Construction of a pyrido[4,3-d]pyrimidine system on the basis of N-cyanobenzamidine and diethyl acetone-1,3-dicarboxylate

Article abstract of DOI:10.1007/s11172-007-0361-0

Nickel acetate promoted reaction of diethyl acetone-1,3-dicarboxylate with N-cyanobenzamidine led to ethyl 4-amino-6-ethoxycarbonylmethyl-2- phenylpyrimidine-5-carboxylate, upon treatment of which with RNH₂, the corresponding 6-(carbamoylmethyl)pyrimidines were obtained. Cyclization of the latter upon treatment with MeONa afforded 6-R-4-amino-7-hydroxy-2- phenylpyrido[4,3-d]pyrimidin-5(6H)-ones.

Full text of DOI:10.1007/s11172-007-0361-0

Russian Chemical Bulletin, International Edition, Vol. 56, No. 11, pp. 2290—2292, November, 2007
2290
Construction of a pyrido[4,3ꢀd]pyrimidine system on the basis
of Nꢀcyanobenzamidine and diethyl acetoneꢀ1,3ꢀdicarboxylate
A. V. Komkov and V. A. Dorokhovꢀ
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: vador@ioc.ac.ru
Nickel acetate promoted reaction of diethyl acetoneꢀ1,3ꢀdicarboxylate with Nꢀcyanoꢀ
benzamidine led to ethyl 4ꢀaminoꢀ6ꢀethoxycarbonylmethylꢀ2ꢀphenylpyrimidineꢀ5ꢀcarboxyꢀ
late, upon treatment of which with RNH2, the corresponding 6ꢀ(carbamoylmethyl)pyrimidines
were obtained. Cyclization of the latter upon treatment with MeONa afforded 6ꢀRꢀ4ꢀaminoꢀ
7ꢀhydroxyꢀ2ꢀphenylpyrido[4,3ꢀd]pyrimidinꢀ5(6Н )ꢀones.
Key words: Nꢀcyanobenzamidine, diethyl acetoneꢀ1,3ꢀdicarboxylate, nickel acetate, ethyl
4ꢀaminoꢀ6ꢀethoxycarbonylmethylꢀ2ꢀphenylpyrimidineꢀ5ꢀcarboxylate, 6ꢀalkylꢀ4ꢀaminoꢀ7ꢀ
hydroxyꢀ2ꢀphenylpyrido[4,3ꢀd]pyrimidinꢀ5(6H )ꢀones, heterocyclization.
Scheme 1
Nickel salts and complexes promote addition of
the methyleneꢀactive βꢀdicarbonyl compounds at the
С≡N bond of cyanamides.1—4 In particular, it was found
that βꢀdiketones and βꢀketoesters react with Nꢀcyanoꢀ
amidines in the presence of Ni(OAc)2 to form 5ꢀacylꢀ4ꢀ
aminopyrimidines and 4ꢀaminopyrimidineꢀ5ꢀcarboxylic
acid esters, respectively.5—7 These pyrimidines with the
vicinal functional groups were shown to be convenient
starting compounds for the construction of bicyclic sysꢀ
tems by the annulation of the second nitrogenꢀcontaining
ring. Thus, for example, we proposed various versions
for the synthesis of pyrido[2,3ꢀd]pyrimidine derivatives,
starting from 2,6ꢀdisubstituted 5ꢀacetylꢀ4ꢀaminopyrimiꢀ
dines.6—9
Recently,10 we also showed that the nickel acetylꢀ
acetonate catalyzed addition of acetoneꢀ1,3ꢀdicarboxylic
acid esters to cyanoamide resulted in the heterocycliꢀ
zation, which led to 2ꢀaminoꢀ4ꢀhydroxyꢀ6ꢀoxoꢀ1,6ꢀ
dihydropyridineꢀ3ꢀcarboxylic acid esters.
