was inserted in an electric furnace capable of maintaining a temperature of 420-470°C and monitored by an electric probe placed inside the furnace. The drawn out end of the tube was connected to a receiver immersed in liquid nitrogen. The exit tube of the receiver was connected to a vacuum pump. The alcohol was distilled under reduced pressure through the Pyrex tube while maintaining a temperature of 420-470°C. This afforded styrene-a.-d] as a colourless liquid (4.16 g, 81 %) with 78% deuteration at Cl confirmed by IH NMR and mass spectrometry. IH NMR (300 MHz, CDCh) 87.41 - 7.20 (m, 5H), 6.71 (dd, J= 11.2, 18 Hz, IH) 5.77-71 (m, IH), 5.21 (d, J= 1.5 Hz, IH).
Styrene-a.-d1
ox D
OH
I"" ~
3.16
3.11
I-Phenylethanol-l-dj (0.340 g, 2.76 mmol) was placed in a round bottom flask connected to a purpose built Pyrex tube drawn out at one end and packed with alumina that had been dried in an electric furnace at 420-470°C for 5 hours. The drawn out end of the tube was connected to a receiver immersed in liquid nitrogen. The exit tube of the receiver was connected to a vacuum pump. The alcohol was distilled under reduced pressure through the Pyrex tube while maintaining a temperature of 420-470°C. This afforded styrene-a.-d] as a
184
Chapter Eight - Experimental
colourless liquid (0.244 g, 84 %) with 60% deuteration at Cl confinned by IH NMR and mass spectrometry. III NMR (300 MHz, CDCb) 67.41 - 7.20 (m, 5H), 6.71 (dd, J= 11.2, 17.6 Hz, IH) 5.77-71 (m, IH), 5.23 (d, J== 4.4 Hz, IH). 2H NMR (46MHz, CHCb) 6 6.64 (s).
Styrene-dl-8
3.16 3.18
I-Phenylethanol-l-dj (0.326 g, 2.65 mmol) was placed in a round bottom flask connected to a purpose built Pyrex tube drawn out at one end and packed with alumina that had been dried in an electric furnace at 420-470°C for 5 hours, saturated with D20 (5 mL) and left to absorb for 24 hours. This process was repeated. The drawn out end of the tube was connected to a receiver immersed in liquid nitrogen. The exit tube of the receiver was connected to a vacuum pump. The alcohol was distilled under reduced pressure through the Pyrex tube while maintaining a temperature of 420-470°C. This afforded styrene partially deuterated at d u positions as a colourless liquid (0.232 g, 78 %) confinned by IH NMR and 2H NMR. IH NMR (300 MHz, CDCb) 6 7.40 - 7.19 (m, 5H), 6.67-6.69 (m, Ill) 5.7771 (m, IH), 5.74-5.68 (m, IH), 5.22-5.19 (m, IH). 2H NMR (46MHz, CHCb) 6 6.64 (s), 5.66 (s), 5.l6 (s).
185
Chapter Eight - Experimental
Styrene-a.-dJ 14
cr D
OH
I~ '~
KHS04, /',. 200°C .. cat. p-methoxyphenol
3.16
3.11
A mixture of I-phenylethanol-l-dl (3.76 g, 30.5 mmol), fused potassium bisulphate (0.368 g) and p-methoxyphenol (5 mg) was heated at 200°C and the product-water azeotrope was distilled out. The wet product was extracted with ether and dried over MgS04. Removal of the solvent and fractional distillation afforded styrene-a-dz as a colorless liquid (2.50 g, 78 %) with> 98% deuterium incorporation at the Cl position confirmed by IH NMR. IH NMR (300 MHz, CDCh) 07.42 -7.22 (m, 5H), 5.75-73 (m, 1H), 5.23 (d, J= 1.4 Hz, 1H). 2H NMR (46 MHz, CHCh) 0 6.73 (s).
(1S)-1-phenyl-l,2-ethanediol-l-dJ
AD-mix a
3.11
... 3.14
Styrene-a-d1 (1.0 g, 9.5 mmol) was added to a vigorously stirring solution of AD-mix-a (11.76 g) in tertiary butyl alcohol (42 mL) and water (42 mL) at O°C. The solution was stirred for 48 hours at O°C. Sodium metabisulphite (12.60 g, 39 mmol) was added and the reaction mixture was stirred for two hours, warming to room temperature. The reaction mixture was diluted with CH2Clz, the organic layer separated and the aqueous layer extracted with ethyl acetate. The solvent was removed under reduced pressure and flash chromatography on silica gel (ethyl acetate / petroleum ether) gave (1S)-1-phenyl-l,2ethanediol-1-d1 as white crystals (0.92 g, 69 %). IH NMR (300 MHz, CDCh) 0 7.37-7.27
Chapter Eight - Experimental
186
(m, 5H), 3.71 (d, J= 11.7 Hz, 1H), 3.62 (d, J= 11.2 Hz, 1H), 3.29 (bs, IH), 2.90 (bs, IH). 2H NMR (46 MHz, CHCh) 0 4.80 (s).
(S)-Styrene oxide-a-dl
~~ OH
OH
1. MeC{MeOh Me3SiCI )ilia 2. K2C03 { MeOH
3.14
3.3
Trimethylsilyl chloride (0.457 mL, 3.62 mmol) was added to a stirring solution of trimethylorthoacetate (0.461 mL, 3.62 mmol) and (1S)-1-phenyl-1,2-ethanediol-l-d1 (0.5 g, 3.62 mmol) in CH2Ch (10 mL) at O°C. After one hour, the solvent was removed under reduced pressure and the residue di~solved in methanol (10 mL). K2C03 (1.21 g, 22 mmol) was added, the mixture was stirred for 2 hours and the solvent was removed under reduced pressure. The residue was partitioned between H20 and CH2Ch. The organic layer was separated and dried over NaS04, filtered and the solvent evaporated under reduced pressure to give a yellow liquid. The product was purified by flash chromatography on silica gel (10% ether : pentane) to obtain (S)-styrene oxide-a-d1 as a colourless liquid (0.347 g, 80%). [litY [a]22D +24.6 (c 1.37, CHCi), ee 96%)]. IH NMR (300 MHz, CDCh) 07.38-7.27 (m, 5H), 3.86 (dd, J (dd, J = 2.9,5.9 Hz, IH).
