Potassium phosphate or silica sulfuric acid catalyzed conjugate addition of thiols to α,β-unsaturated ketones at room temperature under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2006.10.114

Potassium phosphate and silica sulfuric acid have been found to be useful and highly efficient catalysts for conjugate addition of thiols to α,β-unsaturated ketones under solvent-free conditions, at room temperature. Silica sulfuric acid (SSA) was found t

Full text of DOI:10.1016/j.tetlet.2006.10.114

Tetrahedron Letters 47 (2006) 9325–9328
Potassium phosphate or silica sulfuric acid catalyzed
conjugate addition of thiols to a,b-unsaturated ketones at
room temperature under solvent-free conditions
a
a,
a
b
D. M. Pore,a,* M. S. Soudagar, U. V. Desai, T. S. Thopate and P. P. Wadagaonkar
*
aDepartment of Chemistry, Shivaji University, Kolhapur 416 004, India
bPolymer Science and Engineering Division, National Chemical Laboratory, Pune 411 008, India
Received 25 August 2006; revised 12 October 2006; accepted 19 October 2006
Abstract—Potassium phosphate and silica sulfuric acid have been found to be useful and highly efficient catalysts for conjugate
addition of thiols to a,b-unsaturated ketones under solvent-free conditions, at room temperature. Silica sulfuric acid (SSA) was
found to be suitable for electron-deficient enones while potassium phosphate was found to effect thia-Michael addition with both,
electron-deficient as well as electron-rich conjugated ketones.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Conjugate addition of thiols to a,b-unsaturated ketones
to form a carbon–sulfur bond constitutes a key reaction
in biosynthetic processes as well as in organic synthe-
sis.1,2 It is known that the resultant b-sulfido carbonyl
compounds serve as starting materials for the generation
of b-acylvinyl cation equivalents3 and homoenolate
equivalents.4 The reaction is also important to organic
chemists as a protecting strategy for double bonds as
the olefin can be very easily regenerated by the removal
of the sulfur moiety through Cu(I)-induced elimination
or by oxidative elimiation.5,6 Consequently, a large
number of methods have been reported for 1,4-conju-
gate addition of thiols to electron-deficient olefins.7
The reaction has been investigated using Lewis acids
such as Hf(OTf)3,8a Bi(OTf)3,8b Cu(BF4)2,8c InBr3,8d
Bi(NO3)3,8e I2.8f Quite recently, bis(trifluoromethansul-
fon)imide9a and Nafion SAC-139b have been reported
as efficient Bronsted acids and H3PW12O409c as a hetero-
poly acid catalyst for this reaction. In addition, ionic
liquids like (Bmim)PF6/H2O10a and molten tetrabutyl-
ammonium bromide10b have been employed as efficient
catalysts-reaction media in the thia-Michael addition
reaction. However, the use of toxic and expensive metal
precursors limit the use of Lewis acids as catalysts, while
those involving the use of Bronsted acids or basic cata-
lysts need an aqueous work-up for the separation of cat-
alysts. Furthermore, in many cases, yields as well as
selectivities are far from satisfactory due to side reac-
tions.11 Thus, the development of a simple but highly
efficient method for the thia-Michael addition reaction
is desirable. Herein, we report the use of potassium
phosphate as well as silica sulfuric acid as highly useful
catalysts for the addition of thiols to a,b-unsaturated
ketones, at room temperature, under solvent-free
conditions.
In the last few years, the use of silica sulfuric acid
(SSA)12 as a reusable, heterogeneous, solid Bronsted
acid catalyst has received much attention.13–17 From
our laboratory, we have investigated SSA catalyzed,
chemoselective tetrahydropyranylation of alcohols over
phenols,18a chemoselective dithioacetalization of alde-
hydes over ketones,18b chemoselective conversion of
aldehydes to acylals18c as well as the synthesis of a-
aminonitriles.18d These earlier studies with SSA
prompted us to test the efficacy of silica sulfuric acid
in the conjugate addition of thiols to a,b-unsaturated
ketones.
