Synthesis of pyrrolo[3,2-d][1,3]thiazoles

Article abstract of DOI:10.1134/S1070428007050181

By oxidation of monothiooxamides with K₃[Fe(CN) ₆]pyrrolo[3,2-d][1,3]thiazoledicarboxylic acid was obtained used further in the synthesis of 2,4,5-trimethyl-4H-pyrrolo[3,2-d][1,3]thiazole. Nauka/Interperiodica 2007.

Full text of DOI:10.1134/S1070428007050181

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 5, pp. 753−757. © Pleiades Publishing, Ltd., 2007.
Original Russian Text © I.B. Zavarzin, N.G. Smirnova, V.N. Yarovenko, M.M. Krayushkin, 2007, published in Zhurnal Organicheskoi Khimii,
2007, Vol. 43, No. 5, pp. 756−759.
Synthesis of Pyrrolo[3,2-d][1,3]thiazoles
I. B. Zavarzin, N. G. Smirnova, V. N. Yarovenko, and M. M. Krayushkin
Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, 119991 Russia
e-mail: zavi@ioc.ac.ru
Received December 10, 2005
Abstract—By oxidation of monothiooxamides with K3[Fe(CN)6] pyrrolo[3,2-d][1,3]thiazoledicarboxylic acid was
obtained used further in the synthesis of 2,4,5-trimethyl-4H-pyrrolo[3,2-d][1,3]thiazole.
DOI: 10.1134/S1070428007050181
We report here on the synthesis of monothiooxamides
based on pyrrole and on their cyclization into a pyr-
rolothiazole substances whose derivatives are used as
anti-phlogistic pharmaceuticals and immunomodulators
[6], inhibitors and anticoagulants for prevention and
treatment of thrombosis and embolism [7, 8], and also as
We showed formerly that oxidation in alkaline solutions
with K3[Fe(CN)6] of monothiooxamides containing phenyl
or heteroaromatic rings resulted in formation of fused
thiazoles I–V in good yield [1–5].
R
S
N
S
components of photomaterials [9].
R'
R'
Ethyl 4-amino-1-methyl-1H-pyrrole-2-carboxylate
hydrochloride (VI) [10, 11] was applied as initial
compound. Its treatment with chloroacetamides and sulfur
in the presence of triethylamine by the procedure we have
previously developed [1–5] gives thiooxamides VIIa–
VIIc in 55–66% yield. The oxidative cyclization of the
latter with the thiazole system formation occurred at the
treatment with K3[Fe(CN)6] in 20% solution of NaOH
at 20°C. Therewith in all cases a single product was
N
X
N
III
I, II
S
N
S
R'
R'
N
Me
S
Me
S
IV
V
X = CH (I), N (II); R' = CONH2, CONHAlk, CONHAr.
O
NHR
HN
H2N
S8, Et3N
OEt
HCl
S
ClCH2CONHR
N
EtOOC
N
O
Me
VI
Me
VIIa_VIIc
O
OH
N
HN
COOH
NaOH
NaOH
S
S
K3[Fe(CN)6]
N
HOOC
HOOC
N
Me
Me
VIII
IX
R = Ph (a), 4-ClC6H4 (b), H (c).
753

ZAVARZIN et al.
754
obtained, 4-methyl-4H-pyrrole[3,2-d][1,3]thiazole-2,5-
dicarboxylic acid (IX), evidently through intermediate
formation of diacid VIII resulting from the hydrolysis.
Reactions of thiazole XI with chloroacetyl chloride
and glutaryl dichloride in the presence of aluminum
chloride led to the formation of acyl derivatives XIV and
Special experiments demonstrated that diacid VIII
readily formed at treating compounds VIIa–VIIc with
20% solution of NaOH already at room temperature, and
under the conditions of the oxidative cyclization it turned
into diacid IX in good yield.
XV.
