Amino acid catalyzed thio-Michael addition reactions

Article abstract of DOI:10.1016/j.tet.2007.08.033

Using amino acid as a catalyst, an inexpensive, nontoxic, environmentally friendly, metal-free reaction procedure for C-S bond formation via thio-Michael addition reaction has been developed. The thio-Michael addition products were obtained in excellent yields under mild and neutral conditions. This metal-free catalytic protocol was found to be a good alternative to the existing metal catalyst methodology for the thio-Michael addition reaction.

Full text of DOI:10.1016/j.tet.2007.08.033

Tetrahedron 63 (2007) 11086–11092
Amino acid catalyzed thio-Michael addition reactions
*
Atul Kumar and Akanksha
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226001, Uttar Pradesh, India
Received 30 April 2007; revised 24 July 2007; accepted 10 August 2007
Available online 15 August 2007
Abstract—Using amino acid as a catalyst, an inexpensive, nontoxic, environmentally friendly, metal-free reaction procedure for C–S bond
formation via thio-Michael addition reaction has been developed. The thio-Michael addition products were obtained in excellent yields under
mild and neutral conditions. This metal-free catalytic protocol was found to be a good alternative to the existing metal catalyst methodology
for the thio-Michael addition reaction.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Thus, the development of an environmentally benign and
metal-free catalytic reaction is currently our objective. Re-
cently, aminocatalysis has gained much importance in the
field of asymmetric organic synthesis. Most attention has
been focused on the use of proline, an inexpensive and read-
ily available amino acid in either L or D form. L-Proline has
been found to be very effective in enamine based direct cat-
alytic asymmetric aldol,17 Mannich,18 Diels–Alder,19 and
Knoevenagel type of reactions.20
The thio-Michael addition reaction has emerged as one of
the most powerful tools for C–S bond formation.1 Thio-
Michael addition provides a widespread synthetic utility in
organic chemistry (i) for chemoselective protection of ole-
finic double bond in unsaturated carbonyl compound,2 (ii)
for the generation of acyl vinyl cation equivalents3 and ho-
moenolate anion equivalents,4 and (iii) for the synthesis of
medicinally important compounds like Diltiazem.5 Gener-
ally, the 1,4-conjugate addition of a thiol requires activation
of acceptor olefin by Lewis acid or deprotonation of thiol by
base.6 Consequently, there are several methods reported for
thiol addition to electron deficient olefins such as Bi(OTf)3,7
InBr3,8 Hf(OTf)3,9 alumina in DMF,10 NafionSAC-13,11
iodine,12 InCl3,13 andCu(BF4)2$xH2O.14 More recently, ionic
liquids have attracted much attention in thiol addition due to
its green chemistry. Yadav et al. used [Bmin]PF6/H2O,15
while Ranu et al. reported thiol addition in [Pmin]PF6.16
However, ionic liquids have been shown to have serious
drawbacks, especially imidazolium systems with PF6 and
BF4 anions, which are as toxic as benzene to certain aquatic
ecosystems and also liberate hazardous HF during recycling.
In addition, the high cost and disposability of these solvents
also limit their utility. The various disadvantages of previ-
ously reported methods such as long reaction time, high reac-
tion temperatures, use of expensive catalysts, stringent dry
conditions, moderate yields, use of stoichiometric amount
of catalysts, and expensive metal precursors that are harmful
to the environment necessitates the development of newer
methods for thio-Michael addition.6–16
Herein, we disclose the (S)-proline and other amino acid
catalyzed, green, cost effective, environment friendly, and
high yielding procedure for the synthesis of thio-Michael
adducts.
2. Results and discussion
The focus of our project was to develop a direct amino acid
catalyzed thio-Michael reaction with a broad variety of
enones (1) with alkyl and aryl thiols (2) to obtain the thio-
Michael adduct (3) (Scheme 1).
R4
R2
R1
R2 R3
S
R3
Aminocatalyst-30mol%
solvent,r.t.
R4SH
+
R1
O
O
1
2
3
Scheme 1. Amino acid catalyzed thio-Michael conjugate addition.
For the optimization process, we first examined the catalytic
efficiency of (S)-proline in our model reaction of chalcone
(1a) with thiophenol (2a) in methanol at room temperature.
The conjugated addition product (3a) was obtained within
2–3 min in high yield. In addition to (S)-proline, we also
Keywords: Thio-Michael; Aminocatalysis; Amino acid; Green synthesis.
* Corresponding author. Tel.: +91 522 2612411; fax: +91 522 2623405;
e-mail: dratulsax@gmail.com
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.08.033

A. Kumar, Akanksha / Tetrahedron 63 (2007) 11086–11092
11087
S
COOH
and provided synthetically useful yields with modest stereo-
control. Although thiazolidine-4-carboxylic acid gave good
results, (S)-proline (Ia) was found to be the best catalyst
from efficiency and commercial point of view and it was
chosen for further optimization.
COOH
N
H
N
H
II a: L-thiazolidine-4-corboxylicacid
I a: L-proline
HO
COOR
COOH
N
H
N
H
We also examined effect of solvents and catalyst loading on
the (S)-proline catalyzed thio-Michael reaction of chalcone
(1a) with thiophenol (2a) in order to enhance the selectivity.
IV a: L-proline ester
III a: L-trans- 4-hydroxy proline
COOH
H
NH2
COOH COOH
N
H2N
VI b: L- glutamic acid
Interestingly, we observed that the dielectric constants of the
solvents and temperature had a remarkable effect on the
(S)-proline catalyzed thio-Michael reaction (Table 2). The re-
action in water did not proceed at all due to the immiscibility
of the starting chalcones in water. Halogenated solvents
CHCl3 and DCM (Table 2, entries 6 and 7) gave better yield.
