Palladium-catalysed enantiodivergent synthesis of cis- and trans-4-aminocyclohex-2-enols

Article abstract of DOI:10.1039/a600779a

Enantiomerically pure cis- and trans-4-aminocyclohex-2-enols are prepared from cyclohexa-1,3-diene via (-)-cis-(1R,4S)-4-acetoxycyclohex-2-enol (-)-2a using palladium(0) chemistry. Benzylamine and diethylamine are tested in the Pd⁰-catalysed allylic amination reactions. Since acetate is too slow as a leaving group and gave considerable amounts of side products, a number of leaving groups have been investigated. Of these phosphinate and 2,4-dichlorobenzoate are excellent leaving groups and result in efficient and highly stereoselective reactions; chloride as allylic leaving group also gives good results. By variation of the leaving group and proper choice of the protecting group it is possible to synthesise all four stereoisomers of 4-aminocyclohex-2-enol in good yield and high enantiomeric excess.

Full text of DOI:10.1039/a600779a

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Palladium-catalysed enantiodivergent synthesis of cis- and
trans-4-aminocyclohex-2-enols
Roberto G. P. Gatti, Anna L. E. Larsson and Jan-E. Bäckvall*
Department of Organic Chemistry, University of Uppsala, Box 531, S-751 21 Uppsala,
Sweden
Enantiomerically pure cis- and trans-4-aminocyclohex-2-enols are prepared from cyclohexa-1,3-diene
via (Ϫ)-cis-(1R,4S)-4-acetoxycyclohex-2-enol (Ϫ)-2a using palladium(0) chemistry. Benzylamine and
diethylamine are tested in the Pd0-catalysed allylic amination reactions. Since acetate is too slow as
a leaving group and gave considerable amounts of side products, a number of leaving groups have been
investigated. Of these phosphinate and 2,4-dichlorobenzoate are excellent leaving groups and result
in efficient and highly stereoselective reactions; chloride as allylic leaving group also gives good results.
By variation of the leaving group and proper choice of the protecting group it is possible to
synthesise all four stereoisomers of 4-aminocyclohex-2-enol in good yield and high enantiomeric
excess.
Introduction
4-Aminocyclohex-2-enols are important structural elements in
a number of biologically active compounds such as condur-
amines1 and derivatives.2 In connection with a project dealing
with new substances for treatment of bronchitis complications,
there was a need for a general synthesis of optically pure 4-
aminocyclohex-2-enols.
We recently reported a method for an enantiodivergent syn-
thesis of 4-substituted 2-cycloalkenols from cycloalka-1,3-
dienes with a combination of palladium and enzyme chemistry
(Scheme 1).3 The method allows for preparation of both enan-
tiomers with high selectivity.
Scheme 2
Results and discussion
(A) Racemates
The objective was to synthesise cis- and trans-4-aminocyclohex-
2-enols in optically pure form starting from (Ϫ)-2a.4 Diethyl-
amine and benzylamine (BnNH2) were employed as represent-
ative amines in the palladium(0)-catalysed allylic aminations.
First, the allylic amination was performed to produce a racemic
mixture of the amino alcohols (Scheme 3). Thus, cis-4-
diethylaminocyclohex-2-enol 6a and cis-4-benzylaminocyclo-
hex-2-enol 6b were prepared starting from cis-1-acetoxy-4-
chlorocyclohex-2-ene 8.5
The racemic trans stereoisomers were synthesised from (±)-
2a.6 Substitution of the OH by chloride with PPh3 and N-
chlorosuccinimide (NCS)7 in THF afforded trans-1-acetoxy-4-
chlorocyclohex-2-ene 9. Pd0-catalysed allylic amination of
chloroacetate 9 with diethylamine or benzylamine gave after
hydrolysis trans-4-diethylaminocyclohex-2-enol 7a or trans-4-
benzylaminocyclohex-2-enol 7b, respectively. Amino alcohols 6
and 7 were used to set up a method for determination of the ee.
However, with 9 as the allylic substrate, a moderate regio-
selectivity was observed. Using conditions A in Scheme 3 and
diethylamine as the nucleophile about 20% of the γ-substitution
product (of trans stereochemistry) was obtained. Usually,
Scheme 1
In the present paper we have used enantiomerically pure (Ϫ)-
cis-(1R,4S)-4-acetoxycyclohex-2-enol (Ϫ)-2a as a key inter-
mediate for further stereocontrolled palladium(0)-catalysed
functionalisation and report on the enantiocontrolled synthesis
of all four stereoisomers of 4-aminocyclohex-2-enol (Scheme
2). An interesting observation is that phosphinates are excellent
leaving groups in the Pd0-catalysed allylic substitution with
primary and secondary amines.
J. Chem. Soc., Perkin Trans. 1, 1997
577

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catalysed allylic amination 10 but carbonate 12 gave the non-
desired carbamate 13 on reaction with benzylamine [eqn. (1)].‡
The same results for similar substrates have been reported
earlier in our laboratory11 and elsewhere.12 The use of trifluoro-
acetate 14 in the corresponding reaction gave 2a and N-
benzyltrifluoroacetamide, presumably because of faster nitro-
gen attack at the carbonyl carbon rather than formation of the
π-allyl complex. Attempts to use a diethylphosphate ester 9d,e as
the leaving group, failed since 15 was very sensitive and hydro-
lysed quickly after preparation.
Scheme 3 Reagents and conditions: A, 5% Pd(dba)2, 15% PPh3, 1.2–3
equiv. NHR1R2, 3 equiv. Et3N in THF, RT, N2 or Ar atm: 10a (77%),
10b (81%); B, K2CO3 in MeOH–H2O at RT: 6a (95%), 6b (98%), 7a
(96%), 7b (98%); C, NCS, PPh3, THF, RT (97%); D, reagents as for A
but longer reaction times and 25% LiCl added to the reaction mixture:
11a (71%), 11b (76%)
We next tried diphenylphosphinic and benzoate esters.
Diphenylphosphinic ester 16 was prepared from enantiomeri-
cally pure (Ϫ)-2a (89%) according to Liebeskind et al.13 and 2,4-
dichlorobenzoate ester 17 was prepared (80% yield) by esterifi-
cation of (Ϫ)-2a following the method of Hassner.14 Both 16
and 17 were excellent substrates in the Pd0-catalysed allylic
amination with diethylamine and benzylamine and afforded
the amino acetates (1S,4R)-10a and (1S,4R)-10b, which upon
hydrolysis yielded the amino alcohols (1S,4R)-6a and (1S,4R)-
6b, respectively (Scheme 4). In each case the allylic amination
Fig. 1 Weaker bond in the 2-position because of steric interactions
which increase the relative amount of γ-substitution product
attack at the 4-position relative to the acetate is strongly
favoured in analogous 1,4-disubstituted alk-2-enes.5 However,
due to steric interaction between the acetate and the L2Pd-
group in π-allyl intermediate I (Fig. 1) palladium is forced away
from the acetate which weakens the palladium–carbon bond in
the 2-position.8 This will increase the relative rate of attack at
the 2-position in I. When R is tert-butyl II the relative amount
of attack in the 2-position increased to 50–60% in the corre-
sponding reaction (vide infra).
The reaction conditions were further investigated by vari-
ation of the solvent, amount of catalyst and ligand and by
addition of salt (LiCl). The system with Pd(dba)2 and PPh3 in
THF with an addition of 25 mol% LiCl decreased the amount
of γ-product of I from 20 to 13% with Et2NH and from 12 to
5% with BnNH2.
