Conversion of thioamide to benzothiazole with oxidizing agents

Article abstract of DOI:10.14233/ajchem.2014.16042

In order to search for novel chemotherapeutical agents, we tried reactions of lutidine(s) with active methyl group and anilines in the presence of sulfur and we report synthesis of amide from thioamide by using SeO₂, ZrO₂ or KMnO

Full text of DOI:10.14233/ajchem.2014.16042

Asian Journal of Chemistry; Vol. 26, No. 13 (2014), 3937-3940
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.16042
Conversion of Thioamide to Benzothiazole with Oxidizing Agents
DO-HUN LEE
Department of Chemistry, Dong-A University, Busan 604-714, Republic of Korea
*Corresponding author: Tel: +82 51 2001053; E-mail: dohlee@dau.ac.kr
Received: 12 July 2013; Accepted: 16 October 2013;
Published online: 23 June 2014;
AJC-15378
In order to search for novel chemotherapeutical agents, we tried reactions of lutidine(s) with active methyl group and anilines in the
presence of sulfur and we report synthesis of amide from thioamide by using SeO2, ZrO2 or KMnO4. Benzothiazoles was formed by the
oxidative cyclization of thioamides with oxidizing agent (SeO2, ZrO2 and KMnO4) in an alkaline solution. We know reactivity of SeO2 as
an oxidizing agent is higher than that of ZrO2 and KMnO4.
Keywords: Thioamide, Benzothiazole, Oxidizing agent, Oxidaive cyclization.
obtain a great quantity of benzothiazoles, we needed novel
reaction conditions. When a mixture of synthesized thioamide
1 with SeO2 was heated at 180 °C, but amide 3 not benzo-
thiazole 2 was obtained. In case of ZrO2 in Na2CO3 solution,
only benzothiazole 2 was formed. And also we now report
reactions of synthesized thioamides with SeO2, ZrO2 and
KMnO4.
INTRODUCTION
Thioamides and amides are very reactive compounds and
have, because of the diversity of their chemical properties,
found wide application in technology, in agriculture, in
medicine and not least in synthetic practice. The amide moiety
is an important constituent of many biologically significant
compounds and an understanding of the formation, property
and reaction of amides is future development in such areas as
polypeptide and protein chemistry1. Benzothiazoles are
bicyclic ring system. A number of 2-amino-benzothiazoles
have been studied as central muscle relaxants and found to
interfere with glutamate neurotransmission in biochemical,
electrophysiological and behavioral experiments2,3. Benzothia-
zole derivatives have been studied and found to have various
chemical reactivity and biological activity. Benzothiazole ring
found to be possessing pharmacological activities such as anti-
viral4, antibacterial5, antimicrobial6 and fungicidal activities7.
They are also useful as antiallergic8, antidiabetic9, antitumor10,
antiinflammatory11, anthelmintic12 and anti-HIV agents. Com-
pounds having an active methyl group with para (or meta)-
substituted anilines in the presence of sulfur according to the
modify Willgerodt-Kindler reaction easily afforded to
corresponding thioamides 1 and benzothiazoles 213-18. The latter
2 was also formed by the oxidative cyclization of the former 1
with potassium ferricyanate in an alkaline solution according
to the modified Jacobson method19,20. In order to search for novel
chemotherapeutical agents, we tried reactions of 2,6-lutidine
with active methyl group and anilines in the presence of sulfur.
All the executed reactions gave the desired thioamides 1
(Scheme-I) but failed to obtain benzothiazoles 2. In order to
NH2
S
H
+
N
H3C
N
CH3
C
S
N
H3C
R
R
1
R : 1b = p – CH
R :1a = m –CH3 : 49 %
1d = p – OCH3 : 62 %
R : 1c = m – OCH
3 : 53 %
: 45 %
3
1e = m – OCH H5 : 47 %
1f = p – OC2H5 : 57 %
1i = m – Br : 41 %
2
1h = p – cl
: 42 %
1g = m – Cl
1j = p – Br
: 39 %
: 38 %
Scheme-I: Isolated yields of thioamides
EXPERIMENTAL
The typical experimental procedure for N-(6'-methyl-2'-
pyridinecarbothionyl)-3-methyl-aminobenzene (1a) is as
follows: A mixture of 2,6-lutidine (1.07 g, 10 mmol) and 3-
methylaniline (1.07 g, 10 mmol) with sulfur powder (0.4 g,
12.5 mmol) was refluxed at 150 °C for 5 h, H2S gas was vigo-
rously evolved. The unchanged 2,6-lutidine and 3-methyl-
aniline were completely removed by vaccum distillation in an
oil bath. The residue was refluxed with hot 3N NaOH solution
(50 mL × 3) and chloroform 100 mL. The combined extracts

3938 Lee
Asian J. Chem.
