Synthesis of new trichloromethyl- and alkoxy-substituted pyrido[2,3-d]pyrimidine derivatives

Article abstract of DOI:10.1007/s11172-019-2394-6

A series of new trichloromethyl- and alkoxy-substituted pyrido[2,3-d]pyrimidine derivatives were obtained from trichloromethyl-substituted pyrimidines with vicinal amino and acyl groups synthesized based on the reaction of trichloroacetonitrile with β-dik

Full text of DOI:10.1007/s11172-019-2394-6

Russian Chemical Bulletin, International Edition, Vol. 68, No. 2, pp. 365—373, February, 2019
365
Synthesis of new trichloromethyl- and alkoxy-substituted
pyrido[2,3-d]pyrimidine derivatives*
A. V. Komkov, T. V. Potapova, M. I. Zuev, S. V. Baranin, and Yu. N. Bubnov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Е-mail: svbar@ioc.ac.ru
A series of new trichloromethyl- and alkoxy-substituted pyrido[2,3-d]pyrimidine derivatives
were obtained from trichloromethyl-substituted pyrimidines with vicinal amino and acyl groups
synthesized based on the reaction of trichloroacetonitrile with β-diketone diaminomethylidene
derivatives.
Key words: trichloroacetonitlile, α,α-diacyl ketene aminals, N-acyl-α-acetyl ketene aminals,
amidines, pyrimidines, pyrido[2,3-d]pyrimidines.
In recent years, the design and study of chemical
properties and biological activity of molecules containing
heterocycles bonded directly and through spacers or con-
densed ones became one of the rapidly developing direc-
tions of organic synthesis.1 It should also be noted that
nitrogen-containing heterocyclic compounds are used as
efficient ligands for the preparation of active palladium
catalysts for cross-coupling reactions in aqueous media.2
A great number of articles and reviews have been devoted
in recent years to pyridopyrimidines,3—9 which belong to
the most important class of condensed azaheterocyclic
systems. The interest to these compounds, especially to
pyrido[2,3-d]pyrimidine derivatives, is primarily due to
their very broad spectrum of biological activity, for ex-
ample, anticancer,10—12 antimicrobial,13—15 antiinflam-
matory and analgesic,16,17 hypotensive,18 antihistamine.19
The approaches to the design and the application of
pyrido[2,3-d]pyrimidines are described in detail in a re-
cently published review,20 which includes our works21—24
reporting on the synthesis of substituted pyrido[2,3-d]-
pyrimidines by the annulation of a pyridine ring to
a pyrimidine one containing vicinal amino and acyl
groups.25 Later we reported26 that 4-amino-2-trichloro-
methylpyrimidine-5-carboxylic esters can be obtained by
heating of α-acetyl-α-alkoxycarbonyl ketene aminals with
trichloroacetonitrile in toluene in a sealed tube. In the
present work, in continuation of this research we studied
the reaction of α,α-diacyl- and α-acetyl ketene aminals
with trichloroacetonitrile.
of benzoylcyanamide to β-diketones with subsequent
debenzoylation of adducts 2 (Scheme 1).27
We found that ketene aminal 1а obtained from acetyl-
acetone reacted with trichloroacetonitrile upon reflux in
THF to give pyrimidine 4а in 82% yield. However, ketene
aminals 1b,c synthesized from dibenzoylmethane and
benzoylacetone, respectively, did not give target pyrimid-
ines 4b,c under similar conditions, rather, they were ob-
tained under more drastic conditions (heating of aminals
1b,c with ССl3CN in toluene at 120—130 °C in a sealed
tube). Note that the reaction of ketene aminal 1с synthe-
sized from unsymmetrical diketone (benzoylacetone)
together with heterocycle 4с also gives its isomer pyrimid-
ine 5с in about 4 : 1 ratio (1Н NMR data), i.e., the cycliz-
ation of intermediate 3с can involve both the benzoyl and
the acetyl fragment. Pyrimidine 5с, unlike its isomer 4с,
is poorly soluble in a number of organic solvents (aceto-
nitrile, benzene, toluene), therefore, both isomers 4c and
5c were easily isolated in the individual state.
Earlier,23 pyrimidines 4 were alternatively synthesized
by heating a mixture of N-cyanotrichloroacetamidine 6
with acetylacetone to 130—140 °C in the presence of an
equimolar amount of Ni(OAc)2 (see Scheme 1). However,
such drastic conditions led in both cases to the formation
of a by-product, pyrimidine 7 (~18%), which was isolated
in the individual state in the synthesis of pyrimidine 4b.
The formation of compound 7 can apparently be explained
by the possibility of the 1,3-С≡N migration of the benzoyl
group (Scheme 2).
The starting α,α-diacyl ketene aminals 1а—с were
synthesized by the Ni(acac)2-catalyzed addition reaction
Colorless 2-trichloromethylpyrimidines 4а—с and 7
are well soluble in chloroform, acetone, benzene, toluene
and poorly soluble in light petroleum ether. Their mass
1
spectra contain peaks of molecular ions. Their H NMR
* Dedicated to Corresponding Member of the Russian Academy
of Sciences G. I. Nikishin on the occasion of his 90th birthday.
spectra (CDCl3) exhibit, along with the signals for the Me
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 0365—0373, February, 2019.
1066-5285/19/6802-0365 © 2019 Springer Science+Business Media, Inc.

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Russ. Chem. Bull., Int. Ed., Vol. 68, No. 2, February, 2019
Komkov et al.
Scheme 1
R1 = R2 = Me (a); Ph (b); R1 = Me, R2 = Ph (c)
Reagents and conditions: i. 3—5 mol.% of Ni(acac)2, THF, Δ; ii. MeONa, MeOH, 20 °C; iii. CCl3CN, THF, Δ or toluene, 120—130 °C;
iv. R1COCH2COR2, Ni(OAc)2, 130—140 °C.
Scheme 2
and Ph group protons, broad singlets for the protons of
the NH2 group. The IR spectra (CHCl3) contain absorp-
tion bands in the following regions: 1660—1665 cm–1
(COMe), 1645—1650 cm–1 (COPh), 3495—3505 and
3360—3400 cm–1 (NH2). The structures of isomeric pyr-
imidines 4c and 5c were confirmed by 13C NMR spectra.
