New approach to the synthesis of 2-carbamoylbenzothiazoles

Article abstract of DOI:10.1023/A:1015082318393

The reactions of substituted anilines with chloroacetamide and sulfur in the presence of triethylamine afforded monothiooxamides. When treated with K3Fe(CN)6, the latter underwent cyclization to form 2-carbamoyIbenzothiazoles. The reactions were accompanied by the formation of the corresponding thiooxanilic acids, which also underwent cyclization to form benzothiazole-2-carboxylic acids.

Full text of DOI:10.1023/A:1015082318393

144
Russian Chemical Bulletin, International Edition, Vol. 51, No. 1, pp. 144—147, January, 2002
New approach to the synthesis of 2ꢀcarbamoylbenzothiazoles

V. N. Yarovenko, F. M. Stoyanovich, O. Yu. Zolotarskaya, E. I. Chernoburova,
I. V. Zavarzin, and M. M. Krayushkin
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5328. Eꢀmail: yarov@ioc.ac.ru
The reactions of substituted anilines with chloroacetamide and sulfur in the presence of
triethylamine afforded monothiooxamides. When treated with K3Fe(CN)6, the latter underꢀ
went cyclization to form 2ꢀcarbamoylbenzothiazoles. The reactions were accompanied by the
formation of the corresponding thiooxanilic acids, which also underwent cyclization to form
benzothiazoleꢀ2ꢀcarboxylic acids.
Key words: monothiooxamides, 2ꢀcarbamoylbenzothiazoles, thiooxanilic acids, benzoꢀ
thiazoleꢀ2ꢀcarboxylic acids.
2ꢀCarbamoylbenzothiazoles are used in the synthesis
prepare a solution of aniline 2a—g, sulfur, and triethylꢀ
of polycyclic systems. For example, these compounds were
used for the preparation of a series of 2ꢀ(thiazolyl)benzoꢀ
thiazoles possessing antiꢀinflammatory activity1,2 as well
as for the synthesis of the natural compound, viz.,
D(–)ꢀ2ꢀ(6ꢀhydroxybenzothiazolꢀ2ꢀyl)ꢀ4,5ꢀdihydrothiꢀ
azoleꢀ4ꢀcarboxylic acid (luciferin),3,4 and its analogs.5 It
should be noted that procedures for the preparation of
2ꢀcarbamoylbenzothiazoles described in the literature are
multiꢀstep and laborious and, moreover, afford products
in low total yields. The most rational scheme was emꢀ
ployed in the studies.4,5 The first step of the latter process
involves the preparation of monothiooxamides from
readily accessible anilines followed by cyclization under
the action of K3Fe(CN)6. However, when we started our
studies, convenient procedures for the preparation of
monothiooxamides were lacking. N SꢀArylthiooxamides
were synthesized4,5 by the reactions of carbamoylthioꢀ
carbonylthioacetic acid with aromatic amines in ethanol
performed during three days, and the yields were at most
50%. Carbamoylthiocarbonylthioacetic acid, in turn, was
prepared by the reaction of H2S with trichloroacetamide
in ethanol followed by treatment with an aqueous soluꢀ
tion of monochloroacetic acid and potassium carbonate.
In the present study, we developed a procedure for the
synthesis of 2ꢀcarbamoylbenzothiazoles.
amine in DMF followed by the addition of chloroꢀ
acetamide. When the reagents were mixed in this order,
monothiooxamides were obtained in 60—80% yields
(Scheme 1).
Scheme 1
a
b
c
d
e
f
g
R
R1
R2
4ꢀMeO
H
H
2ꢀMeO 4ꢀBr 4ꢀCl 2ꢀMeO
3ꢀMeO
4ꢀMeO
5ꢀMeO
3ꢀMe
5ꢀMe
H
H
H
H
H
H
H
5ꢀMeO
H
The study of cyclization of monothiooxamides 1a—g
under the action of K3Fe(CN)6 in alkaline solutions demꢀ
onstrated that the syntheses of 2ꢀcarbamoylbenzothiazoles
3a—g were always accompanied by the formation of the
corresponding thiooxanilic acids 4a—g as byꢀproducts
(Scheme 2).
Results and Discussion
Monothiooxamides 1a—g were synthesized according
to the procedure proposed by us previously,6 which was
based on the reactions of the corresponding anilines with
chloroacetamide in the presence of sulfur and triethylꢀ
amine. For the reactions to proceed, it was necessary to
The yields and the ratio of the reaction products deꢀ
pend on the nature of the substituents in the phenyl ring.
Electronꢀdonating substituents facilitate cyclization,
whereas electronꢀwithdrawing substituents inhibit this proꢀ
cess, which is indicative of its electrophilic character.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 136—138, January, 2002.
1066ꢀ5285/02/5101ꢀ144 $27.00 © 2002 Plenum Publishing Corporation