were carefully acidified with dil. HCl. The combined chloroform
was dried over anhydrous Na2SO4, filtered and concentrated
in vacuo. The residue was purified by flash column chroma-
tography on silica gel eluted with n-hexane and ethyl acetate
(50:1, v/v), to provide the N-(6'-methyl-2'-pyridinecarbo-
thionyl)-3-methylaminobenzene (1a) as a yellow crystalline
solid (1.09 g, 45 %).
3H, OCH3), 7.26-8.59 (m, 7H, ph); Mass: m/z (rel. Int, %):
258 (100), 243 (6), 225 (64), 119 (16), 92 (38), 77 (18), 65
(20).
N-(6-Methyl-2-pyridinecarbothionyl)-4-methoxy-
aminobenzene (1d): Yield 62 %; m.p. 144-145 °C; Rf 0.63
1
(TLC eluent; n-hexane:ethyl acetate = 6:1, v/v); H NMR
(CDCl3): δ 1.55 (s, 1H, NH), 2.63 (s, 3H, CH3), 3.85 (s, 3H,
OCH3), 7.00-8.63 (m, 7H, ph); Mass: m/z (rel. Int, %): 258
(73.5), 243 (9.3), 225 (100), 140 (24.2), 119 (14.7), 92 (48.5),
77 (8.1), 65 (19.2).
N-(6-Methyl-2-pyridinecarbothionyl)-3-methylamino-
benzene (1a): Yield 49 %; m.p. 142-143 °C; Rf 0.66 (TLC
eluent; n-Hexane: Ethyl acetate = 6: 1, v/v); IR (KBr, νmax, cm-1)
1350 (C=S); 1H NMR (CDCl3): δ 1.59 (s, 1H, NH), 2.42 (s,
3H, CH3), 2.63 (s, 3H, CH3), 7.08-8.62 (m, 7H, ph); Mass:
m/z (rel. Int, %): 242 (100), 227 (33.8), 209 (84.7), 119 (15.3),
92 (34), 65 (37.9).
N-(6-Methyl-2-pyridinecarbothionyl)-3-ethoxy-
aminobenzene (1e): Yield 47 %; m.p. 141-143 °C; Rf 0.62
1
(TLC eluent; n-hexane:ethyl acetate = 6:1, v/v); H NMR
(CDCl3): δ 1.40 (t, 3H, CH3), 2.62 (s, 3H, CH3), 4.02-4.12 (q,
2H, CH2), 6.94-8.63 (m, 7H, ph); Mass: m/z (rel. Int, %): 272
(56.0), 239 (100), 207 (25.5), 154 (15.3), 92 (37.6), 136 (42.5),
119 (24.1), 92 (92.5), 65 (53.3).
N-(6-Methyl-2-pyridinecarbothionyl)-4-methylamino
benzene (1b): Yield 45 %; m.p. 144-145 °C; Rf 0.65 (TLC
eluent; n-Hexane: Ethyl acetate = 6: 1, v/v; 1H NMR (CDCl3):
δ 1.59 (s, 1H, NH), 2.42 (s, 3H, CH3), 2.63 (s, 3H, CH3),
7.08-8.62 (m, 7H, ph); Mass: m/z (rel. Int, %): 242 (100), 227
(33.8), 209 (84.7), 119 (15.3), 92 (34), 65 (37.9).
