One-pot synthesis of 4-aryl-2-cyanoimino-3,4-dihydro-1h-pyrimidines and their reactions

Article abstract of DOI:10.1007/s10593-012-1034-y

A series of 4-aryl-2-cyanoimino-3,4-dihydro-1H-pyrimidines was obtained as a result of a multicomponent Biginelli reaction using 1,3-dicarbonyl compounds, aromatic aldehydes, and cyanamide. Alkylation of the obtained compounds with benzyl chloride takes place at the two nitrogen atoms of the tetrahydropyrimidine ring, while oxidation with manganese dioxide leads to the corresponding 1-(pyrimidin-2-yl)carbamides or pyrimidine-2-amines, depending on the conditions.

Full text of DOI:10.1007/s10593-012-1034-y

Chemistry of Heterocyclic Compounds, Vol. 48, No. 4, July, 2012 (Russian Original Vol. 48, No. 4, April, 2012)
ONE-POT SYNTHESIS OF 4-ARYL-2-CYANOIMINO-
3,4-DIHYDRO-1H-PYRIMIDINES AND THEIR REACTIONS
A. H. Moustafa1*, A. S. Shestakov1, and Kh. S. Shikhaliev1
A series of 4-aryl-2-cyanoimino-3,4-dihydro-1H-pyrimidines was obtained as a result of a
multicomponent Biginelli reaction using 1,3-dicarbonyl compounds, aromatic aldehydes, and
cyanamide. Alkylation of the obtained compounds with benzyl chloride takes place at the two nitrogen
atoms of the tetrahydropyrimidine ring, while oxidation with manganese dioxide leads to the
corresponding 1-(pyrimidin-2-yl)carbamides or pyrimidine-2-amines, depending on the conditions.
Keywords: cyanamide, N-cyanoimine, dihydropyrimidine, alkylation, Biginelli reaction, oxidation.
N-Cyanoimines are similar in structure to cyanamides. The difference is in the presence of the C=N
bond, which appreciably increases the basicity of the nitrile group nitrogen atom [1] and extends the
possibilities of using these compounds as synthons [2]. Antimycotic [3] and hypoglycaemic [4, 5] activity has
been detected in certain cyanoiminopyrimidines.
The synthesis of N-cyanoimines is most often based on the use of bis-electrophiles containing the
structural fragment C=N–C≡N: dimethyl cyanoimidodithiocarbonate [4-8] or diphenyl cyanoimidocarbonate
[9]. Cyanoguanidine leads to the required cyanoiminodihydropyrimidines upon condensation with acrylic acid
derivatives [10] or upon successive interaction with aldehydes and 1,3-dicarbonyl compounds [11, 12]. In the
last case the methodology of the Biginelli reaction was employed; this proved productive also in the case where
two equivalents of the cyanamide serve as the nitrogen-containing component [13]. The aim of the present study
was investigation of the three-component reaction of the formation of 3,4-dihydro-1H-pyrimidines and their
derivatives.
The reaction of aromatic aldehydes with 1,3-dicarbonyl compounds and cyanamide takes place upon
refluxing in a water–alcohol mixture in the presence of sodium acetate and hydrochloric acid. These conditions
are optimal [13] for production of the target cyanoiminodihydropyrimidines 1.
At the present time the following order of the reagents' mixing is generally accepted for the Biginelli
reaction: aldehyde + amino component + ethyl acetoacetate [14]. This makes it possible to suppose that
nucleophilic addition of the cyanamide to the aldehyde occurs at the first stage. Under the conditions of acid
catalysis the intermediate A is formed, and this quickly adds a second molecule of cyanamide. Such a direction
of reaction is promoted by the weakly acidic medium (pH ~5) created by acetate buffer. The intermediate B,
thus formed carrying a positive charge, adds a molecule of ethyl acetoacetate with formation of the intermediate
compound C. The aldehyde carbon atom acts as the electrophilic center. This is confirmed by the
_______
*To whom correspondence should be addressed, e-mail: amr_hassanegypt@ymail.com.
1Voronezh State University, 1 Universitetskaya Sq., Voronezh 394006, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 658-664, April, 2012. Original
article submitted January, 25, 2012.
0009-3122/12/4804-0613©2012 Springer Science+Business Media, Inc.
613