Keywords: Michael addition; Chalcones; Conjugated enones; Silica
sulfuric acid; Potassium phosphate; Thiols; a,b-Unsaturated ketones.
Corresponding authors. Tel.: +91 231 2690571; fax: +91 231 2692333
Cyclohexenone and thiophenol were chosen as a model
enone and thiol. The reaction of an equimolar (2 mmol,
each) mixture of cyclohexenone and thiophenol in the
*
(D.M.P.); e-mail: p_dattaprasad@rediffmail.com
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.114

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D. M. Pore et al. / Tetrahedron Letters 47 (2006) 9325–9328
O
results summarized in Table 1 highlight the general
O
SSA / K3PO4
RT, neat
applicability of this reaction. It was noticed that the
reactions of thiols with enones such as cyclohexenone,
cyclopentenone and ethyl vinyl ketone yielded the de-
sired thia-Michael addition products rapidly (10–
25 min) and in an excellent yields (73–96%). In addition,
the reaction between cyclohexenone and ethane-1,2-
dithiol yielded the double Michael addition product in
excellent yield (91%). However, when the reaction was
extended towards chalcones, the expected thia-Michael
addition products were obtained in very poor yields
(15–20%) and attempts to increase the yields by increas-
ing the amount of catalyst, time as well as temperature
of the reaction mixture were unsuccessful. Thus, the
conjugate addition of thiols to enones must been gov-
erned by electronic as well as steric effects. Certainly,
due to steric hindrance as well as the p-resonance effect
of phenyl groups, chalcones become less electrophilic
R
R
R"SH
+
R'
SR''
R'
1
2
3
Scheme 1.
presence of silica sulfuric acid (0.2 g, 25 mol %) pro-
ceeded via an exothermic reaction and afforded the cor-
responding 1,4-addition product (TLC) in an 89% yield,
in a very short time, (10 min) at room temperature, in
the absence of an organic solvent (Scheme 1).
Encouraged by this initial success, the reactions were
then performed between a variety of a,b-unsaturated
cyclic as well as acyclic ketones with different thiols un-
der solvent-free conditions, at room temperature. The
Table 1. Potassium phosphate/silica sulfuric acid (SSA)-catalyzed Michael addition of thiols to a,b-unsaturated ketones
Entry
Enone
Thiol
Producta
Time (min)
K3PO4
Yieldb (%)
K3PO4
1
2
3
SSA
SSA
2a
2b
2c
2d
2e
2f
3aa
3ab
3ac
3ad
3ae
3af
10
10
20
10
15
15
30
—
25
39
25
—
89
94
94
95
93
73
85
—
81
90
90
—
O
O
A
SR
1a
2a
2b
2c
2d
2e
2f
3ba
3bb
3bc
3bd
3be
3bf
15
15
15
25
30
15
60
—
35
30
40
—
93
95
86
94
90
91
95
—
95
98
95
95
O
O
B
S
R
1b
O
O
C
2g
2a
3ag
3da
10
55
25
91
—
84
89
S
2
1a
O
O
D
NP
SR
1d
O
O
E
F
2g
2d
3dg
3ed
NP
70
30
30
—
26
72
79
S
1d
2
O
O
O
O
R
S
1e
2a: thiophenol; 2b: p-methylthiophenol; 2c: p-chlorothiophenol; 2d: benzylthiol; 2e: n-butanethiol; 2f: cyclohexylthiol; 2g: ethane-1,2-dithiol.
a All products showed satisfactory spectroscopic data. (IR, 1H NMR).
b Yields refer to pure, isolated products.

D. M. Pore et al. / Tetrahedron Letters 47 (2006) 9325–9328
9327
and make the conjugate addition difficult. From these
observations, it was concluded that though silica sulfuric
acid was an efficient solid acid catalyst for thia-Michael
addition to electron-deficient and sterically unhindered
conjugated enones, it was unsuitable as a catalyst for
sterically hindered conjugated enones. This led us to
the development of an alternative and more general pro-
tocol for the Michael addition of thiols to chalcones
using an inexpensive, highly efficient and easy to handle
catalyst.
thiols having pKa values in the range 7–1121 to convert
them to their conjugate bases and assist the thia-Michael
addition. Thus, we evaluated the catalytic efficiency of
potassium phosphate in the thia-Michael addition
reaction.
trans-1,3-Diphenylpropenone 4a and thiophenol were
selected as model substrates and ethanol as the solvent.