N-(6-Methyl-2-pyridinecarbothionyl)-4-ethoxy-
aminobenzene (1f): Yield 57 %; m.p. 147-148 °C; Rf 0.62
1
(TLC eluent; n-hexane:ethyl acetate = 6:1, v/v); H NMR
N-(6-Methyl-2-pyridinecarbothionyl)-3-methoxy-
aminobenzene (1c): Yield 53 %; m.p. 140-142 °C; Rf
(CDCl3): δ 1.40-1.47 (t, 3H, CH3), 2.62 (s, 3H, CH3), 4.02-
4.13 (q, 2H, CH2), 6.94~8.62 (m, 7H, ph); Mass: m/z (rel. Int,
%): 272 (64.9), 239 (100), 211 (25.5), 154 (20.2), 136 (32.7),
119 (13.8), 92 (48.1), 65 (28.6).
1
0.63 (TLC eluent; n-hexane:ethyl acetate = 6:1, v/v); H
NMR (CDCl3): δ 1.55 (s, 1H, NH), 2.64 (s, 3H, CH3), 3.87 (s,
TABLE-1
SYNTHESIZED AMIDES FROM THIOAMIDES
Thioamide
Amide Oxidizing agent
Yield* (%)
SeO2
ZrO2
96
68
15
1a
H3C
2a
H3C
H
H
N
C
CH3
N
N
N
CH3
N
N
C
O
S
KMnO4
H
SeO2
ZrO2
89
56
21
1b
H3C
2b
H3C
H
N
N
C
C
O
S
CH3
KMnO4
CH3
H
SeO2
ZrO2
95
62
3
1c
2c
N
C
OCH3
H
N
H3C
N
OCH3
S
H3C
N
C
O
KMnO4
H
SeO2
ZrO2
98
73
12
1e
2d
H3C
H
N
N
C
OC2H5
H3C
N
OC2H5
N
C
O
S
KMnO4
SeO2
ZrO2
97
67
10
1i
2e
2f
H
H
N
C
Br
N
Br
H3C
N
H3C
H3C
N
C
S
O
KMnO4
SeO2
ZrO2
87
59
16
1j
H
H
N
N
C
H3C
N
N
C
O
S
KMnO4
Br
Br
*Isolated yield

Vol. 26, No. 13 (2014)
Conversion of Thioamide to Benzothiazole with Oxidizing Agents 3939
N-(6-Methyl-2-pyridinecarbothionyl)-3-chloroa-
minobenzene (1g):Yield 39 %; m.p. 144-145 °C; Rf 0.66 (TLC
eluent; n-hexane:ethyl acetate = 6:1, v/v); 1H NMR (CDCl3):
δ 2.62 (s, 1H, NH), 2.86 (s, 3H, CH3), 7.45-8.48 (m, 7H, ph);
Mass: m/z (rel. Int, %): 261 (100), 229 (60.1), 119 (15.2), 92
(43.6), 65 (25.6).
(s, 3H, CH3), 2.63 (s, 3H, CH3), 6.94-8.12 (m, 7H, ph); Mass:
m/z (rel. Int, %): 226 (74.1), 197, 93 (100), 77, 65.
6-Methyl-pyridine-2-carboxylic acid p-tolylamide (2b):
Yield 89 %; m.p. 97-98 °C; Rf 0.46 (TLC eluent; n-hexane:
1
ethyl acetate = 6:1, v/v); H NMR (CDCl3): δ 2.38 (s, 3H,
CH3), 2.63 (s, 3H, CH3), 6.94-8.12 (m, 7H, ph); Mass: m/z
(rel. Int, %): 226 (74.1), 197 (16.7), 93 (100), 77 (13.9), 65
(30.6), 52 (7.4).
N-(6-Methyl-2-pyridinecarbothionyl)-4-chloroamino-
benzene (1h): Yield 42 %; m.p. 148-149 °C; Rf 0.66 (TLC
eluent; n-hexane:ethyl acetate = 6:1, v/v); Mass: m/z (rel. Int,
%): 261 (100), 229 (86.8), 119 (23.3), 92 (55), 65 (30.6).
N-(6-Methyl-2- pyridinecarbothionyl)-3-bromoamino-
benzene (1i): Yield 45 %; m.p. 138-140 °C; Rf 0.68 (TLC
eluent; n-hexane:ethyl acetate = 6:1, v/v); IR (KBr, νmax, cm-1)
6-Methyl-pyridine-2-carboxylic acid (3-methoxy-
phenyl)-amide (2c):Yield 95 %; m.p. 96-98 °C; Rf 0.43 (TLC
eluent; n-hexane:ethyl acetate = 6:1, v/v); 1H NMR (CDCl3):
δ 2.64 (s, 3H, CH3), 3.86 (s, 3H, OCH3), 7.25-8.12 (m, 7H,
ph); Mass: m/z (rel. Int, %): 242 (56), 213 (16), 93 (100), 65
(25.3), 52 (8).
