Reactions of nitrogen nucleophiles with enantiopure cyclohexenyl electrophiles: A stereo- and regio- selective study

Article abstract of DOI:10.1002/poc.3183

The reactions of enantiopure cyclohexene epoxides and trans-1,2- bromoacetates, derived from the corresponding substituted benzene cis-dihydrodiol metabolites, with nitrogen nucleophiles, were examined and possible mechanisms proposed. An initial objective was the synthesis of new 1,2-aminoalcohol enantiomers as potential chiral ligands and synthetic scaffolds for library generation. These apparently simple substitution reactions proved to be more complex than initially anticipated and were found to involve a combination of different reaction mechanisms. Allylic trans-1,2-azidohydrins were prepared by Lewis acid-catalysed ring-opening of cyclic vinyl epoxides with sodium azide via an S_N2 mechanism. On heating, these trans-1,2-azidohydrins isomerized to the corresponding trans-1,4-azidohydrins via a suprafacial allyl azide [3,3]-sigmatropic rearrangement mechanism. Conversion of a 1,2-azidohydrin to a 1,2-azidoacetate moved the equilibrium position in favour of the 1,4-substitution product. Allylic trans-1,2- bromoacetates reacted with sodium azide at room temperature to give C-2 and C-4 substituted products. A clean inversion of configuration at C-2 was found, as expected, from a concerted S_N2-pathway. However, substitution at C-4 was not stereoselective and resulted in mixtures of 1,4-cis and 1,4-trans products. This observation can be rationalized in terms of competitive S _N2 and S_N2′ reactions allied to a [3,3]-sigmatropic rearrangement. cis-1,2-Azidohydrins and cis-1,2-azidoacetates were much more prone to rearrange than the corresponding trans-isomers. Reaction of the softer tosamide nucleophile with trans-1,2-bromoacetates resulted, predominantly, in C-4 substitution via a syn-S_N2′ mechanism. One application of the reaction of secondary amines with allylic cyclohexene epoxides, to give trans-1,2-aminoalcohols, is in the synthesis of the anticholinergic drug vesamicol, via an S_N2 mechanism. Copyright 2013 John Wiley & Sons, Ltd. Multiple reaction pathways including S_N2, S _N2′, and [3,3]-sigmatropic rearrangement mechanisms are required to rationalize the formation of products obtained from the reaction of cyclohexene epoxides and trans-bromoacetates with azide and other nitrogen nucleophiles. Copyright

Full text of DOI:10.1002/poc.3183

Special Issue Article
Received: 23 April 2013,
Revised: 14 June 2013,
Accepted: 3 July 2013,
Published online in Wiley Online Library: 14 August 2013
(wileyonlinelibrary.com) DOI: 10.1002/poc.3183
Reactions of nitrogen nucleophiles with
enantiopure cyclohexenyl electrophiles:
a stereo- and regio- selective study†‡
Derek R. Boyda*, Narain D. Sharmaa, Tayeb Belhocinea, John F. Malonea,
Stuart T. McGregora, Jordan Atchisona, Peter A. B. McIntyrea and
Paul J. Stevensona*
The reactions of enantiopure cyclohexene epoxides and trans-1,2-bromoacetates, derived from the corresponding
substituted benzene cis-dihydrodiol metabolites, with nitrogen nucleophiles, were examined and possible mechanisms
proposed. An initial objective was the synthesis of new 1,2-aminoalcohol enantiomers as potential chiral ligands and
synthetic scaffolds for library generation. These apparently simple substitution reactions proved to be more complex
than initially anticipated and were found to involve a combination of different reaction mechanisms.
Allylic trans-1,2-azidohydrins were prepared by Lewis acid-catalysed ring-opening of cyclic vinyl epoxides with
sodium azide via an SN2 mechanism. On heating, these trans-1,2-azidohydrins isomerized to the corresponding
trans-1,4-azidohydrins via a suprafacial allyl azide [3,3]-sigmatropic rearrangement mechanism. Conversion of a
1,2-azidohydrin to a 1,2-azidoacetate moved the equilibrium position in favour of the 1,4-substitution product.
Allylic trans-1,2-bromoacetates reacted with sodium azide at room temperature to give C-2 and C-4 substituted
products. A clean inversion of configuration at C-2 was found, as expected, from a concerted SN2-pathway. However,
substitution at C-4 was not stereoselective and resulted in mixtures of 1,4-cis and 1,4-trans products. This observation
can be rationalized in terms of competitive SN2 and SN2′ reactions allied to a [3,3]-sigmatropic rearrangement. cis-1,2-
Azidohydrins and cis-1,2-azidoacetates were much more prone to rearrange than the corresponding trans-isomers.
Reaction of the softer tosamide nucleophile with trans-1,2-bromoacetates resulted, predominantly, in C-4 substi-
tution via a syn-SN2′ mechanism. One application of the reaction of secondary amines with allylic cyclohexene
epoxides, to give trans-1,2-aminoalcohols, is in the synthesis of the anticholinergic drug vesamicol, via an SN2
mechanism. Copyright © 2013 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this paper.
Keywords: dihydrodiols; vinyl epoxides; bromoacetates; SN2, SN2′; sigmatropic rearrangement mechanisms
In this context, we became interested in activating, and indi-
rectly replacing, the allylic hydroxyl group in cis-tetrahydrodiols
INTRODUCTION
3 with nitrogen nucleophiles via electrophilic compounds of
type 4 and 5. This was initially considered as a possible route
to a new range of monocyclic 1,2-aminoalcohols. It was, how-
ever, recognized that, in general, the reaction of nucleophiles
with allylic electrophiles may be more complex due to a number
of factors. For compounds 4 and 5 (Scheme 1), a regiochemical
issue arises, as there are two possible electrophilic positions for
Mutant strains of the bacterium Pseudomonas putida, e.g. 39/D or
UV4, and Escherichia coli recombinant bacterial strains, e.g.
JM109(pDTG601) or CL-4 t, each containing the toluene
dioxygenase enzyme (TDO), can catalyse the cis-dihydroxylation
of a wide range of monocyclic aromatic substrates 1, in both regio-
and stereo-selective manner. The resulting highly functionalized
cis-dihydrodiols 2 (Scheme 1) have enormous potential as chiral
building blocks in organic synthesis.[1,2] A major advantage of
this biocatalytic route is that these processes are easily and
cheaply scaled to give large quantities (multigram to kilogram)
of enantiopure monocyclic arene cis-1,2-dihydrodiols 2, e.g.
R = Cl (2a), Br (2b), and Ph (2c). To date, these compounds have
been extensively used in the synthesis of homochiral natural
products, including alkaloids,[2–5] and of novel chiral ligands
required for transition metal catalysis.[6,7a-d] The unsubstituted
alkene bond in these cis-dihydrodiol bioproducts 2 can be
regioselectively reduced by catalytic hydrogenation to give the
much more stable, and easier to handle, cis-tetrahydrodiol
precursors 3, e.g. R = Cl (3a), Br (3b), and Ph (3c) and ultimately
their electrophilic derivatives 4 and 5.[6,8]
* Correspondence to: Paul Stevenson and Derek Boyd, School of Chemistry and
Chemical Engineering, Queen’s University, Belfast, BT9 5AG, UK.
E-mail: p.stevenson@qub.ac.uk, dr.boyd@qub.ac.uk
†
This article is dedicated to the memory of Professor Rory A. More O’ Ferrall, an
excellent scientist and a wonderful friend.
‡
This article is published in Journal of Physical Organic Chemistry as a Special
issue: In Memoriam edited by Michael Page (University of Huddersfield,
Chemistry, Queensgate, Huddersfield, HD1 3DH, United Kingdom).
a D. R. Boyd, N. D. Sharma, T. Belhocine, J. F. Malone, S. T. McGregor, J. Atchison,
P. A. B. McIntyre, P. J. Stevenson
School of Chemistry and Chemical Engineering, Queen’s University, Belfast, BT9
5AG, UK
J. Phys. Org. Chem. 2013, 26 997–1008
Copyright © 2013 John Wiley & Sons, Ltd.

D. R. BOYD ET AL.
substituted arenes 1, as precursors of a new range of monocyclic
1,2-aminoalcohol ligands, was examined. This would ideally
involve cleanly substituting an allylic leaving group with a range
of nitrogen nucleophiles in a predictable stereo- and regio-
selective fashion. Extensive studies have previously been carried
out on ring-opening reactions of cyclohexenyl epoxides and
mesylate displacements with nitrogen nucleophiles including
azides.[12] In most cases, the products of such reactions have been
successfully employed in the early stages of complex organic
synthetic sequences thus indicating that these reactions generally
proceed in an efficient manner.
Scheme 1. Synthesis of compounds 2–5
nucleophilic attack resulting in direct substitution (C-2) or indirect
substitution with allylic rearrangement (C-4, Scheme 2). Further-
more, there are stereochemical issues where the nucleophile
can add either syn or anti with respect to the leaving group. If
the C-2 substitution proceeds via an SN2 mechanism, then
inversion of configuration is expected. Substitution via an SN1
pathway may lead to loss of stereochemical integrity at C-2
(with either inversion or retention of configuration), and the
delocalized allylic carbocation (C-2/C-4) may react at either
position with no stereoelectronic preference again leading to
mixtures of diastereoisomers. If C-4 substitution is a true
bimolecular process, in which the nucleophile approaches the
alkene first, then this reaction is classically described as SN2′.[9]
In the case of an acyclic allyl electrophile undergoing an SN2′
reaction, the nucleophile adds syn with respect to the leaving
group, with the electrophile reacting from either an s-cis or s-
trans conformation; this conformational flexibility adds further
complexity to any stereochemical analysis of the reaction.