We also carried out the reaction in toluene at ꢀ20 ꢁC but
very low yield was obtained. As all solvents gave moderate
to good yield, further, we tried 10, 20, and 30 mol % of
(S)-proline in methanol at room temperature (Table 2, entries
9–11). Surprisingly at 30 mol % of (S)-proline, the reaction
took 3 min to complete and the product itself precipitated in
the reaction mixture. The results clearly indicate that solvent
of high dielectric constants facilitate the amino catalytic re-
action (Table 2). Methanol (de¼30) was found to be superior
to acetonitrile (de¼36.3) as it probably enhances the
enamine formation through hydrogen bonding. Therefore,
at 30 mol % of (S)-proline, methanol is the solvent of choice.
Ph
N
H
H2N
COOH
VII c: L-Histidine
V a: DL-2-phenylglycine
Figure 1. Aminocatalysts used in thio-Michael reaction.
investigated other amino acid catalysts (IIa–VIIc) and their
ability to mediate the model reaction (Fig. 1).
In order to obtain better results in terms of yield and enantio-
selectivity, we applied these amino acid catalysts to our
model reaction of chalcone 1a with thiophenol 2a under
two different solvent systems; (i) methanol at ꢀ20 ꢁC, as
lowering in temperature induces better asymmetric induc-
tion, and (ii) methanol at room temperature (Table 1).
It was observed that the catalytic effects of cyclic neutral
amino acids (Ia), (IIa) and (IIIa) were almost similar but
when proline ester (IVa) was taken as the catalyst, the prod-
uct yield decreased. Neutral amino acid DL-phenylglycine
(IVa), acidic amino acid glutamic acid (VIb), and basic ami-
no acid histidine (VIIc), which have a primary amino group,
when used as catalysts were found to be less effective in
comparison to a secondary amino group. The results of Table
1 led us to assume that cyclic amino acid with a secondary
nitrogen is essential for better catalytic activity as it has pro-
vided the highest yield of product in the shortest time.
The thio-Michael reaction of compounds 3a–d, 3f, and 5a
with (S)-proline in methanol at ꢀ20 ꢁC was performed and
their enantioselectivity was determined by HPLC Chiralpak
OD-H column (Table 3). The synthesized compounds had
enantiomeric excess in the range of 24–45%. As the enantio-
selectivity of this process was low (45%), the yield, short re-
action time, and exceptional simplicity of the procedure
prompted us to investigate the scope of this novel amino cat-
alytic reaction.
Replacing the CH2 of proline (Ia) by S (IIa) and with CHOH
(IIIa) gave comparable yields but required much longer
time. Proline (Ia), thio-proline (IIa), and hydroxyl-proline
(IIIa) (Table 1, entries 2–4) in methanol at ꢀ20 ꢁC as well
as in methanol at room temperature followed the same trend
In order to study the catalytic potentiality of (S)-proline cata-
lyzed thio-Michael reaction, we performed the conjugate
addition of aryl as well as alkyl thiols to various substituted
chalcones (Schemes 2 and 3). Excellent results were ob-
tained in each case. The reaction was in general very fast
Table 1. Aminocatalysts screened for the direct thio-Michael reaction of
chalcone (1a) and thiophenol (2a)a–e
Table 2. Optimization studies of (S)-proline catalyzed thio-Michael reaction
between 1a and 2a under different organic solventsa–d
Entry Aminocatalysta
Methnol at ꢀ20 ꢁC
MeOH at rt
ee %d tb Yieldc
Entry
Solventa
deb
Conditionc
Yield (%)d
tb
Yieldc
1
2
3
4
5
6
7
8
Neat
H2O
C6H6
—
—
2.27
2.37
2.37
4.64
8.9
1 equiv, rt, 2–3 days
1 equiv, rt, 24 h
15
—
40
65
35
70
74
80
65
88
98
1
2
3
4
5
6
7
8
None
Ia
IIa
IIIa
IVa
Va
—
Neutral 1.2
Neutral 2.0
Neutral 2.5
—
92
68
65
58
45
35
25
—
39
20
10
<10
<8
<5
nd
—
—
3e 98
0.5 92
1.2 90
2.0 65
1.8 70
2.5 35
3.0 30
30 mol %, rt, 8 h
30 mol %, rt, 6 h
35 mol %, ꢀ20 ꢁC, 6 h
30 mol %, rt, 2 h
30 mol %, rt, 1.8 h
30 mol %, rt, 2.0 h
10 mol %, rt, 1.2 h
20 mol %, rt, 0.5 h
30 mol %, rt, 3 min
Toluene
Toluene
CHCl3
DCM
CH3CN
MeOH
MeOH
MeOH
—
Neutral 5.0
5.5
VI b
VI1c
Acidic
Basic
5.6
8.0
36.2
9
10
11
30
30
30
a
b
c
d
Reaction conditions: 30 mol % of amino catalyst.
Time in hour.
Isolated yield (%).
a
Reaction conditions: distilled solvents used, no need to dry.
Dielectric constants of solvents.
mol % of (S)-proline.
b
c
d
Determined by chiral HPLC (Chiralpak OD-H, n-hexane/i-PrOH 98:2,
l¼270 nm).
e
Time in minute.
Isolated yields.

