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Epoxidation using dioxiranesEpoxidation using dioxiranes
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Pilklngton Library
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26 JUN 1998
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Loughborough University of Technology Department of Chemistry
Epoxidation Using Dioxiranes
By
Lesley Walton.
A Doctoral Thesis.
Submitted In Partial Fulfilment Of The Requirements For The Award Of Doctor Of Philosophy Of The
Loughborough University Of Technology.
Supervisor: Professor BA Marples.
© L. Walton. August 1996
This thesis is dedicated in loving memory to my grandparents
Bert and Lily
and
To my mother Joan and sister Janet with love.
Abstract
Chapter 1 contains a brief review of the historical background of dioxiranes
and an outline of their more recent chemistry.
The preparation of homochiral 2-fluoro-2-substituted-1-tetralones and ethyl
2-fluoro-1-indanone-2-carboxylate is described in Chapter 2 and the X-ray
crystal structure of (1' R,2' R,5' R)-( -)-menthyl 2S-fluoro-1-tetralone-2-
carboxylate presented. The synthesis of racemic 2,5,7 -trifluoro-1-indanone-2-
carboxylate is also discussed.
The dioxirane derivatives of the above ketones have been prepared in situ
and have been shown to epoxidise trans-stilbene, trans-~-methylstyrene and
6-chloro-2,2-dimethyl-2H-1-benzopyran, but not enantioselectively. The
individual results of these epoxidations are given in Chapter 3. The
incorporation of fluorine into the aromatic ring of aryl alkyl ketones is shown to
increase dioxirane reactivity.
Chapter 4 briefly describes the reactions carried out in order to ascertain the
optimum conditions for the epoxidation of alkenes by in situ derived
dioxiranes. The rate of this oxidation was shown to be highly dependent on
the concentration of the dioxirane in the organic phase.
Described in Chapter 5 are the procedures used for the isolation of the
dioxirane derivatives of dimethyldioxirane, 1,1, 1-trifluoroacetone, 2,2,2-
trifluoroacetophenone, hexafluoroacetone and cyclohexanone, in solutions of
the corresponding ketone with or without dichloromethane.
Contents
Acknowledgements. I - 11
11 Abbreviations. III
III Introduction ..
Chapter 1. Review of dioxirane chemistry.
1.1 A brief historical note.
1.2 Preparation of dioxiranes.
1.3 Oxygen atom transfer by dioxiranes.
1.3.1 Epoxidation reactions.
1.3.2 Asymmetric epoxidations.
1.3.3 Epoxidation of allenes.
1 - 39
1
4
7
8
11
12
1.3.4 Table 1: Recent epoxidation reactions. 13
·1.3.5 Oxidation of carbon - hydrogen bonds using dioxiranes. 20
1.3.6 Table 2: Oxidation of carbon - hydrogen bonds. 21
1.3.7 Oxidations of organic sulfur, silicon, selenium and
nitrogen containing substrates. 25
1.3.8 Table 3: Oxidations of organic sulfur, silicon, selenium
and nitrogen containing substrates. 26
1.3.9 Oxidations of metal enolates and metal complexes. 31
1.3.10 Table 4: Oxidation of metal enolates and metal
complexes. 31
1.4 Other aspects of dioxirane reactivity. 33
1.4.1 Effect of solvent on reactions. 33
1.4.2 Electrophilic character I Mode of oxygen transfer. 34
1.4.3 Decomposition of dioxiranes. 35
1.4.4 Carbonyl oxides and dioxiranes. 36
IV Results and Discussion
Chapter 2. Epoxidation of alkenes using homochiral
dioxiranes.
2.1 Introduction to the Project.
2.2 Synthesis of the 1-tetralone and
40 - 57
40
1-indanone derivatives. 41
2.2.1 Synthesis of the 2,2-disubstituted tetralones. 42
Synthesis of ethyI1-tetralone-2-carboxylate. 43 Synthesis of methyI1-tetralone-2-carboxylate. 44 Synthesis of menthyI1-tetralone-2-carboxylate. 44
2.2.2 Fluorination of the alkyl 1-tetralone-2-carboxylates. 47
2.3 Separation of the diastereomers of menthyl 2-fluoro-1-
tetralone-2-carboxylate 48
2.4 Separation of the enantiomers of the tetralone derivatives
(31c) and (34) via an imine derivative. 50
Separation of the ester derivative. 50 Separation of the tertiary alcohol derivative. 51
2.5 Synthesis of the ethyl 2-fluoro-1-indanone-2-carboxylate. 51
2.6 Separation of the enantiomers of the 1-indanone derivative
via an imine derivative. 52
2.7 Synthesis of methyl 2,5,7 -trifluoro-1-indanone-2-carboxylate. 53
2.8 Synthesis of 1 S-methoxy-1 S-phenylacetone. 58
Chapter 3. Dioxirane Reactions. 59 - 62
3.1 Use of the 1-tetralone and 1-indanone dioxirane derivatives
in the oxidation of alkenes.
3.2 Results of the epoxidations.
59
59
Chapter 4. Optimizing conditions. 63 - 68
4.1 Optimizing the conditions of the dioxirane epoxidation
reaction. 63
v
VI
VII
Chapter 5. Isolation of dioxiranes in solution.
5.1 Preparation of solutions of dioxiranes.
5.2 Determination of the molarity of a dioxirane solution by
titration.
Conclusion.
Experimental.
Chapter 2, Experimental.
Chapter 3, Experimental.
Chapter 4, Experimental.
Chapter 5, Experimental.
References.
69 -71
69
69
72
73 -132
73
115
117
119
133 -144
Acknowledgements
This research was carried out at Loughborough University of Technology
during the period 1st November 1991 to 31st October 1994 in collaboration
with Smith Kline Beecham Pharmaceuticals, New Frontiers Science Park,
Third Avenue, Harlow, Essex.
I would like to thank the following:
Smith Kline Beecham and Professor BA Marples for funding the work.
Professor BA Marples for his invaluable supervision and guidance
throughout this work at Loughborough.
Professor Curci for allowing me to work within his laboratory in Bari and for
his much needed advice. Also his research group, Caterina, Lucia, Teresa,
Anna and Michele for their help friendship and support during my month in
Bari.
Dr. P. Smith for his help and supervision at Smith Kline Beecham and his
useful discussions over the past three years.
Mr. G. Freer and Dr. G. Taylor and their colleges at the New Frontiers
Science Park for their help and friendship during my two months at
SmithKline Beecham.
Smith Kline Beecham for running some mass spectra and high field NMR
spectra.
Dr. D.S. Brown for his X-ray crystallography work.
The following technical staff at Loughborough: Mr. Alastair Daley and Mr. Paul Hartopp for their help and daily running of the
research laboratory. Mr. John Kershaw for assistance with GLC experiments, running of high field
NMR spectra and his invaluable friendship and support.
Mr. John Greenfield for running mass spectra.
Mr. Alastair Daley for running microanalysis experiments.
I wish to thank the following for their friendship and help at Loughborough:
Tracey Ross, Gabrielle Loftus, Vicki Waddington, Mark Elliot, Bob and Violeta
Marmon, Sue Toh, Gi Cheung, Craig Baldwin, Jon Eddols, Dave Riddock,
Chris Frost, Jon Roffey, Dave Miller, Dave Price, Hank Cheung, Noeleen
O'Sullivan, Liz Swann, Dave Corser and all the other members of organic
research past and present 1991 -1994.
I would like to thank the following for their friendship and moral support:
Lesley Reid, Vicky Hardman and Micheal Brown, Cherry and Ken Ross,
Steve and Glenda Rooney, Penny Muncie, Jenny Glass, Julia Gunby, Andrea
Banham and Ron Mc Keating.
I extend my thanks and admiration to my mother for her constant support
throughout my endeavours.
11
IR.
NMR.
MS.
ppm.
8. Hz.
J. TLC.
Rf·
GLC.
THF.
HCI.
OCM.
HMPA.
TBAHS.
Oxone®.
EOTA.Na2·
LOA.
Eu(hfch
aq.
lit.
Me.
Et.
Men.
bpt.
mpt.
ee.
eq.
Abbreviations
Infrared. Nuclear Magnetic Resonance.
Mass Spectrometry.
Parts Per Million.
Chemical Shift.
Hertz.
Coupling Constant.
Thin Layer Chromatography.
Retention Factor.
Gas Liquid Chromatography.
Tetrohydrofuran.
Hydrochloric acid.
Dichloromethane.
Hexamethylphosphoramide.
Tetrabutylammonium hydrogen sulfate.
Potassium peroxymonosulphate
(2KHS05 .KHS04.K2SO), Aldrich Chemical
Company.
Ethylenediaminetetraacetic acid disodium salt.
Lithium diisopropyl amide.
Europium D-3-heptafluorobutyrylcamphorate.
Aqueous.
Literature.
Methyl.
Ethyl.
J.Menthyl.
Boiling Point.
Melting Point.
Enantiomeric Excess.
Equivalents.
III
Chapter 1
Chapter 1.
Review of Dioxirane Chemistry.
1.1 A Brief Historical Note
Dioxiranes (1) represent the class of most strained cyclic, organic
peroxides, comprising one carbon and two oxygen atoms in a three
membered ring.
The first literature reference to a dioxirane (1) was made by Baeyer and
Villiger,1 in 1899, in a publication describing a reaction which today bears
their names. They suggested that a dioxirane was the intermediate involved
in the conversion of the cyclic ketone, menthone, to its lactone by
monoperoxysulfuric acid. This theory later lost out to a competing
mechanism, primarily as a result of an 180 study by Doering and Dorfman.2
Recent work by Rozen et a1' on the complex HOF.CH3CN has revived the
theory proposed by Baeyer and Villiger. 1 Using 180 labelled reagent, it was
found that ketone oxidation, using the HOF.CH3CN reagent, proceeds
through the original dioxirane mechanism (Scheme 1).
-- +
Scheme 1: Conversion of a ketone to a lactone using HOF.CH3CN.
The first apparent report of the preparation of a dioxirane is contained in a
1
1972 patent. 4 The authors claim to have isolated perfluorodimethyldioxirane
(3) by low-temperature gas chromatography (Scheme 2). The dioxirane was
synthesised by fluorine oxidation of the precursor dialkoxide (2).
(2)
Fluorine Oxidation ..
(3)
Scheme 2: Dioxirane (3) synthesis by fluorine oxidation of the precursor dialkoxide (2).
It was Montgomery,5 in 1974, who first observed that certain ketones
enhanced the rate of decomposition of monoperoxysulphuric acid. He also
noted that a number of oxidation reactions of caroate were catalysed by the
presence of ketones. From these observations he proposed that the
monoperoxysulphate anion (5) adds to the ketone (4) to give the adduct (6).
Since a variety of ketones enhanced the rate, he suggested that the adduct
(6) further reacted to give the dioxirane (1). He did not, however, propose that
the dioxirane was acting as the oxidant. As Montgomery worked using a
slightly alkaline medium, as opposed"to the acidic conditions of the Baeyer
Villiger reaction,1 he revived the idea that dioxiranes could be involved in
these reactions.
Edwards, Curci and co_workers6.7 ,8,9,1o,11 have since carried out kinetic
studies and 180-labelling experiments which have presented strong evidence
for the presence of dioxiranes in the ketone I caroate system. Their work also
showed that dioxirane itself was a very powerful oxidant. The reactions were
performed in an aqueous medium containing the ketone, Oxone® (caroate)
and the substrate. For efficient oxidation, the pH was strictly controlled at pH
7.5. At this pH, Edwards and co-workers6 noted that with most ketones, there
was little or no competition from the Baeyer-Villiger reaction.1 From this work
they postulated the mechanism of dioxirane formation and decomposition
(Figure 1).6
2
Figure 1:
Mechanism of Dioxirane Fonnation and Decompositions
5: + so ... --+ so
BV = Baeyer-Villiger pathway
1- 50;
R 0
RXL (1)
-oosoi .. R2C=0 + 0-0
R2C=O + 0-0
+ 50;-
A recent paper by Armstrong et al,12 discusses their 180 labelling study of
dioxirane epoxidation reactions. Their results lead them to conclude "that a
dioxirane intermediate is probably not responsible for alkene epoxidation in a
ketone-accelerated axone" epoxidation system" (Scheme 3). These workers
assumed that the addition of KHSOs to the carbonyl group is non
stereoselective and that either of the diastereotopic oxygen atoms is
geometrically capable of being transferred to the alkene. This being the case,
the resulting dioxirane intermediate would result in 50% label incorporation
into the epoxide. However, no such label was observed in the product (8).
They also noted that this in situ'system only gave the syn-isomer (8), whereas
epoxidation with isolated dimethyldioxirane (9) afforded a mixture of syn- and
anti-isomers.
3
Scheme 3: Epoxidation of the ketone (7) using the biphasic Oxone® system. i = Oxone®, Bu.NHSO., EDTA.Na2, aqueous NaHC03, CH2Cb, O°C to room temperature.
180 180
• 0
(7) (8)
t 180-0
16118 0
6 • 0 '6118
They postulated that the tetrahedral species (6) resulting from the addition
of HSOs- to the carbonyl group is capable of alkene epoxidation, and this
epoxidation reaction is faster than ring closure to the dioxirane.
1.2 Preparation of Dioxiranes
In 1985, Murray and Jeyaraman '3 prepared solutions of dioxiranes in their
parent ketones. They used these solutions to carry out a variety of
synthetically useful reactions.
In 1988, Curci et a/14 published the synthesis and characterisation of
methyl(trifluoromethyl)dioxirane from 1,1, 1-trifluoropropanone and potassium
peroxymonosulfate. They reported concentrations of the dioxirane in the
parent ketone ranging from 0.65 - 0.82 M. Despite the oxidising properties of
methyl(trifluoromethyl)dioxirane, its use has been somewhat restricted due to
a problem in its preparation. Some commercially available batches of 1,1,1-
trifluoropropanone failed to produce the dioxirane when treated with Oxone®
4
under the conditions described by the aforementioned workers.14 Recent
studies have shown this to be due to the presence of diethyl ether. This
impurity induces the decomposition of the dioxirane in a concentration
dependent manner.15
In 1991 Adam and co-workers 16 published a simple procedure for the
preparation of dimethyldioxirane (9) in its parent ketone (Scheme 4). The
method involved the addition of solid Oxone® (caroate), in five portions, at
three minute intervals, to a vigorously stirred solution of water, acetone and
sodium hydrogen carbonate at low temperature. After three minutes from the
last addition, the cooling was removed and a slight vacuum applied. The
dimethyldioxirane (9) in acetone was then distilled into a cooled (-78°C)
receiving flask. Concentrations of up to 0.1 M were reported.
Me
Oxone ® 5 - 10°C
pH 7.4
Scheme 4: Preparation of Dimethyldioxirane (9).
)=0 Me
In 1992, Murray, Singh and Jeyaraman 17 published a method which they
had developed to prepare solutions of less volatile dioxiranes, e.g. the
dioxirane derivative of cyclohexanone. This method involved the rapid
addition of cooled Oxone® to a solution of cooled ketone, phosphate buffer
and ice. The pH was regulated by the addition of potassium hydroxide
solution. After stirring the solution for three minutes, the dioxirane I ketone
mixture was "salted out" from the aqueous layer. The two layers were then
separable, yielding a solution of the dioxirane in its ketone. Concentrations of
0.65 - O.82M were reported.
Difluorodioxirane (10), apparently the first dioxirane stable in the gas
phase at room temperature, was synthesised and characterised by Russo
and DesMarteau in 1993.18 The synthesis involved the formation of the anion
5
FOCFZO- by nucleophilic attack of fluoride ion on the unstable FC(O)OF
molecule followed by its oxidation using CIF (Scheme 5). This dioxirane is
reputed to be the most reactive of all dioxiranes.
Scheme 5: The proposed, electron transfer, mechanism for the formation of difluorodioxirane. Xz = Clz, CIF, Fz.
0 F o- F O· F)lO/F
CsF X2 .. FXO-F
.. X F O-F
~ F 0 F 0
X2 +F- + XI • XI + x"2- + F F 0 F 0
(10)
In order to confirm the actual structure of difluorodioxirane (10), Burger et
aP9 carried out a detailed study of its high resolution mid-infrared FT
spectrum. Their results corroborate, unambiguously, the previously proposed
symmetrical dioxirane structure for this molecule (Figure 2).
131.5 pm",\ (1~.9 pm
F~J I
" .' /CS 157.6pm
F 109.050 0
Figure 2: The molecular structure and present best estimate of structural parameters of difluorodioxirane, as determined from its i.r. spectrum.
At the beginning of 1994, Jones et a/ published a novel procedure for the
preparation of dimethyldioxirane (9) from neutralised Care's acid, at ambient
temperatures. 20 The important aspects of the process were that Caro's acid
was partially neutralised to below a pH of 2, in order to minimise
6
peroxymonosulfate losses and to avoid a raised H20 2 content. The second
neutralisation stage was carried out using NaHC03 buffer solutions. Their
procedure allowed dimethyldioxirane to be prepared in situ and ex situ,
as appropriate. They recorded ex situdimethyldioxirane concentrations of
0.12 M.
In 1994 dimesityldioxirane (12) was isolated at room temperature in both
solution and pure form. This is the first dioxirane to be isolated as a solid and
in a pure form. Sander et ar synthesised this dioxirane by irradiation of its
diazo derivative (11) in CFCI3 at 183K. The best yield was 50% on irradiation
with A. > 495 nm and up to 10 mg of dioxirane could be obtained in a single
run.
k hv Q-
c,. kp hv ~
~C-N' --- ~C' --- ~=' --- ~d °2 'I ' ° --
(11 ) (12)
Scheme 6: Synthesis of dimesityldioxirane (12).
1.3 Oxygen Atom Transfer By Dioxiranes
Dioxirane chemistry has rapidly expanded in recent years and there are
now several publications which comprehensively review the area.22 Since the
most recent review in 1995,229 literature has continued to appear which
describes the ever increasing uses of these molecules. The remaining part of
this Introduction is dedicated to the chemistry of dioxiranes. Tables 1 - 4
(Pages 13 to 32) represent some of the chemistry which has recently
emerged using these oxidants.
7
1.3.1 Epoxidation Reactions of Dioxiranes
The most widely studied dioxirane in epoxidations has been
dimethyldioxirane (9). It has been shown to rapidly epoxidize alkenes in high
yields.6-11,13,23,24 Baumstark and McCloskey composed a relative reactivity
series for the epoxidation of alkenes using this reagent. 23 This work showed
the reaction to be particularly sensitive to steric factors and suggested the
involvement of a spirotransition state (Figure 3).
Figure 3: Spirotransition state for the epoxidation of alkenes by dioxiranes.
In addition to steric interactions, solvent effects are thought to play a major
role. 13,25 The presence of water has been shown to increase the rate of these
epoxidations (et Section 1.4.1).24
Scheme 7.' In situ preparation of dioxiranes.
® Oxone
Phosphate Buffer
pH7,~.
EDTA.Na2 KOH
2 _ScC
Oxone® = caroate = potassium peroxymonosulphate
+
PTC = [Me(CH2h14NHS04 = tetrabutyl ammonium hydrogen sulphate
Edwards et af have shown that their in situ method of preparing
8
dioxiranes can be used to carry out a number of O-atom transfer reactions.
They demonstrated that olefins were epoxidized in a syn stereospecific
manner and in high yield. This work was extended to water-insoluble 0lefins7
by the use of a phase transfer catalyst (Scheme 7).
Denmark26 has recently looked at optimizing the conditions of the dioxirane
epoxidation reaction. He found that many of the key experimental variables in
the biphasic system are interdependent, and therefore found he was unable
to systematically examine all permutations. The results of his findings are
listed:
• The stoichiometry of the ketone has a dramatic effect on the overall
oxidation.
• The rate of Oxone® addition affects the reaction. Slower addition rates,
while maintaing a pH between 7.8 and 8.0, led to more efficient
conversions to the epoxide.
• Oxidation continues long after the addition of Oxone® is complete.
• The rate of dioxirane formation exhibited strong pH dependence, with a
maximum at pH 7.5 - 8.0. Oxidation rates were different at different pH,
and decrease in the order 8.0 > 7.8 > 7.5. The slower rate but complete
oxidation at lower pH has practical consequences for slow reacting
substrates because of the slower rate of Oxone® consumption at pH 7.5.
• The rate of oxidation increased with increasing olefin substitution: tetra>
tri > di > mono and isolated olefin reacted faster than conjugated alkenes
and allylic alcohols.
The ability of the ketone to serve as a promoter for epoxidation involves two
crucial features:
• the ability to efficiently form a dioxirane.
9
• the ability to efficiently transfer the oxygen to the substrate.
The effect of the ketone structure:
• a-substitution in acyclic ketones significantly decreased epoxidising
efficiency.
• Steric congestion about the carbonyl carbon decreased the rate of
oxidation.
• Employment of electronically activated ketones increased the rate of
oxidation, provided the ketones were not too hydrophilic.
• Oxidation efficiency was strongly ring size dependent for cyclic ketones.
The trend was explained in terms of the facility of rehybridisation of the
carbonyl carbon (Sp2 to Sp3) and the eclipsing interactions with the a
methylenes.
• Amalgamation of the carbonyl precurser of the dioxirane with the
ammonium function of the phase transfer catalyst, unless sterically
hindering, had a profound beneficial effect on the efficiency of oxidation.
• The nature of a counterion (in ketones containing a quaternary nitrogen)
greatly influenced the rate of oxidation: SF 4- > CF3S03- > N03- > CI04- (at
pH 7.S); pH was also noted to effect this influence.
• Increasing the lipophilicity of a salt was crucial for successful oxidation.
Chain length, not just carbon count, was important.
Their results confirmed the results of Edwards and Curci.6-11
The standard oxidation protocol selected by Denmark et a/ 26 consisted of :
• 10 equivalents of Oxone® (S hour addition),
• 2 equivalents of ketone,
10
• 0.1 equivalent of phase transfer catalyst,
• 24 hour reaction time I 0 QC I pH 7.8
The best catalysts under biphasic conditions were found to be 4-
oxopiperidinium salts.
1.3.2 Asymmetric Epoxidation
The first report of asymmetric epoxidation using chiral dioxiranes was
published by Curci and co-workers. 10 They reported that chiral ketones can
be converted to dioxiranes by caroate. These dioxiranes reacted with
prochiral alkenes to give epoxides with enantiomeric excesses in the 9-
12.5% range. Such enantioselectivities are superior to those given by
standard reagents, such as (+)-monoperoxycamphoric acid. The optically
active parent ketone can be recovered unchanged at the end of the reaction,
hence the reaction is catalytic rather than stoichiometric. Curci has continued
to study this area of dioxirane chemistry.27 He reports asymmetric epoxidation
of the prochiral alkenes, trans-p-methylstyrene, trans-2-octene and cis-2-
methyl-2-octadecene, of 12 - 20% using (+ )-3-(trifluoroacetyl)camphor, or
R( +)- and S( -)-3-methoxy-3-phenyl-4,4,4-trifluorobutan-2-one (13) as
precursors for chiral dioxiranes generated in situ. He also reports that the
adoption of chiral ketones carrying electron-withdrawing groups as dioxirane
precursors was advantageous as far as reaction times and yields. These
results are in agreement with those previously found within this
Department.154 In the same publication he has suggested that the structure of
the chiral dioxirane oxidant and of the prochiral alkene have little influence on
the enantioselectivity. In this, dioxiranes resemble other non-metal
asymmetric epoxidising agents, relying solely on non-bonded interactions in
the transition state to achieve enantiofacial selectivity. An additional limitation
that arises with dioxiranes, is that the seemingly diastereotopic oxygens are
both available for oxygen transfer. However, given a preferential geometry of
11
approach (e.g. spiro orientation) and certain steric interactions, the chiral
recognition would still have to take place via one of four diastereotopic
transition states (Figure 4).
Figure 4: The four diastereomeric transition states for the epoxidation of trans-f3-methylstyrene by R-(13)
The work in this thesis is largely concerned with the use of homochiral 2-
fluoro-2-substituted-1-tetralones and -Hndanones in asymmetric
epoxidations. Some of this work has recently been published.28
1.3.3 Epoxidation of Allenes
Crandall et a/have shown that dimethyldioxirane provides access to the
fragile diepoxides of allenes.29 They have further examined its oxidation of
allenes bearing nucleophilic groups and have reported the formation of highly
functionalised oxygen heterocycles derived from cyclisation of the
intermediate mono- and di- epoxides. 3O They have now studied the oxidative
cyclisations of allenic aldehydes (Table 1, Entry 24)51 and allenic
sulfonamides (Table 1, Entry 25),52 and report a novel and efficient route to
highly functionalised heterocyclic systems.
12
1.3.4 Table 1: Recent Epoxidatlon Reactions
Entry Substrate Dioxirane31 Method32 Products No. Yield (%1
Ref.
o&=>
c")<l !'.
1 A ~ 4~,5Il-epoxide(-15%) 33
CH:; 0 4Cl.5a-epoxide (-5%) o (80%)
!'. !'.
2 O~H'OAC CH«I ~ 4a,5a-epoxide (0 - 14%)
A 1 a,2a-epoxide (0 - 21 %) 33 CH 0 1p,2fi.epoxide (0 - 4%)
o (61 - 81%)
0 ~ 1~ Major 34
3 ~
:~ A o<lo-i, J. :x Product
• lo+o
I DiD""" OMe
H
OM. H
+ 0
~ Minor
o~o+o~ Product
OMe H
-
~, 4
~" c")<l A i~tl" 35
+
CH:; 0
(50%) (45%)
Ph ro »5-Me
WM. _ M.
A R 0 0
5 CH)<j A la) IZ)-Ib)
R = H; >95% (a) 36
CH3 0 R '" OMs; >95% (b)
I I 1.2 - 1.4 equivalents
R = H, OMe + hv
R@'T~
6 .et CH,xl A $-);; CH, J 37,38
1 equivalent (a) (b) 0 ~~ 0 H, Ac: (a) > 95% ['H NMA ]) R = MeO: Ibl> 95% ['H NMA j)
7 cxS-Me
CHxY cf1M' + cf~ 37
CHl 6 A 00
,n\ (75%) M.
1.2 • 1.4 equivalents
CX:>«Me 0
(14%) .
13
Entry No.
8
9
10
11
12
13
Substrate
ct·o:C~ (E-a) 92: 8 (Z-a)
~MO
::Q5-"' M.
I M.
'" 0
"'
~H; \ COCH2X
A = Me, Et, iPr, t-Bu
X =H,Ci
Dioxirane31 Method:J2
A
CH,V!
cH(''1! A
CHi,/? cH/"'!
A
C')<i CH; 0
A
1.2 . 1.4 equivalent
A
A
Products Yield (%1
~:- [00:] (76%) (E·)
R, ...
R,~R' Me .... R,~ R, - ~~o
• (a) "' (b) (71 • :>95%); (a) fonred in each
case except where A3 -Me, OMe
~MO
I H OMo
l I m~: OEd i coc,
ICOC~ '-m""- Mo ~CN ~O+O~N
eEt Me eN
R
c:Qtc~ , COCIY(
I r.t.. >5h i •
d): , COCI-\:x
(:>95o/ •• except when A .. t·Bu,
decomposition
products only)
I
oJ<~ , COC~X
14
ReI.
39
39
39
4041
42
43
Entry Substrate Dioxirane31 Method32 Products Ref. No. Yield I%l
14 aY :~ A ~ (100%)
43
\ in CH2CI 2 COCH3 COCH,
cx;vY CH,xl ~R + ~ 44 15 A CH; 0
0 0
(trans or eis, respectively) (tJans or cis) (16-41%) R (21 -51%) (+ minor products)
Q D ~ ~ R ...
16 - B 45 .. Ol~ 01
0-0 C--'O worst (27%, cis .- trans; 25 :75) X
O
best (100%. cis: trans: 4: 96)
OA AD'" &0 6·· ab.",,, 01 '01000. 00 """"0"
17 6 B + ;;;0 or opposite selectivity Observed. 45
Ol~ 01 worst yield (40%, cis: ITafl.t ; 13: 87)
0---0 0-0 worst selectivity {59%, cis: ttans: 36· 64) X
best yield and selectivity (770/., cis: rnrns; 10: 90)
~ :~ 0
18 A R"A 46 A OCONH2
A OCONH:, R - H. 0
OMe C""X
O OMe
19 ~OM. CH, ~ A ~OM. 47
in CH2CI 2
HO OAc HO OAc (100%)
OM.
~ 20 ~OM. c'Xl A
~ .• " CHQ OM.
47
CH, ~ in CH 2CI 2
HO OH 0
0 0
21 6' CH)<j A to 6::H 48 .. CH3 0 'oH
(a) (b)
A 1 : 1 mixture of (a) : (b) observed. Ills
suggested (b) possibly arises from opening of the anti-epoxlde (b) with neighbouring-group participation from the ketone carbonyl.