Reactions of allylic electrophiles with organometallic reagents
may result in allylic rearrangement, with formal anti-addition
of the alkyl group, but it is unlikely that these reactions proceed
via a concerted SN2′ mechanism.[10] The detailed mechanisms
for these processes are undoubtedly multistep, involving organ-
ometallic intermediates. There is continuing intense interest in
the development of new chiral ligands for reactions of this type
involving both achiral and racemic allylic electrophiles[11] leading
to chiral products with high ee values. In this context, the current
study of the structure/stereochemistry of products, and possible
mechanisms involved in the reactions of nitrogen nucleophiles
with the chiral electrophilic cycloalkenes 4 and 5, was undertaken.
(i) Synthesis of trans-bromoacetates 4a–c and epoxides 5a–c
The previously described biotransformation of chlorobenzene
1a, bromobenzene 1b, and biphenyl 1c, using whole cells
of P. putida UV4, gave the corresponding relatively unstable cis-
dihydrodiol metabolites 2a–c which were found to readily
dehydrate to give phenols.[13] This prompted the synthesis of the
corresponding substituted cyclohexenes 3a–c, 4a–c, and 5a–c as
more stable derivatives. Regioselective catalytic hydrogenation of
the unsubstituted alkene double bond gave the corresponding
cis-tetrahydrodiols 3a–c (Scheme 1).[14] Chemoselective activa-
tion of diols 3a–c was readily accomplished using Maddock’s
reagent (1-bromocarbonyl-1-methylethyl acetate)[15] and gave
trans-bromoacetates 4a–c.[14] Using sodium methoxide as base,
treatment of compounds 4a–c, gave the corresponding vinyl
epoxides 5a–c.[14] The new phenyl-substituted compounds 3c–5c
were synthesized and characterized while compounds 2a–c, 3a,
3b, 4a, 4b, 5a, and 5b had been reported earlier and were
available for this study.[14] Cyclic compounds 4 and 5 were
considered as ideal substrates for studying subsequent stereo-
and regio-selective reactions, as all the possible products of these
reactions were readily identified and distinguished by NMR
spectroscopy. Furthermore, for geometrical reasons, all of the
compounds studied adopted s-cis conformations, which greatly
simplified subsequent stereochemical analysis. As larger quantities
of cis-dihydrodiols 2a and 2b and their derivatives, 3a, 3b, 4a, 4b,
5a, and 5b, were available from our earlier studies, they provided
the major focus of the current programme.
(ii) Reaction of sodium azide with epoxide 5a
RESULTS AND DISCUSSION
The C-2 substitution chemistry of electrophilic epoxide 5a using
nitrogen nucleophiles was examined first. As expected, treatment
of epoxide 5a with sodium azide in methanol containing zinc
chloride gave predominantly trans-azidohydrin 6a (Scheme 2).
However, a more careful 1H-NMR spectroscopic analysis of the
products from epoxide 5a showed that partial rearrangement of
1,2-azidohydrin 6a to the 1,4-isomer 7a was occurring slowly at
room temperature in deuteriated chloroform during the course
of one day. On subsequent heating in CDCl3, further isomeriza-
tion took place to give an equilibrium mixture of compounds
6a:7a (75:25). A similar reaction of sodium azide with epoxide
5a in hot DMF again occurred to give virtually the same product
mixture of azidohydrins 6a:7a (73:27).
The potential of enantiopure arene cis-1,2-diol scaffolds 2 and 3,
derived from our continuing biotransformation programme on
It is well known that allylic azides are prone to undergo facile
thermal [3,3]-sigmatropic rearrangements. This rearrangement
was first observed by Vander Werf[16] and studied in detail by
Winstein.[17] With acyclic substrates, this reaction proceeds at
room temperature thus limiting its use in synthesis, unless the
alkene is anchored by additional conjugation,[18] steric strain,[19]
Scheme 2. Substitution reaction of epoxide 5a with sodium azide and
rearrangement products
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ENANTIOPURE CYCLOHEXENE EPOXIDE AND TRANS-1,2-BROMOACETATE REACTIONS
or when one of the azides can be chemoselectively removed
from the equilibrium.[20] Recent theoretical studies indicate
that allylic azidohydrins have a lower activation energy for
rearrangement due to intramolecular hydrogen bonding between
the alcohol and the azide.[21] However, for cyclic alkenes, the
rearrangement is much less facile and, with the exception of
studies by Trost,[22] Berchtold[23], and more recently Chang[24] this
rearrangement reaction has remained largely unused in synthesis.
Cyclohexadiene azidoacetates show no tendency to rearrange as
this would result in loss of conjugation.[25] Indeed, six- membered
ring allylic azides have been routinely used in organic synthesis,
without the report of competing rearrangement,[26] have been
recrystallized from chloroform,[27] and have survived heating at
50 °C for 24 h.[28] Furthermore, heterocyclic nine-membered ring
allylic azidohydrins can be heated to 130°C for 2 h without
rearrangement.[29] Conditions for the zinc chloride-catalysed
epoxide ring-opening, using sodium azide, were sufficiently mild
to suppress the subsequent sigmatropic rearrangement making
trans-azidohydrin 6a suitable as a substrate for further synthetic
manipulation.
and 1,4-azidoacetate 9a (50:50). The configuration at the C-1
position of the trans azidoalcohol 6a was inverted using the
Mitsunobu reaction[30]; this proceeded cleanly and gave cis 1,2-
azido p-nitrobenzoate 10a. However, this compound also
rearranged very slowly on standing to give a mixture of 1,2-
and 1,4-azido p-nitrobenzoates. Hydrolysis of p-nitrobenzoyl
ester 10a to give azidohydrin ent-13a followed by acylation gave
a mixture of authentic samples of cis-azido acetates ent-11a and
ent-12a; thermal equilibration of this mixture gave a slight
excess of 1,4-isomer ent-12a over 1,2-isomer ent-11a (58:42,
Table 1, entry 1).
(iii) Reaction of sodium azide with trans-bromoacetates 4a
and 4c
It is noteworthy that the reaction of sodium azide with epoxide
5a, initially, yielded the corresponding azide product 6a, from
substitution with inversion of configuration at C-2 (Scheme 2,
Table 1 entry 5). A facile isomerization process then occurred
to give a second isomeric product 7a, via a suprafacial allyl azide
[3,3]-sigmatropic rearrangement (Table 1 entry 6). A more
comprehensive 1H-NMR spectroscopic study of the structure
and stereochemistry of products obtained from the reaction of
the azide nucleophile with the electrophilic trans-bromoacetate
4a was required as four isomeric products were obtained at
60 °C (Table 1, entry 1).
Alcohols 6a and 7a were acylated to give acetates 8a and 9a,
respectively (Scheme 2). These authentic samples were required
later for comparison with the potential products arising from
azide substitution of the allylic bromine present in trans-
bromoacetate 4a, (Scheme 3). It is interesting to note that the
equilibrium ratio favouring 1,2-azidoalcohol 6a over 1,4-
azidoalcohol 7a (75:25) was different with 1,2-azidoacetate 8a
Scheme 3. Substitution/rearrangement reactions of compounds 4a and 4c with sodium azide
Table 1. Relative proportions of substitution (Substit) and rearrangement (Rearrr.) products obtained with inversion (Inver.) or re-
tention (Retent.) of configuration from nucleophilic nitrogen attack of substrates (Sub.) 4a–c and 5a–c
Entry
Sub
Nucleophile
NaN3
NaN3
NaN3
NaN3
NaN3
NaN3
NaN3
NaNHTs
NaNHTs
Morpholine
4-Phenyl piperidine
Temp. Substit. Inver. (%) Rearr. Inver. (%) Rearr. Retent. (%) Substit. Retent. (%)
1
2
3
4
5
6
7
8
4a
4a
4c
4c
5a
5a
5b
4b
4c
5a
5b
60 °C
25 °C
60 °C
25 °C
25 °C
60 °C
25 °C
60 °C
60 °C
25 °C
25 °C
11a (25)
11a (45)
11c (24)
11c (43)
6a (100)
6a (75)
12a (35)
12a (44)
12c (32)
12c (50)
9a (20)
9a (11)
9c (21)
9c (7)
8a (20)
a
8c (23)
a
7a (25)
6b (100)
19b
19c
9
10
11
20a
21b
aisomer not observed by proton NMR spectroscopy
J. Phys. Org. Chem. 2013, 26 997–1008
Copyright © 2013 John Wiley & Sons, Ltd.
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D. R. BOYD ET AL.
When sodium azide reacted with bromoacetate 4a, in DMF at
60 °C, this resulted in an inseparable mixture of four isomeric
products 8a, 9a, 11a, and 12a, (Scheme 3, Table 1 entry 1),
whose structures were mainly based on 1H-NMR analysis and
comparison with the previously prepared authentic samples of
8a, 9a, ent-11a, and ent-12a (Scheme 2). It should be noted that
compounds ent-11a and ent-12a (Scheme 2) are spectroscopi-
cally indistinguishable from their respective opposite enantio-
mers 11a and 12a (Scheme 3). To complicate matters further,
the 1,2-substitution products 8a and 11a were in equilibrium
with the 1,4-substitution products 9a and 12a, obtained via a
suprafacial allyl azide [3,3]-sigmatropic rearrangement mecha-
nism as previously demonstrated in (Scheme 2).
by the different multiplicity patterns. At 300 MHz, there was little
overlap of the chemical shifts for each of these proton signals
which were used to quantify the ratio of components of the
mixture by 1H-NMR spectroscopy (Table 1). A corresponding
analysis was carried out on the vinyl proton signals, but this
suffered from multiplet overlap. The authentic samples of these
compounds, required for comparison with these isomers, and
for independently establishing the position of equilibrium, were
previously prepared as outlined in Scheme 2.