Cl
O
N
AlCl3
ClCH2COCl
Me
XI
S
Me
N
COOH
N
Me
XIV
S
O
HOOC
O
N
Me
Me
N
N
Me
AlCl3
ClCO(CH2)3COCl
IX
S
S
COOMe
N
N
N
Me
Me
CH2N2
Me
Me
S
MeOOC
XV
THF
N
Me
In reaction of compound XI with 3,4-dichlorocyclobut-
3-ene-1,2-dione only one chlorine atom was replaced.
Reaction product 4-(2,4,5-trimethyl-4H-pyrrole[3,2-
d][1,]thiazol-6-yl)-3-chlorocyclobut-3-ene-1,2-dione
(XVI) cleanly reacted with aniline and morpholine in THF
giving the corresponding amino derivatives XVIIa and
XVIIb.
X
N
Me
AlCl3, LiAlH4
THF
S
Me
N
Me
XI
O
O
O
O
Under the treatment with diazo methane diacid IX
was converted into ester X that then was reduced with
LiAlH4 in the presence ofAlCl3 in anhydrous THF yield-
ing 2,4,5-trimethyl-4H-pyrrole[3,2-d]-[1,3]thiazole (XI).
N
Cl
Cl
Me
XI
Cl
AlCl3
S
Me
O
The latter was readily involved into electrophilic
substitutions that provided in good yields 2,4,5-trimethyl-
4H-pyrrole[3,2-d][1,3]thiazole-6-carbaldehyde (XII) and
6-bromo-2,4,5-trimethyl-4H-pyrrole[3,2-d][1,3]-thiazole
(XIII) respectively.
N
Me
XVI
O
RR'NH
THF
N
O
Me
NRR'
N
H
S
Me
Me
CHCl2OEt, AlCl3
(ClCH2)2
N
XI
S
Me
Me
XVIIa, XVIIb
N
Me
XII
R = H, R’ = Ph (a), R, R' = (CH2)2O(CH2)2 (b).
Br
Me
N
Me
Br2
EXPERIMENTAL
CHCl3
S
1H NMR spectra were registered on a spectrometer
BrukerAC-300 (300 MHz) from solutions in CDCl3 and
DMSO-d6. Mass spectra were taken on Kratos instru-
N
Me
XIII
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 5 2007

SYNTHESIS OF PYRROLO[3,2-d][1,3]THIAZOLES
755
was acidified and extracted with ethyl acetate, the extract
was dried and evaporated. Yield 98%, mp 178–180°C
(EtOH). 1H NMR spectrum (DMSO-d6), δ, ppm: 3.89 s
(3H, CH3), 7.30 s (1H, Ht), 8.19 s (1H, Ht), 12.39 s (1H,
NH). Mass spectrum, m/z: 228 [M]+. Found, %: C 42.22;
H 3.70; N 12.46; S 13.80. C8H8N2O4S. Calculated, %:
C 42.10; H 3.53; N 12.27; S 14.05. M 228.22.
ment with a direct sample admission into the ion source,
ionizing electrons energy 70 eV, control voltage 1.75 kV.
Melting points were measured on a Boetius heating block
and are given uncorrected. We used in the study
commercial reagents of Acros.
..
Monothiooxamides VIIa–VIIc. To a preliminary
prepared mixture of 0.96 g (5.7 mmol) of salt VI, 1.0 g of
sulfur, and 1 ml of Et3N in 5 ml of DMF was added
5.3 mmol of an appropriate chloroacetamide. The mixture
was stirred for 8 h at 20°C, then it was diluted with water,
extracted with ethyl acetate, the extract was washed with
water, dried with magnesium sulfate, evaporated, and the
residue was subjected to chromatography on silica gel
(eluent ethyl acetate–petroleum ether, 1:2). Yields are
reported with respect to initial chloroacetamide.