15
Entry Substrate Dioxirane31 Method32 Products Ref. No. Yield (%)
('(~ ::><! A % % 49 22 'Vy
+ K2COS I CH, CH, CH, 'V\
(14%) 0 (13%)
~R' OH
RX~ OH
~~ RX:' CH'Xl o + +
23 CH, ! A R, R, '" 50
At constant temperature. amount of enone This paper looks at decreased with increasing substitution at epoxidation versusC-H C::C. At lower temperatures. more enona insertion. formed, except for the trimethyl derivative.
..
:?R' ::;><! y>R' 51 24 A
R, Rt 0 R3
o R, R. R. Depending on conditions used, i.e. in the presence of a nucleophile or acid, several
cyclisation products were obtained.
N >= ~:;><! ..... " ()n 52 25 . C»n A and B
TsHN TsHN n = 1,2,3 Depending on conditions used, i.e. in the
presence of a nucleophile or acid, several cyclisation products were obtained.
o CN CH)<j ltiCN
26 ~R" A (73%) 53
CH, 0 OR"
A" = (1 S)-camphanoyl R" = (1 S)-camphanoyl
27 X-COOH CHXO B k COOH
54
CH, ! Product yield decreased when two carbonyl
0.5 - 2.5 hrs groups or an amide group present.
0 0
~ 0
~ 55 28 ::;><! A ~
x--l1 Kinetics of epoxidation (>95%)
studied Reaction found to be second order
0 CH,xl o~o 29 A 56
0 CH; 0 H H
16
Entry No.
30
31
32
33
34
Ra'
Substrate
0 H
E-isomer
(Z_)
o
Dioxirane31 Method32
CH"V'?
CH{'6
CH)<j
CH3 ~ in CH:zC1 2
CH,.x1
CH3 0
in CH 2CI 2
CH3.xl
CH3 0
::t<l 3.2 equivalents
(in CH,CI,)
A
A
A
A
A
R
(73 - 86%)
~ .. O£O. o 0 0 0
(.)~ CbI
R = H: (a) (15%), (b) (10%); R = OC2H5: (b) (14%); R = Me, Cl, Br. (a) (-18%).
o l Base
Cyclization Products:
3-Hydroxy1lavones and
2-(-<t-hydroxybenlyl)-3-coumaranones.
17
Ref.
'ST.
58
58
59
60
Entry Substrate Dioxirane31 Method" Products
Ref. No. Yield (%)
"''''
.1" ci CH'.Xl 35 A 60
~ CH, 0
t~ R=H,Ac, 3.0 equivalents (60%)
p-SrCoH.Co. inCH,q
RO"'U AO"~'
0 "6; -["+t; 1 - R'Xx~ oA R, oJ-N• R,
CI<I I I
36 A R R ., o I R, CH 0 ~ H2O ha
R R = Me. Sugar. R. = H. Me;
R"&R, R~= Ht Me;A.1= H, Me. R"~~ A ... ~~ A OH OH
o I R, o N R I , R R
o CH,OR, CH,.><l o CH2OR,
37 00~0,==,",R, A R,)lO~°'"\-TR' 62
CH, 0 0
~ CHX1 ~ 38 0""- A 0""-
63 CH, 0
0 R, 1.0 equivalent R2
R, = Me; A, = H,F. (85 - 96%). Dlepoxide fOlTIloo with further dloxlrane.
CH'.Xl
~ ~ CH, 0 39 0""- A 0""- 63
1.0 equivalent 0
~ or R,
A, = CFl ; R, = H. CH><l DMD: 42% (12 days); TFMD: 85% (3 min.).
CF, 0 Diepoxide fonned with further dioxirane. 1.4 equivalents
Meo::X; » 40 CH'.><l A Mea 0 64
MeO CH, 0 MeO (89%)
OM. OMe
18
Entry No.
41
42
43
44
45
46
47
Substrate
.oms
o=XH .'
T6S0'
~~~~o __ OR HO Jc~
R = SiMe,But; H.
Other examples of alkyne : epoxidation given, but not
shown here.
bn
BnO Bn
0=<:c!J 'Bn
0--/;-0 0=<;;J.bJ , Bn
Dioxirane31
CH,xl CH; 0
1.0 equivalent InCH,q
CH>d CH; 0
CH", A CH!\~
CH,v'i
cH/"'~
Method32
A
A
A
A
A
A
A
Products Yield (%)
o~~.o Meo..("··' ...• /; (98"10)
0 .. ·· '", ob o -.(CH,b
KJ~..oT8S
~OH mso' (41%)
Ph~H 0 ~AoO 0
; ,,--PhMo· .. · ,',0 ;: J-O : AGO
OH OCOPh
t'oO/
75 . 15 10 _ (42"10 isolated)
BoO-Z""_a r ..oq OS(Ph)"t8u
,~ a,~ BnO Bn I \ 08n t B
'. ' OB, \_
~n~ en ( ... Bn~ OHQ ~
i re. Complete inversion 01 Bn~- configuration. BoO~
0--/;-0 0=<;;J.N , Bn
2.3
0~9 +O-:'~ ,
Bn
: 1
19
Ref.
65
66 .
68
69
70
70
Entry Substrate Dioxirane31 Method32 Products .No. Yield (%1
48 ~ A 0.-( CH)<j db , 0'-'< Sn CH:] 0 ,
Sn
~ON' i) -78 - r.t ~" :&: 49 :::xI A
ii) TBAF, THF, 94 6_ r.t. (~%)
CYP" CHX'1 ~ 50 A CH:] 0
0 H
-"
~ 51 :::xI A
"
1_3.5 Oxidation of Carbon - Hydrogen Bonds using Dioxiranes
The ability of dioxiranes to insert into C - H bonds is demonstrative of their
remarkable reactivityn,81,82 Dioxiranes oxidise tertiary alkanes into their
respective alcohols and secondary alkanes into ketones. Oxidations with
dimethyldioxirane proceed stereoselectively with retention of configuration, as
the reactions with cis-decalin (14) (Scheme 8) and trans-decalin (15)
(Scheme 9) demonstrate.74 This also illustrates that the oxidation of
equatorial positions is preferred to that of axial positions.
K6 17hours LT - . Hob V -(84%)
(14)
Scheme 8: Oxidation of cis-decalin (14) by dimethyldioxirane (9).
20
Ref.
70
71
72
72
17 hours ~ H (20%)
(15)
Scheme 9: Oxidation of trans-decalin (15) by dimethyldioxirane (9).
The high selectivity of dimethyldioxirane in its oxidation is also illustrated by
its oxygen insertion into toluene, ethylbenzene and isopropylbenzene." The
oxidation at the benzylic position is in the order PhCH(CH,), > PhCH,CH, >
PhCH,. Similarly, in the reaction with saturated hydrocarbons, oxidation has
been shown to occur preferentially at the tertiary carbon atoms."·7'
1.3.6 Table 1: Oxidation of Carbon - Hydrogen Bonds
Entry Substrate Dioxirane" Method" Products No. Yield (%)
1 QtP 1.4 CHXi CH, 0
A ~ 1/
o 137%\
QtP ~ CF>d A i _,t,j 2 IN CH, 0 o 0 (95%)
3 C'o;9 CF,)<l A ~ Q;Y )fY 0 .... d CH, 0
(3;"') OAc os_ .... (38%) OAc cl«HatWe (21"')
4 J!to CH>d CH, ~ A ~(10%)
~ ~O-5 CH>d A _I "0< I I ~ lX_a..l1.Y.H2 CH, 0 ~ +r:r lX_a_H.Y-H, 2X_a·H. Y.O
3X .Srr:...cI.sIJ.Y -H2 X 2X_a_H, Y=O 3X.Br (!Ia'1S diasl.), Y",H 2 (>90%)
;:#~ DfW' H
~ ~ H OH
6 AcO ;: c"Xl A AcO ; H H
A,= R,=H; CH3 0 (40· 50% conversion) A, = iPr. R,= H; R, = Et. A, = H: NB. When carbonyl at C-17 position.
A. = OAc. A. = H. no reaction observed,
21
Ref.
75
75
75
75
76
n
Entry Substrate Dioxirane31 Method" Products Ref.
No. Yield (%)
# ~" H
7 CH')<j A n ~ h H H
AcO ;- CH, 0 AcO i H H
A, = Me, R,l = H; (40% conversion)
mJS I) CH,)<I ~A' 8 B 78
CH:> 0
IQ H,SO •. CH,C" MoO MoO
~'~~ laYVCO''''' 0"
I I ~ :::><1 79 9 I I ~ J ~ A ]' AcO '-1: H H
A/B ring system contains Ar£) OH (35%)
the only as ring junction. NB. Retention at confiQuration
10 ~' c')<j A ~= 7.
H ~2 CH; 0 Ar£)
AoO A, A,
R, = OH. R, = H (40%); R,=R,=H. R, = H. R, = OH (11%).
~ , '(
_ J"ii';i;~ A ' (30%) 80 11
C 11J 1 'J" V; CH>d
~ CH, 0 , .,(
X. in CHllCI~
'. i (50%) 17~.21 ~·isomer
~ ~~I 'hl ':f 22 ,1.}lJ'" H
12 (11 ," c)<j A 80
~)i X. CH:! 0
Other isomers oxidised in CH2CI2 17a,21~·: (10%). separately: 17a,21!l-:
17~.21CL·: (15%). 17~.21CL·; 17a,21CL' 17a.21 CL' : rStartlno matenai).
d0-< ~H 13 CF,xl A ,& ,~,
60 0"'1 H
O( CH, 0
,?,~
AO .. ·(Jb 3.0 eqivalents
0 In CH2CI,
AO'
ReI: Table 1. Entru No. 34
22
Entry Substrate Dioxirane31 Method" Products Ref. No. Yield (%)
JtR
CH')<I [~R] -H,O ~R 14 CH3 0 A - 81
":,I;' OH
CF')<I (OMO: 52 • 99% conversion [2 - 70hrs]; CH3 0 TFMO: 96 - >98% conversion [10 - 15 min.]).
15 H cYI [JiR] 'H,O R~R 8' CH:; 0 A -R A or OH
H o~ CF')<I (OMD: 50 - >96% conversion [4 - 4Bhrs]; CH3 0 TFMD: 92·95% conversion [40·100 min.]).
OH
OH &0 16 &OH
8'
CH><f A (80·90%)
CH3 0 The corresponding 1.3-d/ol also gave the 1 ,3-Acyclic 1 .2,. 1.3- and 1.4· 1.5 sq. ketoalcohol (92%) . Even with excess DMD, no
dials also looked at. Similar apprechiable formation of the diketone results observed. observed. However, oxidation of the 1,4-<:1101
gave the 1 ,4-ketoa/cohol (53%) and the diketone /37O/~)'
cI1 ::;<1 ° 17 A en: 83
1.5 sq. (85%)
~ OH OH
18 .,' 9H
.... ·OSitBuMe, CH><f A >Q ..... OSitBuMe2 84
R R' , , CH3 0 ~ :::.
0;< 6->< R = H, OH 85 - 88%
)<~~ )<~ 19 OA CH,xl A 84
0
O-\: CH, 0
R = -CH,Ph; -CH,-p-BrPh; o-\: -CH,p-CNPh;
-CH -2-Naohlhvl.
~ H~ 20 >( OCH,Ph CH')<j A 84
HO CH,Ph OH CH, 0 OH
90%
21 H'~PH CHXi A H:,~PH as
OH CH, 0
23
Entry Substrate Dioxirane31 Method32 Products No. Yield (%)
Ref.
OH ffc~'dC~OH 22 xdCH,
c~xl A 86
CH, 0 (97%) "--/ (2 - 3%)
X = OMe; Me; H; F; 1.5 eq.
~>! Cl; Br, CN.
c~ 0
23 (A!t) :::xI A (A!p c~ Vf:!{:; 87
OH OH
24 t} :::xI A N°+MoH 87
2.2eq. (29%) (21%) i) 3 eq. LOA.
~~soX2: ~o~~ 25 5eq. TMSCI.
A H~ THF. -78-
88
25"c. TBOMSO' IQ CH,C~
RC COzMe 'aTMS MeCz
~'C02M8
:::xI 2.3 1 H (R=t :tratioH:TMS)
i) HBF. aq.l
C~CN
HO~~fn'N1i:2 ~C~)-;;'NH:! ii) CH,x'l
26 CF) 0 A 89
/CH,CI2 (95·99%)
Ketoneiree TFMO In keton ... free solution Is stable towards
iii) Na2COy strong acid. This allows oxyfunctlonalisation of the side-chain. provided pro1onation pro1ec1s
CH,Cl2 the amine.
i) HBF. aq./
C~CN CH3CON~
~C~C'NH:! ii) CH,x'l
( H2ln'N~ 27 CF, 0 A 89
/ CH:!Cl2 The carbocation intermediate, produced from
In this case, a brlger reaction Ketoneiree the tertiary alcohol in strong acid medium, is
time is allocated for the iii) Na2CO" trapped by acetonitrile (Ritter reaction) to give
reaction with the TFMO. the above product (96 -97%).
CH,Cl2
i) HBF. aq.l
[R~~]'~~ C~CN
ii) CH,x'l
28 R~N~ CF, 0 A 89
/ CH,Cl2 (90 - 95%)
o atom insertion occurs exclusivefy at the &-
Ketoneiree methylene group. On permethylation of the
iii) Na2COy ammonium nm-ogen centre (RNMe,), l;-oxidation becomes competaUve and no
CH,CI2 cycUsation products observed.
24
Entry Substrate Dioxirane31 Method32 Products No. Yield ('Ye)
H :>1 #. 0 • R'(H) ~~'(H) 29 o • or A
~o ::xI OH
OCOCF3
30 R/'oo..R' ::xI A RAR'
R = alkyl, aryt PrIrnaIy and secondary C-H bonds were R' = H, alkyl, aryt (CF,CO),o selectively monohydroxylated when carried out
In presence of 10 fold excess of lriftuomacetlc OCM,O'C anhydride. Over oxidation to carboxytic acids or
ketones not observed.
1.3.7 Oxidation of Organic Sulfur, Silicon, Selenium and Nitrogen containing Substrates
Primary amines are oxidised by dioxiranes, rapidly and often quantitatively,
to their corresponding nitro compounds. This usually occurs via a stepwise
process, as outlined in Scheme 10.92,93 This process is supported by the fact
that both hydroxylamines and nitroso compounds are oxidised to their nitro
derivatives. It should be noted, however, that amine hydrochloride salts are
oxidised directly to their nitro compound. 94 In general secondary amines are
converted to the corresponding hydroxylamine and tertiary amines to the
amine oxides.92 In both these cases, reaction conditions are critical if the
hydroxylamine or amine oxide is to be the desired product. It should however
be noted, that in the case of tertiary amines, excess dioxirane leads to
deoxygenation of the amine oxide and regeneration of the amine'92
Scheme 10: Oxidation of primary amines.
RNH2 + 1e ..
1e -
OH R-N
/
'H
R-NO
OH , R-N
\
~20 OH
25
Ref.
90
91
Among the sulfur nucleophiles, sulfides are oxidised by dioxiranes to
sulfoxides and these, in turn, to sulfones (Scheme 11). The reaction can,
however, be controlled at the sulfoxide stage.95 The yields are practically
quantititative, and the oxidation of the sulfide is so rapid and complete that
sulfides such as p-tolylmethyl sulfide can be used for quantitative analysis of
the dioxirane content in solutions or to quench dioxirane during oxidations of
less reactive substrates.96
Scheme 11: Oxidation of sulfides.
[0] [0]
Dimethyldioxirane (9) is also a convenient oxidant for converting silanes to
silanols by Si - H insertion (Scheme 12)?2C When optically active
trialkylsilanes are used, the Si - H insertion proceed with complete retention
of configuration. 97 Hydroxylating silanes under these strictly neutral
conditions means that siloxanes are not produced.
Scheme 12: Oxidation of silanes.
[0]
1.3.8 Table 1: Oxidation of Organic Sulfur, Silicon, Selenium and
Nitrogen containing Substrates
Entry Substrate Dioxirane31 Method32 Products No. Yield (0/0)
0 0 0
1 c6:: ::t<! A c6:> c6:: , , H in CH2CI2
H (45%) (40%)
0 0 0
::t<! c6::. WH 2 c6:: A , , ,
InH,O H H H - (70%) (21%)
26
Ref.
98
98
Entry Substrate Dioxirane" Method"
Products Ref.
No. Yield (%) 0
CH')<j 0
3 cCx: A cxXB 98 CH, 0 ,
" in EtOH (77%)
0 CH')<j 0 0
4 ~&R' A ~~;( ":((' sA CH, 0 9. •
I '" in CH2CI2
o I R, H H
(32·37%) (40·55%)
)) CH'Xl +s-O 5 A 98 CH3 0
I 2 I H in CH,CI, H m'lo)
CH'XY Ph
Phse~ \ 48 6 A ,se"---<, OCONH2 CH, 0 o CONH2
Me I
CH')<j
CS? CH, 6 Me
7 A I 99 cx;:o + ArCHO
(2.0eq) + hv
A r = Phenyl, 2·Naphthyl. Ne. 0 Chemiluminescence noted in this reaction.
8 Q ~:t<! A 0 - C).o '00
I I H O· OH
CH,OAc CHXl CH,OAc
9 ACOC~CH'N(ll'r), A AcOC~COOH 101
AcOCH, CH, 0
AcOCH, CH,OAc -4 equivalents CH20Ac
10 Ar2CN
2 CH~ A Ar2CO 102
CH 0
11 6 :::x! A Q (95%) + 6> (5%)
102
~ C~CI:!
0 CHXi
0
12 11 A HO . 11
'0' N,~P(OEt)2 >-P(OEl" (100%)
CH3 0 HO
R'~ o 0
13 CHXl A R('~~R2 ,o4 N, CH:] ! O.(H2O) (89 - 100%)
Rp R, = aliphatic or aromatic
27
Entry No.
14
15
16
17
18
19
20
21
22
Substrate
R1• R2 = aliphatic or aromatic
NOH
R1AH R1 = aliphatic or aromatic
7HX R~N
o X = Protectina Groun.
/~~1
CbZ~o,CH,
! Cbz~O'CH,
Dioxirane31
or CH,,~
CF,AJ
Method32
A
A
A
A
A
A
A
B
A
Products Yield (0/0)
~ (85-100%) R, R2
Starting material only
Ph'6 (58%)
[ ~(~ -Q ~.,O" ()--2w \\ 1 N
0" (85%)
[c:lsh]- J--~ c",)(", rH, CH,cc
cH{ '0- (66%)
NB. For easily oxidised hydrazines single electron transfer (This example) is more
rapid than the usual oxygen transfer (Table 1 Entry 1 B) shown by DMD.
t-IHX 0 NHX
R~H'-'Ry~: o 0
Predominantly in hydrated form.
28
Ref.
'04
'05
106
107
'08
108
109
110
110
-
Entry Substrate Dioxirane31 Method32 Products Ref.
No. Yield (%)
C;q
23 ~(
CH; A ~/ -0 III or \
CH,.><l
CF, J C;q
~fBF3 CH; . ~tl-BF3 111 24 A or o \ CH,.><l CF, J
OC~ Ph ~O'H
25
0\ ::;<I B 112 Co,H
M , 6cH, ~ CO;zH
I OcH,
OR OR
><~' (15~~.
OR OA
26 "~ CH:xI A "ro!,~,.;..oH (33%) 1 13 ~~ CH) I '\ 1 R • SlMe2""
0, OROA ~
'r< . N"' 1 ',.I., ~b. A R (8%)
HU . [)( A
y ? (S) 27 ::;<I HJ=( (100%) o ,
N~ ~ 114 100% e,e.
Y = Br R = CO,CH,C,H, 0 Y = Cl R = CO,CH,C,H, R Y = F R = CO,CH,C,H, Y= F R=
CO,CH,OCOCICH,\,
'( X:b::X o ,
::;<I 28 fl 'A 0 '14
X = BrY = H R = CO,CH,Ph j& (100%) X = F Y = H R = CO,CH,Ph X = BrY = F R = CO,CH,Ph 100% e e X = BrY = Br R = CO,CH,Ph o I X = Br Y = Br R = CO,CH(PhJ, R X= BrY= Br R =CO,H X = BrY = Br R = CH,OH X=BrY=BrR=
CO,CH,OCOCMe,
.
29
Dioxirane31 Method32 Products Ref.
Entry Substrate Yield (%) No.
R'~ ~ A R2"'" . R, .. ' 0
CH)<j s-s 115 29
0' R2"'" CHa 0 S-S in CH2CI2 Up to 18: 1 diastereoselectivity observed.
Major isomer always trans.
+'9 CH)<j A +'9 116
30 CH3 0
inCH,C~ CH3-Si-CH3 CH3-Si-CH,
1 1 H OH
~'R 0 CH)<j 11 X ""- A ~S'R 117
31 CH3 0
X = H, R = CH,CO,H; Cl-2'C X = CO,H, R = Mo;
0.65 eq. (47·99 %)
X = H, R = CH,CH,OH; Smin. X = CH,OH, R = Mo;
X = H, R = ·CH=CHCO,H.
0 S'R o 0
117 CH)<j \\11 X ""- A
DS'R 32
CHa 0 X = H, R = CH,CO,H;
20'C X (35 _ 97 %)
X = CO,H, R = Mo; 1.35 eq. X = H, R = CH,CH,OH; 1-2 hrs. X = CH,OH, R = Mo;
X = H R = -CH=CHCO H. ..
[+t~-<] ! r.t.
+sJ-< CH)<j A 0
+~-s-< 1 la 33
+s-w-< CH, 0
o 53% o 30%
>-s-~-< +I-s+ o 10% 5%
X X
2 2 119 C:Xl
A and B 34 CHa 0
I' 1 N-..;-~ I' 1
0-N........"N
X - H, Me, MeO, Cl Authors suggest SN2 mechanism
30
1.3.9 Oxidation Of Metal Enolates and Metal Complexes
Over the past five years the oxidation of organic substrates by dioxiranes
has been extensively investigated,22 but relatively little published on
organometallic substrates. Adam et a/have looked at the oxidation of metal
enolates. They found that silyl enol ethers afford the corresponding
epoxides120 whereas the enolates of lithium, sodium and titanium yield the «
hydroxy carbonyl products. 121
Lluch et aJ 22 have shown that dimethyldioxirane provides an efficient
reagent for the oxidative decomplexation of Fischer carbene complexes
(Scheme 13). The reaction affords good conversion yields, is clean and
highly chemoselective. In all cases comparable or better yields of the ketone
were obtained than with conventional methods.
Scheme 13: Decomplexation of Fischer carbene complexes.
[0) -1.3.10 Table 4: Oxidation Of Metal Enolates and Metal Complexes
Entry Substrate Dioxirane31 Method32 Products No. Yield (%)
~, 0
Ph~Me 1 Ph O-T~A' A
Ph~M8 + ?- I . Me 0 ... '~ OH OH
Ar·~ C"Xl (A) (20.67 %) (S) .. "'
A, CH3 0 (5·63%ee)
Major isomer usually derived from reside attack
2 J:: A A, , A 'A,Y-yA, CH)<'f OH
ML, = Ti(OrPr),; Ti(NEt,),; CHi 0 Paper looks at diastereoselective
TiCP2C1; Na; SiM 8,. hydroxylation of chiral metal enolates.
31
Ref.
123
124
Entry Substrate Dioxirane31 Method32 Products Ref. No. Yield (%)
(CO)3Cr R (CObCr . R ~R: 3 ~~ ~:><1
A 125
~R, SR, -0
Excellent yields and diastereoselectivity observed.
0 RS:Q 4 RS:Q
c"xl A \ I (-45%, -90% d.e.) 126
\1 tBu ,
ISu """ \ cHi 0 Cr(CO)3
Cr(CO), Diastereoselectivity of onho substituted complexes determined and found to be
dramatically reversed when changed from methyl to tert-butvl.
tr(CO)' H Cr(CO),
5 ~"Me c~ A ~ 127
- s NMe2 CHi E (2.4 eq.)
E
Enantiomericallv nure
6 A A ~oe 128 R2 0 Cr(CO), CH><i
R, = H: o-CH,OH: CH:! 0
m-CH,OH: p-CH,OH: 20°C OCH,CH=CH,.
OMe (CO)5Cr==< CH)<j OMe
7 R2 A O=< 128
CHi 0 R2 = H; o-CH2OH; _20°C R2
m-CH,OH: p-CH,OH: OCH,CH=CH,.
8
Me 0 J;:;<:;:R2
CH,xl A 128 (CO)3CO--CO (CO), CH, J MeO R2
R2 = H; o-CH2OH; _20°C m-CH,OH: p-CH,OH:
OCH CH=CH .
(COI3FeD"~ Cl<! -(J"'~ 9 CH 0 A (CO),Fe 129
(3 equivalents) (41% yield, 59% conversion) 56'C
Some decomposition of the iron tricarbonyl complex was noted.
OEt
::«! O=<Ph
10 (CO)5Cr~Ph
A 130 NEt2
NEt2 (3 equivalents) (52%) 2O'C Major pathway involves oxidation of the
enamino double bond.
32
1.4 Other Aspects of Dioxirane Reactivity
1.4.1 Effect of Solvent on Reactions
In 1993, Murray and Gu 131 reported that the rate of the dimethyldioxirane
epoxidation reaction is dependent on the nature of the second solvent, when
binary solvents containing 50% acetone are used for the reaction. The rate of
epoxidation was shown to be enhanced by hydrogen-bond donor solvents
and inhibited by hydrogen-bond acceptor solvents. More recently they have
shown that the dimethyldioxirane C-H insertion reaction is also favoured by
solvents with greater hydrogen-bond donor capacitY,132 although the effect is
less pronounced. Both the epoxidation 131 and C-H insertion 132 reactions were
found to follow second order kinetics, using solvents in which it could be
shown that there were no competing first or second order processes.
As previously postulated for the epoxidation reaction (16),131 these workers
believed a spirotransition state (17), for the C-H insertion reaction, 132 was
most consistent with their results.
Figure 5:
Spiro transition state for epoxidation and C-H insertion reactions.131.132.22e
(16) (H-S = Solvent) (17)
Murray has continued to study the effect of solvent on dimethyldioxira~e
(9) epoxidation and C-H insertion reactions. In a recent publication he
describes the effect of solvent on the diastereoselectivity of the oxidation. l33
He found that the diastereoselectivity of the epoxidation of cyclohex-2-en-1-01
(18) was essentially tuneable depending on solvent choice. For example,
methanol! acetone (90 !1 0) gave an epoxide distribution of 2 : 1 in favour of
33
the (rans epoxide; whereas tetrachloromethane f acetone (95 f 5) gave
almost exclusively the cis epoxide. From his results he suggested that the -
OH group of (18) exerts a H-bonding effect favouring cis selectivity. Hence in
the presence of tetrachloromethane, the association between the dioxirane
and acetone would be diluted such that the intramolecular H-bonding ef:ect
was more competitive. The distribution of diastereomers in the absence of
this effect was appar.ently determined largely by steric effects. The epoxide:
enone ratio was also found to be solvent dependent.
cS (18)
1.4.2 Electrophilic character I Mode of Oxygen Transfer
While most oxygen transfer reactions of dioxiranes appear to take place by
direct substitution (SN2) on the dioxirane peroxide bond by the nucleophile,22
more complex electron transfer activity has been implicated, particularly for
substrates with low oxygen potentials. 134 Adam and Golsch 135 have,
therefore, compared the relative rates of the dimethyldioxirane oxidation of
nitrogen heteroarenes with those of methylation by methyl iodide. Their
results revealed that an SN2 mechanism rather than an electron transfer
applied for the dimethyldioxirane oxidation.
The nucleophilic (oxidation at the sulfoxide Site, i.e. SO in SSO) versus
electrophilic (oxidation at the sulfide site, i.e. Sin SSO) nature of oxidants has
previously been examined using thianthrene 5-oxide (SSO) as a mechanistic
probe. 136 The results obtained by Adam and Golsch,137 using this reagent to
assess the electrophilic character of dioxiranes, at first seemed to suggest a
dominant nucleophilic character and therefore were in contrast with the
established electrophilic character of the oxidant. 138 These results were
explained in terms of the energy requirements of the oxidations. The
activation barrier for sulfide oxidation (24.4 kcallmol) was significantly higher
34
than for sulfoxide oxidation (9.6 kcallmol).138 It was also pointed out that
these were gas phase results and that the sulfide transition state has a higher
dipole moment than the sulfoxide transition state and consequently should
experience the greater stabilisation on transfer to a polar solvent. In his
review, Murray22a suggested that oxidation of sulfoxide may be initiated by
attack of dimethyldioxirane on the oxygen rather than at the sulfur (Scheme
14). However, further work by Clennan and Yang 139 showed this mechanism
(Scheme 14) to be incorrect.