Figure 1-ii shows a mixture of independently synthesized
authentic samples of compounds 8a:9a (71:29). Figure 1-iii
shows the same sample after equilibrium had been established
(50:50) after two weeks at room temperature. It is clear that in
the crude reaction mixture, using trans-bromoacetate 4a as
electrophile, equilibrium was established between compounds
8a and 9a. Likewise, equilibrium was established between com-
pounds 11a and 12a under conditions used for the substitution
reaction. The ratio of isomeric products 11a:12a (42:58, Table 1
entry 1) was close to the independently confirmed equilibrium
ratio with a small but distinct preference for the allylic
rearranged product 12a.
1
In Figure 1-i is presented an expansion of the H-NMR spec-
trum of the mixture of isomers (8a, 9a, 11a, and 12a). It shows
the signals for the H-2 proton of the C-2 substitution products
11a (d, δ 4.21, 25%) and 8a (d, δ 3.93, 20%) and also the H-4
proton for the allylic rearranged products 12a (t, δ 3.96, 35%)
and 9a (t, δ 4.03, 20%). The formal C-2 substitution products
11a and 8a (H-2, doublets) were also readily distinguished from
the C-4 substitution products 12a and 9a (H-4, apparent triplets)
The relevant coupling constants of all four isomers 8a, 9a, 11a,
and 12a that could potentially give useful information on both
preferred conformations and configurations are listed in Table 2.
In cyclohexene, the ring inversion barrier between half chair
conformers (5.3 kcal molÀ1) is much lower than the correspond-
ing value for cyclohexane (11 kcal molÀ1), making the unsatu-
rated ring much more flexible. Figure 2 shows half chair
conformations of compounds 8a, 9a, 11a, and 12a. Theoretical
optimized models of both half chair forms of cyclohexenes
8aX/8aY and 9aX/9aY, 11aX/11aY, and 12aX/12aY, respec-
tively, were generated using Density Function Theory BLYP 6-
31*. It is known that this level of theory is insufficient to calculate
the accurate free energies of the half chair conformers;[31]
nevertheless, it does give some indication of the relevant
dihedral angles in each half chair conformer.
In compound 11a, proton H-1 has a large diaxial coupling
constant J1,6a of 11.2 Hz. This value provides strong evidence
for conformer homogeneity with the acetate group occupying
an equatorial position with conformer 11aX being dominant.
The azide group was pseudoaxial, as confirmed by an axial/equa-
torial coupling constant of J1,2 of 4.1 Hz.
The 1H-NMR spectrum of trans-azidoacetate 8a provided
information on both relative configuration and preferred confor-
mation. For 1,2-azidoacetate 8a proton H-2 was a doublet with a
Table 2. 1H-NMR coupling constants for compounds 8a, 9a,
11a, 12a, 19b, and 19c
Entry
Compound
J1,2
J1,6a
J1,6e
J4,5a
J4,5e
1
2
3
4
5
6
11a
12a
9a
8a
19b
19c
4.1
11.2
7.3
4.5
4.7
4.1
3.8
4.1
3.3
4.3
4.7
4.1
3.8
4.7
4.3
4.7
4.3
4.2
Figure 1. In Figures 1-i, 1-ii, and 1-iii are presented the characteristic
signals of 1H-NMR spectra which show: (i) the H-2 signal for isomers 8a
and 11a and the H-4 signal for isomers 9a and 12a, (ii) in the authentic
samples, the H-2 signal in compound 8a and the H-4 signal in compound
9a, and (iii) H-2 and H-4 signals for compounds 8a and 9a after equilib-
rium was established
6.9a
4.3
4.3
b
b
aJ4,NH
bPeak was too broad to extract coupling constants
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J. Phys. Org. Chem. 2013, 26 997–1008

ENANTIOPURE CYCLOHEXENE EPOXIDE AND TRANS-1,2-BROMOACETATE REACTIONS
Figure 2. Half chair conformers of substituted cyclohexenes 8aX/8aY, 9aX/9aY, 11aX/11aY, and 12aX/12aY
(Scheme 3), were mainly assigned following extensive 1H-
coupling constant of 4.2 Hz. Molecular modelling, using Density
Function Theory with BPY-6-31* suggested a dihedral angle
between protons H-1 and H-2 of 71° in conformer 8aX and
168° for conformer 8aY. Ignoring the effect of electronegativity
of the nitrogen and oxygen substituents, this equates to
coupling constants of 2.8 Hz and 12.5 Hz, respectively. If the
observed coupling constant is the weighted average of both
conformers 8aX and 8aY, then clearly the weighting lies heavily
in favour of conformation 8aX. Proton H-1 was an apparent
quartet, J 4.7 Hz, confirming that proton H-1 of the major con-
former 8aX occupied an equatorial position with no substantial
diaxial coupling to H-6.
For the rearranged products 9a and 12a, both azide and
acetate groups occupy allylic positions and are thus designated
as pseudo axial and pseudo equatorial which made the detailed
analysis of their 1H-NMR spectra more difficult. For 1,4-
azidoacetate 9a, protons, H-1 and H-4 were apparent triplets, J
4.3 and 4.3 Hz, respectively, suggesting that these protons were
largely pseudoequatorial and that conformer 9aX was dominant.
In compound 12a, J1,6a was substantially larger than J4,5 indicat-
ing that the conformer ratio was marginally weighted towards
conformation 12aX, (Figure 2). Based on the coupling constant
values for all four azidoacetate isomers (8a, 9a, 11a, and 12a),
the dominant half chair conformers (8aX, 9aX, 11aX, and
12aX) existed with the azide group occupying a pseudoaxial
position. In both cis (11a and 12a) and trans azidoacetates (8a
and 9a), the azido group adopted the correct position to
undergo an allylic [3,3]-sigmatropic rearrangement. However, cis-
isomer 11a is much more labile than the trans-isomer 8a and
rapidly equilibrates, to give predominantly the 1,4-azidoacetate
12a, even on storage in the refrigerator. It is not clear why the
trans-azidoacetates are less prone to undergo sigmatropic
rearrangement than the cis-azidoacetates. The origin of this
differential reactivity may be stereoelectronic in nature.
NMR spectroscopic analysis (Table 2).
(iv) Possible mechanisms to account for the formation of
azidoacetates 8, 9, 11, and 12 from the corresponding
trans-bromoacetates 4
Several possible mechanisms could be involved in the formation
of compounds 8a, 9a, 11a, and 12a from compound 4a. A
pathway, proceeding via a stepwise dissociative C-2-N bond
cleavage followed by a subsequent C-4-N or C-2-N recombina-
tion is unlikely, as on heating pure azidoacetate 11a, it
equilibrated to a mixture of isomers 11a:12a (1:2) with no sign
of the potential dissociation products 9a and 8a. The formation
of C-2 substitution product 11a and the C-4 substitution product
9a could, in principle, result from SN2 and syn-selective SN2′
displacements, respectively, from compound 4a. Thermal
sigmatropic rearrangements of azidoacetates 9a and 11a would
then give azidoacetates 8a and 12a, respectively (Scheme 3). At
60 °C, the proportion of substitution with inversion products
11a/12a was higher (60%) compared to substitution with reten-
tion of configuration products 9a/8a (40%), Table 1 entry 1.
Repeating the reaction at room temperature (Table 1 entry 2)
had a profound effect on the product ratio and gave predomi-
nantly the inversion products 11a and 12a (89%) along with a
small amount of compound 9a (11%). Since compound 8a was
not observed at this lower temperature, therefore compound
9a was not derived from compound 8a in this instance. A similar
product distribution of compounds 8c, 9c, 11c, and 12c was
observed from the reaction of bromoacetate 4c with sodium
azide (Table 1, entries 3 and 4).
Formation of all the isomeric azidoacetates 8, 9, 11, and 12
from bromoacetates 4 could also, in principle, occur via an SN1
reaction mechanism involving carbocation intermediates
(Scheme 4). However, since none of the substitution products,
with retention of configuration, 8a and 8c, are observed at room
temperature (Table 1, entries 2 and 4), the involvement of an SN1
mechanism seems less likely. Our preferred explanation for the
observed distribution of azidoacetates 8, 9, 11, and 12, is that;
(i) compound 11 formed via an SN2 mechanism, (ii) compound
12 by a suprafacial [3,3]-sigmatropic rearrangement of 11, (iii)
compound 8 by an SN2′ mechanism, and (iv) compound 9 also
by a [3,3]-sigmatropic rearrangement of compound 8. At lower
temperature, the rearrangement linking trans-azidoacetates 9
and 8 was not observed but occurred for cis-azidoacetates 11
and 12 which were much more labile.
The earlier reaction of sodium azide with trans-bromoacetate
4a, to yield the four isomeric products 8a, 9a, 11a, and 12a
(Scheme 3), was repeated using compound 4c, and similar
results were obtained by 1H-NMR analysis (Table 1). Thus,
two cis-azidoacetates 11c (δ 4.58, d, H-2, 43%) and 12c (δ
4.37, t, H-4, 50%), along with a minor amount of trans-
azidoacetate 9c (δ 4.48, t, H-4, 7%), were observed at room
temperature, while a mixture of cis-isomers 11c (24%) and
12c (32%), and both trans-isomers 9c (δ 4.48, t, H-4, 21%)
and 8c (δ 4.37, d, H-2, 23%) was obtained when the reaction
was carried out at 60 °C. The structures of each of the eight
cis- and trans-azidoacetates, found to be present in the insep-
arable mixtures obtained from trans-bromoacetates 4a or 4c
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D. R. BOYD ET AL.
