Sulfated tungstate: An efficient catalyst for synthesis of thioamides via Kindler reaction

Article abstract of DOI:10.1016/j.apcata.2012.03.012

New application of sulfated tungstate, a mildly acidic solid inorganic acid, as reusable heterogeneous catalyst for efficient Kindler reaction, a three component reactions of aldehydes, amines and sulfur, for synthesis of thioamides is discussed.

Full text of DOI:10.1016/j.apcata.2012.03.012

Applied Catalysis A: General 425–426 (2012) 125–129
Contents lists available at SciVerse ScienceDirect
Applied Catalysis A: General
journal homepage: www.elsevier.com/locate/apcata
Sulfated tungstate: An efficient catalyst for synthesis of thioamides via Kindler
reaction
Sagar P. Pathare, Pramod S. Chaudhari, Krishnacharya G. Akamanchi∗
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga, Mumbai 400 019, India
a r t i c l e i n f o
a b s t r a c t
Article history:
New application of sulfated tungstate, a mildly acidic solid inorganic acid, as reusable heterogeneous
catalyst for efficient Kindler reaction, a three component reactions of aldehydes, amines and sulfur, for
synthesis of thioamides is discussed.
Received 11 December 2011
Received in revised form 3 March 2012
Accepted 5 March 2012
© 2012 Elsevier B.V. All rights reserved.
Available online 14 March 2012
Keywords:
Kindler reaction
Thioamides
Sulfated tungstate
Heterogeneous catalysis
Amines
Aldehydes
Sulfur
1. Introduction
six membered heterocycles [14–17], and active pharmaceutical
ingredients such as fentiazac, fenclosic acid and febuxostate
Appreciating the campaign for green chemistry and continuing
pressure on limiting resources, chemical sustainability has become
a focal point of research. One of the approaches toward chemical
sustainability can be through development of catalytic meth-
ods with environmentally benign, easy to recover and reusable
catalyst. Recently our group, working toward this goal, has syn-
thesized and well characterized sulfated tungstate [1], as green,
reusable, heterogeneous, mildly acidic catalyst and demonstrated
its effectiveness in amide bond formation [1,2], Biginelli [3],
Willgerodt–Kindler [4] and Strecker [5] reactions. On the same
track it was thought that sulfated tungstate might catalyze Kindler
reaction [6], a three component reaction of aldehyde, amine and
sulfur satisfactorily conducted under acid catalyzed conditions, for
synthesis of thioamides and indeed this was observed. Thioamides
are an important class of compounds and show broad spectrum of
bioactivity such as antibacterial, antimycobacterial, antiulcerative,
fungicidal, anticancer and spasmolytic [7–13]. Ethionamide and
prothionamide are two examples of thioamide containing drugs
which are in clinical use for treatment tuberculosis. Thioamides
find wide applications as intermediates in synthesis of five and
[18,19]. A good number of preparative methods are available in
literature for synthesis of thioamides and the most frequently
used methods are based on thionation of amides. Thionation of
amides is affected using thionating reagents, such as P4S10 [20–25],
diethylthiocarbamoyl chloride [26], ethylaluminum sulfide [27],
boron sulfide [28,29], use of PSCl3/H2O/Et3N system [30] and
Lawesson’s reagent [31]. Thionation of amides is also achieved by
activation of amides with electrophilic reagents, such as oxalyl
chloride and phosphorousoxychloride and benzyltriethylammo-
nium tetrathiomolybdate [32] and hexamethyldisilathiane [33],
followed by treatment with thionating agents. These approaches
suffer from drawbacks like toxicity of reagents, bad odor, cor-
rosive nature, explosive properties, formation of uncontrolled
by-products with lower yields. In the past few years, improved
reagents such as fluorous based Lawesson’s reagents [34], encap-
sulated P4S10 [35] and polymer supported thionating agents
[36] have been developed to address some of these drawbacks.
