Novel methods for the synthesis of 5-substituted-3-carboxy-2,5- and 4,5-dihydrothiophenes and 5-substituted 2- and 3-sulfolenes

Article abstract of DOI:10.1016/j.tet.2006.11.061

Various approaches to the syntheses of 5-substituted-3-carbomethoxy-2,5-dihydrothiophenes and their product sulfolenes, required as synthetic precursors for tangutorine, are described. An efficient route to 3,5-disubstituted-4,5-dihydrothiophenes and henc

Full text of DOI:10.1016/j.tet.2006.11.061

Tetrahedron 63 (2007) 1065–1073
Novel methods for the synthesis of 5-substituted-3-carboxy-2,5-
and 4,5-dihydrothiophenes and 5-substituted 2- and 3-sulfolenes
a
a
b
James A. Wilkinson,a, Nicolas Ardes-Guisot, Sylvie Ducki and John Leonard
*
aCentre for Drug Design, Biosciences Research Institute, Cockcroft Building, University of Salford, Salford M5 4WT, UK
bAstraZeneca Process R+D, Silk Road, Macclesfield, Cheshire SK10 2NG, UK
Received 22 September 2006; revised 8 November 2006; accepted 23 November 2006
Available online 13 December 2006
Abstract—Various approaches to the syntheses of 5-substituted-3-carbomethoxy-2,5-dihydrothiophenes and their product sulfolenes,
required as synthetic precursors for tangutorine, are described. An efficient route to 3,5-disubstituted-4,5-dihydrothiophenes and hence
3,5-disubstituted-2-sulfolenes by radical chemistry is also described.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
corresponding dihydrothiophenes makes use of a conjugate
addition/Claisen reaction protocol.
Dihydrothiophenes are highly useful as synthetic intermedi-
ates for a wide range of purposes, containing both a sulfur
atom and a reactive double bond. 2,3-Dihydrothiophenes
have been used as intermediates in the synthesis of thio-
nucleosides and penicillin analogues while 2,5-dihydro-
thiophenes have shown considerable potential as antivirals.1
2. Results and discussion
2.1. Synthesis of 5-substituted-3-carboxy-2,5-dihydro-
thiophenes and their 1,1-dioxides
Sulfolenes, the oxidation products of dihydrothiophenes,
have found application in synthesis as masked diene precur-
sors for Diels Alder reactions. Both 2- and 3-sulfolenes can
be converted to 1,3-dienes with predictable double bond
geometry.2
Approaches to the synthesis of 3-carboxy-2,5-dihydrothio-
phenes generally involve formation of the double bond by
phosphorus chemistry.5 5-Substituted 3-carboxy examples
in the literature are rare since direct alkylation of the readily
available 3-carboxy-2,5-dihydrothiophenes and 1,1-dioxy
derivatives to give 5-substitution is impossible.6 The
5-carboxymethyl derivative is known via intramolecular
conjugate addition of a thiol and the 5-ethyl compound has
been made by McIntosh and Sieler.7 The 5-trifluoro-
methyl-3-cyano-2,5-dihydrothiophene has been made by
addition of cyanide to a ketone followed by elimination.8
Our group has an interest in the total synthesis of the bioac-
tive alkaloid tangutorine.3 Our approach via intramolecular
Diels Alder reaction required either a 2 or 3-sulfolene (1
or 2, respectively) as a masked diene precursor (Scheme 1).4
Here we describe novel chemistry leading to syntheses of
compounds of the form 1 and 2. The approach to 2-sulfo-
lenes 1 via 4,5-dihydrothiophenes utilises radical chemistry,
while the successful synthesis of 3-sulfolenes 2 and their
Our first target was compound 3, a 5-substituted-3-carboxy-
2,5-dihydrothiophene. Initially an approach based on an
intramolecular Dieckmann cyclisation was investigated
MeO2C
MeO2C
H
N
N
H
H
OR
OPG
OPG
OH
S
S
O2
H
O2
1
2
see ref 4
Tangutorine
Scheme 1.
Keywords: Sulfolene; Dihydrothiophene; Xanthate radical transfer.
* Corresponding author. Tel.: +44 161 295 4046; fax: +44 161 295 5111; e-mail: j.a.wilkinson@salford.ac.uk
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.11.061

1066
J. A. Wilkinson et al. / Tetrahedron 63 (2007) 1065–1073
R'O2C
O
CO2H
CO2R
b
see ref 10
OBn
OBn
OBn
HO2C
Cl
S
5 R = H
6 R = Me
4a R' = Et
4b R' = Me
a
c
RO2C
RO2C
OH
OBn
OBn
S
S
3
Scheme 2. Reagents and conditions: (a) MeOH, SOCl2, 0 ꢀC, then rt, 16 h, 80%; (b) (i) MeO2CCH2CH2SH, NaH, Et2O/DMF, 0 ꢀC, then rt, 18 h, 64%; (ii)
NaOMe, toluene, 0 ꢀC, then reflux 3 h, 44%; (c) NaBH4 or LiBH4 or NaCNBH3, various solvents and temperatures.
since Cheney’s group had shown previously that this
approach could be used to form the keto-ester 4a by chlori-
nation of a known malonic acid derivative to give 5 after
decarboxylation, substitution with a thiol and intramolecular
Dieckmann cyclisation.9 This route was followed from the
methyl ester 6 giving, in our hands, a moderate overall yield
of b-keto ester 4b (Scheme 2). The seemingly simple reduc-
tion to the corresponding hydroxy ketone could not be
realised in acceptable yield under any of the conditions
attempted. The enol form of 4b predominated in a ratio of
around 1.7:1 and it is likely that basic reducing agents
such as borohydride would simply form an enolate but
sodium cyanoborohydride at lower pH was equally unsuc-
cessful. As a result, a variation on this theme was adopted,
using an intramolecular Claisen reaction.
conditions resulted in complex mixtures of products from
which neither 7, cyclisation product nor any derivatives
could be isolated.
It was clear that an aldehyde in the side chain could not be
supported and would need to be masked for the Claisen route
to succeed. This entailed the synthesis of 12 with a protected
hydroxy function (Scheme 4). The methyl ester 6 was re-
acted with thioacetic acid to give 11. This was fully reduced,
used in a conjugate addition to methyl acrylate and then
selectively oxidised to the aldehyde 12. This cyclised to
a mixture of hydroxy acids 13, which were not isolated but
used directly. The concomitant saponification of the ester
was disappointing since it later had to be replaced but adjust-
ment of the conditions failed to suppress this side-reaction.
Mesylation, elimination and re-esterification provided the
desired dihydrothiophene 3 in an overall yield of 34%
from the aldehyde. This is the first time an intramolecular
Claisen approach has been used to prepare 5-substituted-3-
carboxy-2,5-dihydrothiophenes and though the overall route
is long it is reasonably efficient. S-oxidation proceeded in
acceptable yield with Oxone to give 14. To the best of our
Our first route via an intramolecular Claisen reaction was
based on the cyclisation of a dialdehyde 7 to give hydroxy
ester 10 directly. Cyclopentadiene was reacted with
methyl-3-mercaptopropionate in the presence of ethyl
aluminium dichloride to give the sulfide 8 (Scheme 3).10
Ozonolysis of 8, or its S-oxidation product 9, under various
O
c
a
MeO2C
O
MeO2C
X
X
CO2Me
HS
7
8 X = S
b
9 X = SO2
MeO2C
OH
O
X
10
Scheme 3. Reagents and conditions: (a) EtAlCl2, toluene, rt, 36 h, 68%; (b) Oxone, water, 0 ꢀC, 1 h, 92%; (c) O3, various solvents and work-up procedures
or NaIO4, various solvents and temperatures.
O
CO2Me
MeO2C
CO2Me
b
a
MeO2C
OBn
OBn
OBn
OBn
S
AcS
e
Cl
6
11
12
c
MeO2C
HO2C
OH
d
OBn
OBn
S
S
S
O2
14
3
13
Scheme 4. Reagents and conditions: (a) NaH, AcSH, Et2O/DMF, 0 ꢀC–rt, 20 h, 82%; (b) (i) LiAlH4, Et2O, 0 ꢀC, 1 h, 88%; (ii) methyl acrylate, NEt3, rt, 18 h,
87%; (iii) oxalyl chloride, NEt3, DMSO, CH2Cl2, ꢁ50 ꢀC–rt, 1 h, 93%; (c) NaOMe, toluene, 0 ꢀC, then reflux, 2 h; (d) (i) MsCl, NEt3, CH2Cl2, 0 ꢀC, 1 h; (ii)
2 M HCl; (iii) SOCl2, MeOH, rt, 1 h, 34% over four steps; (e) Oxone, MeOH, 0 ꢀC, 30 min, 55%.

J. A. Wilkinson et al. / Tetrahedron 63 (2007) 1065–1073
1067
knowledge this is the first 5-substituted-3-carboxy-3-sulfo-
lene to be synthesised.11
corresponding nitrile to 22, was also undertaken (Scheme 6).
