One-pot synthesis of trans-4-alkylthio- And 4-arylthio-cinnamic acids from trans-4-chlorosulfonylcinnamic acid in an aqueous medium

Article abstract of DOI:10.3184/030823408X347576

A one-pot syntheses of trans-4-alkylthio- and 4-arylthio-cinnamic acids were achieved in high yields by reduction of trans-4-chlorosulfonylcinnamic acid with stannous chloride dihydrate followed by alkylation and arylation of the resulting trans-4-thiocinnamic acid with various kinds of alkyl and activated aryl halides in an aqueous medium.

Full text of DOI:10.3184/030823408X347576

546 RESEARCH PAPER
SEPTEMBER, 546–548
JOURNAL OF CHEMICAL RESEARCH 2008
One-pot synthesis of trans-4-alkylthio- and 4-arylthio-cinnamic acids
from trans-4-chlorosulfonylcinnamic acid in an aqueous medium
Wensheng Zhanga,b, Chunxiang Kuanga* and Qing Yangc*
aDepartment of Chemistry, Tongji University, Siping Road 1239, Shanghai 200092, P.R. China
bDepartment of Chemistry, Jiaozuo Teachers’ College, Shanyang Road 998, Jiaozuo 454001, P.R. China
cSchool of Pharmacy, Fudan University, Yixueyuan Road 138, Shanghai 200032, P.R. China
A one-pot syntheses of trans-4-alkylthio- and 4-arylthio-cinnamic acids were achieved in high yields by reduction
of trans-4-chlorosulfonylcinnamic acid with stannous chloride dihydrate followed by alkylation and arylation of the
resulting trans-4-thiocinnamic acid with various kinds of alkyl and activated aryl halides in an aqueous medium.
Keywords: cinnamic acid, aqueous medium, alkylarylsulfide, diarylsulfide, trans-β-arylvinyl bromide, 4-chlorosulforyl-
cinnamie acid
Alkyl, arylanddiarylsulfidesareusefulsyntheticintermediates
in organic and medicinal chemistry.1 In addition, the scope
and application of organosulfur chemistry in organic synthetic
reactions has increased tremendously since sulfur-containing
groups serve as valuable auxiliary functions in synthetic
sequences.2 A variety of synthetic methods has been reported.
Among these methods, the synthetic process involving the
reaction of thiols and halogens in the presence of a strong
base is the most general method.3 Another important method
is the efficient transformation of sulfur-containing compounds
mediated by transition-metal catalysts (Pd or Cu).4-15
However, the use of thiols limits the synthetic scope of these
methods. Because thiols are unstable to oxidation and are
easily converted into undesirable disulfides (R–S–S–R), many
inconvenient procedures are needed in previous synthetic
procedures, including storage under an atmosphere of inert
gas and keeping the thiols from oxidants or substances that
give free radicals. In order to overcome this problem, one-pot
procedures for alkyl aryl sulfides by reaction between alkyl
halides and lithium arene thiolates or arene thiolate anions
prepared in situ have recently been reported.16,17
to prepare a series of trans-4-alkylthio- and 4-arylthio-
cinnamic acids 4 by a one-pot reaction starting from trans-4-
chlorosulfonylcinnamic acid 1 in an aqueous medium without
separation and purification of the intermediate 2 (Scheme 1).
In recent years, increasing attention has been focused
on organic reactions in aqueous media. Water is the
most favourable solvent in terms of operating cost and
environmental impact. The use of water as a solvent in organic
synthesis is often surprisingly effective even for reactions
that are traditionally carried out under anhydrous conditions.
Generally, sulfides are prepared by the reaction of alkali metal
salts of thiols with alkyl halides in organic solvents such as
DMF, DMSO, MeCN, i-PrOH and EtOH.20-23 Only one case
of the synthesis of an alkyl aryl sulfide in an aqueous medium
CO2
H
CO2H
1 ) Sn Cl2 2H2O
HCl(aq.)/HO Ac
70oC - rt
ClO2
S
HS
1
2
CO2
H
R-X(3) / NaOH-H2O
rt - 90o
C
Trans 4-alkylthio- and 4-arylthio-cinnamic acids containing
both sulfide and cinnamic acid groups are used as versatile
building blocks in the syntheses of various antibacterials,
antifungals, compounds with antiparasitical activity, natural
products and polymers.18,19 Here we report a facile strategy
RS
4
Scheme 1 One-pot synthesis of trans-4-alkylthio- and 4-
arylthio-cinnamic acids.