1
1350 (C=S); H NMR (CDCl3): δ 2.17 (s, 1H, NH), 2.64
(s, 3H, CH3), 7.26-8.60 (m, 7H, ph); Mass: m/z (rel. Int, %):
307 (100), 273 (50.6), 227 (17.1), 119 (23.8), 92 (55.9), 65
(31.9).
6-Methyl-pyridine-2-carboxylic acid (3-ethoxy-
phenyl)amide (2d):Yield 98 %; m.p. 95-97 °C; Rf 0.45 (TLC
eluent; n-hexane:ethyl acetate = 6:1, v/v); 1H NMR (CDCl3):
δ 1.41-1.44 (t, 3H, CH3), 2.62 (s, 3H, CH3), 3.98-4.08 (q, H,
CH2) 6.88-8.11 (m, 7H, ph); Mass: m/z (rel. Int, %): 256 (89.8),
227 (20.4), 120 (39.8), 92 (100), 65 (40.7), 52 (1.2).
6-Methyl-pyridine-2-carboxylic acid (3-bromo-
phenyl)amide (2e):Yield 97 %; m.p. 92-93 °C; Rf 0.48 (TLC
eluent; n-hexane:ethyl acetate = 6:1, v/v); 1H NMR (CDCl3):
δ 2.16 (s, H, NH), 2.62 (s, 3H, CH3), 7.25-8.10 (m, 7H, ph);
Mass: m/z (rel. Int, %): 292 (36.7), 263 (4), 120 (8.7), 93 (100),
65 (36.7), 52 (5.3); IR (KBr, νmax, cm-1): 1683 (C=O).
6-Methyl-pyridine-2-carboxylic acid (4-bromo-
phenyl)amide (2f):Yield 87 %; m.p. 92-93 °C; Rf 0.48 (TLC
eluent; n-hexane:ethyl acetate = 6:1, v/v); 1H NMR (CDCl3):
δ 2.16 (s, H, NH), 2.62 (s, 3H, CH3), 7.25-8.10 (m, 7H, ph);
Mass: m/z (rel. Int, %): 292 (36.7), 263 (4), 120 (8.7), 93 (100),
65 (36.7), 52 (5.3); IR (KBr, νmax, cm-1): 1683 (C=O).
General procedure for the synthesis of 5-methoxy-2-
(6-methylpyridyl)benzothiazole (3c): A mixture of N-(6-
methyl-2-pyridinecarbothionyl)-3-methoxy-aminobenzene
N-(6-Methyl-2-pyridinecarbothionyl)-4-bromoamino-
benzene (1j): Yield 38 %; m.p. 141-143 °C; Rf 0.68 (TLC
eluent; n-hexane:ethyl acetate = 6:1, v/v); 1H NMR (CDCl3):
δ 2.17 (s, 1H, NH), 2.64 (s, 3H, CH3), 7.26-8.60 (m, 7H, ph);
Mass: m/z (rel. Int, %): 307 (100), 275 (49.6), 227 (14.6), 119
(16.1), 92 (42.4), 65 (24.2).
Typical experimental procedure for conversion of thio-
amide 1 to amide: A mixture of 6-methyl-pyridine-2-carbo-
thioic acid m-tolylamide 1a and SeO2 was heated at 140 for
10 h. After cooling, chloroform (100 mL) was added. The
reaction mixture was filtered to remove SeO2. The combined
organic layers were dried over anhydrous Na2SO4, filtered and
concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel eluted with n-hexane
and ethylacetate (80:1, v/v), to provide 6-methyl-pyridine-2-
carboxylic acid m-tolylamide.
