Preparation of 6-unsubstituted 3,4-dihydropyrimidin-2(1H)-ones and 2-(arylamino)pyrimidines

Article abstract of DOI:10.1007/s10593-014-1428-0

The Biginelli reaction of methyl propiolate and of methyl 3-diethylaminoacrylate has yielded a novel series of 6-unsubstituted 3,4-dihydropyrimidin-2(1H)-ones. The successie oxidation of the pyrimidine ring, chlorination of the 2-oxo group, and substitution of the chlorine atom by an aromatic amine give previously unknown 2-(arylamino)pyrimidines. 2-Oxo- and 2-(arylamino)pyrimidine-5-carboxylic acids have been obtained.

Full text of DOI:10.1007/s10593-014-1428-0

Chemistry of Heterocyclic Compounds, Vol. 49, No. 12, March, 2014 (Russian Original Vol. 49, No. 12, December, 2013)
PREPARATION OF 6-UNSUBSTITUTED 3,4-DIHYDROPYRIMIDIN-
2(1H)-ONES AND 2-(ARYLAMINO)PYRIMIDINES
S. Terentjeva1, D. Muceniece1, and V. Lusis1*
The Biginelli reaction of methyl propiolate and of methyl 3-diethylaminoacrylate has yielded a novel
series of 6-unsubstituted 3,4-dihydropyrimidin-2(1H)-ones. The successie oxidation of the pyrimidine
ring, chlorination of the 2-oxo group, and substitution of the chlorine atom by an aromatic amine give
previously unknown 2-(arylamino)pyrimidines. 2-Oxo- and 2-(arylamino)pyrimidine-5-carboxylic acids
have been obtained.
Keywords: 2-(arylamino)pyrimidines, 2-chloropyrimidines, 2-oxo-1,2-dihydropyrimidines, 2-oxo-1,2,3,4-
tetrahydropyrimidines, Biginelli reaction.
The Biginelli reaction is a three-component cyclocondensation of a -dicarbonyl compound, an
aldehyde, and urea, and is a generally acknowledged method for the preparation of polyfunctional 3,4-di-
hydropyrimidines [1-4]. For the synthesis of specific pyrimidines, the possible variation of all three components
has been studied but most attention has been focussed on expanding the range of -dicarbonyl component
equivalents including their vinylogs, enaminones, propiolic acid, its amides and esters [5-11].
The aim of our work was a search for routes to 6-unsubstituted 2-(arylamino)pyrimidines using
Biginelli compounds. The amino derivatives of the 6-unsubstituted pyrimidines are referred as basic structural
units within many biologically active compounds including tyrosine kinase inhibitors (many of which contain a
4-(3-pyridyl) substituent (imatinib, WBZ-7, and CPG-53716)). 4-Aryl-3,4-dihydropyrimidine-2(1H)-thiones are
also of interest as motor protein inhibitors (including monastrol). 2-(5-Iodo-2-methylphenylamino)pyrimidines
merit special attention as potential intermediate products from the viewpoint of tyrosine kinase inhibitors [12].
Scheme 1
N
N
–2
Co+2 / S2O8
MeO2C
Me
MeO2C
NH
NH
N
H
O
N
H
O
1
2
_______
*To whom correspondence should be addressed, e-mail: lusis@osi.lv.
1Latvian Institute of Organic Synthesis, 21 Aizkraukles St., Riga LV-1006, Latvia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1896-1909, December, 2013.
Original article submitted October 28, 2013.
0009-3122/14/4912-1757©2014 Springer Science+Business Media New York
1757

At first glance, the most promising possibility of preparing 4-aryl-6-unsubstituted dihydropyrimi-
dinones (or pyrimidinones) is an oxidative demethylation of the readily available 4-aryl-6-methyl-3,4-di-
hydropyrimidin-2-ones using Co(NO3)2K2SO4 [13] but this proved unsuitable for synthesis of compound 2
from the corresponding 4-(3-pyridyl)pyrimidine 1 (Scheme 1).
The use of propiolic acid derivatives [10, 11] with an activated triple bond in the Biginelli reaction can
also give 2-oxo-1,2,3,4-tetrahydropyrimidines which do not have a substituent at position 6. We have carried
out the reaction of methyl propiolate with aromatic aldehydes and urea in refluxing acetic acid (Method A) and
obtained methyl 4-aryl-1,2,3,4-tetrahydropyrimidine-5-carboxylates 3a-f in moderate yields (48-73%)
(Scheme 2).
Scheme 2
R
HC
CO2Me
(NH2)2C=O
AcOH, , 24 h
A.
R
MeO2C
B.Et2NCH=CHCO2Me
(NH2)2C=O
TFA, DMF, 85°C, 21 h
NH
O
H
N
H
O
3a–f
a R = H, b R = 4-Me, c R = 4-OMe, d R = 4-Br, e R = 3-NO2, f R = 4-NO2
Analysis of the reaction mixtures by LC/MS showed that the reaction is nonspecific and forms side
products. Similar nonspecific reactions have been reported before [11] where one of the side products of the
reaction of ethyl propiolate with benzaldehyde and N-methylurea was a 1,4-dihydropyridine. This was also
confirmed by isolation of side products in the synthesis of pyrimidinone 2 from 3-pyridylcarbaldehyde, urea,
and methyl propiolate (Scheme 3).
Scheme 3
HC
(NH2)2C=O
CO2Me
N
H
AcOH, 80°C, 18 h
N
MeO2C
N
O
N
+
+
+
2
CO2Me
MeO2C
MeO2C
NH
MeO2C
NH
H2NOC
CONH2
N
H
N
H
N
H
O
4
6
5
We propose that the formation of the dihydropyridine can be explained as interaction of the ammonia
produced by urea under reaction conditions with the propiolate to form a -aminoacrylate which then reacts
with an aromatic aldehyde to give the 1,4-dihydropyridine 4. A similar addition of urea to a triple bond and
subsequent reaction with an aldehyde or imine formed from an aldehyde and urea leads to compound 6 [14].
The mechanism of formation of the pyrimidinone 5 is not obvious.
1
1
The structures of compounds 5 and 6 were established from 2D heteronuclear H–13C HMBC and H–
15N HMQC NMR spectra. The key spin-spin interactions in the NMR spectra of the obtained compounds
confirmed the structures and are shown in Figure 1.
1758

