Cyclocondensation of methyl 2-(1,3-benzothiazol-2-ylimino)-3,3,3- trifluoropropionate with C,N-binucleophiles

Article abstract of DOI:10.1134/S1070363211050161

Reactions of methyl 2-(1,3-benzothiazol-2-ylimino)-3,3,3- trifluoropropionate with 1,3-C,N-binucleophiles, methyl 2-aminobut-2-enoate, 2-aminobut-2-enenitrile and N-substituted 6-aminouracils and 3-aminocyclohex-2-en-1-ones, led to the formation of triflu

Full text of DOI:10.1134/S1070363211050161

ISSN 1070-3632, Russian Journal of General Chemistry, 2011, Vol. 81, No. 5, pp. 934–936. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © V.B. Sokolov, A.Yu. Aksinenko, 2011, published in Zhurnal Obshchei Khimii, 2011, Vol. 81, No. 5, pp. 847–849.
Cyclocondensation of Methyl 2-(1,3-Benzothiazol-2-ylimino)-
3,3,3-trifluoropropionate with C,N-Binucleophiles
V. B. Sokolov and A. Yu. Aksinenko
Institute of Physiologically Active Substances, Russian Academy of Sciences, Chernogolovka, Moscow oblast, 142432 Russia
e-mail: alaks@ipac.ac.ru
Received April 22, 2010
Abstract—Reactions of methyl 2-(1,3-benzothiazol-2-ylimino)-3,3,3-trifluoropropionate with 1,3-C,N-
binucleophiles, methyl 2-aminobut-2-enoate, 2-aminobut-2-enenitrile and N-substituted 6-aminouracils and 3-
aminocyclohex-2-en-1-ones, led to the formation of trifluoromethyl-substituted heterocycles, dihydro-1H-
pyrroles, hexahydro-1H-pyrrolo[2,3-d]pyrimidine-2,4,6-triones, and hexahydro-1H-indole-2,4-diones.
DOI: 10.1134/S1070363211050161
Cyclocondensations of N-substituted methyl 2-imino-
3,3,3-trifluoropropionates with difunctional nucleo-
philes underlie effective methods for the synthesis of
novel trifluoromethyl-substituted five-membered hetero-
cycles [1–4]. While developing studies in this line, in
the present communication we report on trans-
formations of methyl 2-(1,3-benzothiazol-2-ylimino)-
3,3,3-trifluoropropionate (I), which was synthesized by
us previously [5], in cyclocondensations with 1,3-
binucleophiles to obtain trifluoromethyl-containing
heterocyclic N-substituted 2-aminobenzothiazole deriva-
tives. It should be noted that 2-aminobenzothiazole
R
CF3
N
S
R
NH
CH3
NH2
IIа, IIb
CH3
NH
O
Va, Vb
O
R
N
O
O
N
NH2
CF3
N
S
R
R'
NH
N
S
N
CF3
IIIа, IIIb
N
O
C(O)OCH3
O
N
NH
I
R'
VIa, VIb
O
O
CH3
CH3
CF3
NH
N
S
NHR
CH3
CH3
IVа−IVd
O
N
R
VIIa−VIId
II, V, R = MeOC(O) (a), CN (b); III, VI, R = R′ = Me (a), R = H, R′ = PhCH2 (b); IV, VII, R = Ph (a), PhCH2 (b), pyridin-
3-ylmethyl (c), 4-MeOC6H4 (d).
934