4-Methyl-4H-pyrrolo[3,2-d][1,3]thiazole-2,5-
dicarboxylic acid (IX). In 8.4 mmol of 20% NaOH was
dissolved 0.2 mmol of monothiooxamide VIIa–VIIc. The
solution was filtered, and to the filtrate was added
dropwise at stirring 0.44 mmol of K3[Fe(CN)6] in
0.44 ml of water. The mixture was stirred for 24 h, then
it was acidified and extracted with ethyl acetate, the
extract was dried and evaporated. Yield 90%, mp 218–
220°C (EtOH). 1H NMR spectrum (DMSO-d6), δ, ppm:
4.09 s (3H, CH3), 7.36 s (1H, Ht). Mass spectrum, m/z:
226 [M]+. Found, %: C 42.60; H 2.47; N 12.20; S 14.04.
C8H6N2O4S. Calculated, %: C 42.48; H 2.67; N 12.38;
S 14.18.
Ethyl 4-[(2-anilino-2-oxoethanethioyl)amino]-1-
methyl-1H-pyrrole-2-carboxylate (VIIa). Yield 55%,
1
mp 121–123°C (EtOH). H NMR spectrum (DMSO-
d6), δ, ppm: 1.30 t (3H, CH3, J 7.12 Hz), 3.90 s (3H,
CH3), 4.28 m (2H, CH2), 7.20 m (1Harom), 7.40 m
(2Harom), 7.54 C (1H, pyrrole), 7.80 d (2Harom, J 7.78 Hz),
8.27 s (1H, pyrrole), 10.43 s (1H, NH), 12.59 s (1H, NH).
Mass spectrum, m/z: 331 [M]+. Found, %: C 58.29;
H 5.33; N 12.51; S 9.49. C16H17N3O3S. Calculated, %:
C 57.99; H 5.17; N 12.68; S 9.68. M 331.39.
Dimethyl 4-methyl-4H-pyrrolo[3,2-d][1,3]-
thiazole-2,5-dicarboxylate (X). In anhydrous THF was
dissolved 0.01 mol of acid IX, and at 1°C 0.024 mol of
diazomethane ether solution was added. The reaction
mixture was left overnight, then the solvent was distilled
1
off. Yield 96%, mp 138–140°C. H NMR spectrum
Ethyl 4-({2-[(4-chlorophenyl)amino]-2-oxo-
ethanethioyl}amino)-1-methyl-1H-pyrrole-2-
carboxylate (VIIb). Yield 60%, mp 144–145°C (EtOH).
1H NMR spectrum (DMSO-d6), δ, ppm: 1.30 t (3H, CH3,
J 7.14 Hz), 3.90 s (3H, CH3), 4.25 m (2H, CH2), 7.43 d
(DMSO-d6), δ, ppm: 3.85 s (3H, OCH3), 3.95 s (3H,
OCH3), 4.10 s (3H, CH3), 7.42 s (1H, Ht). Mass
spectrum, m/z: 254 [M]+. Found, %: C 47.05; H 3.73;
N 11.15; S 12.40. C10H10N2O4S. Calculated, %: C 47.14;
H 3.96; N 11.02; S 12.61. M 254.26.
(2Harom, J 8.59 Hz), 7.50 s (1H, Ht), 7.82 d (2Harom
,
2,4,5-Trimethyl-4H-pyrrolo[3,2-d][1,3]thiazole
(XI). To 3.5 mmol of AlCl3 in 20 ml of anhydrous THF
was added 0.4 mmol of dicarboxylate X, then 6 mmol of
LiAlH4 was added to the solution in one portion. The
reaction mixture was stirred for 2 h, then 20 ml of benzene
was added, and the mixture was carefully diluted with
10 ml of water. The organic layer was separated, washed
with water, dried with magnesium sulfate, and evaporated.
J 8.50 Hz), 8.21 s (1H, Ht), 10.55 s (1H, NH), 12.53 s
(1H, NH). Mass spectrum, m/z: 365 [M]+. Found, %:
C 52.30; H 4.22; Cl 9.80; N 11.64; S 8.90.
C16H16ClN3O3S. Calculated, %: C 52.53; H 4.41; Cl 9.69;
N 11.49; S 8.77. M 365.83.
