Iodine catalyzed conjugate addition of mercaptans to α,β- unsaturated carboxylic acids under solvent-free condition

Article abstract of DOI:10.1016/j.tetlet.2006.01.080

We have described herein molecular iodine catalyzed Michael addition of thiol to α,β-unsaturated carboxylic acids. This environmentally benign catalytic system (iodine) used under mild and solvent-free conditions to achieve the corresponding adducts in excellent yield.

Full text of DOI:10.1016/j.tetlet.2006.01.080

Tetrahedron Letters 47 (2006) 1889–1893
Iodine catalyzed conjugate addition of mercaptans
to a,b-unsaturated carboxylic acids under
solvent-free condition
Shijay Gao, Tingkai Tzeng, M. N. V. Sastry, Cheng-Ming Chu, Ju-Tsung Liu,
Chunchi Lin and Ching-Fa Yao*
Department of Chemistry, National Taiwan Normal University 88, Sec. 4, Tingchow Road, Taipei 116, Taiwan, ROC
Received 3 December 2005; revised 13 January 2006; accepted 18 January 2006
Available online 3 February 2006
Abstract—We have described herein molecular iodine catalyzed Michael addition of thiol to a,b-unsaturated carboxylic acids. This
environmentally benign catalytic system (iodine) used under mild and solvent-free conditions to achieve the corresponding adducts
in excellent yield.
ꢀ 2006 Published by Elsevier Ltd.
1. Introduction
environmental concern. Over the past few years, mole-
cular iodine (I2) has been emerged as a powerful catalyst
for various organic transformations to afford the corre-
sponding products in good to excellent yields.7,8 Addi-
tionally many advantages such as simplicity of the
reagent, high yields and both economic and environ-
mental factors make iodine as an effective catalyst for
different organic reactions such as Michael additions
as well as other organic transformations.9
Michael addition is one of the efficient methods in
organic synthesis for the formation of carbon–carbon,
carbon–sulfur, and carbon–nitrogen bonds.1 Among
various nucleophilic additions, the 1,4 addition of thiols
to various substrates to form a carbon–sulfur bond is of
much importance, as it comprises a key reaction in the
synthesis of several biologically active compounds.2 A
number of methods have been reported in the literature,
regarding the conjugate addition of thiol to unsaturated
carbonyl compounds such as a,b-unsaturated aldehyde,
ketone, ester, and nitrile.3 However, conjugate addition
of thiol to a,b-unsaturated carboxylic acids is more
difficult, due to less reactivity and the acid group itself
involves or even destroys such reaction.4 To carry out
these reactions under conventional condition involves
a three-step process such as protection, 1,4-addition
and deprotection.5 The alternative approach using free
acid results in lower product yields.4 The similar reac-
tion has been reported early.6 Thus, exploring proper
reagent as catalyst and the development of simple,
economic and ecofriendly procedures are essential not
only for the improved and better results, but also of
2. Results and discussion
As part of our enduring efforts to explore the catalytic
activity of the iodine10, we had the opportunity to look
into the Michael addition of various thiol compounds to
a,b-unsaturated carboxylic acids. Herein, we wish to re-
port the novel application of iodine as an efficient cata-
lyst for the 1,4-conjugate addition of thiols to a,b-
unsaturated carboxylic acids under solvent-free condi-
tion. Preliminary efforts were mainly focused for the cat-
alytic evaluation of iodine by taking cinnamic acid and
thiophenol as model substrates. To observe the effect
of temperature, as well as the amount of iodine required,
different reactions were carried out using 1 equiv
(2 mmol) of trans-cinnamic acid 1d and 1.5 equiv
(3 mmol) of thiophenol 2a in the presence of iodine
under solvent-free condition at different temperatures
(Eq. 1).
Keywords: Conjugate addition; Thiols; a,b-Unsaturated carboxylic
acid; Iodine; Solvent free.
*
Corresponding author. Tel./fax: +886
cheyaocf@scc.ntnu.edu.tw
2
29309092; e-mail:
0040-4039/$ - see front matter ꢀ 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.01.080