= 2.9, 4.4
Hz, IH), 3.14 (dd, J
= 3.9, 5.4
Hz, IH), 2.80
187
Chapter Eight - Experimental
(lR)-1-phenyl-l,2-ethanediol-l-d17
OH
AD-mix
p
OH
... ~~
3.11
3.17
Styrene-a-d1 (0.5 g, 4.75 mmol) was added to a vigorously stirring solution of AD-mix-p
(5.88 g) in tertiary butyl alcohol (21 mL) and water (21 mL) at O°C. The solution was stirred for 48 hours at O°C. Sodium metabisulphite (3.72 g, 19.6 mmol) was added and the reaction mixture was stirred for two hours, and allowed to wann to room temperature. The reaction mixture was diluted with CH2Ch, the organic layer separated and the aqueous layer extracted with ethyl acetate. The solvent was removed under reduced pressure and flash chromatography on silica gel (ethyl acetate I petroleum ether) gave (lR)-I-phenyl1,2-ethanediol-1-dj as white crystals (0,41 g, 62 %). mp 72 - 74°C. [tit. s [a]2oD -67 (c 0.90, CHCh, ee> 97%) for undeuterated material]. IH NMR (300 MHz, CDCh) 3 7.38-7.28 (m, 5H), 3.77 (d, J
11.0 Hz, IH), 3.67 (d, J= 11.0 Hz, IH), 2.57 (bs, 1H), 2.14 (bs, IH). BC
NMR (75 MHz, CDCh) 3 137,4, 129.0, 126.0, 74.0 (t, JeD
21.3 Hz), 67.8. 2H NMR
(46MHz, CHCh) 3 4.80 (s).
(R)-Styrene oxide-a-d1
o OH
3.17
OH 1. MeC(MeO)g Me3SiCI ,..
2. KZC03 1 MeOH
3.6
Trimethylsilyl chloride (0.35 mL, 2.79 mmol) was added to a stirring solution of trimethylorthoacetate (0.35 mL, 2.79 mmol) and (lR)-1-phenyl-1,2-ethanediol-1-dl (0.38 g, 2.79 mmol) in CH2Ch (6.5 mL) at O°C. After 30 minutes, the solvent was removed under reduced pressure and the residue dissolved in methanol (6.5 mL). K2C03 (0.94 g, 6.8
Chapter Eight - Experimental
188
mmol) was added and the mixture was stirred for 2 hours before the solvent was removed under reduced pressure. The residue was partitioned between H20 and CH2Ch. The organic layer was separated and dried over NaS04, and the solvent evaporated under reduced pressure to give a yellow liquid. The product was purified by flash chromatography on silica gel (10% ether: pentane) to obtain (R)-styrene oxide-a.-d1 as a colourless liquid (0.24 g, 71 %). [lit.13 [a.]22D -24.1 (c 1.37, CHCb, ee 96%)]. IH NMR (300 MHz, CDCh) (37.38-7.27 (m, 5H), 3.14 (d, J= 5.5 Hz, IH), 2.80 (d, J= 5.5 Hz, IH).
Phenylacetylene-l-d1 15
3.19
3.20
Phenyl acetylene (l1.63g, 113.9 mmol) distilled from CaH2 was added slowly to a filtered ether solution of EtMgBr (prepared from EtBr (8.75 mL) and Mg (3.0 g) in EtzO (15 mL)) under nitrogen. After 10 hours at reflux, D20 (5 mL) was added. The mixture was extracted with pentane, dried over MgS0 4, filtered and concentrated. The product phenylacetylene-l-d1 (9.4 g, 80%) showed greater than 98% deuterium incorporation by IH NMR as the terminal acetylenic resonance of the undeuterated compound could not be detected. IH NMR (300 MHz, CDCh) (3 7.36-7.13 (m, 5H). 2H NMR (46 MHz, CHCh) (3 3.04 (s).
189
Chapter Eight - Experimental
Styrene-cis-~-d/6
~D
1. [CP2ZrCl(H)]x. toluene )100
3.20
[Cp2ZrCI(H)]x
(11.63
g,
3.9
113.9 mmol)
was
suspended
in
toluene
(16
mL).
Deuteriophenylacetylene (1.4 mL, 1.1 equiv.) was added via syringe against an Ar counterflow. The solution was stirred for 4 hours until [Cp2ZrCl(H)]x had dissolved, yielding a dark orange solution. The toluene was removed in vacuo, and the remaining orange residue was dissolved in ether (16 mL). The solution was cooled to O°C, and H 20 (0.4 mL) was slowly &dded via syringe against an argon gas counterflow over 1 hour. [Cp2ZrO]x was filtered off, and the styrene was vacuum-distilled to yield
styrene-cis-~-dj
(1.21 g, 85%). IH NMR spectroscopy showed 94% deuterium incorporation. IH NMR (300 MHz, CDCh) 0 7.42-7.14 (m, 5H), 7.13 (d, J = 8.3, 2H), 6.71 (d, J = 11 Hz, 1H), 5.22 (d, J = 11.1, 1H). 2H NMR (46 IVlHz, CHCh) 0 5.74 (s).
(1S),(2R)-1-Phenyl-l,2-ethanediol-2-dl
AD-mix a )100
3.9
Styrene-cis-~-dj
3.21
(1.21 g, 8.69 mmol) was added to a vigorously stirring solution of AD-
mix-a (12.17 g) in tertiary butyl alcohol (40 mL) and water (40 mL) at O°C. The solution was stirred for 48 hours at O°C. Sodium metabisulphite (7.60 g) was added and the reaction mixture was stirred for two hours, warming to room temperature. The reaction mixture was diluted with CH2Ch, the organic layer separated and the aqueous layer extracted with ethyl acetate. The solvent was removed under reduced pressure and flash chromatography on silica gel (ethyl acetate / petroleum ether) gave (1S),(2R)-1-Phenyl-1,2-ethanediol-2-dj as
Chapter Eight - Experimental
190
white crystals (0.919 g, 76 %). mp 76 - 77°C. IH NMR (300 MHz, CDCb) 0 7.42-7.22 (m, 5H), 4.78 (d, J
2.9 Hz, IH), 3.69 (d, J
=
=
3.0 Hz, IH), 2.60 (bs, IH), 1.70 (bs, IH). 2H
NMR (46 MHz, CHCb) 0 3.71 (s). BC NMR (75 MHz, CDCb) 0 137.3, 129.0, 126.0,67.5 (t, JeD = 21.3 Hz).
