Basic alumina-catalyzed, solvent-free synthesis of diversified thioethers

Article abstract of DOI:10.1080/10426500902998131

Environmentally and economically benign solvent free syntheses of thioethers are performed by the reaction of benzothiazole thiol with different halides on basic aluminaa simple, cheap, robust catalyst that couples a range of substrates with thiol in exce

Full text of DOI:10.1080/10426500902998131

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Phosphorus, Sulfur, and Silicon and the
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Basic Alumina-Catalyzed, Solvent-Free
Synthesis of Diversified Thioethers
K. Prabakaran a & F. Nawaz Khan a b
a Chemistry Division, School of Science and Humanities , VIT
University , Vellore, Tamil Nadu, India
b Syngene International Limited (Biocon) , Banglore, India
Published online: 23 Mar 2010.
To cite this article: K. Prabakaran & F. Nawaz Khan (2010) Basic Alumina-Catalyzed, Solvent-Free
Synthesis of Diversified Thioethers, Phosphorus, Sulfur, and Silicon and the Related Elements, 185:4,
825-831, DOI: 10.1080/10426500902998131
To link to this article: http://dx.doi.org/10.1080/10426500902998131
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Phosphorus, Sulfur, and Silicon, 185:825–831, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500902998131
BASIC ALUMINA-CATALYZED, SOLVENT-FREE
SYNTHESIS OF DIVERSIFIED THIOETHERS
K. Prabakaran1,2 and F. Nawaz Khan1
1Chemistry Division, School of Science and Humanities, VIT University, Vellore,
Tamil Nadu, India
2Syngene International Limited (Biocon), Banglore, India
Environmentally and economically benign solvent free syntheses of thioethers are performed
by the reaction of benzothiazole thiol with different halides on basic alumina—a simple,
cheap, robust catalyst that couples a range of substrates with thiol in excellent yields in
a short time. The in vitro antibacterial screening of compounds 3c, e, g, i, j, and k were
evaluated against the Gram-positive organism Staphylococcus aureus and Gram-negative
organisms. Escherichia coli and Proteus mirabilis by the Agar well diffusion method.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental
file.
Keywords Basic alumina; catalyst; electron-deficient; electron-rich; thioethers
INTRODUCTION
The formation of carbon–sulfur bonds is considered to be important due to the
prevalence of aryl–sulfur bonds in important biological and pharmaceutical materials.1–3
However, only a few studies have been reported on Pd or Ni catalysis4–7 or Cu catalysis.8–11
Recently many methods including 10 mol% CuI, 10 mol% neocuproine, with NaOtBu as the
base12 involving 5 mol% CuI and HOCH2CH2OH as ligand,13 microwave heating 14 using 20
mol% N-methylglycine, 5 mol% CuI, and 2.5 equiv. KOH have been reported.15 However,
the scope is somewhat limited by their use of a strong base and high temperature, and some of
these methods suffer from important problems including the use of stoichiometric amounts
of the reagents and unpleasant odor substrates, long reaction times, unsatisfactory yields,
poor selectivity, and the use of expensive and toxic reagents or catalysts. Fly-ash–supported
synthesis of thioether derivatives under microwave irradiation was reported recently.16
Though satisfying yield of the coupling product is obtained by the above methodologies,
no emphasis was given to its high generality or exceptional level of functional group
Received 1 February 2009; accepted 24 April 2009.
We thank Syngene International Ltd., Bangalore, India, for its generous support in spectral analysis. F. N.
Khan thanks the DST, India, for Fast Track Young Scientist fellowship.
Address correspondence to F. Nawaz Khan, Chemistry Division, School of Science and Humanities, VIT
University, Vellore 632 014, Tamil Nadu, India. E-mail: nawaz f@yahoo.co.in
825