Synthesis of 2ꢀcarbamoylbenzothiazoles
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 1, January, 2002
145
Scheme 2
It should be noted that saponification of thiooxamides
1 proceeded readily even at ∼20 °C to form thiooxanilic
acids 4 in 70—80% yields.
1a—c
4a—c
However, the aboveꢀmentioned fact has only a slight
effect on the yields of 2ꢀcarbamoylbenzothiazoles because
cyclization in the course of oxidation of monothioꢀ
oxamides with K3Fe(CN)6 proceeded rather rapidly
(15—30 min).
Thiooxanilic acids 4 can also undergo cyclization to
benzothiazoleꢀ2ꢀcarboxylic acids 5 under the action of
K3Fe(CN)6.
R
R1
R2
R
R1
R2
3a 6ꢀMeO
3b 4ꢀMeO
6ꢀBr
6ꢀCl
3e 4ꢀMeO
3f 5ꢀMeO
H
H
H
H
H
H
H
H
4a 4ꢀMeO
4b 2ꢀMeO
4ꢀBr
4ꢀCl
4e 2ꢀMeO
H
H
H
H
H
H
H
H
3c
3d
4c
4d
H
H
7ꢀMeO
6ꢀMeO
7ꢀMe
5ꢀMeO
4ꢀMeO
5ꢀMe
7ꢀMeO 4f 3ꢀMeO
4g 3ꢀMe
5ꢀMeO
H
3g
5ꢀMe
H
Thus, monothiooxamides 1a,b,e,g containing the methyl
and methoxy groups produced 2ꢀcarbamoylbenzothiazoles
3a,b,e,g in 76—92% yields, whereas chloro and bromo
derivatives 1c,d gave benzothiazoles 3c,d in low yields
(3—10%). The reverse situation was observed in the case
of thiooxanilic acids, viz., compounds 1c,d containing
electronꢀwithdrawing substituents were transformed into
acids 4c,d in 60—70% yields, whereas the yields of
thiooxanilic acids 4a,b,e,g bearing electronꢀdonating subꢀ
stituents fell to 2—10%.
This makes it possible to prepare the target products
containing the benzothiazole system in the cases where
2ꢀcarbamoylbenzothiazoles are formed in low yields.
It should be noted that cyclization of monothioꢀ
oxamides to give the benzothiazole system was completed
in 15—30 min, whereas the duration of the reaction in the
case of thiooxanilic acids increased to 48 h.
To summarize, we developed a new approach to the
synthesis of 2ꢀcarbamoylbenzothiazoles based on cyclizaꢀ
tion of monothiooxamides, which are prepared by the
Table 1. Yields, melting points, and results of elemental analysis of the compounds
Comꢀ
pound
Yield*
(%)
M.p./°C
(lit. data)
Found
Calculated
Molecular
formula
(%)
C
H
—
N
—
S
1a
1b
1c
1d
1e
1f
80
72
65
72
76
68
76
80
76
183—185
(182—185)4
129—131
—
—
—
51.62 4.90 12.94 15.07
51.41 4.79 13.32 15.25
C9H10N2O2S
186—188
(187)7
185—186
(184)7
—
—
—
—
—
—
—
—
—
—
—
118—119
50.17 5.09 11.34
49.99 5.03 11.66
C10H12N2O3S
C11H14N2O4S
C10H12N2OS
—
146—147
128—131
49.00 5.26 10.24 11.70
48.88 5.26 10.36 11.86
57.80 5.54 13.62 15.24
57.67 5.81 13.45 15.39
1g
3a
3b
257—258
(258—260)3
213—214
(214—215)5
—
—
—
—
—
—
—
—
—
(to be continued)

