Cyclocondensation of methyl 2-(5-methylisoxazol-3-yl)imino-3,3,3- trifluoropropionate with 1,3-binucleophiles

Article abstract of DOI:10.1134/S1070363214010137

Cyclocondensation of methyl 2-(5-methylisoxazol-3-yl)imino-3,3,3- trifluoropropionate with 1,3-binucleophiles such as benzamidines, aminothiazoline, and 2-aminocrotonic acid nitrile results in trifluoromethyl-containing 3,5-dihydro-4-ones, 2,3-dihydro-6H-

Full text of DOI:10.1134/S1070363214010137

ISSN 1070-3632, Russian Journal of General Chemistry, 2014, Vol. 84, No. 1, pp. 86–88. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © V.B. Sokolov, A.Yu. Aksinenko, I.V. Martynov, 2014, published in Zhurnal Obshchei Khimii, 2014, Vol. 84, No. 1, pp. 90–92.
Cyclocondensation of Methyl
2-(5-Methylisoxazol-3-yl)imino-3,3,3-trifluoropropionate
with 1,3- Binucleophiles
V. B. Sokolov, A. Yu. Aksinenko, and I. V. Martynov
Institute of Physiologically Active Compounds, Russian Academy of Sciences,
1 Severnyi pr., Chernogolovka, Moscow oblast, 142432 Russia
e-mail: alaks@ipac.ac.ru
Received March 21, 2013
Abstract―Cyclocondensation of methyl 2-(5-methylisoxazol-3-yl)imino-3,3,3-trifluoropropionate with 1,3-bi-
nucleophiles such as benzamidines, aminothiazoline, and 2-aminocrotonic acid nitrile results in trifluoro-
methyl-containing 3,5-dihydro-4-ones, 2,3-dihydro-6H-imidazo[2,1-b]thiazol-5-one, and 4,5-dihydro-1H-pyrrole-
3-carbonitrile.
DOI: 10.1134/S1070363214010137
Imines of N-substituted methyl trifluoropyruvates
react with 1,3-binucleophiles to form trifluoromethyl-
containing five-membered heterocycles [1–4]. In this
work we report on the synthetic approach to prepare
heterocycles from trifluoromethyl-containing 1,2-
biselectrophiles. The previously unknown 2-(5-methyl-
isoxazol-3-yl)imino-3,3,3-trifluoropropionate III was
used as the fluorine-containing component in the
studied cyclocondensation.
The proposed method to obtain imine III consisted
in the sequential addition of equimolar amounts of
pyridine, methyl trifluoropyruvate II, and SOCl2 to
solution of 2-amino-5-methylisoxazole I.
C(O)OCH3
N
C(O)OCH3
N
SOCl2, Py
O
O
N
NH2 + O
CF3
CF3
CH3
CH3
I
II
III
Imine III was a high-boiling compound, its com-
position and structure being confirmed by elemental
analysis and NMR spectroscopy. 19F NMR spectra of
III contained the signal of trifluoromethyl group at the
azomethine bond (δF 7.02 ppm) [5].
methy-2,3-dihydro-6Н-imidazo[2,1-b]-thiazol-5-one
VIII, and 2-methyl-4-(5-methylisoxazol-3-ylamino)-5-
oxo-4-trifluoromethyl-4,5-dihydro-1H-pyrrole-3-carbo-
nitrile IX with yields of 72–80% (see Scheme 1).
The prepared 5-trifluoromethyl-3,5-dihydroimidazol-
4-ones VIIa and VIIb, 6-trifluoromethyl-2,3-dihydro-
6H-imidazo[2,1-b]thiazol-5-one VIII, and 5-oxo-4-
trifluoromethyl-4,5-dihydro-1H-pyrrole-3-carbonitrile
N-(Isoxazol-3-yl)imine of methyl trifluoropyruvate
III reacted exothermically with highly reactive 1,3-
N,N- and 1,3-C,N-binucleophiles (such as benz-
amidines IVa and IVb, 2-aminothiazoline V, and 3-
aminocrotonate VI) via cyclocondensation: 1,3-
addition of the binucleophile at the C=N bond of III
followed by cyclization and elimination of methanol.
In order to reach complete conversion, short-time
heating at 50°C was necessary, the products being the
corresponding 5-(5-methylisoxazol-3-ylamino)-2-phenyl-
5-trifluoromethyl-3,5-dihydroimidazol-4-ones VIIa and
VIIb, 6-(5-methylisoxazol-3-ylamino)-6-trifluoro-
1
IX were colorless crystalline solids. In the H NMR
spectra of VII–IX, the CH protons of isoxazole ring
resonated at 5.6–5.8 ppm; the NH protons signals of
benzamide substituent were observed at 9–10 ppm.
The 19F NMR spectra contained the signals of CF3
group at 0.4–3.9 ppm.
To conclude, we have proposed a novel synthetic
approach to functionalize 2-amino-5-methylisoxazole
using various trifluoromethyl-containing five-membered
86

