Synthesis of 2-carbamoylthieno[3,2-d]thiazoles

Article abstract of DOI:10.1023/B:RUJO.0000010186.57208.c4

A preparation procedure was developed for previously unknown 2-carbamoylthieno[3,2-d]-thiazoles consisting in cyclization effected by K ₃Fe(CN)₆ of monothiooxamides obtained from 2-methyl-4-aminothiophene, chloroacetamides, and sulfur in the presence of triethylamine.

Full text of DOI:10.1023/B:RUJO.0000010186.57208.c4

Russian Journal of Organic Chemistry, Vol. 39, No. 8, 2003, pp. 1161 1163. Translated from Zhurnal Organicheskoi Khimii, Vol. 39, No. 8, 2003,
pp. 1232 1234.
Original Russian Text Copyright
2003 by Yarovenko, Smirnova, Bulgakova, Zavarzin, Krayushkin.
Synthesis of 2-Carbamoylthieno[3,2-d]thiazoles
V. N. Yarovenko, N. G. Smirnova, V. N. Bulgakova, I. V. Zavarzin,
and M. M. Krayushkin
Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, 119991 Russia
Received December 15, 2002
Abstract A preparation procedure was developed for previously unknown 2-carbamoylthieno[3,2-d]-
thiazoles consisting in cyclization effected by K3Fe(CN)6 of monothiooxamides obtained from 2-methyl-4-
aminothiophene, chloroacetamides, and sulfur in the presence of triethylamine.
Heterocyclic compounds with an amide function
are used in the synthesis of biologically active
compounds [1, 2]. We developed formerly a simple
procedure for preparation of monothiooxamides [3],
and it was demonstrated that they were convenient
initial compounds for the synthesis of various dif-
ficultly available carbamoyl-containing heterocycles,
namely, carbamoylimidazolines [4], carbamoyl-1,2,4-
oxadiazoles [5], carbamoyl-1,3,4-oxadiazoles [6],
biscarbamoylfuroxanes [6], carbamoyl-1,2,4-triazoles
[7], 2-carbamoylbenzothiazoles [8]. The approach we
used in the latter case looked promising also for
preparation of compounds with fuzed structures, in
particular, of previously unknown 2-carbamoylthieno-
[3,2-d]thiazoles. The published methods of thieno-
thiazoles preparation [9, 10] are scanty, labor-con-
suming, multistage, and they do not permit the syn-
thesis of thieno[3,2-d]thiazoles containing a carbamo-
yl group. For instance, the overall yield of 2-methyl-
thieno[3,2-d]thiazole with respect to the initial thio-
phene did not exceed 1.5% [10]. The target of this
study was a development of a convenient preparation
procedure for 2-carbamoylthieno[3,2-d]thiazoles.
thus forming 2-methyl-4-azidothiophene (II) was
reduced with LiAlH4 in THF.
Amine III was mixed with sulfur and triethylamine
in DMF. Then to the mixture was added chloroacet-
amides IVa d at 20 C, and in 8 h monothiooxamides
Va d were isolated in 50 65% yield.
To the synthesis of 2-carbamoylthieno[3,2-d]-
thiazoles (VIa c) we applied the approach we had
previously used [8] in the preparation of 2-carbamo-
ylbenzothiazoles including the reaction of the cor-
responding amines with chloroacetamides and sulfur
in the presence of triethylamine followed by cycliz-
ation of the arising monothiooxamides by the action
of K3Fe(CN)6.
R = Ph (a), 4-MeC6H4 (b), CH2Ph (c), 4-FC6H4 (d).
In the mass spectra of compounds Va d are
observed molecular ion peaks. In the 1H NMR spectra
alongside the proton signals of methyl group and
aromatic ring appear also singlets from two protons
of the thiophene ring ( 7.35 7.40 and 8.45 ppm),
and typical for monothiooxamides proton signals
from amide ( 9.25 10.52 ppm) and thioamide
12.35 12.55 ppm) groups. The composition of
compounds Va d is also confirmed by elemental
analysis.
The initial compound, previously unknown
2-methyl-4-aminothiophene (III) was synthesized
from easily accessible 2-methyl-4-bromothiophene (I)
by a two-stage procedure we developed [11].
(
Bromide I was treated with BuLi in ether and then
at 70 C a p-toluenesulfonyl azide was added. The
The cyclization of monothiooxamides Va d into a
thiazole system occurs cleanly at 20 C as with
1070-4280/03/3908-1161$25.00 2003 MAIK Nauka/Interperiodica