To a stirred solution of 4a (2 mmol) and thiophenol
(2 mmol) in ethanol (5 mL) was added potassium phos-
phate (0.05 g, 25 mol %). An exothermic reaction took
place which was completed in 10 min at room tempera-
ture and furnished the desired thia-Michael addition
product 6a (91%), as characterized by comparison of
the mp and the spectral data with that reported.22 The
generality of the protocol was investigated by reacting
a variety of chalcones possessing electron-donating as
well as electron-withdrawing groups with various thiols
to furnish the corresponding thia-Michael addition
product (Scheme 1) in acceptable yields (78–98%). The
results are summarized in Table 2. As expected, the reac-
tion between thiols as well as dithiol with enones such as
cyclohexenone, cyclopentenone and ethyl vinyl ketone
also yielded the corresponding Michael addition prod-
ucts in excellent yields (Table 1). It is interesting to note
that there was no formation of a disulfide as a side
From a mechanistic viewpoint, for the successful conju-
gate addition of thiols to chalcones, it is essential that Cb
be sufficiently electrophilic. It is known that the use of a
metal salt as catalyst allows the metal ion to form a
strong coordinate bond with the carbonyl oxygen and
thereby makes Cb sufficiently electrophilic to assist the
thia-Michael addition (Scheme 2). Furthermore, for a
strong coordinate bond, the metal ion must be suffi-
ciently oxophilic which is the case if the counter anion
of the metal salt is highly electron-withdrawing. In line
with these requirements, Chakraborti et al.19 have dem-
onstrated the usefulness of triflates as well as perchl-
orates of group I and II elements as efficient catalysts
for the conjugate addition of thiols to chalcones. With
this in mind, it was surmised that the easily available,
inexpensive, nontoxic, potassium phosphate20 might
serve as an efficient catalyst in the thia-Michael addition
reaction. This is because (i) potassium phosphate has a
strong electron-withdrawing counter anion, namely
Table 2. Potassium phosphate-catalyzed Michael addition of thiols to
chalcones
Entry
R
R0
R00
Time (min)
Yield (%)
PO4 to make the K+ ion oxophilic enough to form a
3ꢀ
strong coordinate bond with the oxygen atom of the en-
one and thereby make Cb sufficiently electrophilic, and
(ii) potassium phosphate is basic enough to deprotonate
a
b
c
d
e
f
H
H
Cl
Cl
Cl
F
F
F
Cl
Cl
F
H
H
H
H
H
H
OMe
H
CH3
CH3
H
Ph
n-Bu
n-Bu
4-Cl C6H4
Ph
PhCH2
4-Cl C6H4
Ph
4-Cl C6H4
n-Bu
10
15
10
5
5
10
8
10
8
15
10
20
91
80
96
96
91
78
93
84
98
82
84
92
'
SR'' O
O
K3PO4
g
h
i
+
R"-SH
EtOH, RT
R'
R'
R
R
j
4
5
6
k
l
4-Cl C6H4
n-Bu
F
H
Scheme 2.
Table 3. Comparison of the catalytic efficacy of SSA/K3PO4 with other catalysts
Entry
Product
Cat. (mol %)
Solvent
Time (h)
Yield (%)
Ref.
1
2
3
4
5
6
7
8
9
InBr3 (10)
Bi(NO3)3 (15)
Bi(OTf)3 (5)
Zn(ClO4)2 (1)
H3PW12O40 (1)
(Bmim)PF6
(Bu)4N+Brꢀ
Iodine
CH2Cl2
CH2Cl2
CH3CN
Neat
24
4
74
65
72
90
95
95
92
97
89
91
8d
8e
8b
19
9c
10a
10b
8f
—
—
1.5
5a
5a
S
O
Neat
Ph
(Bmim)PF6
(Bu)4N+Brꢀ
Neat
Neat
Neat
10a
30
3
SSA
K3PO4
15
10
10
Ph
11
12
13
14
15
Zn(ClO4)2
(Bmim)PF6
InCl3
SSA
K3PO4
Neat
(Bmim)PF6
EtOH
C2H5OH
C2H5OH
1.5
15
1
24
25a
87
95
95
15
91
19
10a
22
—
—
SPh
O
Ph
a Time in minutes.