11088
A. Kumar, Akanksha / Tetrahedron 63 (2007) 11086–11092
Table 3. Asymmetric thio-Michael addition catalyzed by (S)-prolinea–e
and completed within 5–10 min. It was gratifying to observe
the conjugate addition product also precipitates from the re-
action mixture in most of these cases. Electronic factors play
a crucial role in this reaction. It was observed that the chal-
cone containing electron donating group facilitates the rate
and yield of reaction while the chalcone carrying the electron
withdrawing substituent (Table 4, entries 8–10) compara-
tively decreases the rate and yield of reaction. Similarly elec-
tronic factors in thiols also influence the rate of reaction.
Generally rapid conversion and excellent yield was observed
when the reactionwas carried out with aryl thiols (Scheme2).
c
Entry Product ee %b
Yield
td
tR minore
tR majore
1
2
3
4
5
6
3a
3b
3c
3d
3f
45
25
24
25
39
2
92
94
90
92
94
88
1.2
1.2
1.5
1.3
0.5
2.8
11.3
11.5
19.1
21.6
14.7
4.51
12.1
12.9
20.0
23.1
17.0
5.21
5a
a
Reaction conditions: chalcone (1 mmol), thiol (1.5 mmol thiophenol, and
2.0 mmol of ethanthiol), 30 mol % of (S)-proline stir at ꢀ20 ꢁC in meth-
anol.
b
Determined by chiral HPLC (Chiralpak OD-H, n-hexane/i-PrOH 98:2,
l¼270 nm).
c
d
e
While, the (S)-proline catalyzed conjugate addition of alkyl
thiols and mercapto carboxylic acid to chalcones required
longer reaction time in comparison to aryl thiols (Scheme
3). The results of Schemes 2 and 3 are summarized in Table 4.
Isolated yield (%) of pure products after crystallization.
Time in hour.
Retention time of minor and major isomer.
On comparing our results with the recently reported
methods, we found that (S)-proline efficiently catalyzed
the reaction of chalcone with thiol in methanol in shortest
time. As recently reported copper(II) tetrafluroborate re-
quired longer reaction time for conjugate addition of thiol
to chalcone in methanol at room temperature and not com-
patible with weakly polar solvents (DCM, THF, dioxane,
etc.).14 Molten tetra butyl bromide fails to react with chal-
cone.21 Zn(ClO4)2$6H2O also require refluxing condition
and longer reaction time for thiol additon.22 InCl3
(10 mol %) catalyzed thiol addition to chalcone strictly re-
quired dry condition as this reaction was very much moisture
sensitive and did not catalyze reaction in other conventional
solvents.13
R1
R1
O
O
SH
S
Ia (30 mol %)
+
MeOH, r.t.
R4
R4
2
R3
R3
R2
3a - j
R2
1a-g
Scheme 2.
R1
R1
O
Another notable feature of the amino catalytic reaction lies
in its chemoselectivity. To explore the intermolecular
chemoselectivity of this procedure, we carried out a compet-
itive study of 1,4-conjugate addition of other nucleophiles
such as amines, carbamates, and phenols to 1,3-diphenylpro-
penone (1a) in the presence of different thiols. It was ob-
served that all the reactions proceeded with high
chemoselectivity in favor of C–S bond formation and lead-
ing to high yields of the thio-Michael adduct (Scheme 4).
O
R3
S
SH
Ia (30 mol %)
+
MeOH, r.t.
R3
R2
5a-h
R2
4
1a-
e
Scheme 3.
Table 4. (S)-Proline catalyzed thio-Michael addition of aryl as well as alkyl thiols to diarylpropenones (Schemes 2 and 3)a–h
Entry
R1
R2
R3
R4
td
Yielde
Productf,h
Entry
R1
R2
R3
td
Yielde
Productg,h
1
2
3
4
5
6
7
8
9
10
H
H
H
H
H
H
OCH3
OCH3
OCH3
H
H
H
H
H
H
H
H
H
H
Cl
Cl
H
H
CH3
H
CH3
H
H
CH3
H
CH3
H
2
2
3
7
3
5
5
10
8
15
98
96
98
92
94
97
98
80
82
89
3a
3b
3c
3d
3e
3f
3g
3h
3i
11
12
13
14
15
16
17
18
—
—
H
H
H
OCH3
OCH3
OCH3
OH
H
H
H
H
H
H
OCH3
H
C4H4O
—
—
Me
30
60
60
35
60
30
40
30
—
—
90
82
88
89
78
90
70
80
—
—
5a
5b
5c
5d
5e
5f
5g
5h
—
—
CO2H
CH2CO2H
Me
CH2CO2H
Me
Me
Me
—
—
OCH3
OCH3
H
OCH3
OCH3
CH3
CH3
OH
—
—
3j
a
Reaction conditions: 1 equiv of enone, 1.8 equiv of aryl thiol, 2.0 equiv of alkyl thiol, and 2.5 equiv of mercapto corboxylic acid, 30 mol % of L-proline.
MeOH as a solvent (2–3 mL).
All reactions were carried out at room temperature.
Time in minute.
b
c
d
e
f
Isolated yield (%).
Scheme 2.
Scheme 3.
g
h
All products were characterized by 1H NMR, 13C NMR, IR spectroscopy, and MS.