1162
YAROVENKO et al.
N,S-aroylthiooxamides [8]. The target 2-carbamoyl-
thieno[3,2-d]thiazoles VIa c were obtained in fair
yields.
ether layer was separated, the water layer was
extracted with ether. The combined ether solutions
were washed with water, dried with MgSO4, filtered,
and evaporated. The red-brown residue obtained was
subjected to column chromatography on silica gel
(eluent petroleum ether). We obtained 2.0 g (48%) of
4-azido-2-methylthiophene (II).
4-Amino-2-methylthiophene (III). In 15 ml of
anhydrous THF was dissolved 0.83 g (6 mmol) of
4-azido-2-methylthiophene (II), and to the solution
was added at stirring dropwise a suspension of 0.41 g
(12 mmol) of LiAlH4 in 15 ml of THF under argon
at room temperature. After stirring for 2 h at 20 C to
the stirred suspension was added dropwise 50 ml of
water, the reaction products were extracted into
ether, the extract was washed with water, dried with
MgSO4, and the solvent was evaporated. The residue
(0.64 g of compound III), yellow-brown oily sub-
stance, was used in further syntheses without addi-
tional purification.
VI, R = 4-MeC6H4 (a), CH2Ph (b), 4-FC6H4 (c).
The structure and composition of compounds
VIa c were proved by elemental analyses, mass
1
spectra and H NMR spectra. In the mass spectra of
compounds VIa c were present the molecular ion
1
peaks. In the H NMR spectra alongside the signals
of the methyl group and the aromatic ring appeared
the proton peaks of the thiophene ring (7.35
7.40 ppm), and also of an amino group in the region
9.47 10.75 ppm.
Thus we developed a convenient preparation
procedure for 2-carbamoylthieno[3,2-d]thiazoles from
monothiooxamides obtained by reaction of amino-
thiophene with chloroacetamides and sulfur in the
presence of Et3N followed by cyclization effected by
K3Fe(CN)6.
Monothiooxamides Va d. To a preliminary prepared
mixture of 0.64 g (5.7 mmol) of 4-amino-2-methyl-
thiophene (III), 0.7 g of sulfur, and 1 ml of Et3N in
5 ml of DMF was added 5.3 mmol of chloroacet-
amide. The mixture was stirred at 20 C for 8 hand
then diluted with water. The separated precipitate was
filtered off, washed with water, dried, dissolved in
10 ml of acetone, and filtered. On evaporation of
acetone the residue was crystallized from 95%
ethanol. The yields are calculated with respect to
initial chloroacetamides.
EXPERIMENTAL
1H NMR spectra were registered on spectrometer
Bruker AC-300 (operating frequency 300 MHz) from
solutions in DMSO-d6. Mass spectra were measured
on Kratos instrument with direct admission of the
sample into the ion source, ionizing electrons energy
70 eV, controlling voltage 1.75 kV. In the study were
used commercial reagents from Aldrich. Chloroacet-
amides IVa d were obtained as in [3].
N-Phenyl-2-[(5-methylthien-3-yl)amino]-2-thi-
oxoacetamide (Va). Yield 51%; mp 88 90 C (EtOH).
1H NMR spectrum, , ppm: 2.45 s (3H, CH3);
7.20 m (1H arom); 7.40 m (1H of thiophene,
2H arom); 7.80 d (2H arom, J 7.27); 8.45 s (1H of
thiophene); 10.45 s (1H, NH); 12.55 s (1H, NH).
Mass spectrum, m/z: 276 [M]+ . Found, %: C 56.52;
H 4.35; N 10.14; S 23.18. C13H12N2OS2. Calculated,
%: C 56.49; H 4.30; N 10.17; S 23.23.
4-Azido-2-methylthiophene (II). To a solution of
5.34 g (0.03 mol) of 4-bromo-2-methylthiophene (I)
[11] in 80 ml of anhydrous ether at 70 C under
argon was added while stirring 60 ml (0.06 mol) of
BuLi as 1.6 M solution in hexane. The mixture was
stirred for 18 min, and then at 70 C was added drop-
wise 14.8 g (0.075 mol) of p-toluenesulfonyl azide.
Therewith separated a yellow precipitate. The reac-
tion mixture was stirred for 5 h at 70 C, then the
temperature was slowly (within 1.5 h) raised to
40 C, and to reaction mixture was added a solution
of 11.4 g (0.05 mol) of ethylendiaminetetraacetic acid
disodium salt in 125 ml of water maintaining the
temperature below 0 C. After stirring for 15 min at
0 C the reaction mixture was warmed to the room
temperature and stirred for 12 h more. The red-brown
N-(4-Methylphenyl)-2-[(5-methylthien-3-yl)-
2-amino]-2-thioxoacetamide (Vb). Yield 60%;
1
mp 154 156 C (EtOH). H NMR spectrum, , ppm:
2.30 s (3H, CH3); 2.45 s (3H, CH3); 7.20 d (2H arom,
J 8.13 Hz); 7.35 s (1H of thiophene); 7.70d(2Harom,
J 8.32 Hz); 8.45 s (1H of thiophene); 10.35 s (1H,
NH); 12.55 s (1H, NH). Mass spectrum, m/z: 290
[M]+ . Found, %: C 57.93; H 4.83; N 9.65; S 22.07.
C14H14N2OS2. Calculated,%: C 57.94; H4.74; N9.72;
S 22.14.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 8 2003