146
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 1, January, 2002
Yarovenko et al.
Table 1 (continued)
Comꢀ
pound
Yield*
(%)
M.p./°C
(lit. data)
Found
Calculated
Molecular
formula
(%)
C
H
N
S
3c
3d
3e
3f
10
3
280—287
36.92 1.79 10.68 12.25
37.37 1.96 10.90 12.47
C8H5BrN2OS
—
283—285
(284)1
245—247
—
—
—
—
70
50.49 4.23 11.72 13.34
50.41 4.23 11.76 13.46
49.36 4.48 10.68 12.06
49.25 4.51 10.44 11.95
58.20 4.90 13.57 15.28
58.23 4.89 13.58 15.54
C10H10N2O3S
C11H12N2O4S
C10H10N2OS
—
16
150—151.5
215—217
3g
4a
4b
4c
4d
4e
4f
92
8 (71)
8 (70)
71 (78)
60
135—137
(134)7
135—137
(136.5)7
167—169
(171)8
133—134
(136)7
111—112
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
8
49.43 4.36 5.56 12.98
49.78 4.60 5.81 13.29
48.56 4.62 4.87 11.62
48.70 4.83 5.16 11.82
57.63 5.48 6.47 14.97
57.40 5.30 6.69 15.32
C10H11NO4S
C11H13NO5S
C10H11NO2S
60
148—149
116—118
4g
2
* The yields of thioacids prepared by hydrolysis of monothiooxamides are given in parenꢀ
theses.
The acetone was removed and the residue was crystallized from
95% EtOH.
reactions of substituted anilines with chloroacetamide and
sulfur in the presence of triethylamine, under the action
of K3Fe(CN)6.
Synthesis of 2ꢀcarbamoylbenzothiazoles 3a—g and thiooxaꢀ
nilic acids 4a—g (general procedure). Monothiooxamide 1a—g
(0.01 mol) was dissolved in a 10% NaOH solution (0.42 mol).
The resulting solution was filtered and added dropwise with
stirring to a solution of K3Fe(CN)6 (12.5 g, 0.038 mol) in water
(38 mL). The precipitate of amide 3a—g that formed was filꢀ
tered off, washed with water, dried, and recrystallized. The filꢀ
trate was acidified with HCl. The precipitate of thioacid 4a—g
that formed was filtered off, washed with water, dried, and reꢀ
crystallized from 95% EtOH.
Synthesis of thiooxanilic acids 4a—c from monothiooxamides
(general procedure). Monothiooxamide 1a—c (0.01 mol) was
dissolved in a 10% aqueous solution of NaOH (0.42 mol). The
resulting solution was kept at 20 °C for 48 h and then acidified
with HCl. The precipitate that formed was filtered off. The
resulting acid was dissolved in a 10% aqueous solution of
NaHCO3 and acidified with HCl. The precipitate of the correꢀ
sponding acid that formed was washed with water and recrystalꢀ
lized from 95% EtOH.
Experimental
The 1H NMR spectra were recorded on Bruker ACꢀ200
(200 MHz) and Bruker WMꢀ250 (250 MHz) instruments in
DMSOꢀd6. The mass spectra were measured on a Varian
MAT CHꢀ6 instrument with direct introduction of the samples
into the ion source; the energy of ionizing electrons was 70 eV;
the controlling voltage was 1.75 kV. The melting points were
measured on a Boetius stage and were not corrected. The yields,
the melting points, and the results of elemental analysis of the
1
compounds are given in Table 1. The data from H NMR specꢀ
troscopy and mass spectrometry are listed in Table 2. The comꢀ
mercial reagents were purchased from Aldrich.
Synthesis of N Sꢀarylthiooxamides 1a—g (general procedure).
Chloroacetamide (0.5 g, 5.3 mmol) was added to a mixture of
substituted aniline 2a—g (5.7 mmol), sulfur (0.7 g), and Et3N
(1 mL) in DMF (5 mL). The reaction mixture was stirred at
∼20 °C for 8 h and diluted with water. The precipitate that
formed was filtered off, washed with water, and dried. The reꢀ
sulting compound was dissolved in acetone (10 mL) and filtered.
6ꢀMethoxybenzothiazoleꢀ2ꢀcarboxylic acid (5). Thiooxanilic
acid 4a (0.01 mol) was dissolved in a 10% aqueous solution of
NaOH and then added with stirring to a solution of K3Fe(CN)6
(0.038 mol) in water (38 mL) at ∼20 °C. The reaction mixture
was kept at ∼20 °C for 48 h and then acidified with HCl. The