8.93
H
O
N
164.9
CH3O
N
151.7
8.88
O
1
H
H
H
8.32
6.56
O
131.9
125.5
133.6
91.9
N
CH3O
2
78.1
N
H
5.92
158.1
6.52
H
H
O
5.91
4.77
H
9.52
H
3
H
H
165.0
CH3O
6.76
N
H
8.00
119.8
52.4
NH
O
154.0
NH2
H
N
H
O
7.21
6
5
Fig. 1. Basic correlations (1H–13C HMBC) and signal assignments (chemical shifts in ppm) in the 1H, 13C,
and 15N NMR spectra of compounds 5 and 6.
The 1H–13C HMBC spectrum of compound 5 shows interaction of pyrimidine 4-CH proton and pyridine
H-2 proton with carbon atoms of the vinyl fragment enabling to localize the position of this fragment in the
1
molecule. In the H NMR spectrum the spin-spin coupling constants of the pyridine ring protons are 1.7 Hz in
all cases which indicates that they are at positions 3 and 5. The position of the ester group in the pyridine ring is
confirmed by 1H–13C interaction of the pyrimidine 4,6-CH protons with carbonyl carbon of the ester group.
From the 1H–15N HMQC and 1H–13C HMBC spectra it was possible to identify an interaction of the NH
and NH2 groups with the corresponding carbamide carbon atoms in the 2-CHNH(CO)NH2 and 3-NH(CO)NH2
1
fragments in compound 6. The H NMR signal for the NH2 group protons in the 3-NH(CO)NH2 fragment
appeared as a broad singlet hence it was not possible to find a correlation of these protons with the nitrogen
atom in the 1H–15N HMQC spectrum.
The 3,4-dihydropyrimidine esters 3a-f (yield 55-66%) were also prepared by condensation of an
aromatic aldehyde, urea, and methyl 3-diethylaminoacrylate which has not been used before in the Biginelli
reaction (Scheme 2, method B). The cyclocondensation was carried out in the presence of trifluoroacetic acid in
DMF solution at 85ºC. Under such conditions, 3-pyridylcarbaldehyde, methyl 3-diethylaminoacrylate, and urea
or thiourea gave the pyrimidinone 2 or pyrimidinethione 7 in 76 and 50% yields, respectively (Scheme 4).
Scheme 4
N
N
N
Et2NCH=CHCO2Me
(NH2)2C=S
N
H
MeI, K2CO3
MeOH, 26 h
MeO2C
MeO2C
TFA, DMF, 85°C, 21 h
NH
O
N
H
S
N
H
15
SMe
Et2NCH=CHCO2Me
(NH2)2C=O
TFA, DMF, 85°C, 21 h
7
2
1759

There had been no satisfactory preparative method for the oxidation of 2-oxo-1,2,3,4-tetrahydro-
pyrimidines to their 1,2-dihydro derivatives despite studies of many different oxidative systems (KMnO4,
HNO3, DDQ, CAN, NaNO2/AcOH, H2O2/AcOH, CrO3/H2SO4 etc.) [15-23]. The majority of the oxidants or
oxidative processes are of little practical use due to the difficult oxidation of 2-oxo-1,2,3,4-tetrahydro-
pyrimidines [4, 23, 25]. For classical Biginelli compounds, this is explained by the sensitivity of the methyl
group at the C-6 atom and the inertness of the pyrimidine ring towards oxidants.
We have prepared the pyrimidinones 8b,d-f by the oxidation of the 2-oxotetrahydro derivatives 3b,d-f
using 50% nitric acid at room temperature or with brief heating at 45-90ºC (Scheme 5). Under such conditions,
no kind of side products previously mentioned [25, 26] are observed. However, we were not able to prepare the
corresponding oxidation products of the 4-(3-pyridyl)-1,2,3,4-tetrahydropyrimidines 2 or 7 either by treatment
with 50% HNO3 or with the use of other oxidants (e.g., KMnO4, HNO3, DDQ, CAN, NaNO2/AcOH,
H2O2/AcOH, or CrO3/H2SO4 in the case of pyrimidinone 2 or DDQ and chloranil in the case of the
pyrimidinethione 7).
Scheme 5
R
R
(from 3b,d–f)
50% HNO3
POCl3
3a,b,d–f
(from 3a)
MeO2C
MeO2C
, 40 min
N
N
N
H
O
N
Cl
8b,d–f
9b,d–f
1 N NaOH
MeOH, H2O
, 18 h
Me
(from 8e)
(from 9b,d,e)
H2N
I
HO2C
NH
EtOH
NO2
N
H
O
R
11
HO2C
Me
N
MeO2C
N
N
H
12
O
I
N
H
N
10b,d,e
1 N NaOH
MeOH h
(from 10e)
N
NO2
HO2C
1 N NaOH
MeOH
NH
2
Me
HO2C
N
H
O
N
I
N
H
N
14
13
a R = H, b R = 4-Me, d R = 4-Br, e R = 3-NO2, f R = 4-NO2
1760

The 2-chloro pyrimidines 9b,d-f were prepared by refluxing pyrimidinones 8b,d-f with POCl3 (Scheme 5).
It is known [27-29] that the substitution of the halogen in 2-chloropyrimidines reacting with aromatic
amines occurs both in the presence and the absence of base. We have found that reaction of compounds 9b,d,e
with 5-iodo-2-methylaniline in absolute ethanol occurs quite slowly and full conversion is not achieved, even
when refluxed for 48 h (Scheme 5). LC/MS has shown that substitution of the chlorine by an ethoxy group
occurs in the course of the reaction (the corresponding products have not been isolated). This may be the reason
for moderate yields (32-70%) of the arylaminopyrimidines obtained 10b,d,e. We have still not studied the use
of pyrimidines 10b,d,e in substitution reactions of iodine for any kind of functional group but it is known that
the arylation of 4-(4-methylpiperazin-1-yl)methylbenzamide by 2-(5-iodo-2-methylphenyl)-4-pyridyl-
pyrimidine leads to the formation of imatinib [12].
Hydrolysis of the pyrimidinecarboxylates 2, 3a, 8e, 10e, formed at different stages of the process, gave
the corresponding acids 11-14 which can be decarboxylated or give acid derivatives (Scheme 5).
In order to introduce an aryl substituent into position 2 of a pyrimidine ring, sulfur-containing
pyrimidines are sometimes used (most often 2-methylsulfonyl derivatives) since the SO2Me is found to be a
good leaving group and is readily prepared by the oxidation of a 2-methylsulfanyl group [8, 30, 31]. The first
example of a direct oxidative coupling of 4-aryl-3,4-dihydropyrimidine-2(1H)-thiones and secondary amines
leading to the formation of new С–N or S–N bonds and, consequently, to 2-amino- or 2-aminosulfanyl-
pyrimidine derivatives has been recently reported [32].
The methyl derivative 15 has been prepared by methylation of the pyrimidinethione 7 (Scheme 4), and
its structure as methyl 2-methylsulfanyl-4-(pyridin-3-yl)-1,4-dihydropyrimidine-5-carboxylate has been proved
by X-ray analysis (Fig. 2).
Fig. 2. Molecular structure of compound 15 with representation of atoms by thermal vibration
ellipsoids of 50% probability.
The dihydropyrimidine ring is characterized as a "flattened bath" type conformation. The deviations of
the N(1) and C(4) atoms from the atomic plane C(2), N(3), C(5), and C(6) are only 0.160(4) and 0.275(4) Å,
respectively. The pyridine ring is virtually perpendicular to the dihydropyrimidine ring, the dihedral angle
between their planes being 88.0º.
A rather strong intermolecular hydrogen bond NH···N occurs in the crystal structure between the NH
group and the pyridine ring nitrogen atom, the bond length being 2.884(4) Å (H···N = 1.97 Å and NH···N
angle 176º).
1761