A. Kumar, Akanksha / Tetrahedron 63 (2007) 11086–11092
11089
SH
1a
+
+
N
H
2a
A
SH
OH
NH2
O
SH
Me
H2N
O
1a
+
+
+
1a
+
+
(i)
A
E
2a
B
D
X
2b
(iv)
(ii)
O
S
E
O
HN
major
X=H =3a
X=Me=3b
Ph
Ph
minor- 15%
B
D
+
C
(iii)
SH
1a
+
+
N
H
2b
C
Me
Scheme 4. (S)-Proline catalyzed intermolecular chemoselective conjugate addition of thiol to chalcone. Reaction conditions: (i) 1a (1 mmol), A (2 mmol),
2a (1.5 mmol), 30 mol % (S)-proline, methanol, rt (1–12 h); (ii) 1a (1 mmol), B (2 mmol), D (2 mmol), 2a (1.5 mmol), 30 mol % (S)-proline, methanol,
rt (2–3 h); (iii) 1a (1 mmol), C (2 mmol), 2b (1.5 mmol), 30 mol % (S)-proline, DMSO, rt; (iv) 1a (1 mmol), E (2 mmol), 2b (1.5 mmol), 30 mol % (S)-proline,
methanol, rt.
To further expand the scope of the (S)-proline catalyzed C–S
bond forming reaction, we next applied our optimized proce-
dure to acyclic and cyclic enones. The (S)-proline catalyzed
thio-Michael addition was found equally compatible with
acyclic and cyclic enones. The results are summarized in
Table 5.
alternative to existing methods for the synthesis of thio-
Michael adducts.
4. Experimental
4.1. Materials and general
Table 5. (S)-proline catalyzed thio-Michael addition of aryl as well as alkyl
thiols to acyclic and cyclic enonesa–d
All the reactions were carried out at room temperature, that
is, 28–32 ꢁC. Unless otherwise specified, all the reagents
were purchased from Sigma–Aldrich Chemical Co and Lan-
caster, and were used directly without any further purifica-
tion. NMR spectra were obtained using the Brucker DRX
200 MHz spectrometer. Chemical shifts (d) are given in parts
per million relative to TMS and coupling constants (J) in
hertz. Mass spectra were obtained using JEOL SX-102
(FAB+) instrument. Elemental analysis was preformed using
a Perkin–Elmer Autosystem XL Analyzer. Reactions were
monitored by thin layer chromatography (TLC) carried out
on 0.25 mm silica gel plates visualized with UV light.
B
B
Ia (30 mol %)
MeOH, r.t.
R4SH
2, 4
+
R4
S
A
7
A
6
Entry
A
B
R4
Ph
4-Me-Ph
Et
Ph
Ph
4-Me-Ph
Ph
t (min)
Yieldd
19
20
21
22
23
24
25
H
H
H
H
COMe
COMe
COMe
CN
3
2
5
3
10
8
98
96
90
94
92
89
94
4,4-(Me)2C6H6O
4,4-(Me)2C6H6O
C6H8O
5
4.2. General procedure for amino catalytic thio-Michael
addition
a
Reaction conditions: 1 equiv of acyclic enone, 1.5 equiv of aryl thiol,
2.0 equiv of alky thiol, and 30 mol % of (S)-proline.
MeOH as a solvent (2–3 mL).
All reactions were carried out at room temperature.
Isolated yield (%).
b
c
d
4.2.1. Typical experimental procedure for conjugate
addition of aryl thiols to chalcone (Scheme 2).
4.2.1.1. Representative procedure for the synthesis of
compounds of Scheme 2 [1,3-Diphenyl-3-phenylsul-
fanyl-propan-1-one]. To a magnetically stirred mixture
of 1,3-diphenylpropenone (1a) (1 mmol) and (S)-proline
(Ia) (30 mol %) in methanol (1–2 mL), thiophenol
(1.8 mmol) was added dropwise with the help of syringe.
The reaction mixture was stirred at room temperature. The
precipitation occurs within 2–3 min. The precipitate was fil-
tered, washed with methanol, and crystallized by ethyl ace-
tate and hexane to obtain pure product in high yield. The
3. Conclusion
In conclusion, we have developed a simple and efficient
amino acid catalyzed methodology for the synthesis of
thio-Michael adducts. The methodology was found to be
high yielding, green, and cost effective. Short reaction
time, room temperature, high yield, and avoidance of anhy-
drous conditions should make this protocol a useful

11090
A. Kumar, Akanksha / Tetrahedron 63 (2007) 11086–11092
same procedure was followed for the synthesis of all com-
pounds of Scheme 2.
dC (50 MHz, CDCl3) 195.8, 164.0, 141.7, 134.7, 133.0,
130.7, 130.3, 129.2, 128.8, 128.2, 127.8, 127.7, 114.1,
55.8, 48.7, 44.7; m/z 349 (80, MH+), 297 (75), 239 (75),
135 (100%).
4.2.2. Typical experimental procedure for conjugate
addition of alkyl thiols to chalcone (Scheme 3).
4.2.2.1. Representative procedure for the synthesis of
compounds of Scheme 3 [3-Ethylsulfanyl-1,3-diphenyl-
propan-1-one]. In a typical experiment 1,3-diphenylpro-
penone (1a) (1 mmol) and (S)-proline (Ia) (30 mol %) in
MeOH (2–3 mL) were mixed together and then ethanthiol
(2a) (2 mmol) was added dropwise with help of syringe.
The solution was stirred at room temperature under an air
atmosphere for appropriate time of period. After the comple-
tion of the reaction (monitored by TLC and IR), the reaction
mixture was worked up by simple extraction with ethyl ace-
tate and water. The filtrate was evaporated under vacuum on
a rotary evaporator to afford the desired product in high pu-
rity. The further purification was performed by crystalliza-
tion with ethyl acetate and hexane. The above-described
procedure was also used for the synthesis of compounds of
Table 5.
