A fortuitously straightforward synthesis of 4-acetoxy-2-propyltetrahydrothiophene

Article abstract of DOI:10.3184/174751915X14476078040135

4-Acetoxy-2-propyltetrahydrothiophene was synthesised from 1-hepten-4-ol by a three-step route involving epoxidation and mesylation to 1,2-epoxy-4-heptyl mesylate and then reaction with thioacetate. An acetoxylated cyclic product was formed instead of the expected thioacetate, and a mechanism for its formation using an intramolecular transesterification is proposed.

Full text of DOI:10.3184/174751915X14476078040135

724 RESEARCH PAPER
VOL. 39 DECEMBER, 724–726
JOURNAL OF CHEMICAL RESEARCH 2015
A fortuitously straightforward synthesis of 4-acetoxy-2-propyltetrahydrothiophene
Bianbian Maa, Shaoxiang Yanga, Feiyan Taob, Baoguo Suna, Yongguo Liua and Hongyu Tiana,*
aBeijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing Key Laboratory of Flavour Chemistry, Beijing Technology and Business
University, Beijing 100048, P.R. China
bTechnical Research & Development Center, Chuanyu Branch of China Tobacco Corporation, Chengdu, P.R. China
4-Acetoxy-2-propyltetrahydrothiophene was synthesised from 1-hepten-4-ol by a three-step route involving epoxidation and mesylation
to 1,2-epoxy-4-heptyl mesylate and then reaction with thioacetate. An acetoxylated cyclic product was formed instead of the expected
thioacetate, and a mechanism for its formation using an intramolecular transesterification is proposed.
Keywords: 1-hepten-4-ol, 1,2-epoxy-4-heptanol, 1,2-epoxy-4-heptyl mesylate, 4-acetoxy-2-propyltetrahydrothiophene, thioacetate
Tetrahydrothiophenes occur widely as important building
blocks of many biologically active molecules, such as 3´-hetero-
dideoxy nucleoside analogues as potential anti-HIV agents,1,2
modified dideoxy isonucleosides with antiviral activity,3
the essential coenzyme biotin as a water-soluble vitamin
with important biological functions,4 so do their derivatives,
such as the corresponding cyclic sulfonium salts, the potent
a-glucosidase inhibitors salacinol,5,6 kotalanol,7 salaprinol
and ponkoranol8,9 isolated from several Salacia plant species,
and the related cyclic sulfolanes as high-affinity P2 ligands
for HIV-1 protease inhibitors.10 A comprehensive review
about the methods for the synthesis of tetrahydrothiophenes,
provided by Benetti et al.,11 included several different ways
to produce chiral nonracemic tetrahydrothiophenes and
some typical synthetic routes for the racemates. However, the
available synthetic methods for both racemic and nonracemic
tetrahydrothiophenes are still insufficient in view of the
significance of tetrahydrothiophenes as basic scaffolds of many
potential biologically active molecules and their versatilities
in the field of applications.12-15 More practically feasible routes
with operational simplicity, high chemo- and regioselectivities
and high yields awaited development.
In our present work concerning the synthesis of flavour
compounds with 1,3-oxygen-sulfur functionality, the reaction
of 1,2-epoxy-4-heptyl mesylate with thioacetic acid gave an
unexpected product, 4-acetoxy-2-propyltetrahydrothiophene 1.
As far as we know, there are only a few methods reported in
the literature to prepare such analogues. One of the analogues,
nonracemic 5-[(benzyloxy)methyl]tetrahydrothiophen-3-ol was
prepared by starting from diacetone-D-glucose through a 12-
step route,1,2 and the other one, 5-methyltetrahydrothiophene-
3-ol was obtained by starting from ethyl 3-bromobutanoate
the method we discovered fortuitously is more straightforward.
We now show that 4-acetoxy-2-propyltetrahydrothiophene can
be prepared easily by starting from 1-hepten-4-ol.
