Methyl trifluoropyruvate N-(pyrimidin-2-yl)imines in cyclocondensation reactions with 1,3-binucleophilic reagents

Article abstract of DOI:10.1007/s10593-013-1265-6

Cyclocondensation reactions of methyl trifluoropyruvate N-(pyrimidin-2-yl)imines with N-substituted ureas, N-benzylbenzamidine, 2-aminothiazoline, methyl 3-aminocrotonate, and 6-aminouracils leading to imidazolidine-2,4-diones, 3,5-dihydroimidazol-4-ones,

Full text of DOI:10.1007/s10593-013-1265-6

Chemistry of Heterocyclic Compounds, Vol. 49, No. 3, June, 2013 (Russian Original Vol. 49, No. 3, March, 2013)
METHYL TRIFLUOROPYRUVATE N-(PYRIMIDIN-2-YL)IMINES
IN CYCLOCONDENSATION REACTIONS WITH
1,3-BINUCLEOPHILIC REAGENTS
V. B. Sokolov1*, A. Yu. Aksinenko1, T. A. Epishina1, and T. V. Goreva1
Cyclocondensation reactions of methyl trifluoropyruvate N-(pyrimidin-2-yl)imines with N-substituted
ureas, N-benzylbenzamidine, 2-aminothiazoline, methyl 3-aminocrotonate, and 6-aminouracils leading
to imidazolidine-2,4-diones, 3,5-dihydroimidazol-4-ones, 2,3-dihydroimidazo[2,1-d][1,3]thiazol-5(6H)-
one, 4,5-dihydro-1H-pyrroles, and 5,7-dihydro-1H-pyrrolo[2,3-d]pyrimidine-2,4,6-triones have been
studied.
Keywords: 2-aminothiazoline, 6-aminouracils, N-benzylbenzamidine, 3,5-dihydroimidazol-4-ones,
2,3-dihydroimidazo[2,1-d][1,3]thiazol-5(6H)-one, 4,5-dihydro-1H-pyrroles, 5,7-dihydro-1H-pyrrolo[2,3-d]-
pyrimidine-2,4,6-triones, imidazolidine-2,4-dione, methyl 3-aminocrotonate, methyl trifluoropyruvate
N-(pyrimidin-2-yl)imines, N-substituted ureas, cyclocondensation.
The modification of physiologically active compounds (PACs) is one of the most fruitful directions in
organic chemistry. In this context the functionalization of PACs with fluorine-containing (including
heterocyclic) substituents is particularly attractive. The introduction of fluorine-containing fragments into PAC
molecules does not generally lead to a lowering of biological activity, but rather induces specific
physicochemical properties which, in turn, can bring about an improvement and, in certain examples, a tunable
change in the pharmacological parameters [1-5].
We have previously studied the behavior of methyl trifluoropyruvate (MTFP) N-substituted imines and
hexafluoroacetone in cyclocondensation reactions with 1,3-C,N-, 1,3-C,O-, and 1,3-N,N-binucleophiles and
demonstrated the synthetic potential of these reactions for obtaining various trifluoromethyl-containing five-
and six-membered heterocycles [6-10]. This allowed us to propose an original approach to the molecular design
of biologically active amides and amines.
The aim of this work was to study the cyclocondensation reactions of our previously synthesized MTFP
N-(pyrimidin-2-yl)imines [11] with 1,3-binucleophilic reagents: N-substituted ureas, N-benzylbenzamidine,
2-aminothiazoline, methyl 3-aminocrotonate, and 6-aminouracils. It should be noted that the 2-aminopyrimidine
pharmacophoric fragment occurs in the structures of diverse biologically active compounds including, for
example, inhibitors of dihydrofolate reductase [12], tyrosine kinase [13], and protein kinases [14].
_______
*To whom correspondence should be addressed, e-mail: alaks@ipac.ac.ru.
1Institute of Physiologically Active Compounds, the Russian Academy of Sciences, 1 Severnyi Proezd, 142432
Chernogolovka, Russia.
________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 468-473, March, 2013. Original
article submitted April 23, 2012.
0009-3122/13/4903-0435©2013 Springer Science+Business Media New York
435

We have shown that the MTFP N-(pyrimidin-2-yl)imines behaved as 1,2-bielectrophiles in the
examined reactions and reacted with the aforementioned 1,3-N,N- and 1,3-C,N-binucleophiles in two stages.
The binucleophile at first added to the C=N bond, followed by heterocyclization with elimination of methanol.