Thus, compound 4c has characteristic signals at δ 31.5
(MeCO) and 203.0 (COMe), whereas heterocycle 5с
at δ 22.1 (6-Me) and 195.0 (COPh). In the IR spec-
trum (CHCl3) of benzoylaminopyrimidine 7, absorp-
tion bands are observed at 3400 cm–1 (NH) and
1695 cm–1 (СОN), while its 1H NMR spectrum (CDCl3)
exhibits a singlet at δ 8.88 (H(5)) and a broad singlet at δ
8.80 (NH).
We further found that N-acyl-α-acetyl ketene aminals
8a,b obtained by Co(OAc)2-catalyzed selective C-de-
acetylation of the corresponding diacetyl ketene aminals
2 (see Ref. 28) react with CCl3CN upon reflux in THF.
However, instead of the expected N-acylamino-2-tri-
chloromethylpyrimidines 9a,b this reaction led to 2-methyl-
and 2-phenyl-substituted 5-acetyl-4-amino-6-trichloro-
methylpyrimidine 10a and 10b, respectively, with an ad-
mixture of ~13% of derivative 9b (Scheme 3).
Pyrimidines 10a,b are apparently resulted from the
attack of trichloroacetonitrile on the nucleophilic C atom
of ketene aminals 8a,b, which is accompanied by the
cyclization of intermediates 11a,b involving the acylamide
fragment. The structures of compounds 10a,b were con-

New pyrido[2,3-d]pyrimidine derivatives
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 2, February, 2019
367
Scheme 3
R = Me (a), Ph (b)
Reagents and conditions: i. CCl3CN, THF, Δ.
firmed by IR, H and 13C NMR spectroscopy, and mass
spectrometry (see Experimental). Note that 4-amino-5-
acetylpyrimidines 10a,b and 4а,с are structural isomers in
the position of CCl3 and Me (or Ph) groups in the pyr-
imidine ring. In the 1H NMR spectra (CDCl3) of hetero-
cycles 10a,b, the singlet for the NH2 protons is observed
in the higher field compared to that of pyrimidines 4a,c
(δ 5.58—5.62 for 10a,b and 6.78—6.91 for 4a,с). The IR
spectra (CHCl3) of compounds 10a,b exhibit two sharp
absorption bands of the NH2 group (3510—3512 and
3400—3404 cm–1), whereas pyrimidines 4a,с have one
sharp (3495—3500 cm–1) and one broad band (3360—
3380 cm–1). In addition, a high-frequency shift of the
acetyl carbonyl group is observed for compounds 10a,b
(1688—1690 cm–1 for 10a,b and 1660—1665 cm–1 for
4a,с). These spectral data can be explained by the absence
in pyrimidines 10a,b, in contrast to compounds 4a,c, of
the intramolecular hydrogen bond between the NH2 and
COMe groups, which may be due to the reduced basicity
of the NH2 group. The mass spectra of pyrimidines 10a,b
contain the peaks of molecular ions. The 1H NMR spec-
trum of compound 10b exhibits a low-field value (δ 8.45)
of the signal for the ortho-protons of the Ph group, which
confirms its localization between the nitrogen atoms of the
pyrimidine ring.
[2,3-d]pyrimidine system involves the reaction of pyrimid-
1
ines 4 and 10 with amide acetals and subsequent annula-
tion of the pyridine ring under the action of Na alkoxides.
We used this method previously to obtain pyrido[2,3-d]-
pyrimidine derivatives containing no CCl3 group,22,32, as
well as functionally substituted furazano[2,3-b]naphthyr-
idines33 and thieno[2,3-b;4,5-b´]bipyridine derivatives.34
It was found that pyrimidine 4a readily reacts with
dimethylformamide (DMF) and dimethylacetamide
(DMAA) dimethyl acetals in refluxing benzene to form
amidines 12a,b, which then upon reflux with EtONa in
EtOH undergo cyclization to pyrido[2,3-d] pyrimidinones
13a,b (Scheme 4). The CCl3 group remains intact when
Scheme 4
Note that there are patent data on the possibility of
using a number of 2-trichloromethylpyrimidine derivatives
as fungicides.29—31
The synthesized pyrimidines 4а,с and 10a,b with
vicinal NH2 and COMe groups are convenient blocks for the
preparation of fused heterocyclic systems. Earlier, we have
shown23 that compound 4a reacts with diethyl oxalate in
MeOH in the presence of MeONa to form methyl 4-meth-
yl-5-oxo-2-trichloromethyl-5,8-dihydropyrido[2,3-d]-
pyrimidine-7-carboxylate. Another way to build a pyrido-
R = H (a), Me (b)
Reagents and conditions: i. (MeO)2C(R)NMe2, PhH, Δ;
ii. EtONa, EtOH, Δ or MeONa, MeOH, Δ.

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Russ. Chem. Bull., Int. Ed., Vol. 68, No. 2, February, 2019
Komkov et al.
Scheme 5
Reagents and conditions: i. (MeO)2CНNMe2, PhH, Δ; ii. MeONa, MeOH, Δ.
amidine 12a is refluxed for 6 h with a large excess of
MeONa (20 equiv.) in MeOH; in this case, the yield of
bicyclic compound 13a is 85%.
50—66% yields (see Scheme 6). In turn, pyrimidines 19,
like compounds 10a,b, can be used to obtain pyridopyr-
imidinones. Using heterocycle 19b as an example, it was
shown that its reaction with DMF dimethyl acetal in re-
fluxing benzene resulted in the corresponding amidine 20,
which treated with MeONa in MeOH was converted to
pyridopyrimidinone 18c.
A similar reaction of a 4 : 1 mixture of pyrimidines 4c
and 5c with DMF dimethyl acetal leads to a mixture of
amidines 14 and 15, treatment of which with MeONa in
refluxing MeOH results in the intramolecular cyclization
of amidine 14 to pyridopyrimidinone 16 (Scheme 5). The
low solubility of the latter in МеОН allowed us to easily
isolate it in the individual state in 78% yield.
Amidines 17а—с and 20 are well soluble in chloroform,
benzene, acetone and poorly soluble in light petroleum
ether. Compounds 17b,с are poorly soluble in alcohols.
