Microwave-Assisted Conversion of Nitriles to Thioamides in Solvent-Free Condition

Article abstract of DOI:10.1081/SCC-120026857

Nitriles are efficiently transformed to thiomorpholides via the Willgerodt-Kindler reaction under microwave irradiation in solvent-free conditions.

Full text of DOI:10.1081/SCC-120026857

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Microwave-Assisted Conversion of Nitriles to
Thioamides in Solvent-Free Condition
a
a
a
Firouz Matloubi Moghaddam , Leila Hojabri & Mohammad Dohendou
a
Sharif University of Technology, Department of Chemistry, Tehran, Iran
Published online: 21 Aug 2006.
To cite this article: Firouz Matloubi Moghaddam , Leila Hojabri & Mohammad Dohendou (2003) Microwave-Assisted
Conversion of Nitriles to Thioamides in Solvent-Free Condition, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 33:24, 4279-4284, DOI: 10.1081/SCC-120026857
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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 24, pp. 4279–4284, 2003
Microwave-Assisted Conversion of Nitriles to
Thioamides in Solvent-Free Condition
Firouz Matloubi Moghaddam,* Leila Hojabri,
and Mohammad Dohendou
Sharif University of Technology,
Department of Chemistry, Tehran, Iran
ABSTRACT
Nitriles are efficiently transformed to thiomorpholides via the
Willgerodt-Kindler reaction under microwave irradiation in
solvent-free conditions.
Key Words: Nitriles; Thiomorpholides; Willgerodt-Kindler reac-
tion; Microwave irradiation.
*
Correspondence: Firouz Matloubi Moghaddam, Sharif University of
Technology, Department of Chemistry, P.O. Box 11365-9516, Tehran, Iran;
E-mail: matloubi@sharif.edu.
4
279
DOI: 10.1081/SCC-120026857
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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4
280
Moghaddam, Hojabri, and Dohendou
Thioamides have widespread uses such as versatile intermediates in
[2,3]
organic synthesis, pesticides,
[1]
[2]
anti inflammatory, and antiulcer
[4]
agents. A recent review published in the literature, also shows the
importance of these compounds for the preparation of heterocyclic
[5]
compounds.
Many different methods to prepare thioamides have been reported in
[6]
the literature.
The classical route for their synthesis is the
Willgerodt-Kindler reaction of aryl alkyl ketones, already has been
extended from the original forms to many other functional groups such
as aldehydes, unsaturated hydrocarbons, nitriles, amines, imines,
[
7]
ꢀ
epoxides, and alcohols. High temperature (120 C) and long refluxing
[
8]
time (6 h) are required in the classical route. Recently, we and others
have shown the efficiency of microwave-heating for the synthesis of
[
thioamides from styrenes, aldehydes, and ketones.
9]
[10,11]
In the present
work, we wish to report the preparation of thioamides from nitriles via
Willgerodt-Kindler reaction assisted by microwave irradiation in
solvent-free conditions (Sch. 1). Morpholine as an inexpensive and read-
ily available secondary amine was used and found to be most suitable in
the reaction conditions. The reaction conditions were optimized by
examination of different parameters, such as time of irradiation, the
ratio of sulfur to morpholine and nitriles. After performing several
experiments, the optimum molar ratio of nitrile:sulfur:morpholine was
found to be 1:2.5:5.
In a typical procedure, nitrile (3 mmol), elemental sulfur (7.5 mmol),
and morpholine (15 mmol) were mixed and placed in a closed teflon vessel
(
ꢁ10 mL) and subjected to microwave irradiation for a given time (see
Table 1). After conventional work-up the thiomorpholides were obtained
in good to excellent yields. The results are summarized in Table 1.
When benzylnitriles were used as starting materials, the same
products were obtained as with benzonitriles (Table 1, Entries 1,5). In
general, there is no proven mechanism for Willgerodt reaction, especially
for the nitriles as starting materials, which has received little attention.
HN
O
S
S
RCN
R
N
MW
O
1
a
2b
R=Aryl, benzyl
Scheme 1.

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Conversion of Nitriles to Thioamides
4281
Table 1. Microwave-assisted conversion of nitriles to thiomorpholides.
a
Entry
1
Substrate(a)
Product(b)
Time (min) Yield (%)
CN
S
O
N
4.5
70
1b
CN
S
N
2
3
4
2.5
95
O
O
H C
3
H C
3
2
b
CN
S
N
3
80
30
EtO
EtO
Cl
3
b
CN
S
N
4.5
O
Cl
4b
S
5
6
CN
1
1
83
O
N
5
b
N
S
CN
I ¼ 20
O
Cl
Cl
Cl
6
b
I
S
+
O
N
II
II ¼ 60
a
All yield refer to isolated products.
However, our results are in accordance with the reported literature
results.
[8,12]
p-Chlorobenzylnitrile (Table 1, Entry 6) produces the
respected compound in 20% yield along with p-chlorobenzothiomor-
pholide (60%). To the best of our knowledge, the case of nitriles has
not been studied yet by this methodology. It is a convenient method
for rapid and high-yielding production of thioamides from nitriles by
microwave activation. Further investigations of this reaction and its
mechanism are now in progress in our laboratory.