It is known that, in the reaction of 2-methylsulfanylpyrimidines with arylamines, substitution of the
methylsulfanyl group by an arylamino group occurs in the presence of base or acid catalysts as well as without a
catalyst in high-boiling solvents [8, 33, 34]. We were unsuccessful in attempts to react the 1,4-dihydro-
pyrimidine 15 with 5-iodo-2-methylaniline under different conditions (refluxing in dioxane, dimethylacetamide,
DMF, or MeOH without catalyst or refluxing in dioxane, dimethylacetamide or MeOH in the presence of a
catalytic amount of HCl or methanesulfonic acid). Only in the experiment in dioxane, dimethylacetamide, and
MeOH without catalyst traces (LC/MS) of the methyl 2-(5-iodo-2-methyl-phenylamino)-4-(3-pyridyl)-
pyrimidine-5-carboxylate were found.
Hence we have shown that the methyl esters of propiolic and 3-diethylaminoacrylic acids are suitable
starting materials for the Biginelli synthesis of 6-unsubstituted 3,4-dihydropyrimidin-2(1H)-ones. The 3,4-di-
hydropyrimidin-2(1H)-ones can undergo successive oxidation of the pyrimidine ring, chlorination of the 2-oxo
group, and substitution of the chlorine atom by aromatic amine to give previously unknown 2-(5-iodo-
2-methylamino)pyrimidines. Hydrolysis of the 2-oxo- and 2-(arylamino)pyrimidine esters gives the
corresponding carboxylic acids.
EXPERIMENTAL
1H and 13C NMR spectra were recorded on a Varian 600 MR spectrometer (600 and 125 МHz,
13
respectively) – compounds 12 (1H and C NMR spectra) and 13 (13C NMR spectra), or on a Varian 400 MR
spectrometer (400 and 100 МHz, respectively) – other compounds. 15N NMR spectra were recorded on a Varian
600 MR spectrometer (60 MHz). The residual signals of the solvent were used as an internal reference ( 7.26
1
1
ppm for H nuclei in CDCl3, 2.50 ppm for H nuclei and 39.52 ppm for 13С nuclei in DMSO-d6, 5.84 ppm for
1H nuclei in СD3OD and 4.79 ppm for 1H nuclei in D2O). The low-resolution mass spectra were recorded on an
Acquity UPLC LC system coupled with a Waters Micromass Q-TOF mass spectrometer, chromatography
column Waters XBridge C18 (3.5 μm, 2.1×50 mm), gradient elution with MeCN–HCOOH (0.1%) in water,
ionization method – positive and negative ESI. The high-resolution mass spectra were recorded on an Agilent
UPLC (Agilent 6230 TOF LC/MS) instrument, chromatography column Extend C18 (1.8 μm, 2.1×50 mm),
gradient elution with MeCN–HCOOH (0.1%) in water, ionization method – positive ESI. The elemental analysis
was carried out on an EA 1106 (Carlo Erba Instruments) analyzer. Melting points were determined on a Kofler
hot bench. The purity of the synthesized compounds was determined by TLC on Merck plates. The chemicals
and solvents were purchased from Acros and Alfa Aesar and were used without further purification. Silica gel
60 (35-70 m) was used for column chromatography.
Methyl 3-diethylaminoacrylate was synthesized by the method [35].
Methyl 6-Methyl-2-oxo-4-(pyridin-3-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate (1). A mixture of
methyl acetoacetate (6.5 ml, 0.06 mol), pyridine-3-carbaldehyde (5.6 ml, 0.06 mol), and urea (3.6 g, 0.06 mol)
in the presence of HCl (0.1 ml added every 24 h) was refluxed in MeOH (60 ml) for 48 h. The reaction mixture
was cooled to room temperature, and the resulting precipitate was filtered off and recrystallized from MeOH.
Yield 5.9 g (40%), mp 235-238°С (mp 236-238°С (EtOH) [36]).
Methyl 4-Aryl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates 3а-f (General Method).
А. A mixture of methyl propiolate (1.0 ml, 0.01 mol), urea (1.80 g, 0.03 mol), and the corresponding aldehyde
(0.01 mol) in acetic acid (20 ml) was refluxed for 24 h. The progress of the reaction was controlled by LC/MS.
The reaction mixture was cooled to room temperature, evaporated in vacuo to dryness, and the residue was
recrystallized.
B. Trifluoroacetic acid (0.24 ml, 3.1 mmol) was added to a mixture of methyl 3-diethylaminoacrylate
(1.00 g, 6.4 mmol), urea (0.40 g, 6.7 mmol), and the corresponding aldehyde (6.4 mmol) in DMF (10 ml). The
reaction mixture was heated for 21 h at 85°С, then evaporated. The oily residue was triturated with ЕtOH
(5 ml). The resulting precipitate was filtered off and recrystallized (compounds 2, 3a,е, and 7) or purified by
1762