While synthesis of the xanthate 23 and the radical addition to
1-pivaloyloxy-pent-4-ene giving 24 were both straight-
forward and proceeded in similar yields to those obtained
in the ester series, xanthate cleavage and cyclisation were
more challenging. Ethylenediamine appeared to react with
the nitrile in 24 and produced a complex mixture of products,
leading us to investigate a series of bases (NH3, KOH,
NaOH, NaOMe) and reducing agents (LiBH4, NaBH4) all
of which led to cleavage of the pivalate as well as the
xanthate. The resulting hydroxy thiol was not isolated but
exposure to acidic ion-exchange resin to remove the acetal
followed by trifluoroacetic acid induced it to cyclise giving,
as the major product, 25, a 3-cyano-4,5-dihydrothiophene
with a trifluoroacetate protection. Cleavage and oxidation
were straightforward giving 27 in a comparable yield to
that obtained for 22.
2.2. Synthesis of 5-substituted-3-carboxy-4,5-dihydro-
thiophenes and their 1,1-dioxides
Past approaches for the synthesis of 3-carboxy-4,5-dihydro-
thiophenes have involved rearrangements of thiolactones
and enethiols, eliminations and cyclopropylphosphonium
chemistry.12 The methodology we adopted was Zard’s
xanthate radical transfer protocol.13 This had been shown
to be an excellent method for the preparation of xanthate-
substituted acetals, themselves good precursors for 4,5-
dihydrothiophenes.
The xanthate precursor 18 was prepared from methyl
methoxyacrylate 16 in 37% overall yield (Scheme 5). Puri-
fication of 18 proved difficult as a number of minor side-
products were formed, this accounts for the rather poor yield.
The radical addition, under Zard’s standard conditions, pro-
ceeded well with a good yield of product 19 obtained. The
product was then subjected to cleavage of the xanthate and
acid-catalysed cyclisation, which provided the dihydrothio-
phene 20. Compound 20 was subjected to gentle cleavage
with methoxide giving 21 before oxidation to the target
sulfolene 22, in just over 25% yield from the starting olefin.
In conclusion, new routes have been developed for the syn-
thesis of two important classes of sulfur heterocycle and
their S,S-dioxo forms bearing difficult substitution patterns.
3. Experimental
3.1. General
Because the ester was found to be labile in a later Pictet
Spengler reaction (see Ref. 4), the synthesis of 27, the
Melting points were determined on a Gallenkamp electro-
thermal apparatus and are uncorrected. Infrared absorption
MeO2C
MeO2C
MeO
17
CO2Me
a
S
S
b
Br
OMe
18
MeO
O
MeO
16
MeO
c
OPiv
CO2Me
CO2Me
CO2Me
MeO
d
f
MeO
S
S
RO
HO
22
S
S
PivO
O
OEt
O
19
20 R = Piv
21 R = H
e
Scheme 5. Reagents and conditions: (a) NBS, MeOH, 0 ꢀC; (b) (i) NaI, Et2O, rt, 1 h; (ii) KSC(S)OEt, Et2O, 0 ꢀC–rt, 18 h, 37% for three steps; (c) lauroyl per-
oxide (16 mol %), 1,2-DCE, reflux, 2 h, 89%; (d) (i) ethylenediamine, EtOH, rt, 1 h; (ii) TFA, CH2Cl2, rt, 1 h, 71%; (e) NaOMe, MeOH, 0 ꢀC–rt, 20 h, 70%;
(f) Oxone, MeOH, H2O, 0 ꢀC, 15 min, 55%.
CN
MeO
MeO
PivO
NC
CN
c
a, b
S
S
24
OEt
MeO
O
S
MeO
OPiv
MeO
S
23
d
CN
CN
O
f
RO
HO
S
S
O
25 R = COCF3
26 R = H
27
e
Scheme 6. Reagents and conditions: (a) NIS, MeOH, 0 ꢀC–rt, 3 h, 88%; (b) KSC(S)OEt, Et2O, 0 ꢀC–rt, 22 h, 47%; (c) lauroyl peroxide (16 mol %), 1,2-DCE,
reflux, 6 h, 90%; (d) (i) NaOMe, MeOH, 0 ꢀC–rt, 24 h; (ii) Amberlite H-120; (iii) TFA, CH2Cl2, rt, 1 h, 41% over three steps; (e) KOH, MeOH/H2O, 0 ꢀC, 1 h,
63%; (f) Oxone, MeOH/H2O, 0 ꢀC, 1 h, 65%.

1068
J. A. Wilkinson et al. / Tetrahedron 63 (2007) 1065–1073
spectra were recorded on a Bruker VECTOR-200 instru-
ment, as liquid films or solutions in chloroform. NMR spec-
tra (1H and 13C) were recorded on a Bruker AC-400
slowly added methyl 5-benzyloxy-2-(2-methoxycarbonyl-
ethylsulfanyl)-pentanoate (6.7 g, 19.7 mmol) in toluene
(50 mL). The reaction mixture was stirred at 0 ꢀC for 1 h,
then heated at reflux for 3 h. Most of the solvent was
removed in vacuo and the residue was diluted with water
(50 mL), cooled, acidified with acetic acid (50 mL) and
extracted with toluene (3ꢂ60 mL). The organic layers
were washed with water (2ꢂ50 mL), brine (2ꢂ50 mL),
evaporated in vacuo, diluted in ether (50 mL) and shaken
with a saturated aqueous solution of cupric acetate
(35 mL). Layers were separated and the aqueous layer was
extracted with ether (50 mL). The combined ethereal layers
were concentrated in vacuo to a third of original volume and
Pet. ether (30 mL) was added to initiate crystallisation. The
green crystals were collected by filtration and washed with
water (3ꢂ10 mL) and Pet. ether (2ꢂ10 mL).
1
instrument, operating at 400 MHz for H and 100 MHz for
13C NMR. Chemical shifts are reported in parts per million
relative to trimethylsilane as an internal standard. Mass
spectra (MS) were measured on a JEOL JMS-DX303 or
JEOL JMN-SX-102A instruments, chemical ionisation
with methane was used throughout. All new compounds
were determined to be >95% pure by signal/noise ratio in
the 13C NMR. Flash chromatography was carried out with
silica gel, Merck Type 60 (70–325 mesh ASTM) or Merck
Type 60 (230–400 mesh ASTM). Compounds 5,9 and 16–
1814 were prepared by literature procedures.
3.1.1. Methyl 5-(3-benzyloxypropyl)-4-oxo-tetrahydro-
thiophene-3-carboxylate (4b). To a solution of 5-benzyl-
oxy-2-chloro-pentanoic acid 5 (9.76 g, 40.2 mmol) in
methanol (500 mL), cooled to 0 ꢀC, was added dropwise
thionyl chloride (5.00 mL, 61.7 mmol). Once the addition
was completed, the reaction mixture was stirred at rt for
16 h. Most of the methanol was evaporated in vacuo and
the residual oil was taken up in ether (50 mL), washed
with water (2ꢂ30 mL), saturated sodium bicarbonate
(2ꢂ30 mL), brine (30 mL), dried over MgSO4, filtered and
concentrated. Further purification by flash chromatography
(Pet. ether/EtOAc 4:1) gave methyl 5-benzyloxy-2-chloro-
pentanoate (6) (8.25 g, 80%) as pale yellow oil, Rf (Pet.