Scheme 14:
o 11
(XI SY') """ S~
•
0-0 ..... I
(XI S+~ """ S~
Theelectrophilic nature of dimethyldioxirane, and also
(trifluoromethyl)methyldioxirane, have been examined by Ballistreri et a[14O
They, like others, looked at the relative reactivity of thioethers and sulfoxides,
and also the competitive oxidation of sulfoxides, towards oxygen-transfer by
these reagents. They concluded, as previous workers have done, that
dimethyldioxirane and (trifluoromethyl)methyldioxirane are definitely
electrophiles, the latter being less selective than the former, and the mixtures
of products obtained in the reactions, were due to the small reactivity ratio of
the sulfur centres.
1.4.3 Decomposition of Dioxiranes
Hull and Budhai142 have studied the decomposition of dimethyldioxirane
using u.v./vis. spectroscopy at 340 nm. They found that at high
concentrations (-0.1 M), decomposition had an induction period followed by
rapid decay, the latter being due to the presence of reaction products. The
phenomenon has previously been observed by Adam and Murray.143
However, Hull and Budhai also reported that at low concentrations (-0.02 M)
35
decomposition was first order with an activation energy of 24.9 kcal/mol and
that its apparent thermal stability is due to the very strain energy that would,
at first, seem to make the species so unstable.
Dioxiranes have also been shown to be decomposed by ethers (cf.
Preparation of Dioxiranes, p 4).15 Photochemical and thermal initiated free
radical activity has previously been noted in the decompositon of
dioxiranes. 141• A free-radical pathway has recently been reported for the
oxyfunctionalization of adamantane, triggered by the presence of CCbBr or
the presence of an argon blanket. 141b
1.5 Carbonyl Oxides and Dioxiranes
The recent development of dioxiranes as potent oxygen transfer agents has
stimulated much interest in the similarities, and differences, between
dioxiranes and their isomers, the carbonyl oXides. 144,145 It is now well
established that dioxirane (1) is more stable than its dioxygen ylide and the
respective barriers for their inter-conversion are sufficiently high that each
exhibits its own chemical behaviour when independently generated. Although
for many carbonyl oxides, dioxirane formation seems to be ruled out,
cyclisation of carbonyl oxides to dioxiranes have been reported. 144
Scheme 15: Proposed formation of dioxirane in gas phase ozonolysis of tetramethylethylene.
-+
In a recent publication, Murray et a/146 have suggested the involvement of a
dioxirane species in the ozonolysis of tetramethylethylene. This they have
36
done in order to explain some of the observed products of its gas phase
ozonolysis (Scheme 15).
Kopecky et al, 147 in 1993, published the first example of dioxirane formation
from ozonolysis in solution. They found that addition of excess ozone to E- or
Z-1,2-dimethoxy-1,2-diphenylethene, in inert solvents, resulted in formation of
up to 0.7 mole of (methoxy)phenyldioxirane.
Further work in this field has shown that isomerisation is facilitated by the
presence of It-donors on the phenyl substituent of the carbonyl oxide
(Scheme 16).148 It has also been suggested that under some conditions, the
carbonyl oxide thus substituted could mainly isomerise into the dioxirane, the
extent of isomerisation being related to concentration and solvent polarity.
H R1 , /
C=C / , Ar-C--O C02Me
1,-o
Scheme 16: Proposed cyclisation of carbonyl oxide when Ar substituted with an electron-donating group.
Scheme 17: Cyclisation of carbonyl oxide to dioxirane during irradiation of decafluorodiphenylcarbene in an oxygen matrix.
o· 0/ F
F
F F 35 K F F
F F F F F F
F F F F
F
1 /... > 480 nm
F 0-0 F
F ,:? F
F ~ F F F
0 XXF F I A> 350 nm
F o ~ F ~
F F F
F
37
A further case in which cyclisation of carbonyl oxides to dioxiranes has
been observed, was during the photolysis of carbenes in 02-doped argon
matrices. 149,150 Both dioxiranes and carbonyl oxides have been characterised
by u. v.lvis. and i.r. spectroscopy during the course of this reaction, though as
yet, neither have been isolated (Scheme 17149 and Scheme 18150).
Scheme 18: Cyclisation of carbonyl oxide to dioxirane during irradiation of propinal O-oxide in an oxygen doped argon matrix.
o· '0+
H ( N /"
H
~ q-o ( 480nm H • H .-, t. 35 K hv 590 nm H '< H 'N2 H +02
H
~ 0+-0'/
H I( H
Cremer et ar1 have investigated the equilibrium geometries, dipole
moments, infrared spectra, heats of formation and isomerisation energies of
carbonyl oxides and dioxiranes.
They conclude that:
i) the electronic structure of the carbonyl oxide is closer to that of a
zwitterion than has previously been predicted by ab initio calculations.
ii) identification of both carbonyl oxides and dioxiranes in a reaction
mixture is possible with the help of i.r. spectroscopy. The CO and 00
stretching modes of carbonyl oxides should be very intense and
appear at 1200 and 880 cm·1.
o iii) The heats of formation LlH, (298) for carbonyl oxide and dioxirane
are 30.2 and 6.0 kcall mol.
38
iv) Decomposition of carbonyl oxide and dioxirane to CO, CO2, H20,
and H2 is thermodynamically favourable, while fragmentation to CH2,
O2 or ° is not.
39
Chapter 2
Chapter 2
2.1 Introduction to the Project
In the last decade or so, dioxiranes (1) have been shown to be extremely
versatile oxidants.22 However, very few homochiral dioxiranes have been
used and only low enantioselectivity has so far been reported. 10 In the course
of our research with dioxiranes,152 a new group of chiral dioxiranes generated
in situ from 1-tetralones (19) and 1-indanones (20) substituted at the C-2
position with a fluorine and either an alkoxycarbonyl or a 2-hydroxyisopropyl
group, have been looked at. To some extent these may be regarded as the
cyclic equivalents of trifluoroacetophenone and related ring fluorinated
acetophenones, which have been shown to generate a reactive dioxirane in
situ. 153,154
roe. R'
""'" . I F %.
(19)
R3 ° ~C02R2 R3~F
(20)
Rl = C02CH3, C(CH3)20H, (-)-Menthyl
R2 = CH2CH"CH,
R3 = H; F
It was thought that the planar aromatic ring and substituents, a large group
(L) and a small group (S), at the C-2 position might be important in directing
the approach of a trans-alkene to the dioxirane, which is known 152. to react in
a spiro transition state, It was initially assumed that the larger group would
take up the usually preferred equatorial conformation in the half-chair, and
therefore some selectivity of the oxygen to be delivered should be observed,
As previously described in the Introduction (p, 12, Figure 4). there are four
possible diastereomeric transition states for the epoxidation of an
unsymmetrical alkene using a homochiral ketone, The two transition states,
believed to be favoured for the epoxidation of trans-stilbene (23) using the
dioxirane derivative of a homochiral tetralone (19), are illustrated below (21)
and (22). A highly electronegative fluorine was incorporated, as the small
group (S), [j,- to the dioxirane ring system, to increase the electrophilicity of
40
the oxygen to be delivered.
s
(21) (22)
It was thought that this L conformation would be
P h less energetically , favourable because of ~ the steric interaction of
the phenyl group and the large group on C-2 of the tetralone.
An alkoxycarbonyl group was introduced at position 2 of the tetralone, as
the large group (L). Since these groups are slightly electron-withdrawing, it
was anticipated that they would also help increase the electrophilicity of the
oxygen to be delivered.
Cl
(23) (24)
o (25)
Me
Me
The synthesis and separation of the diastereomers and enantiomers of
some 2-substituted-2-fluoro-1-tetralones (19) and 1-indanones (20) was
therefore undertaken. The investigation of in situdioxirane generation from
the homochiral parent ketones and their potential in enantioselective alkene
oxidation was also conducted. The alkenes used, were trans-stilbene (23),
trans-~-methylstyrene (24) and 6-chloro-2,2-dimethyl-2H-1-benzopyran (25).
2.2 Synthesis of the 1-tetralone (19) and 1-indanone (20) derivatives
The synthesis of enantiomerically pure 2-hydroxy-2-substituted-1-
tetralones 155 using oxidation of the enolates with enantiomerically pure
(camphorylsulfonyl)oxaziridines (Scheme 19), and the formation of
homochiral 2,2-disubstituted-1-tetralols 156 via Grignard reactions with optically
active (1-tetralone)-tricarbonyl chromium derivatives have been reported
(Scheme 20).
41
Scheme 19
Scheme 20
~A i) Base
A'U) A = Me, Et, PhCH2
X=CH2,0
ii) ~~~I ~'o 2
"w~" (5) (90 - 95%ee)
hv •
Recently, the reduction of racemic 2-alkoxycarbonyl-1-tetralones by chiral
ruthenium(ll) catalysts has been realised by kinetic resolution (Scheme
21).157
Scheme 21
o OH OH ruCOEt .7,. . 2 L'AuX
~o I ~ 5 "
W ",·.c02Et
MeO I or
" -EX)
' C02Et
MeO I "'" (S,A) (R,S)
7-MeO (R)-MeO-BiphepAuBr2 d.e. = 97% (trans) e.e. = 95% (S,A)
5-MeO (S)-BinapAuBr2 d.e_=97%(trans) e.e.=92%(A,S)
No work, however, has been reported which describes the separation of
racemic mixtures of 2,2-disubstituted-1-tetralones_ The following sections
describe the preparation and separation of the diastereomers of menthyl 2-
fluoro-1-tetralone-2-carboxylate (31 c) by chromatography, and the
preparation and separation of enantiomers of 2,2-disubstituted-1-tetralones
(19) and -1-indanones (20) via synthesis of their (RJ-(+)-a.-methylbenzylimine
(32 and 38) derivatives.
2.2.1 Synthesis of the 2,2-disubstituted-1-tetralones (19)
Several methods have been reported for the synthesis of 2-alkoxycarbonyl
Hetralones and 1-indanones. These include the use of Mander's reagent 158
(methyl cyanoformate) and Stork 159 methodology, both of which are reported
42
to alleviate the frequently encountered problem of O-acylation during
attempted C-acylation of ketone enolates. 160
Synthesis of ethyI1-tetralone-2-carboxylate (26)
Ethyl 1-tetralone-2-carboxylate (26) was the first of these compounds to be
prepared. Two methods were used as indicated (Scheme 22 and Scheme
23); the latter proved simpler and gave higher yields. I.r. and n.m.r.
spectrometry data were in agreement with those in the literature for this
compound. 161 ,162
Scheme 22
Scheme 23
i) LDA, HMPA
EtC02CN *
THF
o OH
ro~ I C02~E=t="" 0& ~ _ "" C02Et
h : I (51%)
(26)
i) NaH,(EtOhCOroO CO Et OH
I1HF -:? 2 0&"" CO2 Et -~:....--. I oo====='" I iQ t-ft ~ h '" (90%)
(26)
A general mechanism for the base promoted reactions involved in
Schemes 22 and 23 is given in Scheme 24.
Scheme 24
rod R
I +
'"
R = EtC02, MeC02 and X = CN, EtO, MeO
43
Synthesis of methyl 1- tetralone-2-carboxylate (27)
Since the method in Scheme 23, for the synthesis of ethyl 1-tetralone-2-
carboxylate, gave the higher yield, its methyl analogue was prepared similarly
as shown in Scheme 25. I.r. and n.m.r. spectroscopic data agree with resul;;
previously obtained within this Oepartment.161
Scheme 25
o
06 i) NaH, (MeO)2COoerO
rfl-iF ,:7 C02Me ----------~ I iQH+ ~
(27)
Synthesis of menthyI1-tetralone-2-carboxylate (28)
Oimenthyl carbonate is not commercially available, so the synthesis of
menthyl 1-tetralone-2-carboxylate was attempted using menthyl
chloroformate with sodium hydride in THF (Scheme 26). This method proved
unsuccessful.
Scheme 26
0-t i [ o i)NaH, l 0 C(Xf0 ex OH 0 X·
cD A 17 0"" CJC{0"" I X' I I THF ~
(28)
The reaction was then carried out using LOA, a stronger base, in THF, in
the presence of DMPU (Scheme 27). L-Menthyl chloroformate was again
used as the source of the ester group. Although the reaction proceeded well,
only a 40% yield of pure product was obtained because the product proved to
be difficult to purify by chromatography owing to the presence of impurities
having Rt values close to that of the product. There were two major
impurities, a carbamate (29) and the O-acylated product (30). The carbamate
44
(29) was produced when LOA, still present in the reaction mixture on the
addition of the menthyl chloroform ate, reacted with the menthyl
chloroformate.
Scheme 27
~I 0 i)_~~;THF, • ~o",·6 ~ " 1: 10 , .. 6 ~ ii)DMPU,-78"C U0 ~ OJ' ~
'iii) ~ -78o
'C U (28) (40%)
, O~I A iv)H+
(29) (30)
This reaction gave a comparable yield when using HMPA rather than
OMPU, but still with minor impurities present. OMPU was preferred because
of the high toxicity of the HMPA. HMPA has been shown to encourage the
formation of O-acylated products over C-acylated products. In order to
produce the C-acylated product only, the reaction was attempted in the
absence of both OMPU and HMPA. However no observable C- or O-acylated
products were obtained.
Because of the difficulty in purifying the menthyl 1-tetralone-2-carboxylate
in the above reaction (Scheme 27), alternative methods of its preparation
were looked at.
With butyllithium in THF, and menthyl chloroform ate (Scheme 28). a 15%
yield of the desired product was obtained. No O-acylated product was
formed, hence the purification was comparatively easy. A similar experiment
was carried out using methyllithium in place of the butyllithium, but as with
butyllithium, the yield was low (10%).
45
Scheme 28 i :
(28) (15°/.l
A
Increasing the strength of the base did not produce sufficiently high yields.
A further alternative approach to produce the menthyl esters, via the enamine
derivatives of 1-tetralone (Scheme 29 and Scheme 30), was attempted.
Previous work, carried out by Stork and colleagues,163 had shown that ~
ketoesters can be made by enamine acylation. These workers also found
that two equivalents of the enamine must be used, to one equivalent of the
acyl chloride in the formation of the ketoester. Methods using triethylamine to
mop up the acid produced as a by-product of the reaction, in place of the
second equivalent of enamine, proved unsuccessful.
Scheme 29
o i)A 0
o N ~)...CI oox QEt20. ~ ~ A ~I 0"" -_. ~ X 'l.vV ii) TiCI. "'- Solvent. Reflux
(77%) ii) Ho0· 11 (28) = Solvents used: Benzene ~ §
Et20 OH 0 (') ro .. ··~ Preparation of the enamines was carried out using a method devised by
White and Weingarten. 164 As shown in Scheme 29, approximately half an
equivalent of titanium tetrachloride was used to three equivalents of the
amine and one of the tetralone. The use of one equivalent of the titanium
tetrachloride and three equivalents of the amine to one equivalent of the
tetralone was also used as shown in Scheme 30. I.r and n.m.r. data were
found to be consistent with the formation of the enamines. However, as
46
shown in Schemes 29 and Scheme 30, all attempts to acylate the enamines
failed.
Scheme 30
o C) C) ex) i) Et2 0. H, 001
"'"
ii) TiCI. %.
. (68%)
0~ i) :oe, ~O
-A'----'-\X!---· WO'" A ~ (28) j
Benzene, Reflux
ocYox In General and as indicated in Schemes 23, 25 and 27
Both tautomers were clearly visible in the 1H n.m.r. spectrum of the 2-
alkoxycarbonyl-1-tetralones (26), (27) and (28); the OH of the enol appearing
at approximately OH 12.5 (singlet), and the proton at the C-2 position of the
keto form at OH 3.6 (double doublet). The signals from the proton at the C-8
position of the aromatic ring were also clearly distinguishable; OH 8.0 (double
doublet) for the keto form, and OH 7.8 (double doublet) for the enol form.
These protons appeared as double doublets due to coupling with the protons
on C-7 and C-6 of the aromatic ring.
2.2.2 Fluorination of the alkyl 1-tetralone-2-carboxylates (26, 27 and 28)
In order to fluorinate, the acylated compounds, the electrophilic fluorinating
agent, N-chloromethyl-N-fluoro ethylenediamine bis(tetrafluoroborate), was
used. This compound, was supplied by Air Products as a white solid known
as Selectfluor. Previous work has shown it to be useful for the fluorination of
metal enolates. Following a method published by Banks,165 sodium hydride
was used to abstract the proton at the C-2 position of the tetralone with DMF
as the solvent. On generation of the anion, the Selectfluor reagent was added
47
as a solution in DMF. The general mechanism by which this reaction occurs,
is shown in Scheme 31. All fluorination reactions resulted in yields of over
71 %. The lH n.m.r. spectra of these products no longer showed evidence of
the enol form. No signal was observed for the OH proton of the enol ester (8H
12.5) or the proton at the C-2 position of the ketoester starting material (8H
3.6). Only one signal was observed for the proton at the C-B position of the
tetralone at 8H B.1. The signal for the carbon at position 2 in the 13C n.m.r.
spectra, in each case, showed a coupling constant of approximately 200 Hz.
Coupling constants of this magnitude are often observed for C-F bonds,
suggesting that the fluorine is incorporated at this position. l66
Scheme 31
~ ~O/R ____ • ~O/R l.)lJ-~ F ~3~=Et
+ H2 ~()I - SF; ((31 b»= MMe
N 31e = ..,
+Na l' (1)_ + l.!. _ +BF4 b + BF; I + SF,
H,cl CH,ct
2.3 Separation of the diastereomers of menthyl 2-fluoro-1-tetralone-2-
carboxylate (31c)
The diastereomers of (31c) were separated by flash chromatography to
yield the homochiral tetralones. The more polar diastereomer (by tic) was
obtained as a solid. X-ray crystallograph/ 67 revealed it to be (1'R,2'R,5'R)-
(-)-menthyl 25-fluoro-Hetralone-2-carboxylate (31 c-DU) and showed that the
bulky ester residue was in an axial conformation (Figure 6).
48
Figure 6:
X-Ray Crystal Structure of (1'R,2'R,5'R}-(-)-Menthyl 2S
fluoro-1-tetralone-2-carboxylate (31 c-DIJ)
(31c-DlI)
49
2.4 Separation of enantiomers of (31 b) and (34) via an imine derivative
Separation of the ester derivative (31 b)
Attempts to synthesise the acetal derivatives of the enantiomers of
(31 b) 168 using the optically active alcohol, (2R,4R)-( -)-pentanediol proved
unsuccessful.'69.170.171 The imine (32), derived from (R)-(+)-a.
methylbenzylamine, was synthesised using titanium tetrachloride as catalyst
(Scheme 32).172
Scheme 32 MeyPh
o 0 H NH
~o...Me _M_e_.·'~_'··~_· h_'_li_iC_I'., ~I ~ ~0/M_e_2_M_HC_I ... ~ Me
VU'F Benzene UJF DCM W'F 0-
(31 b) (32) (31 b)
There are four possible diastereomers of (32). These are the syn- and anti
isomers of both the (R,R)- and the (R,S)-imine. On chromatographic
separation of the diastereomers of (32), the syn- and anti- isomers of (R,R)
(32) eluted together, as did the syn- and anti- isomers of (R,S)-(32). This fact
was determined using 'H n.m.r. spectroscopy, and the chiral shift reagent,
Eu(hfch, on the separated enantiomers of the de protected ketone (31 b).
Figure 7: The four possible isomers of the imine (32).
Me Me Ph Ph
Y-Ph Y-Ph Me~ Me~ N 0 N 0 N '0 N 0 cx)<' ,Me I ' ""F 0 . rolo
/
Me
I S F a)<' ,Me I ' ····F 0 rolo,Me I S F
syn-(R,R) syn-(R,S) an6-(R.S) anti-(R.R)
The syn- and anti- isomers of the less polar diastereomer (32-01) were
isolated as an oil, whereas those of the more polar diastereomer (32-011)
were isolated as a solid.
Only one signal (OH 3.33)was observed in the 'H n.m.r. spectrum for the
OMe protons of the isomers in (32-01). The signals for the OMe protons of
the anti- and syn- isomers of (32-011) appeared in the 'H n.m.r. at oH 3.87 and
50
3.83. It was noted that these latter syn- and anti- isomers partially
interconverted on recrystallization from methanol.
Hydrolysis of the imine (32-01) and (32-011) yielded the ketones (31 b-EI)
and (31 b-EII), respectively. Chiral shift 1 H n.m.r. spectroscopy studies
showed that (31b-EII) had been isolated in >95% e.e. (no [31 b-EI] apparently
present) and (31 b-EI) in 80% e.e .. The low e.e. in the latter case is due to
incomplete separation (32-01) from (32-011) by the chromatographic method
used, and this was confirmed by the 1H n.m.r. spectrum of the less polar
fraction.
Separation of the tertiary alcohol derivative (34)
Synthesis of the hydroxyketone, 2-fluoro-2-(2'-hydroxypropyl)-1-tetralone
(34), via the imine (32) was attempted with methyllithium and
methylmagnesium iodide using various reaction times and temperatures. The
best yield, albeit low, was obtained using methyllithlum, at O°C and quenching
after 1 - 1.5 hours (Scheme 33). Flash chromatography of the reaction
mixture containing the hydroxyimines (33) yielded the diastereomers (33-01)
and (33-011) and recovered starting material (32). The diastereomers were
deprotected with dilute acid to give the hydroxyketone enantiomers (34-EI)
and (34-EII), respectively. The imines proved fairly stable to the acid, and
required overnight stirring with 2M HCI for complete hydrolysis. Chiral shift 1H
n.m.r. spectroscopy studies showed that (34-EI) had been isolated in >95%
e.e. (2% of [34-EII]) and that (34-EII) had been isolated in 90% e.e ..
Scheme 33
MeyPh
N 0
~o/Me MeU/THF
U0 "F 1.5 hours
(32) Lt.
2MHCI
[)CM w~
(34)
2.5 Synthesis of the ethyl 2-fluoro-1-indanone-2-carboxylate (37)
EthyI2-fluoro-1-indanone-2-carboxylate was synthesised from 1-indanone
51
with diethyl carbonate and sodium hydride under the same conditions as
used for the synthesis of methyI1-tetralone-2-carboxylate (31b). Fluorination
was carried out using N-fluoro-N'-chloromethyltriethylenediamine
bis(tetrafluoroborate) (Scheme 34).
Scheme 34
o orrC02Et ij NaHIDMF I •
"'" iij ~ (36) ~"\ SF;
~BF' tH,CI'
i) NaH. (EIO),CO
ITHF .. (35) (37)
2.6 Separation of enar.tiomers of (37) via imine derivative (38)
The imine (38), derived from (R)-(+)-u-methylbenzylamine, was obtained
by the method described for (32) (Scheme 35).19
Scheme 35
MeyPh
~N o/Et
:... I * F 0 2MHCI
~ DCM
(38)
The isomers of the imine (38) proved slightly more problematic to separate
than those of the tetralone imine derivatives (32).
Figure 8: The four possible isomer of the imine (38)
Me Me Ph Ph
~Ph ~Ph Me~ Me~ N 0 N 0 N 0 N 0 W/E1 ~~o/EI ~/Et ~~O/Et I ' ·· .. F 0 I S F I ' ····F 0 I S F
"'" "'" "'" syn-(R.R) syn-(R.S) anti-{R.S) anti-(R.R)
The four individual isomers were visible by tic. Two of the isomers could be
crystallised out together from the racemic mixture using ethanol. These were
the fastest running and third fastest running compounds on the tic plate. The
least polar compound was the more abundant of. the two isomers in the solid
52
(38-01) (ca. 9: 1 by 1H n.m.r. spectroscopy). Removal of the imine group from
these isomers (38-01) yielded the ketone (37-EI), which was shown be one
enantiomer (> 95% e.e.) using 1H n.m.r. spectroscopy, and the chiral shift
reagent, Eu(hfch, The two isomers in the solid (38-01) must therefore have
been the syn- and anti- isomers of either (R,R)-(38) or (R,S)-(38) isomer.
The two remaining syn- and anti- isomers were isolated as an oil (38-011).
This oil contained approximately 20% of (38-01), hence the enantiomeric
excess of the deprotected ketone (37-EII) was not determined using 1H n.m.r.
spectroscopy, and the chiral shift reagent, Eu(hfch.
2.7 Synthesis of methyl 2,5,7 -trifluoro-1-indanone-2-carboxylate (47)
In order to further increase the activity of the dioxirane derivatives of the 2-
acyl-2-fluoro-1-indanone, fluorine was incorporated into the aromatic ring.
Previous work in this Department154 has shown that fluorine positioned ortho
or para- to the carbonyl substituent increases the oxidising ability of the
dioxirane derivative to a greater extent than if incorporated at a meta
position. 3,5-Difluorobenzaldehyde (39) was chosen as the starting ketone
because the cyclization of the 3-(3,5-difluorophenyl)propionic acid (42), in a
later step, produces only one product, the 5,7 -difluoro-1-indanone (43) in
which the fluorines are situated ortho- and para- to the carbonyl substituent.
Ethyl 3-(3,5-difluorophenyl)-2,3-dehydropropionate (40) was synthesised
by two methods:
i) from 3,5-difluorobenzaldehyde (39) and triethyl phosphonoacetate using
the Wadsworth-Emmons Reaction (Scheme 36).173 This reaction involved the
generation of the phosphonate anion using sodium hydride. Because of the
thermal instability of this anion, and the necessity for heat to aid its formation,
the 3,5-difluorobenzaldehyde was added before heat was applied.
ii) from 3,5-difluorobenzaldehyde (39) and (carbethoxymethylene)triphenyl
phosphorane using the Wittig Reaction (Scheme 37).174 The latter method
proved to be much quicker and simpler.
53
Scheme 36
Scheme 37
F
,;?
+ F ~
H
(39) 0
o H 11 1
OeNa'" 1
(EtO)2 P-C-G02Et __ e
~H (EtO)2i1 +
H,~/C02Et
A(C'H
, , , , , t
Ar
40 H "-11 1
(EtO)2 P-C-C02Et
~-6-H I Ar
(C6H5hP=CHC02C2f-is
-----.
• F
o
+ (40)
e9 ~ (EtO)2 P-rC-C02Et ,:,)""
O-C-H I Ar
F
,;?
~ ..? CO2 Et
(40)
The reaction resulted in a 91 % yield of the alkene (40). The coupling
constant of the alkene protons in the lH n.m.r. spectrum was 16.0 Hz. A
vicinal coupling constant of this magnitude for protons of an alkene show the
protons to be trans. This alkene (40) was then hydrogenated using 10%
palladium on carbon catalyst, in ethyl acetate, under an atmosphere of
hydrogen, (Scheme 38). This gave a 97% yield of ethyl 3-(3,5-
difluorophenyl)propionate (41).
Scheme 38
F F 10% Pd/C
H2 EtOAc F (40) F (41)
This ester (41) was then hydrolyzed using potassium hydroxide in ethanol
and water. The resulting intermediate then undergoes acyl-oxygen cleavage
54
to give the acid (42) (Scheme 39). This mechanism is generally referred to as
BAC2 (base-catalyzed, acyl-oxygen cleavage, bimolecular).
I Scheme 39
F K'
YJI cr-OH ~ / ~
EtO 0 . F (41)
Fyjl + EtO---> C + K;
~ , o OH F (42)
A cyclization step, analogous to the one required in this synthesis, has
been reported by Metz.'7S Following his procedure, using an excess of
polyphosphoric acid and a reaction temperature of 45°e, the cyclized product
(43) was obtained in 97% yield (Scheme 40). The reaction was carried
initially out at a temperature of 100oe, but only a 41 % yield was obtained.
Scheme 40
® = phosphate group
F~ F 0
-(43)
Since only low yields, typically 5% or less, were obtained for acylation of
the indanone (43) using the method used previously, namely sodium hydride
and diethyl carbonate, an alternative approach was needed. The next
approach was to attempt the synthesis of the trimethylsilyl enol ether, which
then could be reacted with lithium diisopropylamide followed by methyl
cyanoformate to give the desired product. Olah et al 176 have successfully
synthesised the TMS enol ether of 1-tetralone (44) using
trimethylchlorosilane, triethylamine and lithium sulfide in acetonitrile, at
ambient temperature (Scheme 41).
55
Scheme 41 '76
U2S TMSCI Et3N
Idry MeCN
16 hrs 81 QC
OTMS
~(75%) VU (44)
Attempts at using this method to produce the TMS enol ether of the 1-
inganone derivative proved unsuccessful. The reaction was difficult to follow
by proton n.m.r. because the triethylamine masked the alkyl proton signals.