effect of the substituent nature on the reaction yield: the appearance of electron-donating methoxy and ethoxy
substituents at position 4 of the aromatic ring reduces the yield, whereas a nitro group at position 2 increases it.
The mechanism as a whole corresponds to that proposed earlier for the formation of 4-aryl-2-cyanoimino-
6-methyl-3,4-dihydro-1H-pyrimidines [13].
With acetylacetone the reaction is not so straightforward. The respective dihydropyrimidines could only
be obtained with 4-NO2- and 4-Cl-benzaldehydes. It is known that cyanamide with 1,3-diketones in aqueous
media gives the corresponding 2-aminopyrimidines along with the linear addition products [15]. In this case,
another side reaction apparently occurs. Acetylacetone reacts less vigorously with compound B, and the
cyanamide begins to compete with it, leading to formation of the intermediate D, which undergoes cyclization
to compound E. Thus, when 4-MeO- and 4-EtO-benzaldehydes were used a mixture of products was obtained
where according to spectral data the compound containing the aromatic ring and the fragment with five
magnetically inequivalent protons predominated. This suggestion is also supported by the fact that compound 2,
the formation of which likewise does not involve the 1,3-dicarbonyl component, was isolated earlier in the
absence of ethanol from the reaction mixture [13].
R2
R2
R2
R1
O
R2
δ–
O
H2NCN
H+
O
H2NCN
Me
1
R
H
N
δ+
– H2O
CN
N
N
N
Me
CN
O
O
NH+
H2N
H2N
N
B
A
C
H2NCN
R2
– H2O
R2
R2
O
H
H
N
1
R
O
NH
NH
N
HN
NH
CN
CN
CN
HN
N
N
N
CN
Me
N
N
H
HN
N
N
H2N
N
H
H
2 [13]
D
E
1a–n
a–g R1 = OEt, h,i R1 = Me, j,k R1 = Ph, l–n R1 = OMe; a R2 = 2-Me, b,m R2 = 4-Me,
c,n R2 = 4-OMe, d R2 = 4-OEt, e,h,j R2 = 4-Cl, f R2 = 4-F, g R2 = 2-NO2, i R2 = 4-NO2, k,l R2 = 2-Cl
The dihydropyrimidines 1 can exist in various tautomeric forms. The data from quantum-chemical
calculations, performed for compound 1e, give preference for tautomer F. Its energy is 43.16 kJ/mol lower than
the energy of tautomer G and 75.82 kJ/mol lower than that of tautomer H. The results of the calculations are
confirmed by the data from NOESY spectroscopy. In the spectrum of compound 1e there is a correlation peak at
5.27/9.15 ppm, corresponding to the interaction of the protons at positions 4 and 3 of the dihydropyrimidine
ring, and there are correlation peaks at 5.27/7.26 and 7.26/9.15 ppm, which correspond to the interaction of
these protons with the ortho-protons of the aromatic ring. In addition, the spectrum contains a correlation peak
at 2.32/10.21 ppm, corresponding to interaction of the methyl group protons with the proton at position 1 of the
pyrimidine system. Analogous correlation peaks are observed in the NOESY spectrum of compound 1i.
The presence of sufficiently mobile protons at positions 1 and 3 of the dihydropyrimidines 1 makes it
possible to use these compounds in alkylation reactions. According to data from quantum-chemical calculations,
the separation energy of the NH proton at positions 1 and 3 amounts to 1424.67 and 1451.94 kJ/mol.
614

Cl
Cl
Cl
O
O
O
EtO
Me
EtO
Me
EtO
Me
N
NH
NH
CN
CN
CN
N
H
H
N
H
F
N
N
N
N
H
H
G
respectively, which indicates almost identical probability that both nitrogen atoms participate in the alkylation.
In fact, attempts to obtain the monoalkyl derivatives of the dihydropyrimidines 1b,e by treatment of their
sodium salts with an equimolar amount of benzyl chloride led, according to data from TLC, to a mixture of
products. With a threefold excess of benzyl chloride under the same conditions it was possible to obtain the
dialkyl derivatives 3a,b.
R
1) NaOMe
MeOH
DMF
O
2) PhCH2Cl
EtO
Me
1b,e
N
CN
N
N
3a,b
a R = Me, b R = Cl
Oxidation of the dihydropyrimidines 1b,e leads to the pyrimidines 4a,b or 5a,b, depending on the
conditions [12]. Under mild conditions with refluxing in acetone, the 2-carbamoylaminopyrimidines 4a,b are
formed. Refluxing in xylene leads to the 2-aminopyrimidines 5a,b.
R2
R2
R2
O
H2O
H2O
MnO2
– H2O
O
O
1b,e
EtO
Me
N
EtO
Me
N
O
EtO
Me
N
N
NH2
CN
N
4a,b
N
NH2
5a,b
N
H
N
H
I
a R2 = Me, b R2 = Cl
The oxidation processes are easily followed by means of the IR spectra of compounds 1, 4, and 5. Thus,
after mild oxidation the absorption bands at 2175 and 1633 cm−1 corresponding to the nitrile group and the C=N
bond between the carbon at position 2 of the dihydropyrimidine ring and the exocyclic nitrogen atom, disappear
in the spectra of the starting dihydropyrimidines. In the spectrum of the obtained compound 4a, an absorption
1
band corresponding to vibrations of the amide fragment appears at 1694 cm−1. In the H NMR spectrum
615