Scheme 4 Reagents and conditions: A, 5% Pd(dba)2, 15% PPh3, 1.2–3
equiv. NHR1R2, 3 equiv. Et3N in THF at RT, N2 or Ar atm: 16 to 10a
(82%), 16 to 10b (79%), 17 to 10a (73%), 17 to 10b (70%); B, K2CO3 in
MeOH–H2O at RT: yields as for step B shown in Scheme 3
(B) cis Enantiomers
It has been shown that acetate can be used as a leaving group in
Pd0-catalysed allylic amination with both primary and second-
ary amines.9 However, when (±)-2a was treated with ben-
zylamine in the presence of Pd(dba)2, PPh3 and Et3N in THF
the conversion was low. In an attempt to improve the reaction,
different catalysts, ligands and solvents were tried together with
variation of the concentration and temperature. The best
results were obtained with acetonitrile as the solvent at a reac-
tion temperature of 40 ЊC. However, the yield of the desired
product 6 was still unsatisfactory with considerable amounts of
γ-product as well as inversion and elimination products.†
Therefore better leaving groups were called for. To increase the
reactivity in the Pd0-catalysed nucleophilic displacement, the
hydroxy group in 2a was transformed into a reactive leaving
group. It has been reported in the literature that ethyl and
methyl carbonate can be used as a leaving group in Pd0-
was highly stereoselective and the enantiomeric excess (ee) of
the amino alcohols was ≥98% in both cases. For (1S,4R)-6a 2%
of the trans isomer was observed. An explanation could be
isomerisation of the π-allyl intermediate by nucleophilic attack
by free Pd0 on the allyl ligand.15
To form a carbon–nitrogen bond at the other allylic carbon in
(Ϫ)-2a, it was necessary to protect the hydroxy group and then
selectively hydrolyse the acetate before attachment of a leaving
group (Scheme 5).
The hydroxy acetate (Ϫ)-2a was transformed into the alcohol
18a with tetrahydropyran (THP) protection 16 and subsequent
hydrolysis of the acetoxy group. The alcohol 18a was trans-
formed into its 2,4-dichlorobenzoate ester 19 (vide supra) which
on Pd0-catalysed amination and subsequent removal of the
THP group afforded (1R,4S)-6a and (1R,4S)-6b.
† Loss of regio- and stereo-selectivity has previously been observed in
Pd-catalysed reaction of allylic acetates with amines.9b,g
‡ The reaction proceeds via a (π-allyl)palladium intermediate.11
578
J. Chem. Soc., Perkin Trans. 1, 1997

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Scheme 5 Reagents and conditions: A, i, DHP, PPTS in CH2Cl2 at RT
(98%); ii, 20% K2CO3 in MeOH–H2O at RT (86%); B, 2,4-
dichlorobenzoic acid, DCC, DMAP in CH2Cl2 at RT (87%); C, i, 5%
Pd(dba)2, 15% PPh3, 1.2–3 equiv. NHR1R2, 3 equiv. Et3N in THF at RT,
N2 or Ar atm; ii, p-TsOH, MeOH, RT, 6a 55% yield in two steps, 6b 65%
yield in two steps
Scheme 6
(C) trans Enantiomers
Reaction of the enantiomerically pure hydroxy acetate (Ϫ)-2a
with NCS and PPh3 in THF afforded optically active (1S,4S)-9
with high stereospecificity (cf. racemic reaction, Scheme 3).
Subsequent Pd0-catalysed allylic amination employing Et2NH
and BnNH2 followed by hydrolysis gave (1S,4S)-7a and
(1S,4S)-7b, respectively [eqn. (2)]. The yields were the same
Scheme 7 Reagents and conditions: A, TBDMS-Cl, imidazole, CH2Cl2,
0 ЊC to RT (99%); B, i, 20% KOH in MeOH at RT (98%); ii, MsCl,
LiCl, Et3N in CH2Cl2, Ϫ20 ЊC to RT (91%); C, i, TBAF in THF at RT;
ii, Ac2O (83%); D, i, 5% Pd(dba)2, 15% PPh3, 25% LiCl, 1.2–3 equiv.
NHR1R2, 0–3 equiv. Et3N in THF at RT; ii, K2CO3 in MeOH–H2O at
RT: yields as in Scheme 3
as for the racemates (Scheme 3) and the ee was in each
case ≥ 98%.
When preparing the other trans enantiomer, the group at the
other stereogenic carbon had to be substituted. Some difficul-
ties were encountered when solving this problem. Substitution
of the hydroxy group in 18a by chloride with inversion using
LiCl, methanesulfonyl chloride (MsCl), 2,4,6-trimethylpyridine
in DMF and subsequent Pd0-catalysed allylic amination of the
allylic chloride 20a should in analogy to the preparation of
(1S,4S)-7 from (1S,4S)-9 give (1R,4R)-7 after removal of the
protecting group. Unfortunately, and to a much greater extent
than what had been seen for 9, the predominant product was
the γ-substitution product (vide supra). Using pivalate§ as pro-
tecting group instead of THP led to the same discouraging
result (Scheme 6). For example, with the pivalate 20b the
amount of γ-substitution product was 50–60% with diethyl-
amine. This result supports the explanation suggested in Fig. 1
for the increased relative amount of γ-isomer. The use of
tert-butyldimethylsilyl (TBDMS)¶ led to decomposition of the
silyl ether bond in the amination. Another way to reach the
other trans enantiomer (1R,4R)-7 would be by a Mitsunobu
reaction 18 of 6. However, reaction of 6b under Mitsunobu con-
ditions failed, even when the amine was protected with tert-
butoxycarbonyl (TBOC).||
described in Scheme 7. Silylation of (Ϫ)-2a with TBDMS-Cl
gave cis-(1S,4R)-1-acetoxy-4-(tert-butyldimethylsilyloxy)cyclo-
hex-2-ene 21c. This compound was converted into (1R,4R)-9 in
the following way: hydrolysis of the acetate in 21c and stereo-
specific substitution of the hydroxy group by chloride with
inversion of configuration using MsCl, LiCl and Et3N in meth-
ylene dichloride gave trans-(1R,4R)-1-chloro-4-(tert-butyldi-
methylsilyloxy)cyclohex-2-ene 20c. Deprotection of TBDMS
with tetrabutylammonium fluoride (TBAF) followed by
quenching with acetic anhydride gave (1R,4R)-9 (83%). Trans-
formation of (1R,4R)-9 into (1R,4R)-7a and (1R,4R)-7b was
done as shown in eqn. (2) and the ee obtained was ≥98%.19
Conclusion
All four stereoisomers of biologically interesting 4-amino-
cyclohex-2-enols have been prepared in enantiomerically
pure form by palladium(0)-catalysed reactions from the same
starting material, (Ϫ)-cis-(1R,4S)-4-acetoxycyclohex-2-enol
(Ϫ)-2a.
To solve the problem of obtaining the trans-(1R,4R)-
enantiomer of the amino alcohol we prepared (1R,4R)-9 as
Experimental
1H and 13C NMR spectra were recorded for CDCl3 solutions at
300 or 400 and 75.4 or 100.6 MHz, respectively. 19F NMR spec-
tra were recorded for CDCl3 solutions at 376.3 MHz. Chemical
shifts are reported in ppm with CDCl3 as internal standard
§ Prepared by selective hydrolysis of the acetate (Na2CO3, MeOH,
RT)17 in (±)-cis-1-acetoxy-4-pivaloyloxycyclohex-2-ene. The latter was
obtained from esterification of (±)-2a.
¶ For an experimental procedure see preparation of 20c in the Experi-
mental section.
|| The protection was done by mixing the aminoacetate with (BOC)2O,
Et3N and catalytic amounts DMAP in methylene dichloride. Before the
Mitsunobu reaction the acetate was hydrolysed.
1
(7.26 for H and 77.00 ppm for 13C) and coupling constants (J)
are given in Hz. Assignment of 13C was done with HETCOR
and COSY experiments. Mass spectra were recorded on a
J. Chem. Soc., Perkin Trans. 1, 1997
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Finnigan MAT INCOS 50 or a Hewlett Packard 5971 series
instrument at 70 eV. Where indicated, mass spectra were
recorded with pneumatically assisted electrospray mass spec-
trometry (ES-MS) on a Micromass VG Platform apparatus
using direct inlet of a solution in acetonitrile or with an LC-
column (Kromasil 100 × 4.6 mm, acetonitrile–water gradient
with 5 m formic acid). Optical rotations, recorded in units of
10Ϫ1 deg cm2 gϪ1 measured at 25.0 ЊC on a Perkin–Elmer 241
polarimeter and concentrations are expressed as g 100 mlϪ1
in spectroscopically pure ethanol or methylene dichloride.