In the case of MTFP N-(pyrimidin-2-yl)imine (1a) reaction with N-benzylurea (2a) we isolated the amide 3 as
the addition product, heating of which for 2 h in DMF at 80°C in the presence of a catalytic amount of
triethylamine gave the imidazolidine-2,4-dione 4a.
N
CF3
N
H2NCONHCH2Ph
+
DMF, 20°C
N
N
CO2Me
2a
1a
CF3
CF3
NH
N
NH
NH
Et3N
NHCONHCH2Ph
N
DMF, 80°C
N
O
N
O
CO2Me
CH2Ph
3
4a
The imidazolidine-2,4-diones 4b-d were prepared without isolation of the intermediate addition
products (type 3 amides) by heating equimolar amounts of the reagents in DMF in the presence of catalytic
amounts of Et3N.
H2NCONHR1
CF3
R
N
2a–c
Et3N
H
N
NH
N
O
N
R1
O
HN
HN
4a–d
Ph
CF3
R
N
CH2Ph
H
N
N
5
N
O
N
Ph
8a,b
S
CH2Ph
H2N
Me
N
CF3
N
N
N
CF3
6
R
H
N
N
N
DMF
80°C
N
CO2Me
O
N
S
CO2Me
Me
R
1a–c
9
H2N
Me
O
CF3
N
CO2Me
7
H
N
N
O
N
Me
O
H
10a,b
NH
H2N
N
R2
CF3
O
N
R
H
N
NH
11a,b
N
O
N
N
R2
O
Et3N
12a–c
H
1a, 4a,b, 8a, 10a, 12a,b R = H, 1b, 4c, 8b, 10b, 12c R = 4,6-Me2, 1c, 4d R = 5-Br;
2a, 4a,c R1 = CH2Ph, 2b, 4d R1 = Me, 2c, 4b R1 = CH2CH2Ph;
11a, 12a R2 = CH2CH2Ph, 11b, 12b,c R2 = 2-furylmethyl
436

The N-benzylbenzamidine (5), 2-aminothiazoline (6), and methyl 3-aminocrotonate (7) reacted
exothermically with the MTFP N-(pyrimidin-2-yl)imines 1a-c without a catalyst to form the 3,5-di-
hydroimidazol-4-ones 8a,b, the 2,3-dihydro-6H-imidazo[2,1-d]thiazol-5-one 9, and the 4,5-dihydro-1H-pyrroles
10a,b. Complete heterocyclization required heating for 1 h at 80°C. The less nucleophilic 6-aminouracils 11a,b
reacted with the MTFP N-(pyrimidin-2-yl)imines 1a,b when heated for 2 h in DMF at 80°C in the presence of
catalytic amounts of Et3N, to give the 5,7-dihydro-1H-pyrrolo[2,3-d]pyrimidine-2,4,6-triones 12a-c.
The synthesized compounds 4a-d, 8a,b, 9, 10a,b, and 12a-d were solid, colorless crystals, the
1
composition and structure of which were confirmed by elemental analysis and by H and 19F NMR
spectroscopy.
Hence, the examined cyclocondensation reactions of MTFP N-(pyrimidin-2-yl)imines with 1,3-N,N-
and 1,3-C,N-binucleophiles allowed the functionalization of pharmaceutically significant 2-aminopyrimidines
with trifluoromethyl-containing five-membered heterocycles.
EXPERIMENTAL
1
The H and 19F NMR spectra were recorded on a Bruker DPX-200 instrument (200 and 188 MHz,
respectively) using DMSO-d6 relative to TMS as internal standard and CF3COOH as external standard,
respectively. Elemental analysis was performed on a vario MICRO cube CHNS/O analyzer. Melting points
were determined in glass capillaries on a Manual Mel-Temp instrument. The N-(pyrimidin-2-yl)imines 1a-c
were synthesized by method [11]. The N-substituted ureas 2a-c, N-benzylbenzamidine (5), 2-aminothiazoline
(6), methyl 3-aminocrotonate (7), and 6-aminouracils 11a,b (Sigma-Aldrich) were used without preliminary
purification.