1890
S. Gao et al. / Tetrahedron Letters 47 (2006) 1889–1893
O
O
Table 2. Effect of solvent on the reaction of 1d with 2a in the presence
of I2
a
I
2
+
PhSH
HO
HO
PhS
ð1Þ
3dab (%)
1db (%)
neat, different temp
Entry
Solvent
Ph
Ph
1d
2a
3da
1
2
3
4
5
6
7
8
9
10
11
12
13
Neat
Hexane
C6H6
CH2Cl2
THF
H2O
EA
CH3CN
Et2O
DMF
DMSO
MeOH
Acetone
99
50
81
58
0
0
0
0
0
0
0
0
0
0
50
19
42
99
99
99
99
99
99
99
99
99
The yields of the reactions were checked by the crude
1H NMR and the optimum results are provided in Table
1.
Initially, a blank reaction was conducted using the sub-
strates 1d and 2a at 50 ꢁC for 24 h resulted in the recov-
ery of starting materials without a trace of the product
3da (entry 1). The catalytic effect was apparently ob-
served when the mixture was stirred in the presence of
I2. Thus, in a reaction using 10 mol % iodine afforded
the product 3da in 63% yield within 1 h. As expected,
the increase in the amount of iodine (20 mol %) notice-
ably improved the product yield (94%). On the other
hand, increase in reaction temperature (50 ꢁC) using
10 mol % of iodine provided excellent product yield
(99%). Solvents considerably influenced the product
yields. In most of the solvents the reaction did not pro-
gress at all. However, nonpolar solvents such as benzene
(81%) and hexane (50%) provided better yields of the
product, when compared to other polar solvents. Con-
ducting the reaction in chlorinated solvent such as
dichloromethane afforded the product 3da in 58% yield.
After screening different solvents, we observed that none
of the solvents gave better yields. On the other hand, sol-
vent free condition (neat) provided maximum yield of
the product (Table 2).
a Condition: 1 equiv (2 mmol) of 1d was treated with 1.5 equiv
(3 mmol) of 2a in the presence 20 mol % of I2 at room temperature
for 1.5 h.
b The yields were determined by the crude 1H NMR.
reaction occurred either at room temperature or even
at 50 ꢁC (Eq. 2).
O
I2
neat, different temp
no reaction
PhSH
ð2Þ
HO
+
I
4ai
2a
This clearly indicates that the formation of thio adduct
3aa does not take place via the iodo adduct. We next
investigated the reason for the formation of iodo
adduct. In this connection, we attempted a reaction
between 1a and 2a in the presence of molecular iodine
(20 mol %) under identical reaction conditions. A de-
tailed 1H NMR study of the reaction mixture at different
intervals of time revealed that there is a competition be-
tween PhSꢀ and Iꢀ during the reaction (Fig. 1). A plot
between the product yield versus time of the reaction
mixture clearly represents that both thio adduct and
iodo adducts are formed simultaneously. Owing to
greater nucleophilicity of the PhSꢀ over Iꢀ, more
amount of thio adducts were observed in all cases. How-
ever, the reason for no iodo adduct formation in case
of b-substituted acids can be explained on the basis of
b-substituted steric strain, which prevents the bulky
Iꢀ nucleophile to attack b-substituted acid. Thus, the
formation of iodo adduct was found to be dependent
on steric effects of b-substituted acid.
In order to evaluate the efficiency of the iodine cata-
lyzed Michael additions, the generality of the reaction
has been verified by taking a variety of acid substrates
as well as different thiophenols. Both aromatic as well
as aliphatic thiols reacted with different a,b-unsaturated
carboxylic acids to provide the adducts in good to
excellent yield (Table 3). Surprisingly, in case of acrylic
acid (1a) and methylacrylic acid (1b) the formation of
thio adducts were accompanied by a small amount of
iodo adducts. Whereas in case of crotonic acid (1c),
trans-cinnamic acid (1d) and 3,3-dimethylacrylic acid
(1e) only thio adducts were observed. It is noteworthy
to observe that when there is a b-substitution in the
acid, no iodo adduct was observed. We investigated
the fate of iodo adduct formed during the reaction.
The iodo adduct was isolated and subjected to a reac-
tion with thiol in the presence of I2 (20 mol %), no
Steric and electronic factors played a crucial role in case
of both acid as well as thiol. In order to overcome the
b,b-disubstituted steric strain, the reaction of 1e and
2a requires little harsh conditions (more amount of I2
and high temperature), when compared to the corre-
sponding counterparts. This clearly signifies the crucial
role played by the steric factors. Similarly electronic fac-
tors in the thiol also affected the reaction rate as well as
product yields. The reaction time of acids with aryl
thiols such as thiophenol (2a), a-toluenethiol (2b), and
2-naphthalenethiol (2e) are less than that of alkyl thiol
Table 1. Reaction of 1d with 2a under different conditionsa
Entry I2 (mol %) Temperature Time 3dab (%) 1db (%)
(ꢁC)
(h)
1
2
3
4
0
10
20
10
50
rt
rt
24
1
1
0
63
94
99
99
37
6
50
1
0
a Condition: 1 equiv (2 mmol) of 1d was treated with 1.5 equiv
(3 mmol) of 2a under a solvent-free condition.
b The yields were determined by the crude 1H NMR.

