Intramolecular heterocyclization of N-(pyrimidin-2-yl)imines of methyl trifluoropyruvate

Article abstract of DOI:10.1007/s11172-009-0198-9

The reactions of N-(pyrimidin-2-yl)imines of methyl trifluoropyruvate with trimethyl phosphite afforded methyl 3-fluoroimidazo[1, 2-a]pyrimidin-2- carboxylates, which were transformed into V-substituted methyl 3-aminoimidazo[1, 2-a]pyrimidine-2-carboxylates by the reactions with amines.

Full text of DOI:10.1007/s11172-009-0198-9

Russian Chemical Bulletin, International Edition, Vol. 58, No. 7, pp. 1476—1448, July, 2009
1476
Intramolecular heterocyclization
of Nꢀ(pyrimidinꢀ2ꢀyl)imines of methyl trifluoropyruvate
V. B. Sokolov and A. Yu. Aksinenko
Institute of Physiologically Active Compounds, Russian Academy of Sciences,
1 Severnyi proezd, 142432 Chernogolovka, Moscow Region, Russian Federation.
Fax: +7 (496) 524 9508. Eꢀmail: alaks@ipac.ac.ru
The reactions of Nꢀ(pyrimidinꢀ2ꢀyl)imines of methyl trifluoropyruvate with trimethyl phosꢀ
phite afforded methyl 3ꢀfluoroimidazo[1,2ꢀa]pyrimidinꢀ2ꢀcarboxylates, which were transformed
into Nꢀsubstituted methyl 3ꢀaminoimidazo[1,2ꢀa]pyrimidineꢀ2ꢀcarboxylates by the reactions
with amines.
Key words: 2ꢀaminopyrimidines, methyl trifluoropyruvate, Nꢀ(pyrimidinꢀ2ꢀyl)imines of
methyl trifluoropyruvate, trimethylphosphite, methyl 3ꢀfluoroimidazo[1,2ꢀa]pyrimidineꢀ2ꢀ
carboxylates, Nꢀsubstituted methyl 3ꢀaminoimidazo[1,2ꢀa]pyrimidineꢀ2ꢀcarboxylates, amines,
heterocyclization, nucleophilic substitution.
Scheme 1
The rational synthesis of heterocycles by intramolecuꢀ
lar reactions of carbenoid systems is an important probꢀ
lem of organic chemistry in spite of the wellꢀdeveloped
methodology for these transformations. The aim of the
present study was to extend this approach to the synthesis
of derivatives of 3ꢀfluoroimidazo[1,2ꢀa]pyrimidineꢀ2ꢀcarꢀ
boxylic acids, whose unfluorinated representatives belong
to an interesting class of biologically active compounds.1—5
The present study was based on our previous research6
on the intramolecular cyclization of 2ꢀpyridylimines of
methyl trifluoropyruvate (MTFP) with trimethyl phosꢀ
phite giving imidazo[1,2ꢀa]pyridineꢀ2ꢀcarboxylates, as
well as on the data on the heterocyclization of acylimines
of hexafluoroacetone with tin dichloride7—12 and zinc13,14
yielding fluorineꢀcontaining oxazoles. All these transforꢀ
mations were accompanied by the defluorination of the
trifluoromethyl group.
The purpose of the present study was to examine the
possibility of performing the defluorocyclization of the
previously unknown Nꢀ(pyrimidinꢀ2ꢀyl)imines of MTFP
(Scheme 1).
R = H (2а,3a); 4,6ꢀMe2 (2b,3b); R = H (5a); 5,7ꢀMe2 (5b)
The successive addition of methyl trifluoropyruvate (1),
pyridine, and SOCl2 in benzene to a suspension of 2ꢀamiꢀ
nopyrimidines 2а,b (20 °C, the reaction time was 1.5—2 h)
afforded Nꢀ(pyrimidinꢀ2ꢀyl)imines of MTFP 3а,b in 78
and 71% yields, respectively. The 19F NMR spectra of
imines 3a,b show characteristic singlets for the trifluoroꢀ
methyl group at δ 7.68 and 7.81. Imines 3a,b thus syntheꢀ
sized undergo the cyclization to give methyl 3ꢀfluoroimidꢀ
azo[1,2ꢀa]pyrimidineꢀ2ꢀcarboxylates 5a,b under reflux
in acetonitrile with an equimolar amount of trimethyl
phosphite 4.
Crystalline compounds 5a,b were synthesized in 82
and 76% yields, respectively. Their compositions and
structures were established by 1H and 19F NMR spectrosꢀ
copy. The 19F NMR spectra of compounds 5a,b have
a characteristic singlet at δ –63.70 for 5a and a characterꢀ
istic quartet at δ –58.22 for 5b.
The fluorine atom at position 3 of the imidazole ring
proved to be reactive with respect to nucleophiles. Thus
the refluxing of compound 5a in acetonitrile with two
equivalents of benzylꢀ and 2ꢀfurfurylmethylamines 6a,b
leads to the quantitative replacement of the fluorine atom
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1433—1435, July, 2009.
1066ꢀ5285/09/5807ꢀ1476 © 2009 Springer Science+Business Media, Inc.