To overcome this the reaction was carried out using an ion exchange resin
(Amberlyst A-21, supplied as the free base, -N[CH3h) to mop up the
hydrochloric acid produced in the reaction. In both cases the major product
was identified as the dimer (45). The characteristic m\z values of 73 and 75,
attributable to TMS were not present in the mass spectrum of this compound.
However, the m\z value of 331 was present, which corresponds to the
molecular ion, MH+', of the sulfur-bridged dimer. The signal in the 13C n.m.r. '-'
spectrum for the carbon at position 7 of the indanone (43) appears at Qc
159.9, as a double doublet. The coupling constants, 266.6 and 14.1 Hz,
correspond to coupling to the fluorine to which it bonded, and to the fluorine
at the C-5 position, respectively. In the 13C n.m.r. spectrum of the product
(45), the signal for the carbon at position 7 appeared as a doublet. The larger
coupling had been lost, and only the smaller coupling (10.1 Hz) with the
fluorine at the C-5 position was present. Attempts to synthesise the TMS enol
ether of 1-tetralone (44) following the procedure published by Olah,176 only
gave a 17 % yield, much less than was quoted in the paper.
f
(45)
56
In the reaction with diethyl carbonate, the difluorinated indanone (43)
appeared to be more open to nucleophilic attack by the difluorinated
indanone anion than the diethyl carbonate since only what appeared to be
the dimeric products were produced. In order to determine the conditions for
base-initiated deprotonation at the C-2 position, without reaction of the
produced anion with the starting indanone, a deuteration experiment was
carried out. A small quantity of 5,7 -difluoro-1-indanone (43) was added
slowly to a solution LOA at "78 ac. The reaction was quenched with d4-acetic
acid and the deuterium incorporation determined from comparison of the
electron impact mass spectrum of the crude product and that of the starting
material. It was deduced from these results that thirty eight percent of the
indanone molecules contained at least one deuterium atom. The integration
(I) in the proton n.m.r. spectrum of the crude product for the protons on C-2
(IiH 2.67 - 2.62; I = 26 mm) was markedly reduced compared to that for the
protons on C-3 (OH 3.11 - 3.07; I = 40 mm). However the proton n.m.r.
spectrum showed no evidence of any dimer formation and it was decided to
proceed using this method. Oropwise addition of the indanone (43) to LOA at
-78°C, followed by the addition of Mander's reagent, 158 gave the required
ester (46) in 64% yield (Scheme 42). Fluorination was achieved using the
usual method and produced the methyI2,5,7-trifluoro-1-indanone-2-
carboxylate (47) in high yield (Scheme 43).
Scheme 42
FM (43)
i) LDA/THF -7aoC ..
ii) MeOCOCN
F o
F
57
F 0
~ C02Me
FAJ-)<F
(47)
2.8 Synthesis of 1S-methoxy-1S-phenylacetone (50)
Curci et aiD found that the in situ generated dioxirane derivative of the
methyl ketone of Moshers acid (a-methoxy-a-trifluoromethylphenylacetone)
gave low enantioselectivity in its epoxidation of alkenes. The synthesis of 1 S
methoxy-1 S-phenylacetone (50) was therefore undertaken and achieved from
commercially available (S)-(+)-a-methoxyphenylacetic acid using a method
developed by Nahm and Weinreb (Scheme 44).191
Scheme 44 Ph (COCQ2 Ph
MeO~C02H • MeO~COCI DCM
+ Me 1 H N' CI-2 , OMe
pyridine
Ph Ph OMe
~Me MeU ~~ MeO • MeO .... Me
(50) 0 H+ (49)
Epoxidation of trans-stilbene using the in situ generated dioxirane of this
ketone (50) rapidly converted the alkene to the epoxide. However due to the
small scale of the reaction, chiral shift studies were unsuccessful on the
epoxide.
58
Chapter 3
Chapter 3
3.1 Use of the 1-tetralone (19) and 1-indanone (20) dioxirane derivatives
in the oxidation of alkenes.
The dioxiranes were generated in situ from the tetralone (19) and
indanone (20) derivatives. The concentration of ketone in the
dichloromethane appears to have a dramatic effect on the rate of the
reaction, therefore this was standardised using a 0.5 M solution of the ketone
in the dichloromethane. Potassium peroxymonosulphate (Oxone®) was
added in small portions. Reactions were monitored by 'H n.m.r or G.C.
analysis and sufficient Oxone® added until enough epoxide had been formed
for chiral shift analysis to be performed. The reaction times of the
experiments carried out, ranged from a few hours to several days.
The alkenes were first epoxidised using an isolated solution of
dimethyldioxirane in acetone.'6. 20 Chiral shift studies were then carried out on
the resulting epoxides to determine the amount of chiral shift reagent,
Eu(hfch, required for baseline separation of the peaks of the enantiomers in
the 'H n.m.r. spectrum (et. p. 116, Chapter 3, Experimental). The
enantiomeric ratio of the epoxide produced in each of the in situ reactions
was then determined using these results as a standard.
Each of the alkenes were subjected to a blank run, in which no ketone was
used in the reaction. After the addition of sixty equivalents of Oxone®, no
epoxidation was noted for trans-stilbene (23) or the chromene (24), and only
1.5% epoxidation for trans-~-methylstyrene (25). From these results we can
conclude that the dioxirane derived from the ketone is playing the major role
in the alkene epoxidations.
3.2 Results of Epoxidations
No enantioselectivity was observed for the epoxidation reactions using the
dioxirane derivatives of (31 b) and (31 c). It was thought that this may have
been due to conformational mobility of the saturated ring in the tetralone
59
system. The fact that, in the solid state, the ester residue prefers to take up
the axial conformation supports this view (Figure 1).
Table 5: Results of Epoxidations using the Isolated Diastereomers of (31c)
Olastereomer 11 Olastereomer I -Enantiorrer Ratio ~
%Cooversion of ciJo2 o 0 2 Alkene to EpOlGde WO'" "~F
.
? 50:50 50:50
14% 19% RI
240
/ 50:50 50:50
84% 76%
120
~ 50:50 50:50
56% 49%
180
Equivalents of Oxone
Table 6: Results of Epoxidations using the Isolated Enantiorners of (31b)
~
Enantiomer I Enantiomer 11 Enantiomer Ratio 0 0 0 0
% Conversion of Alkene cXi/~ CJCf, /Me
to Epoxide I • F 0 I • F 0
rPh 50: 50 50: 50
Me 100% 98%+ 120
Equivalents of Ox one
60
No enantioselectivity was observed in these epoxidation reactions. This
may be due to conformational mobility of the saturated ring in the tetra lone
system. We thought that incorporating a hydroxy group beta to the ketone,
may confer some conformational stability via hydrogen bonding to one of the
oxygen in the dioxirane ring. The results that we obtained for the epoxidation
of alkenes using the dioxirane derivative (48) of such a ketone (34) did not
show any improvement on our previous results.
Table 7: Results of Epoxidations using the Isolated HydroxyEnantiomers of (34)
Enantiomer Ratio
% Conversion to Alkene
Me
r' Ph
240
Equivalents of Ox one
Enantiomer I o OH
Me • Me
F
50 :50
96",(,
Enantiomer 11 o OH
50 :50
95%
From models ofthe 1-tetralones (19) and 1-indanones (20), it appeared
that the indanone (37) had less conformational flexibility than that of the
tetralone (31). We, therefore, hoped that with this more conformationally.
stable structure, the dioxirane derivative of the indanone (37) would show
some enantioselectivity in its epoxidation of alkenes. From our results, it can
be seen that no enantioselectivity was observed.
61
Table 8: Results of Epoxidations using the Isolated Enantiomers {,f (37)
EnantiornerJ Enantiornerll
Enantiomer Ratio 0 0 0 0
~~Et ~o~Et % Conversion of I • F 0
Alkene to Epoxide
Me 50::'50 ;I
Ph 98% 60
Equivalents of Ox one
Since no enantioselectivity was observed, when using the above
homochiral ketones, in the epoxidation of the alkenes, we deemed it
unnecessary to separate the enantiomers ofthe methyI2,5,7-trifluoro-1-
indanone-2-carboxylate (47), We have included this molecule in this report to
show the influence of fluorine on the rate of the reaction,
Table 9: In Summary -
Ketone % Conversion of alkene to epoxide
(Equivalents of Oxone used)
Alkene 31b-E1 31c-DII 31c-D1 34-E1 37-E1 47
- 14% 19% - - -21 - (240) (240) - - -
100% 84% 76% 98% 98% 100% 22 (120) (120) (120) (240) (60) (30)
- 56% 49% - - -23 (180) (180) - - - -
Table 9 shows the general reactivity of the dioxirane derivatives of the
ketones, Le" in decreasing order of reactivity: (47), (37), (31b), (31c), (34),
The result of the epoxidation reaction using the dioxirane derivative of methyl
2,5,7 -trifluoro-1-indanone-2-carboxylate (47) confirms our previous findings.
62
Chapter 4
Chapter 4
4.1 Optimising the conditions of the dioxirane epoxidation reaction
In order to acquire experience of the two phase dioxirane epoxidation
reaction, two reactions involving the in situ generation of the dioxirane
derivative of 1 ,1 ,1-trifluoroacetophenone were initially carried out. These
reactions are described in Chapter 4, Experimental (p117). The first
reaction involved the epoxidation of cholesterol using this dioxirane. The
epoxide was obtained in thirty percent yield. Trans-stilbene (23) was then
used in the reaction, forty percent being converted to the epoxide. These
results were in agreement with those previously obtained in this
Departmenl,l54 Since trans-stilbene (23) proved more susceptible to
epoxidation, it was initially used as the substrate in the dioxirane reactions.
The dioxirane derivatives of the 2-substituted tetralones (19) were used to
epoxidise trans-stilbene (23) using the conditions described on p118. The
results of these epoxidations are shown in Table 10.
Table 10
Ketone Precursor Number of Days Percentage Epoxide
26a 3 40
31a 2 45
31b 3 100
31 c-DII 7 0
37 6 6
As anticipated, the dioxirane derivative of ethyI2-methyl-1-tetralone-2-
carboxylate (26a) proved slower at epoxidations than the ethyl 2-fluoro-1-
tetralone-2-carboxylate (31 a). The methyl 2-fluoro-1-tetralone-2-carboxylate
(31b) app.eared to be a more efficient epoxidizing agent than the ethyl
analogue (31a). No evidence of epoxide formation was noted, using this
63
method, with the menthyl 2-fluoro-1-tetralone-2-carboxylate (31c-01l). On
optimising the conditions of the dioxirane reaction, alkene epoxidation using
the dioxirane derivative of this tetralone (31-011) was achieved (refer to
Chapter 3, Table 9).
The epoxidizing ability of ethyl 2-fluoro-1-indanone-2-carboxylate (37) was
also assessed. After six days only 6% of the epoxide and 94% of the starting
alkene was observed. None of the original indanone was found by GC-MS.A
series of experiments was carried out to find the best conditions for the
dioxirane reaction. These included changing the pH, the amount of phase
transfer catalyst, Oxone®, ketone and dichloromethane (refer to p 65 - 68).
The variables having the greatest effect were:
• pH: optimum approximately 7.5
• the concentration of the ketone in the dichloromethane: decreasing the
volume of dichloromethane, but using the same quantity of ketone,
significantly increased the rate at which the epoxidation reaction
proceeded.
• the concentration of phase transfer catalyst: increasing the quantity of
phase transfer catalyst increased the rate at which the epoxidation
reaction proceeded, but not to a very significant extent.
These results are in agreement with those found by Denmark et al. 26 The
experimental procedure which was eventually used is described in the
Experimental, Chapter 3.
64
Ol (Jl
Entry
1
2
3
4
5
6
7
8
9
10
11
12
13
Alkene Ketone
trans- J
31b stilbene trans- 31b
stilbene trans- 31b
stilbene trans- 31b
stilbene trans- 31b
stilbene trans-
31b stilbene trans-
31b stilbene trans- 31b
stilbene trans- 31b
stilbene trans- 31b
stilbene trans- 31b
stilbene trans- 31b
stilbene trans- 31b
stilbene
Ketone TBAHS Phosphate (Quantity) (eq.) Buffer (mll
1.95 9 1.0 40 2.0 ~g. 0.27 9 1.0 40 2.0eq. 0.19 9 1.0 40 2.0eQ. 0.19 9 1.0 40 2.0eq. 0.27 9 1.0 40 2.0eq. 0.10 9
1.0 10 2.0eq. 0.20g
5.0 14 2.0eq. 0.30g
5.0 14 3.0 eg, 0.48 9 5.0 66 10.0
0.07g 10.0 20
5.0eq. 0.07g
10.0 20 5.0eQ. 0.07g
10.0 20 5.0~
0.07g 10.0 20 5.0eq.
pH Oxonee Number DCM EDTA.Na, Epoxide
(eQ.) of days (ml) (Q) (%)
7.5 50x 3 3 40 1 0
7.5 50x 3 3 40 1 100
7.5 50x4 4 40 1 0
7.5 50x 3 3 40 1 0
7.5 50x 5 5 30 1 0
7.5 50x7 7 10 0.33 0
7.5 50 x 1 1 10 0.35 0
7.5 50 x 1 1 10 0.35 -2
7.5 50x7 7 22 18mg -2
6.5 50x 2 1 6 10mg 0
6.5 50 x 16 B 6 10mg 0
6.5 50xB 4 6 10 mg 2
6.5 50x 10 5 6 10 mg 92
(J) (J)
Entry
14
15
16
17
18
19
20
21
22
23
Alkene
ll-methyl-stvrene
p-methyl-stvrene Irans-
stilbene Irans-
stilbene Irans-
stilbene ~-methyl-styrene
trans-stilbene
Irans-stilbene
Irans-stilbene
Irans-stilbene
Ketone Ketone TBAHS
(Quantity) (eQ.)
31b 1.009 0.02 2.0 eq.
31b 1.009 0.02 2.0eq.
31a 0.28 9 5.0 4.0 eQ.
31a 0. 14 9 1.0 2.0eQ.
31a 0.14 9 1.0 2.0eQ.
37 1.209 0.02 2.0eQ.
0 0.679 ctCF3
1.0 1.0 eq.
0 0.67 9 ctCF3
1.0 1.0 eq.
0 0.67 9 ctCF3
1.0 3.0 eq.
0 0.67 9 ctCF
,
1.0 3.0eq.
Phosphate pH
Oxone" Number DCM EDTA.Na, Epoxide Buffer (ml) (eQ.) of days (ml) (g) (%)
15 7.5 30x3 1 25 * 0
25 7.5 47.5 x 1 1 10 * 78
15 7.5 50x 5 5 10 0.4 <2
15 7.5 60x2 2 10 0.4 0
15 7.5 60x2 3 10 0.4 0
20 7.5 30x5 3 15 * 14
40 7.5 50 xl 1 40 1 11
40 7.5 50 Xl 1 30 1 40
40 7.5 50 xl 1 30 1 <10
40 10.5 50x 1 1 30 1 0
Entry Alkene Ketone Ketone TBAHS Phosphate
pH Oxonee Number DCM EDTA.Na, Epoxide
(quantity) (eq.) Buffer (ml) (eq.) of days (ml) (g) (%)
trans-0
0.67g 24 ciCF3
1.0 40 7.5 50 x 1 1 30 1 7 stilbene 3.0eq.
25 trans- d CF3
0.67 9 1.0 40 7.5 50 x 1 1 30 1 32 stilbene 3.0eq.
trans-0 0.67g
26 ciCF3 5.0 40 7.5 50 x 1 1 30 1 77
stilbene 3.0eq.
trans- :>=0 0.22 9 27 stilbene 3.0eq.
1.0 40 7.5 50 x 1 1 30 1 10
28 trans- 43 0.02 9 5.0 20 7.5 50 x 2 1 6 . 0.5 mg 29
stilbene 2.0 eq.
29 trans- 43 0.02g
5.0 20 7.5 50 x 1 1 6 0.5 mg 8 stilbene 2.0 eq.
30 trans- 43 0.02 9 5.0 20 7.0 50 x 1 1 6 0.5 mg -1
stilbene 2.0eq.
31 trans- 43 0.05 9 10.0 20 6.5 50x 6 6 6 0.5 mg 7
stilbene 5.0eq.
32 trans- 43 0.05 9 10.0 20 7.0 50 x6 6 6 0.5 mg 19
stilbene 5.0eq.
33 trans- 43 0.05 9 10.0 20 6.5 50 x 2 1 6 10mg 2
stilbene 5.0eq.
34 trans- 43 0.05g 10.0 22 6.5 50 x 10 5 6 10mg 2
stilbene 5.0
m Cl)
Entry
35
36
37
Alkene
trans-stilbene trans-
stilbene p-methyl-styrene
Ketone Ketone TBAHS
. (quantity) (eq.)
43 0.05g 10.0
5.0
43 0.05 9 10.0 5.0
43 1.00 9 0.04 2.0 eq.
Phosphate pH
Oxone® Number DCM EDTA.Na, Epoxide Buffer (ml) (eq.) of days (ml) (q) . (%)
22 7.5 50 x2 1 6 10 mg -1
22 7.5 50x 2 1 6 10 mg 2
20 7.5 30x 6 2 15 • 39
Chapter 5
Chapter 5
5.1 Preparation of solutions of dioxiranes
The dioxirane derivatives of acetone, 1,1,1-trifluoroacetone and
cyclohexanone were prepared in solutions of their ketones, with molarities of
0.09 M, 0.68 M and 0.09 M being obtained, respectively. Attempts to prepare
the dioxirane derivatives of hexafluoroacetone and 1,1,1-
trifluoroacetophenone in solutions of their ketones with dichloromethane as
an additional solvent were carried out, albeit with little success. The molarities
obtained for these were 0.02 M and 0 M, respectively.
The resulting dimethyldioxirane solution was used to epoxidise various
alkenes. A slight excess of the dioxirane was used in each epoxidation. The
results were as follows:
trans-stilbene oxide 100%
trans-~-methylstyrene oxide 89%
6-acetyl-2,2-dimethyl-2H-1-benzopyran 85%
6-chloro -2,2-dimethyl-2H-1-benzopyran 89%
6-cyano -2,2-dimethyl-2H-1-benzopyran 89%
The solution of the dioxirane derivative of cyclohexane was used to oxidise
Metaclopramide. This gave the N-oxide in 73% yield (32% after
recrystallisation).
5.2 Determination of the molarity of a dioxirane solution by titration
The molarity of a dioxirane solution was determined by titration of the
iodine, which a known volume of the dioxirane solution liberated from
potassium iodide, against a thiosullate solution 01 known molarity.
69
Chemical equations for the titration
Reaction of the dioxirane with iodine:
o R 2KI + IX + H20 o R
R 12 + O=< + 2KOH
R
Reaction of the iodine with sodium thiosu/fate:
The molarity of the dioxirane solution is calculated:-
Number of moles of sodium
thiosulfate solution used = V Na2S,03 X M Na2Sp3
1000
Since 2 moles of potassium iodide react with 1 mole of the dioxirane to give 1
mole of iodine, and the iodine reacts with 2 moles of sodium thiosulfate:
1 mole dioxirane == 2 moles sodium thiosulfate
Number of moles of
dioxirane used =
1000 x 2
Mo larity of the
dioxirane solution
V Na2Sp3 X M Na2SP3 x..J.Oe(J
..J.Ge(} x 2 x V dioxirane
where M Na2S
20
3 = molarity of the sodium thiosulfate solution
V N so = volume of sodium thiosulfate used a 2 2 3
V dioxirane = volume of dioxirane solution used
Example Calculation:
Titration of a freshly prepared solution of dimethyldioxirane:
Volume of dioxirane solution taken: 0.2 ml
Molarity of the sodium thiosulfate solution: 0.01182 N
70
Volume of sodium thiosulfate solution needed (titre): 2.56 ml
= 2.56 x 0.01182 = 0.076 M 0.2 x 2
71
i
/' .
Conclusion
Conclusion
Although no enantioselectivity was observed for the epoxidation reactions
using the dioxirane derivatives of (19) and (20). these compounds have been
shown to efficiently epoxidise a variety of alkenes. The rate of epoxidation
was shown to be dependent on steric factors and the incorporation of fluorine
into the aromatic ring of arylalkyl ketones. The rate of epoxidation was also
shown to be highly dependent on dilution factors. i.e. on the concentration of
the dioxirane in the organic phase.
72
Experimental
Experimental
General
1H NMR spectra were recorded on a Bruker 250 MHz NMR Spectrometer. All
samples were recorded with tetramethylsilane as internal standard. Chemical
shifts (0) are reported in ppm. Multiplicities are reported as follows: br
(broad), s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet).
13C NMR spectra were recorded on a Bruker 250 MHz NMR Spectrometer
19F NMR spectra were obtained on a 400 MHz NMR Spectrometer.
IR spectra were recorded on a Nicolet 205 series FT-IR Spectrometer.
Mass spectra were obtained on a Kratos MS80 Spectrometer with OS-55
data system.
Column chromatography was carried out using the flash chromatography
technique with Matrex Silica 60, 35-70 micron (Fisons Scientific Equipment)
unless otherwise noted.
Thin layer chromatography was carried out using aluminium sheet silica gel
60 F254, 0.2 mm layer thickness (Merck) or aluminium sheet aluminium oxide
60 F254 neutral (type E), 0.2 mm layer thickness (Merck).
Preparative TLC was performed on 0.2 metre glass backed plates coated
with Kieselgel 60PF254 (Merck).
Optical Rotation. The [0.]0 values were measured using an Optical Activity
AA 100 polarimeter.
Melting points were obtained on a Reichert Manual Melting Point Apparatus.
pH Stat. experiments were controlled using a Radiometer autotitrator. Type
ABU 11b.
Microanalysis was performed at Medac Ltd. (Brunei University), or within this Department.
73
Chapter 2, Experimental
EthYI-1-tetralone-2-carboxylate (26)161, 162 (Ethyl 1 ,2,3,4-tetrahydro-1-oxonaphthalene-2-carboxylic acid) cD . 0 °o,Et
Method 1158, 161, 162
To a stirred solution of diisopropylamine (1.27 ml, 9.03 mmole) at 0 cC,
under argon, was added butyllithium (2,5 M solution in hexane, 3.61 ml, 9.03
mmole). This gave a thick gel, to which was added dry THF (20 ml). The
resulting solution was stirred for twenty minutes then the temperature was
lowered to -78 cC. A solution of 1-tetralone (1.00 ml, 7.52 mmole) was added
and stirring continued for 1 hour at 0 cC. The temperature was lowered again
to -78 cC, and HMPA (1.31 ml, 7.52 mmole) followed by ethyl cyanoformate
(0.89 rnl, 9.03 mmole) added. The reaction mixture was allowed to warm to
room temperature and left to stir for ten minutes. After this time, the solution,
was poured into cold water (80 ml), extracted with dichloromethane (2 x 80
ml), dried (Na2S04) and concentrated in vacuo to yield a brown liquid (3.43 g).
Tic analysis (silica with 9 : 1 light petroleum [b,p. 40 - 60 cC] : ethyl acetate)
showed three spots; 0.75 (desired product [26]), 0.51 (1-tetralone) and
baseline material. The product was isolated by column chromatography (silica
with 9 : 1 light petroleum [b.p. 40 - 60 cC] : ethyl acetate) yielding a pale
yellow liquid (0.835 g, 51%); vmax (neat) 3060,2976 (C-H), 1738 (ester C=O),
1684 (a.-arylketone C=O), 1642 (enol ester C=O), 1618 (enol ester C=O),
1596, 1568 and 1452 cm,1 (arene C-C); OH (250 MHz, CDCla) 12.49 (1 H, s, J
enolic H), 8.04 (1 H, d,d, J7.8, 1.2 Hz, ketoester 8-H), 7.80 (1 H, d,d, J7.5,
1.6 Hz, enol 8-H), 7,52 - 7.17 (6 H, m, ketoester and enol 5-H, 6-H, 7-H), 4.27
(4 H, q, J7.2 Hz, ketoester and enol CH2CHa), 3.59 (1 H, d,d, J10.3, 4.9 Hz,
ketoester 2-H), 3.04 - 2.48 (8 H, m, ketoester and enol3-H and 4-H), 1.34 (3
H, t, J7.1 Hz, ketoester CH2CHa), 1.30 (3 H, t, J7.2 Hz, enol CH2CHa); Oc
74
(62.5 MHz, CDCb) 193.2 (ketone 1-C), 172.7 and 170.2 (ketone and enol2-
C02Et), 165.0 (enoI1-C), 143.7 and 139.4 (ketone and enoI8a-C), 133.8 and
130.5 (ketone and enoI8-C), 131.8 and 130.0 (ketone and enoI4a-C), 128.8
and 127.6 (ketone and enoI7-C), 127.4 and 126.8 (ketone and enoI6-C),
126.5 and 124.3 (ketone and enol 5-C), 97.0 (enoI2-C), 54.4 (ketone 2-C),
61.2 and 60.5 (ketone and enol 2-C02CH2CH3), 27.7 and 27.6 (ketone and
enol 4-C), 26.4 and 20.5 (ketone and enol 3-C), 14.3 and 14.2 (ketone and
enol 2-C02CH2CH3). Ratio of ketoester : enol was 1 : 1. After chromatography
with petroleum ether only, no ketoester was observed, but gradually the ratio
moved towards 1 : 1 on standing at room temperature.
Method 2161
1-Tetralone (4.00 g, 3.88 ml, 27.36 mmole) was added to a stirred
suspension of sodium hydride (60% dispersion in oil, 1.32 g, 32.84 mmole) in
dry diethyl carbonate (19.50 g, 20 ml, 165 mmol), under an atmosphere of
" argon. On application of heat for five minutes, a solid formed. The reaction
mixture was allowed to cool. Tic analysis of the solid showed no evidence of
1-tetralone. The solid was dissolved in 2 M HCI (100 ml) and extracted with
ethyl acetate (3 x 100 ml). The organic extracts were dried (Na2S04) then
concentrated in vacuo to yield a brown liquid (12.006 g). The product was
purified by column chromatography (silica with 9 : 1 light petroleum [b.p. 40 -
60 ·C] : ethyl acetate) followed by Kugelrohr distillation to yield a pale yellow
liquid (5.483 g, 92%); b.p. 190·C (1 mm Hg). I.r. and n.m.r. data as above.
75
Methyl 1-tetralone-2-carboxylate (27) 161.177
(Methyl 1.2,3,4-tetrahydro-1-oxonaphthalene-2-carboxylic acid)
o
1-Tetralone (2.50 g, 2.78 ml, 17.10 mmole) was added to a stirred
suspension of sodium hydride (60% dispersion in oil, 0.821 g, 20.52 mmole)
in dry dimethyl carbonate (19.50 g, 20 ml, 165 mmole), under an atmosphere
of nitrogen. The reaction mixture was heated for fifteen minutes during which
time a lilac and white solid formed. Further dry dimethyl carbonate (5 ml) was
added via syringe. Tic analysis of the solid showed no evidence of 1-
tetralone. The solid was allowed to cool to room temperature, dissolved in
hydrochloric acid (aqueous 2M, 50 ml) and extracted with ethyl acetate (4 x
50 ml). The combined extracts were dried (MgS04) and concentrated in
vacuo to yield a brown oil (4.328 g). This crude product was purified by flash
chromatography (silica with 9 : 1 light petroleum [b.p. 40 - 60 QC] : ethyl
acetate) to yield a colourless crystalline solid (27) (3.411 g, 98%); m.p. 61.5
QC - 69.5 QC; b.p. 200 QC (2 mmHg); vmax (neat) 2951 (C-H), 1745 (ester
C=O), 1685 (a-aryl ketone C=O) 1650, 1648, 1620, 1600, 1570, 1453, 1441,
1363 cm'1; OH (250 MHz, CDCI3) 12.41 (1 H, s, enol OH), 8.01 (1 H, d,d, J7.8,
1.4 Hz, ketoester 8-H), 7.77 (1 H, d,d, J7.0, 1.6 Hz), 7.45 - 7.13 (6 H, m,
keto ester and enol 7-H, 6-H and 5-H, 3.78 (3 H, s, enol CH3), 3.74 (3 H, s,
ketoester CH3), 3.01 - 2.91 (2 H, m, ketoester 4-H), 2.79 - 2.73 (2 H, s, enol
4-H), 2.63 - 2.08 (4 H, m, ketoester and enol 3-H); Bc (62.5 MHz, CDCI3)
192.9 (ketone 1-C), 173.0 and 170.6 (ketone and enol 2-C02Me), 165.0 (enol
1-C), 143.7 and 139.4 (ketone and enoI8a-C), 133.9 and 130.5 (ketone and
enoI7-C), 131.6 and 129.9 (ketone and enoI4a-C), 128.8 and 127.7 (ketone
and enol 6-C), 127.4 and 126.9 (ketone and enol 5-C), 126.5 and 124.3
(ketone and enol 8-C), 96.8 (enol 2-C), 54.4 (ketone 2-C), 52.3 and 51.6
(ketone and enoI2-C02 CH3), 27.7 and 27.6 (ketone and enoI4-C), 26.3 and
20.5 (ketone and enol ~-C).