Willgerodt–Kindler [37,38] and Kindler reactions [6], classical
three component reactions of ketones/aldehydes, amines and
sulfur, are direct oxidative sulfurization methods for thioamide
synthesis. Kindler reaction, where the three components are alde-
hyde, primary/secondary amines, ammonia or ammonium salt and
sulfur, has potential for wide applicability for synthesis of diverse
set of useful thioamides in one pot with high atom economy and
with water as the only condensation by-product, because a large
∗
Corresponding author. Tel.: +91 22 33611111/2222; fax: +91 22 33611020.
E-mail addresses: kg.akamanchi@ictmumbai.edu.in, kgap@rediffmail.com
(K.G. Akamanchi).
0926-860X/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.apcata.2012.03.012

126
S.P. Pathare et al. / Applied Catalysis A: General 425–426 (2012) 125–129
O
S
H2N
catalyst
solvent/110 oC
H
N
H
S8
+
+
Thiobenzanilide
Scheme 1. Kindler thioamidation reaction of benzaldehyde, aniline and sulfur.
Table 1
Table 3
Optimization of catalyst amount and solvent.a
Effect of different acid catalysts for formation of N-phenylthiobenzamide.a
Entry Solvent Sulfated
tungstate (wt%)
Temperature (◦C) Time (h) Yieldb (%)
Entry
Acid catalyst
wt%
Time (h)
24
12
12
12
12
8
Yieldb (%)
1
2
3
4
5
6
Nil
Acetic acid
p-Toluenesulfonic acid
Silica
Tungstic acid
Sulfated tungstate
–
20
20
20
20
10
15
40
64
34
17
90
1
2
3
4
5
6
7
8
9
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Neat
Neat
DMSO
NMP
–
1
5
110
110
110
110
110
rt
24
12
12
8
15
34
69
90
91
–
10
20
10
10
10
–
10
10
10
8
12
12
12
24
12
12
12
a
Reaction conditions: benzaldehyde (1 g, 9.4 mmol), aniline (1.1 g, 11.8 mmol),
and sulfur (0.38 g, 11.8 mmol) at 110 ◦C in DMF for 8 h.
60
90
110
110
130
150
26
65
10
56
79
60
b
Isolated yield.
10
11
12
relative to tetramethylsilane (Me4Si) signal as internal reference. IR
spectra were recorded as KBr pellet. All compounds were analyzed
using the same HPLC conditions: isocratic elution (0.05% CF3COOH,
Water/CH3CN 15:85), flow rate = 0.5 ml/min, T = 25 ◦C, UV detection
at 260 nm with column Purosphere, RP-18e (5 ␮m). All the solvents
were purchased from commercial sources and were used with-
out further purification. Preparation and characterization details
of sulfated tungstate are given in our previous work [1].
a
Reaction condition: benzaldehyde (1 g, 9.4 mmol), aniline (1.1 g, 11.8 mmol) and
sulfur (0.38 g, 11.8 mmol) at different temperature.
b
Isolated yield.
number of aldehydes and primary/secondary amines, ammonia
and its salts are readily and commercially available. The classical
Kindler reaction method has many drawbacks, however, some
attempts have been made toward improvement by Oliver Kappe
et al. by using microwave flash heating in N-methylpyrrolidone as
solvent [39]. This modification, though does not show any poten-
tial for large scale application, has allowed preparation of wide
range of thioamides in good yields. Another recent modification,
developed by Kanbara and co-workers [40] using Na2S·9H2O,
gave promising results; however, the method still suffered from
drawbacks like long reaction time, requirement of relatively large
amount of catalyst and removal of trace amounts of catalyst from
reaction products. Having seen the present status of various meth-
ods for thioamide synthesis, with many drawbacks as indicated by
literature, clearly show that there is a scope for newer and better
methods. Therefore we got interested in investigating suitability of
sulfated tungstate as heterogeneous catalyst for Kindler reaction
and the results are presented here.