Elemental analyses were performed by Analytische Laborat-
orien, Engelskirchen, Germany. Bis(dibenzylideneacetone)-
palladium(0) [Pd(dba)2] was prepared according to a literature
procedure.20 THF was distilled under nitrogen from sodium
benzophenone ketyl. Pyridine and methylene dichloride were
distilled under nitrogen from calcium hydride. Benzylamine,
diethylamine and triethylamine were distilled from KOH and
stored over KOH under nitrogen until used. Thin-layer chroma-
tography (TLC) was run on Merck pre-coated silica gel 60-F254
plates. All reactions were carried out in oven-dried glassware
and the Pd0-catalysed reactions also under an argon or
nitrogen atmosphere unless otherwise stated. Progress of reac-
tion was followed by TLC until judged complete for all reac-
tions. For flash chromatography Merck Kieselgel 60 (230–400
mesh) was used. Enantiomeric excess (ee) was checked with
1H and 19F NMR in CDCl3 by Mosher esterification 21 for
the diethylaminocyclohex-2-enols and by salt formation with
optically pure (S)-mandelic acid,22 for the 4-benzylamino-
cyclohex-2-enols.
H, m, CHNEt2), 5.26–5.38 (1 H, m, CHOAc), 5.64–5.73 (1 H,
m, olefinic) and 5.67–5.85 (1 H, m, olefinic); δC(100.6 MHz;
CDCl3, 10 peaks) 14.4 (NCH2CH3), 21.3 (CH3CO2), 22.3
(CH2CHN), 28.3 (CH2CHOAc), 44.1 (NCH2), 56.4 (CHN),
70.2 (CHOAc), 129.2 (olefinic, CHCHN), 134.8 (olefinic,
CHCHOAc) and 170.8 (C᎐O).
᎐
cis-(1S,4R)-1-Acetoxy-4-diethylaminocyclohex-2-ene
(1S,4R)-10a. The synthesis was carried out according to the
general procedure. Amounts used were allylic substrate 16 (616
mg, 1.718 mmol), Pd(dba)2 (51 mg, 0.086 mmol), PPh3 (68 mg,
0.258 mmol), Et2NH (151 mg, 2.06 mmol), Et3N (521 mg, 5.15
mmol) and THF (20 ml); reaction time 2 h; yield 298 mg, 82%.
Allylic substrate 17 (485 mg, 1.473 mmol), Pd(dba)2 (44 mg,
0.074 mmol), PPh3 (58 mg, 0.221 mmol), Et2NH (183 mg, 2.50
mmol), Et3N (447 mg, 4.42 mmol) and THF (20 ml); reaction
time 6 h; yield 228 mg, 73%. Spectral data are in accordance
with the racemate.
(±)-cis-4-Diethylaminocyclohex-2-enol 6a. The amino acetate
10a (250 mg, 1.19 mmol) was dissolved in a stirred solution of
K2CO3 (9 mg, 0.06 mmol) in MeOH–H2O (4:1; 10 ml) at RT.
After 5 h the mixture was evaporated, diluted with diethyl ether
(100 ml), washed with water (10 ml) and brine (10 ml), dried
(K2CO3) and evaporated. Purification of the residue on silica
(gradient of diethyl ether–pentane 60:40 to ethyl acetate–
MeOH 90:10) gave the title compound 6a (191 mg, 95%)
(Found for the HCl-salt: C, 58.3; H, 9.7. Calc. for C10H20ClNO:
C, 58.4; H, 9.8%); δH (300 MHz; CDCl3) 1.04 (6 H, app t, CH3),
1.56–1.71 (3 H, m, 6-H and 5-H), 1.79–1.89 (1 H, m, 5-H),
1.96–2.14 (1 H, br s, OH), 2.38–2.65 (4 H, m, CH2), 3.26–3.33
(1 H, m, 1-H), 4.07–4.12 (1 H, m, 4-H) and 5.79–5.91 (2 H,
m, 5-H and 6-H); δC(75.4 MHz; CDCl3, 8 peaks) 14.2 (CH3),
17.9 (CH2), 30.2 (CH2), 44.2 (NCH2), 56.7 (CHNEt2), 63.4
(CHOAc), 130.2 (CH, olefinic), 135.4 (CH, olefinic); νmax/cmϪ1
3346 (OH, br), 2967, 2937, 2871, 1386 and 1066.
General procedure for the Pd0-catalysed aminations exemplified
by the synthesis of (±)-cis-1-acetoxy-4-benzylaminocyclohex-2-
ene 10b
To a solution that had been stirred at room temperature (RT)
for 20 min containing Pd(dba)2 (172 mg, 0.29 mmol), PPh3
(225 mg, 0.86 mmol), BnNH2 (737 mg, 6.87 mmol) and Et3N
(1.74 g, 17.18 mmol) in THF (30 ml) was added the cis-chloro
acetate 8 (1.00 g, 5.73 mmol) in THF (10 ml). The reaction
mixture was stirred at RT for 8 h and then evaporated. The
residue was dissolved in diethyl ether (20 ml) and extracted with
1  aq. HCl (3 × 50 ml). The aqueous phase was charged with
fresh ether (80 ml) and the pH was adjusted to >10 with K2CO3
and KOH followed by two more extractions with ether (50 ml).
The combined ether extracts were dried (K2CO3) and concen-
trated. The crude product was purified on silica (ethyl acetate–
pentane gradient) to give 10b (1.14 g, 81%). The silica was first
conditioned with 2% Et3N in pentane (Found for the HCl-salt:
C, 63.9; H, 7.05. Calc. for C15H20ClNO2: C, 63.9; H, 7.15%);
δH (400 MHz; CDCl3) 1.3–1.5 (1 H, br s, NH), 1.58–1.71 (1 H,
m, CH2), 1.73–1.84 (1 H, m, CH2), 1.84–1.93 (2 H, m, CH2),
2.04 (3 H, s, COCH3), 3.14–3.21 (1 H, m, CHNHBn), 3.85,
3.88 (2 H, AB-system, JAB 13.1, PhCH2), 5.13–5.25 (1 H, m,
CHOAc), 5.79 (1 H, ddd, J 10.0, 3.5 and 1.7, olefinic), 6.00
(1 H, dd, J 10.1 and 2.7, olefinic) and 7.21–7.37 (5 H, m, Ph);
δC(100.6 MHz; CDCl3, 13 peaks) 21.3 (COCH3), 25.3
(CH2CHOAc), 26.1 (CH2CHN), 51.0 (CH2Ph), 52.3 (CHN),
67.2 (CHOAc), 126.3 (CH, Ph), 126.9 (olefinic, CHCHOAc),
128.1 (CH, Ph), 128.4 (CH, Ph), 135.4 (olefinic, CHCHN),
(Ϫ)-cis-(1S,4R)-4-Diethylaminocyclohex-2-enol (Ϫ)-(1S,4R)-
6a. Starting from (1S,4R)-10a and applying the same conditions
as for the preparation of (±)-6a yielded (Ϫ)-6a. Spectral data are
in accordance with (±)-6a; [α]D25 Ϫ70 (c 1.91 in EtOH); ee ≥98%.