Synthesis of 2ꢀcarbamoylbenzothiazoles
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 1, January, 2002
147
Table 2. 1H NMR spectra and mass spectra of the compounds
Comꢀ Mass
1H NMR, δ (J/Hz)
Comꢀ Mass
1H NMR, δ (J/Hz)
poꢀ spectrum
und
poꢀ spectrum
und
NH
(s, 1 H)
NH2
Other signals
NH
(s, 1 H)
NH2
Other signals
[М]+/m/z
[М]+/m/z
1b
210
11.83
8.21
(br.s,
2 H)
3.90 (s, 3 H, ОMe);
7.05 (t, 1 H, J = 7.75);
7.20 (d, 1 H, J = 8.10);
7.32 (t, 1 H, J = 7.75);
8.70 (d, 1 H, J = 7.90)
3.71 (s, 3 H, ОMe);
3e
238
7.90
3.91 (s, 3 H, ОMe);
(s, 1 H); 3.98 (s, 3 H, ОMe);
8.20
(s, 1 H)
7.03 (s, 2 H)
3f
268
206
—
7.95 (br.s, 3.87 (s, 3 H, ОMe);
1 H); 8.13 3.95 (s, 3 H, ОMe);
(br.s,
1 H)
7.11 (br.s, 2.55 (s, 3 H, Me);
1 H); 8.71 3.45 (s, 3 H, Me);
(br.s,
1 H)
1e
—
11.84
8.25
(s, 1 H); 3.85 (s, 3 H, ОMe);
8.30
(s, 1 H)
4.05 (s, 3 H, ОMe);
7.41 (s, 1 H)
6.89 (d, 1 H, J = 8.90);
7.10 (s, 1 H); 8.51
(d, 1 H, J = 8.90)
3g
4e
1f
270
208
—
11.84
11.87
8.05
3.70 (s, 3 H, ОMe);
7.20 (s, 1 H);
7.70 (s, 1 H)
(s, 1 H); 3.78 (s, 6 H, 2 ОMe);
8.15
(s, 1 H)
7.95
7.60 (s, 2 H)
11.60
3.72 (s, 3 H, ОMe);
3.85 (s, 3 H, ОMe);
6.90 (d, 1 H, J = 8.95);
7.10 (d, 1 H, J = 8.95);
8.03 (s, 1 H)
3.76 (s, 3 H, ОMe);
3.77 (s, 6 H, 2 ОMe);
3.47 (s, 2 H)
2.30 (s, 6 H, 2 Me);
7.20 (s, 1 H);
1g
3с
2.30 (s, 6 H, 2 Me);
(s, 1 H); 7.20 (s, 1 H);
8.07
(s, 1 H)
8.00
(s, 1 H); 8.05 (d, 1 H);
8.40
7.57 (s, 2 H)
4f
—
12.19
12.09
7.75 (d, 1 H);
8.51 (s, 1 H)
4g
208
(s, 1 H)
7.51 (s, 2 H)
precipitate that formed was filtered off, washed with water,
and dried. The yield was 50%, m.p. 107—109 °C. 1H NMR
(acetoneꢀd6), δ: 3.91 (s, 3 H); 7.17 (d, 1 H); 7.65 (s, 1 H); 8.00
(d, 1 H); 9.07 (s, 1 H).
4. Sh. Seto, K. Ogura, and Y. Nishiyama, Bull. Chem. Soc. Jpn.,
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M. M. Krayushkin, The 18th Intern. Symp. on the Organic
Chemistry of Sulfur (13—18 July, 1998), Abstrs., Florence
(Italy), Pꢀ106.
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Received March 27, 2001;
in revised form September 20, 2001