ether/EtOAc 4:1) 0.39; nmax (cmꢁ1) (thin film) 1755
(C]O), 1176–1104 (C–O), 1027 (C–O); d 1H NMR
(400 MHz, CDCl3) 1.68–1.86 (2H, m, CH2CH2), 1.98–
2.22 (2H, m, CH2CH), 3.51 (2H, t, J¼6.1 Hz, CH2O), 3.78
(3H, s, CH3O), 4.33 (1H, dd, J¼8.2, 5.8 Hz, CH), 4.50
(2H, s, CH2 benzyl), 7.19–7.31 (5H, m, CH aromatic);
The crystals were suspended in ether (100 mL) and 2 M
sulfuric acid (50 mL) was added. The layers were separated
and the organic layer was washed with 2 M sulfuric acid
(2ꢂ50 mL), water (2ꢂ50 mL), brine (50 mL), dried over
MgSO4, filtered and concentrated in vacuo to give methyl
5-(3-benzyloxypropyl)-4-oxo-tetrahydrothiophene-3-carb-
oxylate (4b) as a dark brown oil (2.65 g, 44%) as a mixture
of keto and enol forms in a ratio of 1:1.7, respectively, nmax
(cmꢁ1) (thin film) 1731 (C]O), 1665 (C]O), 1625, 1105,
1
1028; d H NMR (400 MHz, CDCl3) (keto form exists as
a mixture of diastereomers partially discernible in 13C
NMR) 1.64–2.19 (4H, m, 2ꢂCH2), 3.13 (1H, ddd, J¼11.9,
8.1, 3.9 Hz, CHS), 3.32–3.50 (4H, m, CH2O+CH2S), 3.72–
3.74 (1H, m, CHCO2Me), 3.78 (3H, s, CH3O), 4.49 (2H, s,
CH2O benzyl), 7.27–7.37 (5H, m, CH aromatic); (enol
form) 1.64–2.19 (4H, m, CH2), 3.43 (2H, t, J¼5.7 Hz,
CH2O), 3.68 (2H, dd, J¼7.6, 2.7 Hz, CH2S), 3.79 (3H, s,
CH3O), 4.22–4.23 (1H, m, CHS), 4.50 (2H, s, CH2O ben-
zyl), 7.27–7.37 (5H, m, CH aromatic), 10.98 (1H, s, OH);
d
13C NMR (100 MHz, CDCl3) 26.0, 31.7, 52.6, 56.9,
68.9, 72.7, 127.4, 128.2, 138.1, 169.9; m/z 257 ([M+H]+,
40%), HRMS C13H18ClO3 [M+H]+ required 257.0944,
found 257.0939.
d
13C NMR (100 MHz, CDCl3) (keto form) 24.4 and 26.5,
26.9, 27.5, 27.7, 52.2, 52.8, 55.5, 55.6, 69.1, 69.2, 69.4,
73.0, 127.5, 128.3, 138.3, 138.4, 168.2, 168.4, 206.5,
207.2; (enol form) 27.2, 27.8, 31.4, 52.0, 53.5, 69.4, 72.9,
98.7, 127.6, 128.3, 138.2, 148.5, 172.0; m/z 309 ([M+H]+,
21%), HRMS C16H24NO4S [M+NH4]+ required 326.1426,
found 326.1421.
To a suspension of sodium hydride (1.25 g, 31.25 mmol) in
ether (10 mL) cooled to 0 ꢀC was added dropwise methyl
3-mercapto-propionate (4.31 g, 35.15 mmol) in ether
(40 mL). The mixture was stirred for 15 min at 0 ꢀC, then
for 1.5 h at rt. The mixture was cooled to 0 ꢀC and methyl
5-benzyloxy-2-chloro-pentanoate (6) (7.30 g, 28.44 mmol)
in dry ether (30 mL) was added dropwise, followed by dry
DMF (30 mL). After 20 min stirring at 0 ꢀC, the mixture
was stirred for 18 h at rt. The residual oil was distilled under
reduced pressure to give methyl 5-benzyloxy-2-(2-methoxy-
carbonyl-ethylsulfanyl)-pentanoate as a colourless oil (6.20 g,
64%), bp 199–200 ꢀC/0.2 mmHg; nmax (cmꢁ1) (thin film)
3.1.2. Methyl 3-(cyclopent-2-enylsulfanyl)-propionate
(8). To 3-methyl mercaptopropionate (23.76 g, 0.191 mol)
at 10 ꢀC under argon was added a 25 wt % solution of ethyl
aluminium dichloride in toluene (4.4 mL, 0.006 mol), then
freshly cracked cyclopentadiene (18.37 g, 0.278 mol) was
added dropwise via cannula. After 1 h of vigorous stirring,
the solution was warmed to rt for 36 h. The dark green reac-
tion mixture was poured into water (200 mL), diluted with
diethyl ether (200 mL) and partitioned. The aqueous layer
was extracted with ethyl acetate (3ꢂ100 mL). The combined
organic extracts (yellow solution) were washed with water
(2ꢂ100 mL), then brine (2ꢂ100 mL), dried over MgSO4,
filtered and concentrated under reduced pressure. The resid-
ual crude orange oil was distilled under reduced pressure to
give methyl 3-(cyclopent-2-enylsulfanyl)-propionate (8) as
a brown oil (24.22 g, 68%), bp 89–92 ꢀC/0.1 mmHg; nmax
(cmꢁ1) (thin film) 3056, 1730 (C]O), 1609, 1172 (C–O);
1
1735 (C]O), 1102 (C–O); d H NMR (400 MHz, CDCl3)
1.61–2.05 (4H, m, 2ꢂCH2), 2.60 (2H, dt, J¼7.2, 2.8 Hz,
CH2CO), 2.81–2.93 (2H, m, CH2S), 3.30 (1H, dd, J¼8.1,
6.8 Hz, CH), 3.48 (2H, t, J¼6.1 Hz, CH2O), 3.69 (3H, s,
CH3O), 3.74 (3H, s, CH3O), 4.49 (2H, s, CH2O benzyl),
7.27–7.38 (5H, m, CH aromatic); d 13C NMR (100 MHz,
CDCl3) 26.2, 27.4, 28.2, 34.5, 46.4, 51.8, 52.3, 69.5, 72.9,
127.6, 128.4, 138.4, 172.0, 173.0; m/z 341 ([M+H]+, 40%),
HRMS C17H25O5S required 341.1417, found 341.1420.
1
To a solution of sodium methoxide [from sodium (3.0 g,
130.4 mmol) and methanol (80 mL)], cooled to 0 ꢀC was
d H NMR (400 MHz, CDCl3) 1.89–1.96 (1H, m, one of
allylic CH2), 2.28–2.39 (2H, m, CH2), 2.43–2.55 (1H, m,

J. A. Wilkinson et al. / Tetrahedron 63 (2007) 1065–1073
1069
one of allylic CH2), 2.61 (2H, dd, J¼11.3, 4.3 Hz,
CH2CO2Me), 2.79 (2H, dd, J¼11.3, 4.3 Hz, CH2S), 3.70
(3H, s, CH3OCO), 3.85–3.92 (1H, m, CH), 5.70–5.73 (1H,
m, CH olefinic), 5.87 (1H, ddd, J¼5.9, 3.9, 1.9 Hz, CH
olefinic); d 13C NMR (100 MHz, CDCl3) 25.3, 31.6, 31.7,
34.9, 49.9, 51.7, 131.3, 132.9, 172.4; m/z 187 ([M+H]+,
100%), HRMS C9H15O2S [M+H]+ required 187.0793, found
187.0788.