9328
D. M. Pore et al. / Tetrahedron Letters 47 (2006) 9325–9328
Sastry, M. N. V.; Yao, C.-F. Tetrahedron Lett. 2005, 46,
4971.
product even though potassium phosphate catalyzed
oxidative coupling of thiols to disulfides has already
been reported.21
9. (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) Firouzabadi, H.;
Iranpoor, N.; Jafari, A. A. Synlett 2005, 2, 299.
10. (a) Yadav, J. S.; Reddy, B. Y. S.; Baishya, G. J. Org.
Chem. 2003, 68, 7098; (b) Ranu, B. C.; Dey, S. S.; Hajra,
A. Tetrahedron 2003, 59, 2417.
11. Yadav, J. S.; Reddy, B. V. S.; Baishya, G. J. Org. Chem.
2003, 59, 2117.
12. Zolfigol, M. A. Tetrahedron 2001, 57, 9509.
13. Yakaih, T.; Venkat Reddy, G.; Narsaiah, P.; Shanthan
Rao, P. Synth. Commun. 2005, 35, 1307.
When the catalytic efficiency of potassium phosphate
was compared with other reported catalysts (Table 3),
it was revealed that potassium phosphate is better suited
for this reaction for the reasons of low cost, ease of
availability, yields, reaction temperature as well as
work-up procedure. In all cases, on completion of the
reaction, chloroform was added, the catalyst was
filtered, washed with chloroform and the solvent was
removed to yield the almost pure thia-Michael addition
product.24
14. Chen, W. Y.; Lu, J. Synlett 2005, 15, 2293.
15. Jin, T.-S.; Tian, R.-F.; Liu, L.-B.; Zhao, Y.; Li, T. S.
Synth. Commun. 2006, 36, 1823.
In summary, we have described herein the usefulness of
silica sulfuric acid as well as potassium phosphate as
highly efficient and cost effective catalysts for the thia-
Michael addition reaction under solvent-free conditions,
(except chalcones) at room temperature. Short reaction
times, high yields, and avoidance of anhydrous condi-
tions should make this protocol a useful alternative to
existing methods.
16. Hajipour, A. Synthesis 2006, 1680.
17. Schulze, A.; Pagaona, G.; Giallis, A. Synth. Commun.
2006, 34, 1147.
18. (a) Pore, D. M.; Desai, U. V.; Mane, R. B.; Wadgaonkar,
P. P. Synth. Commun. 2004, 34, 2135; (b) Pore, D. M.;
Desai, U. V.; Mane, R. B.; Wadgaonkar, P. P. Indian J.
Chem. 2006, B, 1291; (c) Thopate, T. S.; Desai, U. V.;
Pore, D. M.; Wadgaonkar, P. P. Cat. Commun. 2006, 7,
506; (d) Thopate, T. S. Unpublished results from the
Ph.D. thesis of T. S. Thopate.
19. Chakraborti, A. K.; Garg, S. K.; Kumar, R. Synlett 2005,
9, 1370.
References and notes
20. (a) Desai, U. V.; Pore, D. M.; Mane, R. B.; Solabannavar,
S. B.; Wadgaonkar, P. P. Synth. Commun. 2004, 34, 25;
(b) Desai, U. V.; Pore, D. M.; Mane, R. B.; Solabannavar,
S. B.; Wadgaonkar, P. P. Synth. Commun. 2004, 34, 19.
21. Joshi, A. V.; Bhusare, S.; Baidossi, M.; Qafisheh, N.;
Sasson, Y. Tetrahedron Lett. 2005, 46, 3583.