4.3.3. 1-(4-Methoxy-phenyl)-3-p-tolylsulfanyl-propan-1-
one (4). White solid; mp 98–100 ꢁC [Found: C, 75.80; H,
5.77. C22H20O2S requires C, 75.83; H, 5.79%.]; nmax
(KBr) 3420, 1683, 1600 cmꢀ1; dH (200 MHz CDCl3) 7.83
(2H, d, J 8.8 Hz, Ph), 7.40–7.00 (9H, m, Ph), 6.86 (2H, d,
J 8.8 Hz, Ph), 4.83 (1H, dd, J 6.4, 6.3 Hz, SCH), 3.85 (3H,
s, OMe), 3.57–3.51 (2H, m, COCH2), 2.29 (3H, s, Me); dC
(50 MHz, CDCl3) 196.0, 163.9, 141.8, 138.1, 133.8, 130.7,
130.0, 128.9, 128.7, 128.2, 127.6, 114.1, 55.8, 49.1, 44.5,
21.5; m/z 363 (85, MH+), 239 (50), 135 (92%).
4.3.4. 3-(4-Methoxy-phenyl)-1-phenyl-3-phenylsulfanyl
propan-1-one (5). White solid; mp 87–88 ꢁC [Found: C,
75.80; H, 5.77. C22H20O2S requires C, 75.83; H, 5.79%.];
nmax (KBr) 3445, 1683, 1580 cmꢀ1; dH (200 MHz, CDCl3)
7.85 (2H, d, J 7.4 Hz, Ph), 7.54–7.26 (10H, m, Ph), 6.78
(2H, d, J 8.6 Hz, Ph), 4.91 (1H, dd J 8.2, 6.0 Hz, SCH),
3.78 (3H, s, OMe), 3.59–3.52 (2H, m, COCH2); dC
(50 MHz, CDCl3) 195.8, 164.0, 141.7, 134.7, 133.0, 130.7,
130.3, 129.2, 128.8, 128.2, 127.8, 127.7, 114.1, 55.8, 48.7,
44.7; m/z 349 (80, MH+), 297 (75), 239 (75), 135 (100%).
4.2.3. Typical experimental procedure for the intermo-
lecular chemoselective reaction (Scheme 4). To a magnet-
ically stirred mixture of 1,3-diphenylpropenone (1a)
(1 mmol), and (S)-proline (Ia) (30 mol %) in MeOH
(2 mL) indole (2 mmol) and thiophenol (1.5 mmol) were
added at room temperature. The reaction was stirred for ap-
propriate time. The precipitate was filtered and washed with
water and methanol. The solid residue was crystallized by
ethyl acetate and hexane to afford the pure product in high
4.3.5. 1,3-Bis-(4-methoxy-phenyl)-3-phenylsulfanyl-
propan-1-one (6). White solid; mp 120–122 ꢁC [Found:
C, 72.96; H, 5.87. C23H22O3S requires C, 72.99; H,
5.86%.]; nmax (KBr) 3435, 1670, 1599 cmꢀ1
;
dH
1
yield. The product was characterized by H and 13C NMR
(200 MHz, CDCl3) 7.83 (2H, d, J 8.8 Hz, Ph), 7.20–7.35
(7H, m, Ph), 6.86 (2H, d, J 8.8 Hz, Ph), 6.75 (2H, d, J
8.6 Hz, Ph), 4.89 (1H, t, J 6.1 Hz, SCH), 3.84 (3H, s,
OMe), 3.74 (3H, s, OMe), 3.57–3.49 (2H, m, COCH2); dC
(50 MHz, CDCl3) 196.1, 163.9, 159.0, 134.9, 133.6, 132.9,
130.8, 130.2, 129.2, 127.7, 114.1, 55.8, 55.6, 44.7, 48.1;
m/z 378 (60, MH+), 269 (100), 161 (30), 135 (42%).
spectroscopy, it gave the thio-Michael adduct as a sole prod-
uct. The same protocol was also applied for other nucleo-
philes.
All the compounds reported in Tables 4 and 5 were properly
1
characterized by their spectroscopic data. The IR, H and
13C NMR spectral data, and elemental analysis, confirms
the identities of compounds. The compounds (1, 2, 19–22,
25)8–16,21,22 that are known their spectroscopic data was
found to be consistent with that of reported in literature.
The spectroscopic details of all compounds are given below.
4.3.6. 1,3-Bis-(4-methoxy-phenyl)-3-p-tolylsulfanyl-
propan-1-one (7). White solid; mp 130–135 ꢁC [Found:
C, 73.46; H, 6.46. C24H24O3S requires C, 73.44; H,
6.16%.] nmax (KBr) 3445, 1677, 1590 cmꢀ1; dH (200 MHz,
CDCl3) 7.87 (2H, d, J 8.8 Hz, Ph), 7.25–7.20 (4H, m, Ph),
7.05 (2H, d, J 8.0 Hz, Ph), 6.90 (2H, d, J 8.8 Hz, Ph), 6.79
(2H, d, J 8.6 Hz, Ph), 4.88 (1H, t, J 6.1 Hz, SCH), 3.84
(3H, s, OMe), 3.74 (3H, s, OMe), 3.55–3.47 (2H, m,
COCH2), 2.29 (3H, s, Me); dC (50 MHz, CDCl3) 196.2,
163.9, 159.0, 138.0, 133.7, 131.0, 130.7, 130.3, 130.0,
129.2, 114.1, 55.8, 55.6, 48.6, 44.7, 21.5; m/z 392 (50,
MH+), 269 (100%).
4.3. Spectroscopic and analytical data of compounds
4.3.1. 1,3-Diphenyl-3-phenylsulfanyl-propan-1-one (1).
White solid; mp 118–120 ꢁC [Found: C, 79.33; H, 5.74.