Ethyl 4-[(2-amino-2-oxoethanethioyl)amino]-1-
methyl-1H-pyrrole-2-carboxylate (VIIc). Yield 66%,
1
Yield 87%, oily substance. 1
H NMR spec-trum (DMSO-
mp 176–178°C (EtOH). H NMR spectrum (DMSO-
d6), δ, ppm: 1.30 t (3H, CH3, J 6.98 Hz), 3.90 s (3H,
CH3), 4.25 m (2H, CH2), 7.50 s (1H, Ht), 7.92 s (1H,
NH2), 8.05 s (1H, NH2), 8.20 s (1H, Ht), 12.29 s (1H,
NH). Mass spectrum, m/z: 255 [M]+. Found, %: C 47.25;
H 5.04; N 16.60; S 12.40. C10H13N3O3S. Calculated, %:
C 47.05; H 5.13; N 16.46; S 12.56. M 255.29.
d6), δ, ppm: 2.30 s (3H, CH3), 2.63 s (3H, CH3), 3.60 s
(3H, CH3), 6.15 s (1H, Ht). Mass spectrum, m/z: 166
[M]+. Found, %: C 57.93; H 5.83; N 16.99; S 19.04.
C8H10N2S. Calculated, %: C 57.80; H 6.06; N 16.85; S
19.29. M 166.24.
2,4,5-Trimethyl-4H-pyrrolo[3,2-d][1,3]thiazole-
6-carbaldehyde (XII). In anhydrous dichloroethane was
dissolved 0.5 mmol of azole XI, 1.05 mmol ofAlCl3 was
added at stirring, then to the mixture was added dropwise
0.6 mmol of CHCl2OEt. The stirring was continued till
4-[(Carboxycarbothioyl)amino]-1-methyl-1H-
pyrrole-2-carboxylic acid (VIII). In 8.4 mmol of 20%
NaOH was dissolved 0.2 mmol of monothiooxamide
VIIa–VIIc. The mixture was stirred for 24 h, then it
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 5 2007

ZAVARZIN et al.
756
1H NMR spectrum (CDCl3), δ, ppm: 2.60 s (6H, CH3),
2.71 s (6H, CH3), 3.35 s (2H, CH2), 3.65 br.s (10H,
CH3 + CH2). Mass spectrum, m/z: 428 [M]+. Found, %:
C 58.98; H 5.13; N 13.22; S 14.78. C21H24N4O2S2.
Calculated, %: C 58.85; H 5.04; N 13.07; S 14.96. M 428.57.
disappearance of the initial substrate from the reaction
mixture, then the mixture was poured into water, extracted
with dichloromethane, the extract was washed with water,
dried, and evaporated. Yield 94%, mp 133–135°C (EtOH).
1H NMR spectrum (DMSO-d6), δ, ppm: 2.62 s (3H,
CH3), 2.73 s (3H, CH3), 3.72 s (3H, CH3), 10.00 s (1H,
CHO). Mass spectrum, m/z: 194 [M]+. Found, %: C 55.79;
H 5.36; N 14.27; S 16.31. C9H10N2OS. Calculated, %: C
55.65; H 5.19; N 14.42; S 16.51. M 194.25.
3-Chloro-4-(2,4,5-trimethyl-4H-pyrrolo[3,2-d]-
[1,3]thiazol-6-yl)cyclobut-3-ene-1,2-dione (XVI). To
a mixture of 2.56 mmol of azole XI, 10.27 mmol ofAlCl3
in 80 ml of dichloroethane and 25 ml of heptane was
added in an argon flow 0.387 g (2.56 mmol) of 3,4-di-
chloro-3-cyclobutene-1,2-dione in 20 ml of dichloro-
ethanethe reactin mixture was stirred for 5 h (TLC
monitoring). The mixture was poured on ice, extracted
with dichloromethane (3×50 ml), the organic layer was
washed with 2% water solution of NaHCO3, with
saturated NaCl solution, and dried with MgSO4. The
solvent was evaporated, and the residue was subjected
to chromatography on silica gel (eluent ethyl acetate–
petroleum ether, 1:1). Yield 65%, mp 189–190°C (EtOH).