SYNTHESIS OF 2-CARBAMOYLTHIENO[3,2-d]THIAZOLES
1163
N-Benzyl-2-[(5-methylthien-3-yl)amino]-2-thio-
xoacetamide (Vc). Yield 65%; mp 120 122 C
(EtOH). H NMR spectrum, , ppm: 2.45 s (3H,
N-(4-Fluorobenzyl)-5-methylthieno[3,2-d][1,3]-
thiazole-2-carboxamide (VIc). Yield 50%; mp 185
187 C (EtOH). H NMR spectrum, , ppm: 2.45 s
1
1
CH3); 4.45 d (2H, CH2, J 6.28 Hz); 7.35 m (1H of
thiophene; 5H arom); 8.45 s (1H of thiophene);
9.21 s (1H, NH); 12.35 s (1H, NH). Mass spectrum,
m/z: 290 [M]+ . Found, %: C 57.93; H 4.83; N 9.65;
S 22.07. C14H14N2OS2. Calculated %: C 57.94;
H 4.81; N 9.70; S 22.03.
(3H, CH3); 7.20 m (1H arom); 7.38 s (1H of thio-
phene); 7.90 s (2H arom); 11.00 s (1H, NH). Mass
spectrum, m/z: 292 [M]+ . Found, %: C 53.42; H3.08;
N 9.59; S 21.92. C13H9FN2OS2. Calculated, %:
C 53.50; H 3.10; N 9.50; S 21.84.
The study was carried out under financial support
of the International Scientific and Technological
Center (grant no. 2117).
N-(4-Fluorophenyl-2-[(5-methylthien-3-yl)-
amino]-2-thioxoacetamide (Vd). Yield 50%; mp
128 130 C (EtOH). 1H NMR spectrum, , ppm:
2.45 s (3 H, CH3); 7.20 m (1 H arom); 7.35 s (1H of
thiophene); 7.85 m (2H arom); 8.45 s (1H of thioph-
ene); 10.52 s (1H, NH); 12.55 s (1H, NH). Mass
spectrum, m/z: 294[M]+ . Found, %: C 53.06; H3.74;
N 9.52; S 21.77. C13H11FN2OS2. Calculated, %:
C 53.07; H 3.85; N 9.41; S 21.60.
REFERENCES
1. Patent 064763, 1995, Chem. Abstr., 1996, vol. 121,
pp. 9761d.
2. Patent 4233195, 1994, Chem. Abstr., 1994, vol. 120,
pp. 323579m.
2-Carbamoylthieno[3, 2-d]thiazoles VIa c.
Monothiooxoamides Va d (0.2 mmol) were dissolved
in 10% solution of NaOH (8.4 ml), the solution was
filtered, and at stirring thereto was added dropwise
0.44 mol of K3Fe(CN)6 in 4.4 ml of water. The
separated precipitate of thienothiazoles VIa c was
filtered off, washed with water, dried, and recrystal-
lized from 95% EtOH. The yields are given with
respect to the initial monothiooxamides.
3. Zavarzin, I.V., Yarovenko, V.N., Martynkin, A.Yu.,
and Krayushkin, M.M., Abstracts of Papers, The
18th Intern. Symp. on the Organic Chemistry of
Sulfur, Italy, 1998.
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1999, p. 753.
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skaya, O.Yu., Chernoburova, E.I., Zavarzin, I.V.,
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2002, p. 136.
N-(4-Methylphenyl)-5-methylthieno[3,2-d][1,3]-
thiazole-2-carboxamide (VIa). Yield 44%; mp 183
1
184 C (EtOH). H NMR spectrum, , ppm: 2.30 s
(3 H, CH3); 2.65 s (3 H, CH3); 7.18 d (2H arom, J
8.17 Hz); 7.40 s (1H of thiophene); 7.78 d (2H arom,
J 8.14 Hz); 10.75 s (1H, NH). Mass spectrum, m/z:
288 [M]+ . Found, %: C 58.33; H 4.17; N 9.72;
S 22.22. C14H12N2OS2. Calculated, %: C 58.44;
H 4.18; N 9.60; S 22.20.
N-Benzyl-5-methylthieno[3,2-d][1,3]thiazole-2-
carboxamide (VIb). Yield 51%; mp 149 151 C
1
9. Hill, B., de Vleeschauwer, M., Houde, K., and
Belley, M., Synlett., 1998, p. 407.
(EtOH). H NMR spectrum, , ppm: 2.50 s (3 H,
CH3); 4.50 d (2H, CH2, J 6.29 Hz); 7.35 m (1H of
thiophene; 5H arom); 9.47 s (1H, NH). Mass spec-
trum, m/z: 288 [M]+ . Found %: C 58.33; H 4.17;
N 9.72; S 22.22. C14H12N2OS2. Calculated %:
C 58.40; H 4.20; N 9.65; S 22.18.
10. Zhiryakov, V.G., Khim. Nauka i Prom., 1959,
p. 680.
11. Gol,dfarb, Ya.L., Vol,kenshtein, Yu.B., Lopa-
tin, B.V., Zh. Obshch. Khim., 1963, p. 969.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 8 2003