Nꢀ(Pyrimidinꢀ2ꢀyl)imines
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 7, July, 2009
1477
Methyl 3ꢀfluoroimidazo[1,2ꢀa]pyrimidineꢀ2ꢀcarboxylate (5а).
Trimethyl phosphite 4 (1.24 g, 0.01 mol) was added with stirring
to a solution of 2ꢀpyrimidylimine of methyl trifluoropyruvate 3a
(2.33 g, 0.01 mol) in CH3CN (20 mL). After the completion of
the exothermic reaction, the reaction mixture was refluxed for
1 h, poured into water (50 mL), and neutralized with a 5% K2CO3
solution. The precipitate that formed was filtered off and recrysꢀ
tallized from 50% EtOH. The yield of 5а was 1.6 g (82%),
m.p. 219—221 °C. Found (%): C, 49.01; H, 3.33; N, 21.75.
C8H6FN3O2. Calculated (%): C, 49.24; H, 3.10; N, 21.53.
1H NMR (DMSOꢀd6), δ: 3.87 (s, 3 H, MeO); 7.18 (dt, 1 H,
Jd = 7.7 Hz, Jt =2.3 Hz); 8.65 (t, 1 H, J =2.3 Hz); 8.81 (d, 1 H,
J = 7.7 Hz). 19F NMR (DMSOꢀd6), δ: –63.70 s.
by the alkylamino group and the formation of Nꢀsubstitutꢀ
ed methyl 3ꢀaminoimidazo[1,2ꢀa]pyrimidineꢀ2ꢀcarbꢀ
oxylates 7a,b (Scheme 2).
Scheme 2
Methyl 3ꢀfluoroꢀ5,7ꢀdimethylimidazo[1,2ꢀa]pyrimidineꢀ2ꢀ
carboxylate (5b) was synthesized analogously to compound 5а.
The yield of 5b was 1.7 g (76%), m.p. 203—205 °C. Found (%):
C, 53.59; H, 4.71; N, 18.62. C10H10FN3O2. Calculated (%):
C, 53.81; H, 4.52; N, 18.83. 1H NMR (DMSOꢀd6), δ: 2.47 (s, 3 H,
Me); 2.70 (d, 3 H, Me, J = 4.9 Hz); 3.85 (s, 3 H, MeO); 6.87
(s, 1 H). 19F NMR (DMSOꢀd6), δ: –58.22 (q, J = 4.9 Hz).
Methyl 3ꢀbenzylaminoimidazo[1,2ꢀa]pyrimidineꢀ2ꢀcarboxyꢀ
late (7а). A solution of methyl 3ꢀfluoroꢀ5,7ꢀdimethylimidaꢀ
zo[1,2ꢀa]pyrimidineꢀ2ꢀcarboxylate 5a (1.95 g, 0.01 mol) and
benzylamine 6а (2.2 g, 0.02 mol) in CH3CN (20 mL) was reꢀ
fluxed for 1 h and then poured into water (50 mL). The precipiꢀ
tate that formed was filtered off and recrystallized from 50%
EtOH. The yield of 7а was 2.2 g (78%), m.p. 85—87 °C.
Found (%): C, 64.08; H, 5.21; N, 19.61. C15H14N4O2. Calculatꢀ
R = PhCH2 (6a, 7a); 2ꢀC4H3O—CH2 (6b, 7b)
Crystalline methyl esters 7a,b were synthesized in 78
and 74% yields, respectively. Their compositions and
structures were established by elemental analysis and
1H NMR spectroscopy.
Hence, we developed a synthetic approach to the forꢀ
mation of the imidazopyrimidine system based on the inꢀ
tramolecular heterocyclization of Nꢀ(2ꢀpyrimidyl)imines
of methyl trifluoropyruvate in the reaction with triꢀ