hydride (1.07 g, 26.79 mmol) in ether (50 mL) cooled to
0 ꢀC was added dropwise 2-acetylsulfanyl-5-benzyloxy-
pentanoate (11) (1.99 g, 6.71 mmol) in ether (20 mL) over
15 min. Once the addition was complete, the mixture was
stirred for 15 min at 0 ꢀC, then for 1 h at rt and carefully
quenched at 0 ꢀC with wet ether (75 mL; Et2O/H2O 1:1,
v/v). Once the mixture had turned white, it was transferred
into a separating funnel and 2 M aqueous H2SO4 (50 mL)
was added. The layers were separated and the aqueous layer
was extracted with ether (3ꢂ30 mL). The combined ethereal
extracts were washed with brine (30 mL), dried over
MgSO4, filtered and concentrated. Further purification by
flash chromatography (Pet. ether/EtOAc 7:3) gave 5-benzyl-
oxy-2-mercapto-pentan-1-ol (1.34 g, 88%) as a yellow oil,
Rf (Pet. ether/EtOAc 7:3) 0.42; nmax (cmꢁ1) (thin film)
3.1.3. Methyl 3-(cyclopent-2-enylsulfonyl)-propionate
(9). OxoneÒ (27.0 g, 43.83 mmol) in water (210 mL) was
added over 30 min to a solution of 3-(cyclopent-2-enylsul-
fanyl)-propionic acid methyl ester (8) (5.20 g, 27.9 mmol)
in methanol (60 mL) cooled to 0 ꢀC. After 30 min stirring,
the reaction mixture was extracted with ethyl acetate
(3ꢂ75 mL). The combined organic extracts were dried
over MgSO4. The solvents were removed under reduced
pressure to give a colourless oil, which was purified by flash
chromatography (Pet. ether/EtOAc: 1:1) yielding methyl
3-(cyclopent-2-enylsulfonyl)-propionate (5.60 g, 92%) as
colourless needles, mp 39–41 ꢀC; Rf (Pet. ether/EtOAc
1:1) 0.41; nmax (cmꢁ1) (thin film) 1739 (C]O), 1439,
1
3386 (O–H), 1096 (C–O); d H NMR (400 MHz, CDCl3)
1.34 (1H, d, J¼8.4 Hz, SH), 1.49–1.93 (4H, m, 2ꢂCH2),
2.27 (1H, br s, OH), 2.89 (1H, tdt, J¼8.4, 7.4, 4.9 Hz,
CH), 3.45–3.51 (3H, m, CH2OBn+one of CH2OH), 3.70
(1H, dd, J¼11.2, 4.9 Hz, one of CH2OH), 4.50 (2H, s,
CH2 benzyl), 7.27–7.37 (5H, m, CH aromatic); d 13C
NMR (100 MHz, CDCl3) 27.1, 31.4, 43.6, 67.8, 69.7, 72.9,
127.6, 128.3, 138.3; m/z 227 ([M+H]+, 8%), HRMS no
satisfactory data assignment could be obtained.
1
1366, 1121 (C–O); d H NMR (400 MHz, CDCl3) 2.26–
2.45 (2H, m, ring CH2), 2.46–2.55 (1H, m, one of allylic
CH2), 2.60–2.70 (1H, m, one of allylic CH2), 2.88 (2H,
t, J¼7.5 Hz, CH2CO), 3.23 (2H, tq, J¼13.8, 7.5 Hz,
CH2SO2), 3.73 (3H, s, CH3O), 4.17–4.23 (1H, m, CH),
5.80 (1H, qd, J¼5.7, 2.3 Hz, CH olefinic), 6.27 (1H, ddd,
J¼5.7, 4.3, 2.3 Hz, CH olefinic); d 13C NMR (100 MHz,
CDCl3) 24.1, 26.0, 32.2, 44.9, 52.4, 70.4, 122.8, 140.6,
171.1; m/z 219 ([M+H]+, 100%), HRMS C9H18NO4S
[M+NH4]+ required 236.0957, found 236.0952.
Triethylamine (2.50 mL, 17.85 mmol) was added to 5-benz-
yloxy-2-mercapto-pentan-1-ol (5.12 g, 22.62 mmol) at rt.
The mixture was stirred for 10 min, then methyl acrylate
(5.00 mL, 54.62 mmol) was added dropwise. The reaction
mixture was stirred for 18 h, concentrated and purified by
flash chromatography (Pet. ether/EtOAc 3:2) to give methyl
3-(4-benzyloxy-1-hydroxymethyl-butylsulfanyl)-propionate
(6.31 g, 87%) as a yellow oil, Rf (Pet. ether/EtOAc 3:2) 0.24;
nmax (cmꢁ1) (thin film) 3445 (O–H), 1731 (C]O), 1247–
3.1.4. Methyl 2-acetylsulfanyl-5-benzyloxy-pentanoate
(11). To a suspension of a 60% dispersion of sodium hydride
(0.43 g, 10.75 mmol) in diethyl ether (20 mL) was added
dropwise thioacetic acid (0.8 mL, 10.89 mmol) in ether
(5 mL) at 0 ꢀC after which the mixture was stirred for
5 min at 0 ꢀC, then for 1 h at rt. The mixture was then cooled
to 0 ꢀC and methyl 5-benzyloxy-2-chloro-pentanoate (6)
(2.08 g, 8.11 mmol) in ether (5 mL) was added, followed
by DMF (5 mL). The solution was kept at 0 ꢀC for 10 min,
then stirred at rt for 20 h and diluted with water (20 mL).
The aqueous layer was extracted with ether (3ꢂ25 mL).
The combined organic layers were washed with water
(3ꢂ20 mL), brine (25 mL), dried over MgSO4, filtered and
concentrated. Further purification by flash chromatography
(Pet. ether/EtOAc 4:1) gave methyl 2-acetylsulfanyl-5-
benzyloxy-pentanoate (11) (1.97 g, 82%) as a yellow oil, Rf
(Pet. ether/EtOAc 4:1) 0.39; nmax (cmꢁ1) (thin film) 1739
(C]O), 1698 (C]O), 1197, 1110 (C–O); d 1H NMR
(400 MHz, CDCl3) 1.62–1.78 (2H, m, CH2CH2), 1.81–1.90
(1H, m, one of CH2CHS), 2.04 (1H, dddd, J¼16.9, 9.8, 7.2,
5.9 Hz, one of CH2CHS), 2.35 (3H, s, CH3CO), 3.47 (2H,
t, J¼6.3 Hz, CH2O), 3.72 (3H, s, CH3O), 4.23 (1H, t,
J¼7.2 Hz, CHS), 4.49 (2H, s, CH2O benzyl), 7.27–7.38
(5H, m, CH aromatic); d 13C NMR (100 MHz, CDCl3)
27.2, 28.6, 30.2, 45.6, 52.6, 69.3, 72.9, 127.6, 128.3, 138.4,
172.0, 193.7; m/z 297 (M+, 10%), HRMS C15H20O4S
required 297.1155, found 297.1159.
1
1094; d H NMR (400 MHz, CDCl3) 1.44–1.84 (4H, m,
2ꢂCH2), 1.93 (1H, br s, OH), 2.59 (2H, t, J¼7.3 Hz,
CH2CO), 2.72–2.84 (3H, m, CH2S+CH), 3.47–3.54 (3H,
m, CH2OBn+one of CH2OH), 3.67 (1H, dd, J¼12.7,
7.9 Hz, one of CH2OH), 3.70 (3H, s, CH3O), 4.50 (2H, s,
CH2O benzyl), 7.27–7.38 (5H, m, CH aromatic); d 13C
NMR (100 MHz, CDCl3) 25.1, 26.9, 28.1, 34.6, 49.1, 51.7,
64.1, 69.7, 72.7, 127.4, 127.5, 128.2, 138.2, 172.2; m/z 313
([M+H]+, 5%), HRMS C16H25O4S [M+H]+ required
313.1474, found 313.1469.
To a solution of oxalyl chloride (1.9 mL, 2.7 g, 21.6 mmol)
in dichloromethane (45 mL), cooled to between ꢁ50 and
ꢁ60 ꢀC under argon, was added a solution of DMSO
(3.8 mL, 4.2 g, 53.5 mmol) in dichloromethane (42 mL).
The reaction mixture was stirred for 3 min and then a solu-
tion of methyl 3-(4-benzyloxy-1-hydroxymethyl-butylsul-
fanyl)-propionate (6.3 g, 20.2 mmol) in dichloromethane
(19 mL) was added over 5 min and the mixture was stirred
for 15 min. Triethylamine (14.0 mL, 10.1 g, 99.9 mmol)
was then added and the reaction mixture was allowed to
warm to rt and stirred for 1 h. Water (50 mL) was added
and the aqueous layer was extracted with dichloromethane
(3ꢂ100 mL). The combined organic extracts were washed
withbrine(3ꢂ100 mL),2 MaqueousHCl(2ꢂ100 mL),water
(4ꢂ100 mL), saturated aqueous Na2CO3 (2ꢂ100 mL),
water (2ꢂ100 mL), dried over MgSO4, filtered and con-
centrated. Further purification by flash chromatography
(Pet. ether/EtOAc 3:2) gave methyl 3-(4-benzyloxy-1-
3.1.5. Methyl 3-(4-benzyloxy-1-formyl-butylsulfanyl)-
propionate (12). To a suspension of lithium aluminium

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J. A. Wilkinson et al. / Tetrahedron 63 (2007) 1065–1073
formyl-butylsulfanyl)-propionate (12) (5.8 g, 93%) as a yel-
low oil, Rf (Pet. ether/EtOAc 3:2) 0.60; nmax (cmꢁ1) (thin
film) 1732 (C]O), 1712 (C]O), 1177, 1100; d H NMR
1:1) 0.41; nmax (cmꢁ1) (thin film) 1717 (C]O), 1642
(C]C), 1256, 1089, 739; d H NMR (400 MHz, CDCl3)
1
1
1.79–2.15 (4H, m, 2ꢂCH2), 3.50–3.59 (2H, m, CH2S),
3.81 (3H, s, CH3O), 3.94–3.97 (3H, m, CH2O+CHS), 4.50
(2H, s, CH2O benzyl), 6.96–6.98 (1H, m, CH olefinic),
7.26–7.37 (5H, m, CH aromatic); d 13C NMR (100 MHz,
CDCl3) 27.3, 33.0, 52.2, 56.7, 64.2, 70.1, 73.1, 127.4,
128.5, 133.8, 138.3, 144.2, 164.8; m/z 325 ([M+H]+, 35%),
HRMS C16H21O5S required 325.1101, found 325.1109.