Results and discussion
Our three-step synthesis is shown in Scheme 1. 1-Hepten-4-ol 2,
prepared by the Grignard reaction of allylmagnesium chloride
with n-butanal, was epoxidised with MCPBA to produce
1,2-epoxy-4-heptanol 3, as previously described by us.19 3 was
then reacted with MsCl to give 1,2-epoxy-4-heptyl mesylate
1
4. The H NMR spectra of epoxy alcohol 3 and its mesylate 4
showed that both of them were a mixture of diasteroisomers with
a ratio of about 1/1. The original plan was that thioacetylation of
mesylate 4 would be achieved by treatment with thioacetic acid
in MeCN in the presence of potassium carbonate. However,
the 13C NMR spectrum of the crude product indicated that no
thioacetyl group was present since there was not a signal at d
about 195, which is characteristic of the C=O of a thioacetyl
group.17,18 The unknown mixture was analysed by GC/MS
which showed that it consisted of two major components in a
ratio of about 1/1. It was tentatively deduced that the two major
components were a pair of isomers based on the high similarity
of their EI mass spectra. The two components were separated
on a silica column with an effluent of petroleum ether/ethyl
acetate, 50/1. 1H and 13C NMR spectra of both products
indicated that the mesyl group and the epoxy group in the
substrate 4 have disappeared. The signals at d around 77 and
170 in the 13C NMR spectrum and at d around 5.4 in 1H NMR
spectrum demonstrated the possible presence of an ester group
in the two products, although the signals at d around 5.4 in the
1H NMR spectrum appeared at a lower field than is used for the
proton on a carbon attached directly to an acetoxy group.
and
substitution,
ethyl
2-mercaptoacetate
intramolecular
through
Claisen
nucleophilic
condensation,
In order to identify the structures of the two products, the
two samples were analysed further using high resolution
mass spectroscopy, DEPT, H,H- and H,C-correlation, and
HMBC methods. Both products were identified to have the
same molecular formula of C9H16O2S by high resolution mass
spectroscopy. It could be concluded based on all the obtained
data that the two products should be cis- and trans-4-acetoxy-
hydrolysis and decarboxylation, and reduction.10 In addition,
5-[(methoxycarbonyl)methylene]tetrahydrothiophen-3-ol was
prepared by the reaction of d-chloromethyl a,b-unsaturated
d-lactone with thioacetic acid followed by treatment with
potassium carbonate.16 Compared with these synthetic routes,
AcO
OMs
OH
OH
O
O
MCPBA
MsCl
AcSK
S
3
2
4
1
Scheme 1
* Correspondent. E-mail: tianhy@btbu.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2015 725
O
O
AcS-
O
O-
S
SAc
OMs
R
O
S
O
R
R
R
AcS-
SAc
4
5
SAc
6
AcO
AcS
AcO
OAc
S
R
R
R
S
S
SAc
7
1a,b
Scheme 2
by addition of 5% HCl solution at 0–5 °C. The reaction mixture was
then extracted with CH2Cl2, and the combined organic phases were
washed with saturated aqueous NaHCO3 solution and saturated brine
successively, dried over MgSO4, and concentrated under reduced
pressure. After concentration, the residue was purified by column
chromatography (petroleum ether/ethyl acetate, 6:1) to give 4 (3.8
H
OAc
H
H
H
H
H
H
S
AcO
S
H
H
-n
-n
H
7
H
C3
C3
7
H
H
H
1b trans-
1a cis-
,
,
1
g, 91% yield) as a light yellow oil. H NMR (CDCl3) d 0.94 (m, 3 H,
H–C-7), 1.32–1.52 (m, 2 H, H–C-6), 1.64-1.86 (m, 3 H, H–C-3 and
H–C-5), 1.98–2.11 (m, 1 H, H´–C-3), 2.48 (dd, J = 4.8, 2.7 Hz, 0.56
H, H–C-1, major diastereoisomer), 2.52 (dd, J = 5.1, 2.7 Hz, 0.44 H,
H–C-1, minor diastereoisomer), 2.78 (t, J = 4.8 Hz, 0.56 H, H–C-1,
major diastereoisomer), 2.83 (t, J = 5.1 Hz, 0.44 H, H–C-1, minor
diastereoisomer), 3.00–3.10 (m, 4 H, H–C-2 and Me (mesyl)),
4.89 (m, 1 H, H–C-4); 13C NMR (CDCl3) d 13.60 (C-7, major
diastereoisomer), 13.64 (C-7, minor diastereoisomer), 18.05 (C-6,
minor diastereoisomer), 18.33 (C-6, major diastereoisomer), 36.55 (C-
3, major diastereoisomer), 37.07 (C-3, minor diastereoisomer), 37.65
(C-5, major diastereoisomer), 37.70 (C-5, minor diastereoisomer),
38.30 (Me (mesyl), minor diastereoisomer), 38.41 (Me (mesyl), major
diastereoisomer), 46.04 (C-1, major diastereoisomer), 47.18 (C-1,
minor diastereoisomer), 48.40 (C-2, major diastereoisomer), 48.48 (C-
2, minor diastereoisomer), 80.93 (C-4, minor diastereoisomer), 81.03
(C-4, major diastereoisomer); HRESIMS, m/z 231.066074 [M+Na+]
(Calcd. for C8H16NaO4S, 231.066151).