S. Gao et al. / Tetrahedron Letters 47 (2006) 1889–1893
1891
Table 3. Iodine-catalyzed the Michael addition of thiol to different kind of a,b-unsaturated carboxylic acida
Entry
Acid 1 thiol 2
Temperature (ꢁC)/time (h)
Product 3 yield (%)b
Product 4 yield (%)b
O
HO
O
O
1a
HO
HO
SR
I
1
2
3
4
5
2a: R = Ph
rt/2
rt/2
rt/7
rt/7
rt/4
3aa 78
3ab 82
3ac 87
3ad 89
3ae 78c
164ai 18
4ai 6
4ai 9
4ai 7
2b: R = C6H5CH2
2c: R = c-C6H11
2d: R = C3H7
2e: R = 2-naphthyl
4ai 18
O
HO
O
O
1b
HO
HO
SR
I
6
7
8
9
2a: R = Ph
50/3
50/3
50/48
50/16
3ba 75
3bb 44
123bc 64
3bd 84
174bi 21
4bi 9
4bi 22
4bi 12
2b: R = C6H5CH2
2c: R = c-C6H11
2d: R = C3H7
O
O
HO
1c
HO
SPh
10
2a: R = Ph
50/2.5
3ca 97
O
O
HO
1d
HO
Ph
Ph SR
11
12
13
14
15
2a: R = Ph
rt/1.5
50/2
50/4.5
50/4
3da 97
3db 97
133dc 95
143dd 97
153de 94c
2b: R = C6H5CH2
2c: R = c-C6H11
2d: R = C3H7
2e: R = 2-naphthyl
50/2
O
O
HO
1e
HO
SPh
16
2a: R = Ph
50/5d
3ea 95
a All reactions were performed by using 1 equiv (2 mmol) of unsaturated acids 1 and 1.5 equiv (3 mmol) of thiol 2 in the presence 20 mol% of I2 under
solvent free condition.11
b Isolated yields.
c Reaction was carried out in 0.5 mL of CH2CI2.
d The reaction was in the presence 50 mol% of I2.
nistic details of this reaction are not yet fully under-
stood, a feasible pathway might involve the complex
role of iodine as a Lewis acid by activating the carbonyl
function of the carboxylic acid. The indirect evidence
can be obtained from the slow reaction of methylacrylic
acid (1b) with thiophenol. This may be explained on the
basis of steric strain of the methyl group at a-position
and coordination of iodine with carbonyl function
makes the atmosphere more crowded and thus lowers
the reaction rate. Further studies are in progress to
understand the mechanism of iodine catalysis.
100
80
60
40
20
0
1a
2a
3aa
4ai
time (min)
Figure 1. 1H NMR study of the reaction mixture at different intervals
of time.
3. Conclusion
such as cyclohexyl mercaptan (2c) and 1-propanethiol
(2d). However, in most cases steric factors dominated
over the electronic factors. Though the intimate mecha-
In conclusion, we have successfully developed an easy
and efficient method for the Michael addition of various
thiol derivatives to a,b-unsaturated carboxylic acids.