(400 MHz, CDCl3) 1.68–1.97 (4H, m, 2ꢂCH2), 2.54–2.59
(4H, m, COCH2, SCH2), 3.16 (1H, ddd, J¼8.0, 6.3, 4.5 Hz,
CH), 3.49 (2H, t, J¼5.7 Hz, CH2O), 3.69 (3H, s, CH3O),
4.48 (2H, s, CH2O benzyl), 7.27–7.38 (5H, m, CH aromatic),
9.20 (1H, d, J¼4.5 Hz, CHO); d 13C NMR (100 MHz,
CDCl3) 24.6, 24.9, 27.1, 34.2, 51.8, 53.0, 69.2, 72.9, 127.6,
128.3, 138.2, 171.8, 193.6; m/z 311 ([M+H]+, 100%),
HRMS C16H23O4S [M+H]+ required 311.1317, found
311.1314.
3.1.8. Methyl 2-dimethoxymethyl-7-(2,2-dimethylpropio-
nyloxy)-4-ethoxythiocarbonylsulfanyl-heptanoate (19).
To a refluxing solution of methyl 2-ethoxythiocarbonylsul-
fanyl-3,3-dimethoxypropionate (18) (1.80 g, 6.71 mmol)
and 2,2-dimethyl-propionic acid pent-4-enyl ester (1.26 g,
7.42 mmol) in 1,2-dichloroethane (15 mL, previously
degassed by refluxing under an atmosphere of argon for
2 h) was added lauroyl peroxide (0.56 g, 1.34 mmol)
portionwise (0.14 g every hour for 4 h) as a solid charge.
The reaction mixture was then heated under reflux for a
further 2 h, cooled and concentrated under reduced pressure.
Further purification by flash chromatography gave methyl
2-dimethoxymethyl-7-(2,2-dimethylpropionyloxy)-4-ethoxy-
thiocarbonylsulfanyl-heptanoate (19) (2.61 g, 89%) as an
inseparable mixture of diastereoisomers (1.1:1) as a yellow
oil, Rf (Pet. ether/EtOAc 4:1) 0.34; nmax (cmꢁ1) (thin film)
3.1.6. 5-(3-Benzyloxypropyl)-3-carboxymethyl-2,5-di-
hydrothiophene (3). To a solution of sodium methoxide
[prepared from sodium (0.77 g, 33.58 mmol) in methanol
(30 mL)] cooled to 0 ꢀC was added dropwise methyl 3-(4-
benzyloxy-1-formyl-butylsulfanyl)-propionate (12) (5.80 g,
18.68 mmol) in toluene (10 mL) over 20 min. Once addition
was complete the reaction mixture was heated under reflux
for 2 h, cooled and diluted with water (100 mL). Most of
the methanol was removed in vacuo and the mixture was
acidified with 2 M aqueous HCl (50 mL) and extracted
with ether (3ꢂ100 mL). The combined organic extracts
were washed with water (2ꢂ100 mL), brine (100 mL), dried
over MgSO4, filtered and concentrated. The residue was dis-
solved in dry dichloromethane (40 mL) and cooled to 0 ꢀC
before triethylamine (10.00 mL, 0.07 mol) was added and
the reaction mixture was stirred for 5 min. Methanesulfonyl
chloride (2.00 mL, 0.02 mol) was added and the mixture was
stirred at 0 ꢀC for 10 min, then for 45 min at rt, diluted with
dichloromethane (50 mL), washed with 2 M aqueous HCl
(2ꢂ20 mL), dried over MgSO4, filtered and concentrated.
The residual oil was dissolved in MeOH (50 mL) and cooled
to 0 ꢀC. Thionyl chloride (5.00 mL, 68.50 mmol) was added
dropwise and the reaction mixture was stirred at rt for 1 h
and then concentrated. Purification by flash chromatography
(Pet. ether/EtOAc 9:1) gave 5-(3-benzyloxypropyl)-3-carb-
oxymethyl-2,5-dihydrothiophene (3) (1.85 g, 34% from
aldehyde 12) as a pale brown oil, Rf (Pet. ether/EtOAc 9:1)
0.25; nmax (cmꢁ1) (thin film) 1720 (C]O), 1648 (C]C),
1257, 1089; d 1H NMR (400 MHz, CDCl3) 1.66–1.95 (4H,
m, 2ꢂCH2), 3.49 (2H, t, J¼6.2 Hz, CH2O), 3.76 (3H, s,
CH3O), 3.84–3.94 (2H, m, CH2S), 4.31–4.41 (1H, m, CH),
4.50 (2H, s, CH2O benzyl), 6.79 (1H, dd, J¼4.7, 2.1 Hz,
CH olefinic), 7.27–7.37 (5H, m, CH aromatic); d 13C
NMR (100 MHz, CDCl3) 27.6, 34.2, 36.6, 51.9, 55.0, 69.7,
72.9, 127.6, 128.3, 134.0, 138.4, 144.6, 164.4; m/z 293
([M+H]+, 25%), HRMS C16H18O3S required for [Mꢁ2]
290.0971, found 290.0967.
1
2958, 2873, 1730 (C]O), 1444, 1158, 1055; d H NMR
(400 MHz, CDCl3) (major diastereomer) 1.19 (9H, s,
3ꢂCH3), 1.41 (3H, t, J¼7.1 Hz, CH3CH2), 1.56–2.14
(6H, m, 3ꢂCH2), 3.02 (1H, ddd, J¼11.2, 7.0, 3.0 Hz,
CHCO2Me), 3.32 (3H, s, CH3O), 3.36 (3H, s, CH3O),
3.39–3.43 (1H, m, CHS), 3.71 (3H, s, CH3OCO), 4.01–
4.08 (2H, m, CH2OPiv), 4.51 (1H, d, J¼7.0 Hz, CHOMe),
4.59–4.62 (2H, m, CH2OCS); (minor diastereomer) 1.20
(9H, s, 3ꢂCH3), 1.42 (3H, t, J¼7.2 Hz, CH3CH2), 1.56–
2.14 (6H, m, 3ꢂCH2), 2.87 (1H, ddd, J¼9.8, 7.8, 4.2 Hz,
CHCO2Me), 3.34 (3H, s, CH3O), 3.36 (3H, s, CH3O),
3.39–3.43 (1H, m, CHS), 3.73 (3H, s, CH3OCO), 4.01–
4.08 (2H, m, CH2OPiv), 4.49 (1H, d, J¼7.8 Hz, CHOMe),
4.59–4.62 (2H, m, CH2OCS); d 13C NMR (100 MHz,
CDCl3) (major diastereomer) 13.3, 25.8, 27.1, 31.2, 32.2,
38.7, 46.5, 49.4, 52.0, 53.1, 54.6, 63.8, 69.9, 104.4, 172.8,
178.4, 213.9; (minor diastereomer) 15.2, 25.8, 27.1, 29.7,
32.7, 38.7, 47.0, 49.0, 51.9, 53.4, 54.6, 63.6, 69.8, 104.7,
172.6, 178.4, 213.5; m/z 407 ([MꢁMeOꢃ]+, 12%), HRMS
no satisfactory data assignment could be obtained.
