Iodine-catalyzed Michael addition of mercaptans to α,β- unsaturated ketones under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2005.05.099

A simple and efficient method for the Michael reaction between various mercaptans and α,β-unsaturated ketones using a catalytic amount of iodine (5 mol %) to generate the 1,4-adduct has been reported. The significant features of the iodine catalyzed Micha

Full text of DOI:10.1016/j.tetlet.2005.05.099

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4971–4974
Iodine-catalyzed Michael addition of mercaptans to
a,b-unsaturated ketones under solvent-free conditions
Cheng-Ming Chu, Shijay Gao, M. N. V. Sastry and Ching-Fa Yao*
Department of Chemistry, National Taiwan Normal University, 88, Sec. 4, Tingchow Road, Taipei, Taiwan 116, ROC
Received 6 April 2005; revised 12 May 2005; accepted 20 May 2005
Available online 13 June 2005
Abstract—A simple and efficient method for the Michael reaction between various mercaptans and a,b-unsaturated ketones using a
catalytic amount of iodine (5 mol %) to generate the 1,4-adduct has been reported. The significant features of the iodine catalyzed
Michael addition are (a) operational simplicity, (b) inexpensive reagents, (c) high yields of products, (d) the use of relatively low or
nontoxic reagents and (e) solvent-free conditions.
ꢀ 2005 Published by Elsevier Ltd.
The 1,4-addition of thiols to a,b-unsaturated carbonyl
compounds to form carbon–sulfur bonds constitutes a
key reaction in various biosynthetic processes as well
as in organic synthesis.1,2 Numerous methods have been
reported in the literature regarding the 1,4-addition of
thiols to electron-deficient olefins activated by different
bases.3 Alternatively, these reactions were also investi-
gated using different Lewis acids4,5 such as Hf(OTf)3,4a
InBr3,4b Bi(NO3)3,4c Bi(OTf)3,4d InCl34e and Cu(BF4)2.4f
However, the practice of expensive and toxic metal pre-
cursors not only limits the use of these methods, but also
turn out to be a serious concern under the aspects of
green chemistry. In addition to the above characteristics,
some of the methods also involve the use of either acidic
or basic work-up procedures for the catalyst separation,
recycling and disposal. Besides the drawback of using an
expensive catalyst, some of the methods involve strin-
gent and/or dry conditions, extended reaction times,
complex work-up procedures and the use of stoichio-
metric and/or relatively expensive reagents.
Thus, the development of more efficient methods and
exploring proper reagents as catalysts are still in demand
to make the available procedures more convenient and
simple. Over the past few years, molecular iodine (I2)
has emerged as a powerful catalyst for various organic
O
O
R3
R3
I2 (5 mol%)
R4SH
R
R
+
Neat
R1
SR4
R1
R2
R2
1
2
3
1a: R + R1 = -(CH2)3-, R2 = R3 = H
1b: R + R1 = -(CH2)2-, R2 = R3 = H
1c: R = Me, R1 = R2 = R3 = H
1d: R = Me, R2 = Ph, R1 = R3 = H
1e: R = Ph, R2 = Ph, R1 = R3 = H
1f: R = Ph, R1 = R2 = Me, R3 = H
1g: R = Me, R2 + R3 = -(CH2)4- , R1 = H
2a: R4 = Ph
2b: R4 = c-C6H11
2c: R4 = C6H5CH2
2d: R4 = C3H7
2e: R4 = CH2=CHCH2
2f: R4 = ICH2CH2
Scheme 1.
Keywords: Michael addition; Solvent free; Molecular iodine; Catalytic amounts; Various thiols; Unsaturated ketones; Ecofriendly.
*
Corresponding author. Tel.: +886 2 2930 9092; fax: +886 2 2932 4249; e-mail: cheyaocf@scc.ntnu.edu.tw
0040-4039/$ - see front matter ꢀ 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.05.099