826
K. PRABAKARAN AND F. N. KHAN
R
X
S
N
S
2
SH
S
R
N
Catalyst
3
1
Scheme 1
toleration. Therefore, it is desirable to find a better alternative method for synthesis of
thioethers.
In continuation of our interests on C–C bond formation and organosulfur com-
pounds,17–23 in this article we describe C–S bond formation in the synthesis of thioethers
by simple, economical, and environmentally benign procedures, by avoiding volatile and
toxic organic solvents (Scheme 1, Tables I–III) in the presence of Montmorillonite K10
catalyst or other inorganic catalysts such as basic alumina, bentonite, etc. (Table II). The
reactions carried out utilizing Montmorillonite K10 clay gave low yield. However, the reac-
tion took less time in the presence of basic alumina. The optimization of catalyst amount was
also performed (Table III). The reusability of the catalyst in synthesis has also been explored
(Table S1, available online in the Supplemental Materials). The antimicrobial activities of
compounds have been evaluated for a range of bacterial species (Table S2, Supplemental
Materials). From the data, it is obvious that the reaction proceeds very smoothly in a simple,
clean, and easier protocol. Also the formation of disulfide, a common side reaction in thiol
chemistry, is very much suppressed.
RESULTS AND DISCUSSION
As a part of our research, synthesis of thioether (3a) from benzothiazole (1) and
1-(chloromethyl)-4-chlorobenzene (2a) was performed in the presence of Montmorillonite
K-10, silica gel, and basic alumina catalysts, the results of which (Table II) indicated the
formation of thioether in high yields exclusively in basic alumina catalyst. The essence of
the basic alumina catalyst can be understood from following facts: When benzothiazole
thiol (1) was treated with basic alumina under conventional heating in the presence of
1-(chloromethyl)-4-chlorobenzene (2a), the product 3a was obtained in quantitative yield
(entry 5, Table II), and that the same reaction when performed without basic alumina
catalyst, the product 3a was obtained in much lower yield in 2 h (entry 1, Table III). The
optimization of the reaction with different amounts of basic alumina was carried out, and
the results show at 0.14 g, yield was good (Table III). Diversified thioethers have been
synthesized (Scheme 1) and are summarized (Tables I–III).
Reusability of Catalyst
The reusability of the catalyst was explored by checking the successive runs of
reactions on recycled catalyst, i.e., catalyst recovered by filtration from the reaction mixture,

BASIC ALUMINA-CATALYZED, SOLVENT-FREE SYNTHESIS
827
Table I Synthesis of thioethers by solvent-free, basic alumina catalysisa
Heating at 50◦C under solvent-free conditions
Sl. No
1
Reactant 2
Time taken (h)
Product, 3a–j
Yieldc%
0.5
86.2
S
S
N
Cl
Cl
Cl
3a
2a
2
0.5
60.6
S
S
N
CH3
CF3
N
N
F3C
Cl
3b
2b
3
4
0.5
0.5
97.8
91.5
S
S
N
N
O
O
N
Br
3c
2c
S
N
Br
S
CH2
CH2
3d
2d
5b
0.5
75.8
86.8
S
S
C
H
Cl
CH3
N
2e
3e
3f
6b
1
S
N
H
N
S
N
N
N
H
Cl
2f
7b
overnight
91.6
S
S
O
N
N
N
Cl
O
2g
3g
(Continued on next page)

828
K. PRABAKARAN AND F. N. KHAN
Table I Synthesis of thioethers by solvent-free, basic alumina catalysisa (Continued)
Heating at 50 ◦C under solvent-free conditions
Sl. No
8b
Reactant 2
Time taken (h)
2
Product, 3a–j
Yieldc%
86.6
S
S
N
Cl
N
N
2h
2i
3h
3i
9b
1
88.3
32.4
S
N
Br
Br
S
10b
overnight
S
N
S
N
N
2j
3j
11
1
76.2
S
S
O
Br
Br
O
O
N
O
3k
2k
12
13
0.5
0.5
95.2
94.5
S
S
CH
CH
N
2l
3l
Cl
S
S
N
2m
3m
a1 = 1 equiv, 2 = 1.2 equiv, catalyst = 0.14 g.
bAll products were characterized by 1H NMR and IR spectroscopic data.
c3 in isolated yields after column chromatography.
washed with ethyl acetate, and dried. Then it was utilized in a second run of reaction process.
It was noticed that subsequent experiments gave almost similar yields, (Table S2) and the
catalyst is not leached.

BASIC ALUMINA-CATALYZED, SOLVENT-FREE SYNTHESIS
829
Table II Selection of catalysta
Refluxing at 50◦C solvent-free conditions
Sl.No.
Catalyst used
Amount of Catalyst used (mg)
Time (h)
Product 3a
1
2
3
4
5
6
7
8
Silica Gel, 60–120
Bentonite
Montmorillonite KSF
Montmorillonite K10
Ammonium chloride/ H2O
Bu4NBr
100
100
100
100
100
100
100
100
4
4
4
4
24
4
Nil
Nil
Nil
23.1
36.8
41.2
Nil
Acidic alumina
Basic alumina
4
0.5
77.4
aBenzothiazole thiol 1 (1 equiv) and 1-(chloromethyl)-4-chlorobenzene- 2a (1.2 equiv).
Table III Optimization of catalyst concentration in the synthesis of 2-(4-chlorobenzylthio)benzo[d]thiazolea
Refluxing at 50◦C solvent free conditions
Sl.No.
1
Halide, R R X
Basic alumina G
None
Time (h)
2
Product 3a (R)
Yieldb (%)
Nil
S
S
N
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
Br
Br
2
3
4
5
6
7
8
0.02
0.04
0.06
0.08
0.1
1
30.5
43.6
65.6
72.7
77.4
81.7
86.2
S
S
N
1
S
S
N
1
S
S
N
0.5
0.5
0.5
0.5
S
S
N
S
S
N
0.12
0.14
S
S
N
S
S
N
a1 = 1 equiv, 2a = 1.2 equiv.
b3a in isolated yield.

