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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