2.2. General procedure for sulfated tungstate mediated synthesis
of thioamides
Sulfated tungstate (10% w/w) was added to a mixture of
benzaldehyde (1 g, 9.43 mmol), aniline (1.1 g, 11.8 mmol) and sul-
fur (0.38 g, 11.8 mmol) in DMF (10 ml) and the suspension was
stirred at 110 ◦C for 8 h. The progress of the reaction was moni-
tored by TLC. After completion of reaction, the reaction mixture
was diluted with EtOAc (15 ml) and filtered to recover the cat-
alyst. The organic layer was washed with saturated aq. NH4Cl
solution (20 ml), water (2 × 50 ml), dried over Na2SO4 and con-
centrated under reduced pressure to get crude product; which
was purified by chromatography on silica gel with hexane–ethyl
acetate (8:2) as eluent to get pure thiobenzanilide as pale yellow
solid (Scheme 1), m.p. 97–98 ◦C (lit. [40] 99 ◦C); IR (KBr): 3328,
1497, 1445, 1208 cm−1 1H NMR (300 MHz, CDCl3): ı = 9.0 (br.
;
2. Experimental
s. 1H), 7.31–7.16 (m, 10H). 13C NMR (75 MHz, CDCl3): ı = 127.0,
127.5,128.7,129.1,131.0,135.7,140.5,189.2.
2.1. Materials and methods
All the products were known compounds and were charac-
terized by IR, 1H NMR spectroscopic data, melting points and
compared with reported values.
General: 1H NMR of all the products were recorded at 300 MHz
in CDCl3 as solvent and chemical shift values are expressed in ı ppm
Table 2
Mole ratio study.a
Table 4
Reusability study.a
Entry
Benzaldehyde:aniline (mole ratio)
Sulfur (mole ratio)
Yieldb (%)
Run no.b
% Yield of N-phenylthiobenzamide
1
2
3
4
5
6
1:1
1
1
1.25
1.50
2
76
80
90
92
92
74%
1:1.25
1:1.25
1:1.50
1:1.50
1.25:1
Fresh
90
89
88
86
86
First recycle
Second recycle
Third recycle
Fourth recycle
1.25
a
a
Reaction was performed with 1 g, 9.4 mmol of benzaldehyde and appropriate
mmol of other reactants with 10 wt% of catalyst in DMF for 8 h at 110 ◦C.
Reaction condition: benzaldehyde (1 g, 9.4 mmol), aniline (1.1 g, 11.8 mmol) and
sulfur (0.38 g, 11.8 mmol) at 110 ◦C for 8 h.
b
b
Isolated yield.
Loss of catalyst (<5%) during handling.

S.P. Pathare et al. / Applied Catalysis A: General 425–426 (2012) 125–129
127
Table 5
Substrate scope.a
S
O
Sulfated
tungstate
R2
HN
R3
R2
S8
+
+
R1
N
R1
H
DMF/110 oC/8h
R3
.
Entry
R1
R2
R3
H
Product
Yield
76b
S
NH2
1
2
C6H5
H
H
S
NH2
4-MeOC6H4
H
H
60b
H3CO
S
NH2
3
4
4-ClC6H4
H
63b
Cl
S
NH2
3-O2NC6H4
H
H
H
66b
NO2
S
NH2
5
6
4-O2NC6H4
H
H
56b
O2N
S
C6H5
C6H5
90
N
H
CH3
OCH3
Cl
S
7
8
C6H5
4-MeC6H4
H
H
90
90
N
H
S
C6H5
4-MeOC6H4
N
H
S
9
C6H5
4-ClC6H4
H
H
81
70
N
H
S
10
C6H5
2-ClC6H4
C6H5CH2
N
H
Cl
S
N
H
11
12
C6H5
C6H5
H
H
91
84
S
N
H
C6H5CH2CH2
S
13
C6H5
c-Hex
H
90
N
H

128
S.P. Pathare et al. / Applied Catalysis A: General 425–426 (2012) 125–129
Table 5 (Continued)
Entry
R1
R2
R3
H
Product
Yield
85
S
N
H
14
15
4-HOC6H4
C6H5
HO
S
N
4-MeOC6H4
4-MeOC6H4
C6H5
H
H
88
89
H
H3CO
OCH3
S
16
4-MeOC6H4
N
H
H3CO
S
S
S
S
S
17
18
19
C6H5
2-pyridyl
3-pyridyl
c-Hex
H
H
H
82
84
90
N
N
H
N
C6H5
N
H
2-furyl
N
H
O
S
20
21
2-thiophenyl
C6H5
H
H
89
90
N
H
2-methylpropyl
c-Hex
N
H
S
22
C6H5
(CH2)5
N
91
89
S
N
23
C6H5
(CH2)2
O (CH2)2
O
a
Conditions: benzaldehyde (1.0 equiv), aniline (1.25 equiv), sulfur (1.25 equiv) and catalyst (10 wt%) at 110 ◦C in DMF.