Fig. 1 cis- and trans-4-Acetoxy-2-propyltetrahydrothiophene.
2-propyltetrahydrothiophene 1a,b respectively as shown in Fig.
1. The two isomers were analysed further by conducting NOE
experiments with the irradiation of signal of H–C-2 or H–C-4.
The results of NOE difference spectra permitted the assignment
of the cis isomer (1a) and indicated that the signal of H–C-4 (d
5.31) of the cis-isomer appeared at a relatively higher field than
that (d 5.50) of the trans-isomer (1b).
The proposed pathway of formation of 1a and 1b is shown in
Scheme 2. The mesylate 4 suffered two successive nucleophilic
substitutions by thioacetate to produce the intermediate 5,
which underwent an intramolecular transfer of an acetyl
group through a six-membered cyclic intermediate 6 to give
intermediate 7. The final product, which was formed via an
intramolecular nucleophilic displacement of a thioacetyl group
by an alkylthio group in intermediate 7, was a mixture of cis-
and trans-4-acetoxy-2-propyltetrahydrothiophene 1a,b.
We plan to extend the application of this efficient synthetic
route to a wide range of homoallylic alcohols with different
substituents to give novel disubstituted tetrahydrothiophenes. In
addition, chiral non-racemic disubstituted tetrahydrothiophenes
could easily be prepared using this route since the preparation
of optically active homoallylic alcohols and asymmetric
epoxidation can be achieved by many well-known methods.
4-Acetoxy-2-propyltetrahydrothiophene (1): Thioacetic acid (2.0
mL, 28 mmol) was added to a mixture of anhydrous potassium
carbonate (5.5 g, 40 mmol), absolute acetonitrile (100 mL) and
18-crown-6 (0.26 g, 1 mmol). The mixture was stirred at room
temperature for 15 min and 1,2-epoxy-4-heptyl mesylate 4 (4.2 g, 20
mmol）was added. After the addition, the mixture was heated at reflux
for 12 h. The reaction mixture was cooled to room temperature and
filtered. The filtrate was acidified with 5% aqueous HCl, and then
extracted with diethyl ether. The combined organic layers were washed
with saturated aqueous NaHCO3 solution and brine successively and
dried over MgSO4. After concentration under vacuum, the residue was
submitted to column chromatography (petroleum ether/ethyl acetate,
50:1) to give cis- and trans-isomer of 1 separately as a light yellow oil.
Experimental
Allyl chloride (98%) and m-chloroperoxybenzoic acid (MCPBA, 70%)
were purchased from Beijing Bailingwei Science and Technology
Company (Beijing, China). The other chemicals and all solvents were
purchased from Beijing Huaxue Shiji Company (Beijing, China). NMR
spectra were obtained on a Bruker AV300 or 600 MHz NMR (1H NMR
at 300 or 600 MHz, 13C NMR at 75 or 150 MHz) in CDCl3 using TMS
as internal standard. Chemical shifts (d) are given in ppm and coupling
constants (J) in Hz. The high resolution mass spectra were obtained on
a Bruker Apex IV FTMS.