Table 1 One-pot synthesis of 4 from trans-4-chlorosulfonylcinnamic acid 1 and alkyl and activated aryl halides 3
Entry
R–X (3)
Product (4)
t/h
T/°C
Yielda/%
87
CO2
H
1
Mel
3a
3b
4a
4b
2
rt
MeS
CO2
H
2
3
n-BuBr
5
5
70
90
83
82
n-BuS
CO2
H
PhCH2Cl
3c
4c
Ph CH2
S
O2
N
CO2
H
4
5
3d
3e
4d
4e
5
5
90
90
83
80
O2
N
Cl
S
CO2
H
NO2
Cl
S
NO2
aIsolated yield based on acid 1.
* Correspondent. E-mail: kuangcx@mail.tongji.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2008 547
has been reported.24 Because of the excellent solubility
of compound 2 in dilute aqueous sodium hydroxide, we
attempted to develop a novel one-pot synthetic procedure for
the preparation of trans-4-alkylthio- and 4-arylthio-cinnamic
acids from trans-4-chlorosulfonylcinnamic acid in an aqueous
medium.
CO 2H
B r
NBS, LiOAc
S
S
CH3CN / H2
rt, 3 h
O
NO2
NO2
(5e)
(4e)
Reduction of trans-4-chlorosulfonylcinnamic acid 1 (1.0
equiv.) with stannous chloride dihydrate (5.0 equiv.) followed
by alkylation and arylation of the resulting 2 with various
kinds of alkyl and activated aryl halides (1.1 equiv.) at room
temperature –90°C in an aqueous medium proceeded in high
yields. Results and reaction conditions are shown in Table 1.
To our knowledge, this is the first case of a one-pot procedure
for the synthesis of both alkyl aryl sulfides and dialkyl
sulfides starting from easily available arylsulfonyl chloride
derivatives in an aqueous medium. Applying the one-pot
protocol, methyl iodide (3a) was reacted at room temperature
and the yield of 4a was considerably improved compared
to a two-step method in which compound 2 was separated
from the reduction step and 4a was obtained by the
successive alkylation of 2 only in 65% yield. This is mainly
due to the instability of 2 which is easily converted into
disulfide when exposed to the air and is difficult to purify by
crystallisation.25
Scheme 2 Bromodecarboxylation of trans-4-(2-
nitrophenylthio) cinnamic acid (4e).
(1125 mg, 5 mmol) in hydrochloric acid (1.1 ml) at 70°C and the
resulting colourless solution was allowed to reach room temperature
for 2 h until a large amount of white solid appeared. To the stirred
solution was added 20% aqueous sodium hydroxide (15 ml) to basify
the reaction system to a pH of 9 and then halides 3 (1.1 mmol) were
added at the reaction temperature specified in Table 1. The reaction
mixture was stirred for 2 h at the corresponding reaction temperature,
cooled to room temperature, acidified with 6 M aqueous hydrochloric
acid (12 ml) and filtered. The solid was washed with 6 M aqueous
hydrochloric acid (30 ml), cooled water (3 × 15 ml), and dried under
reduced pressure to give the crude products. Purification of the crude
products by column chromatography on silica gel (petroleum ether/
ethyl acetate/HOAc = 80/40/1) provided the desired products 4.
Trans-4-methylthiocinnamic acid (4a): Following the general
procedure at room temperature, trans-4-chlorosulfonyl cinnamic acid
1 (247 mg, 1 mmol) was converted into trans-4-methylthiocinnamic
acid 4a. This was a white powder (169 mg, 95% yield). M.p. 172–
1
173°C; H NMR (400 MHz, DMSO-d6): δ 2.52 (3H, s), 6.47 (1H,
The reactions of n-butyl bromide 3b and benzyl chloride 3c
with 2 proceeded smoothly to give trans-4-alkylthiocinnamic
acids 4b and 4c in good yields at 70°C and 90°C, respectively.
Experiments were also carried out between the intermediate
2 and activated aryl halides such as 4-chloronitrobenzene
3d and 2-chloronitrobenzene 3e. The reactions proceeded at
90°C and gave the corresponding trans-4-arylthiocinnamic
acids 4d and 4e in high yields.