CYCLOCONDENSATION OF METHYL 2-(1,3-BENZOTHIAZOL-2-YLIMINO)-…
935
fragment is a structural unit of molecules of some
biologically active substances, e.g., nitric oxide
synthase inhibitors [6] and anticonvulsants [7].
according to [10], and methyl 3-aminobut-2-enoate
(IIa) and 3-aminobut-2-enenitrile were commercial
products (Aldrich) which were used without pre-
liminary purification.
Methyl 2-(1,3-benzothiazol-2-ylimino)-3,3,3-trifluoro-
propionate (I) turned out to be less reactive toward 1,3-
C,N-binucleophiles, as compared to N-substituted
analogs studied previously [8]. Compound I reacted
with methyl 2-aminobut-2-enoate (IIa) and 2-
aminobut-2-enenitrile (IIb) at 90°C (reaction time 1 h)
to give the corresponding 4-(benzothiazol-2-ylamino)-
2-methyl-5-oxo-4-trifluoromethyl-4,5-dihydro-1H-
pyrrole-3-carboxylic acid derivatives Va and Vb. The
reactions of I with 6-aminouracils IIIa and IIIb and 3-
aminocyclohex-2-en-1-ones IVa–IVd required heating
of the reaction mixtures for 6 h at 90°C in the presence
of a catalytic amount of triethylamine to be complete.
As a result, hexahydro-1H-pyrrolo[2,3-d]pyrimidine-
2,4,6-triones VIa and VIb and hexahydro-1H-indole-
2,4-diones VIIa–VIId were obtained in 66–78% yield.
Methyl 4-(1,3-benzothiazol-2-ylamino)-2-methyl-
5-oxo-4-trifluoromethyl-4,5-dihydro-1H-pyrrole-3-
carboxylate (Va). Compound I, 5 mmol, was
dissolved in 10 ml of DMF, 5 mmol of compound IIa
was added under stirring at 20°C, and the mixture was
stirred for 1 h at 90°C, cooled, and poured into 50 ml
of water. The precipitate was filtered off and re-
crystallized from 50% ethanol. Yield 1.3 g (70%), mp
1
123–125°C. H NMR spectrum (DMSO-d6), δ, ppm:
2.37 s (3H, Me), 3.57 s (3H, MeO), 6.97 t (1H, Harom
,
J = 7.7 Hz), 7.13 t (1H, Harom, J = 7.7 Hz), 7.24 d (1H,
Harom, J = 7.7 Hz), 7.55 d (1H, Harom, J = 7.7 Hz), 9.04
s (1H, NH), 10.95 s (1H, NH). 19F NMR spectrum
(DMSO-d6): δF 0.49 ppm. Found, %: C 48.39; H 3.13;
N 11.19. C15H12F3N3O3S. Calculated, %: C 48.52; H
3.26; N 11.22.
5-Oxo-4-trifluoromethyl-4,5-dihydro-1H-pyrroles V,
5-trifluoromethyl-5,7-dihydro-1H-pyrrolo[2,3-d]pyr-
imidine-2,4,6-trionyes VI, and 3-trifluoromethyl-
3,5,6,7-tetrahydro-1H-indole-2,4-diones VII were iso-
lated as crystalline substances which displayed
characteristic signals in the NMR spectra. The NH
proton at C2 in the benzothiazole fragment resonated in
4-(1,3-Benzothiazol-2-ylamino)-2-methyl-5-oxo-
4-trifluoromethyl-4,5-dihydro-1H-pyrrole-3-carbo-
nitrile (Vb) was synthesized in a similar way. Yield
1
68%. mp 131–132°C. H NMR spectrum (DMSO-d6),
δ, ppm: 2.27 s (3H, CH3), 7.05 t (1H, Harom, J =
7.7 Hz), 7.20 t (1H, Harom, J = 7.7 Hz), 7.35 d (1H,
1
H
arom, J = 7.7 Hz), 7.60 d (1H, Harom, J = 7.7 Hz), 9.40
the H NMR spectra of V–VII at δ 9–10 ppm, and the
s (1H, NH), 11.33 s (1H, NH). 19F NMR spectrum
(DMSO-d6): δF 2.50 ppm. Found, %: C 49.48; H 2.91;
N 17.08. C14H9F3N4OS. Calculated, %: C 49.70; H
2.68; N 16.85.
CF3 signal was located at δF 0.4–3.9 ppm in the 19F
NMR spectra.
Thus we have proposed a novel synthetic approach
to 2-aminobenzothiazole derivatives having different
trifluoromethyl-containing five-membered heterocyclic
substituents on the exocyclic nitrogen atom via
cyclocondensation of methyl 2-(1,3-benzothiazol-2-
ylimino)-3,3,3-trifluoropropionate with 1,3-C,N-bi-
nucleophiles.
5-(1,3-Benzothiazol-2-ylamino)-1,3-dimethyl-5-
trifluoromethyl-5,7-dihydro-1H-pyrrolo[2,3-d]pyr-
imidine-2,4,6(3H)-trione (VIa). Compound IIIa,
5 mmol, was added under stirring at 20°C to a solution
of 5 mmol of compound I in 10 ml of DMF. The
mixture was stirred for 1 h at 90°C, 0.1 g of tri-
ethylamine was added, and the mixture was heated for
6 h at 90°C, cooled, and poured into 50 ml of water.
The precipitate was filtered off and recrystallized from
EXPERIMENTAL
1
The H and 19F NMR spectra were recorded on a
1
Bruker DPX-200 spectrometer at 200.13 and 188.29 MHz,
respectively, using tetramethylsilane (1H, internal) or
CF3COOH (19F, external) as reference. The melting
points were determined by heating samples in glass
capillaries. Methyl 2-(1,3-benzothiazol-2-ylimino)-3,3,3-
trifluoropropionate (I) was synthesized according to
the procedure reported in [5]. Initial 6-aminouracils
IIIa and IIIb were prepared as described in [9], 3-
aminocyclohex-2-en-1-ones IVa–IVd were obtained
50% ethanol. Yield 1.6 g (78%), mp 233–235°C. H
NMR spectrum (DMSO-d6), δ, ppm: 3.12 s and 3.48 s
(3H each, MeN), 6.92 t (1H, Harom, J = 7.4 Hz), 7.19 t
(1H, Harom, J = 7.4 Hz), 7.26 d (1H, Harom, J = 7.4 Hz),
7.49 d (1H, Harom, J = 7.4 Hz), 9.43 s (1H, NH), 12.19
s (1H, NH). 19F NMR spectrum (DMSO-d6): δF 3.91
ppm. Found, %: C 46.58; H 2.81; N 17.16.
C16H12F3N5O3S. Calculated, %: C 46.72; H 2.94; N
17.02.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 5 2011