chromatography (column size 2.540 сm, eluent EtOAc, 2nd fraction collected (~100 ml), TLC control)
followed by recrystallization.
Methyl 2-Oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (3a). Yield 1.5 g (64%, method
А), 0.8 g (55%, method B), mp 247-249 °С (MeOH). 1Н NMR spectrum (DMSO-d6), , ppm (J, Hz)): 3.54 (3Н,
s, CO2СН3); 5.12 (1Н, d, J = 3.0, 4-CH); 7.23-7.36 (6Н, m, 6-CH, H Ph); 7.69 (1Н, t, J = 3.0, 3-NH), 9.20 (1Н,
dd, J = 5.9, J = 3.0, 1-NH). 13С NMR spectrum (DMSO-d6), , ppm: 51.0; 53.9; 102.7; 126.3; 127.5; 128.4;
136.7; 144.2; 151.6; 165.1. Found, %: С 62.00; Н 5.17; N 12.04. C12H12N2O3. Calculated, %: C 62.06; Н 5.21;
N 12.06.
Methyl 4-(4-Methylphenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (3b). Yield 1.5 g
(60%, method А), 0.91 g (59%, method B), mp 213-215°С (ЕtOH). 1Н NMR spectrum (DMSO-d6), , ppm (J,
Hz): 2.26 (3Н, s, СН3); 3.54 (3Н, s, CO2СН3); 5.07 (1Н, d, J = 3.0, 4-CH); 7.11 (4Н, s, H Ar); 7.26 (1Н, d,
J = 5.9, 6-CH); 7.64 (1Н, t, J = 3.0, 3-NH); 9.17 (1Н, dd, J = 5.9, J = 3.0, 1-NH). 13С NMR spectrum (DMSO-d6),
, ppm: 20.6; 50.9; 53.5; 102.8; 126.2; 128.9; 136.5; 136.6; 141.3; 151.5; 165.0. Found, %: С 63.19; Н 5.67;
N 11.32. C13H14N2O3. Calculated, %: C 63.40; Н 5.73; N 11.38.
Methyl 4-(4-Methoxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (3c). Yield 1.4 g
1
(53%, method А), 0.91 g (56%, method B), mp 198-199°С (2-PrOH). Н NMR spectrum (DMSO-d6), , ppm
(J, Hz): 3.51 (3Н, s, ОСН3); 3.69 (3Н, s, CO2СН3); 5.03 (1Н, d, J = 2.8, 4-CH); 6.85 (2Н, d, J = 8.7, Н-3,5 Ar);
7.13 (2Н, d, J = 8.7, Н-2,6 Ar); 7.23 (1Н, d, J = 6.0, 6-CH); 7.59 (1Н, t, J = 2.8, 3-NH); 9.12 (1Н, dd, J = 6.0,
J = 2.8, 1-NH). 13С NMR spectrum (DMSO-d6), , ppm: 50.9; 53.2; 55.0; 102.9; 113.7; 127.4; 131.0; 136.3;
151.4; 158.5; 165.0. Found, %: С 59.23; Н 5.34; N 10.48. C13H14N2O3. Calculated, %: C 59.54; Н 5.38;
N 10.68.
Methyl 4-(4-Bromophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (3d). Yield 1.6 g (48%,
1
method А), 1.2 g (61%, method B), mp 231-233°С (2-PrOH). Н NMR spectrum (DMSO-d6), , ppm (J, Hz):
3.51 (3Н, s, CO2СН3); 5.08 (1Н, d, J = 2.9, 4-CH); 7.18 (2Н, d, J = 8.4, Н-2,6 Ar); 7.26 (1Н, d, J = 6.0, 6-СН);
7.50 (2Н, d, J = 8.4, Н-3,5 Ar); 7.69 (1Н, t, J = 2.9, 3-NH); 9.22 (1Н, dd, J = 6.0, J = 2.9, 1-NH). 13С NMR
spectrum (DMSO-d6), , ppm: 51.0; 53.5; 102.1; 120.5; 128.6; 131.3; 136.9; 143.5; 151.2; 164.9. Found, %:
С 46.10; Н 3.58; N 8.94. C12H11BrN2O3. Calculated, %: C 46.32; Н 3.56; N 9.00.
Methyl 4-(3-Nitrophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (3e). Yield 2.0 g (73%,
1
method А), 1.1 g (66%, method B), mp 267-269°С (2-PrOH). Н NMR spectrum (DMSO-d6), , ppm (J, Hz):
3.56 (3Н, s, CO2СН3); 5.32 (1Н, d, J = 2.8, 4-CH); 7.36 (1Н, d, J = 6.0, 6-CH); 7.67 (1Н, t, J = 7.9, Н-5 Ar);
7.73 (1Н, dt, J = 7.9, J = 1.2, Н-6 Ar); 7.85 (1Н, t, J = 2.8, 3-NH); 8.09 (1Н, dd, J = 2.3, J = 1.2, Н-2 Ar); 8.15
(1Н, ddd, J = 7.9, J = 2.3, J = 1.2, Н-4 Ar); 9.38 (1Н, dd, J = 6.0, J = 2.8, 1-NH). 13С NMR spectrum (DMSO-d6),
, ppm: 51.1; 53.5; 101.6; 121.0; 122.5; 130.2; 133.2; 137.5; 146.2; 147.7; 151.1; 164.9. Found, %: С 51.97;
Н 4.06; N 15.10. C12H11N3O5. Calculated, %: C 51.99; Н 4.00; N 15.16.
Methyl 4-(4-Nitrophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (3f). Yield 1.4 g (54%,
1
method A), 1.0 г (59%, method B), mp 238-240°С (2-PrOH). Н NMR spectrum (DMSO-d6), , ppm (J, Hz):
3.55 (3Н, s, CO2СН3); 5.28 (1Н, d, J = 2.9, 4-CH); 7.34 (1Н, d, J = 5.9, 6-CH); 7.54 (2Н, d, J = 8.8, Н-2,6 Ar);
7.84 (1Н, t, J = 2.9, 3-NH); 8.22 (2Н, d, J = 8.8, H-3,5 Ar); 9.37 (1Н, dd, J = 5.9, J = 2.9, 1-NH). 13С NMR
spectrum (DMSO-d6), , ppm: 51.1; 53.5; 101.5; 123.8; 127.8; 137.4; 146.8; 151.1; 151.2; 164.9. Found, %:
С 52.08; Н 3.99; N 14.90. C12H11N3O5. Calculated, %: C 51.99; Н 4.00; N 15.16.
Methyl 2-oxо-4-(pyridin-3-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate (2) was obtained from
methyl 3-diethylaminoacrylate, urea, and 3-pyridinecarbaldehyde following method B. Yield 1.1 g (76%), mp
227-229°С (ЕtOH). 1Н NMR spectrum (DMSO-d6), , ppm (J, Hz): 3.55 (3Н, s, CO2СН3); 5.20 (1Н, d, J = 2.8,
4-CH); 7.33 (1Н, d, J = 5.8, 6-CH); 7.38 (1Н, dd, J = 7.9, J =4.9, Н-5 Py); 7.64 (1Н, dt, J = 7.9, J = 2.0, Н-6
Py); 7.75 (1Н, t, J = 2.8, 3-NH); 8.44-8.50 (2Н, m, Н-2,4 Py), 9.31 (1Н, dd, J = 5.8, J = 2.8, 1-NH). 13С NMR
spectrum (DMSO-d6), , ppm: 51.1; 52.0; 101.7; 123.9; 134.1; 137.3; 139.5; 147.9; 148.7; 151.2; 164.9.
Found, %: С 56.52; Н 4.78; N 17.66. C11H11N3O3. Calculated, %: C 56.65; Н 4.75; N 18.02.
1763