C21H18OS requires C, 79.21; H, 5.70%.]; nmax (KBr) 3042,
1679, 1592 cmꢀ1; dH (200 MHz, CDCl3) 7.85 (2H, d, J
7.5 Hz, Ph), 7.54–7.13 (13H, m, Ph), 4.91 (1H, dd, J 7.6,
6.0 Hz, SCH), 3.73–3.50 (2H, m, COCH2); dC NMR
(50 MHz, CDCl3) 197.4, 141.6, 137.1, 134.6, 133.6, 133.1,
129.2, 129.0, 128.8, 128.4, 128.2, 127.9, 127.7, 48.6, 45.1;
m/z 318 (100, MH+), 209 (80), 105 (65%).
4.3.7. 3-(3-Chloro-phenyl)-3-phenylsulfanyl-1-p-tolyl-
propan-1-one (8). White solid; mp 106–108 ꢁC [Found:
C, 72.08; H, 5.25. C22H19ClOS requires C, 72.02; H, 5.22
%.] nmax (KBr) 3420, 1674, 1601 cmꢀ1; dH (200 MHz,
CDCl3) 7.80 (2H, d, J 7.7 Hz, Ph), 7.31–7.16 (11H, m,
Ph), 4.89 (1H, t, J 7.0 Hz, SCH), 3.54 (2H, d, J 7.0 Hz,
COCH2), 2.39 (3H, s, Me); dC (50 MHz, CDCl3) 196.1,
144.0, 143.8, 141.1, 133.7, 130.7, 129.2, 129.0, 128.7,
128.2, 128.0, 127.6, 126.6, 126.4, 47.3, 44.5, 22.8; m/z 367
(80, MH+), 256 (100%).
4.3.2. 1-(4-Methoxy-phenyl)-3-phenyl-3-phenylsulfanyl-
propan-1-one (3). White solid; mp 80–82 ꢁC [Found: C,
75.80; H, 5.77. C22H20O2S requires C, 75.83; H, 5.79%.];
nmax (KBr) 3429, 1665, 1602 cmꢀ1; dH (200 MHz, CDCl3)
7.83 (2H, d, J 8.8 Hz, Ph), 7.34–7.16 (10H, m, Ph), 6.86
(2H, d, J 8.8 Hz, Ph), 4.91 (1H, t, J 6.3 Hz, SCH), 3.83
(3H, s, OMe), 3.59–3.52 (2H, dd, J 6.2, 4.7 Hz, COCH2);

A. Kumar, Akanksha / Tetrahedron 63 (2007) 11086–11092
11091
4.3.8. 3-(3-Chloro-phenyl)-1-p-tolyl-3-p-tolylsulfanyl-
propan-1-one (9). White solid; mp 100–104 ꢁC [Found:
C, 72.50; H, 5.60. C23H21ClOS requires C, 72.52; H,
5.56%.] nmax (KBr) 3420, 1674, 1601 cmꢀ1; dH (200 MHz,
CDCl3) 7.77 (2H, d, J 7.8 Hz, Ph), 7.31–7.11 (10H, m,
Ph), 4.83 (1H, t, J 7.2 Hz, SCH), 3.57 (2H, d, J 7.2 Hz,
COCH2), 2.40 (3H, s, Me), 2.32 (3H, s, Me); dC (50 MHz,
CDCl3) 196.6, 144.6, 144.0, 141.1, 133.9, 130.7, 129.9,
129.7, 128.5, 128.3, 128.2, 127.8, 126.8, 126.4, 47.6, 44.7,
22.0, 21.0; m/z 381 (70, MH+), 256 (90%).
130.3, 129.2, 128.8, 128.2, 127.8, 127.7, 114.1, 55.8, 45.3,
44.6, 25.8, 14.7; m/z 301 (80 MH+), 289 (45), 239 (80),
116 (92%).
4.3.14. 3-[3-(4-Methoxy-phenyl)-3-oxo-1-phenyl-propyl-
sulfanyl]-propionic acid (15). Yellow semi solid [Found:
C, 66.30; H, 5.80. C19H20O4S requires C, 71.96; H,
6.71%.]; nmax (KBr) 3407, 1602, 1599, 1502 cmꢀ1; dH
(200 MHz, CDCl3) 7.91 (2H, d, J 8.8 Hz, Ph), 7.43–7.26
(5H, m, Ph), 6.92 (2H, d, J 8.8 Hz, Ph), 4.58 (1H, t, J
6.9 Hz, SCH), 3.85 (3H, s, OMe), 3.49 (2H, d, J 6.9 Hz,
COCH2), 2.60–2.51(4H, m, SCH2CH2CO2H); dC
(50 MHz, CDCl3) 195.7, 178.0, 142.2, 132.7, 130.8, 130.1,
129.0, 128.2, 127.8, 114.1, 55.8, 45.2, 34.7, 26.4; m/z 345
(80, MH+), 314 (20%).
4.3.9. 1-(4-Hydroxy-phenyl)-3-phenyl-3-phenylsulfanyl-
propan-1-one (10). White solid; mp 103–105 ꢁC [Found:
C, 75.46; H, 5.46. C21H18O2S requires C, 75.42; H,
5.43%.] nmax (KBr) 3420, 1663, 1602 cmꢀ1; dH (200 MHz,
CDCl3) 7.78 (2H, d, J 8.4 Hz, Ph), 7.42–7.16 (10H, m,
Ph), 6.80 (2H, d, J 8.7 Hz, Ph), 4.89 (1H, t, J 7.1 Hz,
SCH), 3.67–3.44 (2H, m, COCH2); dC (50 MHz, CDCl3)
196.6, 161.1, 141.5, 134.6, 133.1, 131.5, 131.2, 129.2,
128.8, 128.1, 127.9, 127.7, 115.8, 48.8, 44.6; m/z 334 (80,
MH+), 225 (92%).