Colorless pyridopyrimidinones 18a—d, like their analogs
13a,b and 16 containing a CCl3 group, are poorly soluble
in organic solvents and only moderately soluble in DMSO.
The mass spectra of bicycles 18a—d exhibit peaks of
molecular ions. The 1H NMR spectra of these compounds
contain signals for the OMe and OEt protons; for the rest,
they are similar to the spectra of pyridopyrimidinones
13a,b and 16. Colorless crystalline 5-acetyl-4-amino-6-
methoxypyrimidines 19a,b are well soluble in chloroform,
benzene, moderately soluble in ethanol, and poorly soluble
in light petroleum ether. Their structures were confirmed
by IR and 1Н NMR spectroscopy and mass spectrometry
1
Amidines 12a,b (characterized by H NMR spectra
and elemental analysis) are well soluble in organic solvents
except light petroleum ether, while pyridopyrimidinones
13a,b and 16 are poorly soluble in chloroform, acetone,
benzene, moderately soluble in alcohols, and well soluble
in DMSO. The mass spectra of bicycles 13a,b and 16
exhibit abundant peaks of [M]+ and [M – Cl]+ions. The
IR spectra (KBr) contain absorption bands of the CO
1
groups at 1650—1658 cm–1, while the Н NMR spectra
(DMSO-d6) contain two doublets at δ 6.22—6.24 (H(6))
and 7.91—7.97 (H(7)) for compounds 13a and 16 and
a singlet at δ 6.14 (H(6)) for heterocycle 13b, as well as
broad singlets for the NH protons at δ 12.50—12.75. The
13C NMR spectrum of compound 13a exhibits a signal at
δ 177.8 attributed to the carbonyl group.
The reaction of 6-trichloromethylpyrimidines 10a,b
with amide acetals in refluxing benzene also gives the cor-
responding amidines 17а—с. However, it turned out that
reflux of the latter with an excess of Na alkoxide in alcohol
leads not only to the pyridine ring closure, but also to
the replacement of the CCl3 group by the alkoxy one,
giving 4-alkoxypyrido[2,3-d]pyrimidin-5-ones 18a—d in
58—85% isolated yields (Scheme 6).
1
(see Experimental). In the Н NMR spectra (CDCl3) of
these compounds, in contrast to the spectra of heterocycles
4a—c, 5c, 10a,b and similar pyrimidines22,32,35 having
alkyl, aryl, and methylsulfanyl substituents instead of the
CCl3 group, the NH2 group appears as two broad singlets
at δ 5.75—5.80 and 9.02—9.18. Their IR spectra (CHCl3)
exhibit a low-frequency absorption band of the carbonyl
group (1632—1635 cm–1; cf. with the IR spectra for pyr-
imidines 4а,с (1660—1665 cm–1) and pyrimidines 10a,b
(1688—1690 cm–1)). Apparently, this can be explained by
the presence of an intermolecular hydrogen bond between
the NH2 and COMe groups.
It was also found that the CCl3 group in pyrimidines
10a,b can be also replaced by an alkoxy one. Thus, their
reflux with MeONa in MeOH gave the correspond-
ing 5-acetyl-4-amino-6-methoxypyrimidines 19a,b in
In conclusion, using the reaction of diaminomethyl-
idene derivatives of β-diketones with trichloroacetonitrile
leading to trichloromethyl-substituted pyrimidines with

New pyrido[2,3-d]pyrimidine derivatives
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 2, February, 2019
369
Scheme 6
10a
Me
—
10b
Ph
—
17a
Me
Me
—
17b
Ph
H
17c
Ph
Me
—
18a
Me
Me
Me
18b
Me
Me
Et
18c
Ph
H
18d
Ph
Me
Me
19a
Me
—
19b
Ph
—
20
Ph
H
R
R´
R′′
—
—
—
Me
Me
Me
Me
Reagents and conditions: i. (MeO)2C(R´)NMe2, PhH, Δ; ii. R´´ONa, R´´OH, Δ.
δ, E/Z-isomers in the ratio of ~1 : 1: 1.79/1.87 (s, 3 H, Me);
7.40—8.20 (m, 10 H, 2 Ph); 9.90/10.00 (br.s, 1 H, NH);
10.50/11.10 (br.s, 1 H, NH); 14.40/15.00 (br.s, 1 H, NH).
2-(Diaminomethylidene)-1-phenylbutane-1,3-dione (1с).
A mixture of ketene aminal 2с (3.08 g, 10 mmol) and MeONa
(10 mmol) in МеОН (12 mL) was stirred for 20 min at 20 °C,
acidified with АсОН, concentrated in vacuo, the residue was
chromatographed on a column with SiO2 (eluent benzene, then
mixtures of benzene—chloroform and chloroform—acetone).
The solvents were evaporated in vacuo, the residue was recrystal-
lized from a mixture of benzene—hexane to obtain ketene aminal
1с (1.42 g, 70%), m.p. 150—152 °C. Found (%): C, 64.61; H, 5.99;
N, 13.64. C11H12N2O2. Calculated (%): C, 64.69; H, 5.92;
N, 13.72. IR (CHCl3), ν/cm–1: 3470 (NH), 3300—3000 (NH,
vicinal amino and acyl groups as a basis, we have developed
an approach to the synthesis of 2-trichloromethyl- and
4-alkoxy-substituted pyrido[2,3-d]pyrimidin-5(8Н)-one
derivatives, which are of interest for biological screening.
Experimental
1Н and 13С NMR spectra were recorded on a Bruker AM-300
spectrometer (300 МHz), using residual signals of nondeuter-
ated solvent as a reference (δ 7.27 for CDCl3 and δ 2.50 for
1
DMSO-d6 in Н NMR spectra and δ 39.50 for DMSO-d6 in
13С NMR spectra). IR spectra were recorded on a Specord-M
82 spectrometer. Mass spectra were recorded on a Kratos MS-30
instrument (EI, 70 eV, the ionization chamber temperature was
250 °C, direct injection of the sample). In the mass spectra of
trichloromethylpyrimidines, only peaks for isotope 35Cl are in-
dicated. Aminals of α,α-diacyl ketenes 1a,b,27 N-acylaminals of
α-monoacetyl ketenes 8a,b,28 N-cyanоtrichloroacetamidine 636
were synthesized according to the known procedures. Trichloro-
acetonitrile used in the synthesis was purchased from Lancaster.