(1S),(2R)-Styrene oxide-cis-p-d1
~~ OH
OH
3.21
1. MeC(MeOb Me3SiCI ,., 2. K2C0 3 ! MeOH
3.1
Trimethylsilyl chloride (0.37 mL, 3.0 mmol) was added to a stirring solution of trimethylorthoacetate (0.37 mL, 3.0 mmol) and (1 S),(2R)-I-Phenyl-l,2-ethanediol-2-dl (0.4 g, 2.9 mmol) in CH2Ch (9 mL) at O°C. After one hour, the solvent was removed under reduced pressure and the residue dissolved in methanol (9 mL). K2C03 (1.0 g, 8 mmol) was added, the mixture was stirred for 2 hours and the solvent was removed under reduced pressure. The residue was partitioned between H20 and CH2Ch. The organic layer was separated and dried over NaS04, filtered and the solvent evaporated under reduced pressure to give a yellow liquid. The product was purified by flash chromatography on silica gel (10% ether: pentane) to obtain (1S),(2R)-styrene oxide-cis-p-d1 as a colourless liquid (0.31 g, 89%). IH NMR (300 MHz, CDCb) 0 7.39-7.28 (m, 5H), 3.86 (d, 4.4 Hz, IH), 3.12 (d, J
4.4 Hz, IH). 2H NMR (46 MHz, CHCb) 0 2.80 (s).
191
Chapter Eight - Experimental
(IR),(2S)- Phenyl-l,2-ethanediol-2-d1
ADmix- p
...
~~
~~ 0
rr _
~
;/
3.22
3.9
Styrene-cis-p-dj (3.22 g, 30.62 mmol) was added to a vigorously stirring solution of AD mix-p (42.89 g) in tertiary butyl alcohol (150 mL) and water (150 mL) at ODC. The solution was stirred for 48 hours at ODC. The reaction mixture was diluted with CH2Ch, the organic layer separated and the aqueous layer extracted with ethyl acetate. The solvent was removed under reduced pressure and flash chromatography on silica gel (ethyl acetate / petroleum ether) gave 3.19 as white crystals (3.30 g, 78 %). mp 76 - 77 DC. [a]20D -68.5 (c 1.5, CHCh). IH NMR (500 MHz, CDCh) 8 7.37-7.26 (m, 5H), 4.79 (d, J 3.61 (d, J
=
=
8.3 Hz, IH),
8.7 Hz, IH), 3.20 (bs, IH), 2.78 (bs, IH). 2H NMR (CHCh) 8 3.72 (s).
13 C
NMR (75 MHz, CDCh) 8137.3,129.0,126.0,67.5 (t, Jen = 21.3 Hz).
(IR),(2S)-Styrene oxide-p-dl
" cr OH
-
~
OH U'H
0
;/
3.22
1. MeC(MeOb Me3SiCI ... 2. K2C0 3 / MeOH
o
~'~ 3.4
Trimethylsilyl chloride (2.8 mL, 18.0 mmol) was added to a stirring solution of trimethylorthoacetate (2.8 mL, 18.0 mmol) and (1R,2S)-phenyl-l,2-ethanediol-2-dj (2.5 g, 18.1 mmol) in CH2Ch (56 mL) at ODC. After 30 minutes, the solvent was removed under reduced pressure and the residue dissolved in methanol (38 mL). K 2C03 (6.4 g, 50 mmol) was added and the mixture was stirred for 2 hours before the solvent was removed under reduced pressure. The residue was partitioned between H20 and CH2Ch. The organic layer was separated and dried over NaS04, and the solvent evaporated under reduced pressure to
Chapter Eight Experimental
192
give a yellow liquid. The product was purified by flash chromatography on silica gel (10% ether: pentane) to obtain (lR),(2S)-styrene oxide-~-dl as a colourless liquid (2.01 g, 92%). IH NMR (500 MHz, CDCh) (5 7.39-7.27 (m, 5H), 3.86 (d, 4.0 Hz, 1H), 3.13 (d,
3.6 Hz,
1H). 2H NMR (46 MHz, CHCh) (5 2.80 (s).
Styrene-trans-~-dlS
Q-==-H
1. DIBAL-H ...
2.D20
3.19
3.10
Phenylacetylene (4.0 g, 39.2 mmol) distilled from CaH2 was added slowly to aIM solution of diisQbutylaluminium hydride (14.24 mL, 40 mmol) in CH2Ch (8 mL) under N2 at O°C and stirred at room temperature for 24 hours. D20 (2.0 mL) was slowly added and the mixture was stirred for and hour before extracting into pentane four times, filtering, and drying with MgS04. The solvent was removed under reduced pressure to give a clear yellow liquid (2.80 g, 68%). IH NMR spectroscopy showed 87% deuterium incorporation. IH NMR (300 MHz, CDCh)
(5
7.50-7.17 (m, 5H), 6.72 (d, J= 17.6 Hz, 1H), 5.73 (d, J
17.6 Hz, 1H). 2H NMR (46 MHz, CHCh) (5 5.2 (s).
(1S),(2S)-1-Phenyl-l,2-ethanediol-2-dl
oJD 3.10
Styrene-trans-~-dl
AD-mix a -----I .......
~~ OH OH 3.23
(0.483 g, 4.59 mmol) was added to a vigorously stirring solution of AD
mix-a (6.43 g) in tertiary butyl alcohol (25 mL) and water (25 mL) at O°C. The solution was stirred for 48 hours at OoC. Sodium metabisulphite (3.30 g) was added and the reaction
193
Chapter Eight - Experimental
mixture was stirred for two hours, warming to room temperature. The reaction mixture was diluted with CH2Ch, the organic layer separated and the aqueous layer extracted with ethyl acetate. The solvent was removed under reduced pressure and flash chromatography on silica gel (ethyl acetate I petroleum ether) gave (1R),(2R)-I-phenyl-l,2-ethanediol-2-dl as white crystals (0.4599 g, 72 %). mp 76 - 78°C. IH NMR (300 MHz, CDCb) 8 7.38-7.27 (m, 5H), 4.80 (d, J= 8.3 Hz, IH), 3.63 (d, J= 8.3 Hz, IH), 3.05 (bs, IH), 2.61 (bs, IH). 2H NMR (46 MHz, CHCh) 8 3.73 (s).
l3 C
NMR (75 MHz, CDCh) 8 137.3, 129.0, 126.0,67.5
(t, JeD = 21.3 Hz).
(1S),(2S)-S tyrene oxide-IJ-d1
1. MeC(MeOb ... Me3SiCI
2. K2C0 3 / MeOH
3.23
3.2
Trimethylsilyl chloride (0.54 mL, 4.31 mmol) was added to a stirring solution of trimethylorthoacetate (0.55 mL, 4.31 mmol) and (1S),(2S)-I-Phenyl-l,2-ethanediol-2-dl (0.6 g, 4.31 mmol) in CH2Ch (10 mL) at O°C. After one hour, the solvent was removed under reduced pressure and the residue dissolved in methanol (19 mL). K2C03 (1.45 g, 10.5 mmol) was added, the mixture was stirred for 2 hours and the solvent was removed under reduced pressure. The residue was partitioned between H20 and CH2Ch. The organic layer was separated and dried over NaS04, filtered and the solvent evaporated under reduced pressure to give a yellow liquid. The product was purified by flash chromatography on silica gel (10% ether: pentane) to obtain (1S),(2S)-styrene oxide-IJ-dl as a colourless liquid (0.438 g, 84%). IH NMR (500 MHz, CDCh) 8 7.37-7.28 (m, 5H), 3.86 (d, 1.96 Hz, IH), 2.80 (d, J= 2.44 Hz, IH). 2H NMR (46 MHz, CHCh) 8 3.13 (s).