Methyl 4-(pyridin-3-yl)-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (7) was obtained from
methyl 3-diethylaminoacrylate, thiourea, and 3-pyridinecarbaldehyde following method B. Yield 0.8 g (50%),
1
mp 246-248°С (MeOH). Н NMR spectrum (DMSO-d6), , ppm (J, Hz): 3.58 (3Н, с, CO2СН3); 5.23 (1Н,
s, J = 3.0, 4-CH); 7.19 (1Н, d, J = 5.6, 6-CH); 7.41 (1Н, dd, J = 7.8, J =4.8, Н-5 Py); 7.62 (1Н, dt, J = 7.8,
J =1.9, Н-6 Py); 8.46 (1Н, d, J = 1.9, Н-2 Py), 8.51 (1Н, dd, J = 4.9, J = 1.9, Н-4 Py); 9.64 (1Н, br. s,
3-NH); 10.50 (1Н, d, J = 5.6, 1-NH). 13С NMR spectrum (DMSO-d6), , ppm: 51.3; 51.8; 103.4; 123.9;
133.4; 134.2; 138.2; 147.9, 149.0; 164.6; 174.1. Found, %: С 52.57; Н 4.69; N 16.45. C11H11N3O2S.
Calculated, %: C 53.00; Н 4.45; N 16.86.
Interaction of Methyl Propiolate with Urea and Pyridine-3-carboxylate. A mixture of methyl
propiolate (2.0 ml, 0.02 mol), 3-pyridinecarbaldehyde (1.9 ml, 0.02 mol), and urea (3.60 g, 0.06 mol) in acetic
acid (20 ml) was heated at 80°С for 18 h. The reaction mixture was poured onto Na2CO3 (20 g) mixed with ice
(50 g). The precipitated oil was separated, dissolved in СН2Сl2 (100 ml), dried over Na2SO4, evaporated to
dryness, and purified by chromatography (column size 2.5×60 сm, eluent СН2Сl2–MeOH, 20:1, TLC
control). The following products were eluted: 4 (1st fraction, volume 10 ml), 5 (2nd fraction, volume 30 ml),
2 (3rd fraction, volume 30 ml, yield 0.6 g (13%)), and 6 (4th fraction, volume 40 ml).
Dimethyl 1',4'-Dihydro-3,4'-bipyridine-3',5'-dicarboxylate (4). Yield 0.03 g (1%), mp 237-239°С
1
(MeOH). Н NMR spectrum (CDCl3), , ppm (J, Hz): 3.63 (6Н, s, 2CO2СН3); 4.93 (1Н, s, 4'-CH); 6.96-7.03
(1H, m, 1'-NH); 7.19 (1Н, dd, J = 7.7, J =4.7, Н-5); 7.38 (2Н, d, J = 5.4, 2',6'-CH); 7.67 (1Н, ddd, J = 7.7,
J = 2.0, J = 1.8, Н-6); 8.39 (1Н, dd, J = 4.7, J = 1.8, H-4); 8.56 (1Н, d, J = 2.0, Н-2). 13С NMR spectrum
(DMSO-d6), , ppm: 34.8; 50.9; 104.6; 123.4; 134.9; 135.4, 142.1; 147.3; 148.6; 166.4. Found, %: С 61.07;
Н 5.17; N 10.00. C14H14N2O4. Calculated, %: C 61.31; Н 5.14; N 10.21.
Methyl 4-[2-(5-Methoxycarbonylpyridin-3-yl)vinyl]-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
1
(5). Yield 0.04 g (2%), mp 114-116°С (MeOH). Н NMR spectrum (CDCl3), , ppm (J, Hz): 3.75 (3Н, s,
PyСО2СН3); 3.95 (3Н, s, 5-СО2СН3); 5.05 (1H, dd, J = 6.0, J = 2.5, 4-CH); 5.20-5.25 (1H, m, 3-NH); 6.42 (1H,
dd, J = 16.2, J = 6.0, CH=); 6.60 (1H, d, J = 16.2, PyCH=); 6.80 (1H, d, J = 5.8, 1-NH); 7.28 (1H, d, J = 5.8,
1
6-CH); 8.28 (1H, t, J = 1.7, H-6 Py); 8.72 (1H, d, J = 1.7, H-2 Py); 9.06 (1H, d, J = 1.7, H-4 Py). Н NMR
spectrum (DMSO-d6), , ppm (J, Hz): 3.61 (3Н, s, PyСО2СН3); 3.89 (3Н, s, 5-СО2СН3); 4.77 (1H, dd, J = 4.1,
J = 3.3, 4-CH); 6.45-6.53 (2H, m, CH=СН); 7.21 (1H, d, J = 5.8, 6-CH); 7.57 (1H, br. s, 3-NH); 8.32 (1H, t,
J = 1.9, H-6 Py); 8.88 (1H, d, J = 1.9, H-2 Py); 8.93 (1H, d, J = 1.9, H-4 Py); 9.18 (1H, d, J = 5.8, 1-NH).
13С NMR spectrum (DMSO-d6), , ppm: 51.1 (PyСО2CH3); 51.7 (5-СО2CH3); 52.4 (C-4); 100.6 (C-5); 124.3
(C-5 Py); 125.5 (PyCH=); 131.9 (C-3 Py); 133.3 (C-4 Py); 133.6 (PyCH=СН); 137.0 (C-6); 148.5 (C-6 Py);
151.7 (C-2 Py); 151.8 (C-2); 164.9 (PyCOOCH3); 165.0 (5-COOCH3). Found, m/z: 318.1083 [M+H]+.
C15H16N3O5. Calculated, m/z: 318.1084.
Methyl 3-[(Aminocarbonyl)amino]-2-{[(aminocarbonyl)amino](pyridin-3-yl)methyl}acrylate (6).
Yield 0.10 g (6%), mp 186-188°С (MeOH). 1Н NMR spectrum (DMSO-d6), , ppm (J, Hz): 3.57 (3H, s, CH3);
5.91 (1H, d, J = 9.0, 2-СНNH(CO)NH2); 5.92 (2H, s, 2-СНNH(CO)NH2); 6.58 (2H, br. s, 3-NH(CO)NH2); 6.76
(1H, d, J = 9.0, 2-СНNH(CO)NH2); 7.32 (1H, dd, J = 7.9, J = 4.7, H-5 Py); 7.57 (1H, d, J = 7.9, H-6 Py); 8.00
(1H, d, J = 12.5, 3-CH); 8.40 (1H, dd, J = 4.7, J = 1.2, H-4 Py); 8.43 (1H, d, J = 1.2, H-2 Py); 9.52 (1H, d,
J = 12.5, 3-NH(CO)NH2). 13С NMR spectrum (DMSO-d6), , ppm: 46.4 (2-СНNH(CO)NH2); 51.0 (CH3);
105.7 (C-2); 123.1 (C-5 Py); 133.3 (C-6 Py); 136.7 (C-3); 138.2 (C-1 Py); 147.3 (С-4 Py); 147.5 (C-2 Py);
15
154.0 (3-NH(CO)NH2); 158.1 (2-СНNH(CO)NH2); 167.1 (C-1). N NMR spectrum (DMSO-d6), , ppm: 78.1
(2-СНNH(CO)NH2); 91.9 (2-СНNH(CO)NH2); 119.8 (3-NH(CO)NH2). Масс-спектр, m/z (Irel, %): 294
[M+H]+ (100), 234 [M-NH2CONH2]+ (83). Found, m/z: 294.1203 [M+H]+. C12H16N5O4. Calculated, m/z:
294.1197.
Methyl 4-Aryl-2-oxo-1,2-dihydropyrimidine-5-carboxylates 8b,d-f (General Method). A suspension
of tetrahydropyridine 3b,d-f (2.38 mmol) in 50% nitric acid (5 ml) was stirred during 15 min at room
temperature and heated for 15 min (at 25°С in the case of compound 3b, at 45-50°С in the case of compounds
3e,f, at 90°C in the case of compound 3d). The reaction proceeded with liberation of nitric oxide. The obtained
1764