Column chromatography was performed on Merck silica gel 60
(0.063—0.200 mm).
1
СН), 1600 (CO). H NMR (DMSO-d6), δ: 1.50 (s, 3 H, Me);
7.30 (br.s, 2 H, 2 NH); 7.37—7.51 (m, 5 H, Ph); 9.30 (br.s, 2 H,
2 NH).
5-Acetyl-4-amino-6-methyl-2-trichloromethylpyrimidine (4а).
A mixture of ketene aminal 1а (0.57 g, 4 mmol) and CCl3CN
(0.81 mL, 8 mmol) in anhydrous THF (5 mL) was refluxed for
2 h, the solvent was evaporated in vacuo, the residue was dissolved
in toluene and chromatographed on a column with SiO2 (eluent
toluene). The solvent was evaporated, the residue was washed
with hexane to obtain pyrimidine 4а (0.88 g, 82%), m.p.
131—132 °C (Ref. 23: 133—134 °C). 13C NMR (CDCl3), δ: 26.2
(q, Ме, 1J = 129 Hz); 33.0 (q, СОМе, 1J = 129 Hz); 96.4 (CCl3);
113.2 (C(5)); 162.5 (C(4)); 164.4 (C(2)); 167.8 (q, C(6), 2J = 5.0 Hz);
201.3 (q, CO, 3J = 5.0 Hz).
4-Amino-5-benzoyl-6-phenyl-2-trichloromethylpyrimidine (4b)
and 4-benzoylamino-6-phenyl-2-trichloromethylpyrimidine (7).
Method А. A mixture of ketene aminal 1b (0.27 g, 1 mmol) and
CCl3CN (0.35 mL, 3.5 mmol) in anhydrous toluene (5 mL) was
heated in a sealed tube at 130 °C for 10 h. The solvent was
evaporated in vacuo, the residue was chromatographed on
a column with SiO2 (eluent a mixture of benzene—hexane, then
2-[(Benzoylamino)aminomethylidene]-1-phenylbutane-1,3-
dione (2с). A mixture of benzoylcyanamide (2.19 g, 15 mmol),
benzoylacetone (2.43 g, 15 mmol), and Ni(acac)2 (0.12 g,
0.45 mmol) in anhydrous THF (15 mL) was refluxed for 20 h,
the solvent was evaporated in vacuo, the residue was diluted with
benzene (10 mL), the undissolved precipitate of nickel complex
was filtered off. Hexane (20 mL) was added to the filtrate,
a precipitate formed was collected by filtration to obtain ketene
aminal 2с (3.1 g, 67%), m.p. 102—103 °C. Found (%): C, 69.79;
H, 5.08; N, 9.35. C18H16N2O3. Calculated (%): C, 70.11; H, 5.23;
N, 9.09. IR (CHCl3), ν/cm–1: 3340 (NH), 3200—2900 (NH,
1
СН), 1680 (CO), 1630 (CO), 1600, 1530. H NMR (CDCl3),

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Russ. Chem. Bull., Int. Ed., Vol. 68, No. 2, February, 2019
Komkov et al.
benzene). Pyrimidines 7 (0.09 g, 23%) and 4b (0.14 g, 34%) were
sequentially obtained by evaporation of the solvent from the
corresponding fractions.
Method B. A mixture of N-cyanоtrichloroacetamidine 6
(0.51 g, 2.7 mmol), dibenzoylmethane (1.21 g, 5.4 mmol), and
Ni(OAc)2 (0.48 g, 2.7 mmol) was heated for 2 h at 130—140 °C,
cooled to 20 °C, and chromatographed on a column with SiO2
(eluent CCl4). Pyrimidines 7 (0.19 g, 18%) and 4b (0.45 g, 42%)
were sequentially obtained by evaporation of the solvent from the
corresponding fractions.
Pyrimidine 4b, m.p. 159—160 °C (from a mixture of benz-
ene—hexane). Found (%): C, 54.82; H, 3.60; Cl, 26.81; N, 10.46.
C18H12Cl3N3O. Calculated (%): C, 55.06; H, 3.08; Cl, 27.09;
N, 10.70. MS, m/z (Irel (%)): 391 [M]+ (14), 76 (100). IR
(CHCl3), ν/cm–1: 3500 and 3390 (NH2), 1645 (CO), 1605, 1535.
1H NMR (CDCl3), δ: 6.28 (br.s, 2 H, NH2); 7.10—7.40 (m, 6 H,
2 Ph); 7.48—7.65 (m, 4 H, 2 Ph). 13C NMR (CDCl3), δ: 96.9
(CCl3); 111.2 (C(5)); 128.4, 129.4, 130.2, 130.7, 133.4, 137.5, 137.6
(2 Ph); 163.4 (C(4)); 164.9 (C(2)); 166.1 (t, C(6), 3J = 3.5 Hz);
197.4 (t, CO, 3J = 3.5 Hz).
96.3 (CCl3); 112.4 (C(5)); 128.9, 129.7, 131.3, 138.1 (Ph); 162.2
(C(4)); 164.3 (C(2)); 167.3 (C(6)); 203.0 (CO).
Pyrimidine 5с, m.p. 185—186 °C. Found (%): C, 46.91;
H, 2.86; Cl, 31.89; N, 12.51. C13H10Cl3N3O. Calculated (%):
C, 47.23; H, 3.05; Cl, 32.17; N, 12.71. IR (CHCl3), ν/cm–1: 3505
1
and 3400 (NH2), 1650 (CO), 1605, 1545. H NMR (CDCl3),
δ: 2.22 (s, 3 H, Me); 5.82 (br.s, 2 H, NH2); 7.52 (t, 2 H, Ph,
J = 7.5 Hz); 7.68 (t, 1 H, Ph, J = 7.5 Hz); 7.81 (d, 2 H, Ph,
J = 7.5 Hz). 13C NMR (DMSO-d6), δ: 22.1 (Ме); 96.7 (CCl3);
110.2 (C(5)); 129.0, 134.2, 136.1 (Ph); 160.9 (C(4)); 162.2
(q, C(6), 2J = 6.6 Hz); 163.4 (C(2)); 195.0 (t, CO, 3J = 4.2 Hz).