Chapter Eight Experimental
194
(1R),(2R)-1- Phenyl-1,2-ethanediol-2-d1
OH
OH
6 -
~
mix-~
;/
3.24
3.10
Styrene-trans-~-dl
"--<"D H
(2.31 g, 21.97 mmol) was added to a vigorously stirring solution of AD
(30.76 g) in tertiary butyl alcohol (110 mL) and water (110 mL) at O°C. The solution
was stirred for 48 hours at O°C. Sodium metabisulphite (17.2 g) was added and the reaction mixture was stirred for two hours, warming to room temperature. The reaction mixture was diluted with CH2Ch, the organic layer separated and the aqueous layer extracted with ethyl acetate. The solvent was removed under reduced pressure and flash chromatography on silica gel (ethyl acetate / petroleum ether) gave 3.18 as white crystals (2.26 g, 74 % yield). mp 76 - 78°C. IH NMR (300 MHz, CDCh) 6 7.37-7.27 (m, 5H), 4.79 (d, J 3.62 (d, J
8.3 Hz, IH),
8.7 Hz, 1H), 3.10 (bs, 1H), 2.80 (bs, IH). BC NMR (75 MHz, CDCh) 6 137.4,
129.1, 126.0, 74.5, 67.6 (t, JeD = 21.3 Hz). 2H NMR (CHCh) 6 3.71 (s).
(1R),(2R)-Styrene oxide-(3-dl
'(51 , OH
,
~
OH "'D
H
;/
3.24
1. MeC(MeOh Me3SiCI .. 2. K2 C0 3 / MeOH
3.5
Trimethylsilyl chloride (2.1 mL, 13.4 mmol) was added to a stirring solution of trimethylorthoacetate (2.1 mL, 13.4 mmol) and (IR,2R)-phenylethan-l,2-diol-2-d1 (1.86 g, 13.5 mmol) in CH2Ch (42 mL) at O°C. After 30 minutes, the solvent was removed under reduced pressure and the residue dissolved in methanol (28 mL). K2C03 (4.75 g, 38 mmol) was added and the mixture was stirred for 2 hours before the solvent was removed under reduced pressure. The residue was partitioned between H20 and CH2Ch. The organic layer
Chapter Eight Experimental
195
was separated and dried over NaS04, and the solvent evaporated under reduced pressure to give a yellow liquid. The product was purified by flash chromatography on silica gel (10% ether: pentane) to obtain (lR),(2R)-styrene oxide-~-dl as a colourless liquid (1.48 g, 91 %). IHNMR (500 MHz, CDCb) 0 7.38-7.27 (m, 5H), 3.86 (d, 2.8 Hz, IH), 2.79 (d, J= 2.4 Hz, IH).2H NMR (46 MHz, CHCh) 0 3.13 (s).
Chapter Eight Experimental
8.4
196
EXPERIMENTAL WORK DESCRIBED IN CHAPTER FOUR
Rearrangement of epoxides with BF3.0Et2
4.1
BF3.0Eh (13 ilL) was added to a stirring solution of epoxide (35 ilL) in 1,4 dioxane (2.5 mL) under an atmosphere of argon gas. The reaction mixture was stirred at room temperature for 20 minutes, a saturated solution of K2C03 (0.5 mL) was added and the solution was stirred for 30 minutes. Anhydrous K2C03 was added and the solution was filtered and the solvent removed under reduced pressure.
Analysis of rearrangement products
Reduction with LiAIH4
H(D.)
"H(D) , H(D)
QXi ~
I "oi! //
---J,.....
IH:!L4 ----=L=-iA= ether
The crude reaction product from the BF3.0Et2 catalysed rearrangement was dissolved in dry ether (5 mL) and LiAIH4 (24 mg) was added. The suspension was stirred under Ar for 3 hours and sat.
~Cl
was added dropwise until the LiAIH4 residues formed a paste. The
solution was dried (MgS04), filtered and the solvent was removed under reduced pressure.
Chapter Eight - Experimental
197
Esterification
~ H(O) ~.
I,&'.
"H(O) , OH
N02Yi1
H H(O)
+
~<::/Nro I O~O
o
CI
pyridine ..
,&'
The crude reaction mixture from the LiAIH4 reduction was dissolved in dry CH2Ch (5.25 mL), N-(4-nitrophenylsulfonyl)-I-phenylalanyl chloride (0.105 g, 0.28 mmol) and dry pyridine (33 ilL, 0.42 mmol) were added and the solution stirred at room temperature for 3 hours. The solution was washed with HCI (2.5 mL, 1M), saturated Na2C03 (2.5 mL), dried over anhydrous Na2S04 and the solvent removed on a rotary evaporator. The product was purified by flash column chromatography on silica gel (ethyl acetate : petroleum ether).
NMR analysis with Yb(hfch chiral shift reagent
Yb(hfc)J was added portionwise to an NMR sample of 2-phenylethyl (N-4nitrophenylsulfonyl)-(S)-2-amino-3-phenylpropanoate in CDCh until the signals for the two protons
p- to the ester oxygen become resolved. The relative integral of the two peaks
was obtained using a curve-fitting algorithm in the mathematical modeling software package MATLAB.
Chapter Eight - Experimental
198
BF3.OEt2 catalysed rearrangement of (S)-styrene oxide-a.-dl (H R)
(Hs)
I
I
D "HH I '.::: (R) h 0
~
dioxane
H
~ I
+
'.:::
"DH
(S)
0
h
4.8 (1)
4.7 (2)
H migration with retention of
H migration with inversion
configuration (1)
of configuration (2)
1.
54.5
45.5
2.
53.9
46.1
3.
53.5
46.5
Average
53.9
46.1
Reaction
BF3.OEt2 catalysed rearrangement of (R)-styrene oxide-a.-dl
(H R)
cr~~" I "::
(R)
h
4.6
H
BF3·OEt2 dioxane
,..
(Hs)
I
I
cfsi" c0i" I '.::: (S)
h
0
4.7 (1)
+
I '.::: (R)
h
0
4.8 (2)
H migration with retention
H migration with inversion
of configuration (1)
of configuration (2)
1.
47.8
52.2
2.
47.4
52.6
3.