936
SOKOLOV, AKSINENKO
Compounds VIb and VIIa–VIId were synthesized
3-(1,3-Benzothiazol-2-ylamino)-1-(4-methoxy-
in a similar way.
phenyl)-6,6-dimethyl-3-trifluoromethyl-3,5,6,7-
tetrahydro-1H-indole-2,4-dione (VIId). Yield 71%.
5-(1,3-Benzothiazol-2-ylamino)-1-benzyl-5-trifluoro-
methyl-5,7-dihydro-1H-pyrrolo[2,3-d]pyrimidine-
2,4,6(3H)-trione (VIb). Yield 73%. mp 215–216°C.
1H NMR spectrum (DMSO-d6), δ, ppm: 5.14 m (2H,
CH2), 7.13 m (3H, Harom), 7.38 m (5H, Harom), 7.62 d
(1H, Harom, J = 7.9 Hz), 9.56 s (1H, NH), 11.07 s (1H,
NH), 12.36 s (1H, NH). 19F NMR spectrum (DMSO-
d6): δF 3.88 ppm, s. Found, %: C 53.12; H 2.85; N
14.66. C21H14F3N5O3S. Calculated, %: C 53.28; H
2.98; N 14.79.
1
mp 245–246°C. H NMR spectrum (DMSO-d6), δ,
ppm): 0.96 s and 1.12 s (3H each, Me), 2.25 m (2H,
CH2), 2.54 m (2H, CH2), 3.91 s (3H, MeO), 7.09 m
(3H, Harom), 7.22 t (1H, Harom, J = 8.1 Hz), 7.63 d (1H,
H
arom, J = 8.1 Hz), 7.24 m (3H, Harom), 9.62 s (1H,
NH). 19F NMR spectrum (DMSO-d6): δF 3.81 ppm.
Found, %: C 59.75; H 4.31; N 8.26. C25H22F3N3O3S.
Calculated, %: C 59.87; H 4.42; N 8.38.
ACKNOWLEDGMENTS
3-(1,3-Benzothiazol-2-ylamino)-6,6-dimethyl-1-
phenyl-3-trifluoromethyl-3,5,6,7-tetrahydro-1H-
indole-2,4-dione (VIIa). Yield 66%. mp 218–220°C.
1H NMR spectrum (DMSO-d6), δ, ppm: 0.97 s and
1.11 s (3H each, Me), 2.71 m (4H, CH2), 7.07 t (1H,
This study was performed under financial support
by the Russian Academy of Sciences (program
“Medicinal and Biomedical Chemistry”) and by the
Russian Foundation for Basic Research (project no.
08-03-00793a).
Harom, J = 6.7 Hz), 7.26 m (2H, Harom), 7.59 m (6H,
19
H
arom), 9.64 s (1H, NH). F NMR spectrum (DMSO-
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1H NMR spectrum (DMSO-d6), δ, ppm: 0.97 s and
1.08 s (3H each, Me), 2.11 m (2H, CH2), 2.41 m (2H,
CH2), 4.93 m (2H, CH2), 6.99 m (1H, Harom), 7.05 d
(2H, Harom, J = 7.1 Hz), 7.37 m (5H, Harom), 7.57 d (1H,
H
arom, J = 8.3 Hz), 9.46 s (1H, NH). 19F NMR spec-
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H 4.57; N 8.65.
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(pyridin-3-ylmethyl)-3-trifluoromethyl-3,5,6,7-tetra-
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8.2 Hz), 8.56 d (1H, Harom, J = 7.2 Hz), 8.79 s (1H,
19
H
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C24H21F3N4O2S. Calculated, %: C 59.25; H 4.35; N
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 5 2011