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C.-M. Chu et al. / Tetrahedron Letters 46(2005) 4971–4974
Table 1. Reaction of 1 with 2a in the presence of I2 to prepare 3a
addition of indole to enones and several organic trans-
formations has also been reported recently.8
Entry
1
I2 (mol %) Temp( ꢁC) Time (min) 3 (%)b
1
1a
—
25
25
0
60
8
8
3
3
3
3
3
3
8
3
3aa (0)
In continuation of our interest on the catalytic applica-
tions of molecular iodine for various organic transfor-
mations,10 we wish to report the novel application of
inexpensive iodine as an efficient catalyst for the Michael
addition of various thiols to a,b-unsaturated ketones
under solvent-free conditions (Scheme 1).
2
1a 25
1a 25
1a 10
3aa (35)
3aa (90)
3aa (99)
3aa (99)
3ca (99)
3ca (99)
3ca (99)
3da (99)
3da (99)
3da (99)
3
4
0
5
1a
5
0
6
1c 25
1c 10
0
7
0
8
1c
5
0
9
1d 25
1d 10
25
0
In order to examine the effect of temperature as well as
catalyst loading, different reactions were conducted by
using a,b-unsaturated ketones 1a, 1c or 1d and thiophe-
nol 2a in the presence of different amounts of iodine
under solvent-free conditions at different temperatures.
Initially, a reaction was carried out in the absence of io-
dine between 1a and 2a at 25 ꢁC for 60 min, which re-
sulted in the recovery of the starting materials. After
the analysis of the crude mixture by NMR and GCMS
it was observed with no formed product 3aa. To check
the catalytic activity of iodine, a similar reaction was
carried out in the presence of 25 mol % of I2 for the
10
11
1d
5
25
a 1:2a = 1:1.1.
b Determined by GCMS and 1H NMR.
transformations to afford the products in good to excel-
lent yields.6,7 Owing to several advantages such as inex-
pensive, nontoxic, eco-friendly nature, iodine has been
used as a catalyst in the investigation of different organic
reactions.7 The catalytic activity of iodine in the Michael
Table 2. Iodine-catalyzed Michael addition of thiol to enonea,d
Entry
Enone 1
Thiol 2
Product 3
Time (min)
Yield (%)b
1
2
3
4
5
6
2a: R4 = Ph
3aa
3ab
3ac
3ad
3ae
3af
3
3
3
5
5
8
97
97
95
92
95
92
O
O
2b: R4 = c-C6H11
2c: R4 = C6H5CH2
2d: R4 = C3H7
1a
4
SR
2e: R4 = CH2@CHCH2
2fc: R4 = ICH2CH2
O
O
7
2a: R4 = Ph
3ba
3
97
1b
SPh
8
2a: R4 = Ph
3ca
3cb
3cc
3cd
3ce
3
3
3
5
5
97
95
95
95
95
O
2b: R4 = c-C6H11
2c: R4 = C6H5CH2
2d: R4 = C3H7
O
O
9
Me
10
11
12
Me
1c
4
SR
2e: R4 = CH2@CHCH2
O
13
14
15
16
2a: R4 = Ph
2a: R4 = Ph
2a: R4 = Ph
2a: R4 = Ph
3da
3ea
3fa
3ga
3
3
5
8
97
97e
96
93
Me
Ph
Ph
Me
Ph
1d
Ph
Ph
O
SPh
O
O
1e
Ph
Ph
O
SPh
SPh
Ph
Me
1f
Me
Me
Me
O
O
Me
Me
1g
PhS
a 1 equiv of enone 1 was treated with 1.1 equiv of mercaptan 2 in the presence of 5 mol % of Iodine at 0 ꢁC under solvent-free condition.
b Column isolated yield.
c For the preparation of 2f, see Ref. 11.
dReaction was carried out at room temperature.
e Reaction was carried out at room temperature and 1 ml CH2Cl2 was added.