49.5
50.5
Average
48.2
51.8
Reaction
199
Chapter Eight - Experimental
BF3.0Et2 catalysed rearrangement of (1S),(2R)-styrene oxide-~-dl (AD-a cis)
(Hs)
BF 3·OEt2 dioxane
.. c(lD I
4.13
~
0
(H R)
I
+
I
~H 0 I "" (R) ~
c0i I "" ~
+
H
(S)
0
4.18(1)
4.8 (2)
4.7 (3)
H migration
D migration (inv) Hs(retn)
D migration (retn) HR (inv)
a 2HNMR
~2HNMR
~ Hs IHNMR
~HRIHNMR
integral (1)
integral (2+3)
integral (2)
integral (3)
1.
70.9
29.1
failed to distinguish
failed to distinguish
2.
70.7
29.3
1
1.05
Reaction
BF3.0Et2 catalysed rearrangement of (IR),(2S)-styrene oxide-~-dl
(AD-~
(Hs)
o BF3·OEt2 dioxane
... c?~D ~ 0
I
4.18 (1)
4.14
H migration
I +
c0i I "" (R) ~
0
cis)
(H R)
I
H
+
4.8(2) D migration (retn) Hs (inv)
~H 0 I "" ~
(S)
4.7 (3) D migration (inv) HR (retn)
a 2HNMR
~2HNMR
~HSIHNMR
~HRIHNMR
integral (1)
integral (2+3)
integral (2)
integral (3)
1.
76.2
23.8
1
1.03
2.
73.2
26.8
1
1.08
3.
74.8
25.2
1
1.07
Average
74.7±3
25.3±3
1
1.06±0.02
Reaction
200
Chapter Eight - Experimental
BF3.0Et2 catalysed rearrangement of (1S),(2S)-styrene oxide-p-d1 (AD-a. trans) (Hs)
v
H"(~'D O
H
BF 3·OEt2
)Iloo
dioxane
I""
(+
~
I
~H +
OiHD
1
~
0
&i
(R)
""
4.18 (1)
4.15
1
H
(S)
""
~
0
0
4.7 (3)
4.8(2)
o migration (retn) HR (inv)
o migration (inv) Hs(retn)
H migration
Reaction
(H R)
I
a. 2HNMR
p2HNMR
PHs IHNMR
P HRIHNMR
integral (1)
integral (2+3)
integral (2)
integral (3)
60.9
39.1
1
1.35*
1.
BF3.0Et2 catalysed rearrangement of (1R),(2R)-styrene oxide-p-dl (AD-P trans)
(Hs)
oxr H
BF3·0Et2 dioxane
4.16
)Iloo
(HR)
I
H 0
+
O~" 1
""
~
(R)
0
I +
4.18 (1)
4.8 (2)
H migration
o migration (retn) Hs (inv)
&i" 1
""
(S)
~
0
4.7 (3)
o migration (inv) HR (retn)
a. 2HNMR
p2HNMR
PHS1HNMR
P HRIHNMR
integral (1)
integral (2+3)
integral (2)
integral (3)
1.
64.5
35.5
1.14
1
2.
64.5
35.5
1.07
1
3.
65.6
34.4
1.09
1
Average
64.9±3
35.1±3
1.lO±0.03
1
Reaction
201
Chapter Eight - Experimental
8.5
EXPERIMENTAL WORK DESCRIBED IN CHAPTER FIVE
Rearrangement of epoxides with LiCI04/benzene17 o
~ I ""
<:Hb
A
Ha
LiCI04 , t
=x hours
benzene, ~ 80°C
..
The epoxide (100 mg) in a solution of dry benzene (0.5 mL) was injected into a micro distillation apparatus equipped with a reflux condenser under nitrogen containing dry boiling benzene (4.5 mL) and LiCI04 (0.715 g). Aliquots were withdrawn at regular intervals (cooled to O°C) and the solvent removed under vacuum. The material was examined by lH and 2HNMR.
The LiCI04 was dried under vacuum for 48 hours at 160°C using a Gallenkamp heating apparatus. A separate boat of P20 S was used as the drying agent. For the reactions involving an added amount of either MCPBA or MCBA 0.018 g was used.
(±) Styrene oxide18
MCPBA chloroform,
5.14
ooc 5.13
To a solution ofm-chloroperbenzoic acid (MCPBA) (16.9 g, 0.098 mol) in analytical grade chloroform (110 mL) was added styrene (5.10 g, 0.049 mol). The solution was cooled to O°C, covered with tinfoil and stirred for 48 hours in the dark. The reaction mixture was then shaken and stored in the fridge with ice for a further 48 hours. After working up with 10% NaOH solution (600 mL) and H20 (600 mL), extracting with chloroform and drying
202
Chapter Eight - Experimental
over Na2S04 to give (±) styrene oxide (5.59 g, 95%). IH NMR (300 MHz, CDCh) 0 7.387.28 (m, 5H), 3.86 (dd, 2.93, 4.4 Hz, IH), 3.16 (dd, J = 4.4, 5.4 Hz, IH), 2.82 (dd, J = 2.93, 5.9 Hz, IH).
Styrene-trans-~-d/5
5.15
5.16
Phenylacetylene (4.0 g, 39.2 mmol) distilled from CaH2 was added slowly to aiM solution of diisobutylaluminium hydride (14.24 mL, 40 mmol) in CH2Ch (8 mL) under N2 at O°C and stirred at room temperature for 24 hours. D20 (2.0 mL) was slowly added and the mixture was stirred for and hour before extracting into pentane four times, filtering, and drying with MgS04. The solvent was removed under reduced pressure to give a clear yellow liquid (2.80 g, 68%). IH NMR spectroscopy showed 87% deuterium incorporation. IH NMR (300 MHz, CDCb) 0 7.50-7.17 (m, 5H), 6.72 (d, J
17.6 Hz, IH), 5.73 (d, J =
17.6 Hz, IH). 2H NMR (46 MHz, CHCh) 0 5.2 (s).
Phenylacetylene-l-d115
~H 5.15
1. EtMgBr ,..
2.D20 5.18
Phenylacetylene (11.63g, 113.9 mmol) distilled from CaH2 was added slowly to a filtered ether solution of EtMgBr (prepared from EtBr (8.75 mL) and Mg (3.0 g) in EhO (15 mL)) under nitrogen. After 10 hours at reflux, D20 (5 mL) was added. The mixture was extracted with pentane, dried over MgS04, filtered and concentrated. The product
203
Chapter Eight - Experimental
phenylacetylene~l~dl
(9.4 g, 80%) showed greater than 98% deuterium incorporation by
IH NMR as the terminal acetylenic resonance of the undeuterated compound could not be detected. IH NMR (300 MHz, CDCb) 8 7.36-7.13 (m, SH). 2H NMR (46 MHz, CHCh) 0 3.04 (s).