1H NMR spectrum (CDCl3), δ, ppm: 2.79 s (3H, CH3),
2.85 s (3H, CH3), 3.75 s (3H, CH3). Mass spectrum, m/
z: 280 [M]+. Found, %: C 51.52; H 3.40; Cl 12.48; N 9.70;
S 11.60. C12H9ClN2O2S2. Calculated, %: C 51.34; H 3.23;
Cl 12.63; N 9.98; S 11.42. M 280.73.
6-Bromo-2,4,5-trimethyl-4H-pyrrolo[3,2-d][1,3]-
thiazole (XIII). To a solution of 0.6 mmol of azole XI in
chloroform was added 0.6 mmol of Br2, and the mixture
was stirred for 30 min till disappearance of the initial
thiazole. The solution was evaporated in a vacuum, and
the residue was subjected to chromatography on silica
gel (eluent ethyl acetate–petroleum ether, 1:2). Yield 97%,
1
mp 97–99°C (EtOH). H NMR spectrum (DMSO-d6),
δ, ppm: 2.30 s (3H, CH3), 2.69 s (3H, CH3), 3.68 s (3H,
CH3). Mass spectrum, m/z: 245 [M]+. Found, %: C 39.33;
H 3.57; Br 32.47; N 11.47; S 13.07. C8H9BrN2S.
Calculated, %: C 39.20; H 3.70; Br 32.60; N 11.33; S
12.88. M 245.14.
2-Chloro-1-(2,4,5-trimethyl-4H-pyrrolo[3,2-d]-
[1,3]thiazol-6-yl)ethanone (XIV). In anhydrous
dichloroethane was dissolved 0.5 mmol of azole XI,
1.05 mmol of AlCl3 was added at stirring, then to the
mixture was added dropwise 0.6 mmol of ClCH2COCl
till disappearance of the initial thiazole. The reaction
mixture was poured into water, extracted with dichloro-
methane, the extract was washed with water, dried, and
evaporated. Yield 99%, mp 159–161°C (EtOH). 1H NMR
spectrum (DMSO-d6), δ, ppm: 2.65 s (3H, CH3), 2.77 s
(3H, CH3), 3.72 s (3H, CH3), 5.03 s (2H, CH2). Mass
spectrum, m/z: 242 [M]+. Found, %: C 49.67; H 4.32;
Cl 14.46; N 11.72; S 13.07. C10H11ClN2OS. Calculated,
%: C 49.48; H 4.57; Cl 14.61; N 11.54; S 13.21. M 242.72.
Aminotrimethylpyrrolothiazolecyclobutenediones
XVIIa and XVIIb. General procedure. To a stirred
solution of 1 mmol of reagent XVI in THF at room
temperature was added a solution of 1 mmol of amine in
THF. The separated precipitate was filtered off, washed
with THF, and dried.
3-Anilino-4-(2,4,5-trimethyl-4H-pyrrolo-[3,2-
d][1,3]thiazol-6-yl)cyclobut-3-ene-1,2-dione
(XVIIa). Yield 95%, mp 307–309°C. 1H NMR spectrum
(CDCl3), δ, ppm: 2.78 s (3H, CH3), 2.98 s (3H, CH3),
3.68 s (3H, CH3), 7.10 m (1Harom), 7.40 m (2Harom),
7.62 d (2Harom, J 7.92 Hz), 11.90 s (1H, NH). Mass
spectrum, m/z: 337 [M]+. Found, %: C 64.30; H 4.26;
N 12.10; S 9.76. C18H15N3O2S. Calculated, %: C 64.08;
H 4.48; N 12.45; S 9.50. M 337.40.