In the present paper, the reaction of diethyl acetoneꢀ
1,3ꢀdicarboxylate (1) with Nꢀcyanobenzamidine (2) was
studied. The heating of excess diester 1 with amidine 2 in
the presence of equimolar (relatively to the latter) amount
of Ni(OAc)2 (Scheme 1) afforded ethyl 4ꢀaminoꢀ6ꢀ
ethoxycarbonylmethylꢀ2ꢀphenylpyrimidineꢀ5ꢀcarboxyꢀ
late (4). The analytically pure pyrimidine 1 was isolated
by column chromatography and recrystallization of the
residue from EtOH.
Obviously, similarly to the reaction with cyanamide,
the Ni salt promoted addition of ketodiester 1 at the
С≡N bond of cyanoamidine 2 initially takes place to form
adduct 3. However, the intramolecular cyclization of the
latter proceeds with elimination of water, rather than of
ethanol, and leads to the pyrimidine ring closure (simiꢀ
larly to the transformations of cyanoamidines with acetоꢀ
acetic and benzoylacetic acid esters5), rather than pyriꢀ
dine one (as in the reaction of ketodiester 1 with cyanꢀ
amide10). Thus, the functionally substituted pyrimidine 4,
rather than pyridine 5, was obtained.
The crystalline compound 4 is well soluble in chloroꢀ
form, benzene, and acetone, moderately in alcohols, and
poorly in petroleum ether. Its structure was confirmed by
spectroscopy data (mass, IR, and 1Н NMR spectra). Thus,
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2212—2214, November, 2007.
1066ꢀ5285/07/5611ꢀ2290 © 2007 Springer Science+Business Media, Inc.

Construction of pyrido[4,3ꢀd]pyrimidines
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007 2291
in the mass spectrum of pyrimidine 4, there is a peak of
the molecular ion, in the IR spectrum recorded in CHCl3,
absorption bands of the two carbonyl groups (1736 and
1688 cm–1), as well as of the NH2 group (3508 and
substances yellowish in color, poorly soluble in most orꢀ
ganic solvents, but soluble in DMSO under heating. The
structures of compounds 6а,b and 7а,b were confirmed by
1
spectroscopy methods (IR, mass, and Н NMR spectra).
1
3376 cm–1) are observed, and its Н NMR spectrum reꢀ
In the mass spectra of these heterocycles, molecular ions
are observed. In the IR spectra of amides 6а,b in CHCl3,
there is no absorption in the region ~1740 cm–1, characꢀ
teristic of the carbonyl group of the ethoxycarbonylmethyl
fragment of the starting reagent 4. Absorption bands of
the carbonyl groups of the CONH and COOEt fragments
(in position 5 of pyrimidine ring) virtually coincide and
are observed in the region 1680—1685 cm–1. Contrary to
this, in the IR spectra recorded in KBr, the two bands are
observed: 1684 and 1648 cm–1. In the 1Н NMR spectra of
compounds 6а,b, there is a set of signals of only one
ethoxycarbonyl group. As for the IR spectra of pyridoꢀ
pyrimidines 7а and 7b in KBr or in Nujol, absorption
band of the carbonyl group with frequencies of 1672
and 1676 cm–1, respectively, is characteristic of them.
corded in CDCl3 is characterized by the presence of sigꢀ
nals of the two COOEt groups (two triplets at 1.27 and
1.39 ppm; two quartets at 4.19 and 4.36 ppm), a singlet of
the СН2 group at 4.13 ppm, and a very broad signal of the
NH2 group at 5.90 ppm
The oneꢀstep synthesis of this new derivative of pyriꢀ
midineꢀ5ꢀcarboxylic acid, presented in this work, despite
of the moderate yield (32%) of the target product, is noꢀ
table for the availability of the starting compounds. Moreꢀ
over, the presence of the amino group and the ethoxyꢀ
carbonylmethyl fragment in adjacent positions to the
ethoxycarbonyl group in pyrimidine 4 allows one to conꢀ
sider it as the prospective reagent for the construction of
bicyclic systems. To confirm this, we show a scheme for
the construction of pyrido[4,3ꢀd]pyrimidine system,
based on compound 4. It is known that one of the princiꢀ
pal approaches to pyrido[4,3ꢀd]pyrimidines consists in
the annulation of pyridine ring to the corresponding
functionally substituted pyrimidines (see, for example,
Refs 11—13). We found that, when diester 4 is treated
with primary amines (for example, benzylamine or butylꢀ
amine), the CH2СOOEt fragment selectively participates
in the reaction to yield pyrimidinylacetamides 6а,b, treatꢀ
ment of which with the boiling solution of MeONa
in MeOH leads to the pyridine ring closure to form
6ꢀRꢀ4ꢀaminoꢀ7ꢀhydroxyꢀ2ꢀphenylpyrido[4,3ꢀd]pyrimiꢀ
dineꢀ5(6Н )ꢀones 7а,b (Scheme 2).