76
L-Menthyl 1-tetralone-2-carboxylate (28)
(L-Menthyl 1 ,2,3,4-tetrahydro-1-oxonaphthalene-2-carboxylic acid)
o
•
Method 1158
o ..... Men o
To stirred diisopropylamine (0.977 g, 9.65 mmole) under argon, was added
butyllithium (2.3M in hexane, 4.1 ml, 9.65 mmole) at -20 QC. This immediately
formed a clear gel, to which was added tetrahydrofuran (dry, 3 ml) and the
resulting solution left to stir at -20 QC for thirty minutes. The temperature was
lowered then to -78 QC and 1-tetralone (1.200 g, 1.112 ml, 8.00 mmole)
added. The flask was warmed to 0 QC and stirred for one hour, after which
time the temperature was lowered to -78 QC and HMPA (1.44 g, 1.40 ml, 8.00
mmole) followed by L-menthyl chloroformate (2.11 g, 2.07 ml, 9.65 mmole)
added: The reaction mixture was left to stir overnight at room temperature,
then poured into a separating funnel containing distilled water (100 ml). The
aqueous fraction was then extracted with dichloromethane. The organic
extracts were dried (MgS04) and concentrated in vacuo to yield a brown oil
. "(4.289 g). This crude material was purified by flash chromatography (flash
silica with 1:1 dichloromethane : light petroleum [b.p. 40 - 60 QC] followed by
7:1 light petroleum [b.p. 40 - 60 QC] : diethyl ether) to yield the desired
material as a clear oil (1.100 g, 42%). Three products were produced in this
reaction. These appeared (tic analysis using silica with 1:1 dichloromethane :
light petroleum [b.p. 40 - 60 QC]) at R, values of 0.75 (L-Menthyl 3,4-
dihydronaphthalene-1-carbonic acid [30]),.0.57 streaking (L-MenthyI1-
tetralone-2-carboxylate [28]), 0.57 (N,N-diisopropyl L-menthyl carbamate
[29]). Tic analysis using silica with 7 : 1 light petroleum [b.p. 40 - 60 QC] :
diethyl ether gave R, values of 0.65 streaking (L-Menthyl 1-tetralone-2-
carboxylate [28]) and 0.40 (N,N-diisopropyl L-menthyl carbamate [29]).
77
?
L-Menthyl Hetralone-2-carboxylate (28): vmax (neat) 2955 (aromatic C-H),
2932 (C-H), 2870 (saturated C-H), 1734 (ester C=O of ketoester), 1690 (a.
aryl ketone C=O), 1643 (enol ester C=O), 1618 (enol ester C=O), 1570, 1455,
1389,1268,1213,1085 cm-'; OH (250 MHz, CDCI3) 12.60 (1 H, s, OH), 8.05
(1 H, d,d, J7.7, 1.2 Hz, ketoester 8-H), 7.80 (1 H, d,d J6.9, 1.7 Hz, enol ester
8-H), 7.47 (1 H, t,t, J7.5, 1.4, ketoester 7-H), 7.35 -7.15 (5 H, m, enol ester 7-
H, 6-H, 5-H, ketoester 6-H, 5-H), 4.89 -4.79 (2 H, m, enol ester and ketoester
CHO-CO), 3.59 -3.55 (1 H, m, ketoester 2-H), 3.00 - 2.99 (2 H, m, ketoester
4-H), 2.81 (2 H, t, J7.8 Hz, enol ester 4-H), 2.59 - 2.52 (4 H, m, enol ester
and ketoester3-H), 2.25 - 2.12 (2 H, m, menthyl C-H), 1.97 -1.83 (2 H, m,
menthyl C-H), 1.73 - 1.24 (10 H, m, menthyl C-H), 1.20 - 0.69 (7 H, m,
menthyl C-H), 0.94 - 0.90 (12 H, m, enol ester and ketoester CH3 of iso
propyl group), 0.80 (6 H, d, J7.0 Hz, enol ester and ketoester Me); Oc (62.5
MHz, CDCI3) 193.5 (ketone 1-C), 172.4 and 169.6 (ketone and enoI2-C02),
164.9 (enoI1-C), 143.6 and 139.3 (ketone and enoI8a-C), 133.7 and 130.1
(ketonEl and enoI7-C), 130.2 and 131.8 (ketone andenoI4a-C), 128.8 and
127.7 (ketone and enol 6-C), 127.4 and 126.9 (ketone and enol 5-C), 126.5
and 124.2 (ketone and enol 8-C), 97.3 (enol 2-C), 75.4 and 74.5 (ketone and
enol 1 '-C), 47.1 and 46.8 (ketone and enol 2'-C), 41.8 and 40.7 (ketone and
enol 6'-C), 34.3 and 34:2 (ketone and enol 4'-C), 31.4 (CC1--l(CH3M 27.8 and
27.5 (ketone and enol 4-C), 26.6 (5'-C), 26.4 and 20.5 (ketone and enol 3-C),
23.7 (3'-C), 22.0 and 20.7 (2C, CCH( C1--l3)2) , 16.7 (5-CCl-I3).
N,N-diisopropyl L-menthyl carbamate (29): V max (neat) 2956 (aromatic C
H), 2933 (C-H), 2871 (saturated C-H), 1686 (C=O), 1456, 1433, 1368, 1328,
1287,1269 cm-'; OH (250 MHz, CDCI3) 4.66 (1 H, t,t J10.8, 4.3 Hz, CH-O
CO), 3.91 (2 H, broad s, NCH), 2.08 - 1.92 (2 H, m, menthyl C-H), 1.70 - 1.65
78
(2 H, m, menthyl C-H), 1.48 - 1.27 (2 H, m, menthyl C-H), 1.20 (12 H, d, J6.8
Hz, NCH(CH3h), 1.14 - 0.79 (3 H, m, menthyl C-H), 0.90 (6 H, d, J6.9 Hz,
CCH(CH3)2), 0.80 (3 H, d,d, J6.9, 1.7 Hz, Me); oe (62.5 MHz, CDCI3) 155.5
(OCON), 74.2 (1-C), 47.4 (2-C), 45.7 (2C, NQ-l), 41.6 (6-C), 34.5 (4-C), 34.5
and 34.3 (CQ-l(CH3H 26.2 (5'-C), 23.4 (3-C), 22.1 and 20.7 (2C,
CCH(Q-l3h), 21.0 (4C, (Q-l3h CHN), 16.3 (5-CQ-l3); m/z (electron impact)
283.2515 (M+, 2.5%, C17H33N02 requires 283.21129), 284 (4, M++1), 146
(57), 84 (100), 69 (25),55 (26),43 (43).
L-MenthyI3,4-dihydronaphthalene-1-carbonic acid (30): V max (neat) 2956
(aromatic C-H), 2933 (C-H), 2871 (saturated C-H), 1758 (C=O), 1733, 1456
(arene C-C), 1286, 1253, 1226, 1182, 1012 cm-1; OH (250 MHz, CDCI3) 7.20-
7.10 (4 H, m, ArH), 5.78 (1 H, t, J4.7 Hz, 2-H), 4.56 (1 H, t,t, J10.9, 4.4 Hz,
CH-O-CO), 2.84 (2 H, t, J7.9 Hz, 4-H), 2.46 - 2.38 (2 H, m, 3-H), 2.15 - 1.97
(2 H, m, menthyl C-H), 1.72 - 1.67 (1 H, m, menthyl C-H), 1.48 - 1.42 (1 H, m,
menthyl C-H), 1.19 - 0.80 (5 H, m, menthyl C-H), 0.94 - 0.91 (6 H, m, CH3 of
iso-propyl group), 0.85 - 0.82 (3 H, m, Me); Oe (62.5 MHz, CDCI3) 153.2
(OC02), 146.1 (1-C), 136.4 (8a-C), 130.4 (4a-C) , 128.2 (8-C), 128.0 (7-C),
127.5 (6-C), 120.5 (5-C) , 115.0 (2-C), 79.2 (1 '-C), 47.0 (2'-C), 40.6 (6'-C),
34.1 (4'-C), 31.4 (CQ-l(CH3h), 27.4 (4-C), 26.5 (5'-C), 23.4 (3-C), 22.0 (3'-C),
22.0 and 20.7 (2C, CCH(Q-l3h) 16.3 (5-CQ-l3); m/z (electron impact)
328.2051 (M+, 3.0%, C21H2803 requires 328.203845), 146 (100, M+
C02Menthyl), 139 (47), 118 (16), 95 (41), 83 (80), 69 (28), 55 (39), 41 (34),
27 (13).
79
Method 2
To a stirred solution of butyllithium (2.4 M in THF, 1.66 mmole, 3.98
mmole) in THF (0.5 ml), at -78 cC, under nitrogen, was added Hetralone
(0.540 g, 0.500 ml, 3.63 mmole). The solution was left to stir at 0 cC for one
hour. This resulted in an orange coloured solution. The reaction mixture was
returned to -78 cC and L-menthyl chloroformate added to it. This solution was
allowed to warm slowly to room temperature and left to stir overnight. The
solution was poured into a separating funnel containing distilled water (100
ml), extracted with dichloromethane (3 x 100 ml) and dried (MgS04).
Concentration of the dried organic extracts in vacuo yielded a yellow oil. The
desired product was obtained from this oil by column chromatography (silica
with 1:1 light petroleum [b.p. 40 - 60 CC]) as a clear oil (0.177 g, 15%). N.m.r
and Lr. data as above.
Method i64.178
Step I: To a stirring mixture of 1-tetralone (0.500 g, 0.455 ml, 3.42 mmole)
and pyrrolidine (0.730 g, 0.856 ml, 10.26 mmole) in dry diethyl ether (5 ml).
under nitrogen and at 0 cC, was added slowly titanium tetrachloride (0.357 g,
0.206 ml, 1.88 mmole). After one hour, the reaction was allowed to warm to
room temperature and left to stir overnight. Further diethyl ether (5 ml) was
,· .. added, then the solution filtered through celite to remove the titanium (IV)
oxide produced in the reaction. The organic phase was then concentrated in
vacuo to yield a yellow oil (0.528 g, 77%); V max (neat) 3060 (aromatic C-H),
2965, 2931,2877,2826, 1687, 1620 (enamine C=C), 1485, 1372, 1354,
1321, 1287,1186, 1135 cm·1; OH (250 MHz, CDCI3) 7.41 (1 H, d, J7.5 Hz, 8-
H), 7.24 - 7.08 (3 H, m, 7-H, 6-H, 5-H), 5.16 (1 H, t, J4.7 Hz, 2-H), 2.97 - 2.92
(4 H, m, N(CH2h), 2.67 - 2.61 (2 H, m, 3-H), 2.23 - 2.15 (2 H, m, 4-H), 1.96 -
1.82 (m, 4H, NCH2 (CH2)).
Step 11: To a stirring solution of the enamine (0.200 g, 1.00 mmole), in dry
benzene (15 ml), at room temperature and under nitrogen, was added L
menthyl chloroformate (0.110 g, 0.108 ml, 0.50 mmole). The mixture was
heated to reflux for four days. Tic analysis was carried out on the solution, but
80
no evidence of L-menthyI1-tetralone-2-carboxylate was observed. After the
four days, the reaction mixture was concentrated in vacuo to yield a brown oil
(0.437 g). The crude n.m.r. of this material showed no evidence of the ~
ketoester.
Method 4164• 178
Step I: Titanium tetrachloride (0.636 g, 0.368 ml, 3.35 mmole) was added
slowly to a stirring solution of 1-tetralone (0.500 g, 0.455 ml, 3.35 mmole) and
morpholine (0.876 g, 0.877 ml, 10.05 mmole) in dry diethyl ether (5 ml), under
nitrogen and at 0 cC. The reaction was left to stir for one hour at this
temperature. It was then allowed to warm to room temperature and left to stir
for a further six hours. After this time, the titanium (IV) oxide was removed by
filtration through celite and the resulting solution concentrated in vacuo to
yield an orange residue (0.691 g, 96%). The n.m.r. spectrum of this
compound showed the presence of unreacted 1-tetralone. The 1-tetralone
was removed by distillation of the residue (100 cC, 2.5 mm Hg). The
remaining residue was then purified by Kugelrohr distillation (200 cC, 2.5 mm
Hg) to give an orange-tinged gel (0.482 g, 67%); vmax (neat) 2956 (aromatic
C-H), 2933, 2887, 2850, 2827, 1624 (enamine C=C), 1442 (arene C-C),
1370, 1259, 1237, 1119, 1018 cm-'; OH (250 MHz, CDCI3) 7.42 (1 H, d, J7.0
Hz, 8-H);.T22 -7.10 (3 H, m, 7-H, 6-H, 5-H), 5.27 (1 H, t, J4.7 Hz, 2-H), 3.84
(4 H, t, J4.6 Hz, OCH2), 2.82 (4 H, t, J4.6 Hz, NCH2), 2.70 - 2.64 (2 H, m, 4-
H), 2.26 - 2.13 (2 H, m, 3-H).
Step 11: as for Step 11 in Method 3.
81
Ethyl 2-methyl-1-tetralone-2-carboxylate (26a)
o o o o
Sodium hydride (60% dispersion in oil, washed with dry petroleum ether,
0.263 g, 6.57 mmole) was added to a dry 100 ml round-bottomed flask,
followed by dry THF (25 ml). To the stirred suspension, under argon, was
added HMPA (0.981 g, 0.952 ml, 5.47 mmole) and a solution of ethyl 1-
tetralone-2-carboxylate (26) (0.800 g, 5.47 mmole) in dry THF (5 ml). The
reaction mixture was stirred for one hour at room temperature after which
time methyl iodide (1.553 g, 0.681 ml, 10.94 mmole) was added. The course
of the reaction was followed by tic chromatography (silica with 9: light
petroleum [b.p. 40 - 60 QC] : ethyl acetate). No starting material (Rt 0.74) was
visible after five minutes, but a new compound had appeared at Rt 0.49. The
reaction was carefully quenched with saturated ammonium chloride solution
(15 ml). This mixture was then poured into a separating funnel containing
distilled water (15 ml) and diethyl ether (30 ml). The layers were separated
and the aqueous layer further extracted with diethyl ether (3 x 30 ml). The
organic extracts were combined, washed with saturated sodium chloride
solution (4 x 15 ml), dried (MgS04) and concentrated in vacuo to give a deep
yellow liquid (1.195 g). The crude product was purified by flash
chromatography using silica with dichloromethane (Rt of product using this
system was 0.44). The product was obtained with a slight impurity as a yellow
orange liquid (0.150g, 18%) and in pure form as a yellow orange liquid (26a)
(0.553g, 65%); Vmax (neat) 3068,2980 (C-H), 1726 (ester C=O), 1684 (ketone
C=O), 1600 and 1452 cm-1 (arene C-C); OH (250 MHz, CDCI3) 8.06 (1 H, d,d,
J7.9, 1.4 Hz, 8-H), 7.50 - 7.20 (3 H, m, 5-H, 6-H, 7-H), 4.14 (2 H, q, J 14.1,
7.0 Hz, CH2CH3), 3.06 - 2.89 (2 H, m, 4-H), 2.66 - 2.56 (1 H, m, , 3-H), 2.11 -
2.00 (1 H, m, 3-H), 1.51 (3 H, s, 2-Me), 1.19 (3 H, t, J7.1 Hz, CH2CH3)·
82
Ethyl 2-fluoro-1-tetralone-2-carboxylate (31a)
o o o o
.. F
To sodium hydride (60% dispersion in oil, 0.092 g, 2.29 mmole), under dry
nitrogen, at 0 QC, was added ethyl 1-tetralone-2-carboxylate (26) (0.500 g,
2.29 mmole) in dry DMF (6 ml) in a dropwise manner. The reaction mixture
was left to stir for thirty minutes at 20 QC, after which time it was cooled to
-50 QC. To the cooled reaction mixture was added N-fluoro, N-chloromethyl
triethylenediamine bis(tetrafluoroborate) (80% active ingredient, 0.922 g, 2.08
mmole) in dry DMF (6 ml). The reaction was left to stir for fifteen minutes at -
50 QC, then allowed to warm slowly to room temperature.'65 The reaction was
followed by tic chromatography (silica with 9 : 1 light petroleum [b.p. 40 - 60
QC] : ethyl acetate). The reaction appeared to be complete after five minutes,
the starting material (Rr 0.53) having given rise to a new compound (Rr 0.23).
The reaction mixture was diluted with diethyl ether (100 ml). This organic
phase then was washed with NaHC03 solution (10% aqueous, 100 ml) and
NaCI solution (saturated aqueous, 100 ml), dried (MgS04) overnight, then
concentrated in vacuo to yield an orange oil (0.799 g). The desired product
was obtained by flash chromatography (silica with 9 : 1 light petroleum [b.p.
40 - 60 QC] : ethyl acetate). Ethyl 2-fluoro-1-tetralone-2-carboxylate (31 a)
was obtained as a clear oil (0.442 g, 90%); vmax (neat) 2984,2944 (C-H),
1763, 1739 (ester C=O), 1697 (ketone C=O), 1603 and 1310 cm-1; OH (250
MHz, CDCI3) 8.07 (1 H, d,d, J7.9, 1.3 Hz, 8-H), 7.55 (1 H, t,t, J7.5, 1.4 Hz, 7-
H), 7.36 (1 H, t, J7.4 Hz, 6-H), 7.28 (1 H, d, J7.7 Hz, 5-H), 4.29 (2 H, q, J7.1
Hz, C02CH2), 3.16 - 3.09 (2 H, m, 4-H), 2.78 - 2.14 (2 H, m, 3-H) and 1.27 (3
H, t, J7.1 Hz, CH3); OF (376.5 MHz, CDCI3, external reference CF3C02H) -
163.7, three minor impurities, all less than 1 %, also noted at -163.6, -164.1
and -189.8; m/z (electron impact) 237.0930000 (mH+, 3%, C'3H'3F03
requires 237.0926889) 216 (18), 170 (76), 163 (17),143 (12),133 (20),118
83
(100),109 (7). 90 (61),63 (11); Analysis Calculated for C'3H'3F03 (236.245):
C (66.09), H (5.55); Found: C (66.06), H (5.57).
o F
Occasionally, 2-fluoro-1-tetralone was found in the crude product. This was
obtained in purified form as a colourless crystalline solid; V max (neat) 2944 (C
H), 1703 (C=O), 1603, 1274, 1227,929 cm-'; OH (250 MHz, CDCI3) 8.07 (1 H,
d,d, J7.9, 1.4 Hz, 8-H), 7.53 (1 H, t,t, J7.5, 1.5 Hz, 7-H), 7.36 (1 H, t, J7.8
Hz, 6-H), 7.27 (1 H, d, J7.6 Hz, 5-H), 5.15 (1 H, 2d,d, J47.9, 12.7,5.2 Hz, 2-
H), 3.17 (2 H, m, 4-H), 2.64 - 2.30 (2 H, 2m, 3-H); 8c (62.5 MHz, CDCI3) 193.4
(d, J14.8 Hz, 1-C), 143.1 (8a-C), 134.2 (8-C), 131.2 (4a-C) , 128.7 (7-C),
127.8 (6-C), 127.1 (5-C), 91.2 (d, J187.9 Hz, 2-C), 30.3 (4-C), 30.0 (4-C'),
27.1 (3-C), 26.9 (3-C'); Analysis Calculated for C,oHgFO (164.180): C(73.16),
H(5.53); Found: C(73.09), H(5.50).
84
Methyl 2-fluoro-1-tetralone-2-carboxylate (31 b)
.... Me o
•
To a stirred suspension of sodium hydride (60% dispersion in oil, 0.098 g,
2.45 mmole) in DMF (2.5 ml), at 0 QC, under nitrogen, was added methyl 1-
tetralone-2-carboxylate (27) (0.500 g, 2.45 mmole) in DMF (2.5 ml). This was
left to stir at 0 °c for twenty minutes. A solution of N-fluoro, N-chloromethyl
triethylenediamine bis(tetrafluoroborate (0.943 g, 2.13 mmole) in DMF (5 ml)
was added to the above solution at -50°C. '65 The reaction mixture was then
allowed to slowly warm to room temperature and left to stir overnight. After
this time, the reaction mixture was poured into a separating funnel containing
diethyl ether (100 ml). This solution was washed with NaHC03 solution (10%
aqueous, 100 ml) and NaCI solution (saturated aqueous, 100 ml), dried
(MgS04 ) and concentrated in vacuo to yield a yellow oil (0.775 g). Tic
analysis (9 : 1 light petroleum [b.p. 40 - 60°C] : ethyl acetate) of the crude
reaction mixture showed the reaction to be complete after approximately five
minutes (starting material: Rt 0.38, product: R, 0.13). The crude product was
then purified by flash chromatography (silica with 9 : 1 light petroleum [b.p. 40
- 60°C] : ethyl acetate, gradually moving to 4 : 1) followed by recrystalization
from ethanol to give clear columnar-shaped crystals (31 b) (0.334 g, 71 %);
m.p. 75°C; vmax (neat) 2955 (aromatic C-H), 1766 (ester C=O), 1744, 1697
(ketone C=O), 1603, 1457 (arene C-C), 1438, 1312, 1281, 1228, 1199,1088
cm-'; OH (250 MHz, CDCI3) 8.06 (1 H, d,d, J7.9, 1.3 Hz, 8-H), 7.55 (1 H, t,t, J
7.5, 1.5 Hz, 7-H), 7.40 - 7.28 (2 H, m, 5-H, 6-H), 3.62 (3 H, s, Me), 3.18 - 3.09
(2 H, m, 3-H), 2.77 - 2.52 (2 H, m, 4-H); Oc (62.5 MHz, CDCI3) 188.5 (d, J
18.8 Hz, 1-C), 167.7 (2-OJ2Me), 143.2 (8a-C), 134.7 (8-C), 130.5 (4a-C),
128.8 (7-C), 128.5 (6-C), 127.3 (5-C), 93.4 (d, J201 Hz, 2-C), 53.1 (CH3),
31.9 (d, J22.5 Hz, 3-C), 24.8 (d, J7.0 Hz, 4-C); m/z (electron impact)
222.0680 (M+, 7.1 %, C'2H"F03 requires 222.06923), 202 (10), 170 (47), 163
(12), 133 (15), 118 (100), 90 (51), 63 (6); Analysis Calculated for C'2H"F03
(222.218): C(64.86), H(4.99); Found: C(64.74), H(4.93).
85
Menthyl 2-fluoro-1-tetralone-2-carboxylate (31 c)
To a stirred suspension of sodium hydride (60% dispersion in oil, 0.091 g,
2.28 mmole) in DMF (1 ml), at 0 QC and under nitrogen, was added menthyl
1-tetralone-2-carboxylate (28) (0.750 g, 2.28 mmole in DMF (4 ml). This was
left to stir at 0 QC for twenty minutes. A solution 01 N-fluoro, N-chloromethyl
triethylenediamine bis(tetralluoroborate) (80% active ingredient, 0.879 g, 1.99
mmole) in DMF (5 ml) was then added dropwise to the above solution at
-50 QC. 165 The solution was allowed to warm slowly to room temperature and
left to stir for ten minutes, after which time the reaction appeared to be
complete by tic chromatography (silica with 20 : 1 light petroleum [b.p. 40 - 60
QC] : ethyl acetate) (Starting material: RIO.80, product: RI 0.61). The reaction
mixture was poured into a separating lunnel containing diethyl ether (100 ml).
This solution was washed with NaHC03 solution (10% aqueous, 100 ml) and
NaCI solution (saturated aqueous, 100 ml), dried (MgS04) and concentrated
in vacuo to yield a yellow oil (0.802 g). Column chromatography (silica with 1 :
.... 1 dichloromethane : light petroleum [b.p. 40 - 60 QC]) yielded a colourless oil
(31c) (0.647 g, 94%).
Separation 01 the diastereomers was carried out by flash chromatography
using silica with 2 : 1 dichloromethane : light petroleum [b.p. 40 - 60 QC]. The
RI values 01 the diastereomers, using this solvent system, were 0.49
(diastereomer I) and 0.41 (diastereomer 11).
86
Diastereomer I (31c-D1): m.p. 101°C; Optical rotation: [alD -61.5 (22°C,
dichloromethane, 0.260 g 1100 ml); vmax (neat) 2956 C-H), 2931,2871
(saturated C-H), 1759 (ester C=O), 1739, 1698 (ketone C=O), 1603, 1456,
1310, 1277, 1227, 1190 cm-1; OH (250 MHz, COCI3) 8_07 (1 H, d,d, J7.8, 1.1
Hz, 8-H), 7.54 (1 H, t,t, J7.5, 1.4 Hz, 7-H), 7.39 (1 H, t, J7.3 Hz, 6-H), 7.27 (1
H, d, J7.6 Hz, 5-H), 4.78 (1 H, t,t, J10.9, 4.4 Hz, C02CHj, 3.24 - 3.05 (2 H,
m, 4-H), 2.76 - 2.51 (2 H, m, 3-H), 2.10 - 2.06 (1 H, m, 2'-H), 1.69 - 0.85 (8 H,
m, 3'-H, 4'-H, 5'-H, 6'-H, CHPr), 0.90 (3 H, d, J6.5 Hz, 5'-Me), 0.77 (1 H, d, J
7.0 Hz, Me of Pr), 0.69 (1 H, d, J7.0 Hz, Me' of Pr); 3c (62.5 MHz, COCI3) .
188.7 (d, J15.1 Hz, 1-C), 167.0 (d, J25.2 Hz, C02), 142.8 (8a-C), 134.4 (7-
C), 130.8 (4a-C) , 128.7 (6-C), 128.3 (5-C), 127.2 (8-C), 93.4 (d, J193.5 Hz,
2-C), 77.0 (1'-C), 46.7 (2'-C), 40.2 (6'-C), 34.0 (3'-C), 31.7 (d, J21.9 Hz, 3-C),
31.4 (5'-C), 25.9 (a-lPr), 25.0 (d, J7.7 Hz, 4-C), 23.0 (4'-C), 21.9 (Me), 20.7
(Me'), 15.8 (Me"); OF (376.5 MHz, COCI3 , 1H decoupled, external reference
CF3C02H) -163.87 ; mlz (electron impact) no M+ found. Peaks present
suggest compound has undergone a MCLafferty Type Rearrangement (~
cleavage with y-hydrogen transfer) to give mass ion peak of 208 (89, M+-
138),170 (42),164 (21, M+-138 - C02), 138 (15),118 (27), 95 (31),83
(100), 69 (37), 55 (43), 41 (25); Analysis Calculated for C21H27F03 (346.445):
C(72.81), H(7.86); Found: C(72.56), H(7.98). X-ray crystallographic data:167
Crystal (0.50 x 0.21 x 0.20 mm) grown from methanol, C21H27F03, monoclinic,
space group P21, a =11.878(9), b = 12.694(7), c = 6.43(1) A, ~ = 90.2(2)°, Z =
2, Ox = 1.186 gcm-3, T = 293 K. MoKa radiation (/0.. = 0.7169 A), 11 = 0.48 cm-1.
Stoe Stadi-2 diffractometer, 1857 reflections measured of which 1360 with
F/cr(F»5. Structure solved by direct methods and refined to a final R = 0.070,
Rw = 0.070. All non-H atoms treated anisotropically. Phenyl and one
87
methylene H atoms placed in calculated positions. Other H atoms found from
difference map and not refined. The final maximum shift/error = 0.39, IIp
excursions -0.2 to 0.2.
Diastereomer 11 (31c-DII): V max (neat) 2956 (aromatic C-H), 2930, 2871
(saturated C-H), 1760 (ester C=O), 1734, 1698 (ketone C=O), 1601, 1456,
1311,1275,1227,1189 cm"; OH (250 MHz, CDCI3) 8.07 (1 H, d, J7.8 Hz,
8-H), 7.55 (1 H, t, J7.5 Hz, 7-H), 7.36 (1 H, t, J7.5 Hz, 6-H), 7.29 (1 H, d, J
6.8 Hz, 5-H), 4.80 (1 H, t,t, J10.9, 4.4 Hz, C02CH), 3.23 - 3.09 (2 H, m, 4-H),
2.73 - 2.53 (2 H, m, 3-H), 2.06 - 2.02 (1 H, m, 2'-H), 1.75 - 0.85 (8 H, m, 3'-H,
4'-H, 5'-H, 6'-H, CHFr), 0.89 (3 H, d, J6.5 Hz, 5'-Me), 0.81 (3 H, d, J7.0 Hz,
Me of Fr), 0.74 (3 H, d, J7.0 Hz, Me' of Pr); Oc (62.5 MHz, CDCI3)188.6 (d, J
15.1 Hz, 1-C), 167.0 (d, J25.2 Hz, CO2), 143.0 (8a-C), 134.4 (7-C), 130.9
(4a-C), 128.7 (6-C), 128.3 (5-C), 127.2 (8-C), 93.1 (d, J 193.8 Hz, 2-C), 77.0
(1'-C), 46.8 (2'-C), 40.5 (6'-C), 34.0 (3'-C), 32.0 (d, J22.4 Hz, 3-C), 31.4 (5'
C), 25.9 (Q-iFr), 25.1 (d, J7.7 Hz, 4-C), 23.2 (4'-C), 21.9 (Me), 20.8 (Me'),
. J 6.0 (Me").