1,5-Bis(2,4,5-trimethyl-4H-pyrrolo[3,2-d][1,3]-
thiazol-6-yl)pentane-1,5-dione (XV). To a mixture of
0.6 mmol of azole XI and 0.3 mmol of glutaryl dichloride
in 20 ml of dichloromethane was added at cooling 0.8 g
of AlCl3, and the stirring at cooling was continued for
40 min and then for 5 h at room temperature (TLC
monitoring). The mixture was poured on ice, extracted
with dichloromethane (3×50 ml), the organic layer was
washed with 2% water solution of NaHCO3, with
saturated NaCl solution, and dried with MgSO4. The
solvent was evaporated, and the residue was subjected
to chromatography on silica gel (eluent ethyl acetate–
petroleum ether, 2:1). Yield 68%, mp 178–180°C (EtOH).
3-Morpholino-4-(2,4,5-trimethyl-4H-pyrrolo-
[3,2-d][1,3]thiazol-6-yl)cyclobut-3-ene-1,2-dione
1
(XVIIb). Yield 90%, mp >350°C. H NMR spectrum
(CDCl3), δ, ppm: 2.78 s (3H, CH3), 2.98 s (3H, CH3),
3.68 s (3H, CH3), 3.80 m (2H, CH2), 3.85 m (2H, CH2),
4.02 m (2H, CH2), 4.28 m, (2H, CH2). Mass spectrum,
m/z: 331 [M]+. Found, %: C 57.73; H 5.30; N 12.55;
S 9.84. C16H17N3O3S. Calculated, %: C 57.99; H 5.17;
N 12.68; S 9.68. M 331.39.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 5 2007

SYNTHESIS OF PYRROLO[3,2-d][1,3]THIAZOLES
757
Chem. Abstr., 1999, vol. 131, 170342.
REFERENCES
7. Ota, T., Komoritani, S.,Yoshino, T., Uoto, K., Nakamoto, Y.,
Naito, H., Mochizuki, A., Nagata, T., Kanno, H., Hagi-
noya, N., Yoshikawa, K., Nagamochi, M., and Kobaya-
shi, Sh., Japan Patent 2003183286; Chem. Abstr., 2003,
vol. 139, 85363.
8. Ohta, T., Komoriya, S., Yoshino, T., Uoto, K., Nakamoto, Y.,
Naito, H., Mochizuki, A., Nagata, T., Kanno, H., Hagi-
noya, N., Yoshikawa, K., Nagamochi, M., Kobayashi, S.,
Ono, M., WO Patent 2003000657. Chem. Abstr., 2003,
vol. 138, 205076.
9. Nakamura, T., Hioki, T., Ohzeki, K., and Hanaki, N., US Patent
2002058216, US; Chem. Abstr., 2002, vol. 136, 393179.
10. Eldon, E.B., J. Am. Chem. Soc., 1996, vol. 118, p. 6141.
11. Ryabinin, V.A. and Sinyakov, A.N., Bioorg. Khim., 1998,
vol. 24, p. 601.
1. Yarovenko, V.N., Stoyanovich, F.M., Zolotarskaya, O.Yu.,
Chernoburova, E.I., Zavarzin, I.V., and Krayushkin, M.M.,
Izv. Akad. Nauk, Ser.Khim., 2002, p. 136.
2. Yarovenko, V.N., Smirnova, N.G., Bulgakova, V.N., Zavar-
zin, I.V., and Krayushkin, M.M., Zh. Org. Khim., 2003,
vol. 39, p. 1232.
3. Zavarzin, I.V., Smirnova, N.G., Yarovenko, V.N., and
Krayushkin, M.M., Zh. Org. Khim., 2004, vol. 40, p. 146.
4. Zavarzin, I.V., Smirnova, N.G., Yarovenko, V.N., and
Krayushkin, M.M., Izv. Akad. Nauk, Ser. Khim., 2004,
p. 1299.
5. Zavarzin, I.V., Smirnova, N.G., Yarovenko, V.N., and
Krayushkin, M.M., Zh. Org. Khim., 2006, vol. 42, p. 288.
6. Barker,A.J., Kettle, J.G.,and Faull,A.W., WO Patent 9940914;
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 5 2007