5-Acetyl-4-amino-2-methyl-6-trichloromethylpyrimidine (10а).
A mixture of ketene aminal 8а (0.568 g, 4 mmol) and CCl3CN
(0.800 mL, 8 mmol) in anhydrous THF (5 mL) was refluxed for
6 h, the solvent was evaporated in vacuo, the residue was chrom-
atographed on a column with SiO2 (eluent chloroform). The
solvent was evaporated in vacuo, the residue was recrystallized
from a mixture of benzene—hexane (1 : 1) to obtain pyrimidine
10а (0.330 g, 31%), m.p. 204—205 °C. Found (%): C, 35.53;
H, 2.81; Cl, 39.41; N, 15.35. C8H8Cl3N3O. Calculated (%):
C, 35.75; H, 2.98; Cl, 39.66; N, 15.64. MS, m/z (Irel (%)): 267
[M]+ (4), 252 [М – Ме]+ (16), 232 [М – Cl]+ (12), 43 [COМе]+
(100). IR (CHCl3), ν/cm–1: 3510 and 3400 (NH2), 1690 (CO),
1605, 1550. 1H NMR (CDCl3), δ: 2.58 (s, 3 H, Me); 2.70 (s, 3 H,
Me); 5.58 (br.s, 2 H, NH2). 13C NMR (DMSO-d6), δ: 25.3
(q, Ме, 1J = 127.4 Hz); 32.5 (q, СОМе, 1J = 128.8 Hz); 95.9 (CCl3);
Pyrimidine 7, m.p. 154—155 °C (from hexane). Found (%):
C, 55.09; H, 3.19; Cl, 27.29; N, 10.27. C18H12Cl3N3O. Calculat-
ed (%): C, 55.06; H, 3.08; Cl, 27.09; N, 10.70. MS, m/z
(Irel (%)): 391 [M]+ (15), 105 [PhCO]+ (100). IR (CHCl3), ν/cm–1
:
3400 (NH), 1695 (CO), 1590, 1548. 1H NMR (CDCl3), δ:
7.48—7.70 (m, 6 H, 2 Ph); 7.95—8.05 (m, 2 H, Ph); 8.25—8.35
(m, 2 H, Ph); 8.80 (br.s, 1 H, NH); 8.88 (s, 1 H, H(5)). 13C NMR
(CDCl3), δ: 96.9 (CCl3); 105.1 (C(5)); 127.5, 127.8, 129.1, 131.7,
133.2, 136.0 (2 Ph); 159.1 (C(4)); 164.9 (C(2)); 166.3, 166.7
(both t, CO, C(6), 3J = 3.4 Hz).
3
111.7 (t, C(5), J = 4.9 Hz); 157.4 (C(6)); 161.1 (C(4)); 166.1
(q, C(2), 2J = 6.6 Hz); 202.0 (q, CO, J = 6.2 Hz).
5-Acetyl-4-amino-2-phenyl-6-trichloromethylpyrimidine (10b)
and 4-benzoylamino-6-methyl-2-trichloromethylpyrimidine (9b).
A mixture of ketene aminal 8b (0.51 g, 2.5 mmol) and CCl3CN
(0.75 mL, 7.5 mmol) in anhydrous THF (5 mL) was refluxed for
5 h. The solvent was evaporated in vacuo, the residue was chrom-
atographed on a column with SiO2 (eluent benzene). The solvent
was evaporated in vacuo, the residue was recrystallized from
a mixture of benzene—hexane (1 : 2) to obtain pyrimidine 10b
(0.28 g, 34%), m.p. 176—177 °C. Found (%): C, 47.21; H, 3.20;
Cl, 32.45; N, 12.68. C13H10Cl3N3O. Calculated (%): C, 47.23;
H, 3.05; Cl, 32.17; N, 12.71. MS, m/z (Irel (%)): 329 [M]+ (32),
314 [М – Ме]+ (80), 104 [PhC=NH]+ (85), 43 [COМе]+ (100).
IR (CHCl3), ν/cm–1: 3512 and 3404 (NH2), 1688 (CO), 1608,
5-Acetyl-4-amino-6-phenyl-2-trichloromethylpyrimidine (4с)
and 4-amino-5-benzoyl-6-methyl-2-trichloromethylpyrimidine
(5с). Method А. A mixture of ketene aminal 1с (0.204 g, 1 mmol)
and CCl3CN (0.20 mL, 2 mmol) in anhydrous toluene (4 mL)
was heated for 12 h in a sealed tube at 120 °C. The solvent was
evaporated in vacuo, the residue was recrystallized from toluene
to obtain pyrimidine 5с (0.086 g, 26%). The toluene filtrate was
concentrated in vacuo, the residue was chromatographed on
a column with SiO2 (eluent benzene) to obtain a mixture of
pyrimidines 4с and 5с (0.143 g, 43%) in the ratio of 5 : 1
(1Н NMR data).
Method B. A mixture of N-cyanоtrichloroacetamidine 6 (1 g,
5.36 mmol), benzoylacetone (1.74 g, 10.7 mmol), and Ni(OAc)2
(0.95 g, 5.36 mmol) was heated for 2 h at 130—140 °C, then
cooled to 20 °C, and recrystallized from acetonitrile (10 mL)
with hot filtration from Ni complexes to obtain pyrimidine 5с
(0.19 g). The filtrate was concentrated and the residue was re-
crystallized from toluene to additionally obtain pyrimidine 5с
(0.12 g), a total yield of 17.5%. The filtrate was concentrated, the
residue was treated with hexane (20 mL) to obtain a mixture of
pyrimidines 4с and 5с (0.75 g, 42%) in the ratio of 4 : 1 (1Н NMR
data). This mixture was chromatographed on a column with SiO2
(eluent CCl4, then a 5 : 1 mixture of CCl4—chloroform) to obtain
pyrimidine 4с (0.25 g, 14%) (with ~5% of isomer 5с according
to the 1Н NMR data).