Styrene-cis-IJ-d115
Phenylacetylene-l-d1 (1.0 g, 9.69 mmol) was added slowly to aIM solution of diisobutylaluminium hydride (3.S6 mL, 20 mmol) in CH2Ch (20 mL) under N2 at O°C and stirred at room temperature for 24 hours. H20 (1.0 mL) was slowly added and the mixture was stirred for one hour before extracting into pentane four times, filtering, and drying with MgS04 • The solvent was removed under reduced pressure to give a clear yellow liquid (0.94 g, 92%). IH NMR spectroscopy showed 88% deuterium incorporation. IH NMR (SOO MHz, CDCh) 0 7.S1-7.16 (m, SH), 6.71 (d, J
11.2 Hz, 1H), 5.22 (d, J= 11.2
Hz,1H).
ill Styrene oxide-cis-lJ-d/8
~D ____M_C_P_BA__~••
V
5.19
chloroform, OoC 5.20
To a solution of m-chloroperbenzoic acid (MCPBA) (4.8 g, 0.03 mol) in chloroform (31 mL) was added styrene-cis-IJ-dj (1.44 g, 0.013 mol). The solution was cooled to O°C, covered with tinfoil and stirred for 48 hours in the dark. The reaction mixture was then shaken and stored in the fridge with ice for a further 48 hours. After working up with 10%
Chapter Eight - Experimental
204
NaOH solution (250 mL) and H20 (250 mL), extracting with chlorofonn and drying over Na2S04 to give (±) styrene oxide-cis-~-dl (1.43 g, 91 %). IH NMR spectroscopy showed 87% deuterium incorporation. IH NMR (500 MHz, CDCh) 8 7.35-7.29 (m. 5H), 3.86 (d, J 4.4 Hz, 1H), 3.13 (d, J
4.4 Hz, IH).
(±) Styrene oxide-trans-~-dl8
MCPBA
chloroform,OoC
5.17
5.16
To a solution of m-chloroperbenzoic acid (MCPBA) (2.63 g, 0.015 mol) in analytical grade chlorofonn (17 mL) was added
styrene-trans-~-dl
(0.8 g. 7.6 mmol). The solution was
cooled to OGC, covered with tinfoil and stirred for 48 hours in the dark. The reaction mixture was then shaken and stored in the fridge with ice for a further 48 hours. After working up with 10% NaOH solution (250 mL) and H20 (250 mL), extracting with chlorofonn and drying over Na2S04 to give (±) styrene oxide-trans-~-dl (0.70 g, 76%). IH NMR spectroscopy showed 80% deuterium incorporation. IH NMR (500 MHz, CDCb) 8 7.36-7.29 (m, 5H), 3.85 (d, J= 1.95 Hz, 1H), 2.80 (d, J
1.95 Hz, IH).
205
Chapter Eight - Experimental
8.6
EXPERIMENTAL WORK DESCRIBED IN CHAPTER SIX
Rearrangement of epoxides with LiCI04/ether
o
~ c""
i
""
i
//
,,·Hb Ha
6.1
LiCI04 (1.60 g) was added to dry ether (4 mL, 5 M solution) at room temperature. Epoxide (50 /-lL) was added and the solution left to stir for 0.5 - 48 hours at room temperature
(depending on specific reaction). The solution was washed with water, dried (MgS04) and the solvent was removed under reduced pressure. Formation of aldehyde was confirmed by IHNMR.
Analysis of rearrangement products
Reduction with LiAiH4 H(O) "H(O) "" '/H(O) IH::L. 4 I~. oii ---=L=-iA.::.;...
6l //
ether
--'I,... .
The crude reaction product from the LiCI04/ether catalysed rearrangement was dissolved in dry ether and LiAIH4 (15 mg) was added. The suspension was stirred under Ar for 3 hours and sat. NH4CI was added dropwise until the LiAIH4 residues formed a paste. The solution was dried (MgS04), filtered and the solvent was removed under reduced pressure.
206
Chapter Eight - Experimental
Esterification
~ H(D) ~
"H(D) , OH
I~
H H(D)
0;g:O
0r
~
pyridine
)110
N02
'N
I
~° ~
.
H(D) J'f-~ H(D)~ H(D)
V
The crude reaction mixture from the LiAIH4 reduction was dissolved in dry CH2Ch (4 mL), N-(4-nitrophenylsulfonyl)-I-phenylalanyl chloride (0.075 g, 0.20 mmol) and dry pyridine (24 JlL, 0.3 mmol) were added and the solution stirred at room temperature for 3 hours. The solution waS washed with HCI (2.5 mL, 1M), saturated Na2C03 (2.5 mL), dried over anhydrous Na2S04 and the solvent removed on a rotary evaporator. The product was purified by flash column chromatography on silica gel (ethyl acetate : petroleum ether).
NMR analysis with Yb(hfc)3 chiral shift reagent
Yb(hfc)3 was added portionwise to an NMR sample of 2-phenylethyl (N-4nitrophenylsulfonyl)-(S)-2-amino-3-phenylpropanoate in CDCb until the signals for the two protons
p- to the ester oxygen become resolved. The relative integral of the two peaks
was obtained using a curve-fitting algorithm in the mathematical modeling software package MATLAB.
Chapter Eight - Experimental
207
LiCIOJether catalysed rearrangement of (S)-styrene oxide-a.-d) (H R)
(Hs)
I
I
~ I ~
ether
H
D"'HH (R)
i
0
~
+
6.8 (1)
Reaction 5M (BATCH 1) LiCIOJether
1. t=2hr (61 % rearran ed 2. t=24hr 1 3. t=24hr 4. t=48hr 5. t=48hr Reaction 5M (BATCH 2) LiCI0 4/ether
1. t=0.5hr (65% rearranged) 2. t=2hr (100% rearranged) 3. t=24hr (100% rearranged)
~ ~
i
,.DH
(S)
'~
0
6.7 (2)
H migration with retention of configuration (1) 40.3 46.7 47.6 47.6 49.8
H migration with inversion of confi ration (2) 59.7 53.3 52.4 52.4 50.2
H migration with retention of configuration (1) 43.1 48.5 50.0
H migration with inversion of configuration (2) 56.9 51.5 50.0
LiCI04/ether catalysed rearrangement of (R)-styrene oxide-a.-d)
(H R)
(Hs)
I LiCI04 ether
6.6
Reaction 5M (BATCH 2) LiCIOJether
1. t=0.5hr (20% rearranged) 2. t=2hr (50% rearranged) 3. t=4hr (100% rearranged)
...