(v) X-ray crystal structure analysis of derivatives 14c, 16c,
17c, and 18c obtained from azidoacetates 11c, 8c, 9c and 12c
respectively
crystallographic analysis by an extensive combination of
methods including: (i) utilization of enriched mixtures of
compounds, e.g. 11c and 12c, formed at room temperature, or
8c and 9c, found at elevated temperatures, (ii) flash column
and multiple elution preparative layer chromatography (PLC),
and (iii) fractional crystallization. Compounds 15c, 16c, and the
acetate derivative 18c had previously been synthesized during
an earlier model approach to the synthesis of racemic
epibatidine, but were not characterized by X-ray crystallogra-
phy.[32] On the basis of NMR spectroscopy, these com-
pounds were found to be indistinguishable from our samples
of derivatives 15c, 16c, and acetate 18c, obtained by
rearrangement during an alternative model approach to the
synthesis of individual enantiomers of epibatidine. Isolation of
cis-aminoacetamide 14c, where the O-acetyl group initially
formed had migrated to the NH2 group, confirmed that azide
11c was indeed a reaction product.
The earlier study of interconverting isomeric azidoacetate prod-
1
ucts was totally based on H-NMR analyses of the inseparable
mixtures. Therefore, the possibility of forming and separating
crystalline derivatives from azidoacetates 8c, 9c, 11c, and 12c,
which might be suitable for X-ray crystallography, and the
resulting unequivocal determination of structure and relative
stereochemistry, was also investigated. As part of our earlier
unpublished efforts, to synthesize the alkaloid epibatidine from
cis-diols 2b and 2c,[2–4] attempts were made to characterize the
products (8c, 9c, 11c, and 12c) through the formation of their
derivatives. In order to solve the problem of product equilibra-
tion, the azide groups present in compounds 8c, 9c, 11c, and
12c were reduced with trimethyl phosphine, using a Staudinger
reaction. The resulting aminoacetates (from compounds 8c, 9c,
and 12c) were then converted directly to tosamide acetates
and hydrolysed to yield alcohols 16c, 17c, and 15c, (Scheme 5).
Suitable crystalline samples of the alcohol derivatives, 14c, 16c,
17c, and acetate 18c, were finally obtained for X-ray
Single crystal X-ray analyses of acetate 18c (Figure 4-i),
alcohols 14c (Figure 3), 16c (Figure 4-ii), and 17c (Figure 4-iii)
Scheme 4. Substitution/rearrangement reactions of compounds 4a
and 4c
Figure 3. The crystallographic asymmetric unit of hydroxyamide 14c
showing different molecular conformations
Scheme 5. Reactions of bromoacetate 4c with sodium azide to yield azidoacetates 8c, 9c, 11c, and 12c and conversion to the crystalline derivatives
16c, 17c, 14c, and 18c respectively
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ENANTIOPURE CYCLOHEXENE EPOXIDE AND TRANS-1,2-BROMOACETATE REACTIONS
Figure 4. X-ray structures of compounds (i) 18c, (ii) 16c, and (iii) 17c
confirmed their structures, relative configurations and preferred
conformations. In compound 14c, there were two crystallo-
graphically independent molecules in the asymmetric unit, each
having a half-chair conformation of the cyclohexene ring
(Figure 3). One molecule had the OH group axial and the NHAc
group pseudoequatorial, while, conversely, the other had the
OH equatorial and the NHAc group pseudoaxial. Structures 18c,
16c, and 17c were present as single conformations only, and in
each case, the allylic NHTs group was pseudoaxial (Figure 4-i,
4-ii, and 4-iii).
(Figure 4-ii). It was evident, from the 1H-NMR spectra of com-
pounds 19b,c that a rearrangement with retention of configura-
tion had occurred, as the C-2 alkene protons were both doublets.
The 1H-NMR spectrum of 19b was sufficiently resolved to extract
the more important coupling constants. Proton H-1 appeared as
an apparent quartet with coupling constant J 4.1 Hz and proton
H-4 was a doublet of triplets with coupling constants J 6.9, 4.3 Hz
(Table 2, entry 5). The large coupling constant value of J 6.9 Hz
was due to coupling with the NH of the tosamide. Comparing
these values with those for the corresponding trans- and cis-
azidoacetates (12a, Table 2, entries 2 and 3) strongly inferred
that the OAc and NHT groups in azidoacetate 19b were trans
and both occupied pseudoaxial positions.
It was interesting to find that changing the N-nucleophile from
sodium azide (Schemes 3 and 5) to the softer nucleophile NaNHTs
(Scheme 6) reversed the preferred regioselectivity of the reaction,
and stereoselectively gave the allylic rearrangement products
19b and 19c, probably via an SN2′ mechanism.
Finally, reaction of epoxides 5a,b with the secondary amines,
morpholine and 4-phenyl piperidine, under mild Lewis acid
catalysis, resulted in a ring-opening reaction at the allylic C-2
position and gave trans-1,2-aminoalcohols 20a and 21b
(Scheme 7, Table 1, entries 10 and 11). Catalytic hydrogenolysis
of the carbon halogen bonds, followed by hydrogenation of
the resulting alkenes, gave trans-aminoalcohols 22 and 23. This
synthetic approach provided one enantiomer of the racemic
anti-cholinergic drug vesamicol[34] 23, in four steps, from cis-
tetrahydrodiol 3a with an overall yield of 56%.
For crystalline compound 18c, the NHTs and OAc groups were
pseudoaxial and pseudoequatorial, respectively, and as
expected, with more A1,2 strain[33] coming from the phenyl
group than the alkene hydrogen atom (Figure 4-i). Interestingly,
for tosamide 16c, derived from the trans rearranged product
8c, both alcohol and tosyl groups were trans-pseudodiaxial
(Figure 4-ii). In compound 17c, the tosamide and alcohol groups
adopted a trans-axial/pseudoaxial conformation (Figure 4-iii).
Crystal structures, shown in Figures 3 and 4-i, 4-ii, and 4-iii are
consistent with the earlier conclusions from NMR spectroscopy
that the preferred solution conformations for compounds 8c,
9c, 11c, and 12c were correct and complement the results
1
obtained from the detailed H-NMR analyses of compounds 8a,
9a, 11a, and 12a. They also support the assumption that the
allylic azide can readily access the pseudoaxial position preferred
for a subsequent sigmatropic rearrangement.
(vi) Reaction of sodium tosamide with bromoacetates 4b,c
A stated objective of this programme was to synthesize a new
range of cyclohexene cis-1,2-aminoalcohols, from the correspond-
ing cyclohexene cis-dihydrodiols 2, by a generally applicable and
Reaction of bromoacetates 4b,c with sodium tosamide gave
compounds 19b,c as the only identified products (Scheme 6,
Table 1, entries 8 and 9). The structure of ester 19c (Scheme 6)
was confirmed by hydrolysis to give alcohol 16c, a known
compound,[30] unambiguously assigned by X-ray crystallography
Scheme 6. Reactions of bromoacetates 4b,c with sodium tosamide
Scheme 7. Reactions of epoxides 5a,b with cyclic amines
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D. R. BOYD ET AL.
sample of hydrogenated product 3c (10.0g, 99% yield). Purification by col-
umn chromatography (EtOAc:hexane, 1:1), yielded a white solid; mp 92–94 °
C (from EtOAc); (lit, mp 90–92°C)[35]; [α]D À83 (c 0.9, CHCl3) (lit., [α]D À86
(c 1.1, CHCl3)[35]; δH (300 MHz; CDCl3) 2.2–2.5 (4H, m, H-5, H-6), 4.66–4.70
(1H, m, H-1), 4.53–4.61 (1H, m, H-2), 6.17–6.19 (1H, m, H-4), 7.25–7.40
(5H, m, Ar); δC (125MHz; CDCl3) 22.95, 25.32, 68.22, 70.10, 126.30,
127.69, 128.27, 133.90, 137.67, 143.07.
simple route. This objective could not be achieved due to the
mechanistic complexity discussed herein. However, preliminary
studies have shown that some of the azides produced can be
reduced to the corresponding cyclohexene 1,2-aminoalcohols,
albeit via a multistep approach.
CONCLUSION
(1S,2S)-2-Bromo-3-phenylcyclohex-3-enyl acetate 4c
It was demonstrated that cyclic allylic epoxides react with a
range of N-nucleophiles to give both C-2 and or C-4 substitution
products. Good C-2 regioselectivity and trans-stereoselectivity
was obtained in reactions of vinyl epoxides with sodium azide
at room temperature under mild Lewis acid conditions.
Uncatalysed reactions, at elevated temperatures, led to mixtures
of trans C-2 and C-4 substituted products which equilibrated via
an [3,3]-allylazide rearrangement mechanism. Sterically hindered
secondary amines reacted, exclusively at the C-2 position of
vinylic epoxides, under mild Lewis acid catalysis conditions, to
give trans-1,2 aminoalcohols, including a useful precursor to
the drug vesamicol.
Treatment of trans-1,2-bromoacetates with sodium azide at
room temperature led mainly to C-2 and C-4 cis-azidoacetates
via an SN2 reaction. The small amount of C-4 trans-azidoacetate
formed can be attributed to a minor competing SN2′ pathway.
This stereochemical study provides the first hard evidence that
azide does participate in SN2′ reactions. At an elevated tempera-
ture, a mixture of four (cis and trans 1,2- and 1,4-azidoacetate)
isomers was formed. The cis-azidoacetates were more prone to
rearrange than the corresponding trans-isomers, via a [3,3]-
sigmatropic rearrangement mechanism. Reactions of sodium
tosamide with trans-1,2-bromoacetates gave, predominantly,
trans-C-4 substitution products via an SN2′ mechanism.