Ammonia as ammonium acetate.
b
3. Result and discussion
sulfated tungstate (Table 1, entry 4). To optimize catalyst amount,
a set of reactions were carried out with increasing amounts of cat-
alyst in the range of 1–20 wt%. From the results (Table 1, entries
2–5), it was concluded that an amount of 10 wt% is optimum giving
maximum yield and further increase in quantity did not show any
benefits. Reaction under study did not show encouraging results
under solvent-free condition either in absence or presence of the
catalyst even at 110 ◦C (Table 1, entries 9 and 10). The reaction
was investigated using other polar solvents such as DMSO, NMP
respectively, however in both cases, reaction was comparatively
slow and gave lower yields even after 12 h (Table 1, entries 11
and 12). Other solvents like toluene, acetonitrile and water were
also investigated but in all cases practically there was no reac-
tion.
Initial investigations were carried out on thioamidation reaction
using benzaldehyde and aniline as building blocks (Scheme 1).
Reactions were carried out at different temperatures in DMF
and the best results were obtained at 110 ◦C where as, yields were
lower at 60 ◦C and 90 ◦C and reaction did not proceed at room tem-
perature (Table 1, entries 6–8). Investigations were also carried out
to establish the catalytic role and optimize quantity of sulfated
tungstate. A reaction was carried out in the absence of sulfated
tungstate and it was found that, the reaction was very slow and
gave just 15% yield, in 24 h (Table 1, entry 1). Whereas the same
reaction in presence of 10 wt% of sulfated tungstate, got acceler-
ated, to give a yield of 90% in 8 h thus establishing catalytic role of

S.P. Pathare et al. / Applied Catalysis A: General 425–426 (2012) 125–129
129
To optimize mole ratio of substrates, experiments were per-
formed with 10 wt% of catalyst and varying ratios of substrates
and results are given in Table 2. The reaction with equimo-
lar quantities of benzaldehyde, aniline and sulfur shows 76%
yield of N-phenylbenzothioamide (Table 2, entry 1). With fur-
ther investigations optimum mol ratio was arrived at 1:1.25:1.25
of aldehyde:aniline:sulfur respectively giving 90% yield (Table 2,
entry 3) and was chosen for further studies. Increasing mole ratio
of aniline and sulfur to 1.5 and 2 equiv respectively did not show
significant improvement in yields (Table 2, entries 4 and 5). When
aldehyde was in excess over the aniline, yields were only 74%
(Table 2, entries 6).
represents an efficient, improved and cost effective methodology
for Kindler reaction.
4. Conclusion
Sulfated tungstate was found to be suitable as catalyst for
Kindler reaction for synthesis of primary, secondary and tertiary
thioamides in high yields. The remarkable catalytic activity exhib-
ited by sulfated tungstate is superior to other reported methods
with respect to operational simplicity, cleaner reaction profile. The
catalyst is, green, easy to recover and reusable and holds potential
for large scale applications.