1
1524. H NMR (CDCl3), δ: 2.73 (s, 3 H, COMe); 5.62 (br.s,
2 H, NH2), 7.50 (m, 3 H, Ph); 8.45 (m, 2 H, Ph). The filtrate
was concentrated in vacuo, the residue was re-chromatographed
on a column with SiO2 (eluent a mixture of benzene—hexane
(1 : 1), then benzene). The solvent was evaporated in vacuo to
obtain pyrimidine 9b (0.107 g, 13%), m.p. 180—181 °C (from
hexane). Found (%): C, 46.99; H, 2.82; Cl, 32.46; N, 12.69.
C13H10Cl3N3O. Calculated (%): C, 47.23; H, 3.05; Cl, 32.17;
N, 12.71. MS, m/z (Irel (%)): 329 [M]+ (20), 294 [М – Cl]+ (58),
105 [COPh]+ (100). IR (CHCl3), ν/cm–1: 3416 (NH), 1700 (CO),
1596. 1H NMR (CDCl3), δ: 2.69 (s, 3 H, Me); 7.56 (t, 2 H, Ph,
J = 7.8 Hz); 7.62 (t, 1 H, Ph, J = 7.8 Hz); 7.98 (d, 2 H, Ph,
J = 7.8 Hz); 8.78 (br.s, 1 H, NH).
5-Acetyl-4-(dimethylaminomethylidene)amino-6-methyl-2-
trichloromethylpyrimidine (12а). A mixture of pyrimidine 4а
(0.805 g, 3 mmol) and DMF dimethyl acetal (0.800 mL, 6 mmol)
in benzene (15 mL) was refluxed for 2 h, the solvent was evapor-
ated in vacuo, the residue was washed with hexane to obtain
amidine 12а (0.86 g, 89%), m.p. 128—129 °C (from hexane).
Found (%): C, 40.84; H, 4.26; Cl, 33.00; N, 17.41. C11H13Cl3N4O.
Pyrimidine 4с, m.p. 145—146 °C. Found (%): C, 46.95;
H, 2.81; Cl, 31.88; N, 12.37. C13H10Cl3N3O. Calculated (%):
C, 47.23; H, 3.05; Cl, 32.17; N, 12.71. IR (CHCl3), ν/cm–1: 3500
1
and 3380 (NH2), 1665 (CO), 1600, 1532. H NMR (CDCl3),
δ: 1.95 (s, 3 H, Me); 6.78 (br.s, 2 H, NH2); 7.46—7.61 (m, 3 H,
Ph); 7.65—7.72 (m, 2 H, Ph). 13C NMR (CDCl3), δ: 31.5 (Ме);

New pyrido[2,3-d]pyrimidine derivatives
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 2, February, 2019
371
Calculated (%): C, 40.82; H, 4.05; Cl, 32.87; N, 17.31. 1H NMR
(DMSO-d6), δ: 2.31 (s, 3 H, Me); 2.57 (s, 3 H, Me); 3.08, 3.21
(both s, 3 H each, NМе2); 8.72 (s, 1 H, СH).
7.40—7.58 (m, 3 Н, Ph); 7.58—7.68 (m, 2 Н, Ph); 7.97 (d, 1 Н,
Н(7), J = 7.5 Hz); 12.75 (br.s, 1 H, NH).
5-Acetyl-4-[1-(dimethylamino)ethylidene]amino-2-methyl-6-
trichloromethylpyrimidine (17a). A mixture of pyrimidine 10а
(0.27 g, 1 mmol) and DMAA dimethyl acetal (0.44 mL, 3 mmol)
in benzene (5 mL) was refluxed for 4 h, the solvent was evapo-
rated in vacuo. The reaction product was extracted from the
residue by boiling hexane. After cooling to 20 °C, a precipitate
formed was collected by filtration to obtain amidine 17а (0.23 g,
68%), m.p. 105—106 °C. Found (%): C, 42.45; H, 4.39; Cl, 31.22;
N, 16.41. C12H15Cl3N4O. Calculated (%): C, 42.68; H, 4.48;
Cl, 31.50; N, 16.59. 1H NMR (CDCl3), δ: 2.19 (s, 3 H, N=CMe);
2.63 (s, 3 H, Me); 2.65 (s, 3 H, Me); 3.11 (s, 6 H, NМе2).
5-Acetyl-4-(dimethylaminomethylidene)amino-2-phenyl-6-
trichloromethylpyrimidine (17b). A mixture of pyrimidine 10b
(0.33 g, 1 mmol) and DMF dimethyl acetal (0.40 mL, 3 mmol)
in benzene (5 mL) was refluxed for 3 h, the solvent was evapor-
ated in vacuo, the residue was recrystallized from ethanol to
obtain amidine 17b (0.29 g, 76%), m.p. 180—181 °C. Found (%):
C, 49.77; H, 3.97; Cl, 27.72; N, 14.42. C16H15Cl3N4O. Calculat-
ed (%): C, 49.83; H, 3.92; Cl, 27.58; N, 14.53. 1H NMR (CDCl3),
δ: 2.71 (s, 3 H, CОMe); 3.12, 3.21 (both s, 3 H each, NМе2);
7.49 (m, 3 H, Ph); 8.50 (m, 2 H, Ph); 8.88 (s, 1 H, CH).
5-Acetyl-4-[1-(dimethylamino)ethylidene]amino-2-phenyl-6-
trichloromethylpyrimidine (17с) was synthesized similarly to
amidine 17b from pyrimidine 10b and DMAA dimethyl acetal.
The yield was 52%, m.p. 204—205 °C (from ethanol). Found (%):
C, 51.13; H, 4.25; Cl, 26.43; N, 14.03. C17H17Cl3N4O. Calculat-
ed (%): C, 51.08; H, 4.29; Cl, 26.61; N, 14.02. 1H NMR
(DMSO-d6), δ: 2.38 (s, 3 H, N=CMe); 2.58 (s, 3 H, CОMe);
3.12, 3.23 (both s, 3 H each, NМе2); 7.52 (m, 3 H, Ph); 8.38
(m, 2 H, Ph).
4-Alkoxypyrido[2,3-d]pyrimidine-5(8Н)-ones (18a—d) (gen-
eral procedure). A mixture of the corresponding amidine 17а—с
(1 mmol) and MeONa or EtONa (3 mmol) in МеОН or EtOH
(10 mL)) was refluxed for 6 h, cooled to 20 °C, acidified with
АсОН, a precipitate formed was collected by filtration to obtain
compounds 18а—d. The filtrate was concentrated in vacuo, the
residue was washed with water and hot acetonitrile to obtain an
additional amount of bicycles 18а—d. Analytical samples of these
compounds were obtained by recrystallization from ethanol.