1
In the Н NMR spectra of these bicyclic compounds in
DMSOꢀd6, there are no signals of protons of ethoxyꢀ
carbonyl groups, rather a singlet of the Н(8) proton at
5.33—5.39 ppm, two broad signals of two protons of the
NH2 group (at 8.38—8.49 and 9.33—9.42 ppm), as well as
a broad signal of the ОН group (at 12.05—12.18 ppm) are
observed.
It is known that some substituted 4ꢀaminopyriꢀ
do[4,3ꢀd]pyrimidines inhibit tyrosinekinase14 and derivaꢀ
tives of pyrido[4,3ꢀd]pyrimidineꢀ5(6Н )ꢀone have antiꢀ
hypertensive15 and antiallergic properties.16 The syntheꢀ
sized by us compounds of the type 7, apparently, can be
modified by transformations at the unsubstituted amino
group, which seems significant for further quest of biologiꢀ
cally active compounds in pyrido[4,3ꢀd]pyrimidine series.
Scheme 2
Experimental
1
Н NMR spectra were recorded on a Bruker WMꢀ250 specꢀ
trometer, IR spectra were recorded on a SpecordꢀM80 specꢀ
trometer, mass spectra were recorded on a Kratos MSꢀ30 instruꢀ
ment (EI, 70 eV; the ionizing chamber temperature, 250 °С;
direct inlet of a substance).
Ethyl 4ꢀaminoꢀ6ꢀethoxycarbonylmethylꢀ2ꢀphenylpyrimidineꢀ
5ꢀcarboxylate (4). A mixture of cyanoamidine 2 (0.2 g,
1.38 mmol) and Ni(OAc)2 (0.24 g, 1.38 mmol) in diethyl acꢀ
etoneꢀ1,3ꢀdicarboxylate (1) (1 mL, 5.50 mmol) was heated for
5 h at 125—135 °С, cooled to ~20 °С, benzene (2 mL) was added
to this, and the residue was subjected to column chromatoꢀ
graphy on SiO2 (eluent: benzene). The solvent was evaporated
in vacuo, light petroleum (5 mL) was added to the residue,
crystals formed were filtered off and recrystallized from EtOH
(3 mL) to obtain compound 4 (0.217 g, 32%) as white crystals,
m.p. 133—134°С. Found (%): С, 61.88; Н, 5.95; N, 12.58.
С17Н19N3O4. Calculated (%): С, 61.99; Н, 5.81; N, 12.76. MS,
m/z (Irel (%)): 329 [M]+ (15), 284 [M – OEt]+ (10), 257
[M – C2H4 – CO2]+ (33), 185 [M – 2C2H4 – 2CO2]+ (100),
104 [PhC=NH]+ (56). IR (CHCl3), ν/cm–1: 3508, 3376 (NH2);
R = PhCH2 (a), Bu (b)
i. RNH2, 1,4ꢀMe2C6H4, ∆; ii. MeONa, MeOH, ∆.