1-Bromocarbonyl-l-methylethylacetate (14.0 g, 0.07 mol) was added to a
stirred solution of tetrahydrodiol 3c (11.54 g, 0.06 mol) in dry acetonitrile
(100 mL) at 0 °C. After stirring the reaction mixture for 3 h, it was partially
concentrated, diluted with diethyl ether (100 mL), and washed with 2.5%
aqueous NaHCO3 solution (2 × 50 mL). The organic layer was dried over
(Na2SO4) and concentrated under reduced pressure to give unstable
bromoacetate 4c (15.8 g, 90%) as a pale orange oil. As this product was
found to decompose at ambient temperature, it was stored at low tem-
perature or used for the next step without purification; (Found M+
294.0252 C14H15S79BrO2 requires 294.0255); υ max/cmÀ1 1739 (C = O); δH
(500 MHz; CDCl3) 1.98 (1 H, m, H-6a), 2.07 (3 H, s, Me), 2.39 (2 H, m, H-5),
2.47 (1 H, m, H-6b), 5.01 (1 H, br, s, H-2), 5.49 (1 H, m, H-1), 6.25 (1 H, m,
H-4), 7.35 (5 H, m, Ar); δC (125 MHz; CDCl3) 21.07, 21.55, 21.96, 46.30,
72.91, 126.10, 128.08, 128.31, 128.62, 128.89, 129.59, 135.62, 139.62,
170.70; m/z (EI) 294 (M+ 79Br, 5%), 296 (M+ 81Br, 5%), 215 (90), 172 (100).
2-Phenyl-7-oxa-bicyclo[4.1.0]hept-2-ene 5c
Sodium methoxide (5.0 g, in excess) was added to a solution of crude
bromoacetate 4c (5.00 g, 0.017 mol) in dry ether (100 mL), and the reac-
tion mixture was stirred overnight. The inorganic salts were filtered off,
and the solution was concentrated under reduced pressure. Purification
by flash chromatography (EtOAc: hexane, 0.5:9.5) yielded the titled com-
pound 5c (2.33 g, 80%) as a colourless viscous oil; [α]D +112 (c 0.14,
CHCl3); (Found: M+ 172.0888 C12H12O requires 172.0888); δH (500 MHz;
CDCl3) 1.59 (2 H, m, H-5), 2.26 (2 H, m, H-4), 3.64 (2 H, m, H-1 and H-6),
6.17–6.19 (1 H, m, H-3), 7.25–7.40 (5 H, m, Ar); δC (125 MHz; CDCl3) 21.03,
21.10, 55.71, 64.30, 125.42, 126.18, 127.52, 128.81, 135.69, 139.49; m/z
(EI) 172 (M+, 100%).
The formation, and structural/stereochemical assignments, of
azidoalcohol and azidoacetate products, obtained from reactions
of allylic epoxides and trans-1,2-bromoacetates with sodium
azide, have been rationalized in terms of SN2, SN2′ and [3,3]-
sigmatropic rearrangement mechanisms.
(1S,2R)-2-Azido-3-chlorocyclohex-3-enol 6a
Sodium azide (0.62 g, 9.58 mmol) and zinc chloride (1.54 g, 9.58 mmol)
were added to a solution of chloroepoxide 5a (0.50 g, 3.83 mmol) in
MeOH (20 mL). The reaction mixture was stirred at room temperature
overnight, filtered through a pad of celite and the filtrate concentrated
under reduced pressure. The crude product obtained was purified by
flash chromatography (Et2O:hexane, 1:1) to give the titled compound
6a (0.53 g, 80%); [α]D +110 (c 1.63, CHCl3); (Found: M+ 173.0352
C6H8ON335Cl requires 173.0356); υmax/cmÀ1 (KBr) 3372 (O-H), 2096 (N3);
δH (500 MHz; CDCl3) 1.74 (1 H, m, H-6), 1.86 (1 H, m, H-6′), 2.18 (1 H, m,
H-5), 2.25 (1 H, m, H-5′), 3.85 (1 H, d, J 5.4, H-2), 3.88 (1 H, ddd, J 8.6, 5.4,
3.0, H-1), 6.06 (1 H, dd, J 4.7, 2.9, H-4); δC (125 MHz; CDCl3) 23.13, 26.63,
67.83, 71.27, 128.47, 129.68; m/z (EI) 175 (M+ 37Cl, 2%), 173 (M+ 35Cl,
7%), 146 (26), 144 (78), 133 (20), 132 (28), 131 (81), 130 (75), 129 (72),
120 (17), 118 (73), 116 (82),103 (64),101 (100), 97 (13), 95 (54).
EXPERIMENTAL
1H- and 13C-NMR spectra were recorded on Bruker Avance 400, DPX-300,
and DRX-500 instruments. Chemical shifts (δ) are reported in ppm
relative to SiMe4, and coupling constants (J) are given in Hz. Mass spectra
were recorded at 70 eV, on a VG Autospec Mass Spectrometer, using a
heated inlet system. Accurate molecular weights were determined by
the peak matching method, with perfluorokerosene as the standard.
Flash chromatography and PLC were performed on Merck Kieselgel type
60 (250–400 mesh) and PF254/366 plates, respectively. Merck Kieselgel
type 60 F254 analytical plates were employed for TLC. A Perkin Elmer
341 polarimeter was used for optical rotation ([α]D) measurements.
3-Chlorocyclohex-3-ene-1,2-dio1 3a, 3-bromocyclohex-3-ene-1,2-diol
3b, ‘(1S, 2R)-2-bromo-3-chlorocyclohex-3-enyl acetate 4a, (1S, 2R)-2,
3-dibromocyclohex-3-enyl acetate 4b, 2-chloro-7-oxabicyclo[4.1.0]hept-
2-ene 5a, 2-bromo-7-oxabicyclo[4.1.0]hept-2-ene 5b, and 3-phenyl-2-
(p-toluenesulfonamido)cyclohex-2-enyl acetate 18c were available from
earlier studies.[4,14]
Isomerization of (1S,2R)-2-azido-3-chlorocyclohex-3-enol 6a
to yield (1S,4S)-trans-4-azido-3-chlorocyclohex-2-enol 7a and
synthesis of their trans-azidoacetate derivatives 8a and 9a
On heating a sample of pure 6a in CDCl3 at 50 °C for 4 h, new peaks
appeared which were attributed to the rearranged product 7a. An equi-
librium mixture of 6a:7a of 75:25 was established. Important peaks for
identifying rearranged product 7a in the mixture are: δH (300 MHz; CDCl3)
6.07 (1 H, d, J 4.6, H-2), 4.25(1 H, m, H-1), and 3.93 (1 H, t, J 4.9, H-4).
When the reaction of epoxide 5a with sodium azide was repeated in
DMF solution at 60 °C, an equilibrated mixture of azidohydrin 6a and
(1S,2R)-3-Phenylcyclohex-3-ene-1,2-diol 3c
A solution of biphenyl-cis-dihydrodiol 2c (10.00 g, 0.05 mol) in ethyl
acetate (100 mL) was stirred for 4 h in the presence of 3% Pd/C (0.2 g)
under an atmosphere of hydrogen, at ambient temperature and pressure.
The catalyst was filtered off and the filtrate concentrated to give a crude
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ENANTIOPURE CYCLOHEXENE EPOXIDE AND TRANS-1,2-BROMOACETATE REACTIONS
the isomeric azido alcohol 7a (73:27) was also obtained. The mixture of
isomers 6a and 7a could not be separated by chromatography.
Synthesis of (1R,2R)-2-azido-3-chlorocyclohex-3-enyl acetate
ent-11a and (1R,4S)-4-azidochlorocyclohex-2-enyl acetate
ent-12a from (1R,2R)-2-azido-3-chlorocyclohex-3-enol ent-13a
(1S,2R)-2-Azido-3-chlorocyclohex-3-enyl acetate 8a
Acetic anhydride (0.1 mL, 1.06 mmol) was added to an equilibrated
solution of (1R,2R)-2- azido-3-chlorocyclohex-3-enol ent-13a (40 mg,
0.23 mmol) in dry pyridine (0.5 mL). The reaction mixture was stirred
overnight at room temperature. The excess of pyridine was removed
by coevaporation with toluene under vacuum. Purification of the
isomeric mixture of compounds ent-11a and ent-12a was achieved by
flash chromatography and PLC (Et2O:hexane, 2:1), but the isomers were
not separated. (36 mg, 72%); υmax/cmÀ1 (KBr) 2100 (N3), 1745 (C = O);
(Found: (M + Na)+ 238.0353 C8H10ClN3NaO2 requires 238.0354).
Acetic anhydride (0.60 mL, 6.36 mmol) was added to azidohydrin 6a
(0.04 g, 0.23 mmol) in dry pyridine solution (0.4 mL). The reaction mixture
was allowed to stir overnight at room temperature. The pyridine was
removed by coevaporation with toluene under vacuum (3 × 10mL). The
crude sample of azidoacetate 8a was purified by flash chromatography
(Et2O:hexane, 1:1); RF 0.75 to give the titled compound (0.04 g, 81%);
(Found: (M+ NH4)+ 233.0800 C8H14ClN4O2 requires 233.0800); υ max/cm-1
(KBr) 2103 (N3), 1743 (C= O); δH (300 MHz; CDCl3) 1.84 (2H, m, H-6 and
H-6′), 2.09 (3H, s, Me), 2.24 (2H, m, H-5 and H-5′), 3.93 (1H, d, J 4.2H-2),
5.03 (1H, q, J 4.7, H-1), 6.12 (1H, t, J 4.3, H-4); δC (75MHz; CDCl3) 21.43,
22.69, 22.97, 63.63, 72.14, 127.31, 129.94, 170.41.