I ~. ~~H (S) (
~.
0
6.7 (1)
H migration with retention of configuration (1) 36.4 42.2 46.7
I
+
~H I '-':::. (R)
~
0
6.8 (2)
H migration with inversion of configuration (2) 63.6 57.8 53.3
208
Chapter Eight - Experimental
LiCIO,Jether catalysed rearrangement of (1S),(2R)-styrene oxide-p-d1 (AD-a. cis) (HS)
LiCI04 ether
..
6.13
n 1./
(H R)
I
1 "'" ~"
D
(R)
+
0
I
./
+
0
5M (BATCH 2)
1 "'"
(S)
./
0
6.18 (1)
6.8 (2)
6.7 (3)
H migration
o migration (inv)
o migration (retn) HR(inv)
Hs(retn)
Reaction
c0r"
a. 2HNMR
p2HNMR
PHs IHNMR
pHR1HNMR
integral (1)
integral (2+3)
integral (2)
integral (3)
72.7
27.3
fail ed to distinguish'
failed to distinguish'
LiCIOJether 1. t=24hr (100%
rearranged)
LiCIO,Jether catalysed rearrangement of (IR),(2S)-styrene oxide-p-d1 (AD-P cis) (Hs)
LiCI04 ether
,.. ~D 1./ 0
+
H migration
I
cr.i" c01" 1 "'"
(R)
./.
0
+
1 "'"
(S) (
./
0
6.8 (2)
6.18 (1)
6.14
(H R)
I
o migration (retn) Hs (inv)
6.7 (3)
o migration (inv) HR (rein)
Reaction
a. 2HNMR
p2HNMR
P HSIHNMR
pHR1HNMR
5M (BATCH 3) LiCIOJether
integral (1)
integral (2+3)
integral (2)
integral(3)
1. t=24hr (100% rearranged
72.7
27.3
1
1.20
2. t=24hr (100% rearranged
76.6
23.3
1
1.15
3. t=24hr (100% rearranged)
73.1
26.9
1
1.19
Average
74.1±5%
25.9±5%
1
1.18±0.03
209
Chapter Eight - Experimental
oxide-~-dl
LiCIO,Jether catalysed rearrangement of (1S),(2S)-styrene
(AD-a trans)
(Hs)
I
01" &i"
H,,~S)(S>,"D
I§
(1tiH
'§
0
I
+
6.18 (1)
6.15
(R)
(HR)
I ~H § 0 ~ (8)
+
0
6.8 (2)
6.7 (3)
o
o
H migration
Reaction
~
§
I
migration (retn) HR (inv)
migration (inv) Hs(retn)
a, 2HNMR
~2HNMR
~ Hs IHNMR
~HRIHNMR
integral (1)
integral (2+3)
integral (2)
integral (3)
64.7
35.5
1.19+
1
•
5M (BATCH 2) LiCIOJether
I
L t=24hr (100% rearranged)
oxide-~-dl (AD-~ trans)
LiCIO,Jether catalysed rearrangement of (IR),(2R)-styrene
(Hs)
(H R)
I
Cil c01" c?1" H
ether
6.16
§
H 0
0
+
I ~ (~) (H § 0
i
6.8 (2)
H migration
o migration (retn)
1. t=2hr (8% rearranged) 2. t=3hr (8% rearranged) 3. t=6hr (12% rearranged)
a,2HNMR integral (1) 72.2 49.9 86.2
i
4. t=8hr (100% rearranged) 5. t=24hr (100% rearranged) 6. t=48hr (100% rearranged) Average
65.9 67.6 67.1 66.9+5%
5M (BATCH 3) LiCIOJether
+
6.18 (1)
Hs (inv)
Reaction
I
2HNMR tegral (2+3) 27.8 50.1 13.8
I
34.1 32.3 32.9 33.1+5%
I ~ (;) (H § 0 6.7 (3)
D migration (inv) HR (retn)
~ HSIHNMR integral (2)
~HRIHNMR
failed to distinguish
failed to distinguish
failed to distinguish
failed to distinguish
failed to distinguish
failed to distinguish
1.23 1.20 1.23 1.22+0.02
1 1
integral(3)
1 1
Chapter Eight - Experimental
210
Still, W. C.; Kahn, M.; Mitra A J. Org. Chem. 1978,43,2923. Armarego, W. L. F.; Perrin, D. D. Purification ofLaboratory Chemicals, Butterworth-Heinemann, Oxford, 1997, 4th edition. 3 Gerlach, H.; Zagalak, B. Chem. Commun. 1973,274. 4 Miyashita, M.; Yoshikoshi, A; Grieco, P. A J. Org. Chem. 1977,42,3772. 5 Sterzycki, R. S. Synthesis. 1979,724. nd 6 Hudlicky, M. Reductions in Organic Chemistry, ACS Monograph, Oxford, 1996, 2 edition. 7 Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A; Hartung, J.; Jeong, K.; Kwong, H.; Morikawa, K.; Wang, Z.; Xu, D.; Zhang, X. J. Org. Chem. 1992,57,2768. 8 Moussou, P.; Archelas, A; Baratti, J.; Furstoss, R J. Org. Chem. 1998, 63,3532. th 9 Morrison and Boyd. Organic Chemistry, 5 edition. 10 Johnson, M. R; Rickborn B. J. Org. Chem. 1970,35,1041. 11 Organic Synthesis Collective, 3, 312. 12 Hartmuth, C. K.; Sharpless, K. B. Tetrahedron, 1992, 48,10515. 13 Dupin, C.; Dupin, J. F. Bull. Soc. Chim. Fr. 1970,244. 14 Parinello, G.; Stille, J. K. J. Am. Chem. Soc. 1987, 109, 7122. 15 Wood, J. T.; Arney, J. S.; Cortes, D.; Berson, J. A J. Am. Chem. Soc. 1978, 100,3855. 16 Nelson, J. E.; Parkin G.; Bercaw, J. E. Organometallics. 1992, 11, 2181. 17 Rickborn, B.; Gerkin, R J. J. Am. Chem. Soc. 1971,93, 1693. 18 Organic Synthesis Collective, 1,496. 1
2
Appendix A An Example Calculatioll of the Conformers in a BF3.0Et2 Rearrangement Reaction
212
Appendix A
APPENDIX A
Calculation and analysis for: Cis-~-deuterated
styrene oxide rearranged with BF3.OEt2 0
0
0
I ":: ~-;<" crRi<"
. "::. (R) H ~H I ~.
I "::
D
(R)
0%
91.8%
3.5%
BF3 .OEt2 ..,. dioxane
H
~
~
4.7%
(R)
Rearrangement products Hs
HR
I
c«iH c«i0 c«i" OXlOH I~
0
+
I~
0
(8)
(A)
Und euterated
+
H-migration
I~
0
I
+
6
I~.