4-Methoxy-2,7-dimethylpyrido[2,3-d]pyrimidin-5(8Н)-one
(18a). The yield was 78%, m.p. > 300 °C. Found (%): C, 58.24;
H, 5.59; N, 20.06. C10H11N3O2. Calculated (%): C, 58.53; H,
5.40; N, 20.48. MS, m/z (Irel (%)): 205 [M]+ (39), 176 [М – CО –
– Н]+ (21), 134 [М – МеCN – CН2O]+ (100). IR (KBr),
ν/cm–1: 3285—2710 (NH, СН), 1667 (CO), 1600, 1558. 1H NMR
(DMSO-d6), δ: 2.22 (s, 3 H, Me); 2.50 (s, 3 H, Me); 3.99 (s, 3 H,
OMe); 5.91 (s, 1 Н, Н(6)); 11.88 (br.s, 1 H, NH).
5-Acetyl-4-[1-(dimethylamino)ethylidene]amino-6-methyl-2-
trichloromethylpyrimidine (12b). A mixture of pyrimidine 4а
(0.54 g, 2 mmol) and DMAA dimethyl acetal (0.46 mL, 3 mmol)
in benzene ( 10 mL) was refluxed for 4 h. The solvent was
evaporated in vacuo, the residue was chromatographed on
a column with SiO2 (eluent a mixture of CCl4—chloroform, then
chloroform). The solvent was evaporated in vacuo, the residue
was recrystallized from hexane to obtain amidine 12b (0.34 g,
50%), m.p. 126—127 °C. Found (%): C, 42.68; H, 4.51; Cl, 31.07;
N, 16.94. C12H15Cl3N4O. Calculated (%): C, 42.68; H, 4.48;
Cl, 31.50; N, 16.59. 1H NMR (CDCl3), δ: 2.28 (s, 3 H, N=CMe);
2.43 (s, 3 H, Me); 2.57 (s, 3 H, Me); 3.14, 3.15 (both s, 3 H each,
NМе2).
4-Methyl-2-trichloromethylpyrido[2,3-d]pyrimidin-5(8Н)-
one (13а). Method А. A mixture of amidine 12а (0.32 g, 1 mmol)
and EtONa (2 mmol) in EtOH (10 mL) was refluxed for 4 h,
cooled to 20 °C, and acidified with АсОН. A precipitate formed
was collected by filtration to obtain compound 13а (0.08 g). The
filtrate was diluted with water to additionally isolate 0.11 g of the
product, a total yield was 68%.
Method B. A mixture of amidine 12а (0.16 g, 0.5 mmol) and
МеONa (10 mmol) in МеOH (15 mL) was refluxed for 6 h, cooled
to 20 °C, acidified with АсОН, and diluted with water. A pre-
cipitate formed was collected by filtration to obtain bicycle 13а
(0.12 g, 85%), m.p. > 300 °C. Found (%): C, 38.98; H, 2.23;
Cl, 38.13; N, 15.09. C9H6Cl3N3O. Calculated (%): C, 38.81;
H, 2.17; Cl, 38.19; N, 15.09. MS, m/z (Irel (%)): 277 [M]+ (100),
242 [М – Cl]+ (94). IR (KBr), ν/cm–1: 3300—2500 (NH, СН),
1650 (CO), 1627, 1600, 1570, 1545. 1H NMR (DMSO-d6), δ: 2.99
(s, 3 H, Me); 6.24 (d, 1 Н, Н(6), J = 7.7 Hz); 7.91 (d, 1 Н, Н(7),
J = 7.7 Hz); 12.70 (br.s, 1 H, NH). 13C NMR (DMSO-d6), δ:
25.4 (q, Ме, 1J = 130 Hz); 96.2 (CCl3); 114.6 (C(4a)); 115.3 (dd,
C(6), 1J = 168.5 Hz, 2J = 2.6 Hz); 139.9 (dd, C(7), 1J = 180.5 Hz,
2J = 3.9 Hz); 155.5 (d, C(8а), 3J = 9.8 Hz); 162.6 (C(2)); 172.9
(q, C(4), 2J = 7.4 Hz); 177.8 (d, C(5), 2J = 8.8 Hz).
4,7-Dimethyl-2-trichloromethylpyrido[2,3-d]pyrimidin-5(8Н)-
one (13b) was synthesized similarly to compound 13а from
amidine 12b and EtONa in EtOH. The yield was 74%, m.p. > 300 °C.
Found (%): C, 40.74; H, 2.58; Cl, 36.03; N, 13.98. C10H8Cl3N3O.