(1R,2R)-2-Azido-3-chlorocyclohex-3-enyl acetate ent-11a
δH (300 MHz; CDCl3) 1.7–1.83 (2 H, m, H-6 and H-6′), 2.13 (3 H, s, Me),
2.18–2.29 (2 H, m, H-5 and H-5′), 4.21 (1 H, d, J 4.1, H-2), 5.05 (1 H, dt,
J 11.2, 4.1, H-1), 6.04 (1 H, dd, J 4.0, 4.9, H-4); δC (75 MHz; CDCl3)
21.27, 22.15, 24.48, 63.28, 72.05, 128.83, 129.66, 170.66.
(1S,4S)-4-Azido-3-chlorocyclohex-2-enyl acetate 9a
On heating a sample of (1S,2R)-2-azido-3-chlorocyclohex-3-enyl acetate
8a in CDCl3 at 50 °C for 4 h, an inseparable equilibrium mixture of
8a:9a (1:1) was obtained. From this, the relevant NMR spectroscopic data
for compound 9a could be extracted. δH (300 MHz; CDCl3) 1.75 (2 H, m, H-
6 and H-6′), 1.93 (2 H, m, H-5 and H-5′), 2.05 (3 H, s, Me), 4.03 (1 H, t, J, 4.3,
H-4), 5.26 (1 H, dt, J 4.7, 4.3, H-1), 6.14 (1 H, d, J 4.5, H-2); δC (75 MHz; CDCl3)
23.87, 26.37, 30.08, 60.95, 67.00, 127.78, 136.96, 170.61.
(1R,2S)-4-Azido-3-chlorocyclohex-2-enyl acetate ent-12a
δ
H (300MHz; CDCl3) 1.84–1.97 (2 H, m, H-6 and H-6′), 1.97–2.05 (2H, m, H-5
and H-5′), 2.06 (3H, s, Me), 3.96 (1H, t, J 4.7, H-4), 5.26 (5H, m, H-1), 6.07 (1H,
d, J 3.5, H-2); δC (75 MHz; CDCl3) 21.48, 24.17, 27.45, 60.83, 68.71, 127.57,
135.71, 170.83.
Synthesis and X-ray crystal structure analysis of (1S,2R)-2-
acetamido-3-phenylcyclohex-3-enol 14c, (1S,4R)-3-phenyl-4-
(p-toluenesulfonamido)cyclohex-2-enol 15c and (1S,4S)-3-
phenyl-4-(p-toluenesulfonamido)cyclohex-2-enol 16c and
(1S,2S)-3-phenyl-2-(p-toluenesulfonamido)cyclohex-2-enyl
acetate 17c from (1S,2S)-2-bromo-3-phenylcyclohex-3-enyl
acetate 4c
(1R,2R)-2-Azido-3-chlorocyclohex-3-enyl 4′-nitrobenzoate 10a
Diethyldiazocarboxylate (0.6 mL, 3.4 mmol) was added dropwise to an
ice-cooled solution of triphenylphosphine (1.0 g, 3.7 mmol) and (1S,2R)-
2-azido-3-chlorocyclohex-3-eno1 6a (0.50 g, 2.88 mmol) in THF (10 mL)
containing 3A molecular sieves. After stirring the solution at room
temperature for 30 min, p-nitrobenzoic acid (0.60 g, 3.5 mmol) was
added, and the solution was stirred overnight. The molecular sieves were
filtered off, and the solvent removed under reduced pressure. The crude
p-nitrobenzoate was purified by flash chromatography (40% Et2O in
hexane) to yield a white crystalline solid (0.64 g, 69%); mp 88–90 °C;
[α]D +60 (c 0.67, CHCl3); υmax/cmÀ1 (KBr) 2090 (N3), 1717 (C = O); Found:
M+ 322.2057 C13H11O4N335Cl requires 322.2054); δH (500 MHz; CDCl3)
1.99 (2 H, m, H-4, H-4′), 2.35 (2 H, m, H-5, H-5′), 4.36 (1 H, d, J 4.3, H-2),
5.34 (1 H, dt, J 11.5, 4.3, H-1), 6.11 (1 H, dd, J 4.8, 3.5, H-4), 8.27 (2 H, m,
Ar-H), 8.32 (2 H, m, Ar-H); m/z (EI) 322 (M+, 1%), 312 (9), 310 (7), 293
(24), 269, (23), 252 (19), 217 (33), 194 (36), 155 (100), 146 (57), 132 (34),
130 (78), 120 (81), 110 (52), 96 (26), 82 (7), 59 (7). Compound 10a was
used directly after synthesis, as on storage in the refrigerator, within
one day, the rearranged product was found to be present to the extent
of 25%. Distinctive 1H-NMR data for the rearrangement product in the
mixture: δH (500 MHz; CDCl3) 4.05 (1 H, t, J 4.8, H-4), 5.56 (1 H, m, H-1),
6.18 (1 H, d, J 3.8, H-2).
Sodium azide (1.41 g, 0.025 mol) was added to a stirred solution of crude
bromoacetate 4c (5.0 g, 0.017 mol) in dry DMF (50 mL), and the reaction
mixture was stirred at 70 °C overnight. After quenching with water
(50 mL), the cooled reaction mixture was extracted with ethyl acetate (2
× 50 mL). The organic layer was washed with water (3 × 50 mL) and
concentrated under reduced pressure to give an inseparable mixture of
products whose 1H-NMR spectrum was consistent with compounds 8c
(δ 4.37, d, H-2), 9c (δ 4.88, t, H-4) 11c (δ 4.58, d, H-2), and 12c (δ 4.37, t,
H-4) being the major components. The crude mixture of azidoacetates
was dissolved in THF/H2O (9:1, 100 mL), and a trimethylphosphine solution
in THF (1M, 27 mL) was added, and the mixture stirred for 1.5h at 0 °C, then
3 h at room temperature. The acetamide 14c was separated from the
mixture of azido alcohol intermediates. Tosyl chloride (3.67 g, 0.19 mmol)
followed by sodium hydroxide (20 mL, 2 M) was added, and the mix-
ture stirred overnight at room temperature. The solvent was evapo-
rated under reduced pressure, and flash chromatography (EtOAc:
hexane, 1:1) gave compounds 15c–17c. Acetylation of compound
15c to yield compound 18c was carried out under similar conditions
used earlier for azido alcohol 13a.
(1R,2R)-2-Azido-3-chloro-3-cyclohex-3-enol ent-13a
(1R,2R)-2-Azido-3-chloro-cyclohex-3-enyl 4′-nitrobenzoate 10a (0.11 g,
0.34 mmol) was dissolved in MeOH:H2O (20:1) mixture, and potassium
carbonate (0.12 g, 0.85 mmol) was added to the solution. The reaction
mixture was stirred overnight at room temperature. The solvent was re-
moved under reduced pressure, and water (50 mL) was added and
extracted with ethyl acetate (4 × 25 mL), dried over sodium sulfate, and
concentrated. The crude azidohydrin product ent-13a, was purified by
flash chromatography (Et2O:hexane, 1:4) (56 mg, 95%); [α]D +85 (c 1.98,
CHCl3); (Found: M+ 173.0353 C6H8ON335Cl requires 173.0356); δH
(300 MHz; CDCl3) 1.74 (1 H, m, H-6), 1.85 (1 H, m, H-6′), 2.18 (2 H, m, H-5,
H-5′), 3.97 (1 H, m, H-1), 4.14 (1 H, d, J 4.2, H-2), 6.09 (1 H, t, J 3.0, H-4);
m/z (EI) 175 (M+ 37Cl, 2%), 173 (M+ 35Cl, 7%), 146 (15), 144 (10), 133 (7),
131 (24), 130 (16), 128 (33), 117 (44), 110 (100), 103 (34), 101 (61), 93
(45), 82 (83), 67 (54), 55 (45).
(1S,2R)-2-Acetamido-3-phenylcyclohex-3-enol 14c
White crystalline solid; mp 120–121 °C; [α]D À43 (c 0.3, CHCl3); (Found: M+
231.1258 C14H17O2N requires 231.1259); υmax/cmÀ1 1157, 1727; δH
(500 MHz; CDCl3) 1.85 (1 H, ddd, J 9.3, 7.8, 4.4, H-6), 2.01 (1 H, m, H-6′),
2.09 (3 H, s, Me), 2.22–2.42 (2 H, m, H-5, H-5′), 3.92 (l H, m, H-2), 4.98
(1 H, ddd, J 7.2, 4.7, 2.7, H-2), 6.03 (l H, t, J 3.5, H-4), 7.25–7.40 (5 H, m, Ar).
Crystal data for 14c
C14H17N1O2, M = 231.3, monoclinic, a = 5.187(2), b = 18.111(8), c = 13.491
(6) Å, β = 91.88(1)0, U = 1266.6(10) Å3, T = 293(2) K, Mo-Kα radiation,
J. Phys. Org. Chem. 2013, 26 997–1008
Copyright © 2013 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/poc

D. R. BOYD ET AL.
λ = 0.71073 Å, space group P21 (no. 4), Z = 4, F(000) = 496, Dx = 1.213g cmÀ3
,
(1S,4R)-3-Phenyl-4-(p-toluenesulfonamido)cyclohex-2-enyl acetate
18c
NMR spectra in agreement with literature values.[32] δH (500 MHz; CDCl3)
1.90–1.75 (2 H, m, H-6, H-6′), 2.10 (3 H, s, Me), 2.23 (2 H, m, H-5, H-5′), 2.44
(3 H, s, Me), 4.23 (1 H, m, 1 H-4), 4.50 (1 H, d, J 6.1, NH), 5.34 (1 H, m, H-1),
5.92 (1 H, d, J 3.0, H-2), 6.95 (2 H, d, J 8.5, Ar), 7.12 (5 H, m, Ar), 7.50 (2 H, d, J
8.3, Ar).