solution was cooled to room temperature, and a NaOH solution (prepared from NaOH (2.0 g, 0.05 mol) and
water (5 ml)) was added until precipitation occurred (pH 6-7). The precipitate was filtered off, washed with a
minimal amount of water (3 ml), and recrystallized.
Methyl 4-(4-Methylphenyl)-2-oxo-1,2-dihydropyrimidine-5-carboxylate (8b). Yield 0.54 g (93%),
1
mp 204-206°С (ЕtOH). Н NMR spectrum (DMSO-d6), , ppm (J, Hz): 2.37 (3Н, s, СН3); 3.61 (3Н, s,
СО2СН3); 7.26 (2Н, d, J = 8.2, Н-3,5 Ar); 7.38 (2Н, d, J = 8.2, H-2,6 Ar); 8.59 (1Н, s, 6-СН); 12.50 (1Н, s,
NH). 13С NMR spectrum (DMSO-d6), , ppm: 21.0; 51.7; 107.0; 128.4; 128.5; 133.2; 140.3; 155.3; 155.4;
164.4; 170.2. Found, %: С 64.00; Н 4.93; N 11.41. C13H12N2O3. Calculated, %: C 63.93; Н 4.95; N 11.47.
Methyl 4-(4-Bromophenyl)-2-oxo-1,2-dihydropyrimidine-5-carboxylate (8d). Yield 0.6 g (82%),
mp 216-218°С (MeOH). 1Н NMR spectrum (DMSO-d6), , ppm (J, Hz): 3.62 (3Н, s, СО2СН3); 7.43 (2Н, d, J = 8.5,
Н-2,6 Ar); 7.65 (2Н, d, J = 8.5, Н-3,5 Ar); 8.57 (1Н, br. s, 6-СН); 12.65 (1Н, br. s, NH). 13С NMR spectrum
(DMSO-d6), , ppm: 51.7; 106.7; 123.7; 130.3; 130.7; 136.2; 152.0; 155.0; 163.8; 171.9. Found, %: C 46.26;
Н 2.80; N 8.98. C12H9BrN2O3. Calculated, %: С 46.63; Н 2.93; N 9.06.
Methyl 4-(3-Nitrophenyl)-2-oxo-1,2-dihydropyrimidine-5-carboxylate (8e). Yield 0.50 g (76%),
1
mp 224-226°С (MeOH). Н NMR spectrum (DMSO-d6), , ppm (J, Hz): 3.54 (3Н, s, СО2СН3); 7.66 (1Н, dd,
J = 8.0, J = 7.7, Н-5 Ar); 7.83 (1Н, ddd, J = 7.7, J = 1.4, J = 1.0, H-6 Ar); 8.21 (1Н, dd, J = 1.9, J = 1.4, H-2 Ar);
8.26 (1Н, dd, J = 8.0, J = 1.9, J = 1.0, H-4 Ar); 8.65 (1Н, s, 6-СН). 13С NMR spectrum (DMSO-d6), , ppm: 51.7;
106.6; 123.0; 124.4; 129.3; 134.8; 138.8; 147.06; 154.9; 155.0; 163.5; 170.0. Found, %: С 52.47; Н 3.29; N 14.82.
C12H9N3O5. Calculated, %: C 52.37; Н 3.30; N 15.27.
Methyl 4-(4-Nitrophenyl)-2-oxo-1,2-dihydropyrimidine-5-carboxylate (8f). Yield 0.6 g (92%),
1
mp 223-225°C (MeOH). Н NMR spectrum (DMSO-d6), , ppm (J, Hz): 3.60 (3Н, s, СО2СН3); 7.72 (2Н, d,
J = 8.8, Н-2,6 Ar); 8.28 (2Н, d, J = 8.8, H-3,5 Ar); 8.65 (1Н, br. s, 6-СН); 12.81 (1Н, br. s, NH). 13С NMR
spectrum (DMSO-d6), , ppm: 51.7; 106.7; 122.8; 129.5; 144.0; 147.9; 152.7; 154.7; 163.4; 171.5. Found, %:
С 52.15; Н 3.19; N 15.19. C12H9N3O5. Calculated, %: C 52.37; Н 3.30; N 15.27.
Methyl 4-Aryl-2-chloropyrimidine-5-carboxylates 9b,d-f (General Method). A solution of 2-oxo-
pyrimidine 8b,d-f (1.6 mmol) in POCl3 (5 ml) was refluxed for 40 min, then cooled to room temperature and
evaporated in vacuo. The residue was dissolved in EtOAc (10 ml), the solution was extracted with saturated
NaHCO3 solution (7 ml). The organic phase was dried over Na2SO4 and evaporated to dryness. The residue was
recrystallized.
Methyl 2-Chloro-4-(4-methylphenyl)pyrimidine-5-carboxylate (9b). Yield 0.36 g (84%), mp
1
119-120°С (ЕtOH). Н NMR spectrum (DMSO-d6), , ppm (J, Hz): 2.39 (3Н, s, СН3); 3.76 (3Н, s, CО2СН3);
7.34 (2Н, d, J = 8.0, Н-3,5 Ar); 7.53 (2Н, d, J = 8.0, H-2,6 Ar); 9.04 (1Н, s, Н-6). 13С NMR spectrum
(DMSO-d6), , ppm: 20.9; 52.8; 123.0; 128.8; 129.0; 132.5; 141.2; 161.0; 161.1; 165.4; 167.0. Found, %:
С 59.33; Н 4.31; N 10.52. C13H11ClN2O2. Calculated, %: C 59.44; Н 4.22; N 10.66.
Methyl 4-(4-Bromophenyl)-2-chloropyrimidine-5-carboxylate (9d). Yield 0.43
g
(82%),
1
mp 150-152°С (MeOH). Н NMR spectrum (DMSO-d6), , ppm (J, Hz): 3.37 (3Н, s, CО2СН3); 7.57 (2Н, d,
J = 8.7, H-2,6 Ar); 7.74 (2Н, d, J = 8.7, Н-3,5 Ar); 9.12 (1Н, s, Н-6). 13С NMR spectrum (DMSO-d6), , ppm:
52.9; 122.9; 124.8; 131.0; 131.5; 134.8; 161.2; 161.8; 164.9; 166.6. Found, %: С 43.85; Н 2.41; N 8.33.
C12H8BrClN2O2. Calculated, %: C 44.00; Н 2.46; N 8.55.
Methyl 2-Chloro-4-(3-nitrophenyl)pyrimidine-5-carboxylate (9e). Yield 0.23
g
(50%),
1
mp 174-175°С (ЕtOH). Н NMR spectrum (DMSO-d6), , ppm (J, Hz): 3.76 (3Н, s, CО2СН3); 7.82 (1Н, dd,
J = 8.2, J = 7.7, Н-5 Ar); 8.05 (1Н, ddd, J = 7.7, J = 1.5, J = 1.0, H-6 Ar); 8.42 (1Н, ddd, J = 8.2, J = 2.3,
J = 1.0, Н-4 Ar); 8.46 (1H, dd, J = 2.3, J = 1.5, H-2 Ar); 9.23 (1Н, s, Н-6). 13С NMR spectrum (DMSO-d6), ,
ppm: 52.9; 122.8; 123.6; 125.1; 129.9; 135.4; 137.3; 147.4; 161.3; 162.1; 164.1; 165.9. Found, %: С 49.09;
Н 2.64; N 14.30. C12H8ClN3O4. Calculated, %: C 49.08; Н 2.75; N 14.31.
Methyl 2-Chloro-4-(4-nitrophenyl)pyrimidine-5-carboxylate (9f). Yield 0.41 g (87%), mp 155-157°С
1
(ЕtOH). Н NMR spectrum (CDСl3), , ppm (J, Hz): 3.83 (3Н, s, CО2СН3); 7.77 (2Н, d, J = 8.9, Н-2,6 Ar);
8.34 (2Н, d, J = 8.9, H-3,5 Ar); 9.12 (1Н, s, Н-6). 13С NMR spectrum (DMSO-d6), , ppm: 52.3; 123.0; 123.3;
1765