88
Methyl 2-fluoro-1-[( RH + )-a-methylbenzyli mi no ]-tetralone-2-carboxylate
(32)
o o
F ..
To a solution of methyl 2-fluoro-1-tetralone-2-carboxylate (31 b) (2.780 g,
12.510 mmole) and (R}(+)-a-methylbenzylamine (4.548 g, 4.838 ml, 37.531
mmole) in dry benzene (100 ml), at 0-5 QC, was added TiCI4 (1.0 M in
dichloromethane, 6.88 ml, 6.881 mmole) dropwise, via syringe, under
nitrogen. 17o The reaction was left to stir at 0-5 QC for one hour, then allowed
to warm to room temperature and left to stir for a further one hour. After this
time, the reaction mixture was filtered and the filtrate concentrated in vacuoto
yield a reddish white solid (still containing Ti02). This material was purified by
flash chromatography using alumina (basic, activated, Brockmann Type I,
standard grade, 150 mesh) with 19 : 1 light petroleum [b.p. 40 - 60°C] : ethyl
acetate. The solvent was removed in vacuo from the desired fractions to yield
a sticky, pale yellow solid (3.651 g, 90%). Two spots were visible by tic (silica
with 7 : 3 light petroleum [b.p. 40 - 60 QC] : diethyl ether) appearing at Rf 0.53
and 0.45 (cream ish yellow colour when visualised byanisaldehyde).
Recrystallization from methanol yielded a white solid [Diastereomer 11 (32-
011)]. Further purification of the mother liquor using dry flash chromatography
(tic alumina, neutral, with light petroleum [b.p. 40 - 60 QC]) and
recrystallizations using methanol yielded the isolated diastereomers.
Diastereomer I (32-01): colourless oil (0.196 g, 11 %); V max (film) 2926
(aromatic C-H), 1758 (ester C=O), 1634, 1456, 1267, 1089 cm·1; OH (250
MHz, CDCI3 ) 8.24 (1 H, d,d, J6.5, 1.6 Hz, ArH), 7.42 -7.14 (8 H, m, ArH),
5.13 - 5.03 (1 H, m, NCH), 3.33 (3 H, s, OMe protons), 3.00 - 2.77 (2 H, m, 4-
H), 2.48 - 2.15 (2 H, m, 3-H), 1.55 (3 H, d, J6.2 Hz, CMe protons); Oc (62.5
89
MHz, CDCI3) 170.4 (d, J26.1 Hz, C02Me), 154.2 (d, J 15.6 Hz, 1-C), 145.4
(4a-C), 139.1 (NCH[Me)C), 134.0 (d, J3.9 Hz, 8a-C) , 130.2, 128.2 (2 C),
127.5, 127.4, 127.1, 126.6, 126.2 (2 C), 91.1 (d, J 192.2 Hz, 2-C), 60.5 (d, J
3.4 Hz, C02CH3), 52.4 (NCH), 34.6 (d, J23.3 Hz, 3-C), 26.0 (CHCH3). 24.8
(d, J 4.5 Hz, 4-C). Evidence of syn and antiisomers present in the 13C n.m.r.
spectrum. The aromatic tertiary carbons of the minor isomer are visible at Oc 130.4,128.8,128.6,126.9,126.7, 126.0, 125.7. Also visible are Oc 60.0
(C02 a-i3) , 52.3 (NCH), 31.4 (d, 3-C), 26.5 (CHCH3), 25.1 (d, 4-C); m/z
(electron impact) 325.1486 (M+, 6.4%, C2oH20FN02 requires 325.14780),77
(12), 105 (100),118 (9),146 (4),170 (4), 246 (4).
Diastereomer 11 (32-011): colourless crystalline solid (0.281 g, 16%); m.p.
101°C; vmax (film) 2963 (aromatic C-H), 1761 (ester C=O), 1627, 1450, 1265,
1071 cm-1; 8H (250 MHz, CDCI3) 8.26 (1 H, d,d, J6.7, 2.5 Hz, 6-H), 7.47 (2 H,
d, J7.2 Hz, ArH), 7.33 -7.12 (6 H, m, ArH), 5.13 - 5.06 (1 H, m, NOt), 3.87*
& 3.83 (1 H, singlets, OMe protons of syrr and anti- isomers), 2.91 - 2.85 (2
H, m, 4-H), 2.44 - 2.29 (2 H, m, 3-H), 1.60 & 1.42' (3 H, doublet & double
doublet, J6.4 & 6.3, 1.2 Hz, respectively, CMe protons); Oc (62.5 MHz,
CDCI3) 170.7* (d, J25.5 Hz, C02Me), 170.1 (d, J27.1 Hz, C02Me), 159.2 (d,
J20.7 Hz, 1-C), 153.7* (d, J15.7 Hz, 1-C), 145.9 (4a-C) , 145.1' (4a-C) ,
142.4 (NCH[Me)C), 140.8' (NCH[Me)C), 138.1' (d, J3.9 Hz, 8a-C), peaks of
tertiary aromatic carbon of syn and anti isomers: 130.5, 130.1, 128.8, 128.7,
128.4,128.5,127.9,127.8,127.0,126.8,126.7,126.2, 126.0, 125.9,96.1 (d,
J188.8 Hz, 2-C), 90.7* (d, J192.7 Hz, 2-C), 60.6' (d, J4.4 Hz, C02CH3),
59.7 (C02CH3), 52.9' (NCH), 52.3 (NCH), 34.4' (d, J23.4 Hz, 3-C), 32.0 (d, J
24.0 Hz, 3-C), 25.9 (CHCH3), 25.4 (d, J3.0 Hz, 4-C), 24.9 (d, J5.8 Hz, 4-C),
23.9' (CHCH3); m/z (electron impact) 325.1491 (M+, 5.5%, C2oH2QFN02
requires 325.14780),77 (10). 105 (100),117 (6),146 (3),246 (3)
, Peaks of most abundant isomer.
90
Regeneration Of Methyl 2-fluoro-1-tetralone-2-carboxylate (31 b-EI and
31 b-EII)
MeyPh
N 0 0 0
o .... Me o .... Me
F • F
A heterogeneous mixture of hydrochloric acid (aq. 2 M, 15 ml) and methyl
2-fluoro-1-[(R)-( + )-a-methylbenzylimino]-tetralone-2-carboxylate (32) (0.218
g, 0.670 mmole) in dichloromethane (5 ml) was vigorously stirred for 1 hour at
room temperature. After this time, no starting material was visible by tic. The
organic layer was isolated, made to 20 ml, washed with brine (saturated, 20
ml), dried (Na2S04) and concentrated in vacuo to yield a colourless solid
(0.147 g, 99%). This material was run through a silica column to give a
colourless solid (31 b) (0.143 g, 96%).
Removal of the imine from (32-011) yielded the enantiomerically pure
ketone (31 b-EII), and deprotection of (32-01) gave the other enantiomer
(31 b-EI). Both compounds had spectral and physical data as previously
described for (31 b).
Chiral shift studies were carried out on the isolated enantiomers, using the
chiral shift reagent Eu(hfch The proton n.m.r. spectrum for (31b-EII) showed
no splitting of peaks with the chiral shift reagent. On addition of a racemic
mixture of the ketone to the n.m.r. sample, splitting was observed. From this it
can be deduced that the parent imine consists of the syn and anti isomers of
the same diastereomer, either (R,R) or (R,S).
NB! The Eu(hfcb shifts the 6-H proton of (31 b-EII) further downfield than that
of (31 b-EI). Baseline separation was observed for the most downfield proton
with 2.7 equivalents of the chiral shift reagent.
91
2-FI uoro-2-(2-hydroxyisopropyl)-1-[( RH. + )-a.-methylbenzylimino]
tetralone (33)
"Me o
To a solution of the iminoester (32) (1.836 g, 5.643 mmole) in
tetrahydrofuran (dry, 25 ml) was added methyllithium (1.5 M in diethyl ether,
5.64 ml, 8.464 mmole) at 0 QC under nitrogen. The reaction was allowed to
stir at 0 QC for 1.5 hours, after which time it was quenched with an aqueous
solution of ammonium chloride (saturated, 50 ml). The resulting mixture was
extracted with diethyl ether. The ethereal extracts were combined, dried
(Na2S04) and concentrated in vacuo to yield a dark orange oil. This oil was
subjected to flash chromatography (aluminium oxide, Brockmann Grade 11,
standard grade, -150 mesh; 7 : 3 light petroleum [b.p. 40 - 60 QC] : ethyl
acetate). This gave 0.399 g (22%) of the desired hydroxyimine
diastereomers. This initial column afforded some separation of the
diastereomers: the more polar diastereomer (33-01) (0.093 g, 5%), the less
polar diastereomer (33-011) (0.152 g, 8%). Some staring material was
recovered as a colourless oil (0.894 g, 49%).
Spectral data for the more polar diastereomer (33-01): vmax (neat) 3354
(broad, OH), 2975, 2926,1641,1453,1073,1058,964 cm·\ Optical rotation
[ajo +37.0 (20 QC, chloroform, 0.568 g / 100 ml); OH (250 MHz, CDCI3) 7.51 -
7.15 (9 H, m, ArH), 6.20 (1 H. broad s, OH), 504 (1 H, q, J6.4 Hz, NCh),
303 - 2.78 (2 H, m, 4-H), 2.47 - 2.15 (2 H, m, 3-H), 1.51 (3 H, s, C(OH)CH3),
1.49 (3 H, d, J3.4 Hz, NCC}-6'), 1.38 (3 H, S, C(OH)CH3"); Oc (62.5 MHz,
CDCI3 ) 166.6 (d, 24.4 Hz, C=N), 145.1 (NCH[MejC), 141.2 (8a-Cl. 130.3,
129.6 (4a-C), 128.7, 128.4, 127.8, 126.9, 126.1, 125.5,96.9 (d, J188.8 Hz,
92
2-C), 74.2 (d, J24.4 Hz, COH), 60.2 (Q-iMe), 29.6 (d, J23.9 Hz, 3-C), 25.9
(C[OH]CH3), 25.5 (4-C), 25.5 (NCQ-i3'), 24.8 (C[OH]CH3"); m/z (electron
impact) 325.1836 (M+, 0.7%, C2QH2QFN02 requires 325.1842).
Spectral data for the less polar diastereomer (33-DII): vmax (neat) 3379
(broad, OH), 2976, 2940, 1455, 1367, 1072, 964 cm-'; Optical rotation [a]D
+200.7 (20°C, chloroform, 0.304 9 1100 ml); OH (250 MHz, CDCI3) 7.38 - 7.22
(9 H, m, ArH), 6.25 (1 H, broad s, OH), 5.03 (1 H, q, J6.4 Hz, NCh), 3.04-
2.66 (2 H, m, 4-H), 2.46 - 1.83 (2 H, m, 3-H), 1.58 (3 H, d, J6.2 Hz,
NCCH3 ) , 1.43 (3 H, s, C(OH)Cff:l'), 1.13 (3 H, s, C(OH)Cff:l"); Oc (62.5 MHz,
CDCI3) 166.0 (d, 24.4 Hz, C=N), 145.1 (NCH[Me]C), 142.0 (8a-C), 130.4,
129.3 (4a-C) , 128.8, 128.2, 128.0, 127.0, 126.0, 125.7,96.8 (d, J181.9 Hz,
2-C), 74.4 (d, J23.4 Hz, COH), 61.0 (Q-iMe), 30.5 (d, J23.8 Hz, 3-C), 26.2
(C[OH] Q-i3') , 25.7 (4-C), 25.7 (NCQ-i3)' 24.3 (C[OH]Q-i3"); m/z (electron
impact) 325.1828 (M+, 1.1 %, C2QH20FN02 requires 325.1842).
93
Regeneration of 2-fluoro-2-{2-hydroxyisopropyl)-1-tetralone (34-EI and
34-EII)
..
A heterogeneous solution of the hydroxyimine (33-01) (0.301 g, 0.925
mmole) in dichloromethane (10 ml) and dilute hydrochloric acid (2 M, 20 ml)
was vigorously stirred for 20 hours. After this time no starting material was
apparent by tic analysis (7 : 3 light petroleum [b.p. 40 - 60 QC] : diethyl ether,
starting material Rt 0.30 and product Rt 0.19). The aqueous layer was
extracted with dichloromethane (2 x 50 ml). The organic extracts were dried
(Na2S04) and concentrated in vacuo to yield an orange oil. this was purified
by flash chromatography ( basic alumina, Brockmann Grade 11 with 7 : 3 light
petroleum [b.p. 40 - 60 QC] : diethyl ether) The desired fractions were
combined to give a colourless solid (34-EI); m.p. 74 QC; Optical rotation: [alo -
7.6 (25 QC, chloroform, 0.724 g 1100 ml); V max (film) 3781 (broad, OH, H
bonded), 2980 (Aryl C-H), 1684 (C=O), 1601, 1456 (Arene C-G) and 1229
cm-'; 8H (250 MHz, CDCI3) 8.01 (1 H, d,d, J8.0, 1.0 Hz, 8-H), 7.52 (1 H, t,d, J
7.3, 1.3 Hz, 7-H), 7.34 (1 H, t, J7.5 Hz, 6-H), 7.25 (1 H, d, J7.6 Hz, 5-H),
3.54 (1 H, broad s, OH), 3.27 - 2.96 (2 H, m, 4-H), 2.58 - 2.21 (2 H, m, 3-H),
1.38 (3 H, s, Me), 1.37 (3 H, s, Me); 8c (62.5 MHz, CDCI3) 201.4 (1-G), 143.8
(8a-C), 134.2 (7-C), 132.0 (4a-C), 128.5 (6-C), 128.2 (5-C) , 126.9 (8-C), 95.3
(d, J182.6 Hz, 2-C), 74.0 (d, J22.6 Hz, COH), 30.0 (d, J22.8 Hz, 3-C), 25.8
(d, J3.6 Hz, Me), 24.9 (d, J7.8 Hz, 4-C), 24.1 (d, J4.1 Hz, Me); m/z (electron
impact) 222.1061 (M+, 0.4%, C"H,oF20 2 requires 222.1056), 164 (100), 144
(13),131 (9),118 (20), 90 (22),77 (6),63 (8), 59 (33),51 (7),43 (73),31 (8).
94
Ethyl 1-indanone-2-carboxylate (36)161, m
.. ..... Et
o
1-lndanone (35) (0.200 g, 1.51 mmole) in dry diethyl carbonate (distilled
from sodium hydride, 5.5 ml, 45.4 mmole) was added, via syringe, to a stirred
suspension of sodium hydride (0.073 g, 1.82 mmole) in dry diethyl carbonate
(5.5 ml, 45.5 mmole). The solution was heated to reflux for five minutes.
During this time a dark green solid was formed (note that on a larger scale
using 2.00 g of 1-indanone (35). an exotherm was noted and no additional
heat was required for the formation of this solid). Further diethyl carbonate (5
ml) was added. Tic analysis of the solid (silica with 9 : 2 light petroleum [b.p.
40 - 60 QC] : ethyl acetate) showed no evidence of any 1-indanone (35) (Rt
0.47), only the product (36) (Rt 0.56). The reaction mixture was heated to
reflux for a further fifteen minutes, after which time it was allowed to cool to
room temperature. The cooled solid was dissolved in HCI (aqueous 2 M, 50
ml). The aqueous phase was extracted with ethyl acetate (4 x 50 ml). The
combined organic extracts were dried (MgS04) and concentrated in vacuo to
yield a brown oil (0.611 g). The sample was purified by column
chromatography (silica with 9 : 1 light petroleum [b.p. 40 - 60 QC] : ethyl
-·acetate) to yield a colourless oil (36) (0.265 g, 86%); V max (neat) 3009
(aromatic C-H), 1740 (ester C=O of ketoester), 1714 (a-aryl ketone C=O),
1650 (enol ester C=O), 1573, 1465 (arene C-C), 1370, 1258, 1208, 1187,
1153, 1093 cm"; OH (250 MHz, CDCI3) 12.5 (1 H, broad s, OH), 7.74 - 7.32 (8
H, m, keto ester and enol ArH), 4.74 - 4.12 (4 H, m, ketoester and enol
CH2CH3), 3.67 (1 H, d,d, J8.2, 4.1 Hz, 2-H), 3.68 - 3.29 (4 H, m, ketoester
and enol 3-H), 1.38 - 1.26 (6 H, m, ketoester and enol CH2CH3); Oc (62.5
MHz, CDCI3) 199.5 (ketoester 1-C), 169.1 (ketoester 2-C02Et), 153.7 (enoI1-
C), 143.0 (ketoester 7a-C), 135.3 (ketoester 7 -C), 135.2 (ketoester 3a-C),
129.3 (enoI7-C), 127.7 (ketoester 6-C), 126.8 (enoI6-C), 126.6 (ketone 5-C),
124.7 (enoI5-C), 124.4 (ketone 4-C), 120.5 (enoI4-C), 102.5 (enoI2-C), 61.5
(ketoester CH2CH3), 60.0 (enol CH2CH3), 53.3 (ketoester 2-C), 32.5 (enol 3-
C), 30.3 (ketone 3-C), 14.4 (enol CH2 CH3), 14.2 (ketoester CH2 a-i3)·
95
Ethyl 2-fluoro-1-indanone-2-carboxylate (37)165
o ....-Et o
o ....-Et o
To a stirred suspension of sodium hydride (60% dispersion in oil, 0.098 g,
2.45 mmole) in DMF (0.5 ml), at 0 QC and under nitrogen, was added ethyl 1-
indanone-2-carboxylate (36) (0.500 g, 2.45 mmole in DMF (2.5 ml). This was
left to stir at 0 QC for thirty minutes. A solution of N-fluoro, N-chloromethyl
triethylenediamine bis(tetrafluoroborate) (80% active ingredient, 0.986 g, 2.23
mmole) in DMF (5 ml) was then added dropwise to the above solution at -50
QC. The solution was allowed to warm slowly to room temperature and left to
stir for five minutes, after which time the reaction appeared to be complete by
tic chromatography (silica with 9 : 2 light petroleum [b.p. 40 - 60 QC] : ethyl
acetate) (Starting material: R, 0.48 and 0.17, with streaking between; Product:
R, 0.30). The reaction was left to stir for a further twenty five minutes. After
this time, the reaction mixture was poured into a separating funnel containing
diethyl ether (100 ml). This solution was washed with NaHC03 solution (10%
aqueous, 100 ml) and NaCI solution (saturated aqueous, 100 ml), dried
(MgS04
) and concentrated in vacuoto yield a yellow oil (37) (0.635 g). The
crude product was then purified by flash chromatography (silica with 9 : 1 light
petroleum [b.p. 40 - 60 QC] : ethyl acetate) to yield a very pale yellow oil
(73%); V max (neat) 2986 (aromatic C-H), 1766 (ester C=O), 1728 (ketone
C=O), 1608, 1467, 1298, 1216, 1193,1074 cm-1; OH (250 MHz, CDCI3) 7.82
(d, 1 H, J7.6 Hz, 7-H), 7.72 (t, 1 H, J7.6 Hz, 6-H), 7.54 - 7.47 (m, 2H, 5-H, 4-
H), 4.27 (q, 2H, J7.1 Hz, CH2CH3), 3.81 (d,d, 1 H, J 17.7, 11.7 Hz, 3-H), 3.43
(d,d, 1H, J23.4, 17.7 Hz, 3-H'), 1.24 (t, 3H, J7.1 Hz, CH3); lie (62.5 MHz,
CDCI3
) 195.3 (d, J17.5 Hz, 1-C), 167.3 (d, J27.2 Hz, G02Et) , 150.9 (d, J3.2
Hz, 7a-C), 136.7, 133.3 (3a-C), 128.6, 126.6, 125.6,94.5 (d, J200.3 Hz, 2-
C), 62.6 (CH2CH3), 38.3 (d, J23.5 Hz, 3-C), 14.0 (CH2 CH3)·
96
Ethy 1 2-11 uoro-1-[( RH + )-a-methylbenzylimino ]-indanone-2-carboxylate
(38)
o o
F
...-Et o
To a stirring solution of ethyl 2-fluoro-1-indanone-2-carboxylate (37) (3.973
g, 17.88 mmole) and a-methylbenzylamine (6.500 g, 6.92 ml, 53.64 mmole)
in benzene (dry, 100 ml) was added titanium tetrachloride (1.0 M in
dichloromethane, 9.83 ml, 9.83 mmole), at 0 QC and under nitrogen. After one
hour atO QC, the reaction was allowed to warm to room temperature and left
to stir for a further one hour. After this time, the benzene was removed in
vacuo, dichloromethane (100 ml) was added, followed by diethyl ether (50
ml). The resulting suspension was filtered through glasswool. Solvent was
removed in vacuo from the resulting filtrate, which was then purified by flash
chromatography (basic alumina, Brockmann Grade I with 9 : 1 light petroleum
[b.p. 40 - 60 QC]). The imine diastereomers eluted together and were
concentrated in vacuo to yield a colourless residue.
Diastereomer I (38-01) colourless crystalline solid (1.334 g, 23%); m.p. 105
QC; Optical rotation: [alo +13.6 (25 QC, chloroform, 0.568 g 1100 ml); Vrnax
(neat) 2981, 1756, 1659, 1190, 1062 cm-1; 8H (250 MHz, CDCI3) 7.93* (1 H, d,
J7.4 Hz, ArH), 7.77 (1 H, d, J7.7 Hz, ArH), 7.44 -7.19 (8 H from synand 8 H
from antiisomer, m, ArH), 5.42 (1 H, d,q, J2.3, 6.5 Hz, NCH), 5.10* (1 H, d,q,
J2.2, 6.2 Hz, NCH), 4.47 - 4.22 (2 H, m, CH2CH3), 4.07 - 3.89* and 3.81 -
3.68* (2 H, 2 m, CH2CH3), 3.68 - 3.26 (2 H from syn and 2 H from antiisomer,
m, 3-H), 1.60* (3 H, d, J6.3 Hz, Me protons), 1.59 (3 H, d, J6.4 Hz, Me
protons), 1.30 (3 H, t, J7.1 Hz, CH2CH3), 0.84* (3 H, t, J7.2 Hz, CH2CH3);
The isomers of this compound are in a ratio of 9 : 1. This proton spectrum
was decoupled at the methyl group (CH 2CH3 ) appearing at 8H 0.82, causing
97
the multiplets of the methylene protons (CI-kCH3)at &; 4.07 - 3.89 and 3.81 -
3.68 to become doublets; lie (62.5 MHz, CDCI3) 169.6* (d, J28.7 Hz,
C02Me). 162.4* (d, J15.3 Hz, N=C), 146.4 (N-CH(CH3)C), 145.3* (N
CH(CH3)C), 143.7* (d, J3.7 Hz, 7a-C) , 137.6* (d, J3.0 Hz, 3a-C), 132.2:
128.7,128.5,* 128.2,* 128.0,127.7,126.7,* 126.6,126.2: 125.1: 123.6:
94.3* (d, J197.4 Hz, 2-C), 62.0* (CH2CH3), 61.7 (CH2CH3). 60.8* (NCH), 59.4
(NCH), 42.2' (d, J25.4 Hz, 3-C), 39.6 (d, J24.9 Hz, 3-C), 25.9' (Me carbon),
25.1 (Me carbon), 14.3 (CH2CH3), 13.3* (CH2CH3). NB. The quaternary and
aromatic carbons of the minor isomer are not all visible in the carbon
spectrum. Seven peaks are present for the aromatic CH carbons of the major
isomer; only four peaks can be clearly identified for those of the minor isomer;
Analysis Calculated for C20H2oFN02 (325.380): C(73.81), H(6.20), N (4.31);
Found: C(74.14), H(6.41), N (4.30).
'Peaks of most abundant isomer.
Diastereomer (38-011): this contained approximately 20% of (38-01).
Identifiable peaks in the 'H n.m.r. spectrum are OH (250 MHz, CDCI3) 7.90' (1
H, d, J7.9 Hz, ArH), 7.52 - 7.21 (8 H from syn and 8 H from antiisomer, m,
ArH), 5.50 - 5.40 (1 H, NCH), 5.12* (1 H, d,q, J 2.2, 6.4 Hz, NCH), 4.41 -
4.26* (2 H, m, CH2CH3), 4.07 - 3.68 (2 H, 2 m, CH2CH 3), 3.68 - 3.26 (2 H from
syn and 2 H from antiisomer, m, 3-H), 1.68 (3 H, d, J6.6 Hz, NCHCH3), 1.49'
(3 H, d, J6.5 Hz, NCHCH3), 1.32* (3 H, t, J7.1 Hz, CH2 CH3), 1.19 (3 H, t, J
7.2 Hz, CH2 CH3).
98
Regeneration Of Ethyl 2-fluoro-1-indanone-2-carboxylate (37)
...-Et o
o o
F
Ethyl 2-fluoro-1-[(R)-(+)-a-methylbenzylimino]-indanone-2-carboxylate (38-
01) (0.338 g, 1.038 mmole) was dissolved in dichloromethane (7.5 ml). To
this was added 2 M HCI (7.5 ml) and the solution vigorously stirred at room
temperature for one and a half days. The aqueous layer was then extracted
with dichloromethane (3 x 100 ml). The organic extracts were dried (Na2S04),
and concentrated in vacuo to yield an orange oil (0.229 g, 99%). this oil was
purified by flash chromatography (flash silica with 9 : 1 light petroleum [b.p.
40 - 60 cC] : diethyl ether) to yield a colourless solid (37-EI)(0.185 g, 80%);
Optical rotation [a.]D -86.4 (25 cC, chloroform, 0.428 g 1100 ml). Yield not
optimised since still column fractions containing desired material in them, but
in impure form. Spectral data as for racemic (37).
Removal of the imine from (38-01) yielded the enantiomerically pure ketone
(37-EI), and deprotection of (38-011) gave the other enantiomer (37-EII). Both
compounds had spectral and physical data as previously described for the
racemic material (37).
Chiral shift studies were carried out on the isolated enantiomers, using the
chiral shift reagent Eu(hfch The proton n.m.r. spectrum for (37-EI) showed
no splitting of peaks with the chiral shift reagent. On addition of a racemic
mixture of the ketone to the n.m.r. sample, splitting was observed. From this it
can be deduced that the parent imine consists of the syn and anti isomers of
the same diastereomer, either (R,Rj or (R,S).
The Eu(hfcb shifts the 6-H proton of (37-EI) further up field than that of
(37-EII). Baseline separation was observed for the most downfield proton with
2.7 equivalents of the chiral shift reagent.
99
Synthesis of methyl 2,5,7-trifluoro-1-indanone-2-carboxylate (47)
Ethyl 3-(3,5-difluoro)-2,3-dehydropropionate (40)
o F ., F
H
F F
A dry three-necked flask (100 ml), equipped with a magnetic stirrer,
thermometer, condenser and dropping funnel was purged with dry nitrogen,
then charged with sodium hydride (60% dispersion in oil, 0.464 g, 11.61
mmole) and dry benzene (5 ml, filtered from sodium hydride immediately
before use). To this stirred suspension, in an ice-water bath, was added
triethyl phosphonoacetate (2.082 g, 9.29 mmole) in dry benzene (7.5 ml),
over a twenty minute period, in a dropwise manner.'73 After this addition was
complete, the mixture was stirred for twenty minutes at 0 QC. 3,5-Difluoro
benzai'dehyde (39) (1.100 g, 7.74 mmole) was added dropwise to this
solution, resulting in the formation of a gummy precipitate of sodium ethyl
phosphate. A further portion of benzene (5 ml) was added to aid stirring. The
solution was allowed to warm slowly to room temperature and left to stir
·overnight. Water (50 ml) was then added carefully to the reaction mixture
followed by ethyl acetate (35 ml). The organic layer was isolated, then the
aqueous layer further extracted with ethyl acetate (2 x 50 ml). The combined
organic layers were washed with water (100 ml), dried (MgS04) and
concentrated in vacuo to yield a yellow residue (1.693 g). The product was
purified by column chromatography (silica with 19 : 1 light petroleum [b.p. 40 -
60 QC] : ethyl acetate). Tic analysis of the fractions was carriec;i out using silica
with 9 : 1 light petroleum [b.p. 40 - 60 QC] : ethyl acetate, the product having
an RI value of 0.62 with this system. The resulting solid was recrystallized
from light petroleum [b.p. 40 - 60 QC] to give a colourless solid (40) (1.496 g,
91%); mpt. 38.5 - 39.0 QC; V max (neat) 2985 (alkene C-H), 1716 (C=O), 1645,
1621,1593 (a-carbonyl C=C), 1453 (arene C-C), 1440, 1311, 1280, 1181,
100
1121 cm"'; 8H (250 MHz, CDCla) 7.57 (1 H, d, J 16.0 Hz, Cf£0 2) , 7.03 (2 H,
d,d, J8.1, 1.9 Hz, Cf£FCHCFCH), 6.87 - 6.78 (1 H, m, CFCf£F), 4.28 (2 H,
q, J7.2 Hz, CH2CHa), 1.34 (3 H, t, J7.2 Hz, CH2CHa). Coupling constant of
alkene protons shows double bond to be trans.; m/z (electron impact)
212.0502 (M+, 9.4%, C"H,oF20 2 requires 212.06489), 167 (100, M+ - OEt),
139 (22, M+ - [OEt + CO]), 127 (38),101 (11),63 (4).