(C) D migration (retn) Hs (inv)
1
,~
(D)
D migration (inv) HR (retn)
Experimental results Reaction
a 2HNMR
~2HNMR
1. 2. 3. Average
integral (B) 76.2 73.2 74.8 74.7
integral (C+D) 23.8 26.8 25.2 25.3
~ HSIHNMR integral (A+B+D) I 1 1 1
~HRIHNMR integral (A+B+C) 1.03 1.08 1.07 1.06
Calculations
It is necessary to adjust for the prescence ofundeuterated epoxide (4.7%) and the isomeric
trans deuterated epoxide (3.5%) in the mixture to establish the detail of the reaction for pure cis-~-deuterated styrene oxide.
The deuterium spectra give the ratio
Appendix A
213
B C+ D
74.7 25.3
= 2.95
representing 95.3% of the reaction product and A + B + C = 1 and A + B +D 1.06
(where B = CDO measured: C
Deuterium migration with retention: D = Deuterium
migration with inversion).
C + D as % = 25.3
* (91.8 + 3.5) /100 = 24.10%
SoB%= 74.7
C +D
- - - = 2.95 25.3
* (C +D)% = 2.95 * 24.1 0%
B = 2.95
= 71.14% and since A+B+D= 1.06 A+B+C=1 A+B+D A+B+C
1.06 1
[1.06](A +B + C) = A +B + D [1.06] (4.7 + 71.14 + C) 4.98 + 75.41 + 1.06C
4.7 + 71.14 + 24.10 - C 99.94 - C
2.06C = 99.94 - 80.39 => C=9.49%
=>
D= 24.10- C D = 24.10 - 9.49 D = 14.61%
These contain products from the 3.5% of trans epoxide in the calculated ratio (calculated above),
214
Appendix A
therefore B from pure cis-p-deuterated styrene oxide
and C = 9.49 - 0.79
71.14 - 2.21
68.93%
8.70%
D = 14.61 - 0.41 = 14.20%
and this from 91.83% of the starting epoxide mixture. Correcting this to 100% pure cis-pdeuterated styrene oxide gives
B =75.1%
C=9.5% D= 15.4%
AppendtxA
215
Calculation and analysis for: Trans-~-deuterated
styrene oxide rearranged with BF3.0Et2
o
crR)~~
BF3 .OEt2 ,... dioxane
3.7%
0%
4.9%
91.5%
Rearrangement products
O1H .
I
+
0
~
crY I~
D
0
+
(8)
(A) Undeuterated
H-migration
cn
Hs
HH(
I~
0
~
HR
I
I
+
c?1
D migration (retn) Hs (inv)
0
~
(C)
H
(0) D migration (inv) HR (retn)
Experimental results Reaction
a 2HNMR
~2HNMR
1. 2. 3. Average
integral (B) 64.5 64.5 65.6 64.9
integral (C+D) 35.5 35.5 34.4 35.1
~ HSIHNMR integral (A+B+D) 1.14 1.07 1.09 1.10
~HRIHNMR
integral (A+B+C) 1 1 1 1
Calculations
It is necessary to adjust for the prescence of undeuterated epoxide (3.7%) and the isomeric
cis deuterated epoxide (4.9%) in the mixture to establish the detail of the reaction for pure trans-f3-deuterated styrene oxide.
The deuterium spectra give the ratio B C +D
64.9 35.1
=
1.849
representing 96.3% ofthe reaction product
Appendix A
216
and A + B + C = 1.14 and A + B +D = 1
(where B = CDO measured: C
Deuterium migration with retention: D
=
Deuterium
migration with inversion).
C + D as % = 35.1
* (91.47 + 4.87) / 100 = 33.82%
SoB%= ~
C +D
64.9 35.1
- - - = 1.849
B = 1.849 * (C +D)% = 1.849 * 33.82% =62.52% and since A+B+D=l A+B+C=1.14 A+B+D A+B+C
1 1.14
[1. 14](A +B + D) = A +B + C [1.14] (3.66 + 62.52 + 33.82 - C) = 3.66 + 62.52 + C 4.1724 + 71.2728 + 38.5548 - 1.14C = 66.18 + C 2.14C = 47.82
=>
C = 22.35% D = 33.82 - C D = 33.82 - 22.35
=>
D= 11.47%
These contain products from the 4.87% of cis epoxide in the calculated ratio (calculated above),
therefore B from pure trans-~-deuterated styrene oxide
62.52
3.46 = 59.055%
Appendix A
217
and C = 22.35 - 0.462
D=11.47-0.7115
21.888%
10.758%
and this from 91.701 % of the starting epoxide mixture. Correcting this to 100% pure cis-pdeuterated styrene oxide gives
B =64.4% C=23.9% D = 11.7%
AppendixB An Example of a Fujimoto Calculation in a BF3.0Et2 Rearrangement Reaction
AppendixB
219
APPENDIXB
(1+4)/(2+3)=if1-10D=3.00
2=10 3=15 1+4=75 cis-d-epoxide
cis D migrates 15/10 inv.!retn.
24%
(For cis) assume D/C
(from trans ratio) when H. (As can see using D)
=2.00
12%
2.00 3.00
D
A
(
15z
75*(2.00/3.00)
75*(1/3.00)
(4)
(3)
(1 )
H Retn
D Iny
H Iny
migration process:
lOz
D
Hmign(reln)
C
Hmign(inv)
~
(2) D Reln
(2+3)/(1+4)=if1-10D=1.78
1=12 4=24
2+3=64 trans-d-epoxide
trans D migrates 24/12 retn.!inv.
(For trans) assume CID =
-15% 10%
= 1.57
A
( 24z migration process:
1.50 2.50
(from cis ralio) when Hb= D (As can see using D)
64*(1.5012.50) : 12z : 64*(112.50)
(4)
(3)
(1)
D Reln
H Iny
D 1nv
(2) H Retn
C D
~
Hmign(reln) Hmign(inv)
220
AppendtxB
/K A mathematical matrices constant used to solve z
K 15 z
cis
trans
50 15 z 25 lOz
24z 38 12 z 26
38
and 50K= 24 z
24 z
K
50 24 z \ (
15 z
=
38
50 /
360:C= 1900
z
=
2.3
z is a deuterium isotope parameter- the amount deuterium migration is retarded relative to hydrogen migration
I
substituting in z gives:
(4) [ (3) (1) (2)
50 35 25 23
converted to %
(kDHlkHD)
221
AppendixB
Retention
t
64%
cr H
I
~H
.. yH. H
~•
h-.
t
36%
Va
0
Inversion