130.3; 141.9; 148.4; 161.3; 162.0; 164.1; 166.3. Found, %: С 49.19; Н 2.84; N 14.18. C12H8ClN3O4. Calculated,
%: C 49.08; Н 2.75; N 14.31.
Methyl 4-Aryl-2-(5-iodo-2-methylphenylamino)pyrimidine-5-carboxylates 10b,d,e (General Method).
A mixture of chloropyrimidine 9b,d,e (0.68 mmol) and 5-iodo-2-methylphenylamine (0.24 g,1.0 mmol) in
anhydrous EtOH (20 ml) was refluxed for 48 h in the case of compounds 10е,d or for 96 h in the case of
compound 10b. The progress of the reaction was controlled by LC/MS. The precipitate formed upon cooling of
the reaction mixture was filtered off, washed with the appropriate alcohol, and recrystallized from MeOH
(compounds 10b,d) or EtOH (compound 10e).
Methyl 2-(5-Iodo-2-methylphenylamino)-4-(4-methylphenyl)pyrimidine-5-carboxylate (10b). Yield
0.10 g (32%), mp 146-147°С. 1Н NMR spectrum (DMSO-d6), , ppm (J, Hz): 2.19 (3Н, s, 2-СН3-5-IС6Н3); 2.36
(3H, s, 4-CH3C6H4); 3.65 (3H, s, CО2CH3); 7.05 (1H, d, J = 8.0, H-3 2-Me-5-IС6Н3); 7.25 (2H, d, J = 8.3,
4-MeC6H4); 7.41 (2H, d, J = 8.3, 4-MeC6H4); 7.44 (1H, dd, J = 8.0, J = 1.7, H-4 2-Me-5-IС6Н3); 7.90 (1H, br. s,
H-6 MeIС6Н3); 8.77 (1H, s, H-6); 9.59 (1H, s, NH). 13С NMR spectrum (DMSO-d6), , ppm: 17.6; 20.9; 51.7;
90.1; 113.8; 128.4; 128.5; 132.2; 132.4; 133.4; 133.7; 134.9; 138.5; 139.5; 160.6; 160.7; 166.0; 166.9. Found, %:
С 52.07; Н 3.95; N 8.91. C20H18IN3O2. Calculated, %: C 52.30; Н 3.95; N 9.15.
Methyl 4-(4-Bromophenyl)-2-(5-iodo-2-methylphenylamino)pyrimidine-5-carboxylate (10d). Yield
1
0.14 g (39%), mp 117-119°С. Н NMR spectrum (DMSO-d6), , ppm (J, Hz): 2.18 (3Н, s, 2-СН3-5-IС6Н3);
3.65 (3H, s, CО2CH3); 7.05 (1H, d, J = 8.3, H-3 2-Me-5-IС6Н3); 7.43-7.47 (3H, m, Н-2,6 4-BrC6H4; Н-4
2-Me-5-IС6Н3)); 7.64 (2H, d, J = 8.3, Н-3,5 4-BrC6H4); 7.84 (1H, br. s, H-6 2-Me-5-IС6Н3); 8.83 (1H, s, H-6);
13
9.72 (1H, s, NH). С NMR spectrum (DMSO-d6), , ppm: 17.7; 51.9; 90.3; 113.6; 123.3; 130.7; 130.8; 132.4;
132.8; 134.0; 137.3; 138.5; 160.8; 161.3; 161.3; 165.4; 166.6. Found, m/z: 523.9437 [M+H (Br79)]+.
C19H16BrIN3O2. Calculated, m/z: 523.9465.
Methyl 2-(5-Iodo-2-methylphenylamino)-4-(3-nitrophenyl)pyrimidine-5-carboxylate (10e). Yield
0.23 g (70%), mp 152-154°С. 1Н NMR spectrum (DMSO-d6), , ppm (J, Hz): 2.15 (3Н, s, СН3IС6Н3); 3.62 (3Н,
s, CО2СН3); 7.02 (1H, d, J = 7.9, H-3 СН3IС6Н3); 7.42 (1H, dd, J = 7.9, J = 1.6, H-4, СН3IС6Н3); 7.70 (1H, t,
J = 8.0, H-5 NO2C6H4); 7.81 (1H, d, J = 1.6, H-6 СН3IС6Н3); 7.91 (1H, d, J = 8.0, H-4 NO2C6H4); 8.28-8.36
13
(2H, m, H-2,6 NO2C6H4); 8.88 (1H, s, H-6); 9.81 (1H, s, NH). С NMR spectrum (DMSO-d6), , ppm: 17.6;
51.8; 90.2; 113.3; 123.2; 124.1; 129.3; 132.4; 132.8; 133.9; 134.0; 135.3; 138.3; 139.8; 147.3; 160.9; 161.6;
164.9; 165.7. Found, %: С 46.66; Н 3.39; N 11.00. C19H15IN4O4. Calculated, %: C 46.55; Н 3.08; N 11.43.
1,2,3,4-Tetrahydropyrimidine-5-carboxylic acids 11 and 14 were obtained by the hydrolysis of the
corresponding methyl esters 3а and 2 with 1 N NaOH in MeOH at room temperature using a method analogous
to one published in [37].
2-Oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylic Acid (11). Yield 87%. Colorless crystals,
mp 226.0-226.5°С (decomp.). 1Н NMR spectrum (DMSO-d6), , ppm (J, Hz): 5.17 (1H, d, J = 2.9, 4-CH); 6.82
(1H, d, J = 5.4, 6-CH); 7.12-7.18 (2H, m, H Ar, 3-NH); 7.22-7.27 (2H, m, H Ar); 7.29-7.33 (2H, m, H Ar); 8.28
13
(1H, dd, J = 5.4, J = 1.9, 1-NH). С NMR spectrum (DMSO-d6), , ppm: 54.8 (C-4); 112.6 (C-5); 126.5 (С-4
Ar); 126.7 (C-2,6 Ar); 127.9 (C-3,5 Ar); 129.5 (C-6); 146.0 (C-1 Ar); 153.7 (C=O); 170.0 (CO2H). Found, %:
С 60.45; Н 4.50; N 12.67. C11H10N2O3. Calculated, %: C 60.55; Н 4.62; N 12.84.
2-Oxo-4-(pyridin-3-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylic Acid (14). Yield 80%. Colorless
crystals, mp 236-238°С (decomp.). 1Н NMR spectrum (DMSO-d6), , ppm (J, Hz): 5.16 (1H, d, J = 2.8, H-4);
7.25 (1H, d, J = 5.8, H-6); 7.38 (1H, ddd, J = 0.8; J = 4.8; J = 7.8; H-5 Py); 7.63 (1H, dt, J = 2.2; J = 7.8, H-4
Py); 7.67 (1H, dd, J = 2.8; J = 1.6, H-3); 8.45-8.48 (2H, m, J = 2.6, H-2,6 Py); 9.16 (1H, dd, J = 5.8; J = 1.6,
H-1). 13С NMR spectrum (DMSO-d6), , ppm: 50.1 (C-4); 102.9 (C-5); 123.9 (С-5 Py); 134.2 (C-4 Py); 136.6
(C-3 Py); 139.8 (C-6); 148.0 (C-2 Py); 148.7 (C-6 Py); 151.9 (C=O); 166.2 (CO2H). Found, %: С 54.74;
Н 4.10; N 19.44. C10H9N3O3. Calculated, %: C 54.80; Н 4.14; N 19.17.
2-Oxo-4-(3-nitrophenyl)-1,2-dihydropyrimidine-5-carboxylic Acid (12). 1 N aqueous NaOH
solution (7.2 ml) was poured into a suspension of compound 8е (0.38 g, 1.45 mmol) in МеОН (25 ml) and
refluxed for 18 h. The progress of the reaction was controlled by LC/MS. The reaction mixture was cooled to
1766