C.-M. Chu et al. / Tetrahedron Letters 46(2005) 4971–4974
4973
O
O
O
SH
I
(5 mol%)
2
+
+
o
0 C, neat, 8min
OMe
SPh
PhS
SPh
4
2a
5
6
1.1equiv
2.2 equiv
78%
_
10%
>99%
Scheme 2.
preparation of 3. Surprisingly, at ambient temperature
within 8 min 35% of 3aa was observed (entry 2). When
the similar reaction was repeated at 0 ꢁC for the same
time, it resulted in the formation of the product 3aa in
90% yield (entry 3). In order to confirm, the amount
of iodine required for the above transformation, differ-
ent experiments were carried out by varying the amount
of iodine I2. Either using 10 or 5 mol % of catalytic
amounts of iodine at 0 ꢁC, resulted in the quantitative
yield of 3aa with the same efficiency. These results
clearly indicate that, the use of 5 mol % of I2 is sufficient
to catalyze the Michael addition reaction in excellent
yield.9 The reason for the lower product yield with a
higher amount of iodine in case of cyclohexenone may
be ascribed due to the decreased catalytic activity, which
in turn leads to polymerization of the starting materials.
On the other hand, the reaction temperature plays an
important role with different substrates. For instance,
in a reaction with thiol 2a, the enones methlvinyl ketone
1c and benzilideneacetone 1d use 5 mol % of iodine, the
former requires 0 ꢁC and the later needs 25 ꢁC. The
probable reason might be the steric bulkiness of the later
enone. To prove the versatility of iodine catalyzed Mi-
chael addition reactions, a variety of enones 1a–d were
reacted with phenyl thiol 2a in the presence of 5 mol %
of iodine to obtain the quantitative yields of the product
(Table 1).
Encouraged by the above results, we also examined the
reaction of a different enone such as 4-methoxy-3-but-
ene-2-one 4 with 2a under similar conditions. In the
presence of 1.1 equiv of 1a, 78% of 5 and 10% of 6 were
generated (Scheme 2). However, only quantitative yield
of 6 was obtained by changing the amount of 2a from
1.1 to 2.2 equiv. The generation of compound 5 indi-
cates that the reaction proceeds through the substitution
of the methoxy groupof 4 by 2a and the compound 6
has been generated from the addition of another equiv-
alent of 2a to the intermediate product 5.
In conclusion, we have successfully demonstrated a sim-
ple and efficient methodology to prepare a wide variety
of Michael adducts using iodine in catalytic amounts.
The powerful catalytic activity of the iodine for these
transformations can be substantiated by the less reac-
tion times as well as high product yields. This environ-
mentally benign process for the generation of Michael
adducts represents a suitable option to the existing pro-
cedures, especially enones with different substitution.
Acknowledgements
Financial support for this work by the National Science
Council of the Republic of China and National Taiwan
Normal
acknowledged.
University
(ORD93-C)
is
gratefully
After optimizing the best condition using cyclohexenone
1a and thiol 2a, the generality of the iodine catalyzed
reaction was examined by selecting a number of a,b-
unsaturated ketones 1a–g as well as thiols 2a–f11 (Table
2). As expected, excellent yields of product 3 were gener-
ated under solvent-free condition at 0 ꢁC within 2–
8 min. Both cyclic and acyclic enones were reacted with
various thiols to afford the products in excellent yields.
A little decrease in the product yield was observed in a
reaction with 2f using cyclohexenone. In the case of
Michael acceptor such as 1-cyclohexenyl-methyl ketone,
the product was formed in 96% yield using 5 mol % of
iodine as catalyst. b,b-Disubstituted enone 1f and a,b-
disubstituted enone 1g can react with thiophenol 2a rap-
idly to afford Michael adducts in quantitative yield.
According to these results, we found that not only the
unsubstituted enone such as methyl vinyl ketone but
also the b-monosubstituted enone such as 1a, 1b, 1d
and 1e or the b,b-disubstituted enone 1f or a,b-disubsti-
tuted enone 1g can react with thiophenol 2a rapidly.
These results indicate that the I2 catalyzed reactions
were not affected by the presence of the steric hindrance
between 1 and 2 and both alkyl and aryl substituted
groupalso have no effect on the reaction yield.
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9. Typical experimental procedure: In a typical experiment,
cyclohexenone 1a (0.198 g, 2 mmol) and thiophenol 2a
(0.249 g, 2.2 mmol) were mixed together and I2 (0.025 g,
0.1 mmol) was added and stirred at 0 ꢁC for 3 min
(monitored through TLC). After adding the ice cold
saturated sodium thiosulfate solution to the reaction
mixture (to remove the traces of iodine), the solution
was extracted with dichloromethane (2 · 5 mL). The
combined organic layers were dried over magnesium
sulfate, and the crude product passed through a small
plug of silica to obtain the pure product 3aa as a colourless
oil (0.400 g, 97% Y).
10. Some of our unpublished results.
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