101
Ethyl 3-(3,5-difluoro)-2,3-dehydropropionate (40)
o F F
H •
F F
To 3,5-difluorobenzaldehyde (39) (4.1134 g, 28.95 mmole) in dry
dichloromethane (12 ml), under nitrogen and at room temperature, was
carefully added (carboxymethylene)triphenylphosphorane (12.10 g, 34.74
mmole) in dry dichloromethane (12 ml).174 This produced an immediate
exotherm. The reaction was left to cool to room temperature, after which time
it appeared to have gone to completion by tic. Tic analysis was carried out
using silica with 9 : 1 light petroleum [b.p. 40 - 60°C) : ethyl acetate, the
product having an R, value of 0.62 with this system. The dichloromethane
was removed in vacuo to give a colourless solid. To this was added hexane
(3 x 100 ml) and the mixture stirred for several minutes before the hexane
was collected by filtration. The hexane fractions were concentrated in vacuo
to yield an off-white solid (6.796 g). The product was purified by column
chromatography (silica with 19 : 1 light petroleum [b.p. 40 - 60°C] : ethyl
acetate) to give a colourless solid (40) (6.121 g, 99.7%); mpt. 38.5 - 39.0 °C
(recrystallized from light petroleum [b.p. 40 - 60 0c); Vmax (neat) 2985
(alkene C-H), 1716 (C=O), 1645, 1621, 1593 (a-carbonyl C=C), 1453 (arene
C-C), 1440, 1311, 1280, 1181, 1121 cm'1; OH (250 MHz, CDCI3) 7.57 (1 H, d,
J 16.0 Hz, CHC02) , 7.03 (2 H, d,d, J8.1, 1.9 Hz, ChCFCHCFCh), 6.87 - 6.78
(1 H, m, CFCHCF), 4.28 (2 H, q, J7.2 Hz, CH2CH3), 1.34 (3 H, t, J7.2 Hz,
CH2CH3). Coupling constant of alkene protons shows double bond to be
trans.; (Found: m/z 212.0502 (M+·). C11H10F202 requires 212.0649).
102
Ethyl 3-(3,5-difluorophenyl)propionate (41)
F F
F F
To a round bottomed flask (250 ml) was added ethyl 3-(3,5-difluorophenyl)-
2,3-dehydropropionate (40) (1.464 g, 6.90 mmole), 10% Pd/C (0.150 g), ethyl
acetate (100 ml) and a magnetic stirrer. The flask was evacuated, then filled
with hydrogen. This procedure was repeated six times to ensure an
atmosphere of hydrogen. The solution was then left to stir overnight at room
temperature. After this time, the reaction appeared to have gone to
completion by tic analysis (silica with 9 : 1 light petroleum [b.p. 40 - 60 QC] :
ethyl acetate) : The Rt value of the starting material was 0.61 and that of the
product 0.54. The reaction mixture was filtered through celite to remove the
palladium catalyst, then concentrated in vacuo to yield a clear liquid (1.461 g,
99%). This material was purified by column chromatography (silica with 19 : 1
light petroleum [b.p. 40 - 60 QC] : ethyl acetate) to give a clear oil (41) (1.428
g, 97%); vmax (neat) 3093 (aromatic C-H), 2984 (alkene C-H), 2938 (saturated
C-H), 1736 (C=O), 1629, 1597, 1462 (arene C-C), 1376, 1186, 1161 cm-'; OH
(250 MHz, CDCI3) 6.76 (2 H, d,d, J6.4, 2.1 Hz, CFChCCH2), 6.72 - 6.59 (1
H, m, CFChCF), 4.14 (2 H, q, J7.0 Hz, CH2CH3), 2.93 (2 H, t, J7.3 Hz,
CH2C02Et) , 2.61 (2 H, t, J7.3 Hz, ArCH2 ), 1.24 (3 H, t, J7.0 Hz, CH2CH3); Oc
(62.5 MHz, CDCI3) 172.3 (C02), 162.9 (2 C, d,d, J246.5, 12.7 Hz, C-F),
144.6 (t, J9.2 Hz, QCH2h C02Et), 111.2 - 110.9 (2 C, m, CF CHCCH2), 101.6
(t. J25.3, CFCHCF), 60.5 (CH2CH3), 35.0 (ArCH2), 30.5 (CH2C02), 14.0
(CH2CH3); m/z (electron impact) 214.0812 (M+, 33.6%, C"H'2F202 requires
214.08054),169 (19),151 (2), 140 (100),127 (32),101 (13),95 (2),84 (1.5),
43 (2), 29 (2.5).
103
3-(3,5-Difluorophenyl)propionic acid (42) 175
F F
F F
EthyI3-(3,5-difluorophenyl)propionate (41) (0.700 g, 3.27 mmole) was
dissolved in a mixture of ethanol (100 ml) and water (50 ml). To this was
added potassium hydroxide (1.834 g, 32.68 mmole). The mixture was then
heated to reflux for two hours with stirring. Af1er this time, tic analysis of the
reaction mixture (silica with 9 : 1 light petroleum [b.p. 40 - 60°C] : ethyl
acetate) showed baseline material only. The reaction was allowed to cool to
room temperature, then the ethanol removed in vacuo. The aqueous fraction
(made to 100 ml) was washed with dichloromethane (2 x 100 ml), acidified
with hydrochloric acid (aqueous 2 M) until a cloudy white suspension
remained on shaking, then extracted with dichloromethane (3 x 100 ml). The
combined extracts were dried (MgS04 ) and concentrated in vacuo to yield a
pale yellow solid (42) (0.557 g, 92%). This was recrystallized from light
petroleum [b.p. 40 - 60°C] to give a colourless crystalline solid (0.507 g,
84%); mpt. 59 - 60°C (Iiterature175 m.p. 58 -59°C from hexane); Ymax (neat)
3099,3057,2958 (C02H), 1703 (C=O), 1629, 1598, 1462, 1438, 1310, 1116
Cm'l; OH (250 MHz, CDCI3 ) 11.15 (1 H, broad s, C02H), 6.79 - 6.61 (3 H, m,
ArH), 2.94 (2 H, t, J7.6 Hz, ArCH2), 2.68 (2 H, t, J7.5 Hz, CH2C02); lie (62.5
MHz, COCl3) 178.9 (C02H), 166.0 (2 C, d,d, J246.6, 12.8 Hz, C-F), 143.8
(d, CFCHCF), 111.3 - 1109 (2 C, m, CFa-lCCH2), 101.9 (t, J24.9 Hz,
CFa-lCF), 34.8 (ArC1-i2), 30.1 (d, J1.7 Hz, a-l2C02); m/z (electron impact)
186.0461 (M+, 52.0%, CgHaF202 requires 186.04924), 168 (4), 140 (100),
127 (75), 122 (12), 114 (12), 101 (27), 95 (6), 81 (7), 70 (8), 63 (7), 51 (18),
44 (7), 40 (8),29 (2.5); Analysis Calculated for CgHsF202 (186.160): C(58.07),
H(4.33); Found: C(57.97), H(4.28).
104
5,7 -Difluoro-1-indanone (43) 175
F 0
F
.. F
F
Polyphosphoric acid (6.0 g) was added to a round bottomed flask (25 ml),
equipped with a magnetic stirrer and condenser. To this was added 3-(3,5-
difluorophenyl)propionic acid (42) (0.314 g, 1.69 mmole). The mixture was
heated at 45 QC for forty eight hours, with an attempt at stirring. After this
time, the reaction mixture was allowed to cool to room temperature. Water
(distilled, 100 ml) was mixed carefully with the reaction mixture to give a
cloudy white suspension. This aqueous fraction was extracted with
dichloromethane (3 x 100 ml). The organic extracts were reduced in volume,
washed with sodium hydrogen carbonate solution (saturated, 3 x 100 ml),
dried (MgS04), concentrated in vacuo and recrystallised from methanol to
yield a colourless crystalline solid (43) (0.276 g, 97%); m.p. 81 - 81.5 QC
(literature175 m.p. 81 - 82 QC from hexane - chloroform); V max (neat) 3085
(aromatic C-H), 2925 (saturated C-H), 1711 (ester C=O of ketoester), 1679
(a-aryl ketoneC=O), 1619 (enol esterC=O), 1593, 1439, 1326, 1208, 1124
cm-1; OH (400 MHz, CDCI3) 6.96 (1 H, d,d, J7.9, 1.8 Hz, 4-H), 6.74 (1 H, d,t, J
2.0,9.2 Hz, 6-H), 3.15 (2 H, d,t, J6.1, 0.5 Hz, 2-H), 2.75 - 2.72 (2 H, m, 3-H).
No evidence of enol form in n.m.r.; 8c (100 MHz, CDCI3 ) 201.5 (d, JCF7 2.0
Hz, 1-C), 167.8 (d,d, JCF5 257.8 Hz, JcF7 11.1 Hz, 5-C), 159.9 (d,d, JCF7 266.6
Hz, JCF5 14.1 Hz, 7-C), 159.4 (d,d, J 11.1, 4.0 Hz, 3a-C) , 121.1 (d,7a-C),
109.8 (d,d, JCF5 22.14 Hz, JCF7 5.0 Hz, 4-C), 103.8 (d,d, J27.2, 23.1 Hz, 6-C),
37.2 (2-C), 26.4 (d, J2.0 Hz, 3-C) Proton and carbon n.m.r. spectra in
agreement with the Iiterature;175 m/z (electron impact) 168.0351 (M+', 100%,
CgHsF20 requires 168.03868),151 (7),140 (53),132 (4),120 (7),114 (10),
101 (24), 99 (6), 74 (4),63 (7),51 (8),40 (5),31 (3); Analysis Calculated for
CgHsF20 (168.144): C(64.28), H(3.57); Found: C(64.11), H(3.52).
105
2-Deutero-5, 7 -difluoro-1-indanone (43a)
F
H ----l .....
H F
D
To a stirred solution of LOA (0.223 ml, 0.446 mmole, 2.0 M solution in
heptane / tetrahydrofuran / ethyl benzene) in THF (0.5 ml) was added 5,7-
difluoro-1-indanone (0.050 g, 0.297 mmole) in THF (10 ml) over forty five
minutes, at -78°C and under nitrogen. The solution gradually took on a
yellow colour. After thirty minutes stirring at -78 QC, the reaction mixture was
quenched with deuterated acetic acid (0.034 ml, 0.038 g, 0.595 mmole). A
further portion of the deuterated acetic acid was added then the solution
allowed to warm to room temperature. During this period the yellow colour of
the solution disappeared. After reaching room temperature, the reaction
mixture was concentrated in vacuo to yield a yellow residue (0.370 g). The
crude reaction mixture was taken up in CDCI3 and undissolved solid removed
by filtration. Removal of the solvent, after n.m.r. analysis, yielded a yellow
solid (0.048 g). This solid contained both (43a) and (43). Using mass
spectroscopyand 'H n.m.r spectroscopy, the approximate percentage of
molecules having deuterium incorporated at the C-2 position was determined.
Determination of deuterium incorporation in (43a) using electron impact mass spectroscopy.
Proteo(43)
M+ M+' M:t:2 . : M+3 M+4 .<,'-"- ., , .
168 169 170 171 172 86.9 65.0 6.2 1.0 0.5
1 0.748 0.071 0.012 0.006 '. "
106
Deutero (43a)
d" . -d, . --- . d . '.:: ' .. Jo. .d" .d .... , .'
168 169 170 171 172 Mass' - - .;'-.
87.5 85.8 51.9 19.2 4.0 _ Peak Height,": . ;".' Ax
87.5 64.2 3.7 0.2 (0.02) Peak'Height dox Peak HeightM""\ " ' .- -, ',By
21.6 48.2 19.0 4.0 21.6 16.2 1.5 0.3
32.0 17.5 3.7 32.0 23.9 2.3
-6.4 1.4
do + d, + d2
87.5 + 21.6 + 32 = 141.1
(62%) (15%) (23%) (100%)
Therefore there was approximately 38% (Le. 15% + 23%) of the molecules
containing at least one deuterium atom.
The total deuteration was:
N.m.L results
N.m.r
(43a) 400 MHz
For (43a):
(d, x 1) +(d2 x2)
15 + 46
OH of 2-H OH of 3-H
2.77 - 2.73 3.18 - 3.15
= 61 %
Integral Height for protons on C-2
26mm
• 1 proton was equivalent to 20 mm (Le. 40 mm 12).
Integral Height for protons on C-3
40mm
• The integral height for the second proton at the C-2 position, not replaced
by a deuterium was 26 mm - 20 mm = 6 mm.
• The loss of integral height was therefore 20 mm - 6 mm = 14 mm.
• It follows that the percentage of deuterium incorporated at position C-2 of
(43a) was:
14 x 100 = 70 % 20
107
Attempted synthesis of the TMS enol ether of 5,7-difluoro-1-indanone 176
F
To a well stirred suspension of Li2S (0.041 g, 0.892 mmole) in dry
acetonitrile (1 ml) in a 25 ml round-bottomed flask fitted with a water
condenser and under nitrogen was added trimethylsilyl chloride (0.189 ml,
0.162 g, 1.487 mmole). To this was added 5,7-difluoro-1-indanone (43)
(0.100 g, 0.595 mmole) followed by Amberlyst resin A-21 (1 ml of beads
previously washed with dry acetonitrile [15 ml) under nitrogen). [ N.B. The
reaction was also carried out using triethylamine (0.083 ml, 0.060 g, 0.595
mmole) in place of the Amberlyst resin. In this case the reaction proved
difficult to follow because the proton signals of the triethylamine, in the n.m.r.
spectrum of the reaction mixture, obscured the alkyl proton signals of the
indanone). After stirring for five hours at room temperature, no reaction
appeared to have taken place. A further portion of acetonitrile (5 ml) was
added and the reaction heated to reflux overnight. The reaction was then
quenched with d.-acetic acid, the solvent removed in vacuo. The resulting
solid was taken up in d-chloroform and filtered.
The two main compounds in the crude reaction mixture (RI 0.17 and 0.42)
were then isolated by preparative thin layer chromatography (silica with 2 : 1
light petroleum [b.p. 40 - 60 CC) : ethyl acetate). The compound with the RI
value of 0.42 was isolated and shown to be the 5,7 -difluoro-1-indanone
(0.013 g). The compound having the RI value of 0.17 was isolated as
colourless crystals (0.018 g). This was identified as the sulfur-bridged dimer
(45); Vmax (KBr disc) 3068, 2923,1709 (C=O), 1579, 1445, 1290, 1259 cm'l;
108
OH (400 MHz, CDCb) 7.03 (1 H, d,d, J 1.1, 8.0, Hz, 4-H), 6.76 (1 H, d,d, J 2.0,
9.2 Hz, 6-H), 3.15 (2 H, t, J 6.2, 0.5 Hz, 2-H), 2.75 - 2.72 (2 H, m, 3-H). Oc
(100 MHz, CDCI3) 202.9 (1-C), 167.8 (d, J CFS 257.6 Hz, 5-C), 159.7 (d, JCF5
11.1 Hz, 3a-C), 121.1 (d, JCF510.1 Hz, 7-C), 128.2 (d, JCFS 4.0 Hz, 7a-C),
117.4 (d, JCF5 25.2 Hz, 4-C), 112.2 (d, J CFS 22.1 Hz, 6-C), 37.2 (2-C), 25.8 (d,
JCFS 2.0 Hz, 3-C); m\z (electron impact) 330 (M+', 100%), 313 (38), 297 (8),
257 (10), 244 (9),182 (34),165 (10),149 (22), 83 (10), N.B. The
characteristic m/z values of 73 and 75, attributable to TMS, not present; m/z
(chemical impact) 348 (MNH/', 41%),331 (MH+', 100%), 182 (10),168 (24),
151 (30), 149 (22), 120 (7), 109 (6) and 83 (5).
109
Methyl 5,7-difluoro-1-indanone-2-carboxylate (46)
F o F
F F
To a stirred solution of LOA (0.892 ml, 1.78 mmole, 2.0 M solution in
heptane / tetrahydrofuran / ethylbenzene) in THF (dry, 2 ml) was added
slowly dropwise (over forty five minutes), 5,7 -difluoro-1-indanone (43) (0.200
g, 1.19 mmole) in THF (dry, 40 ml), at -78°C and under nitrogen. Stirring was
continued for a further thirty minutes, after which time methyl cyanoformate'58
(0.111 g, 0.104 ml, 1.308 mmole). After stirring for half an hour at -78°C, the
reaction mixture was allowed to warm to room temperature. After five
minutes, at which time the reaction appeared to be complete by tic, the
reaction was poured into cold water (50 ml). The product was then extracted
into diethyl ether (4 x 50 ml). The ethereal extracts were then dried (Na2S04)
and concentrated in vacuo to yield a brown solid (0.968 g). The crude
material was purified by column chromatography (silica with 1 : 1 hexane : .
ethyl acetate) to give a colourless crystalline solid (46) (0.173 g, 64%); m.p.
94 - 95°C; Vmax (KBr disc) 3096 (aromatic C-H), 2934 (saturated C-H), 1735
..... (ester C=O of ketoester), 1700 (a-aryl ketone C=O), 1631 (ester C=O of
ketoester), 1593, 1444, 1222, 1123, 888 cm-'; vmax (neat), 3097, 3050, 2964,
2931,1731,1701,1632 (medium-weak). 1595, 1124 cm-'; OH (400 MHz,
COCI3) 6.99 (1 H, d,d, J8.0, 0.8 Hz, keto 4-H [enol 4-H double doublet
obscured underneath with the most downfield peak just visible at OH 7.01]),
6.78 (1 H, d,t, J2.0, 9.0 Hz, keto 6-H [triplet of enol 6-H appears at OH 6.86]),
3.86 (3 H, s, enol OMe). 3.80 (3 H, s, keto OMe), 3.78 (1 H, d,d, J8.4, 4.0
Hz, keto 2-H), 3.60 - 3.33 (2 H, ABX type system, keto 3-H [peaks of enol 3-H
obscured]). Ratio of keto: enol tautomers is approximately 5: 1; Bc (100
MHz, COCI3) 193.8 (d, J2.0 Hz, keto 1-C), 168.8 (keto C02Me), 168.0 (d,d J
260.6,12.1 Hz, 5-C), 160.2 (d,d, J268.6, 15.1 Hz, keto 7-C), 157.5 (d,d, J
12.1, 3.0 Hz, keto 7a-C), 147.3 (3a-C) , 120.1 (enol 2-C), 109.6 (d,d, J23.1,
110
4.0 Hz, keto 4-C), 108.7 (d, J27.2 Hz, enoI4-C), 104.1 (d,d, J27.2, 23.1, Hz,
keto 6-C), 103.3 (d,d, J 27.2, 23.1 Hz, enol 6-C), 53.8 (keto OMe), 53.0 (keto
2-C), 33.2 (enoI3-C), 30.4 (d, J2.0 Hz, keto 3-C), NB. Quaternary carbons of
enol form not visible in spectrum; m/z (electron impact) 226 (M+, 56%), 195
(24),166 (100),147 (17),138 (56),119 (83),112 (32),99 (42), 93 (20),87
(27),74 (24),69 (23),63 (38), 59 (57), 55 (30), 44 (31); Analysis Calculated
for Cll
HsF20
3 (226.182): C(58.41), H(3.57); Found: C(58.03), H(3.49).
111
Methyl 2,5,7-trifluoro-1-indanone-2-carboxylate (47) .
0
.... Me .... Me 0
• 0 F
F F
To a stirred suspension of sodium hydride (80% dispersion in oil, 0.051 g,
1.703 mmole) in DMF (dry, 2 ml), at 0 °C and under nitrogen, was added
methyI5,7-difluoro-1-indanone-2-carboxylate (46) (0.321 g, 1.419 mmole) in
DMF (dry, 10 ml).165 This was left to stir for twenty minutes at 0 °C then the
temperature was lowered to -50°C and the N-chloromethyl, N-fluoro
ethylenediamine bis(tetrafluoroborate) (0.503 g, 1.419 mmole) added. The
reaction was left to stir at -50°C for ten minutes then allowed to warm to
room temperature. After stirring for one hour at room temperature, the
reaction mixture was poured into a separating funnel containing diethyl ether
(100 ml), washed with a saturated solution of sodium hydrogen carbonate (50
ml) and a saturated solution of sodium chloride (50 ml), dried (Na2S04) and
concentrated in vacuo to yield a pale yellow solid (0.489 g). This was purified
by flash chromatography (silica with 3 : 1 light petroleum [b.p. 40 - 60°C] :
ethyl acetate) to give a colourless solid (47) (0.289 g, 83%); V max (KBr disc)
2968,1764,1733,1620,1602,1415,1327,1229,1213,1126, 854 cm'\ OH
(400 MHz, CDCI3) 7.01 ( 1 H, d,d, J7.6 0.8 Hz, 4-H), 6.85 (1 H, d,d, J8.9, 1.9
Hz, 6-H), 3.84 (3 H, s, OMe), 3.79 (1 H, d,d, J 18.0, 11.4 Hz, 3-H), 3.43 (1 H,
d,d, J22.7, 18.0 Hz, 3-H); Oc (100 MHz, CDCI3) 169.6 (d,d, J262.6, 12.1 Hz,
5-C), 167.2 (d, J28.2 Hz, 7a-C) , 161.0 (d,d, J269.6, 13.1 Hz, 7-C), 154.4 (d,
J 12.1 Hz, 3a-C), 110.1 (d,d, J 23.1, 4.0 Hz, 4-C), 105.2 (d,d, J26.2, 22.1 Hz,
6-C), 94.9 (d, J203.2 Hz, 2-C), 53.7 (OMe), 38.4 (d, J24.1 Hz, 3-C); m/z
(electron impact) 244.0348 (M+, 16.0%, CnH7F303 requires 244.03473),224
(39), 201 (14), 194 (20),185 (100),173 (29),165 (77),156 (23),137 (41),
125 (14),112 (24),107 (10),87 (31), 81 (9),59 (33).
112
N-Methoxy N-methyl 25-methoxy-25-phenylacetamide (49)
~Ph ~e
S N MeO 'OMe
o
To the (S)-(+)-a-methoxyphenylacetic acid (0.258 g, 1.553 mmole),
dissolved in dichloromethane (0.5 ml), was added oxalyl chloride191
(0.493 g,
0.339 ml, 3.881 mmole). The solution was stirred for one hour at room
temperature, after which time effervesence had ceased. The excess oxalyl
chloride and solvent were removed in vacuo to yield a clear oil. To the oil was
added dichloromethane (5 ml), followed by the N,O-dimethylhydroxylamine
hydrochloride 192 (0.167 g, 1.708 mmole). The solution was cooled to OOC and
pyridine (0.270 g, 0.276 ml, 3.416 mmole) added. The mixture was stirred at
room temperature for one hour, then evaporated in vacuo. The residue was
partitioned between brine and a 1:1 mixture of diethyl ether and
dichloromethane. The organic layer was then washed washed with 10%
copper sulfate solution (50 ml), 10% sodium carbonate solution, dried
(Na2S04) and concentrated in vacuo to yield the crude product as a pale
yellow oil (0.218 g, 67 %). The oil was purified by flash chromatography (silica
iNith 1:1 ethyl acetate: dichloromethane) to give the amide (49) as a
colourless oil (0.161 g, 50 %); Vmax (neat) 3508,2938,1674 (C=O), 1456,
1386, 1110, 1089, 971 cm·1; OH (250 MHz, CDCI3) 7.39 - 7.26 (5 H, m, ArH),
5.04 (1 H, s, CH), 3.35 (CH3), 3.32 (CH3), 3.09 (3 H, s, CH3); Oc (62.5 MHz,
CDCI3
) 170.7 (NC=O), 136.2 (ArC), 128.4 (ArCH). 128.3 (ArCH), 128.2 (ArCH),
127.7 (ArCH), 126.9 (ArCH), 80.4 (2-C), 60.6 (NOCH3), 56.7 (OCH3), 32.0
(NCH3 )·
113
1 5-Methoxy-1 5-phenylacetone (50)
S N JyPh ~e
MeO 'OMe
o
J; ~Me MeO' I(
o
To a solution of N-methoxy N-methyl 2S-methoxy-2S-phenylacetamide
(49) (0.059 g, 0.282 mmole) in dry tetrohyrofuran (5 ml) was added
methyllithium'92 (1.4 M solution in diethyl ether, 0.282 ml, 0.395 mmole) at
OOC. The reaction mixture was stirred for one minute, after which time no
amide was visible by tic (silica with 5% methanol in dichloromethane. Rt
[amide) 0.41, Rt [ketone) 0.86). To the reaction mixture, at O°C, was added
5% hydrochloric acid (20 ml). The reaction mixture was then extracted with a
1:1 mixture of diethyl ether and dichloromethane (3 x 20 ml). The organic
extracts were dried (Na2S04) and concentrated in vacuo to yield the crude
product (50) as a pale brown oil (0.059 g); V max (neat) 2932, 2828, 1723
(C=O), 1681, 1455, 1354, 1104 cm"; OH (250 MHz, CDCI3) 7.35 - 7.29 (5 H,
m, ArH), 4.60 (1 H, s, CH), 3.33 (3 H, s, OCH3), 2.06 (3 H, s, O=CCH3); Oc
(62.5 MHz, CDCI3) 207.0 (C=O), 135.8 (MeOCHC[aromatic)),128.8
(ArCH). 128.4 (ArCH), 128.5 (ArCH), 126.9 (2 C, ArCH), 69.3 (1-C), 57.1
(OCH3 ), 25.0 (O=CCH3).
114
Chapter 3, Experimental
General procedure for in situ dioxirane reactions
All apparatus was meticulously washed with EDT A. Na2 solution, 179
followed by distilled acetone, '80 then dried before use. The assembled
glassware was then covered in aluminium foil to help eliminate light.
To the reaction flask, at 0 cC, was added phosphate buffer (25 ml),'81
dichloromethane (X ml, determined by the quantity of ketone used),'82
tetrabutylammonium hydrogen sulphate (- 0.002 g), the alkene (1 equivalent)
and the ketone (2 equivalents, 0.5 M concentration in the dichloromethane).
The pH of the vigorously stirred solution was adjusted to between pH 7.0 and
7.5 by the addition of KOH solution. l83 Solid Oxone ® (30 equivalents) was
added over approximately half an hour, the pH being maintained between pH
7.0 and 7.5 throughout, by the addition of KOH solution. 183 The reaction was
left to stir for a further four hours, then a sample taken for G.C. or 1H n.m.r.
analysis. If the reaction had not gone to completion, a further portion of solid ®
Oxone (30 equivalents) was added, portionwise. The reaction left to stir for
several hours, a G.C. or 'H n.m.r. analysis carried out, and if the epoxidation ®
reaction was still incomplete, further solid Oxone added. This was repeated
until the either the reaction was complete, or, if the reaction was slow, until
sufficient epoxide had been formed for chiral shift analysis to be performed. If
the reaction needed to be left overnight, the stirring was stopped and then
resumed the following morning.
The reaction mixture was then filtered through glasswool into a separating
funnel. Dichloromethane (3 x 35 ml) was then used to rinse out the reaction
flask and extract the aqueous phase. The organic extracts were combined,
dried (Na2S04) and concentrated in vacuo. The resulting residue was
analysed by G.C. and lor 'H n.m.r. spectroscopy. The alkene and ketone
were then isolated by flash chromatography.
115
For the reactions using the dioxirane derivatives of a homochiral ketone,
the optical rotation of the isolated alkene was determined and a chiral shift
experiment, using Eu(hfch, carried out.
Equivalents of chiral shift reagent needed for determination of enantiomer
ratio were:
i) Trans·stilbene (23): 0.05 equivalents.