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Moghaddam, Hojabri, and Dohendou
In conclusion, the reaction described herein represents a simple entry
into the synthesis of thiomorpholides from nitriles. The method has
advantages, of being completed within few minutes, while it produces
thiomorpholides in good to excellent yields.
EXPERIMENTAL
Melting points were measured on a Buchi Melting Point B-540 and
1
are uncorrected. H NMR spectra were measured (CDCl solution) with
3
¨
a Bruker DRX-500 AVANCE spectrometer at 500.1 MHz. Infrared spec-
tra were recorded on a Mattson 1000 FT-IR spectrometer (Unicam).
General Procedure for Willgerodt-Kindler Reaction of Nitriles
A mixture of nitrile (5 mmol), sulfur (12.5 mmol), and morpholine
(
25 mmol) were mixed in a teflon flask (ꢁ10 mL) and was allowed to be
[13]
exposed to microwave irradiation for given time (Table 1). The cooled
reaction mixture was taken up in acetone. After filtration, the solvent
was removed under reduced pressure and the residue was washed with
dilute hydrochloric acid and chloroform. The chloroform portion
was separated and solvent was removed under reduced pressure and the
residue was purified by column chromatography using hexane, ethylace-
tate (2:1) as eluent. Further purification of the compounds were performed
by recrystallization from ethanol. All products were identified by their
1
melting points, IR and H NMR spectra and their physical data are in
[
agreement with the literature 1b,
8,12,14]
[15]
4b, 5b,
[16–18]
[19,20]
6b.
Spectroscopic Data
ꢀ
ꢂ1
1
b. Pale yellow crystal. M.p.: 137–139 C. IR (KBr) (ꢀmax, cm ):
1
1
115 (C¼S), H NMR: ꢁ 3.62 (2H, t, J ¼ 4.6 Hz, CH ), 3.66 (2H, t,
2
J ¼ 4.6 Hz, CH ), 3.90 (2H, t, J ¼ 4.8 Hz, CH ), 4.46 (2H, t, J ¼ 4.8 Hz,
2
2
CH ), 7.29–7.40 (5H, m CH).
2
ꢀ
ꢂ1
2
b. Pale yellow crystal. M.p.: 126–128 C. IR (KBr) (ꢀmax, cm ):
1
1
(
115 (C¼S), H NMR: ꢁ 2.37 (3H, s, CH ), 3.66 (4H, bs, CH ), 3.90
3
2
2H, t, J ¼ 4.8 Hz, CH ), 4.45 (2H, t, J ¼ 4.8 Hz, CH ), 7.20 (4H,
2
2
ABquarted, J ¼ 8.3 Hz, CH).
ꢀ
ꢂ1
3
b. Pale yellow crystal. M.p.: 120–122 C. IR (KBr) (ꢀmax, cm ):
1
1
115 (C¼S), H NMR: ꢁ 1.43 (3H, t, J ¼ 7.0 Hz, CH ), 3.67 (4H, bs,
3

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Conversion of Nitriles to Thioamides
4283
CH ), 3.89 (2H, bs, CH ), 4.06 (2H, q, J ¼ 7.0 Hz, CH ), 4.43 (2H, bs,
2
2
2
CH ), 6.87 (2H, d, J ¼ 8.9 Hz, CH), 7.27(2H, d, J ¼ 8.9 Hz, CH).
2
ꢀ
ꢂ1
4
b. Pale yellow crystal. M.p.: 138–140 C. IR (KBr) (ꢀ , cm ):
max
1
1
115 (C¼S), H NMR: ꢁ 3.64 (4H, m, CH ), 3.91 (2H, t, J ¼ 4.8 Hz,
2
CH ), 4.45 (2H, t, J ¼ 4.8 Hz, CH ), 7.25 (2H, d, J ¼ 8.9 Hz, CH), 7.36
2
2
(
2H, d, J ¼ 8.9 Hz, CH).
5
6
b is similar to 1b.
b. Yellow crystal. M.p.: 102–104 C. IR (KBr) (ꢀmax, cm ): 1115
ꢀ
ꢂ1
1
(
C¼S), H NMR: ꢁ 3.45 (2H, t, J ¼ 5.0 Hz, CH ), 3.62 (2H, t, J ¼ 4.6 Hz,
2
CH ), 3.75 (2H, t, J ¼ 4.6 Hz, CH ), 4.32 (2H, s, CH ), 4.36 (2H, t,
2
2
2
J ¼ 5.0 Hz, CH ), 7.30 (4H, ABquarted, J ¼ 8.4 Hz, CH).
2
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2
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Received in the UK July 24, 2003