(+)-cis-(1R,4S)-4-Diethylaminocyclohex-2-enol (+)-(1R,4S)-
6a. See general procedure according to 10b. Allylic substrate 19
(802 mg, 2.16 mmol), Pd(dba)2 (64 mg, 0.108 mmol), PPh3
(85 mg, 0.324 mmol), Et2NH (174 mg, 2.38 mmol), Et3N (656
mg, 6.48 mmol) and THF (25 ml) for 15 h yielded cis-(1R,4S)-4-
diethylamino-1-(tetrahydropyran-2-yloxy)cyclohex-2-ene (373
mg, 68%). The THP group in the latter product (299 mg, 1.18
mmol) was removed with toluene-p-sulfonic acid (190 mg, 1.00
mmol) in MeOH (5 ml) at RT. After 12 h the mixture was
evaporated and treated with diethyl ether (100 ml) and 1 
NaOH (10 ml). After extraction the organic phase was washed
with water (10 ml) and brine (10 ml), dried (MgSO4) and evap-
orated. Purification of the residue on silica (gradient of diethyl
ether–pentane, 60:40 to ethyl acetate–MeOH, 90:10) gave the
title compound (+)-(1R,4S)-6a (161 mg, 81%; totally 55% in
two steps). Same spectral data as for (±)-6a; [α]D25 +66 (c 1.70 in
EtOH); ee ≥98%.
(±)-cis-1-Acetoxy-4-benzylaminocyclohex-2-ene 10b. This
compound is described above under the general procedure.
cis-(1S,4R)-1-Acetoxy-4-benzylaminocyclohex-2-ene (1S,4R)-
10b. See general procedure for (±)-10b. Pd(PPh3)4 (87 mg, 0.075
mmol) was used instead of Pd(dba)2 for the allylic substrate 16
(539 mg, 1.504 mmol); amounts of reactants used were PPh3
(20 mg, 0.076 mmol), BnNH2 (161 mg, 1.503 mmol), Et3N (340
mg, 3.36 mmol) and THF (17 ml); reaction time 2 h; yield 292
mg, 79%. For the allylic substrate 17 (311 mg, 0.95 mmol) the
following amounts were used: Pd(dba)2 (28 mg, 0.047 mmol),
PPh3 (38 mg, 0.142 mmol), BnNH2 (311 mg, 2.83 mmol) and
THF (17 ml); reaction time 2 h; yield 163 mg, 70%. Spectral
data were in accordance with those of racemic 10b.
140.3 (C, Ph) and 170.7 (C᎐O).
᎐
(A) Synthesis of the cis-4-aminocyclohex-2-enols
(±)-cis-1-Acetoxy-4-diethylaminocyclohex-2-ene 10a. The
synthesis was carried out according to the general procedure
above. Amounts used were allylic substrate 8 (300 mg, 1.718
mmol), Pd(dba)2 (51 mg, 0.086 mmol), PPh3 (68 mg, 0.258
mmol), Et2NH (151 mg, 2.06 mmol), Et3N (521 mg, 5.15 mmol)
and THF (10 ml); reaction time 16 h; yield 280 mg, 77%; δH (300
MHz; CDCl3) 1.04 (6 H, app t, J 7.2, CH3), 1.41–1.61 (2 H,
m, CH2), 1.81–1.91 (1 H, m, CH2), 2.04 (3 H, s, COCH3), 2.11–
2.20 (1 H, m, CH2), 2.34–2.61 (4 H, m, NCH2), 3.40–3.53 (1
(±)-cis-4-Benzylaminocyclohex-2-enol 6b. Prepared from
amino acetate 10b using the same hydrolysis conditions as for
580
J. Chem. Soc., Perkin Trans. 1, 1997

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the preparation of 6a in 98% yield; δH (400 MHz; CDCl3) 1.56–
1.88 (6 H, m, 2 × CH2, OH, NH), 3.09–3.21 (1 H, m, CHN-
HBn), 3.83, 3.87 (2 H, AB-system, JAB 13.0, PhCH2NH), 4.09–
4.18 (1 H, m, CHOH), 5.81–5.89 (2 H, m, olefinic) and 7.22–
7.34 (5 H, m, Ph); δC(100.6 MHz; CDCl3, 11 peaks) 24.9 (CH2),
29.1 (CH2), 51.1 (CH2Ph), 52.3 (CHN), 64.7 (CHOH), 127.0
(CH, Ph), 128.1 (CH, Ph), 128.4 (CH, Ph), 130.7 (CH, olefinic),
133.1 (CH, olefinic) and 140.3 (C, Ph).
(Ϫ)-trans-(1S,4S)-4-Diethylaminocyclohex-2-enol
(Ϫ)-
(1S,4S)-7a. Preparation as for (±)-7a but with (1S,4S)-11a as
the substrate. Same spectral data as for (±)-7a; [α]D25 Ϫ102
(c 1.165 in EtOH); ee ≥98%.
(+)-trans-(1R,4R)-4-Diethylaminocyclohex-2-enol
(+)-
(1R,4R)-7a. Preparation as for (±)-7a but with (1R,4R)-11a as
the substrate. Same spectral data as for (±)-7a; [α]D25 +98 (c 0.600
in EtOH).
(Ϫ)-cis-(1S,4R)-4-Benzylaminocyclohex-2-enol (Ϫ)-(1S,4R)-
6b. Thiscompound wasprepared asabovefor 6bbut startingwith
(1S,4R)-10b. Spectral data are as for (±)-6b; [α]D25 Ϫ4.3 (c 0.845
in EtOH); ee ≥98%.
(+)-cis-(1R,4S)-4-Benzylaminocyclohex-2-enol (+)-(1R,4S)-
6b. See general procedure for 10b. Allylic substrate 19 (557 mg,
1.50 mmol), Pd(dba)2 (45 mg, 0.075 mmol), PPh3 (50 mg, 0.188
mmol), BnNH2 (160 mg, 1.50 mmol), Et3N (340 mg, 3.36
mmol) in THF (12 ml) for 20 h gave cis-(1R,4S)-4-benzyl-
amino-1-(tetrahydropyran-2-yloxy)cyclohex-2-ene (426 mg,
94%). The THP group was removed according to the prepar-
ation of (+)-(1R,4S)-6a in 69% yield (65% in two steps);
spectral data as for (±)-6b; [α]D25 +4.2 (c 1.79 in EtOH);
ee ≥98%.
(±)-trans-1-Acetoxy-4-benzylaminocyclohex-2-ene 11b. The
general procedure described for 10b was used but 25 mol% of
LiCl was added to the reaction mixture together with the cata-
lyst, phosphine and amine. Amounts used were trans-chloro
acetate 9 (720 mg, 4.13 mmol), Pd(dba)2 (124 mg, 0.21 mmol),
PPh3 (162 mg, 0.62 mmol), LiCl (44 mg, 1.03 mmol), BnNH2
(531 mg, 4.95 mmol) and Et3N (1.25 g, 12.37 mmol) in THF (36
ml). The reaction mixture was stirred at RT for 20 h to give, on
work-up, the amino acetate 11b (770 mg, 76%); δH (400 MHz;
CDCl3) 1.45–1.64 (2 H, m, CH2), 1.99–2.19 (2 H, m, CH2), 2.04
(3 H, s, COCH3), 2.58 (1 H, br s, NH), 3.27–3.33 (1 H, m,
CHNHBn), 3.83, 3.86 (2 H, AB-system, JAB 13.2, PhCH2NH),
5.28–5.34 (1 H, m, CHOAc), 5.72 (1 H, dddd, J 10.4, 3.2, 2.0,
1.2, olefinic, CHCHOAc), 5.93 (1 H, dddd, J 10.4, 2.8, 1.6, 1.2,
olefinic, CHCHN) and 7.20–7.45 (5 H, m, Ph); δC(100.6 MHz;
CDCl3, 13 peaks) 21.2 (COCH3), 26.9 (CH2CHOAc), 27.3
(CH2CHN), 50.6 (CH2Ph), 52.2 (CHN), 69.1 (CHOAc), 127.0
(CH, Ph), 127.9 (olefinic, CHCHOAc), 128.1 (CH, Ph), 128.4
(CH, Ph), 133.8 (olefinic, CHCHN), 139.8 (C, Ph) and 170.6
(B) Synthesis of the trans-4-aminocyclohex-2-enols
(±)-trans-1-Acetoxy-4-diethylaminocyclohex-2-ene 11a. The
general procedure described for 10b was used but 25 mol% of
LiCl was added to the reaction mixture together with the cata-
lyst, phosphine and amine. Allylic substrate 9 (131 mg, 0.750
mmol), Pd(dba)2 (22 mg, 0.037 mmol), PPh3 (40 mg, 0.153
mmol), LiCl (8 mg, 0.189 mmol), HNEt2 (165 mg, 2.26 mmol)
in THF (7.5 ml) for 20 h yielded 11a (113 mg, 71%); δH (300
MHz; CDCl3) 1.04 (6 H, app t, J 7.2, CH3), 1.41–1.61 (2 H, m,
CH2), 1.81–1.91 (1 H, m, CH2), 2.04 (3 H, s, COCH3), 2.11–2.20
(1 H, m, CH2), 2.34–2.61 (4 H, m, NCH2), 3.40–3.53 (1 H, m,
CHNEt2), 5.26–5.38 (1 H, m, CHOAc), 5.64–5.73 (1 H, m,
olefinic) and 5.76–5.85 (1 H, m, olefinic); δC(100.6 MHz;
CDCl3, 10 peaks) 14.2 (NCH2CH3), 21.2 (CH3CO2), 22.3
(CH2CHN), 28.2 (CH2CHOAc), 44.1 (NCH2), 56.4 (CHN),
70.1 (CHOAc), 129.2 (olefinic, CHCHN), 134.8 (olefinic,
(C᎐O); m/z (LC prior to ES-MS) 246 ([M + H]+, 100%), 139
᎐
(54%), 108 (3%), 79 (5%) and 61 (6%).
