A simple, efficient, and green procedure for the 1,4-addition of thiols to conjugated alkenes and alkynes catalyzed by sodium acetate in aqueous medium

Article abstract of DOI:10.1071/CH06455

A benign and inexpensive salt, sodium acetate, efficiently catalyzes 1,4-addition of thiols to a variety of conjugated alkenes such as ?,?-unsaturated ketones, aldehydes, carboxylic esters, nitriles, nitro compounds, and chalcones in aqueous THF. The reac

Full text of DOI:10.1071/CH06455

Communication
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2007, 60, 223–227
A Simple, Efficient, and Green Procedure for the 1,4-Addition
of Thiols to Conjugated Alkenes and Alkynes Catalyzed
by Sodium Acetate in Aqueous Medium
Brindaban C. RanuA,B and Tanmay MandalA
ADepartment of Organic Chemistry, Indian Association for the Cultivation of Science,
Jadavpur, Calcutta 700 032, India.
BCorresponding author. Email: ocbcr@iacs.res.in
A benign and inexpensive salt, sodium acetate, efficiently catalyzes 1,4-addition of thiols to a variety of conjugated alkenes
such as α,β-unsaturated ketones, aldehydes, carboxylic esters, nitriles, nitro compounds, and chalcones in aqueous THF.
The reactions are clean, fast, and high yielding.
Manuscript received: 24 October 2006.
Final version: 28 December 2006.
The 1,4-addition of thiols to conjugated alkenes has attracted
considerable interest in recent times[1] as it leads to the syn-
thesis of compounds with promising biological activities.[2]
Traditionally, this conjugate addition is based either on the
activation of thiol by a base[3] or activation of the acceptor
olefins with Lewis acids.[4] However, to avoid side reactions
occasionally encountered in the presence of a strong base or
acid, several clays and inorganic salts such as montmorillonite
K10,[4a] fluorapatite,[5] natural phosphate doped by potassium
fluoride,[6] Na2CaP2O7,[7] Bi(OTf)3,[8] Bi(NO3)3,[9] and ionic
liquids[10] have been introduced. However, these procedures are
also associated with drawbacks such as use of hazardous solvents
like benzene,[4a] chlorinated hydrocarbons,[9] acetonitrile,[8] the
relatively high cost of reagents, and lower yields. Thus, a sim-
ple, cost-effective, green, andefficientprocedure willbe of much
importance. We report here the novel application of a very cheap
and benign reagent, sodium acetate, as an efficient catalyst for
the 1,4-addition of thiols to conjugated alkenes (Scheme 1).
A very simple experimental procedure was developed for the
conjugate addition of thiols to alkenes in aqueous THF (1:1) in
the presence of sodium acetate (15 mol%) at room temperature.
However, the reactions with conjugated alkynes needed to be
carried out at 70◦C. The products were isolated by usual workup
X
X
NaOAc
THF, H2O
rt
RSH ϩ
R1
RS
R1
X ϭ CHO, COMe, COPh, CO2Me, CN, NO2
R1 ϭ alkyl/aryl, R ϭ alkyl/aryl
Scheme 1.
Table 1. 1,4-Addition of thiols to conjugated alkenes catalyzed by NaOAc
Entry
1
Conjugated alkene
Thiol
Time [h]
2.5
Product
Yield [%]A ref.
80 [10b]
O
H
C4H9S
O
n-C4H6SH
H
O
H
O
C2H5S
2
C2H5SH
3.5
73
H
O
O
O
3
4
C6H5SH
2.0
2.5
85 [8]
C6H5S
O
C6H5CH2SH
75 [1f]
C6H5CH2S
(Continued)
© CSIRO 2007
10.1071/CH06455
0004-9425/07/030223