830
K. PRABAKARAN AND F. N. KHAN
Antibacterial Study
The in vitro antibacterial screening of compounds 3c, e, g, i, j and k was evaluated
against the selected Gram-positive organism Staphylococcus aureus and Gram-negative
organisms Escherichia coli and Proteus mirabilis by Agar well diffusion method, and is
presented in the Supplemental Materials (available online).
CONCLUSION
A mild procedure has been found for the coupling reactions of different halides with
thiols using basic alumina as catalyst. The salient features of this method are high generality,
exceptional level of functional group toleration, satisfying yield of the coupling product,
and environmentally and economically benign conditions.
EXPERIMENTAL
All reactions were carried out in resealable tubes, under a high-purity nitrogen at-
mosphere. Flash-column chromatography was performed using neutral alumina. Melting
points were taken in open capillary tubes. IR spectra in KBr pellets were recorded on
Nucon Infrared spectrophotometer. Nuclear magnetic resonance (1H and 13C) spectra were
recorded on a Bruker Spectrospin Avance DPX400 Ultrashield (400 MHz) spectrometer.
General Procedure of the Coupling Reaction
To thiol (1) (1.0 equiv.), halides (2) (1.2 equiv) were added at room temperature under
nitrogen, and then the catalyst was added, the mixture was heated to 50◦C, and stirred at
the same temperature until completion of reaction, monitored by TLC. The mixture was
extracted several times (3 × 20 mL) with DCM or EtOAc. The combined organic layers
were concentrated. Purification of the residue to the thioether (3) was performed by flash
chromatography on neutral alumina (petroleum ether/ethyl acetate).
2-(4-Chlorobenzylthio)benzo[d]thiazole (3a)
Thiol (1) (0.15 g, 0.897 mmol), 1-(chloromethyl)-4-chlorobenzene (2a) (0.173 g,
1.0762 mmol), and basic alumina (140 mg) were taken in a 50-mL RB flask, refluxed at
50◦C for 30 min, and stirred at the same temperature for 1 h. Reaction was monitored by
TLC, and after completion of the reaction, was worked up as above to give crude product 2-
(4-chlorobenzylthio)benzo[d]thiazole (3a), which was purified by column chromatography
using neutral alumina and pet ether:ethyl acetate as eluent (Compound 3a, Table I).
A similar procedure was followed to obtain the other thioether derivatives 3 from
1
different halides 2 (Scheme 1, Table I). Products were characterized by FT-IR, H NMR,
13C NMR, and GCMS spectral techniques, and known compounds have been compared
with reports in the literature.
Analytical Data
Data of a few compounds 3a,b that have not been reported earlier are given in the
following sections. The data of other compounds 3d–m are given as a supporting document,
which is available online in the Supplemental Materials.

BASIC ALUMINA-CATALYZED, SOLVENT-FREE SYNTHESIS
831
2-(4-Chlorobenzylthio)benzo[d]thiazole (3a). Yield 86.2%, Yellow solid, mp
114 ◦C, IR (KBr pellets, ν cm−1) 3058, 2926, 1584, 1491, 1456, 1426, 1309, 1094, 1004,
830, 753, 499. 1H NMR (400 MHz, CDCl3) 7.92–7.89 (d, J = 8.08 Hz, 1H), 7.77–7.75 (d,
J = 8.0Hz, 1H), 7.46–7.39 (m, 3H), 7.34–7.28 (m, 3H), 4.57 (s, 2H); 13C NMR (100 MHz,
CDCl3), δ 153.01, 135.34, 134.97, 133.59, 130.49, 126.13, 124.42, 121.57, 121.05, 36.86;
LC-MS m/z 292.1 (M+); C14H10NS2Cl, Mol. Wt.: 291.1.23,.
2-((6-(Trifluoromethyl)-2-methylpyridin-3-yl)methylthio)benzo[d]thiazole
(3b). Yield 60.6%, Colorless liquid, IR (KBr pellets, ν cm−1) 3064, 2924, 1589, 1460,
1
1428, 1405, 1260, 1181, 1139, 1116, 1018, 997, 759. H NMR (400 MHz, CDCl3)
7.97–7.95 (d, J = 7.88 Hz, 1H), 7.92–7.90 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 4 Hz,
1H), 7.48–7.43 (m, 2H), 7.35–7.33 (t, J = 7.12 Hz, 1H), 4.67 (s, 2H), 2.76 (s, 3H); 13C
NMR (100 MHz, CDCl3), δ 164.65, 158.39, 152.85, 138.58, 138.07, 135.43, 133.70,
126.24, 121.63, 121.16, 118.09, 118.07, 42.67, 34.08, 22.42; LC-MS m/z 341.1 (M+);
C15H11F3N2S2, Mol. Wt.: 340.
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