4.3.15. 3-Ethylsulfanyl-1,3-Bis-(4-methoxy-phenyl)-
propan-1-one (16). White solid; mp 140–141 ꢁC [Found:
C, 69.10; H, 6.72. C19H22O3S requires C, 69.06; H,
6.71%.]; nmax (KBr) 3430, 1680, 1669 cmꢀ1
;
dH
(200 MHz, CDCl3) 7.87 (2H, d, J 8.8 Hz, Ph), 7.30 (2H, d,
J 8.6 Hz, Ph), 6.88–6.80 (4H, m, Ph), 4.51 (1H, t, J
7.0 Hz, SCH), 3.85 (3H, s, OMe), 3.77 (3H, s, OMe),
3.43 (2H, d, J 7.1 Hz, COCH2), 2.38–2.28 (2H, m,
CH2Me), 1.12 (3H, t, J 7.3 Hz, Me); dC (50 MHz, CDCl3)
196.0, 163.9, 158.9, 134.6, 130.8, 130.3, 129.2, 114.2,
55.8, 55.6, 45.5, 44.0, 25.7, 14.7; m/z 330 (20, MH+), 269
(80%).
4.3.10. 3-Ethylsulfanyl-1,3-diphenylpropan-1-one (11).
White solid; mp 60–61 ꢁC [Found: C, 75.53; H, 6.70.
C17H18OS requires C, 75.51; H, 6.71%.] nmax (KBr) 3420,
1677, 1600 cmꢀ1; dH (200 MHz, CDCl3) 7.89 (2H, d, J
7.5 Hz, Ph), 7.54–7.39 (5H, m, Ph), 7.33–7.16 (3H, m,
Ph), 4.55 (1H, t, J 7.0 Hz, SCH), 3.51 (2H, d, J 7.0 Hz,
COCH2), 2.41–2.29 (2H, m, CH2Me), 1.13 (3H, t, J
7.3 Hz, CH2Me); dC (50 MHz, CDCl3) 197.3, 142.6,
137.2, 133.6, 129.0, 128.9, 128.5, 128.2, 127.6, 45.7, 44.4,
25.8, 14.7; m/z 269 (25, MH+), 268 (100), 209 (40), 148
(10%).
4.3.16. 3-Ethylsulfanyl-1-(4-hydroxy-phenyl)-3-phenyl-
propan-1-one (17). White semi solid [Found: C, 71.4; H,
6.38. C17H18O2S requires C, 71.30; H, 6.34%.]; nmax
(KBr) 3422, 1673, 1605 cmꢀ1; dH (200 MHz, CDCl3) 7.85
(2H, d, J 9.8 Hz, Ph), 7.81–7.15 (5H, m, Ph), 6.84 (2H, d,
J 7.7 Hz, Ph), 4.51 (1H, t, J 7.1 Hz, SCH), 3.46 (2H, d, J
7.1 Hz, COCH2), 2.41–2.20 (2H, m, CH2Me), 1.10 (3H, t,
J 7.3 Hz, Me); dC (50 MHz, CDCl3) 197.3, 161.7, 142.4,
131.6, 131.3, 129.7, 128.9, 128.1, 127.6, 116.0, 45.3, 44.8,
25.8, 14.7; m/z 286 (50, MH+), 224 (75%).
4.3.11. 3-(3-Oxo-1,3-diphenyl-propylsulfanyl)-acetic
acid (12). Yellow oil [Found: C, 67.96; H, 5.37.
C17H16O3S requires 67.98; H, 5.35%.]; nmax (KBr) 3407,
1620, 1598 cmꢀ1; dH (200 MHz, CDCl3) 7.82 (2H, d, J
7.4 Hz, Ph), 7.15–7.36 (8H, m, Ph), 4.52 (1H, t, J 6.9 Hz,
SCH), 3.53–3.49 (4H, m, CH2CH2); dC (50 MHz, CDCl3)
197.0, 175.1, 170.5, 141.0, 137.0, 133.7, 129.0, 128.5,
128.2, 127.9, 52.8, 41.4, 44.9; m/z 301 (60, MH+), 209 (78).
4.3.17. 3-Furan-2-yl-1-(4-methoxy-phenyl)-3-phenyl-3-
phenylsulfanyl-propan-1-one (18). White semi solid
[Found: C, 70.9; H, 5.38. C20H18O3S requires C, 70.9; H,
5.36%.]; nmax (KBr) 3422, 1683 cmꢀ1; dH (200 MHz,
CDCl3) 7.80 (2H, d, J 8.8 Hz, Ph), 7.35 (1H, m, Ph), 7.22–
7.11 (5H, m, Ph), 6.80 (2H, d, J 8.8 Hz, Ph), 6.09–6.07
(1H, m, Ph), 5.90 (1H, d, J 3.1 Hz, Ph), 4.92 (1H, t, J
6.9 Hz, SCH), 23.69 (3H, s, OMe), 3.50–3.30 (2H, m,
COCH2); dC (50 MHz, CDCl3) 195.4, 164.1, 153.9, 142.3,
131.6, 131.3, 129.7, 128.9, 128.1, 127.6, 114.2, 110.7,
109.2, 107.7, 55.9, 42.2, 42.0; m/z 339 (20, MH+), 228
(75), 135 (60%).