CYCLOCONDENSATION OF METHYL 2-(5-METHYLISOXAZOL-3-YL)IMINO-...
87
Scheme 1.
HN
CF3
N
HRN
O
NH
O
N
IVа, IVb
CH3
N
R
S
VIIа, VIIb
H2N
CF3
N
N
N
O
O
V
NH
N
III
CH3
CH3
O
N
S
CN
VIII
CF3
H2N
CH3
CN
VI
NH
O
N
CH3
H
IХ
IV, VII: R = H (а), cyclo-C6H11 (b).
heterocycles via cyclocondensation of 2-(5-methyliso-
xazol-3-yl)imino-3,3,3-trifluoropropionate with 1,3-bi-
nucleophiles.
5-(5-Methylisoxazol-3-ylamino)-2-phenyl-5-tri-
fluoromethyl-3,5-dihydroimidazol-4-one (VIIa).
Mixture of 5 mmol of compound III in 10 mL of DMF
and 5 mmol of VIa was stirred at 50°C during 1 h,
cooled down, and poured into 50 mL H2O. The
precipitate was recrystallized from 50% EtOH. Yield
1.3 g (80%), mp 205–207°C. 1H NMR spectrum
(DMSO-d6), δ, ppm: 2.21 s (3H, Me), 5.72 s (1H,
CHAr), 7.46–7.72 m (3H, CHAr), 7.91 s (1H, NH), 7.98
d (2Н, CHAr, J 7.1 Hz), 12.21 s (1H, NH). 19F NMR
spectrum (DMSO-d6): δF 1.15 ppm. Found, %: C
51.99; H 3.59; N 17.10. C14H11F3N4O2. Calculated, %:
C 51.86; H 3.42; N 17.28.
EXPERIMENTAL
1H and 19F NMR spectra were registered with Bruker
DPX 200 spectrometer at 200.13 and 188.29 MHz,
respectively; relative to TMS (internal reference) and
CF3COOH (external reference), respectively. Melting
points were determined in glass capillaries. Benz-
amidines IVa and IVb, 2-aminothiazoline V, and 3-
aminocrotonic acid nitrile VI (Aldrich) were used as
received.
3-Benzyl-5-(5-methylisoxazol-3-ylamino)-2-phe-
nyl-5-trifluoromethyl-3,5-dihydroimidazol-4-one
(VIIb) was prepared similarly. Yield 73%, mp 168–
Methyl 2-(5-methylisoxazol-3-yl)imino-3,3,3-tri-
fluoropropionate (III). Mixture of 0.1 mol of
compound I in 50 mL of benzene, 0.2 mol of pyridine,
and 0.1 mol of II was stirred at 20°C during 30 min.
Then, 0.1 mol of SOCl2 was added, and the mixture
was stirred during 1 h. The formed precipitate was
filtered off. After the solvent removal, the residue was
fractionated. Yield 18.5 g (78%), bp 79–80°C (1 Torr).
1H NMR spectrum (CDCl3), δ, ppm: 2.32 s (3H, Me),
3.69 s (3H, MeO), 5.77 s (1H, CHAr). 19F NMR
spectrum (CDCl3): δF 7.02 ppm. Found, %: С 40.51; Н
2.82; N 11.66. C8H7F3N2O3. Calculated, %: С 40.69; Н
2.99; N 8.68.
1
170°С. H NMR spectrum (DMSO-d6), δ, ppm: 2.22 s
(3H, Me), 4.55–4.77 m (2H, CH2), 5.61 s (1H, CHAr),
6.87–7.07 m (5H, CHAr), 7.14–7.24 m (4H, CHAr),
7.26–7.33 m (1H, CHAr), 7.82 s (1H, NH). 19F NMR
spectrum (DMSO-d6): δF 2.12 ppm. Found, %: C
60.62; H 4.32; N 13.30. C21H17F3N4O2. Calculated, %:
C 60.81; H 4.14; N 13.52.
6-(5-Methylisoxazol-3-ylamino)-6-trifluoromethyl-
2,3-dihydro-6Н-imidazo[2,1-b]thiazol-5-one (VIII)
was prepared similarly. Yield 76%, mp 216–218°С. 1H
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 84 No. 1 2014

88
SOKOLOV et al.
NMR spectrum (DMSO-d6), δ, ppm: 2.19 s (3H, Me),
3.51–3.70 m (1H, CH2), 3.73–3.86 m (2H, CH2), 3.88–
3.03 m (1H, CH2), 5.72 s (1H, CHAr), 7.98 s (1H, NH).
19F NMR spectrum (DMSO-d6): δF 0.2 ppm. Found,
%: C 39.03; H 3.18; N 19.45. C10H9F3N4O2S. Cal-
culated, %: C 39.22; H 2.96; N 18.29.
of the Russian Academy of Sciences “Development of
methods for chemicals and new materials” and
“Medical and Biomedical Chemistry” and was
financially supported by the Russian Foundation for
Basic Research (grant no. 11-03-00496-a).
REFERENCES
2-Methyl-4-(5-methylisoxazol-3-ylamino)-5-oxo-
4-trifluoromethyl-4,5-dihydro-1Н-pyrrole-3-carbo-
nitrile (IX) was prepared similarly. Yield 72%, mp
1. Sokolov, V.B., Aksinenko, A.Yu., Epishina, T.A., Gore-
va, T.V., and Martynov, I.V., Russ. Chem. Bull., 2011,
no. 4, p. 707.
1
223–225°С. H NMR spectrum (DMSO-d6), δ, ppm:
2.21 s (3H, Me), 2.26 s (3H, Me), 5.78 s (1H, CHAr),
7.91 s (1H, NH), 11.38 s (1H, NH). 19F NMR spectrum
(DMSO-d6): δF 2.27 ppm. Found, %: C 43.33; H 3.38;
N 19.29. C11H9F3N4O2. Calculated, %: C 46.16; H
3.17; N 19.58.
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ACKNOWLEDGMENTS
This work was performed in the frame of Programs
of the Department of Chemistry and Materials Science
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 84 No. 1 2014