Spectroscopic data for the corresponding γ-product to 11b:
(±)-trans-4-acetoxy-3-benzylaminocyclohexene; δH (400 MHz;
CDCl3) 1.65–2.05 (3 H, br s and two m overlapping, CH2, NH),
2.10–2.19 (2 H, m, CH2), 3.25–3.33 (1 H, m, CHNH), 3.83, 3.88
(2 H, AB-system, JAB 13.3, PhCH2NH), 4.99 (1 H, ddd, J 8.9,
6.3 and 3.1, CHOAc), 5.62–5.69 (1 H, m, olefinic), 5.76–5.84
(1 H, m, olefinic) and 7.18–7.38 (5 H, m, aromatic); δC(100.6
MHz; CDCl3, 13 peaks) 21.4, 23.2, 25.2, 50.5, 56.5, 72.6, 126.9,
127.1, 128.1, 128.3, 128.8, 140.6 and 170.8.
trans-(1S,4S)-1-Acetoxy-4-benzylaminocyclohex-2-ene
(1S,4S)-11b. The same procedure was used as for racemic 11b
but starting from (Ϫ)-9. Spectral data are in accordance with
the racemate.
CHCHOAc) and 170.8 (C᎐O); m/z (LC prior to ES-MS) 212
᎐
([M + H]+, 82%), 139 (66%), 79 (7%), 61 (13%) and 60 (100%).
Spectroscopic data for the corresponding γ-product to 11a.
(±)-trans-4-Acetoxy-3-diethylaminocyclohexene; δH (400 MHz;
CDCl3) 1.01 (6 H, app t, J 7.1, CH3), 1.56–1.75 (2 H, m, CH2),
1.86–1.96 (1 H, m, CH2), 2.04 (3 H, s, COCH3), 2.07–2.20 (1 H,
m, CH2), 2.53 (4 H, app q, NCH2), 3.36–3.43 (1 H, m,
CHNEt2), 5.00 (1 H, ddd, J 11.1, 7.7, 3.6, CHOAc), 5.53–5.60
(1 H, m, olefinic) and 5.74–5.82 (1 H, m, olefinic); δC(100.6
MHz; CDCl3, 10 peaks) 14.5, 21.5, 24.0, 27.6, 44.4, 60.4, 70.9,
127.7, 128.9 and 170.6.
trans-(1R,4R)-1-Acetoxy-4-benzylaminocyclohex-2-ene
(1R,4R)-11b. The same procedure was used as for racemic 11b
but starting from (+)-9. Spectral data are in accordance with
the racemate.
(±)-trans-4-Benzylaminocyclohex-2-enol 7b. The title com-
pound was prepared from amino acetate 11b using the same
hydrolysis conditions as for 6a in 98% yield; δH (400 MHz;
CDCl3) 1.36–1.51 (2 H, m, CH2), 1.57–1.68 (2 H, br s, NH and
OH), 2.03–2.15 (2 H, m, CH2), 3.24–3.28 (1 H, m, CHNH),
3.82, 3.85 (2 H, AB-system, JAB 13.0, PhCH2NH), 4.23–4.26
(1 H, m, CHOH), 5.75–5.83 (2 H, m, olefinic) and 7.22–7.34
(5 H, m, Ph); δC(100.6 MHz; CDCl3, 11 peaks) 27.9 (CH2), 31.2
(CH2), 50.8 (CH2Ph), 52.7 (CHN), 66.8 (CHOH), 127.1 (CH,
Ph), 128.2 (CH, Ph), 128.5 (CH, Ph), 132.0 (CH, olefinic), 132.1
(CH, olefinic) and 140.1 (C, Ph).
trans-(1S,4S)-1-Acetoxy-4-diethylaminocyclohex-2-ene
(1S,4S)-11a. The same procedure was used as for racemic 11a
but starting from (Ϫ)-9. Spectral data are in accordance with
the racemate.
trans-(1R,4R)-1-Acetoxy-4-diethylaminocyclohex-2-ene
(1R,4R)-11a. The same procedure was used as for racemic 11a
but starting from (+)-9. Spectral data are in accordance with
the racemate.
(Ϫ)-trans-(1S,4S)-4-Benzylaminocyclohex-2-enol
(Ϫ)-
(±)-trans-4-Diethylaminocyclohex-2-enol 7a. This substance
was prepared from amino acetate 11a using the same hydrolysis
conditions as for 6a in 96% yield; δH (300 MHz; CDCl3) 1.01
(6 H, app t, CH3), 1.32–1.53 (2 H, m, 6-H), 1.76–1.89 (1 H, m,
5-H), 2.06–2.18 (1 H, m, 5-H), 2.31–2.59 (4 H, m, NCH2), 2.60–
2.80 (1 H, br s, OH), 3.37–3.47 (1 H, m, 1-H), 4.16–4.28 (1 H, m,
4-H) and 5.63–5.79 (2 H, m, 5-H and 6-H); δC(100.6 MHz;
CDCl3, 8 peaks) 14.1 (CH3), 22.4 (CH2), 32.5 (CH2), 44.1
(NCH2), 56.6 (CHNEt2), 67.3 (CHOAc), 132.4 (CH, olefinic),
133.6 (CH, olefinic); m/z (LC prior to ES-MS) 170 ([M + H]+,
100%); νmax/cmϪ1 3331 (OH, br), 2968, 2935, 2864, 1451, 1384
and 1065.
(1S,4S)-7b. Preparation as for (±)-7b but with (1S,4S)-11b as
the substrate. Same spectral data as for (±)-7b; [α]D25 Ϫ122
(c 1.773 in EtOH); ee ≥98%.
(+)-trans-(1R,4R)-4-Benzylaminocyclohex-2-enol
(+)-
(1R,4R)-7b. Preparation as for (±)-7b but with (1R,4R)-11b as
the substrate. Same spectral data as for (±)-7b; [α]D25 +120
(c 1.394 in EtOH); ee ≥98%.
(C) Synthesis of the allylic substrates
(±)-cis-4-Acetoxycyclohex-2-enol (±)-2a. 1,4-Diacetoxycyclo-
hex-2-ene6 (17.39 g, 87.72 mmol) and K2CO3 (606 mg, 4.39
mmol) were dissolved in methanol–water (4:1; 150 ml) and the
J. Chem. Soc., Perkin Trans. 1, 1997
581

View Article Online
solution stirred at RT for 40 min. It was then neutralised with
1  aq. HCl and the methanol was removed in vacuo. The aque-
ous phase was saturated with NaCl and extracted with EtOAc
and the extract was dried (MgSO4) and concentrated. The resi-
due was separated on silica (gradient EtOAc–pentane) to give
2a (8.118 g, 59%). The spectral data were consistent with those
previously reported.4
(Ϫ)-cis-(1R,4S)-4-Acetoxycyclohex-2-enol (Ϫ)-(1R,4S)-2a.