3.1.9. Methyl 5-[3-(2,2-dimethylpropionyloxy)-propyl]-
4,5-dihydrothiophene-3-carboxylate (20). To a solution
of methyl 2-dimethoxymethyl-7-(2,2-dimethylpropionyl-
oxy)-4-ethoxythiocarbonylsulfanyl-heptanoate 19 (1.12 g,
2.56 mmol) in ethanol (10 mL) was added ethylenediamine
(2.00 mL, 29.76 mmol). Once addition was complete, the
reaction mixture was stirred at rt for 1 h, concentrated under
reduced pressure, diluted with dichloromethane (70 mL) and
water (20 mL) and then acidified with a solution of 1 M HCl
(50 mL). The layers were separated and the organic layer
was washed with water (2ꢂ50 mL), brine (25 mL), dried
over MgSO4, filtered and concentrated in vacuo. The resid-
ual oil was then diluted with dichloromethane (20 mL) and
trifluoroacetic acid (3.00 mL, 38.62 mmol) was then added
via syringe. The reaction mixture was stirred at rt for 1 h,
diluted with dichloromethane (50 mL), washed with water
3.1.7. 5-(3-Benzyloxypropyl)-3-carbomethoxy-3-sulfo-
lene (14). To an ice-cooled solution of 5-(3-benzyloxy-
propyl)-3-carboxymethyl-2,5-dihydrothiophene (3) (661 mg,
2.26 mmol) in methanol (25 mL) was added dropwise a solu-
tion of OxoneÒ (7.00 g, 11.39 mmol) in water (50 mL).
Once addition was complete the reaction mixture was stirred
for 30 min at the same temperature, diluted with water
(50 mL), extracted with dichloromethane (3ꢂ50 mL), dried
with MgSO4, filtered and concentrated. Further purification
by flash chromatography (Pet. ether/EtOAc 1:1) gave
5-(3-benzyloxypropyl)-3-carbomethoxy-3-sulfolene (14)
(401 mg, 55%) as a viscous brown oil, Rf (Pet. ether/EtOAc

J. A. Wilkinson et al. / Tetrahedron 63 (2007) 1065–1073
1071
(20 mL), saturated NaHCO3 (2ꢂ15 mL), water (2ꢂ15 mL),
brine (25 mL), dried over MgSO4, filtered and concentrated
to give a yellow oil. Further purification by flash chromato-
graphy gave methyl 5-[3-(2,2-dimethylpropionyloxy)-pro-
pyl]-4,5-dihydrothiophene-3-carboxylate (20) (0.52 g, 71%)
163.0; m/z 235 ([M+H]+, 10%), HRMS C9H15O5S [M+H]+
required 235.0640, found 235.0636.
3.1.12. O-Ethyl S-(1-cyano-2,2-dimethoxyethyl)-dithio-
carbonate (23). To a well-stirred suspension of N-iodo-
succinimide (77.09 g, 0.325 mol) in methanol (300 mL),
cooled to 0 ꢀC under argon, was added dropwise
3-methoxy-acrylonitrile (28.00 mL, 27.72 g, 0.320 mol).
Once addition was complete, the reaction mixture was
allowed to return to rt and stirred for a further 3 h. Most of
the methanol was removed under reduced pressure and the
residue was filtered and extracted with toluene (5ꢂ
100 mL). The organic layers were then washed with water
(3ꢂ150 mL), brine (150 mL), dried over MgSO4, filtered
and concentrated. The residual oil was distilled under re-
duced pressure to yield 2-iodo-3,3-dimethoxy-propionitrile
as a yellow oil (68.25 g, 88%), bp 98–101 ꢀC/0.4 mmHg;
nmax (cmꢁ1) (thin film) 2839, 2242 (CN), 1117, 1074; d 1H
NMR (400 MHz, CDCl3) 3.48 (3H, s, CH3O), 3.52 (3H, s,
CH3O), 4.32 (1H, d, J¼5.6 Hz), 4.44 (1H, d, J¼5.6 Hz);
as a yellow oil, Rf (Pet. ether/EtOAc 4:1) 0.39; nmax (cmꢁ1
)
(thin film) 1727 (C]O), 1708 (C]O), 1579, 1480, 1437,
1363, 1156, 1079; d 1H NMR (400 MHz, CDCl3) 1.20
(9H, s, 3ꢂCH3), 1.71–1.98 (2H, m, CH2CH2), 2.06–2.16
(2H, m, CH2CH), 2.61 (1H, ddd, J¼17.9, 6.8, 2.5 Hz, one
of ring CH2), 3.24 (ddd, 1H, J¼1.7, 8.2, 17.9 Hz, one of
ring CH2), 3.39 (1H, td, J¼14.7, 7.4 Hz, CH), 3.86 (3H, s,
CH3OCO), 4.13 (2H, dt, J¼6.3, 1.7 Hz, CH2O), 7.31–7.32
(1H, m, CH olefinic); d 13C NMR (100 MHz, CDCl3) 25.0,
26.2, 27.2, 32.5, 38.8, 53.1, 60.1, 63.2, 137.4, 140.0,
162.9, 178.4; m/z 287 ([M+H]+, 12%), HRMS C14H23O4S
[M+H]+ required 287.1312, found 287.1314.
3.1.10. Methyl 5-(3-hydroxypropyl)-4,5-dihydrothio-
phene-3-carboxylate (21). To a solution of methyl
5-[3-(2,2-dimethylpropionyloxy)-propyl]-4,5-dihydrothio-
phene-3-carboxylate (20) (247 mg, 1.23 mmol) in methanol
(2 mL), cooled to 0 ꢀC, was added via syringe a 1 M solution
of NaOMe in methanol (1.00 mL, 1.00 mmol). The reaction
mixture was allowed to return to rt and then stirred for 20 h,
acidified to pH 4 with Amberlite resin IR-120[H], filtered,
washed with methanol (3ꢂ2 mL) and concentrated. Further
purification by flash chromatography (Pet. ether/EtOAc 3:2)
afforded methyl 5-(3-hydroxypropyl)-4,5-dihydrothio-
phene-3-carboxylate (21) (173 mg, 70%) as a yellow oil,
Rf (Pet. ether/EtOAc 3:2) 0.21; nmax (cmꢁ1) (thin film)
3429 (OH), 1703 (C]O), 1577, 1080; d 1H NMR
(400 MHz, CDCl3) 1.32 (1H, br s, OH), 1.62–1.69 (2H, m,
CH2CH2), 1.76–1.82 (2H, m, CH2CH), 2.78 (1H, ddd,
J¼16.2, 6.2, 1.6 Hz, one of ring CH2), 3.14 (1H, ddd, J¼
16.1, 9.4, 2.1 Hz, one of ring CH2), 3.67 (2H, t, J¼6.3 Hz,
CH2O), 3.72 (3H, s, CH3O), 3.87–3.94 (1H, m, ring CH),
7.33–7.34 (1H, m, CH olefinic); d 13C NMR (100 MHz,
CDCl3) 30.6, 33.2, 39.9, 51.2, 51.5, 62.4, 126.5, 141.7,
163.6; m/z 203 ([M+H]+, 35%), HRMS C9H15O3S [M+H]+
required 203.0742, found 203.0736.
d
13C NMR (100 MHz, CDCl3) ꢁ1.22, 55.4, 56.0, 103.4,
116.6; m/z 242 ([M+H]+, 8%), HRMS C5H12N2O2I
[M+NH4]+ required 258.9938, found 258.9941.
To a solution of 2-iodo-3,3-dimethoxy-propionitrile (11.03 g,
45.76 mmol) in acetonitrile (50 mL) was added portionwise
potassium O-ethyl xanthate (7.56 g, 47.16 mmol) as solid
charge over 45 min at 0 ꢀC under argon. Once addition was
complete, the reaction mixture was stirred at 0 ꢀC for
30 min, then allowed to return to rt and stirred overnight
(22 h). Most of the acetonitrile was removed under reduced
pressure and the residue was diluted with Et2O (400 mL),
washed with water (4ꢂ100 mL), brine (100 mL), dried over
MgSO4, filtered and concentrated. The residual oil was puri-
fied by flash chromatography (Pet. ether/EtOAc 4:1) to yield
O-ethyl S-(1-cyano-2,2-dimethoxyethyl)-dithiocarbonate (23)
as a yellow oil (5.05 g, 47%), Rf (Pet. ether/EtOAc 4:1) 0.32;
nmax (cmꢁ1) (thin film) 2839, 2246 (CN), 1112, 1073;
d
1H NMR (400 MHz, CDCl3) 1.46 (3H, t, J¼7.1 Hz,
CH3CH2), 3.51 (3H, s, CH3O), 3.52 (3H, s, CH3O), 4.61
(1H, d, J¼4.3 Hz, CHS), 4.71 (2H, q, J¼7.1 Hz, CH2O),
4.83 (1H, d, J¼4.3 Hz, CHOMe); d 13C NMR (100 MHz,
CDCl3) 13.7, 42.3, 55.7, 56.3, 71.7, 102.2, 115.6, 209.3;
m/z 236 ([M+H]+, 20%), HRMS C8H14NO3S2 [M+H]+
required 236.0415, found 236.0411.