224
B. C. Ranu and T. Mandal
Table 1. Continued
Entry
5
Conjugated alkene
Thiol
Time [h]
Product
Yield [%]A ref.
86
O
O
p-ClC6H4S
p-ClC6H4SH
3.5
3.5
O
C6H5S
O
O
O
O
O
6
7
C6H5SH
85
O
O
C2H5SH
2.5
90 [10b]
SC2H5
SC4H9
SC6H5
O
O
O
O
8
9
n-C4H9SH
2.5
2.0
90 [9]
C6H5SH
90 [10c]
O
O
10
11
C6H5SH
C6H5SH
2.5
3.0
75 [10b]
82 [10b]
OCH3
C6H5S
OCH3
CO2Et
CO2Et
CO2Et
CO2Et
C6H5S
C6H5S
C6H5S
CN
CN
12
13
C6H5SH
C6H5SH
2.5
3.0
72 [10b]
70 [1f]
CN
CN
C6H5S
NO2
NO2
14
15
16
17
C6H5SH
C2H5SH
n-C4H9SH
C6H5SH
45
80
C2H5S
NO2
NO2
O
O
O
O
4.0
3.5
3.0
75
O
O
O
O
O
O
C4H9S
80 [10c]
90 [6]
C6H5S
C6H5S
18
19
C6H5SH
3.5
2.5
80 [10c]
CH3
CH3
O
O
C4H9S
n-C4H9SH
85 [10c]
CH3O
CH3O
(Continued)

A Procedure for 1,4-Addition of Thiols to Conjugated Alkenes and Alkynes
225
Table 1. Continued
Entry
20
Conjugated alkene
Thiol
Time [h]
3.0
Product
C2H5S
Yield [%]A ref.
O
O
C2H5SH
75
Cl
Cl
O
p-ClC6H4S
O
21
22
p-ClC6H4SH
n-C4H9SH
3.5
4.5
76 [10c]
O2N
O2N
C4H9S
O
O
80
O
O
C4H9S
C4H9S
O
O
O
O
23
24
n-C4H9SH
n-C4H9SH
4.0
4.0
80 [10c]
80 [10c]
CH3
CH3
OAc
OAc
SC4H9
O
C4H9S
O
25
26
n-C4H9SH
3.5
3.0
70 [10c]
78
C6H5S
S
O
O
C6H5SH
S
AYields refer to those of pure and isolated products characterized by IR, 1H and 13C NMR spectroscopic data.
Table 2. 1,4-Addition of thiols and dithiols to conjugated acetylinic ketones
Entry
1
Acetylenic ketone
Thiol
Time [h]
3.0
Product
Yield [%]A ref.
75 [13]
O
O
SC2H5
SC2H5
C2H5SH
H
O
O
O
SC4H9
SC4H9
2
3
4
5
6
n-C4H9SH
3.0
2.5
2.5
3.5
3.5
70 [15]
80 [14]
75
H
O
SC6H5
SC6H5
C6H5SH
H
SC6H4p-Cl
SC6H4p-Cl
O
O
O
O
p-ClC6H4SH
HS(CH2)2SH
HS(CH2)3SH
H
O
S
74 [14]
72 [14]
S
S
H
O
S
H
AYields refer to those of pure and isolated products characterized by IR, 1H and 13C NMR spectroscopic data.