methyl phosphite. The nucleophilic substitution of fluoꢀ
rine in the resulting heterocycles by the amino group ofꢀ
fers broad possibilities for the molecular design of imidꢀ
azo[1,2ꢀa]pyrimidineꢀ2ꢀcarboxylic acids.
1
ed (%): C, 63.82; H, 5.00; N, 19.85. H NMR (DMSOꢀd6), δ:
3.87 (s, 3 H, MeO); 4.74 (d, 2 H, J = 5.8 Hz); 7.15 (dt, 1 H,
Jd = 7.7 Hz, Jt = 2.3 Hz); 7.21—7.49 (m, 6 H, CHAr + NH); 8.78
(t, 1 H, J = 2.3 Hz); 9.28 (d, 1 H, J = 7.7 Hz).
Experimental
Methyl 3ꢀ(furfurylamino)imidazo[1,2ꢀa]pyrimidineꢀ2ꢀcarbꢀ
oxylate (7b) was synthesized analogously to compound 7а.
The yield of 5b was 2.0 g (74%), m.p. 113—115 °C. Found (%):
C, 57.52; H, 4.67; N, 20.81. C13H12N4O3. Calculated (%):
C, 57.35; H, 4,44; N, 20.58. 1H NMR (DMSOꢀd6), δ: 3.87
(s, 3 H, MeO); 4.02 (d, 2 H, J = 5.4 Hz); 6.31 (d, 1 H, J = 7.1 Hz);
6.45 (t, 1 H, J = 7.1 Hz); 7.12 (dt, 1 H, Jd = 7.6 Hz, Jt =2.3 Hz);
7.32 (s, 1 H, NH); 7.62 (d, 1 H, J = 7.1 Hz); 8.75 (t, 1 H, J = 2.3 Hz);
9.31 (d, 1 H, J = 7.6 Hz).
The 1H and 19F NMR spectra were recorded on a Bruker
DPX 200 spectrometer operating at 200.13 and 188.29 MHz
with respect to tetramethylsilane (internal standard) and
CF3COOH (external standard), respectively, in CDCl3 (3a,b)
and DMSOꢀd6 (5a,b and 7a,b). The melting points were deterꢀ
mined in glass capillaries. Methyl trifluoropyruvate 1, 2ꢀaminoꢀ
pyrimidines 2a,b, trimethyl phosphite 4, and amines 6a,b (Aldꢀ
rich) were used without preliminary purification.
Methyl 2ꢀ(pyrimidinꢀ2ꢀylimino)ꢀ3,3,3ꢀtrifluoropropionate
(3а). Methyl trifluoropyruvate (1) (15.6 g, 0.1 mol), pyridine
(15.6 g, 0.2 mol), and SOCl2 (12.0 g, 0.1 mol) were successiveꢀ
ly added to a suspension of 2ꢀaminopyrimidine (2a) (9.5 g,
0.1 mol) in benzene. The reaction mixture was stirred for 2 h
and filtered. The filtrate was concentrated, and the residue
was fractionated by distillation in vacuo. The yield of imine 3a
was 18.1 g (78%), b.p. 95—96 °C (2 Torr). Found (%): C, 41.47;
H, 2.32; N, 18.28. C8H6F3N3O2. Calculated (%): C, 41.21;
H, 2.59; N, 18.02. 1H NMR (CDCl3), δ: 3.77 (s, 3 H, MeO); 7.23
(t, 1 H, J = 4.7 Hz); 8.73 (d, 2 H, J = 4.7 Hz). 19F NMR
(CDCl3), δ: 7.68 s.
This study was financially supported by the Russian
Foundation for Basic Research (Project No. 08ꢀ03ꢀ00793ꢀa).
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Received December 29, 2008