TABLE 1. Physicochemical Characteristics of Compounds 1a-n
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Mp, °С
Yield, %
C
H
N
1a
1b
1c
1d
1e
1f
C16H18N4O2
C16H18N4O2
C16H18N4O3
C17H20N4O3
C15H15ClN4O2
C15H15FN4O2
C15H15N5O4
C14H13ClN4O
C14H13N5O3
C19H15ClN4O
C19H15ClN4O
C14H13ClN4O2
C15H16N4O2
C15H16N4O3
64.37
64.41
64.52
64.41
61.12
61.13
62.07
62.18
56.59
56.52
59.56
59.60
54.67
54.71
58.26
58.24
56.17
56.18
65.10
65.05
65.12
65.05
55.11
55.18
63.44
63.37
60.07
59.99
5.98
6.08
6.16
6.08
5.84
5.77
6.14
6.14
4.63
4.74
4.91
5.00
4.64
4.59
4.53
4.54
4.41
4.38
4.24
4.31
4.32
4.31
4.32
4.30
5.56
5.67
5.35
5.37
18.87
18.78
18.76
18.78
17.73
17.82
17.15
17.06
17.66
17.58
18.47
18.53
21.34
21.27
19.48
19.40
23.46
23.40
15.94
15.97
15.81
15.97
18.47
18.39
19.71
19.71
18.73
18.66
298-299
45
51
31
33
42
15
42
26
67
63
38
36
27
25
246-247
235-237
222-225
250-252
267-269
1g
1h
1i
205-207
(205-207 [13])
269
310-312
235-236
304
1j
1k
1l
274-275
237-238
227-228
1m
1n
of compound 4a, the protons of the NH2 group are reflected in two broad signals at 6.89 and 8.43 ppm, that is
apparently due to the formation of an intramolecular hydrogen bond. A similar pattern is observed in the
spectrum of compound 4b. After oxidation in xylene, the absorption bands corresponding to the nitrile and
amide groups are not observed.
Thus, on the basis of the β-ketoesters(diketones), aromatic aldehydes, and cyanamide it is possible to
obtain a wide range of cyanoiminopyrimidines containing a series of reaction centers.
EXPERIMENTAL
The IR spectra were recorded on a Bruker Vertex 70 spectrometer. The 1H NMR spectra were recorded
on a Bruker AC-300 spectrometer (300 MHz) at 27°C in DMSO-d6 with TMS as internal standard. The NOESY
spectra (τmix = 0.6 s) were obtained on a Bruker DRX-500 instrument (500 MHz) at 30°C in DMSO-d6. The
purity of the synthesized compounds and the course of the reactions were monitored by TLC on Merck UV-254
plates (eluent CHCl3–MeOH, 20:1). The quantum-chemical calculations were performed with GAUSSIAN 03
software by the density functional method (B3LYP). Full optimization of the molecular geometry was realized
in the 3-21G* basis set. The electronic structure was calculated in the 6-31G* basis set.
4-Aryl-2-cyanoimino-6-methyl-3,4-dihydro-1H-pyrimidines 1a-n (General Method). Aldehyde
(20 mmol), 1,3-dicarbonyl compound (20 mmol), NaOAc (20 mmol), cyanamide (40 mmol) as 50% aqueous
solution, and conc. HCl (0.4 ml) were added to EtOH (17 ml). The obtained suspension was refluxed for 4 h,
and the precipitate formed on cooling was recrystallized from EtOH. The yields and physicochemical properties
of compounds 1a-n are given in Table 1, and the spectral data are given in Table 2.
616