These synthesised cinnamic acids derivatives could be
further applied to the stereoselective synthesis of valuable
trans-β-arylvinyl bromides,26,27 which are important building
blocks in organic synthesis, especially as intermediates for
carbon–carbon and carbon–hetero atom bond formation
by transition metal-catalysed coupling reactions. The
bromodecarboxylation reaction of 4e with NBS using a
catalytic amount of LiOAc in CH3CN–H2O afforded 5e
(Scheme 2).
In summary, trans-4-alkylthio- and 4-arylthio-cinnamic
acids can be synthesised by a facile one-pot reaction between
trans-4-chlorosulfonylcinnamic acid and alkyl or activated
aryl halides in an aqueous medium. The present method
avoids the oxidation of trans-4-thiocinnamic acid to form the
undesired disulfide, thus enhancing the yields of the products.
This method provides several advantages such as high yields,
simple work-up procedure and is environmentally friendly.
d, J = 15.9 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.54 (1H, d, J = 15.9 Hz),
7.62 (2H, d, J = 8.4 Hz); 13C NMR (500 MHz, DMSO-d6): δ 14.90,
118.36, 126.03, 128.69, 130.76, 141.67, 143.64, 167.93; IR (KBr):
3433, 2961, 1681, 1617, 1591, 1493, 1423, 980, 815, 710 cm-1.
HRMS calc. for C10H10O2S [M]+: 194.0401; found: 194.0402.
Trans-4-(butylthio)cinnamic acid (4b): Following the general
procedure at 70°C, trans-4-chlorosulfonylcinnamic acid 1 (247 mg,
1 mmol) was converted into trans-4-butylthiocinnamic acid 4b. This
was a white powder (195 mg, 83% yield). M.p.139–140°C; 1H NMR
(400 MHz, DMSO-d6): δ 0.85 (3H, t, J = 7.3 Hz), 1.38–1.52 (2H, m),
1.54–1.59 (2H, m), 2.99 (2H, t, J = 7.3 Hz), 6.47 (1H, d, J = 15.9 Hz),
7.23 (2H, d, J = 8.4 Hz), 7.54 (1H, d, J = 15.9 Hz), 7.60 (2H, d, J
= 8.4 Hz); 13C NMR (500 MHz, DMSO-d6): δ 13.70, 21.84, 30.94,
46.64, 118.32, 127.64, 128.36, 130.67, 135.48, 143.60, 168.24; IR
(KBr): 3456, 2958, 2920, 2862, 1681, 1626, 1588, 1493, 1426, 986,
815, 716 cm-1. HRMS calc. for C13H16O2S [M]+: 236.0872; found:
236.0871.
Trans-4-benzylthiocinnamic acid (4c): Following the general
procedure at 90°C, trans-4-chlorosulfonyl cinnamic acid 1 (247 mg,
1 mmol) was converted into trans-4-benzylthiocinnamic acid 4c.
This was a white powder (223 mg, 83% yield). M.p. 194–195°C;
1H NMR (400 MHz, DMSO-d6): δ 4.35 (2H, s), 6.52 (1H, d,
J = 15.9 Hz), 7.26–7.29 (1H, m), 7.33–7.39 (2H, m), 7.36 (2H, d,
J = 8.2 Hz), 7.39–7.44 (2H, m), 7.56 (1H, d, J = 15.9 Hz), 7.64
(2H, d, J = 8.2 Hz), 12.40 (1H, s); 13C NMR (500 MHz, DMSO-
d6): δ 36.87, 118.74, 127.28, 128.06, 128.46, 128.54, 128.89, 131.86,
137.11, 139.56, 143.31, 167.79; IR (KBr): 3429, 2958, 1676, 1618,
1583, 1497, 1419, 978, 816, 715 cm-1. HRMS calc. for C16H14O2S
[M]+: 270.0715; found: 270.0716.
Trans-4-(4-nitrophenylthio)cinnamic acid (4d): Following the
general procedure at 90°C, trans-4-chlorosulfonylcinnamic acid 1
(247 mg, 1 mmol) was converted into trans-4-(4-nitrophenyl-
thio)cinnamic acid 4d. Ths was a pale yellow powder (250 mg,
Experimental
Melting points were recorded using an A. KRÜSS Optronic GmbH
KSPII Melting-Point Meter and were uncorrected. H NMR spectra
1
1
83% yield). M.p. 215.5–216.5°C; H NMR (400 MHz, DMSO-d6):
were recorded using a Bruker AM-400 spectrometer in DMSO-d6
or CDCl3–DMSO-d6 with SiMe4 as an internal standard. 13C NMR
spectra were recorded using a Bruker AM-500 spectrometer in
DMSO-d6 or CDCl3–DMSO-d6 with SiMe4 as an internal standard.