Methyl 2-(3-Benzylcarbamoylamino)-2-(pyrimidin-2-ylamino)-3,3,3-trifluoropropionate (3). Urea
2a (1.50 g, 10 mmol) was added to a solution of the imine 1a (2.33 g, 10 mmol) in DMF (20 ml). The reaction
mixture was stirred for 2 h at 20°C, poured into water, and the precipitate formed was filtered off and
recrystallized from 50% ethanol. Yield 3.50 g (90%). Mp 102-104°C. 1H NMR spectrum, , ppm (J, Hz): 3.82
(3H, s, CH3); 4.06-4.22 (2H, m, CH2); 6.61 (1H, t, J = 4.7, H Ar); 7.20-7.41 (5H, m, H Ph); 7.89 (2H, d, J = 4.7,
H Ar); 8.06 (1H, t, J = 5.1, NH); 8.79 (1H, s, NH); 9.13 (1H, s, NH). 19F NMR spectrum, , ppm: 2.51 (s).
Found, %: С 50.31; H 4.39; N 18.42. C16H16F3N5O3. Calculated, %: С 50.13; Н 4.21; N 18.27.
3-Benzyl-5-(pyrimidin-2-ylamino)-5-(trifluoromethyl)imidazolidine-2,4-dione (4a). A. Et3N (0.1 g,
0.1 mmol) was added to a solution of compound 3 (1.9 g, 5.0 mmol) in DMF (10 ml). The reaction mixture was
heated at 80°C for 2 h, poured into water, the precipitate formed was filtered off and recrystallized from 50%
ethanol. Yield 1.5 g (85%).
B. Urea 2a (0.75 g, 5.0 mmol) was added to a solution of imine 1a (1.17 g, 5.0 mmol) in DMF (20 ml).
The reaction mixture was stirred for 2 h at 20°C and treated with Et3N (0.1 g, 0.1 mmol). The reaction mixture
was then heated at 80°C for 2 h, poured into water, and the precipitate formed was filtered off and recrystallized
from 50% ethanol. Yield 1.40 g (80%). Mp 134-135°C. 1H NMR spectrum, , ppm (J, Hz): 4.67 (2H, s, CH2);
6.67 (1H, t, J = 4.8, H Ar); 7.27-7.48 (5H, m, H Ph); 7.93 (2H, d, J = 4.8, H Ar); 8.79 (1H, s, NH); 9.13 (1H, s,
NH). 19F NMR spectrum, , ppm: -0.11 (s). Found, %: С 51.10; H 3.26, N 20.11. C15H12F3N5O2. Calculated, %:
С 51.29; Н 3.44; N 19.94.
3-(2-Phenylethyl)-5-(pyrimidin-2-ylamino)-5-trifluoromethylimidazolidine-2,4-dione (4b). Prepared
similarly to compound 4a (method B) from the imine 1a (1.2 g, 5 mmol) and the urea 2c (0.8 g, 5 mmol). Yield
1
1.6 g (88%). Mp 123-124°C. H NMR spectrum, , ppm (J, Hz): 2.98 (2H, t, J = 7.7, CH2); 3.65-3.75 (2H, m,
CH2); 6.80 (1H, t, J = 5.1, H Ar); 7.14-7.38 (5H, m, H Ph); 8.34 (2H, d, J = 5.1, H Ar); 8.82 (1H, s, NH); 9.08
(1H, s, NH). 19F NMR spectrum, , ppm: -0.22 (s). Found, %: С 52.40; H 3.68, N 19.33. C16H14F3N5O2.
Calculated, %: С 52.61; Н 3.86; N 19.17.
437

3-Benzyl-5-(4,6-dimethylpyrimidin-2-ylamino)-5-(trifluoromethyl)imidazolidine-2,4-dione
(4c).
Prepared similarly to compound 4a (method B) from the imine 1b (1.30 g, 5 mmol) and the urea 2a (0.75 g,
1
5 mmol). Yield 1.50 g (79%). Mp 135-137°C. H NMR spectrum, , ppm: 2.19 (6H, s, 2CH3); 4.67 (2H, s,
CH2); 6.52 (1H, s, H Ar); 7.25-7.41 (5Н, m, H Ph); 8.48 (1H, s, NH); 9.06 (1H, s, NH). 19F NMR spectrum, ,
ppm: -0.27 (s). Found, %: С 53.66; H 4.42; N 18.29. C17H16F3N5O2. Calculated, %: С 53.83; Н 4.25; N 18.46.
5-(5-Bromopyrimidin-2-ylamino)-3-methyl-5-(trifluoromethyl)imidazolidine-2,4-dione (4d). Obtained
similarly to compound 4a (method B) from the imine 1c (1.6 g, 5 mmol) and the urea 2b (0.37 g, 5 mmol).