To assess the standing of the catalyst, amongst other acid cata-
lysts, a comparative study was performed and results are given in
Table 3. The yield obtained using sulfated tungstate was very high
and even with lesser amount as compared to other acid catalysts
thus indicating its superiority.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.apcata.2012.03.012.
Reusability study was performed, and results presented in
Table 4, indicate that the catalyst was stable and reusable four times
without any loss of activity. It is noteworthy that the catalyst was
recovered simply by filtration without any acidic or basic workup
even after its fourth use.
In order to prove that the reaction is heterogeneous, a standard
leaching experiment was conducted. Two sets of experiments were
conducted and both reactions were proceeded for 1 h. One experi-
ment was worked up, while from the other, the catalyst was filtered
off and the reaction was continued at the same reaction tempera-
ture of 110 ◦C for 12 h and worked up. The yields obtained in both
cases 8% and 11% respectively, were practically same, indicating
that no homogeneous catalyst was involved.
References
[1] P.S. Chaudhari, S.D. Salim, R.V. Sawant, K.G. Akamanchi, Green Chem. 12 (2010)
1707–1709.
[2] K.V. Katkar, P.S. Chaudhari, K.G. Akamanchi, Green Chem. 13 (2011) 835–838.
[3] S.D. Salim, K.G. Akamanchi, Catal. Commun. 12 (2011) 1153–1156.
[4] S.D. Salim, S.P. Pathare, K.G. Akamanchi, Catal. Commun. 13 (2011) 78–81.
[5] S.P. Pathare, K.G. Akamanchi, Tetrahedron Lett. 53 (2012) 871–875.
[6] K. Kindler, Ann. 431 (1923) 222–224.
[7] D.C. Schroeder, Chem. Rev. 55 (1955) 181–228.
[8] J. Kunes, V. Balsanek, M. Pour, K. Waisser, J. Kaustova, Farmaco 57 (2002)
777–782.
[9] K. Gibinski, Curr. Med. Res. Opin. 7 (1981) 516–519.
[10] A.K. Mallams, J.B. Morton, P. Reichert, J. Chem. Soc., Perkin Trans. 1 (1981)
2186–2208.
[11] W. Hu, H. Yu, Y. Chen, Y. Tsai, Y. Chen, C. Liao, L. Chang, J. Wang, Bioorg. Med.
Chem. 16 (2008) 5295–5302.
To explore generality and scope of the method, variety of sub-
strates was used to synthesize primary, secondary and tertiary
thioamides and results are shown in Table 5. The method was
found to be suitable, but with low yields, for preparation of primary
thioamides with benzaldehydes, containing electron donating as
well as electron withdrawing groups and ammonia as ammo-
nium acetate (Table 5, entries 1–5). This is noteworthy feature
because, there are only few reports concerning the synthesis of
primary thioamide by Kindler reaction [39–41]. To investigate
substituent effect, benzaldehydes and anilines, both variously sub-
stituted, were reacted. In all cases, irrespective of substituent being
electron withdrawing or electron donating, reactions were smooth
and gave excellent yields (Table 5, entries 7–8 and 11–13).
In case of halogenated benzaldehdyes, halogen remained intact
and no side products were observed arising from reactions with
amines and sulfur (Table 5, entries 3, 9 and 10). Slightly lower
yields were observed with, sterically hindered, 2-chloroaniline
(Table 5, entry 10). Under similar set of conditions, interestingly,
aliphatic amines and aldehydes gave excellent yields of the respec-
tive thioamides (Table 5, entries 11–13, 19 and 21). The catalyst,
sulfated tungstate, was also effective for the reaction of benzalde-
hyde and heteroaromatic amines (Table 5, entries 17 and 18).
Substrates containing methoxy and phenolic groups were compat-
ible under the reaction conditions (Table 5, entries 2, 8, 14–16).