HRMS were measured by the EI method. IR spectra were performed
δ 6.62 (1H, d, J = 16.2 Hz), 7.34 (2H, d, J = 8.2 Hz), 7.56 (2H, d,
J = 7.9 Hz), 7.63 (1H, d, J = 16.2 Hz), 7.82 (2H, d, J = 7.9 Hz), 8.16
(2H, d, J = 8.2 Hz), 12.53 (1H, s); 13C NMR (500 MHz, DMSO-d6):
δ 121.08, 124.54, 128.27, 129.84, 132.98, 134.08, 135.60, 142.74,
145.84, 146.63, 167.61; IR (KBr): 3429, 1681, 1624, 1583, 1497,
1419, 1338, 978, 845, 738 cm-1. HRMS calc. for C15H11NO4S
[M]+: 301.0409; found: 301.0410.
Trans-4-(2-nitrophenylthio)cinnamic acid (4e): Following
the general procedure at 90°C, trans-4-chlorosulfonyl cinnamic
acid 1 (247 mg, 1 mmol) was converted into trans-4-(2-nitro-
phenylthio)cinnamic acid 4e. This was a yellow solid (241 mg,
80% yield). M.p. 261–262°C; 1H NMR (400 MHz, DMSO-d6):
δ 6.64 (1H, d, J = 15.9 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.40–7.44
(1H, m), 7.58–7.60 (1H, m), 7.62 (2H, d, J = 8.4 Hz), 7.64 (1H, d,
J = 15.9 Hz), 7.84 (2H, d, J = 8.4 Hz), 8.23–8.25 (1H, m), 12.55(1H,
s); 13C NMR (500 MHz, DMSO-d6): δ 121.27, 125.77, 126.27,
129.08, 129.76, 133.01, 134.16, 135.49, 135.65, 136.11, 137.22,
on
a Nexus FT-IR spectrophotometer. Commercially obtained
reagents were used without further purification. All reactions were
monitored by TLC with HuanghaiGF254 silica gel coated plates.
Column chromatography was carried out using 300–400 mesh silica
gel at medium pressure.
Typical procedure for the preparation of trans-4-alkylthio- and 4-
arylthio-cinnamic acids (4)
To a stirred glacial acetic acid (7.4 ml) suspension of trans-4-
chlorosulfonylcinnamic acid (1, 247 mg, 1 mmol), which was prepared
from trans-cinnamic acid and chlorosulfuric acid according to the
procedure of Finn et al.,28 was added stannous chloride dihydrate

548 JOURNAL OF CHEMICAL RESEARCH 2008
4
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978, 854, 822, 781, 724 cm-1. HRMS calc. for C15H11NO4S [M]+:
301.0409; found: 301.0409.
Preparation of trans-4-arylthio arylvinyl bromides (5e): To a
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7
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1
as a yellow solid (326 mg, 97% yield). M.p. 123–124°C; H NMR
(400 MHz, CDCl3): δ 6.87–6.89 (1H, m), 6.91 (1H, d, J = 14.1 Hz),
7.15 (1H, d, J = 14.1 Hz), 7.24–7.26 (1H, m), 7.33–7.37 (1H, m),
7.40 (2H, d, J = 8.2 Hz), 7.54 (2H, d, J = 8.2 Hz), 8.22–8.24 (1H,
m); 13C NMR (500 MHz, CDCl3): δ 108.76, 125.15, 125.73, 127.53,
128.42, 131.15, 133.39, 136.07, 137.43, 138.83, 139.25, 145.33; IR
(KBr): 1598, 1560, 1508, 1453, 1334, 980, 932, 845, 779, 729 cm-1.
HRMS calc. for C14H1079BrNO2S [M]+: 334.9616; found: 334.9617.
This work was supported by the Natural Science Foundation
of Shanghai, China (No. 06ZR14085) and by the Scientific
Research Foundation for the Returned Overseas Chinese
Scholars, State Education Ministry. We would like to thank the
Centre for Instrumental Analysis, Tongji University, China.
Received 20 June 2008; accepted 7 July 2008
Paper 08/5338 doi: 10.3184/030823408X347576
Published online: 8 September 2008
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