3.1.11. 5-(3-Hydroxypropyl)-3-carbomethoxy-2-sulfo-
lene (22). A solution of methyl 5-(3-hydroxypropyl)-4,5-di-
hydrothiophene-3-carboxylate (21) (140 mg, 0.69 mmol) in
methanol (2 mL) was added dropwise via syringe to a solu-
tion of OxoneÒ (1.30 g, 2.11 mmol) in water (5 mL), cooled
to 0 ꢀC. The reaction mixture was stirred for 15 min at the
same temperature, diluted with EtOAc (30 mL) and parti-
tioned. The organic layer was washed with water (2ꢂ
5 mL), brine (5 mL), dried over MgSO4, filtered and concen-
trated. Further purification by flash chromatography (Pet.
ether/EtOAc 1:2) afforded 5-(3-hydroxypropyl)-3-carbo-
methoxy-2-sulfolene (22) (89 mg, 55%) as a thick yellow
oil, Rf (Pet. ether/EtOAc 1:2) 0.13; nmax (cmꢁ1) (thin film)
3533–3451 (OH), 1728 (C]O), 1582, 1299, 1133, 1057;
3.1.13. 2,2-Dimethylpropionic acid 6-cyano-4-ethoxy-
thiocarbonylsulfanyl-7,7-dimethoxyheptyl ester (24). To
a refluxing solution of O-ethyl S-(1-cyano-2,2-dimeth-
oxyethyl)-dithiocarbonate (23) (4.52 g, 19.2 mmol) and
2,2-dimethyl-propionic acid pent-4-enyl ester (3.75 g,
22.0 mmol) in 1,2-dichloroethane (50 mL, previously
degassed by heating at reflux under argon for 2 h) was
added lauroyl peroxide (1.44 g, 3.6 mmol) portionwise
(every hour for 4 h) as a solid charge. The reaction mixture
was then heated at reflux for 2 h, cooled and concentrated
under reduced pressure. Further purification by flash chro-
matography (Pet. ether/EtOAc 9:1) afforded an inseparable
mixture of diastereoisomers (ratio 1.4:1) of 2,2-dimethyl-
propionic acid 6-cyano-4-ethoxythiocarbonylsulfanyl-7,7-
dimethoxyheptyl ester (24) (7.00 g, 90%) as a thick yellow
oil, Rf (Pet. ether/EtOAc 9:1) 0.20; nmax (cmꢁ1) (thin film)
2838, 2246 (CN), 1726 (C]O), 1157, 1115, 1048;
1
d H NMR (400 MHz, CDCl3) 1.66 (1H, br s, OH), 1.73–
2.15 (4H, m, 2ꢂCH2), 2.62 (1H, ddd, J¼18.0, 6.8, 2.5 Hz,
one of ring CH2), 3.24 (1H, ddd, J¼18.0, 8.1, 1.7 Hz, one
of ring CH2), 3.45 (1H, ddd, J¼14.8, 8.1, 6.8 Hz,
CHCH2), 3.69–3.76 (2H, m, CH2O), 3.85 (3H, s, CH3O),
7.29–7.30 (1H, m, CH olefinic); d 13C NMR (100 MHz,
CDCl3) 25.0, 29.7, 32.6, 53.1, 60.4, 62.0, 137.3, 140.2,

1072
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J. A. Wilkinson et al. / Tetrahedron 63 (2007) 1065–1073
d H NMR (400 MHz, CDCl3) (major diastereomer) 1.20
(9H, s, 3ꢂCH3), 1.45 (3H, t, J¼7.1 Hz, CH3CH2), 1.60–
2.06 (6H, m, 3ꢂCH2), 3.12 (1H, ddd, J¼11.3, 5.6, 3.8 Hz,
CHCN), 3.41 (3H, s, CH3O), 3.45 (3H, s, CH3O), 3.89–
3.98 (1H, m, CHS), 4.07 (2H, t, J¼3.9 Hz, CH2OPiv),
4.45 (1H, d, J¼5.6 Hz, CHOMe), 4.67 (2H, dq, J¼7.1,
3.0 Hz, CH3CH2O); (minor diastereomer) 1.20 (9H, s,
3ꢂCH3), 1.44 (3H, t, J¼7.1 Hz, CH3CH2), 1.67–1.89 (4H,
m, 2ꢂCH2), 2.11 (2H, t, J¼7.2 Hz, CH2CHCN), 2.99 (1H,
dt, J¼7.2, 5.3 Hz, CHCN), 3.43 (3H, s, CH3O), 3.48 (3H,
s, CH3O), 3.87–3.97 (1H, m, CHS), 4.08 (2H, t, J¼5.9 Hz,
CH2OPiv), 4.46 (1H, d, J¼5.3 Hz, CHOMe), 4.66 (2H, dq,
J¼7.1, 1.5 Hz, CH3CH2O); d 13C NMR (100 MHz,
CDCl3) (major diastereomer) 13.7, 26.0, 27.2, 29.7, 32.4,
34.6, 38.7, 48.5, 54.4, 55.3, 63.6, 70.4, 102.9, 118.9,
178.4, 212.2; (minor diastereomer) 13.8, 25.9, 27.2, 29.7,
32.1, 33.8, 38.7, 48.3, 55.4, 55.5, 63.4, 70.3, 103.1, 118.7,
178.5, 212.8; m/z 374 ([MꢁMeOꢃ]+, 25%), HRMS no satis-
factory data assignment could be obtained.
dried over MgSO4, filtered and concentrated. Further purifi-
cation by flash chromatography (Pet. ether/EtOAc 4:1 to 1:1)
gave 5-(3-hydroxypropyl)-4,5-dihydrothiophene-3-carbo-
nitrile (26) (38.4 mg, 63%) as a yellow oil, Rf (Pet. ether/
EtOAc 1:1) 0.29; nmax (cmꢁ1) (thin film) 3419 (OH), 2206
1
(CN), 1562 (C]C), 1057; d H NMR (400 MHz, CDCl3)
1.53 (1H, br s, OH), 1.61–1.68 (2H, m, CH2), 1.78–1.84
(2H, m, CH2), 2.72 (1H, ddd, J¼15.8, 6.2, 1.6 Hz, one of
ring CH2), 3.12 (1H, ddd, J¼15.8, 9.3, 2.2 Hz, one of ring
CH2), 3.68 (2H, t, J¼6.2 Hz, CH2O), 3.91–3.98 (1H, m,
CH), 7.12 (1H, t, J¼1.9 Hz, CH olefinic); d 13C NMR
(100 MHz, CDCl3) 30.4, 32.8, 41.8, 51.1, 62.1, 102.8,
116.0, 146.0; m/z 170 [M+H]+, 30%, HRMS C8H15ON2S
[M+NH4]+ required 187.0905, found 187.0902.
3.1.16. 5-(3-Hydroxypropyl)-2-sulfolene-3-carbonitrile
(27). To a solution of 5-(3-hydroxypropyl)-4,5-dihydrothio-
phene-3-carbonitrile (26) (500 mg, 2.98 mmol) in methanol
(5 mL) was added dropwise at 0 ꢀC a solution of OxoneÒ
(9.1 g, 14.80 mmol) in water (50 mL). The reaction mixture
was stirred at this temperature for 1 h. Most of the methanol
was then evaporated and the residue was extracted with
EtOAc (3ꢂ30 mL). The combined organic extracts were
washed with water (3ꢂ20 mL), brine (20 mL), dried over
MgSO4, filtered and concentrated. Further purification by
flash chromatography (Pet. ether/EtOAc 1:4) gave 5-(3-
hydroxypropyl)-2-sulfolene-3-carbonitrile (27) (390 mg,
65%) as a thick yellow oil, Rf (Pet. ether/EtOAc 1:4) 0.35;
nmax (cmꢁ1) (thin film) 3530 (OH), 2230 (CN), 1309,
3.1.14. 3-(3-Cyano-4,5-dihydrothiophene-5-yl)-propyl
trifluoroacetate (25). To a solution of sodium methoxide
[prepared from sodium (4.36 g, 189 mmol) in methanol
(100 mL)] was added dropwise a solution of 2,2-dimethyl-
propionic acid 6-cyano-4-ethoxythiocarbonylsulfanyl-7,7-
dimethoxyheptyl ester (24) (2.51 g, 6.21 mmol) in methanol
(25 mL) at 0 ꢀC. Once addition was complete, the reaction
mixture was allowed to return to rt, stirred for 24 h, acidified
to pH 5 with Amberlite H-120 and filtered. Most of the meth-
anol was evaporated and the residue was dissolved in water
(50 mL) and extracted with dichloromethane (3ꢂ50 mL).