Yield 1.4 g (79%). Mp 166-168°C. 1H NMR spectrum, , ppm: 3.01 (3H, s, СН3); 8.43 (2H, s, H Ar); 9.09 (1H,
s, NH); 9.18 (1H, s, NH). 19F NMR spectrum, , ppm: -0.16 (s). Found, %: С 30.35; H 2.22, N 19.94.
C9H7BrF3N5O2. Calculated, %: С 30.53; Н 1.99; N 19.78.
3-Benzyl-2-phenyl-5-(pyrimidin-2-ylamino)-5-trifluoromethyl-3,5-dihydro-4H-imidazol-4-one (8a).
The amidine 5 (1.05 g, 5 mmol) was added to a solution of the imine 1a (1.2 g, 5 mmol) in DMF (20 ml). The
reaction mixture was stirred for 1 h at 20°C, heated at 80°C for 1 h, poured into water, the precipitate was
filtered off, and recrystallized from 50% ethanol. Yield 1.7 g (83%). Mp 177-179°C. 1H NMR spectrum, , ppm
(J, Hz): 4.77 (2H, s, CH2); 6.69 (1H, t, J = 4.7, H Ar); 7.07-7.19 (2H, m, H Ph); 7.21-7.29 (3H, m, H Ph); 7.29-
7.52 (5H, m, H Ph); 8.12 (2H, d, J = 7.3, H Ar); 8.80 (1H, s, NH). 19F NMR spectrum, , ppm: 0.83 (s). Found,
%: С 61.13; H 3.71; N 17.23. C21H16F3N5O. Calculated, %: С 61.31; Н 3.92; N 17.02.
3-Benzyl-5-(4,6-dimethylpyrimidin-2-ylamino)-2-phenyl-5-trifluoromethyl-3,5-dihydroimidazol-
4-one (8b). Obtained similarly to compound 8a from the imine 1b (1.30 g, 5 mmol) and compound 5 (1.05 g,
5 mmol). Yield 1.70 g (77%). Mp 181-182°C. 1H NMR spectrum, , ppm (J, Hz): 2.34 (6H, s, 2СН3); 4.65 (1H,
d, J = 15.1) and 5.12 (1H, d, J = 15.1, CH2); 6.61 (1H, s, H Ar); 7.29 (2H, d, J = 7.3, H Ph); 7.41-7.49 (3H, m,
19
H Ph); 7.52-7.60 (4H, m, H Ph); 7.63-7.71 (1H, m, H Ph); 8.67 (1H, s, NH). F NMR spectrum, , ppm: 0.92
(s). Found, %: С 62.66; H 4.41; N 16.15. C23H20F3N5O. Calculated, %: С 62.87; Н 4.59; N 15.94.
6-(4,6-Dimethylpyrimidin-2-ylamino)-6-trifluoromethyl-2,3-dihydroimidazo[2,1-d][1,3]thiazol-5(6H)-
one (9). Prepared similarly to compound 8a from the imine 1b (1.2 g, 5 mmol) and compound 6 (0.5 g, 5 mmol).
1
Yield 1.2 g (73%). Mp 145-147°C. H NMR spectrum, , ppm: 2.27 (6H, s, 2СН3); 3.09-3.21 (1H, m, CH2);
3.56-3.74 (2H, m, CH2); 3.78-3.88 (1H, m, CH2); 6.56 (1H, s, H Ar); 8.87 (1H, s, NH). 19F NMR spectrum, , ppm:
1.19 (s). Found, %: С 43.33; H 3.83; N 21.36. C12H12F3N5OS. Calculated, %: С 43.50; Н 3.65; N 21.14.
Methyl 2-Methyl-5-oxo-4-(pyrimidin-2-ylamino)-4-trifluoromethyl-4,5-dihydro-1H-pyrrole-3-carb-
oxylate (10a). Obtained similarly to compound 8a from the imine 1a (1.2 g, 5 mmol) and compound 7 (0.6 g,
5 mmol). Yield 1.2 g (76%). Mp 163-164°C. 1H NMR spectrum, , ppm (J, Hz): 2.37 (3H, s, CH3); 3.60 (3H, s,
CH3O); 6.68 (1H, t, J = 5.4, H Ar); 7.56 (1H, s, NH); 8.25 (2H, d, J = 5.4, H Ar); 10.86 (1H, s, NH). 19F NMR
spectrum, , ppm: 3.15 (s). Found, %: C 45.77; H 3.29; N 17.91. C12H11F3N4O3. Calculated, %: C 45.58;
H 3.51; N 17.72.
