Synthesis of aromatic thioamide from nitrile without handling of gaseous hydrogen sulfide

Article abstract of DOI:10.1081/SCC-200050393

A new method for synthesizing aromatic primary thioamides is described. Simple treatment of aromatic nitriles with sodium hydrogen sulfide and magnesium chloride in dimethylformamide (DMF) gave aromatic primary thioamides in yields of 80-99% without handling of hazardous hydrogen sulfide.

Full text of DOI:10.1081/SCC-200050393

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Synthesis of Aromatic Thioamide from Nitrile
Without Handling of Gaseous Hydrogen
Sulfide
Akira Manaka a & Masakazu Sato a
a Medicinal Chemistry Laboratory, Medicinal Research Laboratories, Taisho
Pharmaceutical Co. Ltd., Kita‐ku, Saitama, Japan
Available online: 20 Aug 2006
To cite this article: Akira Manaka & Masakazu Sato (2005): Synthesis of Aromatic Thioamide from Nitrile
Without Handling of Gaseous Hydrogen Sulfide, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 35:5, 761-764
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Synthetic Communicationsw, 35: 761–764, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200050393
Synthesis of Aromatic Thioamide from
Nitrile Without Handling of Gaseous
Hydrogen Sulfide
Akira Manaka and Masakazu Sato
Medicinal Chemistry Laboratory, Medicinal Research Laboratories,
Taisho Pharmaceutical Co. Ltd., Kita-ku, Saitama, Japan
Abstract: A new method for synthesizing aromatic primary thioamides is described.
Simple treatment of aromatic nitriles with sodium hydrogen sulfide and magnesium
chloride in dimethylformamide (DMF) gave aromatic primary thioamides in yields
of 80–99% without handling of hazardous hydrogen sulfide.
Keywords: Thioamides, nitriles, magnesium chloride
INTRODUCTION
Thioamide derivatives are widely used as fungicides,[1] herbicides,[2] and
important synthetic intermediates for thiazoles,[3] and amidines.[4] They are
generally synthesized from the corresponding amides with diphosphorus penta-
sulfide or Lawesson’s reagent, and from nitrile with hydrogen sulfide.[5]
Aromatic thioamide derivatives are generally synthesized by treatment of the
corresponding nitrile with gaseous hydrogen sulfide in the presence of alkali
metal sulfide or ammonium sulfide in alcohols,[6] triethylamine in pyridine,[7]
sodium sulfide, and phase transfer catalyst in benzene and water,[8] or anion-
exchange resin in alcohols.[9] However, these procedures involve the use of
Received in Japan 26 October 2004
Address correspondence to Akira Manaka, Medicinal Chemistry Laboratory, Medi-
cinal Research Laboratories, Taisho Pharmaceutical Co. Ltd., 1-403, Yoshino-cho,
Kita-ku, Saitama 331-9530, Japan. Fax: þ81-48-652-7254; E-mail: akira.manaka@
po.rd.taisho.co.jp

Table 1. Yields of thioamides
Entry
1
Ar
Solvent
DMF
Eq. of NaSH
2.0
Time (h)
2
Yield (%)a
87
mp (8C)
Ref. mp (8C)
Ph
Ph
116–117
117–118[9]
116–117[8]
149[10]
2
3
Methanol
DMF
2.0
3.0
2
4
21b
93
4-MeOC6H4
147.5–149
148–149[9]
147.5–148.5[11]
189–191[12]
165[13]
4
5
6
7
4-CO2Me-C6H4
3-Ac-C6H4
2-F-C6H4
DMF
DMF
DMF
DMF
2.0
2.0
2.0
2.0
1.5
0.5
1
96
94
89
83
184.5–185.5
161–162
82–83.5
83[14]
3-Pyridyl
1.5
184–185
191–192[8]
190–192[9]
183[7]
8
9c
2-Thienyl
DMF
DMF
2.0
2.0
1
2
90
99
106.5–108
218.5–219.5
107–109[15]
216.5–127.5[16]
aIsolated yield.
bThe starting material was recovered.
cSubstrate:

Synthesis of Aromatic Thioamide
763
a large excess of hazardous hydrogen sulfide gas either bubbling through the
reaction medium or under high-pressure conditions due to its low solubility
in solvents. To avoid these problems, we investigated various conditions and
found a simple, efficient procedure for the synthesis of aromatic thioamides.
Aromatic nitrile was treated with 70% sodium hydrogen sulfide hydrate
and magnesium chloride hexahydrate in dimethylformamide (DMF) at room
temperature for 0.5–4 hours to give the corresponding thioamide in high
yields (Scheme 1). The results with this procedure using various aromatic
nitriles are shown in Table 1. Benzonitrile derivatives substituted with
electron-withdrawing or -donating substituents, and heteroaromatic nitriles
such as pyridylnitrile and thienylnitrile, were suitable under these conditions.
Moreover, substrates with an ester (entry 4) or amide group (entry 9) could be
quantitatively converted to the corresponding thioamides.
Aprotic solvents, such as DMF, are suitable for use in this reaction. Two
or three mass equivalents of sodium hydrogen sulfide and 1–1.5 equivalents
of magnesium chloride hexahydrate, with respect to nitriles, were required
for smooth conversion at room temperature. The use of protic solvents such
as methanol lowered the reaction rate (entry 2).
After the reaction was complete, the resulting mixture was poured into
water, and the product was isolated by extraction with a suitable solvent or
by filtration of the resulting precipitates, followed by washing with dilute
hydrochloric acid or ammonium chloride solution to remove magnesium
dihydroxide. The desired thioamides were usually obtained in high purity
and almost quantitative yield without further purification.
In summary, this procedure represents a simple and widely applicable
method for the synthesis of aromatic thiamides from nitriles.
EXPERIMENTAL
Typical Procedure for the Synthesis of Thioamides
Methyl 4-(thiocarbamoyl) benzoate
To a slurry of 7.9 g (99 mmol) of 70% sodium hydrosulfide hydrate and 10.1 g
(50 mmol) of magnesium chloride hexahydrate in 100 mL of DMF was added
Scheme 1.

764
A. Manaka and M. Sato
8 g (50 mmol) of methyl 4-cyanobenzoate in one portion, and the mixture was
stirred at room temperature for 90 min. The resulting green slurry was poured
into 200 mL of water, and the resulting precipitates were collected by
filtration. The crude product was resuspended in 1 N HCl and stirred
for 20 min, then filtered and washed with water to give 9.3 g (96% yield)
of pure methyl 4-(thiocarbamoyl)benzoate, mp 184.5–185.58C (lit. 189–
1918C).[12]
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