Preparation according to ref. 4.
cis-1-Acetoxy-4-chlorocyclohex-2-ene 8. The preparation was
carried out as in ref. 5 and the spectral data were in accord with
those reported therein.
(±)-trans-1-Acetoxy-4-chlorocyclohex-2-ene 9. To N-chloro-
succinimide (806 mg, 6.04 mmol) in THF (7 ml) under nitrogen
was added a solution of PPh3 (1.575 g, 6.01 mmol) in THF (7
ml). A slightly exothermic reaction ensued. After the reaction
mixture had cooled to room temperature the alcohol 2a (632
mg, 4.047 mmol) dissolved in THF (6 ml) was added to it; the
mixture was then stirred at room temperature for 15 h. The
solvent was removed and the residue was dissolved in a small
amount of CH2Cl2 and purified on silica (diethyl ether–pentane,
5:95) to give the title compound 9 (684 mg, 97%). About 4% of
the corresponding SN 2Ј-product was formed in the reaction.
Spectral data for 9 were in accord with those reported in
ref. 5.
methylene dichloride (50 ml) was stirred at RT for 3 h. Diethyl
ether (50 ml) was added to the reaction mixture which was then
washed with cold 5% aq. HCl (2 × 25 ml) and saturated aque-
ous NaHCO3 (3 × 25 ml), dried (MgSO4) and concentrated. The
crude product was filtered through basic alumina and purified
on silica using MPLC (EtOAc–CH2Cl2, 1:1, gradient in pen-
tane) to give the title compound 17 (1.61 g, 80%); δH (300 MHz;
CDCl3) 1.90–2.06 (4 H, m, 2 × CH2), 2.07 (3 H, s, COCH3),
5.23–5.33 (1 H, m, CHOAc), 5.39–5.51 [1 H, m, CHOC(O)Ar],
5.94–6.05 (2 H, m, olefinic), 7.29 (1 H, dd, J 8.4 and 2.0, ArH),
7.47 (1 H, d, J 2.0, ArH) and 7.79 (1 H, d, J 8.4, ArH);
δC(100.6 MHz; CDCl3, 15 peaks) 21.1 (CH3CO2), 24.8 (CH2),
25.0 (CH2), 67.4 (CHOAc), 68.6 [CHOC(O)Ar], 126.9
(aromatic, CHCHCCl), 128.4 (aromatic, C), 129.3 [olefinic,
CHCHOC(O)Ar], 130.9 (aromatic, CClCHCCl), 131.2 (olefin-
ic, CHCHOAc), 132.4 (aromatic, CCHCH), 134.8 (aromatic,
C), 138.2 (aromatic, C), 164.2 (C᎐O) and 170.4 (C᎐O); m/z 273
᎐
᎐
(0.6%), 271 (5%), 269 (7%), 177 (12%), 175 (65%), 173 (100%),
149 (2%), 147 (8%), 145 (12%), 139 (12%), 96 (43%) and 79
(26%); [α]D25 +56 (c 1.16 in EtOH).
(+)-cis-(1S,4R)-4-(Tetrahydropyran-2-yloxy)cyclohex-2-enol
(+)-(1S,4R)-18a. To (Ϫ)-2a (535 mg, 3.38 mmol) dissolved in
methylene dichloride (30 ml) was added dihydropyran (DHP)
(425 mg, 5.05 mmol) and pyridinium toluene-p-sulfonate
(PPTS) (85 mg, 0.338 mmol). The solution was stirred at RT
for 4 h, after which it was diluted with diethyl ether (100 ml),
washed with brine–water (1:1; 20 ml) and concentrated.
The resulting crude product was dissolved in methanol (5 ml)
and treated with K2CO3 (23 mg, 0.17 mmol) in water (1 ml).
After being stirred at RT for 5 h the reaction mixture was
diluted with water (10 ml) and then concentrated by evapor-
ation of most of the methanol. The aqueous phase was
extracted with diethyl ether (3 × 50 ml) and the combined
organic fractions were then washed with brine (20 ml), dried
(MgSO4) and concentrated. Purification of the residue on sil-
ica (diethyl ether–pentane, 60:40) gave the title compound 18a
(650 mg, 98%) (Found: C, 65.9; H, 8.8. Calc. for C11H18O3: C,
66.6; H, 9.15%); δH (400 MHz; CDCl3) 1.48–1.94 (10 H, m, 5-
H, 6-H, 8-H, 9-H and 10-H), 3.45–3.54 (1 H, m, 11-H), 3.86–
3.97 (1 H, m, 11-H), 4.08–4.18 (2 H, m, 4-H and 7-H), 4.72–
4.78 (1 H, m, 1-H) and 5.88–5.91 (2 H, m, 2-H and 3-H);
δC(100.6 MHz; CDCl3) 19.5 (C-9), 24.3 and 26.2 (C-5), 25.3
and 25.4 (C-10), 28.1 and 28.5 (C-6), 30.9 and 31.0 (C-8), 62.4
and 62.5 (C-11), 65.1 and 65.2 (C-1), 68.9 and 70.0 (C-4), 96.8
and 97.8 (C-7), 130.1 and 131.3 (olefinic), 132.5 and 132.6
(olefinic); m/z (M+, >0.5%) 97 (51%), 85 (90%), 79 (63%), 67
(64%), 57 (65%) and 55 (100%); νmax/cmϪ1 3404 (OH, br),
2942, 2869, 1133, 1074, 1032 and 1000; [α]D25 +38.1 (c 0.91 in
CH2Cl2).
cis-4-Pivaloyloxycyclohex-2-enol 18b. To a solution of the
hydroxyacetate 2a (1.00 g, 6.402 mmol), Et3N (3.24 g, 32.01
mmol) and DMAP (22 mg, 0.180 mmol) in THF (25 ml) was
added pivaloyl chloride (1.58 ml, 12.81 mmol). The reaction
mixture was stirred at 50 ЊC for 24 h after which the solvent
was removed and ether (60 ml) was added to the residue.
The solution was washed with 1  hydrochloric acid (× 3),
sat’d aqueous NaHCO3 and brine, dried (MgSO4) and
concentrated. Separation of the residue on silica (diethyl
ether–pentane, 3:97 then 5:95) yielded cis-4-acetoxy-1-
pivaloyloxycyclohex-2-ene (1.485 g, 95%); δH (400 MHz;
CDCl3) 1.19 (9 H, s, But), 1.77–1.96 (4 H, m, CH2), 2.07 (3 H,
s, COCH3), 5.15–5.24 (2 H, m, CHOAc, CHOPiv) and 5.81–
5.91 (2 H, m, olefinic); δC(100.6 MHz; CDCl3, 11 peaks) 21.3,
24.8, 24.9, 27.1, 38.7, 66.9, 67.4, 130.0, 130.5, 170.5, 178.0.
Selective hydrolysis of the acetate (1.112 g, 4.627 mmol) was
performed with a 10% solution of Na2CO3ؒ10 H2O (133 mg,
0.465 mmol) in MeOH–H2O (4:1, 23 ml) at RT for 9 h. After
removal of the methanol from the mixture it was extracted
with ether and the extract dried (Na2SO4) and concentrated to
give the title compound 18b (839 mg, 92%); δH (400 MHz;
(Ϫ)-trans-(1S,4S)-1-Acetoxy-4-chlorocyclohex-2-ene
(Ϫ)-
(1S,4S)-9. This compound was prepared in the same way as
for the racemic compound 9 starting from (Ϫ)-2a. [α]D25 Ϫ395
(c 1.01 in EtOH); 2.5% of the SN 2Ј-product contaminated the
product.