Amides 6а,b are white crystalline substances, poorly
soluble in aromatic hydrocarbons and alcohols and well
soluble in CHCl3. Pyridopyrimidines 7а,b are crystalline

2292
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007
Komkov and Dorokhov
1
1736 (CO); 1688 (CO); 1596, 1552. H NMR (СDCl3), δ: 1.27
(t, 3 Н, MeCH2, J = 6.8 Hz); 1.39 (t, 3 Н, МеСН2, J = 6.8 Hz);
4.13 (s, 2 Н, CH2); 4.19 (q, 2 Н, CH2Ме, J = 6.8 Hz); 4.36 (q,
2 Н, CH2Ме, J = 6.8 Hz); 5.90 (br.s, NH2); 7.46 (m, 3 Н, Ph);
8.40 (m, 2 Н, Ph).
[M – C4H9NН]+ (68), 211 [M – C4H9NCO]+ (92), 185
[M – С4Н9NCO – C2H2]+ (10), 104 [PhC=NH]+ (91).
IR (KBr), ν/cm–1: 3296 (NH); 3160, 3128, 3060, 2952, 2872,
1672 (СО); 1616, 1580, 1560, 1508. 1H NMR (DMSOꢀd6), δ:
0.90 (t, 3 Н, Me, J = 6.8 Hz); 1.30 (m, 2 Н, CH2); 1.52 (m, 2 Н,
CH2); 3.89 (t, 2 Н, CH2N, J = 6.8 Hz); 5.33 (s, 1 Н, H(8)); 7.62
(m, 3 Н, Ph); 8.09 (m, 2 Н, Ph); 8.38, 9.42 (both br.s, 1 Н each,
NH2); 12.05 (br.s, 1 Н, ОН).
Ethyl 4ꢀaminoꢀ6ꢀbenzylcarbamoylmethylꢀ2ꢀphenylpyrimidineꢀ
5ꢀcarboxylate (6а). A mixture of diester 4 (0.33 g, 1 mmol) and
benzylamine (0.87 mL, 8 mmol) in pꢀxylene (7 mL) was reꢀ
fluxed for 5 h and kept for 12 h at 20 °С. The precipitate formed
was filtered off and washed with light petroleum to obtain comꢀ
pound 6а (0.13 g, 34%), m.p. 192—193 °С. Found (%): С, 67.65;
Н, 5.98; N, 14.00. С22Н22N4O3. Calculated (%): С, 67.68;
Н, 5.68; N, 14.35. MS, m/z (Irel (%)): 390 [M]+ (31), 257 [M –
PhCH2NCO]+ (56), 185 [M – PhCH2NCO – C2H4 – CO2]+
(100), 104 [PhC=NH]+ (44). IR (CHCl3), ν/cm–1: 3508, 3376
(NH2); 1680 (CO); 1596, 1552, 1524. IR (Nujol), ν/cm–1: 3420,
3400, 3288, 3188, 1684 (СО); 1648 (CO); 1632, 1548, 1536.
1H NMR (СDCl3), δ: 1.42 (t, 3 Н, MeCH2, J = 6.8 Hz); 4.11 (s,
2 Н, CH2); 4.41 (q, 2 Н, CH2Ме, J = 6.8 Hz); 4.48 (d, 2 Н,
CH2Ph, J = 5.0 Hz); 7.02 (br.s, 1 Н, NH); 7.27 (s, 5 Н, PhСН2);
7.45 (m, 3 Н, Ph); 8.30 (m, 2 Н, Ph).
This work was financially supported by the Russian
Academy of Sciences (the Presidium of RAS Program for
Basic Research "Development of Methodology of Orꢀ
ganic Synthesis and Creation of Compounds with Valuꢀ
able Applied Properties").
References
1. V. A. Dorokhov, M. F. Gordеev, and Z. K. Demyanets, in
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Amsterdam, 1988, p. 253.