4.3.12. 3-(3-Oxo-1,3-diphenyl-propylsulfanyl)-propionic
acid (13). Yellow oil [Found: C, 68.78; H, 5.75.
C18H18O3S requires C, 68.76; H, 5.77%.]; nmax (KBr)
3407, 1600, 1598 cmꢀ1 dH (200 MHz, CDCl3) 7.88 (2H, d,
J 7.1 Hz, Ph), 7.59–7.19 (8H, m, Ph), 4.59 (1H, t, J
6.9 Hz, SCH), 3.52 (2H, d, J 6.9 Hz, COCH2), 2.60–2.52
(4H, m, SCH2CH2CO2H); dC (50 MHz, CDCl3) 197.1,
177.3, 142.0, 137.0, 133.7, 129.0, 128.5, 128.2, 127.9,
45.6, 44.9, 34.4, 26.4; m/z 315 (20, MH+), 301 (80), 209
(88), 105 (100%).
4.3.18. 4,4-Dimethyl-3-phenylsulfanyl-cyclohexanone
(23). White crystalline solid; mp 66–68 ꢁC [Found: C,
71.78; H, 7.76. C14H18OS requires C, 71.75; H, 7.74%.];
nmax (KBr) 3435, 1710 cmꢀ1; dH (200 MHz, CDCl3) 7.43–
7.38 (2H, m, Ph), 7.34–7.24 (3H, m, Ph), 3.21–3.13 (1H,
m, SCH), 2.62–2.55 (2H, m, CH2), 2.48–2.34 (2H, m,
CH2), 1.89–1.87 (1H, m, CH2), 1.86–1.61 (1H, m, CH2),
1.28 (3H, s, Me), 1.22 (3H, s, Me); dC (50 MHz, CDCl3)
209.4, 135.0, 133.1, 129.5, 127.8, 58.0, 45.8, 39.0, 38.2,
35.0, 29.4, 21.4; m/z 234.
4.3.13. 3-Ethylsulfanyl-1-(4-methoxy-phenyl)-3-phenyl-
propan-1-one (14). White solid; mp 90–92 ꢁC [Found: C,
71.98; H, 6.77. C18H20O2S requires C, 71.96; H, 6.71%.];
nmax (KBr) 3428, 1680, 1600 cmꢀ1; dH (200 MHz, CDCl3)
7.87 (2H, d, J 8.8 Hz, Ph), 7.32–7.19 (5H, m, Ph), 6.86
(2H, d, J 8.8 Hz, Ph), 4.54 (1H, t, J 7.0 Hz, SCH),
3.82 (3H, s, OMe), 3.45 (2H, d, J 7.0 Hz, COCH2), 2.40–
2.28 (2H, m, CH2Me), 1.15 (3H, t, J 7.3 Hz, Me); dC
(50 MHz, CDCl3) 195.0, 164.0, 141.7, 134.7, 133.0, 130.7,

11092
A. Kumar, Akanksha / Tetrahedron 63 (2007) 11086–11092
7. Alam, M. M.; Varala, R.; Adapa, S. R. Tetrahedron Lett. 2003,
44, 5115.
8. Bandini, M.; Cozzi, P. G.; Giacomini, M.; Melchiorre, P.;
Selva, S.; Umani-Ronchi, A. J. Org. Chem. 2002, 67, 3700.
9. Kobyashi, S.; Ogawa, C.; Kawamura, M.; Sugiura, M. Synlett
2001, 983.
10. Cheng, S.; Comer, D. D. Tetrahedron Lett. 2002, 43, 1179.
11. Wabnitz, T. C.; Yu, J.-Q.; Spencer, J. B. Synlett 2003, 1070.
12. Chu, C. M.; Gao, S.; Sastry, M. N. V.; Yao, C.-F. Tetrahedron
Lett. 2005, 46, 4971.
4.3.19. 4,4-Dimethyl-3-p-tolylsulfanyl-cyclohexanone
(24). Yellow solid; mp 75–78 ꢁC; nmax (KBr) 3432,
1709 cmꢀ1; dH (200 MHz, CDCl3) 7.39–7.25 (4H, m, Ph),
3.13–3.05 (1H, m, SCH), 2.59–2.52 (2H, m, CH2), 2.40–
2.37 (2H, m, CH2), 2.31(3H, s, Me), 1.87–1.84 (1H, m,
CH2), 1.80–1.57 (1H, m, CH2), 1.27 (3H, s, Me), 1.20 (3H,
s, Me); dC (50 MHz, CDCl3) 209.6, 134.3, 133.8, 131.2,
130.2, 58.5, 45.7, 39.0, 38.3, 35.0, 29.4, 21.4; m/z 248.
13. Ranu, B. C.; Dey, S. S.; Samanta, S. ARKIVOC 2005, iii, 44.
14. Garg, S. K.; Kumar, R.; Chakraborti, A. K. Tetrahedron Lett.
2005, 46, 1721.
15. Yadav, J. S.; Reddy, B. V. S.; Baishya, G. J. Org. Chem. 2003,
68, 7098.
Acknowledgements
We are thankful to CSIR for the financial assistance. We are
thankful to Mr. R. K. Purshottam for HPLC analysis.
16. Ranu, B. C.; Dey, S. S. Tetrahedron 2004, 60, 4183.
17. (a) Rasalkar, M. S.; Potdar, M. K.; Mohile, S. S.; Salunkhe,
M. M. J. Mol. Catal. A: Chem. 2005, 235, 267; (b) Alcaide,
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Janey, J. M.; Hsiano, Y.; Armstrong, J. D., III. J. Org. Chem.
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Kotrusz, P.; Toma, S. Molecules 2006, 11, 197.
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