The combined organic extracts were dried over MgSO4, fil-
tered and concentrated. The residual oil was diluted with di-
chloromethane (70 mL), and trifluoroacetic acid (3.00 mL,
38.62 mmol) was added dropwise. The reaction mixture
was stirred at rt overnight, washed with water (3ꢂ30 mL),
saturated aqueous NaHCO3 (3ꢂ30 mL), brine (30 mL),
dried over MgSO4, filtered and concentrated. Further purifi-
cation by flash chromatography gave 3-(3-cyano-4,5-di-
hydrothiophene-5-yl)-propyl trifluoroacetate (25) (0.675 g,
41%) as a yellow oil along with deprotected product 26
1
1142, 1056; d H NMR (400 MHz, CDCl3) 1.64 (1H, br s,
OH), 1.69–2.17 (4H, m, 2ꢂCH2), 2.72 (1H, ddd, J¼17.6,
6.9, 2.6 Hz, one of ring CH2), 3.22 (1H, ddd, J¼17.6, 8.1,
1.7 Hz, one of ring CH2), 3.47–3.48 (1H, m, CHCH2),
3.73–3.78 (2H, m, CH2O), 7.30 (1H, m, CH olefinic);
d
13C NMR (100 MHz, CDCl3) 24.8, 29.3, 35.1, 58.8,
61.8, 112.9, 121.6, 142.6; m/z 202 ([M+H]+, 18%), HRMS
C8H12NO3S required 202.0538, found 202.0534.
Acknowledgements
We thank the EPSRC for a project studentship (N.A.-G.). We
thank the EPSRC mass spectrometry service for provision of
accurate mass spectral data. We would also like to thank
Professor Samir Zard for helpful conversations and provi-
sion of experimental detail.
(0.242 g, 23%), Rf (Pet. ether/EtOAc 4:1) 0.29; nmax (cmꢁ1
)
(thin film) 3070, 2208 (CN), 1786 (C]O), 1564, 1156;
d 1H NMR (400 MHz, CDCl3) 1.77–1.89 (4H, m, 2ꢂCH2),
2.73 (1H, ddd, J¼15.9, 5.7, 1.6 Hz, one of ring CH2), 3.16
(1H, ddd, J¼15.9, 9.3, 2.3 Hz, one of ring CH2), 3.88–3.95
(1H, m, CHCH2), 4.37 (2H, dt, J¼6.1, 2.0 Hz, CH2O),
7.12–7.13 (1H, m, CH olefinic); d 13C NMR (100 MHz,
CDCl3) 26.1, 32.5, 41.8, 50.3, 67.2, 103.0, 115.6, 115.7,
145.5, 157.6; d 19F NMR (376 MHz, CDCl3) ꢁ75.9 (s,
CF3); m/z 266 ([M+H]+, 17%), HRMS C10H14F3N2O2S
[M+NH4]+ required 283.0728, found 283.0726.
References and notes
1. Martyres, D. H.; Baldwin, J. E.; Adlington, R. M.; Lee, V.;
Probert, M. R.; Watkin, D. J. Tetrahedron 2001, 57, 4999–
5007; Dong, S.; Paquette, L. A. J. Org. Chem. 2005, 70, 1580–
1596 and refs. cited therein; Zhu, W.; Chong, Y.; Choo, H.;
Mathews, J.; Schinazi, R. F.; Chu, C. K. J. Med. Chem. 2004,
47, 1631–1640; Jeong, L. S.; Kim, H. O.; Moon, H. R.; Hong,
J. H.; Yoo, S. J.; Choi, W. J. J. Med. Chem. 2001, 44, 806–813.
2. (a) 3-Sulfolenes: Leonard, J.; Fearnley, S. P.; Hague, A. B.
Tetrahedron Lett. 1997, 38, 3071–3074 and refs. cited therein;
Lathbury, D. C.; Parsons, P. J.; Pinto, I. J. Chem. Soc., Chem.
Commun. 1988, 81–82; Spino, C.; Rezaei, H.; Dupont-
Gaudet, K.; Belanger, F. J. Am. Chem. Soc. 2004, 126, 9926–
9927; (b) 2-Sulfolenes: Lusinchi, M.; Stanbury, T. V.; Zard,
S. Z. Chem. Commun. 2002, 1532–1533.
3.1.15. 5-(3-Hydroxypropyl)-4,5-dihydrothiophene-3-
carbonitrile (26). To a solution of 3-(4-cyano-2,3-dihydro-
thiophene-2-yl)-propyl trifluoroacetate (25) (95.5 mg,
0.36 mmol) in methanol (2 mL) cooled to 0 ꢀC was added
dropwise a solution of potassium hydroxide (119 mg,
2.13 mmol) in water (5 mL). Once addition was complete,
the reaction mixture was stirred at the same temperature
for 10 min, then at rt for 45 min, acidified with 2 M HCl
and extracted with EtOAc (3ꢂ3 mL). The combined organic
extracts were washed with water (3ꢂ2 mL), brine (3 mL),

J. A. Wilkinson et al. / Tetrahedron 63 (2007) 1065–1073
1073
3. Duan, J.-A.; Williams, I. D.; Che, C.-T. Tetrahedron Lett. 1999,
40, 2593–2596; Liu, B. P. L.; Chong, E. Y. Y.; Cheung, F. W. K.;
Duan, J.-A.; Che, C.-T.; Liu, W. K. Biochem. Pharmacol. 2005,
70, 287–299; For previous syntheses see: Luo, S. J.; Zhao, J. R.;
Zhai, H. B. J. Org. Chem. 2004, 69, 4548–4550; Luo, S. J.;
Zificsak, C. A.; Hsung, R. P. Org. Lett. 2003, 5, 4709–4712;
Putkonen, T.; Tolvanen, A.; Jokela, R. Tetrahedron 2003, 59,
8589–8595 and refs. cited therein.
8. Binder, D.; Noe, C. R.; Baumann, K.; Wildburger, J. M. F. Arch.
Pharm. 1985, 318, 243–249.
9. Cheney, L. C.; Piening, J. R. J. Am. Chem. Soc. 1945, 67, 2213–
2214.
10. Tolstikov, G. A.; Kanzafarov, F. Y.; Sangalov, Y. A. J. Org.
Chem. USSR 1981, 203–211; Zh. Org. Khim. 1981, 17,
251–259.
11. Three 5-substituted-3-carboxy-2,5-dihydrothiophenes have
been reported, see Ref. 8. 3-Carboxy-3-sulfolenes substituted
in position 5 as well as at other positions are also known. See
for example Ref. 5.
12. Representative examples: Duus, F.; Lawesson, S.-O. Tetra-
hedron 1971, 27, 387–399; Dalgaard, L.; Lawesson, S.-O.
Tetrahedron 1972, 28, 2051–2063; Chatterjee, P.; Murphy,
P. J.; Shaw, M. J. Chem. Soc., Perkin Trans. 1 1994, 2403–2406.
13. See Ref. 2b, also: Binot, G.; Zard, S. Z. Tetrahedron Lett. 2003,
44, 7703–7706 and refs. cited therein.
4. Wilkinson, J. A.; Ardes-Guisot, N.; Ducki, S.; Leonard, J.
Tetrahedron Lett. 2005, 46, 8053–8056.
5. McIntosh, J. M.; Hayes, I. E. Can. J. Chem. 1987, 65, 110–113.
6. Treatment of 3-carboxy-3-sulfolene with 1 equiv of base gener-
ally gives 3-substitution while 2 equiv leads to clean 2-substi-
tution, see: Chou, T. S.; Tsai, C. Y.; Huang, L. J. J. Org.
Chem. 1990, 55, 5410–5413; Leonard, J.; Fearnley, S. P.;
Finlay, M. R. J. Chem. Soc., Perkin Trans. 1 1994, 2359–2362.
7. McIntosh, J. M.; Sieler, R. A. Can. J. Chem. 1978, 56, 226–231;
Stotter, P. L.; Roman, S. A.; Edwards, S. A. Tetrahedron Lett.
1972, 4071–4074.
14. Gheorge, A.; Quiclet-Sire, B.; Vila, X.; Zard, S. Org. Lett.
2005, 7, 1653–1656.