In the presence of Eu(hfch, the ChPh proton in the enantiomers was
resolved in the lH n.m.r. spectrum from OH (250 MHz, CDCla) 3.85 (s),
to OH (250 MHz, CDCla) -3.96 and -3.95.
ii) Trans-~-methyl styrene (24): 0.15 equivalents.
The ChPh proton appeared as a doublet at OH (250 MHz, CD Cia) 3.57
(d, J2.0 Hz) in the lH n.m.r. spectrum of (24). In the presence of 0.15
equivalents of Eu(hfch, it appeared at OH (250 MHz, CDCla) -4.12 and
-4.20;
iii) 6-Chloro-2,2-dimethyl-2H-1-benzopyran (25): 0.10 equivalents.
In the presence of Eu(hfch, the proton at C-3 in the enantiomers was
resolved from OH (250 MHz, CDCla) 3.49 (d, J4.4 Hz), to OH (250 MHz,
CDCla) -3.85 and -3.77.
All chiral shift experiments revealed a 1 : 1 ratio of the alkene enantiomers,
consequently no optical rotation was seen in any of the cases.
116
Chapter 4, Experimental
Reaction 1: Preparation and reaction of the dioxirane derivative of
1,1, 1-trifluoroacetophenone with cholesterol
Using the above general procedure, Oxone® (39.8 g, 64.7 mmole) and
disodium ethylenediaminetetraacetate dihydrate (1 g) in distilled water (300
ml) were added, over a two and a half hour period, to cholesterol (0.500 g,
1.29 mmole), dichloromethane (30 ml), 1,1,1-trifluoroacetophenone (0.675 g,
0.545 rnl, 3.88 mmole). pH 7.5 phosphate buffer (40 ml) and
tetrabutylammonium hydrogen sulphate (0.439 g, 1.29 mmole). Work up,
using sodium sulphite (1 g), diethyl ether (100 ml) and sodium chloride
solution (aqueous, saturated, 3 x 100 ml) as in the general procedure, yielded
a crude white residue (1.018 g). Tic analysis (silica with 20 : 30 : 1 diethyl
ether: light petroleum [b.p. 40 - 60 QC] : ethyl acetate) showed cholesterol (Rt
0.35) to be still present, but also showed that formation of its epoxide (Rt
0.12) had taken place. N.m.r. spectroscopy showed there to be 70% of the
starting material [OH (250 MHz, CDCI3) 0.68 (3 H, s, 18-Me)], and 30% of the
epoxide [OH (250 MHz, CDCI3 ) 0.64 (3 H, s, 18-Me) and 0.61 (3 H, s, 18-Me)].
>.' • - "~~eaction 2: Preparation and reaction of the dioxirane derivative of 1,1,1-
trifluoroacetophenone with trans-stilbene
Using the above general procedure, Oxone® (39.2 g, 63.8 mmole) and
disodium ethylenediaminetetraacetate dihydrate (1 g) in distilled water (300
ml) were added, over a four and a half hour period, to trans-stilbene (0.230 g,
1.28 rnmole). dichloromethane (30 ml), 1,1,1-trifluoroacetophenone (0.667 g,
0.538 ml, 3.83 mmole), pH 7.5 phosphate buffer (40 ml) and
tetrabutylammonium hydrogen sulphate (0.433 g, 1.28 mmole). Work up,
using sodium sulphite (1 g), diethyl ether (100 ml) and sodium chloride
solution (aqueous, saturated, 3 x 100 ml) as in the general procedure, yielded
an off white residue (0.279 g). Tic analysis (silica with 1 : 1 toluene: light
petroleum [b.p. 40 - 60 QC]) of the solution showed trans-stilbene (Rt 0.83) to
117
be still present, but also showed that formation of the trans-stilbene oxide (Rt
0.61) had taken place. N.m.r. spectroscopy showed there to be 60% of the
starting material [OH (250 MHz, CDCI3 ) 7.11 (2 H, s, ChPh)) , and 40% of the
epoxide [OH (250 MHz, CDCI3 ) 3.86 (2 H, s, ChPh)).
General procedure for the in situ dioxirane reaction.7
To a three-necked round-bottomed flask was added the alkene in
dichloromethane, followed by the ketone, pH 7.5 buffer and tetrabutyl
ammonium hydrogen sulphate. The mixture was allowed to stir for twenty
minutes at 2 -5 QC. The buffer (pH 7.5 at 5 QC) was made from KH2P04 (1.179
g) and Na2HP04 (4.302 g) dissolved in distilled water (1000 ml). A pH of 7.5
was maintained using a pH stat (5 M KOH). The Oxone® and EDTA.Na2·2H20
were dissolved in distilled water and added dropwise to the vigorously stirring
mixture over several hours. Care was taken not to allow the pH to fluctuate
from pH 7.5. The reaction was then left to stir overnight.
Work up: Sodium sulphite was added to the reaction mixture and stirring
continued for thirty minutes. Further dichloromethane was added, then the
dichloromethane separated from the aqueous layer and concentrated in
vacuo. The resulting residue was redissolved in diethyl ether, washed with
aqueous sodium chloride solution, dried (MgS04) and concentrated in vacuo
to yield a residue containing any unreacted alkene, the ketone and any
oxidized alkene.
118
Chapter 5, Experimental
Preparation of Solutions of Dioxiranes
Titration of isolated dioxirane solutions
All the apparatus to be used was washed with water then acetone, '80 and
dried. An acetic acid I acetone solution'·' (3 ml) was added to a small conical
flask, followed by a solution of potassium iodide'·· (5 ml). The flask was
stoppered and shaken. A portion of the isolated dioxirane solution (0.2 ml)
was pipetted into the flask which was again stoppered and shaken. The
dioxirane oxidises the potassium iodide to produce iodine (I,), which turns the
solution yellow. The resulting solution was titrated against a solution of
sodium thiosulfate.'·7 The end-point of the titration was denoted by the loss of
the yellow colour of the iodine (refer to p.69 for the chemical equations for the
titration) .
119
Preparation of Dimethyldioxirane (9)16
H3CX1 H3C 0
in acetone
The apparatus was covered in foil, flushed with nitrogen and the receiving
flask cooled to -78 ac. Sodium bicarbonate (240 g) was added to the reaction
flask followed by the EDT A. Na2 solution (450 ml).I79 The mixture was stirred
using an overhead stirrer for five minutes after which time the stirring was
stopped and acetone l80 (320 ml) added. The stirring was recommenced and
continued for five minutes. The caroate (500 g) was then added in portions.
The stirring was stopped during each addition then started again when the
addition of a portion was complete. On completion of caroate addition, a
vacuum line was attached to the apparatus. A light vacuum (- 560 mmHg)
was applied using a water pump. Note that the dimethyldioxirane solution
begins to distil over before the vacuum is applied. The distillation of the
dimethyldioxirane solution is complete after approximately one hour. The
molarity of the solution was obtained by titration using the above method.
Molarity of solution: 0.09 M
120
Preparation of Methyl(trifluoromethyl)dioxirane (1. R'= CF3• R2= Me)14
in 1,1, 1-trifluoroacetone
After the apparatus had been covered in foil, a flow of nitrogen was put
through the apparatus and maintained for two hours. After two hours, both
the receiving flasks and trap were cooled to -78 QC. The reaction flask was
then cooled to 0 QC, the flow of nitrogen stopped and the nitrogen inlet
sealed. Sodium bicarbonate was then added to the reaction flask followed by
the EDT A. Na2 solution. 179 The solution was briefly stiired using an overhead
stirrer. The 1,1, 1-triflouoroacetone was added to the reaction flask and the
solution again stirred briefly before the addition of the caroate in one portion.
The solution was vigorously stirred and a light vacuum applied using a water
pump (- 600 - 700 mm Hg). The distillation was complete in approximately
ten minutes.
Molarity of solution: 0.68 M
121
Preparation of the dioxirane derivative of cyclohexanone 17
•
0-0
CS '0 oyclohe"""o",
A mixture of cyclohexanone (40 ml), phosphate buffer1s1 (50 ml) and ice
(14 g) was stirred at 0 cC (ice - salt bath). Oxone® (90 g, cooled) was added
as a slurry in distilled water (200 ml, cooled). Potassium hydroxide (5 M
solution in distilled water) was added simultaneously to maintain a pH of 7 -
8.5. Af1er addition of the Oxone® was complete, the reaction mixture was
stirred for two to three minutes then poured into a beaker containing a cooled
mixture of Na2S04 (32 g), NaH2P04 (16 g) and Na2HP04 (8 g). The combined
mixture was stirred vigorously in an ice - salt bath. The liquid phase was
rapidly transferred to a cooled separating funnel (500 ml) and the aqueous
phase .removed. The deep yellow organic phase (25 ml) was dried (Na2S04,
cooled) then analysed for peroxide content.
Molarity of solution: 0.09 M
122
Attempted preparation of the dioxirane derivative of 1,1,1-
trifluoroacetophenone (1, Rl= CF3 , R2= Ph)
o
~CF' A mixture of 1,1, 1-trifluoroacetophenone (2 ml), phosphate buffer181 (2 ml)
and ice (1 g) was stirred at 0 cC (ice-salt bath). Cooled Oxone® (ice-salt
methanol bath) was added as a slurry in water (10 ml) over ten minutes. A
potassium hydroxide solution (5 M), cooled to 0 cC, was added
simultaneously to maintain the pH at 7 - 8.5. A yellow colour was formed
immediately on combining the reagents. The mixture was stirred vigorously
for two to three minutes and then poured into a beaker containing a cooled
mixture of anhydrous Na2S04 (2.3 g) : NaH2P04.H20 (1.1 g) : Na2HP04.7H20
(0.6 g). The combined mixture was stirred vigorously in an ice-salt bath. The
liquid phase was transferred rapidly to a cooled separatory funnel. NB. At this
point the aqueous phase was separated from rest of the reaction mixture.
The organic phase was dispersed throughout the remaining solid. Using a
cooled pipette, the organic phase was pi petted into a small cooled beaker
containing drying agent (NaS04)' The remaining organic material in the solid
was extracted with dichloromethane (10 ml) and combined with the other
organic phase. The yellow liquid was then filtered into a cooled flask and
tested for peroxide content.
Molarity of solution: None
123
Preparation of the dioxirane derivative of hexafluoroacetone (1. R'= CF3•
R2= CF3) using sodium bicarbonate as buffer
.. F3CX1 F3C 0
in dichloromethane
To a rapidly stirring mixture of sodium hydrogen carbonate (26.7 g, 318.1
mmole), hexafluoroacetone trihydrate (1.00 g, 4.54 mmole), EDTA.Na2
solution 179 (60 ml) and dichloromethane (5 ml) was added solid Oxone®
(41.49 g, 136.3 mmole) in portions, over a period of 4 hours. After addition of
all the Oxone®, the solution was left to stir for 2 hours. At this point no yellow
colour was seen in the dichloromethane phase ( the dichloromethane was
dispersed through the solid and on the surface of the aqueous layer as small
globules). It was noted that some liquid, which appeared to have a slight
yellow colour, was present on the surface of the first cold finger after addition
of approximately half the Oxone®. It was the liquid (- 3 ml) obtained from this
cold finger which was tested for peroxide content after all the Oxone® had
been added. Molarity of solution: 0.013 M
The reaction was continued. To the reaction flask was added further
"dichloromethane (5 ml) and a small quantity of phase transfer catalyst
(tetrabutylammonium hydrogen sulfate [TBAHS], 15 mg). Solid Oxone®
(13.83 g, 45.4 mmole) was added over ten minutes and the solution left to stir
for twenty minutes at 0 aC. The ice-bath was then removed and the mixture
allowed to warm to room temperature. After thirty minutes a slight vacuum
was applied for fifteen minutes. Approximately 4 ml of a slightly yellow
coloured solution was collected in the cold finger. Molarity of solution: 0.018
M.
124
Preparation of the dioxirane derivative of hexafluoroacetone (1, R'= CF3 ,
R2= CF3) using a phosphate buffer
.. F3CX1 F3C 0
in dichloromethane
Oxone® (20.74 g, 68.16 mmole) was added to a vigorously stirring mixture
of hexafluoroacetone.trihydrate (0.500 g, 2.272 mmole), TBAHS (0.015 g),
phosphate bufferl89 (145 ml) and dichloromethane (25 ml) in 2 portions. The
first portion was added over 0.5 hour then the solution left to stir for 1.5 hours
at 0 QC. After this time the remaining Oxone® was added over 0.5 hour and
the solution left to stir for 1 hour then a light vacuum applied for 0.5 hour.
Approximately 5 ml of solution was collected in the cold finger. This was then
tested for its peroxide content.
Molarity of solution: 0.023 M
125
Oxidations using solutions of isolated dioxiranes
In each case all the apparatus was meticulously washed with EDTANa2
solution 179 followed by acetone 180 and dried before use. The reaction flasks
were cover in aluminium foil to exclude light.
Oxidation of trans-stilbene (23)
Ph~ Ph
..
To a stirred solution of trans-stilbene (0.252 g, 1.40 mmole) in acetone180
(20 ml), at 0 °C, was added a solution of dimethyldioxirane in acetone (0.07
M, 20 ml, 1.40 mmole). The reaction was left to stir at 0 °C for 7 hours, after
which time it was stored in the freezer over night. After this time the reaction
mixture was allowed to warm to room temperature. The reaction was followed
by tic (silica with 1 : 1 toluene: light petroleum [b.p. 40 - 60°C]); alkene RI
0.86; epoxide RI 0.68. After 1 hour at room temperature, the reaction
appeared to have gone to completion. The reaction mixture was concentrated
in vacuo to yield a colourless solid (0.274 g, 100%); V max (film) 3036, 2991,
1464, 1452, 1072 cmo1; liH (250 MHz, CDCI3) 7.40 - 7.27 (10 H, m, ArH), 3.85
(2 H, s, PhCH).
Conditions used for G.C. Analysis:
G.C. Apparatus: Pye Series, 104 Chromatograph, Pye Unicam.
Column: 10% Apiezon on Chomosorb W, AW/DMCS, 100/200 mesh.
Gases: Standard machine settings.
Carrier Gas: Nitrogen.
Detector: FID.
Chart Recorder: Omniscribe Recorder, Houston Instruments.
Program: Initial oven temperature: 80°C for 0.5 minute;
Ramp rate: 3 °C I minute;
Final oven temperature: 280°C for 10 minutes.
Retention times of standard solutions:
trans-stilbene : 14 minutes;
trans-stilbene oxide: 18 minutes.
126
Oxidation of tran9-~-methylstyrene (24)'90
Me~ Ph
To trans-~-methylstyrene (0.200 g, 1.692 mmole) was added a solution of
dimethyldioxirane in acetone (23.3 ml, 0.087 M, 2.031 mmole). The reaction
was followed using gas chromatography. The solution was left to stir at 0 °C
for fifteen minutes after which time the reaction appeared to be complete.
Solvent was then removed in vacuo to yield a colourless oil which was taken
up in dichloromethane, dried (Na2S04) and again concentrated to yield a
colourless oil which was purified by column chromatography to yield a
colourless oil (0.202 g, 89%); Vmax (film) 3025, 2915,1496,1442 cm·'; OH (250
MHz, CDCI3) 7.36 - 7.23 (5 H, m, ArH), 3.57 (1 H, d, J2.0 Hz, ChPh), 3.03 ( 1
H, q,d, J5.1, 2.1 Hz, MeCh), 1.44 (3 H, d, J5.1 Hz, Me); Bc (62.5 MHz,
CDCI3) 137.7, 126.4, 128.0, 125.5, 59.5 (Q-iPh), 59.0 (Q-iMe), 17.8 (Q-i3).
GC-MS analysis of the purified material showed evidence of a small amount
of decomposition of the epoxide during chromatography [m/z 105, C(O)Ph;
derived from the decomposition product, H3CCH2C(O)Ph]
Conditions used for G. C. Analysis:
G.C. Apparatus: Pye Series, 104 Chromatograph, Pye Unicam.
Column:
Gases:
10% Apiezon on Chomosorb W, AW/DMCS, 100 1200 mesh.
Standard machine settings.
Carrier Gas: Nitrogen.
Detector: FID.
Chart Recorder: Omniscribe Recorder, Houston Instruments.
Program: Initial oven temperature: 80°C for 0.5 minute;
Ramp rate: 3 °C I minute;
Final oven temperature: 280°C for 10 minutes.
Retention times of standard solutions:
trans-~-methylstyrene : 5.5 minutes;
trans-~-methylstyrene oxide: 8.5 minutes.
127
Oxidation of 6-acetyl-2,2-dimethyl-2H-1-benzopyran
To the 6-acetyl-2,2-dimethyl-2H-1-benzopyran (0.150 g, 0.742 mmole) at 0
QC, was added dimethyldioxirane in acetone (0.037 M, 24.1 ml, 0.890
mmole). This was left to stir, at 0 QC, for 1.5 hours, after which time the
reaction appeared to be complete by tic analysis (silica with 50 : 49 : 1 diethyl
ether: light petroleum [b.p. 40 - 60°C] : dichloromethane); alkene Rt 0.91;
epoxide Rt 0.41. Solvent was removed in vacuo to yield a colourless oil which
was purified by flash chromatography (silica with 50 : 49 : 1 diethyl ether:
light petroleum [b.p. 40 - 60°C] : dichloromethane) to yield a colourless oil
(0.138 g, 85%) which solidified on storing in the fridge for one week; V max
(film) 2980, 2924, 1679 (C=O), 1610, 1272, 1192 cm-1; OH (250 MHz, CDCI3)
8.01 (1 H, d, J2.2 Hz, 5-H), 7.83 (1 H, d,d, J8.5, 2.2 Hz, 7-H), 6.85 (1 H, d, J
8.5 Hz, 8-H), 3.97 (1 H, d, J4.4 Hz, 4-H), 3.53 (1 H, d, J4.4 Hz, 3-H), 2.57 (3
H, s, CH3CO), 1.60 (3 H, S, 2-CCH3')' 1.29 (3 H, s, 2-CCf6").
Conditions used for G. C Analysis (not quantiative):
-·G.C. Apparatus: Pye Series, 104 Chromatograph, Pye Unicam.
Column:
Gases:
10% Apiezon on Chomosorb W, AW/DMCS, 100/200 mesh.
Air: 11; Hydrogen: 17.
Carrier Gas: Nitrogen.
Detector: FID.
Chart Recorder: Omniscribe Recorder, Houston Instruments.
Program: Oven temperature: 180°C;
Retention times of standard solutions:
6-cyano-2,2-dimethyl-2H-1-benzopyran: 2 minutes;
6-cyano-2,2-dimethyl-2H-1-benzopyran oxide: Decomposition noted.
2 peaks: 3 and 3.5 minutes.
128
Oxidation of S-chloro-2,2-dimethyl-2H-1-benzopyran (25)
Cl, Cl,
To 6-chloro-2,2-dimethyl-2H-1-benzopyran (0.075 g, 0.385 mmole) at 0 QC,
was added a solution of dimethyldioxirane in acetone (0.037 M, 12.5 ml,
0.462 mmole). This was left to stir at 0 QC for 1.5 hours after which time the
reaction appeared to have gone to completion by tic analysis (silica with 60 :
39 : 1 light petroleum [b.p. 40 - 60 QC] : diethyl ether: dichloromethane);
alkene Rt 0.85; epoxide Rt 0.62. Concentration of the reaction mixture in
vacuo yielded a colourless oil which was purified by flash chromatography
(silica with 85 : 15 light petroleum [ b. p. 40 - 60 QC] : diethyl ether) to yield a
colourless oil (0.072 g, 89%); Vmax (film) 2976, 2932, 1268, 1204 cm"; OH (250
MHz, CDCI3 ) 7.32 (1 H, d, J2.6 Hz, 5-H), 7.19 (1 H, q, Ja.6, 2.6 Hz, 7-H),
6.75 (1H, d, Ja.7 Hz, 8-H), 3.85 (1 H, d, J4.4 Hz, 4-H), 3.49 (1 H, d, J4.4
Hz, 3-H), 1.56 (3 H, S, 2-CCH3')' 1.24 (3 H,s, 2-CCH3").
Conditions used for G. C. Analysis (not quantiative):
G.C. Apparatus: Pye Series, 104 Chromatograph, Pye Unicam.
Column:
Gases:
10% Apiezon on Chomosorb W, AW/DMCS, 100/200 mesh.
Air: 11; Hydrogen: 17.
Carrier Gas: Nitrogen.
Detector: FID.
Chart Recorder: Omniscribe Recorder, Houston Instruments.
Program: Oven temperature: 1aO QC;
Retention times of standard solutions:
6-cyano-2,2-dimethyl-2H-1-benzopyran: 4.5 minutes;
6-cyano-2,2-dimethyl-2H-1-benzopyran oxide: Decomposition noted.
2 peaks: 6 and 7.75 minutes.
129
Oxidation of 6-cyano-2,2-dimethyl-2H-1-benzopyran
CN CN, o
• o
To 6-cyano-2,2-dimethyl-2H-1-benzopyran (0.150 g, 0.810 mmole) at 0 cC,
was added a solution of dimethyldioxirane in acetone (0.088 M, 11.04 ml,
0.972 mmole). This was left to stir at 0 cC for 10 hours after which time the
reaction appeared to have gone to completion by tic analysis (silica with 70 :
30 light petroleum [b.p. 40 - 60 cC] : diethyl ether); alkene R, 0.28; epoxide R,
0.63. Concentration of the reaction mixture in vacuo yielded a colourless oil
which was purified by flash chromatography (silica with 85 : 15 light
petroleum [ b.p. 40 - 60 cC] : diethyl ether) to yield a colourless solid; (0.072
g, 89%); m.p. 50.5 - 53.5 cC; Vmax (film) 2983,2227 (CN), 1616, 1494, 1279
1162 cm-1; OH (250 MHz, CDCI3) 7.65 (1 H, d, J2.1 Hz, 5-H), 7.52 (1 H, d,d, J
8.6, 2.1 Hz, 7-H), 6.86 (1 H, d, J8.5 Hz, 8-H), 3.91 (1 H, d, J4.3 Hz, 4-H),'
3.54 (1 H, d, J4.3 Hz, 3-H), 1.60 (3 H, S, 2-CCH3')' 1.30 (3 H, S, 2-CCH3"); Oc
(62.5 MHz, CDCI3) 133.3 (8a-C), 134.3 (NC-C=C), 133.7 (NC-C=C'), 121.0
(4a-C), 118.9 (8-C), 118.6 (NC-C), 104.2 (NC), 74.6 (OCMe2), 62.2 (4-C),
49.8 (3-C), 25.4 (a-i3), 22.9 (CH3).
Conditions used for G. C. Analysis (not quantiative):
G.C. Apparatus: Pye Series, 104 Chromatograph, Pye Unicam.
Column: 10% Apiezon on Chomosorb W, AW/DMCS, 100/200 mesh.
Gases: Air: 11; Hydrogen: 17. Carrier Gas: Nitrogen.
Detector: FID.
Chart Recorder: Omniscribe Recorder, Houston Instruments.
Program: Oven temperature: 180 cC;
Retention times of standard solutions:
6-cyano-2,2-dimethyl-2H-1-benzopyran: 4 minutes;
6-cyano-2,2-dimethyl-2H-1-benzopyran oxide: Decomposition noted.
2 peaks: 5.75 and 7 minutes.
130
Oxidation of Metoclopramide
0 Et 0 Et 0 I Cl N~N'Et C N~~
H • H H2N OMe H2N OMe
To metoclopramide (O.1S0 g, O.SOO mmole) was added a solution of the
dioxirane derivative of cyclohexanone in cyclohexanone (0.09 M, S.S6 ml,
O.SOO mmole). this was left to stir over night. After this time a further aliquot of
the dioxirane derivative of cyclohexanone (5.S6 ml, O.SOO mmole) was added
and the solution left to stir at room temperature for 6.S hours. A further aliquot
(S.S6 ml, O.S mmole) was then added and the solution left to stir overnight, at
room temperature. Any remaining oxidant was then destroyed by the addition
of sodium sulfite. After stirring for 1 minute, solvent was removed in vacuo to
yield ari orange residue. This was purified by flash chromatography (alkaline
alumina with dichloromethane to elute the residual cyclohexanone, increasing
to 1 % MeOH in dichloromethane to elute the starting material, then S%
MeOH in dichloromethane to isolate the product). Tic analysis (neutral
alumina with S% MeOH in dichloromethane): metoclopramide: Rr 0.63 and
product: Rr 0.36.
The product was isolated as a yellow solid (0.115 g, 73%). This was
recrystallised from dichloromethane to give a colourless solid (O.OS g, 32%);
bH (400 MHz, CDCI3, DMSO) 8.88 (1 H, m, CON,"", 8.02 (1 H, s, CICC,"",
6.34 (1 H, s, hCCOMe), 4.74 (2 H, s, NH2 ), 3.93 - 3.89 (2 H, q, J6.3 Hz,
CH2NHCO), 3.88 (3 H, s, OC~), 3.39 (2 H, t, J6.3 Hz, CH.!NOEt2), 3.28 (4 H,
q, J7.3 Hz, CH2CH3), 1.33 (6 H, t, J7.3 Hz, CH2CH3 ); be (62.S MHz, CDCI3,
DMSO) 170.0 (C=O), 162.9 (COMe), 152.2 (CNH2), 137.6 (Cl-iCCI), 116.7
(CC=O), 116.0 (CCI), 102.7 (Q-INH2), 67.8 (Q-i2NO), 6S.6 (Cl-i2NH), 61.0
(OQ-i3), 39.S (Cl-i2CH3), 13.8 (CH2 Q-13); m/z (FAB [Positive-ion], glycerol) 316
131
(MH+, 51.6%), 227 (ArCONHEt, 58), 185 (Gly., 79), 184 (ArCO+, 33), 93
(Gly., 100),86 (19),73 (40), 57 (20).
132
References and Notes
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114. Danelon, G.O., Mata, E.G. and M ascaretti , OA, Tetrahedron Lett., 1993, 34 (49),7877. NB. Correction given in: Danelon, G.O., Mata, E.G. and M ascaretti , OA, Tetrahedron Left., 1994, 35 (15),2254.
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167. Carried out by Or. D.S. Brown of this Department. Positional and temperature parameters, bond lengths, and angles have been deposited with the Cambridge Crystallographic Data Centre, Lensfield Road., Cambridge, CB2 1 EW
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143
178. Pandit. U.K., van der Vlugt, FA, van Dalen, AC., Joustra, A.H. and Schenk, H., Tetrahedron Left., 1969, 42, 3693.
179. The EDTA.Na2 solution was composed of 4 9 EDT A.Na2 in 2500 ml of distilled water. The EDT A Na2 was present to sequester any metal ions present in the reaction.
180. The acetone was distilled from KMn04.
181. The phosphate buffer solution was made up using 20 9 [85%] H3P04 in 2000 ml of EDTA.Na2 solution (ct. Ref. 179), made to pH 7.2 with NaOH (-29 g).
182. Dichloromethane was distilled from P205 before use.
183. The KOH solution was made up of 10% KOH in EDTANa2 solution (ct. Ref. 179).
184. Frost, C., Dioxirane Chemistry - Novel Oxidations, Final Year Research Project, Loughborough University, 1991.
185. The acetic acid I acetone solution was made from glacial acetic acid and acetone solution (ct. Ref. 180) in a ratio of 3 : 2 by volume.
186. The potassium iodide solution was made up t01 0% wlv in distilled water.
187. The sodium thiosulfate solution was made to 0.01182 N in distilled water.
188. The phosphate buffer was made from KH2P04 (1.179 g) and Na2HP04 (4.302 g) in distilled water (1000 ml). This gave a pH of 7.5 at 5 ac.
189. The phosphate buffer (pH 7.4) was made from NaH2P04 (174 g) and Na2HP04 (56 g) made to 150 ml in distilled water. NB. Addition of Oxone® (1 g) to this buffer (5 ml) gave a pH of 6.9.
190. Previous syntheses of ~-methylstyrene oxide (optical rotation of enantiomers measured): Irie, R., Noda, K., Ito, Y., Matsumoto, N. and Katsuki, T., Tetrahedron.·Asymmetry, 1991, 2(7), 481; Conte, V., Di Furia, F., Modena, G., Sbampato, G. and Valle, G., Tetrahedron: Asymmetry, 1991, 2(4), 257; Castedo, L., Castro, J.L. and Riguera, R., Tetrahedron Left., 1984, 25(11),1205; Witkop, B. and Foltz, C.M., J Am. Chem. Soc., 1957, 79, 197.
191. Nahm, S. and Weinreb, S., Tetrahedron Lett., 1981, 22(39),3815.
192. Adams, R. and Ulrich, L.H., J Am. Chem. Soc., 1920, 42, 599; Aldrich Technical Information Bulletin Form Number A 74.
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