room temperature, acidified with concentrated HCl (0.7 ml) to рН 1 and evaporated to 2/3 of the original
1
volume. The resulting precipitate was filtered off. Yield 0.24 g (66%), mp 258-260°С. Н NMR spectrum
(DMSO-d6), , ppm (J, Hz): 7.73 (1H, t, J = 7.7, H-5 Ar); 7.94 (1H, dd, J = 7.7, J = 1.4, Н-6 Ar); 8.29-8.33 (1H,
m, H-6 Ar); 8.35 (1H, dd, J = 2.3, J = 1.4, Н-2 Ar); 8.60 (1H, br. s, 6-CH); 12.70 (1H, br. s, NH); 12.90 (1H, br.
s, OH). Mass spectrum, m/z (Irel, %): 260 [M-H]- (100). Found, m/z: 262.0454 [M+H]+. C11H8N3O5. Calculated,
13
m/z: 262.0458. С NMR spectrum (D2O, as Na salt), , ppm: 118.4; 123.2; 124.1; 129.3; 134.8; 140.0; 147.5;
160.4; 166.0; 167.6; 174.4.
2-(5-Iodo-2-methylphenylamino)-4-(3-nitrophenyl)pyrimidine-5-carboxylic Acid (13). 1 N aqueous
NaOH solution (5.5 ml) was added to a solution of compound 10е (0.53 g, 1.1 mmol) in МеОН (25 ml). The
reaction mixture was refluxed for 5 h, cooled to room temperature, and acidified with concentrated HCl (0.5 ml)
until precipitation occurred. The precipitate was filtered off and washed with water. Yield 0.48 g (92%), mp
276-278°С (MeOH). 1Н NMR spectrum (DMSO-d6), , ppm (J, Hz): 2.19 (3H, s, CH3); 7.05 (1H, d, J = 8.0, H-3
2-СН3-5-IС6Н3); 7.45 (1H, dd, J = 8.0, J = 1.8, H-4 2-СН3-5-IС6Н3); 7.73 (1H, t, J = 7.7, H-5 3-NO2C6H4); 7.86
(1H, s, NH); 7.97 (1H, ddd, J = 7.7, J = 1.5, J = 1.1, H-6 3-NO2C6H4); 8.32 (1H, ddd, J = 7.7, J = 2.3, J = 1.1, H-4
3-NO2C6H4); 8.37 (1H, dd, J = 2.3, J = 1.5, H-2 3-NO2C6H4); 8.91 (1H, s, H-6); 9.74 (1H, br. s, H-6 2-СН3-
5-IС6Н3); 12.93 (1H, br. s, OH). 13С NMR spectrum (DMSO-d6), , ppm: 17.7 (СН3); 90.3 (С-I); 114.3 (C-5);
123.4 (C-2 3-NO2C6H4); 124.0 (C-4 3-NO2C6H4); 129.2 (C-5 3-NO2C6H4); 132.4 (C-3 2-СН3-5-IC6H3); 132.8
(C-2 2-СН3-5-IC6H3); 133.9 (C-4 2-СН3-5-IC6H3); 134.0 (C-6 2-СН3-5-IC6H3); 135.4 (C-6 3-NO2C6H4); 138.5
(C-1 2-СН3-5-IC6H3); 140.1 (C-1 3-NO2C6H4); 147.2 (C-3 3-NO2C6H4); 160.9 (C-2); 161.8 (C-6); 165.9 (C-4,
CO2H). Mass spectrum, m/z (Irel, %): 475 [M-H]- (100). Found, m/z: 477.0059 [M+H]+. C18H14IN4O4.
Calculated, m/z: 477.0054. Found, %: С 45.28; Н 2.81; N 11.61. C18H13IN4O4. Calculated, %: C 45.40; Н 2.75;
N 11.76.
Methyl 2-Methylsulfanyl-4-(pyridin-3-yl)-1,4-dihydropyrimidine-5-carboxylate (15). K2СО3
(0.60 g, 4.3 mmol) was added to a suspension of pyrimidinethione 7 (1.00 g, 4.0 mmol) in abs. МеОН (200 ml),
and after 1 h, МеI (0.4 ml, 6.4 mmol) was added. The reaction mixture was stirred for 26 h, then evaporated to
dryness. The progress of the reaction was controlled by LC/MS. CH2Cl2 (40 ml) was added to the residue, and
the resulting suspension was stirred for 5 min, then filtrated. The filtrate was evaporated to dryness. The residue
was recrystalized from 2-PrOH (15 ml). Yield 0.7 g (68%), mp 186-188°С. 1Н NMR spectrum (CD3ОD), , ppm
(J, Hz): 2.39 (3H, s, SCH3); 3.66 (3H, s, CO2CH3); 5.56 (1H, s, 4-CH); 7.41 (1H, ddd, J = 8.0, J = 5.0, J = 0.8,
H-5 Py); 7.42 (1H, s, 6-CH); 7.77 (1H, ddd, J = 8.0, J = 2.3, J = 1.5, H-6 Py); 8.42 (1H, dd, J = 5.0, J = 1.5,
H-4 Py); 8.49 (1H, dd, J = 2.3, J = 0.8, H-2 Py). 13С NMR spectrum (DMSO-d6), , ppm: 12.6; 50.9; 54.2;
102.1; 123.7; 134.2; 138.7; 140.1; 147.9; 148.3; 154.5; 165.8. Found, %: С 55.11; Н 5.18; N 15.82. C12H13N3O2S.
Calculated, %: C 54.74; Н 4.98; N 15.96.
X-ray structural investigation of compound 15 was carried out on a Nonius KappaCDD automatic
diffractometer (MoKα 0.71073 Å). The monocrystals of compound 15, obtained by crystallization from MeOH,
were monoclinic, space group P21/c; a 8.5271(4), b 7.5758(4), c 19.198(1) Å, β 90.279(3); V 1240.2(1) Å3,
F(000) 552,  0.26 mm-, dcalc 1.410 gcm-3, Z 4. The intensities of 2705 independent reflections were collected
to 2max 55 at -100С; 1919 reflections with   3() were used for the calculations. The structure was solved
using the SIR-97 software [38]. The full-matrix least-squares refinement in anisotropic approximation was
carried out with the maXus software [39]. The final probability factor was R 0.062. The complete
crystallographic information on compound 15 has been deposited at the Cambridge Crystallographic Data Center
(deposit CCDC 963027).
This work was carried out with the financial support of the European Fund for Regional Development
(No. 2DP/2.1.1.1.0/10/APIA/VIAA/065.
The authors thank S. Belyakov for carrying out the X-ray structural analysis.
1767

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