6-Methyl-pyridine-2-carboxylic acid m-tolylamide
(2a): (0.45 g, 20 %) m.p. 90-93 °C; 1H NMR (CDCl3): δ 2.38
TABLE-2
BENZOTHIAZOLE FORMATION FROM THIOAMIDE WITH ZrO2 IN Na2CO3 SOLUTION
Thioamide Oxidizing agent Benzothiazole
Yield* (%)
62
1c
3c
OCH3
N
H
N
ZrO2
ZrO2
ZrO2
OCH3
H3C
1e
H3C
N
C
S
N
N
S
H3C
65
51
46
3e
H
N
S
N
N
C
OC2H5
CH3
H3C
S
OC2H5
1a
H3C
3a
N
S
H
N
CH3
N
C
S
N
N
H3C
1i
3i
H
Br
N
S
N
Br
ZrO2
H3C
N
C
S
H3C
*Isolated yield

3940 Lee
Asian J. Chem.
(1c) (0.5 g, 1.9 × 10-3 mol) and zirconium(IV) oxide (0.5 g,
3.8 × 10-3 mol) in 3N-Na2CO3 solution was refluxed for 3 h.
After the reaction was completed, the reaction mixture was
diluted with chloroform 100 mL and neutralized with aqueous
diluted HCl. It was extracted with chloroform (three times),
washed with water, dried (MgSO4) and concentrated in vacuo.
The residue was purified by flash column chlomatography on
silica gel eluted with n-hexane and ethyl acetate (5:1, v/v), to
provide 5-methoxy-2-(6-methylpyridyl)benzothiazole 3c as
yellow crystalline solid (0.16 g, 62 %); m.p. 145 °C; Rf 0.41
solution (Table-2). The reaction mixture was refluxed Na2CO3
in solution for 3 h. The residue was purified by flash column
chromatography or silica gel eluted with hexane and ethyl
acetate to provide benzothiazoles. In conclusion the reactions
of 2,6-lutidine and amines in the presence of sulfur according
to the modified willgerodt-kindler reaction easily afforded to
corresponding thioamides in good yields.
Conversion of thioamides to amides with SeO2 was
executed in high yields. We know reactivity of SeO2 as an
oxidizing agent is higher than that of ZrO2 and KMnO4.
Benzothiazoles was formed by the oxidative cyclization of
thioamides with ZrO2 in Na2CO3 solution. Further investi-
gations will be necessary to clarify the mechanism about
conversion of thioamide to amide and oxidative cyclization of
thioamide.
1
(TLC eluent; n-hexane:ethyl acetate = 3:1, v/v); H NMR
(CDCl3): δ 2.64 (s, 3H, CH3), 3.91 (s, 3H, OCH3), 7.03-8.15
(m, 6H, ph); Mass: m/z (rel. Int, %): 256 (100), 241 (38.4),
213 (35.8), 123 (3.8), 95 (8.2), 69 (2.6).
5-Methoxy-2-(6-methylpyridyl)benzothiazole (3a):
Yield 13 %; m.p. 148-150 °C; Rf 0.40 (TLC eluent; n-hexane:
1
ethyl acetate = 6:1, v/v); H NMR (CDCl3): δ 2.52 (s, 3H,
ACKNOWLEDGEMENTS
CH3), 2.64 (s, 3H, CH3), 7.21-8.13 (m, 7H, ph); Mass: m/z
(rel. Int, %): 241 (100), 121 (29.6), 92 (6.5), 77 (15.7), 65
(13), 51 (6.5).
This work was supported by a grant of Dong-A University
(2013).
5-Bromo-2-(6-methylpyridyl)benzothiazole (3i):Yield
12 %; m.p. 145-147 °C; Rf 0.42 (TLC eluent; n-hexane:ethyl
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RESULTS AND DISCUSSION
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In order to search for novel chemotherapeutical agents,
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anilines in the presence of sulfur. All the executed reactions
gave the desired thioamides 1 (Table-1). In general, various
synthetic methods of amide have been known, we report
synthesis of amide from thioamide by using SeO2, ZrO2 or
KMnO4 (Table-2). Reaction of synthesized thioamides 1 in
the presence of SeO2, ZrO2 or KMnO4 (0.4 g) gave corres-
ponding amides 2. The reaction mixture was heated at 140 °C
for 3 h. Synthesis of amides from thioamides with SeO2 was
executed in high yield (87-98 %). Reactivity of SeO2 as an
oxidizing agent is higher than that of ZrO2 (56-73 %) and
KMnO4 (3-21 %). Benzothiazoles (3a-d) was formed by the
oxidative cyclization of thioamides with ZrO2 in an alkaline
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