(+)-trans-(1R,4R)-1-Acetoxy-4-chlorocyclohex-2-ene
(+)-
(1R,4R)-9. To a solution of compound 20c (594 mg, 2.406
mmol) in THF (15 ml) was added tetrabutylammonium fluor-
ide (TBAF) (1  soln. in THF, 2.53 ml, 2.53 mmol) at room
temperature. After 3 h, acetic anhydride (2.3 ml, 24.4 mmol)
was added to the reaction mixture which was then stirred for an
additional 12 h. It was then evaporated and the residue was
separated on silica (gradient ether–pentane 5:95–15:85) to give
the title compound (+)-9 (347 mg, 83%). Spectral data were in
accord with those reported in ref. 5; [α]D25 +415 (c 0.89 in
EtOH).
cis-(1R,4S)-4-Acetoxycyclohex-2-enyl
diphenylphosphinate
(1R,4S)-16. The title compound was synthesized from the
alcohol (Ϫ)-2a (1.00 g, 6.32 mmol) according to procedure A
reported in ref. 14 (reaction time 30 h) except that in the
aqueous work-up the organic extract was washed with
saturated copper sulfate (3×), water (1×) and brine (1×) before
being dried (MgSO4). After evaporation of the extract the crude
product was filtered through basic alumina eluting with diethyl
ether. Removal of the ether afforded a colourless oil of the title
compound 16 (2.02 g, 89%) which was sufficiently pure for the
next step; δH (400 MHz; CDCl3) 1.80–1.94 (3 H, m, CH2), 2.01–
2.06 (1 H, m, CH2), 2.06 (3 H, s COCH3), 4.84–4.91 [1 H, m,
CHOP(O)Ph2], 5.15–5.20 (1 H, m, CHOAc), 5.83–5.96 (2 H, m,
olefinic), 7.44 (4 H, o-Ph), 7.51 (2 H, m, p-Ph), 7.82 (4 H, tdd,
2JH P 12.6, JH H 8.2, 1.4, o-Ph); δC(100.6 MHz; CDCl3, 13 peaks)
3
21.1 (CH3CO2), 24.6 (CH2CHOAc), 26.9 (d, JCP 3.8,
CH2CHOP), 67.0 (CHOAc), 69.0 (d, 2JCP 6.0, CHOP), 128.4 (d,
3JCP 12.2, aromatic, CH), 129.9 (olefinic, CHCHOAc), 131.5 (d,
2JCP 17.5, aromatic, CH), 131.5 (d, 3JCP 3.0, olefinic, CHCHOP),
1
4
131.87 (d, JCP 136.6, aromatic, C), 131.92 (d, JCP 137.3,
aromatic, C), 132.1 (d, 4JCP 1.5, aromatic, CH) and 170.2 (C᎐O);
᎐
m/z (NH4CO2 added prior to ES-MS) 379 ([M + Na]+, 5%), 374
([M + NH4]+, 4%), 357 ([M + H]+, 50%), 297 (3%), 219 (11%),
139 (100%) and 79 (6%).
cis-(1R,4S)-4-Acetoxycyclohex-2-enyl 2,4-dichlorobenzoate
(1R,4S)-17. A solution of cis-4-acetoxycyclohex-2-enol (Ϫ)-2a
(953 mg, 6.10 mmol), 2,4-dichlorobenzoic acid (1.72 g, 9.00
mmol), dicyclohexylcarbodiimide (DCC) (1.86 g, 9.01 mmol)
and p-dimethylaminopyridine (DMAP) (16 mg, 0.13 mmol) in
582
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
CDCl3) 1.18 (9 H, s, But), 1.62–1.98 (5 H, m, CH2, OH), 4.14–
4.26 (1 H, m, CHOH), 5.10–5.24 (1 H, m, CHOPiv), 5.73–5.84
(1 H, m, olefinic) and 5.90–6.00 (1 H, m, olefinic); δC(100.6
MHz; CDCl3, 9 peaks) 24.9 (C-5), 27.1 (C-9), 28.1 (C-6), 38.7
(C-8), 65.3 (C-1), 66.9 (C-4), 128.0 (C-3), 134.5 (C-2) and
178.1 (C-7); m/z 180 (2%), 113 (3%), 97 (23%), 96 (67%), 95
(14%), 85 (21%), 79 (21%) and 57 (100%).
cis-(1S,4R)-4-(tert-Butyldimethylsilyloxy)cyclohex-2-enol
(1S,4R)-18c. To a stirred solution of 21c (3.256 g, 12.039 mmol)
was added KOH (135 mg, 2.408 mmol) in methanol (40 ml).
The reaction mixture was stirred at RT for 4 h after which the
solvent was removed and the residue was treated with water (30
ml) and diethyl ether (60 ml); the layers were separated and the
pH of the aqueous layer was adjusted to 7 with 1  hydro-
chloric acid; it was then further extracted with ether. The com-
bined organic extracts were dried (MgSO4) and concentrated in
vacuo to give the product (2.698 g, 98%) which was pure enough
for the next step; δH (400 MHz; CDCl3) 0.073 (3 H, s, SiCH3),
0.076 (3 H, s, SiCH3), 0.89 [9 H, s, SiC(CH3)3], 1.60–1.90 (5 H,
m, 2 × CH2, OH), 4.06–4.18 (2 H, two overlapping m, CHOH,
CHOSi), 5.75 (1 H, dd, J 10.2 and 2.4, olefinic) and 5.79 (1 H,
dd, J 10.2 and 3.1, olefinic); δC(100.6 MHz; CDCl3, 10
peaks) Ϫ4.7 (C-7), Ϫ4.6 (C-7Ј), 18.1 (C-8), 25.8 (C-9), 28.2
(C-5), 28.4 (C-6), 64.8 (C-1), 66.3 (C-4), 130.7 (C-2) and 133.9
(C-3); [α]D25 +34 (c 1.58 in EtOH).
cis-(1S,4R)-4-(Tetrahydropyran-2-yloxy)cyclohex-2-enyl 2,4-
dichlorobenzoate (1S,4R)-19. A solution of DCC (1.297 g, 6.285
mmol) and DMAP (13 mg, 0.105 mmol) in methylene dichlo-
ride (10 ml) was added to a stirred solution of 18a (1.246 g,
6.285 mmol) and 2,4-dichlorobenzoic acid (1.200 g, 6.285
mmol) in methylene dichloride (25 ml) at RT. The solution was
stirred at RT for 10 h, after which it was diluted with diethyl
ether (300 ml). The organic phase was washed with 5% aqueous
acetic acid (50 ml), water (20 ml) and brine (20 ml), dried
(MgSO4) and concentrated. Purification of the residue on silica
(diethylether–pentane, 60:40)gavethetitlecompound 19(2.20g,
87%); δH (400 MHz; CDCl3) 1.43–2.07 (10 H, m, 5-H, 6-H, 8-H,
9-H and 10-H), 3.47–3.54 (1 H, m, 11-H), 3.86–3.94 (1 H, m,
11-H), 4.15–4.27 (1 H, two overlapping m, 4-H), 4.73–4.78 (1
H, m, 7-H), 5.39–5.45 (1 H, m, 1-H), 5.89–5.95 (1 H, m, 3-H)
and 6.01–6.09 (1 H, m, 2-H); δC(100.6 MHz; CDCl3) 19.5 and
19.6 (CH2), 24.4 and 26.3 (CH2), 25.2 and 25.4 (CH2), 25.5 and
26.1 (CH2), 30.9 and 31.0 (CH2), 62.5 and 62.6 (CH2), 68.7 and
68.8 [allyl-CHOC(O)Ar], 69.3 and 70.4 (allyl-CHOTHP), 97.0
and 98.1 (THP-OCHO), 126.9 (aromatic, CH), 127.0 and
127.1 [olefinic, CHCHOC(O)Ar], 128.5 (aromatic, C), 130.9
(aromatic, CH), 132.5 (aromatic, CH), 133.8 and 134.9 (olefinic,
CHCHOTHP), 135.8 (aromatic, C), 138.1 (aromatic, C) and
added to a solution of N-chlorosuccinimide (426 mg, 3.19 mmol)
in THF (5 ml) to give slightly exothermic phosphonium salt
formation. After cooling of the reaction mixture to RT
(20 min), 18b (416 mg, 2.098 mmol) in THF (3 ml) was added to
it; it was then stored at RT for 24 h. After this, the solvent was
evaporated from the mixture and pentane was added to the
residue. The precipitated triphenylphosphine oxide and suc-
cinimide were filtered off and the pentane was removed in vacuo
to give a residue which was purified on silica (EtOAc–pentane,
1:99). This afforded 20b (305 mg, 67%) (8% of the reaction
product was derived from the SN 2Ј substitution mechanism);
δH (400 MHz; CDCl3) 1.17 (9 H, s, But), 1.68–1.78 (1 H, m,
CH2), 1.94–2.04 (1 H, m, CH2), 2.12–2.32 (2 H, m, CH2), 4.57–
4.64 (1 H, m, CHCl), 5.20–5.28 (1 H, m, CHOPiv), 5.82–5.89
(1 H, m, olefinic) and 5.98–6.04 (1 H, m, olefinic); δC(100.6
MHz; CDCl3, 9 peaks) 24.8 (CH2), 27.1 (CH3), 28.7 (CH2), 38.7
(C), 53.6 (CHCl), 65.7 (CHOPiv), 128.3 (olefinic, CH), 132.3
(olefinic, CH) and 177.8 (C᎐O).