Methyl 2-Methyl-4-(4,6-dimethylpyrimidin-2-ylamino)-5-oxo-4-trifluoromethyl-4,5-dihydro-1H-
pyrrole-3-carboxylate (10b). Prepared similarly to compound 8a from the imine 1b (1.3 g, 5 mmol) and
1
compound 7 (0.6 g, 5 mmol). Yield 1.2 g (76%). Mp 173-175°C. H NMR spectrum, , ppm: 2.19 (6H, s,
2СН3); 2.32 (3H, s, СН3); 3.58 (3H, s, СН3O); 6.39 (1H, s, H Ar); 7.02 (1H, s, NH); 10.75 (1H, s, NH).
19F NMR spectrum, , ppm: 3.25 (s). Found, %: С 48.66; H 4.15; N 16.08. C14H15F3N4O3. Calculated, %:
С 48.84; Н 4.39; N 16.27.
1-(2-Phenylethyl)-5-(pyrimidin-2-ylamino)-5-trifluoromethyl-5,7-dihydro-1H-pyrrolo[2,3-d]pyrimi-
dine-2,4,6(3H)-trione (12a). The uracil 11a (1.16 g, 5 mmol) was added to a solution of the imine 1a (1.2 g,
5 mmol) in DMF (20 ml). The reaction mixture was stirred for 2 h at 20°C, Et3N (0.1 g, 0.1 mmol) was added.
The mixture was then heated at 80°C for 2 h, poured into water, and the precipitate formed was filtered off and
1
recrystallized from 50% ethanol. Yield 1.6 g (74%). Mp 211-213°C. H NMR spectrum, , ppm (J, Hz): 2.89
(2H, t, J = 5.0, СН2); 3.98-4.12 (2Н, m, СН2); 6.65 (1Н, t, J = 5.0, H Ar); 7.17-7.32 (5H, m, H Ph); 8.25 (2Н, d,
438

19
J = 5.2, H Ar); 8.40 (1Н, s, NH); 10.87 (1Н, s, NH); 12.09 (1Н, s, NH). F NMR spectrum, , ppm: 3.52 (s).
Found, %: С 52.61; H 3.69; N 19.25. C19H15F3N6O3. Calculated, %: С 52.78; Н 3.50; N 19.44.
1-(2-Furylmethyl)-5-(pyrimidin-2-ylamino)-5-trifluoromethyl-5,7-dihydro-1H-pyrrolo[2,3-d]pyri-
midine-2,4,6(3H)-trione (12b). Prepared similarly to compound 12a from the imine 1a (1.2 g, 5 mmol) and the
uracil 11b (1.04 g, 5 mmol). Yield 1.5 g (78%). Mp 223-225°C. 1H NMR spectrum, , ppm (J, Hz): 5.07 (2H,
AB system, J = 18.4, СН2); 6.32-6.44 (2Н, m, H furan); 6.65 (1Н, t, J = 5.0, H Ar); 7.50-7.62 (1Н, m, H furan);
8.18 (2Н, d, J = 5.2, H Ar); 8.35 (1H, s, NH); 10.96 (1H, s, NH); 12.11 (1H, s, NH). 19F NMR spectrum, ,
ppm: 3.61 (s). Found, %: С 47.25; H 2.88; N 20.39. C16H11F3N6O4. Calculated, %: С 47.07; Н 2.72; N 20.58.
1-(2-Furylmethyl)-5-(4,6-dimethylpyrimidin-2-ylamino)-5-trifluoromethyl-5,7-dihydro-1H-pyrrolo-
[2,3-d]pyrimidine-2,4,6(3H)-trione (12c). Prepared similarly to compound 12a from the imine 1b (1.30 g,
5 mmol) and the uracil 11b (1.04 g, 5 mmol). Yield 1.65 g (73%). Mp 231-233°C. 1H NMR spectrum, , ppm:
2.16 (6H, s, 2СН3); 4.99-5.17 (2H, m, CH2); 6.34-6.42 (2Н, m, H furan); 6.45-6.51 (1Н, m, H furan); 7.49 (1Н,
s, H Ar); 7.73 (1H, s, NH); 10.94 (1H, s, NH); 12.06 (1H, s, NH). 19F NMR spectrum, , ppm: 3.64 (s). Found,
%: С 49.34; H 3.22; N 19.02. C18H15F3N6O4. Calculated, %: С 49.55; Н 3.46; N 19.26.
This work was carried out with the financial support from the Department of Chemistry and Material
Sciences of the Russian Academy of Sciences Program "Medicinal Chemistry: Molecular Design of
Physiologically Active Compounds and Drugs".
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