1-Hepten-4-ol (2) and 1,2-epoxy-4-heptanol (3): Both prepared as
previously described; the NMR data were consistent with those we
have already reported.19
1,2-Epoxy-4-heptyl mesylate (4): 1,2-Epoxy-4-heptanol 3 (2.6 g,
20 mmol) was dissolved in dry CH2Cl2 (40 mL) and cooled to 0 °C.
Triethylamine (5.6 mL, 40 mmol) and methanesulfonylchloride (2.3
mL, 30 mmol) were slowly added at 0–5 °C successively. After stirring
at room temperature for 12 h, the reaction mixture was acidified
1
cis-Isomer (1a): Yield 1.6 g (43%). H NMR (CDCl3) d 0.94 (t, J =
7.2 Hz, 3 H, H–C-3´), 1.32–1.48 (m, 2 H, H–C-2´), 1.58–1.74 (m, 2 H,
H–C-1´), 1.80 (dt, J = 12.6, 7.8 Hz, 1 H, H–C-3), 2.08 (s, 3 H, Me(Ac)),
2.41 (dt, J = 12.6, 6.0 Hz, 1 H, H´–C-3), 2.89 (dd, J = 11.4, 6.6 Hz,
1 H, H–C-5), 3.16 (dd, J = 11.4, 6.6 Hz, 1 H, H´–C-5), 3.39 (m, 1 H,
H–C-2), 5.31 (m, 1 H, H–C-4); 13C NMR (CDCl3) d 13.86 (C-3´),
21.15 (Me(Ac)), 21.90 (C-2´), 35.35 (C-5), 40.07 (C-1´), 41.07 (C-3),
44.83 (C-2), 76.52 (C-4), 170.55 (C=O); HRESIMS, m/z 211.076359
[M+Na+] (calcd for C9H16NaO2S, 211.076321).
trans-Isomer (1b): Yield 1.7 g (45%). 1H NMR (CDCl3) d 0.95 (t, J =
7.8 Hz, 3 H, H–C-3´), 1.42 (m, 2 H, H–C-2´), 1.59 (m, 1 H, H–C-1´),
1.65-1.75 (m, 2 H, H–C-3 and H´–C-1´), 2.08 (s, 3 H, Me(Ac)), 2.30
(dd, J = 13.2, 5.4 Hz, 1 H, H´–C-3), 2.93 (d, J = 12.0 Hz, 1 H, H–C-5),
3.23 (dd, J = 12.0, 4.8 Hz, 1 H, H´–C-5), 3.57 (m, 1 H, H–C-2), 5.50
(m, 1 H, H–C-4); 13C NMR (CDCl3) d 13.99 (C-3´), 21.25 (Me(Ac)),

726 JOURNAL OF CHEMICAL RESEARCH 2015
6
7
8
9
M. Yoshikawa, T. Morikawa, H. Matsuda, G. Tanabe and O. Muraoka,
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M. Yoshikawa, T. Murakami, K. Yashiro and H. Matsuda, Chem. Pharm.
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22.49 (C-2´), 37.07 (C-5), 38.81 (C-1´), 42.55 (C-3), 46.77 (C-2), 77.18
(C-4), 170.54 (C=O); HRESIMS, m/z 211.076385 [M+Na+] (calcd for
C9H16NaO2S, 211.076321).
Financial support from the National Natural Science
Foundation of China (No. 31271932 and 31571886), the
National Key Technology R&D Program (2011BAD23B01)
and the Importation and Development of High-Caliber Talents
Project of Beijing Municipal Institutions (CIT&TCD20140306)
is gratefully acknowledged.
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13 M. Davoust, J.-F. Brière, P.-A. Jaffrès and P. Metzner, J. Org. Chem., 2005,
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Received 7 October 2015; accepted 2 November 2015
Paper 1503640 doi: 10.3184/174751915X14476078040135
Published online: 1 December 2015
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