226
B. C. Ranu and T. Mandal
Table 3. IR, and 1H and 13C NMR data and elemental analysis of products
Entries 2, 5, 6, 14, 15, 20, 22, 26 in Table 1 and entry 4 in Table 2
Entry
2
νmax [cm−1
]
δH [ppm]
δC [ppm]
Analysis [%]
1452, 1478, 1724, 2727
1.17 (t, 3H, J 7.41), 2.30–2.39 (m, 2H),
2.95 (d, 2H, J 7.50), 4.37 (t, 1H, J 7.50),
7.25–7.38 (m, 5H), 9.6 (t, 1H, J 1.68)
14.6, 25.5, 43.2, 50.1, 127.9,
128.0 (2C), 129.1 (2C),
141.7, 199.9
Found: C 67.9, H 7.1
C11H14OS requires C 68.0, H 7.3
5
6
1454, 1479, 1708
2.07 (s, 3H), 3.04 (d, 2H, J 7.2), 4.67
(t, 1H, J 7.2), 7.18–7.26 (m, 9H)
31.1, 48.6, 49.6, 127.9,
128.1 (2C), 128.9 (2C),
129.3 (2C), 132.9, 134.2,
134.7 (2C), 141.2, 205.6
Found: C 66.0, H 5.1
C
16H15ClOS requires C 66.1, H 5.1
1039, 1441, 1478, 1715
20.7 (s, 3H), 2.91–2.99 (m, 2H),
4.65 (t, 1H, J 7.52), 5.91 (s, 2H),
6.67–6.71 (m, 2H), 6.82–6.83 (m, 1H),
7.21–7.34 (m, 5H)
31.1, 48.3, 50.1, 101.4,
108.2, 108.3, 121.5, 127.9,
129.2 (2C), 133.0 (2C),
134.4, 135.2, 147.2,
148.1, 205.9
Found: C 67.8, H 5.3
17H16OS requires C 68.0, H 5.4
C
14
15
20
22
1434, 1479, 1546
4.68–4.88 (m, 3H), 7.18–7.21 (m, 2H),
7.27–7.40 (m, 8H)
49.6, 78.7, 129.3 (2C), 129.4
(2C), 129.6 (2C), 129.8
(2C), 134.3 (2C), 134.9,
135.3
Found: C 64.7, H 4.9
C14H13NO2S requires C 64.8, H 5.1
1039, 1444, 1479, 1504,
1556
1.22 (t, 3H, J 7.47), 2.46 (q, 2H, J 7.47),
4.50 (t, 1H, J 7.80), 4.66–4.71 (m, 2H),
5.96 (s, 2H), 6.75–6.79 (m, 2H),
6.85–6.87 (m, 1H)
14.7, 26.0, 46.6, 79.8, 101.7,
108.0, 108.8, 121.7, 131.4,
148.1, 148.6
Found: C 51.6, H 5.0
C11H13NO2S requires C 51.8, H 5.1
1448, 1477
1.18 (t, 3H, J 7.41), 2.29 (m, 2H), 3.50
(d, 2H, J 7.05), 4.57 (t, 1H, J 7.05),
7.26–7.28 (m, 2H), 7.35–7.57 (m, 5H),
7.89–7.92 (m, 2H)
14.7, 25.8, 43.6, 45.6, 128.4
(2C), 129.0 (2C), 129.1
(2C), 129.6 (2C), 133.7,
137.0, 141.2, 143.7, 197.0
Found: C 66.5, H 5.5
C
17H17ClOS requires C 67.0, H 5.6
1170, 1452, 1478, 1598,
1678
0.83 (t, 3H, J 7.29), 1.24–1.34 (m, 2H),
1.43–1.51 (m, 2H), 2.25–2.38 (m, 2H),
3.47 (d, 2H, J 7.05), 4.52–4.64 (m, 3H),
5.29–5.44 (m, 2H), 5.99–6.05 (m, 1H),
6.92 (d, 2H, J 8.79), 7.20–7.32 (m, 3H),
7.40–7.43 (m, 2H), 7.89 (d, 2H, J 8.79)
13.9, 22.3, 31.5, 31.6, 44.8,
45.4, 69.3, 114.8, 118.6,
127.5 (2C), 128.2 (2C),
128.8 (2C), 130.7 (2C),
132.8, 142.8, 144.4,
162.9, 195.8
Found: C 74.5, H 7.3
22H26O2S requires C 74.5, H 7.4
C
26
4
1445, 1475, 1589, 1679
1448, 1479, 1579, 1681
3.57–3.78 (m, 2H), 5.29 (dd, 1H, 1J 7.53,
2J 6.39), 6.84–6.88 (m, 2H), 7.27–7.30
(m, 3H), 7.39–7.59 (m, 6H), 7.92–7.95
(m, 2H)
44.1, 46.1, 124.9, 125.9,
126.9, 128.7, 128.8 (2C),
129.1 (2C), 129.3 (2C),
133.4 (2C), 133.8, 134.2,
136.9, 145.8, 196.9
Found: C 70.3, H 4.9
C19H16OS2 requires C 70.3, H 5.0
3.46 (d, 2H, J 6.81), 5.07 (t, 1H, J 6.81),
7.26 (d, 2H, J 8.49), 7.34–7.60 (m, 9H),
7.85 (d, 2H, J 8.49)
43.9, 53.3, 128.0 (2C),
128.5, 128.6, 129.1 (4C),
129.8 (2C), 131.6, 133.7,
134.4 (4C), 136.2, 136.9,
195.6
Found: C 72.2, H 4.6
C
21H16Cl2OS2 requires C 72.4, H 4.6
followed by purification by column chromatography over
silica gel.
this procedure. The reactions were complete within 2.5–4.5 h.
The yields of isolated products are also very good (70–90%).
The products were characterized by their spectroscopic data and
elemental analysis.
Both aliphatic and aromatic thiols such as ethane thiol,
butane thiol, and thiophenol react with a wide variety of con-
jugated alkenes by this procedure to provide the corresponding
thio-adducts in high yields. The results are summarized in
Table 1. As evident from the results, open-chain α,β-unsaturated
aldehydes, ketones, carboxylic esters, nitriles, and nitro alka-
nes participated in the reaction with thiophenol, butane thiol,
and ethane thiol without any difficulty. The addition of thi-
ols to cyclohexenone also produced high yields. The conjugate
addition of thiols to chalcones which is not always satisfac-
tory with conventional reagents[10b] was also efficiently cat-
alyzed by sodium acetate under the present reaction conditions.
A variety of substituents on the aromatic ring such as OMe,
NO2, ethylenedioxy, and a thiophene moiety are compatible with
The α,β-unsaturated terminal acetylenic ketones underwent
bis-additions with two equivalents of thiol or with one equivalent
of dithiol to provide the corresponding β-keto thioacetals, dithi-
anes, and dithiolanes. The results are reported in Table 2.
The dithianes are very useful intermediates[11] and β-keto
1,3-dithianes, in particular, have been used as key synthons in
the total synthesis of several natural products.[12] The procedures
for synthesis of β-keto dithianes are very limited and the first one
by Michael addition was reported using Al2O3 in 1992.[13]
In general, the reactions are very clean and reasonably fast.
The workup is very simple and short column chromatography is
enough to provide the pure product. Commercial sodium acetate