Calculated (%): C, 41.05; H, 2.76; Cl, 36.36; N, 14.36. MS, m/z
(Irel (%)): 291 [M]+ (100), 256 [М – Cl]+ (32), 228 [М – Cl –
– СО]+ (83). IR (KBr), ν/cm–1: 3300—2500 (NH, СН), 1658
1
(CO), 1635, 1600, 1545, 1500. H NMR (DMSO-d6), δ: 2.30
(s, 3 H, Me); 2.98 (s, 3 H, Me); 6.14 (s, 1 Н, Н(6)); 12.50 (br.s,
1 H, NH).
4-Phenyl-2-trichloromethylpyrido[2,3-d]pyrimidin-5(8Н)-
one (16). A 4 : 1 mixture of pyrimidines 4с (0.28 g, 0.85 mmol)
and 5с and DMF dimethyl acetal (0.22 mL, 1.7 mmol) in benzene
(5 mL) was refluxed for 4 h, the solvent and excessive acetal were
evaporated in vacuo. The residue was treated with MeONa
(1.7 mmol) in МеОН (7 mL) upon reflux for 2 h. The reaction
mixture was cooled to 20 °C, acidified with АсОН, a precipitate
formed was collected by filtration, and washed with МеОН (5 mL)
to obtain compound 16 (0.18 g, 78%), m.p. > 300 °C. Found (%):
C, 49.02; H, 2.15; Cl, 30.95; N, 11.99. C14H8Cl3N3O. Calculat-
ed (%): C, 49.37; H, 2.37; Cl, 31.23; N, 12.34. IR (KBr),
ν/cm–1: 3280—2740 (NH, СН), 1650 (CO), 1620, 1600, 1570,
1530. 1H NMR (DMSO-d6), δ: 6.22 (d, 1 Н, Н(6), J = 7.5 Hz);
2,7-Dimethyl-4-ethoxypyrido[2,3-d]pyrimidin-5(8Н)-one
(18b). The yield was 82%, m.p. >300 °C. Found (%): C, 59.72;
H, 6.19; N, 18.89. C11H13N3O2. Calculated (%): C, 60.26;
H, 5.98; N, 19.17. MS, m/z (Irel (%)): 219 [M]+ (17), 204 [М – Me]+
(6), 191 [М – CO]+ (15), 175 [М – Me – CO – H]+ (24), 134
[М – MeCN – C2H4O]+ (100). IR (KBr), ν/cm–1: 3300—2700
(NH, СН), 1667 (CO), 1560. 1H NMR (DMSO-d6), δ: 1.33
(t, 3 Н, МеСН2, J = 6.9 Hz); 2.22 (s, 3 H, Me); 2.50 (s, 3 H, Me);
4.48 (q, 2 H, СН2, J = 6.9 Hz); 5.89 (s, 1 Н, Н(6)); 11.84 (br.s,
1 H, NH).
4-Methoxy-2-phenylpyrido[2,3-d]pyrimidin-5(8Н)-one (18с).
The yield was 85%, m.p. 286—287 °C. Found (%): C, 66.42;

372
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 2, February, 2019
Komkov et al.
H, 4.32; N, 16.75. C14H11N3O2. Calculated (%): C, 66.39;
H, 4.38; N, 16.59. MS, m/z (Irel (%)): 253 [M]+ (67), 224 [М –
– CO – H]+ (17), 223 [М – CH2O]+ (15), 120 [PhC(NH2)=NH]+
(100). IR (KBr), ν/cm–1: 3340—2720 (NH, СН), 1632 (CO),
1596, 1584, 1560. 1H NMR (DMSO-d6), δ: 4.14 (s, 3 Н, OМе);
6.07 (br.s, 1 Н, Н(6)); 7.75 (m, 3 H, Ph); 7.69 (br.s, 1 Н, Н(7));
8.41 (m, 2 H, Ph); 12.00 (br.s, 1 H, NH). 13C NMR (DMSO-d6),
δ: 53.8 (OМе); 103.8 (C(4a)); 114.8 (C(6)); 128.1, 128.3, 131.3,
136.1 (Ph); 138.0 (C(7)); 157.5 (C(8a)); 162.7 (C(2)); 168.5
(C(4)); 175.4 (C(5)).
synthesis of compounds 18 to obtain pyridopyrimidinone 18с
(0.06 g, 67%).
This work was financially supported by the Presidium
of the Russian Academy of Sciences (Program for Basic
Research I.8P "Development of Methods for Preparation
of Chemical Compounds and Design of New Materials").
References
4-Methoxy-7-methyl-2-phenylpyrido[2,3-d]pyrimidin-5(8Н)-
one (18d). The yield was 58%, m.p. 301—302 °C. Found (%):
C, 66.98; H, 4.87; N, 15.71. C15H13N3O2. Calculated (%):
C, 67.40; H, 4.90; N, 15.72. MS, m/z (Irel (%)): 267 [M]+ (100),
238 [М – CO – H]+ (39), 134 [М – PhCN – CH2O]+ (70). IR
(KBr), ν/cm–1: 3310—2550 (NH, СН), 1652 (CO), 1594, 1560.
1H NMR (DMSO-d6), δ: 2.27 (s, 3 Н, Ме); 4.12 (s, 3 Н, OМе);
5.94 (s, 1 Н, Н(6)); 7.55 (m, 3 H, Ph); 8.42 (m, 2 H, Ph); 11.92
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(CDCl3), δ: 2.40 (s, 3 H, Me); 2.59 (s, 3 H, Me); 4.02 (s, 3 H,
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:
1
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5-Acetyl-4-amino-6-methoxy-2-phenylpyrimidine (19b) was
synthesized similarly to compound 19а from pyrimidine 10b. The
yield was 50%, m.p. 151—152 °C (from hexane). Found (%):
C, 64.24; H, 5.74; N, 17.02. C13H13N3O2. Calculated (%):
C, 64.18; H, 5.39; N, 17.27. MS, m/z (Irel (%)): 243 [M]+ (55),
228 [М – Ме]+ (100), 200 [М – COМе]+ (15), 118 (99), 104
[PhC=NH]+ (90), 77 [Ph]+ (92). IR (CHCl3), ν/cm–1: 3496
and 3324 (NH2), 1632 (CO), 1584, 1560, 1524. 1H NMR
(CDCl3), δ: 2.65 (s, 3 H, COMe); 4.17 (s, 3 H, ОMe); 5.80, 9.18
(both br.s, 1 H each, NH2); 7.48 (m, 3 H, Ph); 8.42 (m, 2 H, Ph).
5-Acetyl-4-(dimethylaminomethylidene)amino-6-methoxy-2-
phenylpyrimidine (20). A mixture of pyrimidine 20b (0.15 g,
0.6 mmol) and DMF dimethyl acetal (0.16 mL, 1.2 mmol) in
benzene (5 mL) was refluxed for 3 h, the solvent was evaporated
in vacuo, the residue was recrystallized from a mixture of benz-
ene—hexane to obtain amidine 20 (0.14 g, 78%), m.p. 124—125 °C.
MS, m/z (Irel (%)): 298 [M]+ (53), 283 [М – Ме]+ (100), 255
[М – COМе]+ (13), 118 (83), 104 [PhC=NH]+ (31), 77 [Ph]+
(65). IR (CHCl3), ν/cm–1: 3350—2790 (СН), 1696 (CO), 1628,
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1
1588, 1552, 1536. H NMR (CDCl3), δ: 2.61 (s, 3 H, CОMe);
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(m, 3 H, Ph); 8.43 (m, 2 H, Ph); 8.85 (s, 1 Н, СН).
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Received December 6, 2018;
in revised form December 21, 2018;
accepted December 24, 2018