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S. Gao et al. / Tetrahedron Letters 47 (2006) 1889–1893
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The advantages such as mild reaction conditions,
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sulfur containing carboxylic acids in excellent yields.
Acknowledgements
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Financial support of this work by the National Taiwan
Normal University (ORD93–C) and National Science
Council of the Republic of China is gratefully
acknowledged.
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11. Typical experimental procedure for Michael addition: To a
mixture of trans-cinnamic acid 1d (1 equiv) and thiophenol
2a (1.5 equiv) I2 (20 mol %) was added and the mixture
was stirred at room temperature for 1.5 h. After comple-
tion of reaction (monitored by TLC), ice cold saturated
sodium thiosulfate solution (15 mL) was added and
extracted with dichloromethane (2 · 20 mL) and the
combined organic extracts were dried and evaporation of
the solvent under reduced pressure afforded quantitative
yield of 3da (>99% by NMR) and the pure product was
obtained by passing through a small pad of silica using
eluent (EtOAc–hexane, 1:10).
12. 3-Cyclohexylsulfanyl-2-methyl-propionic acid (3bc): 1H
NMR (400 MHz, CDCl3): d 1.18–1.36 (m, 8H), 1.60–
1.63 (m, 1H), 1.75–1.80 (m, 2H), 1.95–1.98 (m, 2H), 2.58–
2.72 (m, 3H), 2.88 (dd, 1H, J = 6.6, 12.6 Hz). 13C NMR
(100 MHz, CDCl3): d 16.86, 26.00, 26.27, 33.31, 33.85,
33.87, 40.69, 44.32, 181.60. HRMS (CI) m/z calcd for
C10H18O2S (M+) 202.1028, found 202.1040.
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5. (a) Rosssiter, B. E.; Swingle, N. M. Chem. Rev. 1992, 92,
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Pusch, J. Chem. Ber. 1925, 58, 1632.
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Tetrahedron Lett. 2005, 46, 1751; (b) Bandgar, B. P.;
Shaikh, K. A. Tetrahedron Lett. 2003, 44, 1959; (c) Ji, S.;
Wang, S.; Zhang, Y.; Loh, T. Tetrahedron 2004, 60,
2051.
8. (a) Kim, K. M.; Ryu, E. K. Tetrahedron Lett. 1996, 37,
1441; (b) Firouzabadi, H.; Iranpoor, N.; Hazarkhani, H.
J. Org. Chem. 2001, 66, 7527; (c) Ramalinga, K.;
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2002, 43, 879; (d) Firouzabadi, H.; Iranpoor, N.; Sobhani,
S. Tetrahedron Lett. 2002, 43, 3653; (e) Yadav, J. S.;
13. 3-Cyclohexylsulfanyl-2-phenyl-propionic acid (3dc): 1H
NMR (400 MHz, CDCl3): d 1.10–1.38 (m, 5H), 1.48–
1.56 (m, 1H), 1.59–1.75 (m, 3H), 1.92–1.96 (m, 1H),
2.38–2.45 (m, 1H), 2.81–2.91 (m, 2H), 4.32 (t, 1H, J =
7.6 Hz), 7.18–7.37 (m, 5H), 10.87 (br, 1H). 13C NMR
(100 MHz, CDCl3): d 25.80, 25.85, 25.99, 33.29, 33.62,
42.00, 43.21, 43.43, 127.46, 127.62, 128.65, 141.94, 177.24.
HRMS (CI) m/z calcd for C15H20O2S (M+) 264.1184,
found 264.1185.
14. 3-Phenyl-3-propylsulfanyl-propionic acid (3dd): 1H NMR
(400 MHz, CDCl3): d 0.88 (t, 3H, J = 7.36 Hz), 1.43–1.57
(m, 2H), 2.23–2.35 (m, 2H), 2.84–2.95 (m, 2H), 4.23 (t, 1H,
J = 7.6 Hz), 7.20–7.34 (m, 5H), 10.40 (br, 1H). 13C NMR
(100 MHz, CDCl3): d 13.59, 22.62, 33.44, 41.53, 44.85,
127.64, 127.78, 128.74, 141.43, 177.22. HRMS (CI) m/z
calcd for C12H16O2S (M+) 224.0871, found 224.0871.
15. 3-Naphthylsulfanyl-3-phenyl-propionic acid (3de): 1H NMR
(400 MHz, CDCl3): d 2.95–3.06 (m, 2H), 4.72 (t, 1H,
J = 7.7 Hz), 7.21–7.29 (m, 5H), 7.38 (dd, 1H, J = 1.6,
8.5 Hz), 7.44–7.48 (m, 2H), 7.71–7.73 (m, 2H), 7.77–7.79

S. Gao et al. / Tetrahedron Letters 47 (2006) 1889–1893
1893
(m, 2H). 13C NMR (100 MHz, CDCl3): d 0.22, 40.70,
48.85, 126.68, 127.81, 127.86, 127.95, 128.68, 128.80,
130.58, 130.94, 132.84, 133.71, 140.32, 176.39. HRMS
(CI) m/z calcd for C19H16O2S (M+) 308.0871, found
308.0882.
(CI) m/z calcd for C3H5O2I (M+) 199.9334, found
199.9340.
1
17. 3-Iodo-2-methyl-propionic acid (4bi): H NMR (400 MHz,
CDCl3): d 1.33 (d, 3H, J = 7.0 Hz), 2.84 (m, 1H), 3.28 (dd,
1H, J = 6.16, 9.96 Hz), 3.40 (dd, 1H, J = 6.46, 9.94 Hz).
13C NMR (100 MHz, CDCl3): d 6.12, 18.28, 42.27, 179.53.
HRMS (CI) m/z calcd for C4H7O2I (M+) 213.9491, found
213.9493.
1
16. 3-Iodo-propionic acid (4ai): H NMR (400 MHz, CDCl3):
d 3.05 (t, 2H, J = 7.1 Hz), 3.32 (t, 2H, J = 7.0 Hz). 13C
NMR (100 MHz, CDCl3): d ꢀ4.92, 38.57, 177.44. HRMS