A Procedure for 1,4-Addition of Thiols to Conjugated Alkenes and Alkynes
227
and THF can be used without any pretreatment. Several sensi-
tive functional groups are found to be safe under the reaction
conditions.
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demonstrates the potential of sodium acetate, a benign, readily
available, and cheap material as an efficient catalyst. To the best
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IR spectra were taken as neat for liquids and as KBr pellet for
solids. 1H (300 MHz) and 13C NMR (75 MHz) spectra were run
in CDCl3 solutions. Elemental analyses were done by a Perkin–
Elmer auto-analyzer. Column chromatography was performed
on silica gel (60–120 mesh, SRL).Thiols and conjugated alkenes
are mostly commercial materials and were distilled before use.
Sodium acetate and THF were used as supplied.
General Procedure for 1,4-Addition
A mixture of thiol (1 mmol) and conjugated alkene (1 mmol) in
THF/H2O (1/1) was stirred in the presence of sodium acetate
(15 mol%) at room temperature for a period of time as required
to complete the reaction (monitored by TLC). After the reaction
was complete THF was evaporated from the reaction mixture
under reduced pressure. The mixture was then extracted with
diethyl ether (3 × 15 cm3). The combined ether extracts were
washed with brine, dried over Na2SO4, and evaporated to leave
thecrudeproductwhichwaspurifiedbycolumnchromatography
(hexane/ether) to furnish the pure adduct. This procedure was
followed for all the reactions listed inTables 1 and 2 (for addition
with acetylenic ketones the reaction was carried out at 70◦C).
The known products were identified by comparison of their spec-
troscopic data (IR, and 1H and 13C NMR) with those of reported
ones (reference given in Tables 1 and 2). The unknown com-
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Acknowledgments
This investigation has enjoyed the financial support from CSIR,
New Delhi under grant no. 01(1936)/04. T.M. is also thankful to CSIR for
his fellowship.
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