᎐
trans-(1R,4R)-1-Chloro-4-(tert-butyldimethylsilyloxy)cyclo-
hex-2-ene (1R,4R)-20c. To compound 18c (1.503 g, 6.58 mmol)
was added LiCl (558 mg, 13.16 mmol) and Et3N (2.75 ml, 19.74
mmol) in CH2Cl2 (25 ml). The solution was cooled to Ϫ20 ЊC
and MsCl (610 µl, 7.881 mmol) was added to it via a syringe.
The mixture was brought to RT over 3 h after which it was
stirred for a further 17 h. It was then diluted with water–
NaHCO3 (sat’d) (1:1; 30 ml) and the phases were separated.
The aqueous phase was extracted with diethyl ether (3 × 70 ml).
The combined organic phases were washed with brine (20 ml),
dried (MgSO4) and passed through a silica column packed
with Et3N–diethyl ether–pentane (4:2:94). Elution with diethyl
ether–pentane (2:98 then 5:95) gave the title compound 20c
(1.484 g, 91%); δH (400 MHz; CDCl3) 0.08 (6 H, s, SiCH3 × 2),
0.89 [9 H, s, SiC(CH3)3], 1.60–1.67 (1 H, m, CH2), 1.84–1.93 (1
H, m, CH2), 2.02–2.11 (1 H, m, CH2), 2.29–2.37 (1 H, m, CH2),
4.23–4.27 (1 H, m, CHOSi), 4.56–4.60 (1 H, m, CHCl), 5.77 (1
H, dd, J 10.4 and 3.1, olefinic) and 5.82 (1 H, dd, J 10.4 and 3.2,
olefinic); δC(100.6 MHz; CDCl3, 10 peaks) Ϫ4.7 (C-7), Ϫ4.6
(C-7Ј), 18.2 (C-8), 25.8 (C-9), 29.7 (C-6), 29.9 (C-5), 54.9 (C-1),
64.9 (C-4), 129.5 (C-2) and 133.5 (C-3); m/z 248 (1%), 246 (2%),
191 (24%), 189 (64%), 93 (18%), 77 (15%) and 75 (100%);
[α]D25 +259 (c 1.75 in EtOH).
cis-(1S,4R)-1-Acetoxy-4-(tert-butyldimethylsilyloxy)cyclo-
hex-2-ene (1S,4R)-21c. A solution of TBDMS-Cl (2.665 g, 17.68
mmol) in methylene dichloride (40 ml) was cooled to 0 ЊC and
imidazole (6.74 g, 99.0 mmol) was added to it. After 5 min (Ϫ)-
2a (2.209 g, 14.14 mmol) dissolved in methylene dichloride (30
ml) was added to the mixture which was then stirred at 0 ЊC for
ca. 30 min and then at RT for 20 h. After being quenched with
water (10 ml), the reaction mixture was extracted with meth-
ylene dichloride (3 × 50 ml). The combined organic fractions
were washed with brine (20 ml), dried (Na2SO4), concentrated
and subjected to chromatography (diethyl ether–pentane 5:95)
to give the title compound 21c (3.79 g, 99%); δH (400 MHz;
CDCl3) 0.078 (3 H, s, SiCH3), 0.082 (3 H, s, SiCH3), 0.90 [9 H, s,
SiC(CH3)3], 1.65–1.95 (4 H, m, 2 × CH2), 2.04 (3 H, s, COCH3),
4.15–4.19 (1 H, m, CHOSi), 5.13–5.17 (1 H, m, CHOAc),
5.71–5.75 (1 H, m, olefinic) and 5.85–5.88 (1 H, m, olefinic);
δC(100.6 MHz; CDCl3) Ϫ4.7 (SiCH3), Ϫ4.6 (SiCH3), 18.1 (SiC),
21.2 (COCH3), 25.3 (CH2CHOAc), 25.8 [SiC(CH3)3], 28.4
(CH2CHOSi), 66.3 (CHOSi), 67.0 (CHOAc), 126.2 (olefinic,
164.2 (C᎐O); m/z 273 (19%), 271 (29%), 194 (6%), 192 (61%),
᎐
190 (81%), 177 (12%), 175 (68%), 173 (100%), 147 (12%) and
145 (28%).
trans-1-Chloro-4-(tetrahydropyran-2-yloxy)cyclohex-2-ene
20a. A solution of 18a (100 mg, 0.504 mmol), LiCl (46 mg,
1.08 mmol) and 2,4,6-trimethylpyridine (504 µl, 3.78 mmol) in
DMF (750 µl) was cooled to 0 ЊC and treated with MsCl (58 µl,
0.83 mmol) followed after 20 min by diethyl ether (40 ml).
The solution was washed with water (5 ml) and brine (5 ml),
dried (MgSO4) and concentrated. The residue was purified on
silica (diethyl ether–pentane, 40:60) to give the title com-
pound 20a (98 mg, 90%). Since the product is extremely
unstable it should be prepared directly before further use;
δH (400 MHz; CDCl3) 1.40–2.40 (10 H, m, 5-H, 6-H, 8-H, 9-H,
10-H), 3.43–3.58 (1 H, m, 11-H), 3.83–3.98 (1 H, m, 11-H),
4.16–4.30 (1 H, m, 4-H), 4.54–4.65 (1 H, m, 7-H), 4.66–4.80
(1 H, m, 1-H) and 5.82–6.03 (2 H, m, olefinic); δC(100.6 MHz;
CDCl3) 19.7, 25.4, 25.4, 25.5, 27.5, 29.3, 29.7, 29.8, 31.1, 31.1,
54.6, 54.6, 62.6, 62.7, 68.3, 69.0, 97.3, 98.1, 130.4, 130.6, 131.1
and 131.7.
CHCHOAc), 136.3 (olefinic, CHCHOSi) and 170.6 (C᎐O); m/
᎐
z 210 (2%), 117 (100%), 79 (12%) and 75 (33%); [α]D25 Ϫ40 (c 1.63
in EtOH).
Acknowledgements
Financial support from the Swedish Natural Science Research
Council, The Research Council of the Board of Technical
Development and the Swedish Research Council for Engineer-
ing Sciences is gratefully acknowledged.
trans-1-Chloro-4-pivaloyloxycyclohex-2-ene 20b. Triphenyl-
phosphine (836 mg, 3.19 mmol) dissolved in THF (3 ml) was
J. Chem. Soc., Perkin Trans. 1, 1997
583

View Article Online
J. E. Nyström, Tetrahedron Lett., 1983, 24, 2745; (g) R. E. Nordberg
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Paper 6/00779A
Received 1st February 1996
Accepted 7th October 1996
584
J. Chem. Soc., Perkin Trans. 1, 1997