Even the furan ring, which is prone to polymerization under acidic
condition, was stable and furfural reacted smoothly gave excellent
yield (Table 5, entry 19). Reaction with thiophene aldehyde was
also equally facile (Table 5, entry 20). As expected, cyclic secondary
amines viz. piperidine, morpholine reacted equally well and gave
high yields (Table 5, entries 22 and 23). Thus the protocol developed
[12] A. Bitton, Inflamm. Bowel Dis. 11 (2005) 513–514.
[13] G. Brunhofer, C. Studenik, G. Ecker, T. Erker, Eur. J. Pharm. Sci. 42 (2011)
37–44.
[14] T. Hisano, Y. Yabuta, Chem. Pharm. Bull. 21 (1973) 511–517.
[15] F.M. Moghaddam, M. Ghaffarzadeh, M. Dekamin, J. Chem. Res. (2000) 228–229.
[16] F.M. Moghaddam, M. Ghaffarzadeh, Synth. Commun. 31 (2001) 317–321.
[17] F.M. Moghaddam, L. Hojabri, M. Dohendou, Synth. Commun. 33 (2003)
4279–4284.
[18] D. Lednicer, Strategies for Organic Drug Synthesis and Design, John Wiley press,
2009, pp. 298–299.
[19] D. Lednicer, L. Mitscher, The Organic Chemistry of Drug Synthesis, vol. 7, John
Wiley press, 2008, pp. 100–101.
[20] J.W. Scheeren, P.H.J. Ooms, R.J.F. Nivard, Synthesis (1973) 149–150.
[21] S. Raucher, P. Klein, J. Org. Chem. 46 (1981) 3558–3559.
[22] O.P. Goel, U. Krolls, Synthesis (1987) 162–164.
[23] D. Brillon, Synth. Commun. 20 (1990) 3085–3095.
[24] K. Hartke, H.D. Gerber, J. Prakt. Chem. 338 (1996) 763–765.
[25] T.J. Curphey, J. Org. Chem. 67 (2002) 6461–6473.
[26] M. Ogata, H. Matsumoto, Heterocycles 11 (1978) 139–141.
[27] T. Hirabayashi, K. Inoue, K. Yokota, J. Organomet. Chem. 92 (1975) 139–145.
[28] P.W. Wojtkowski, J.E. Dolfini, O. Kocy, C.M. Cimarusti, J. Am. Chem. Soc. 97
(1975) 5628–5630.
[29] K. Steliou, M. Mrani, J. Am. Chem. Soc. 104 (1982) 3104–3106.
[30] U. Pathak, L.K. Pandey, R. Tank, J. Org. Chem. 73 (2008) 2890–2893.
[31] M.P. Cava, M.I. Levinson, Tetrahedron 41 (1985) 5061–5087.
[32] P. Ilankumaran, A.R. Ramesha, S. Chandrasekaran, Tetrahedron Lett. 36 (1995)
8311–8314.
[33] D.C. Smith, S.W. Lee, P.L. Fuchs, J. Org. Chem. 59 (1994) 348–354.
[34] Z. Kaleta, B.T. Makowski, T. Soos, R. Dembinski, Org. Lett. 8 (2006) 1625–1628.
[35] V. Polshettiwar, M.P. Kaushik, Tetrahedron Lett. 47 (2006) 2315–2317.
[36] S.V. Ley, A.G. Leach, R.I. Storer, J. Chem. Soc., Perkin Trans. 1 (2001) 358–361.
[37] B.P. Mundy, M.G. Ellerd, F.G. Favalore Jr., Name Reactions and Reagents in
Organic Synthesis, 2nd ed., Wiley, 2005.
[38] R. Carlson, T. Lundstedt, R. Shabana, Acta Chem. Scand. B 40 (1986) 534–544.
[39] Z.I. Oleksandr, S. Nikola, C. Oliver Kappe, J. Comb. Chem. 5 (2003) 145–148.
[40] K. Okamoto, T. Yamamoto, T. Kanbara, Synlett 17 (2007) 2687–2690.
[41] E.V. Brown, Synthesis (1975) 358–375.