22. Ranu, B. C.; Dey, S. S.; Samanta, S. ARKIVOC 2005, 3,
44.
23. Jones, J. B.; Middleton, H. W. Can. J. Chem. 1970, 48,
3819.
1. (a) Fluharty, A. L. In The Chemistry of the Thiol Group;
Patai, S., Ed.; Wiley: New York, 1974, Part 2, p 589; (b)
Clark, J. H. Chem. Rev. 1980, 80, 429; (c) Fujita, E.;
Nagao, Y. J. Bioorg. Med. Chem. 1977, 6, 287.
2. (a) Trost, B. M.; Keeley, D. E. J. Org. Chem. 1975, 40,
2013; (b) Shono, T.; Matsumura, Y.; Kashimura, S.;
Hatanaka, K. J. Am. Chem. Soc. 1979, 107, 4752; (c)
Nishimura, K.; Ono, M.; Nagaoka, Y.; Tomioka, K. J.
Am. Chem. Soc. 1997, 119, 12974.
24. General procedure: A mixture of a,b-unsaturated ketone
(2 mmol), thiol (2 mmol) and SSA (0.2 g, 25 mol %)/
K3PO4 (0.05 g, 25 mol %) was stirred at room temperature
for the appropriate time (Table 1 or 2). On completion of
the reaction (TLC), chloroform (20 mL) was added and
the reaction mixture was filtered. The catalyst was washed
with chloroform (2 · 10 mL). Evaporation of the solvent
followed by short column chromatography over silica gel
(petroleum ether/ethyl acetate, 95:5, v/v) afforded pure
thia-Michael adducts, which were characterized by spec-
tral methods.
3. Bakuzia, P.; Bakuzis, M. L. F. J. Org. Chem. 1981, 46,
235.
4. Cherkauskas, J. P.; Cohen, T. J. Org. Chem. 1992, 57, 6.
5. Coben, T.; Mura, A. J., Jr.; Shull, D. W.; Fogel, E. R.;
Ruffner, R. J.; Falck, J. R. J. Org. Chem. 1976, 41, 3218.
6. Trost, B. M.; Keeley, D. E. J. Org. Chem. 1975, 40, 2013.
7. (a) Hiemstra, H.; Wiberg, H. J. Am. Chem. Soc. 1981, 103,
417; (b) Suzuki, K.; Ilekawa, A.; Mukaiyama, T. Bull.
Chem. Soc. Jpn. 1982, 55, 3277; (c) Emori, E.; Arai, T.;
Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1998, 120,
4043.
8. (a) Kobayashi, S.; Ogawa, C.; Kawamura, M.; Sugiura,
M. Synlett 2001, 983; (b) Alam, M. M.; Varala, R.;
Adapa, S. R. Tetrahedron Lett. 2003, 44, 5515; (c) Garg, S.
K.; Kumar, R.; Chakraborti, A. K. Tetrahedron Lett.
2005, 46, 1721; (d) Bandini, M.; Cozzi, P. G.; Giacomini,
M.; Melchiorre, P.; Selva, S.; Umani-Ronchi, A. J. Org.
Chem 2002, 67, 3700; (e) Srivastava, N.; Banik, B. K. J.
Org. Chem. 2003, 68, 2109; (f) Chu, C.-M.; Gao, S.;
Spectral data: 4-[benzylthio]-dihydrofuran-2[3H]-one23
(3ed, Table 1): IR (neat): 2924, 1789 1602, 794,
1
702 cmꢀ1; H NMR (400 MHz, CDCl3): dH 2.4 (1H, AB
q, J = 18 Hz, 7 Hz), 2.73 (1H, AB q, J = 18 Hz, 7 Hz),
3.45 (1H, q, J = 7 Hz), 3.79 (2H, s), 4.04 (1H, AB q,
J = 10 Hz, 7 Hz), 4.36 (1H, AB q, J = 10 Hz, 7 Hz), 7.33
(5H, m); 13C NMR (100 MHz, CDCl3): dC 35.35, 36.05,
37.95, 72.93, 127.57, 128.63, 128.80, 137.31, 174.91.