Ethyl 4ꢀaminoꢀ6ꢀbutylcarbamoylmethylꢀ2ꢀphenylpyrimidineꢀ
5ꢀcarboxylate (6b). A mixture of diester 4 (0.165 g, 0.5 mmol)
and butylamine (0.90 mL, 9.0 mmol) in pꢀxylene (4 mL) was
refluxed for 12 h and kept for 12 h at 20 °С. The precipitate
formed was filtered off and washed with petroleum ether to obꢀ
tain compound 6b (0.075 g, 42%), m.p. 166—167 °С. Found (%):
С, 63.92; Н, 7.01; N, 15.34. С19Н24N4O3. Calculated (%):
С, 64.03; Н, 6.79; N, 15.72. MS, m/z (Irel (%)): 356 [M]+ (8),
284 [M – C4H9NН]+ (35), 257 [M – C4H9NCO]+ (27), 238
[M – C4H9NH – C2H5OH]+ (33), 211 [M – C4H9NCO –
C2H5OH]+ (27), 185 [M – C4H9NCO – C2H4 – CO2]+ (100).
IR (CHCl3), ν/cm–1: 3508, 3372 (NH2); 1684 (CO); 1596, 1552.
IR (KBr), ν/cm–1: 3408, 3292, 3184, 1684 (СО); 1648 (CO);
1624, 1552, 1528. 1H NMR (DMSOꢀd6), δ: 0.83 (t, 3 Н, MeCH2,
J = 6.8 Hz); 1.30 (t, 3 Н, MeCH2O, J = 6.8 Hz); 1.20—1.48 (m,
4 Н, 2 CH2); 3.10 (m, 2 Н, CH2N); 3.90 (s, 2 Н, СН2СО); 4.18
(q, 2 Н, CH2О, J = 6.8 Hz); 7.40—7.58 (m, 5 Н, 3 Н—Ph
and NH2); 7.78 (br.s, 1 Н, NH); 8.32 (m, 2 Н, Ph).
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4ꢀAminoꢀ6ꢀbenzylꢀ7ꢀhydroxyꢀ2ꢀphenylpyrido[4,3ꢀd]pyriꢀ
midinꢀ5(6Н )ꢀone (7а). A mixture of amide 6а (0.13 g, 0.33 mmol)
and MeONa (0.66 mmol) in MeOH (10 mL) was refluxed until
complete dissolution (10 min), cooled to 20 °С, and acidified
with АсОН. The precipitate formed was filtered off and washed
with MeOH (15 mL) to obtain pyridopyrimidine 7а (0.10 g,
87%), m.p. >360 °С. Found (%): С, 69.60; Н, 4.87; N, 15.90.
С
20Н16N4O2. Calculated (%): С, 69.75; Н, 4.68; N, 16.27. MS,
m/z (Irel (%)): 344 [M]+ (50), 316 [M – CO]+ (15), 315
[M – CO – H]+ (20), 211 [M – PhCH2NCO]+ (23), 185
[M – PhCH2NCO – C2H2]+ (100). IR (Nujol), ν/cm–1: 3300
(NH); 3200—3000 (NH, OH, CH); 1676 (СО); 1616, 1592,
1580, 1568, 1508. 1H NMR (DMSOꢀd6), δ: 5.08 (s, 2 Н, CH2);
5.39 (s, 1 Н, H(8)); 7.24 (m, 5 Н, PhСН2); 7.62 (m, 3 Н, Ph);
8.09 (m, 2 Н, Ph); 8.49, 9.33 (both br.s, 1 Н each, NH2); 12.18
(br.s, 1 Н, ОН).
11. T. Sakamoto, Y. Kondo, and H. Yamanaka, Chem. Pharm.
Bull., 1982, 30, 2410.
12. A. Wada, S. Hirai, and M. Hanaoka, Chem. Pharm. Bull.,
1991, 39, 1189.
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cycles, 1998, 47, 871.
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4ꢀAminoꢀ6ꢀbutylꢀ7ꢀhydroxyꢀ2ꢀphenylpyrido[4,3ꢀd]pyrimidinꢀ
5(6Н )ꢀone (7b). The product was synthesized similarly to comꢀ
pound 7а from amide 6b and MeONa in MeOH. The yield was
92%, m.p. >360 °С. Found (%): С, 65.58; Н, 5.97; N, 17.76.
С17Н18N4O2. Calculated (%): С, 65.79; Н, 5.85; N, 18.05. MS,
m/z (Irel (%)): 310 [M]+ (27), 254 [M – C4Н8]+ (100), 238
Received October 18, 2007