μ = 0.081 mmÀ1, Bruker SMART CCD area detector diffractometer, φ/ω
scans, 3.0° < 2θ < 50.0°, measured/independent reflections: 10946/4270,
Rint = 0.064, direct methods solution, full-matrix least squares refinement
on F2o, anisotropic displacement parameters for non-hydrogen atoms;
hydrogen atoms located in a difference Fourier synthesis but included
at positions calculated from the geometry of the molecules using the
riding model, with isotropic vibration parameters. R1 = 0.085 for 2531
data with Fo > 4σ(Fo), 312 parameters, ωR2 = 0.185 (all data), GoF= 1.11,
Δρmin,max = À0.35/0.34 e ÅÀ3. CCDC 930363.
Crystal data for 18c
C21H23N1O4S1, M = 385.5, monoclinic, a = 8.482(3), b = 5.598(2), c = 20.839
(8) Å, β = 99.469(7)0, U = 976.1(6) Å3, T = 293(2) K, Mo-Kα radiation,
λ = 0.71073 Å, space group P21 (no. 4), Z = 2, F(000) = 408, Dx = 1.312 g
cmÀ3, μ = 0.192 mmÀ1, Bruker SMART CCD area detector diffractome-
ter, φ/ω scans, 2.0° < 2θ < 50.0°, measured/independent reflections:
7650/3372, Rint = 0.082, direct methods solution, full-matrix least squares
refinement on F2o, anisotropic displacement parameters for non-hydrogen
atoms; hydrogen atoms located in a difference Fourier synthesis but
included at positions calculated from the geometry of the molecules using
the riding model, with isotropic vibration parameters. R1 = 0.111 for 1509
data with Fo > 4σ(Fo), 247 parameters, ωR2 = 0.345 (all data), GoF= 1.03,
Δρmin,max = À0.28/0.47 e ÅÀ3. CCDC 930364.
(1S,4R)-3-Phenyl-4-(p-toluenesulfonamido)cyclohex-2-enol 15c
White crystalline solid; mp 158–159 °C; (lit., mp 155–156 °C)[32]; [α]D À43
(c 0.3, CHCl3); δH (500 MHz; CDCl3) 1.79 (1 H, m, H-6), 2.02 (1 H, m, H-6′),
2.24 (1 H, m H-7), 2.33 (1 H, m H-7′), 2.44 (3 H, s, CH3), 4.17 (1 H, dt J 6.4,
3.1, H-4), 4.26 (1 H, bm, H-1), 5.08 (1 H, d, J 6.7, NH), 6.0 (1 H, d, J 2.7, H-
2), 6.97 (2 H, d, J 8.1, Ar), 7.12 (5 H, m, Ar), 7.5 (2 H, d, J 8.1, Ar); δC
(125 MHz; CDCl3) 21.49, 26.49, 27.89, 49.18, 66.94, 126.27, 126.96,
127.54, 128.29, 129.47, 133.46, 137.12, 137.97, 138.11, 143.06.
(1S,4S)-3-Phenyl-4-(p-toluenesulfonamido)cyclohex-2-enol 16c
(1S,4S)-3-Bromo-4-(p-toluenesulfonamido)cyclohex-2-enyl acetate
19b
White crystalline solid; mp 193–194 °C; (lit., mp 190–192 °C)[32]; [α]D À25
(c 1.0, CHCl3); physical spectroscopic properties in good agreement with
literature values[32]; δH (500 MHz; CDCl3) 1.72 (l H, m, H-6), 2.06 (3 H, m,
H-5, H-5′, H-6′), 2.42 (3 H, s, Me), 4.27 (l H, m, H-4), 4.34 (1 H, m, H-4), 6.08
(1H, d, J 4.0, H-2), 6.95 (2H, d, J 7.2, Ar), 7.09 (2H, m, Ar), 7.19 (3H, m, Ar),
7.52 (2H, d, J 8.2, Ar)
NaNHTs (0.92 g, 4.8 mmol) and TsNH2 (0.27 g, 1.6 mmol) were added to a
solution of (1S,2R)-bromoacetate 4b (0.95 g, 3.2 mmol) in DMSO and the
mixture heated at 60 °C overnight. The mixture was diluted with ethyl
acetate and washed with brine, dried (Na2SO4), and concentrated.
Purification of the crude product by column chromatography (EtOAc:
hexane, l:1) furnished the titled compound 19b as a clear oil (0.72 g,
63%); RF 0.52 (EtOAc:hexane, 1:1); (Found: (M + 1)+ 388.0218;
C15H19BrNO4S requires 388.0213); δH (500 MHz; CDCl3) 1.74 (1 H, m, H-
5), 1.95 (2 H, m, H-5′, H-6), 2.02 (3 H, s, Me), 2.10 (1 H, m, H-6′), 2.43 (3 H,
s, Me), 3.90 (1 H, dt J 7.5, 4.1, H-4), 5.14 (1 H, q, J 4.3, H-1), 5.84 (1 H, d, J
7.5, N-H), 6.23 (1 H, d, J 4.6, H-2), 7.30 (2 H, d, J 6.8, Ar), 7.79 (2 H, d, J
6.8, Ar); δC (125 MHz; CDCl3) 21.02, 21.57, 23.18, 27.70, 54.89, 67.46,
Crystal data for 16c
C19H21N1O3S1, M = 343.4, monoclinic, a = 8.9058(4), b = 10.5644(5),
c = 9.1348(4) Å, β = 91.233(1),0 U = 859.24(7) Å3, T = 293(2) K, Mo-Kα
radiation, λ = 0.71073 Å, space group P21 (no. 4), Z = 2, F(000) = 364,
Dx = 1.327 g cmÀ3, μ = 0.205 mmÀ1, Bruker SMART CCD area detector
diffractometer, φ/ω scans, 4.5° < 2θ < 56.6°, measured/independent
reflections: 10031/3853, Rint = 0.020, direct methods solution, full-matrix
least squares refinement on F2o, anisotropic displacement parameters
for non-hydrogen atoms; all hydrogen atoms located in a difference
Fourier synthesis but included at positions calculated from the
geometry of the molecules using the riding model, with isotropic
vibration parameters. R1 = 0.045 for 3697 data with Fo > 4σ(Fo), 219
parameters, ωR2 = 0.123 (all data), GoF = 1.05, Δρmin,max = À0.31/0.54
e ÅÀ3. Flack parameter x = 0.02(6) establishes the absolute configuration
as (1S,4S). CCDC 930365
127.35, 127.45, 129.62, 132.14, 137.00, 143.70, 170.30; m/z (CI) 390
+
[(M + 1)+, 81Br, 40%], 388 [(M + 1)
,
79Br, 47%], 329 (36), 327 (33), 174
(30), 172 (53), 155 (34), 91 (100), 65 (36).
(1S,4S)-3-Phenyl-4-(p-toluenesulfonamido)cyclohex-2-enyl acetate
19c
NaNHTs (1.0 g, 5.1 mmol) and H2NTs (0.29 g, 1.7 mmol) were added to a
solution of bromoacetate 4c (1.0 g, 3.4 mmol) in DMSO (20 mL), and the
reaction mixture was heated at 55 °C overnight. The cooled mixture
was diluted with EtOAc (100 mL) and washed with brine containing 2%
NaOH (3 × 50 mL) and saturated NH4Cl solution (75 mL). The organic
phase was dried (Na2SO4) and concentrated under reduced pressure,
and the residue was purified by flash chromatography (pentane:EtOAc
gradient 90:10 → 40:60) to afford compound 19c (1.1 g, 84%) as a white
needles; mp 152–153 °C (from EtOAc) (lit., mp 135 °C)[32]; [α]D À35 (c
1.0, CHCl3); υmax/cmÀ1 1157, 1255, 1729; δH (500 MHz; CDCl3) 1.80 (l H,
m, H-5), 2.01 (3 H, s, Me), 2.05 (3 H, m, H-5′, H-6, H-6′), 2.44 (3 H, s, Me),
4.30 (1 H, m, H-4), 4.55 (1 H, d, J 6.5, NH), 5.34 (1 H, q, J 3.8, H-l), 6.07
(1 H, d, J 4.2, H-2), 6.97 (2 H, d, J 7.2, Ar), 7.09 (2 H, m, Ar), 7.19 (3 H, m,
Ar), 7.53 (2 H, d, J 8.2, Ar).
(1S,2S)-3-Phenyl-2-(p-toluenesulfonamido)cyclohex-2-enyl
acetate 17c
Crystal data for 17c
C19H21N1O3S1, M = 343.4, monoclinic, a = 9.087(4), b = 19.996(9),
c = 10.177(5) Å, β = 91.922(7)0, U = 1848.3(14) Å3, T = 293(2) K, Mo-Kα radi-
ation, λ = 0.71073 Å, space group P21 (no. 4), Z = 4, F(000) = 728, Dx = 1.234
g cmÀ3, μ = 0.191 mmÀ1, Bruker SMART CCD area detector diffractome-
ter, φ/ω scans, 4.0° < 2θ < 45.0°, measured/independent reflections:
13528/4788, Rint = 0.102, direct methods solution, full-matrix least
squares refinement on F2o, anisotropic displacement parameters for
non-hydrogen atoms; hydrogen atoms included at positions calculated
from the geometry of the molecules using the riding model, with isotro-
pic vibration parameters. R1 = 0.137 for 3349 data with Fo > 4σ(Fo), 437
parameters, ωR2 = 0.361 (all data), GoF = 1.19, Δρmin,max = À0.49/0.38 e
(1S,4S)-3-Phenyl-4-(p-toluenesulfonamido)cyclohex-2-enol 16c
To a solution of compound 19c (0.60 g, 1.54 mmol) in MeOH:H2O (15 mL,
4:1) was added potassium carbonate (0.22 g, 1.60 mmol), and the
reaction was stirred overnight at room temperature. The solvents were
evaporated under reduced pressure and the crude product recrystallized
from MeOH/H2O to give compound 16c as white crystals (0.47 g, 90%);
Å
À3. The asymmetric unit contains two crystallographically independent
molecules which do not differ significantly. CCDC 930366.
wileyonlinelibrary.com/journal/poc
Copyright © 2013 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2013, 26 997–1008

ENANTIOPURE CYCLOHEXENE EPOXIDE AND TRANS-1,2-BROMOACETATE REACTIONS
mp 193–194 °C (lit., mp 190–192 °C)[32]; [α]D À25 (c 1.0, CHCl3); (Found:
M+ 343.1248 C19H21NO3S requires 343.1242); υmax/cmÀ1 1014, 1158; δH
(500 MHz; CDCl3) 1.71 (l H, m, H-5), 2.08 (3 H, m, H-5′, H-6, H-6′), 2.46
(3 H, s, Me), 4.27 (2 H, m, H-4, NH), 4.34 (1 H, m, H-1), 6.10 (1 H, d, J 4.1,
H-2), 6.99 (2 H, d, J 7.2, Ar), 7.09 (2 H, m, Ar), 7.19 (3 H, m, Ar), 7.50 (2 H,
dm, J 8.2, Ar); m/z (LSIMS) 343 (M+, 25%).
232 (34), 172 (31), 155 (42), 154 (65), 130 (38), 128 (38), 115 (42), 105
(36), 91 (25), 77 (20).
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12, 2206.
(1S,2R)-3-Chloro-2-morpholinylcyclohex-3-enol 20a
A solution of chloroepoxide 5a (0.34 g, 2.61 mmol) and morpholine
(0.23 mL, 2.61 mmol) in MeOH (25 mL) containing ZnCl2 (18 mg,
0.13 mmol) was stirred at room temperature for 12 h. The solvent was re-
moved under reduced pressure and the crude product purified by PLC
(EtOH) to furnish compound 20a; (0.44 g, 76%); [α]D +10 (c 0.93, CHCl3);
(Found: M+ 217.0868 C10H16O2N35Cl requires 217.0870); δH (500 MHz;
CDCl3); 1.64 (1 H, m, H-6), 1.99 (1 H, m, H-6′), 2.13 (2 H, m, H-5, H-5′),
2.29 (2 H, m, CH2), 3.04 (2 H, m, CH2), 3.13 (1 H, d, J 5.8, H-2), 3.69 (5 H,
m, 2xCH2, H-1), 5.92 (1 H, s, H-4); δC (125 MHz; CDCl3) 24.24, 28.23,
50.15, 68.42, 68.73, 72.62, 129.77; m/z (EI) 219 (M+, 37Cl, 10%), 217 (M+,
35Cl, 32%), 175 (30), 173 (100), 160 (10), 158 (28), 144 (14), 142 (40), 138
(17), 80 (27), 67 (11).
(1S,2R)-3-Bromo-2-(4′-phenylpiperin-1′-yl)cyclohex-3-enol 21b
Zinc chloride (6 mg, 0.043 mmol) was added to
a solution of
bromoepoxide 5b (0.15 g, 0.86 mmol) and 4-phenylpiperidine (0.14 g,
0.86 mmol) in methanol (25 mL) and the reaction mixture stirred at room
temperature for 12 h. The solvent was removed under reduced pressure
and the crude product purified by PLC (Et2O:hexane, 3:7) to give com-
pound 21b as a colourless oil (0.2 g, 70%); [α]D +12.5 (c 0.16, CHCl3);
(Found: M+ 335.0882 C17H22ONBr requires 335.0885); δH (500 MHz; CDCl3)
1.71 (3 H, m, H-6, H-9, H-11), 1.88 (2 H, m, H-9′, H-11′), 2.05 (1 H, m H-6′),
2.13 (2 H, m, H-5, H-5′), 2.57 (1 H, m, H-10), 2.94 (3 H, m, H-8′, H-12, H-
12′), 3.28 (1 H, d, J 5.8, H-2), 3.43 (1 H, t, J 10.8, H-8), 3.76 (1 H, m, H-1),
6.18 (1 H, s, H-4), 7.22 (3 H, m, ArH), 7.31 (2 H, t, J 7.5, ArH); δC (125 MHz;
CDCl3) 25.97, 28.41, 34.95, 35.58, 43.94, 46.28, 54.35, 60.83, 69.33, 73.83,
122.55, 126.55, 127.27, 128.83, 133.60, 146.85, 171.56; m/z (EI) 337 (M+
81Br, 8%) 335 (M+ 79Br 13%), 334 (22), 292 (82), 290 (79), 212 (100), 117
(17), 108 (37), 104 (19), 91 (30), 80 (32), 67 (23).
[4] D.R. Boyd, N.D. Sharma, M. Kaik, P.B.A. McIntyre, P.J. Stevenson, C.C.
R. Allen, Org. Biomol. Chem. 2012, 10, 2774.
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Allen, RSC Adv. 2013, 11, DOI: 10.1039/c3ra42026d
(1S,2S)-2-Morpholinylcyclohexanol 22
[6] D.R. Boyd, M. Bell, K.S. Dunne, B. Kelly, P.J. Stevenson, J.F. Malone, C.
C.R. Allen, Org. Biomol. Chem. 2012, 10, 1388.
To a solution of (1S,2R)-3-chloro-2-morpholinyl-cyclohex-3-enol 20a
(0.33 g, l.22 mmol), in EtOH (10 mL) containing Et3N (0.1 mL), was added
10% Pd-C (10 mg), and the reaction mixture stirred overnight under a
hydrogen atmosphere. The catalyst was filtered off and the crude
product purified by PLC (0.5% NH3 in EtOH) to yield compound 22 as a
white crystalline solid (0.27 g, 94%); (Found: M+ 185.1418 C10H19O2N
requires 185.1415); δH (500 MHz; CDCl3) 0.98 (4H, m, H-4, H-4′, H-5, H-5′),
1.53 (3H, m, H-2, H-3, H-3′), 1.90 (2 H, m, H-6, H-6′), 2.19 (2H, m, H-7, H-10),
2.48 (2H, m, H-7′, H-10′), 3.14 (1H, dt, J 4.7, 10, H-1), 3.47 (4 H, m, H-8, H-8′,
H-9, H-9′); m/z (EI) 185 (M+, 28%), 126 (98), 86 (100).
[7] a) D.R. Boyd, N.D. Sharma, M. Kaik, M. Bell, M.V. Berberian, P.B.A.
McIntyre, B. Kelly, C. Hardacre, P.J. Stevenson, C.C.R. Allen, Adv.
Syn. Cat. 2011, 353, 2455; b) D.R. Boyd, N.D. Sharma, L. Sbircea, D.
Murphy, J.F. Malone, S.L. James, C.C.R. Allen, J.T.G. Hamilton, Org.
Biomol. Chem. 2010, 8, 1081; c) D.R. Boyd, N.D. Sharma, L. Sbircea,
D. Murphy, T. Belhocine, J.F. Malone, S.L. James, C.C.R. Allen, J.T.G.
Hamilton, Chem. Commun. 2008, 5535; d) D.R. Boyd, N.D. Sharma,
N.I. Bowers, P.A. Goodrich, M.R. Groocock, A.J. Blacker, D.A. Clarke,
T. Howard, H. Dalton, Tetrahedron-Asymmetry 1996, 7, 1559.
[8] D.R. Boyd, N.D. Sharma, N.M. Llamas, C.R. O’Dowd, C.C.R. Allen, Org.
Biomol. Chem. 2007, 5, 2267.
(1S,2S)-2-(4′-Phenylpiperidin-1′-yl)cyclohexanol 23
[9] T. Borrmann, W.D. Stohrer, Ann. 1996, 1593; b) W.D. Stohrer, Angew.
Chem. Int. Ed Engl. 1983, 22, 613; c) R.M. Magid, Tetrahedron 1980,
36, 1901.
(1S,2R)-3-Bromo-2-(4′-phenylpiperin-l′-yl)cyclohex-3-enol 21b (0.15 g,
0.45 mmol) was converted into (1S,2S)-2-(4′-phenylpiperidin-l′-yl)
cyclohexanol following the catalytic hydrogenation procedure used for
the synthesis of compound 22. The crude product was purified by crys-
tallization (CH2Cl2) to yield the aminoalcohol 23 a white crystalline solid
(0.10 g, 92%); mp 239–241 °C; [α]D +26 (c 1.03, EtOH); (Found: M+
259.1933 C17H25ON requires 259.1936); δH (500 MHz; CDCl3) 1.34 (8 H,
m, H-3, H-3′, H-4, H-4′, H-5, H-5, H-6, H-6′), 1.81 (1 H, m, H-7), 1.91 (1 H,
m, H-7′), 2.07(1 H, m, H-11), 2.22 (1 H, m, H-11′), 2.65 (1 H, m, H-9), 3.07
(2 H, dt, J 11.0, 2.4, H-8, H-10), 3.30 (1 H, t, J 10.5, H-2), 3.71 (2 H, m, H-8′,
H-10′), 3.83 (1 H, td, J 4.6, 0.8, H-1), 7.27 (3 H, m, ArH), 7.32 (2 H, m, ArH);
δC (125 MHz; CDCl3) 24.39, 24.89, 25.10, 30.95, 31.17, 35.31, 49.05, 53.31,
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J. Phys. Org. Chem. 2013, 26 997–1008