TABLE 2. Spectral Data of Compounds 1a-n
Com-
pound
IR spectrum,
ν, cm–1
1Н NMR, δ, ppm (J, Hz)
3216 (NH), 2209 (С≡N),
1.09 (3Н, t, J = 7.1, CH3CH2); 2.32 (3Н, s, СН3);
1a
1b
1c
1727 (С=О), 1663 (C=N) 2.47 (3Н, s, СН3); 3.97 (2H, q, J = 7.1, CH2CH3);
5.51 (1Н, s, Н-4); 7.04-7.22 (4Н, m, Н Ar); 8.79 (1Н, br. s, NH);
9.82 (1Н, br. s, NH)
3318 (NH), 2204 (С≡N),
1678 (С=О), 1636 (C=N) 2.32 (3Н, s, СН3); 4.02 (2H, q, J = 7.1, CH2CH3);
5.21 (1Н, s, Н-4); 7.01-7.17 (4Н, m, Н Ar);
1.16 (3Н, t, J = 7.1, CH3CH2); 2.30 (3Н, s, СН3);
8.76 (1Н, br. s, NH); 9.91 (1Н, br. s, NH)
3322 (NH), 2197 (С≡N),
1.16 (3Н, t, J = 6.9, CH3CH2); 2.31 (3Н, s, СН3);
1684 (С=О), 1638 (C=N) 3.76 (3Н, s, OСН3); 4.03 (2H, q, J = 6.9, CH2CH3);
5.21 (1Н, s, Н-4); 6.82 (2Н, d, J = 8.1, H-2,6 Ar);
7.17 (2Н, d, J = 8.1, H-3,5 Ar); 8.81 (1Н, br. s, NH);
9.87 (1Н, br. s, NH)
3326 (NH), 2192 (С≡N),
1.16 (3Н, t, J = 7.1, CH3CH2); 1.38 (3Н, t, J = 6.9, CH3CH2);
1d
1e
1687 (С=О), 1631 (C=N) 2.32 (3Н, s, СН3); 4.01 (4H, m, 2 CH2CH3);
5.21 (1Н, s, Н-4); 6.79 (2Н, d, J = 8.5, H-2,6 Ar);
7.15 (2Н, d, J = 8.5, H-3,5 Ar); 8.78 (1Н, br. s, NH);
9.81 (1Н, br. s, NH)
3303 (NH), 2175 (С≡N),
1.15 (3Н, t, J = 7.0, CH3CH2); 2.31 (3Н, s, СН3);
1670 (С=О), 1633 (C=N) 4.04 (2H, q, J = 7.0, CH2CH3); 5.28 (1Н, s, Н-4);
7.25 (2Н, d, J = 8.4, H-2,6 Ar);
7.33 (2Н, d, J = 8.4, H-3,5 Ar); 8.92 (1Н, br. s, NH);
9.98 (1Н, br. s, NH)
3312 (NH), 2184 (С≡N),
1.16 (3Н, t, J = 6.9, CH3CH2); 2.31 (3Н, s, СН3);
1f
1676 (С=О), 1634 (C=N) 4.04 (2H, q, J = 6.9, CH2CH3); 5.29 (1Н, s, Н-4);
7.01 (2Н, m, H-2,6 Ar); 7.30 (2Н, m, H-3,5 Ar);
8.93 (1Н, br. s, NH); 9.91 (1Н, br. s, NH)
3213 (NH), 2204 (С≡N),
0.99 (3Н, t, J = 7.1, CH3CH2); 2.32 (3Н, s, СН3);
1g
1721 (С=О), 1653 (C=N) 3.91 (2H, m, 2 CH2CH3); 6.08 (1Н, s, Н-4);
7.48-7.59 (2Н, m, H Ar); 7.72 (1Н, t, J = 7.8, H Ar);
7.91 (1Н, d, J = 7.8, H Ar); 8.82 (1Н, br. s, NH);
10.11 (1Н, br. s, NH)
3181 (NH), 2196 (С≡N),
1687 (С=О), 1653 (C=N) 7.28-7.37 (4Н, m, H Ar); 9.02 (1Н, br. s, NH);
9.99 (1Н, br. s, NH)
2.14 (3Н, s, СН3); 2.91 (3Н, s, СН3); 5.38 (1Н, s, Н-4);
1h
1i
3202 (NH), 2188 (С≡N),
1683 (С=О), 1629 (C=N) 7.53 (2Н, d, J = 8.4, H-2,6 Ar);
8.18 (2Н, d, J = 8.4, H-3,5 Ar); 9.14 (1Н, br. s, NH);
2.21 (3Н, s, СН3); 2.39 (3Н, s, СН3); 5.51 (1Н, s, Н-4);
10.10 (1Н, br. s, NH)
3253 (NH), 2190 (С≡N),
1.76 (3Н, s, СН3); 5.43 (1Н, s, Н-4);
1j
1650 (С=О), 1638 (C=N) 7.21-7.52 (9Н, m, H Ar); 9.00 (1Н, br. s, NH);
9.97 (1Н, br. s, NH)
3196 (NH), 2197 (С≡N),
1652 (С=О), 1633 (C=N) 7.22-7.55 (9Н, m, H Ar); 8.92 (1Н, br. s, NH);
10.00 (1Н, br. s, NH)
1.72 (3Н, s, СН3); 5.81 (1Н, s, Н-4);
1k
1l
3217 (NH), 2204 (С≡N),
2.31 (3Н, s, СН3); 3.55 (3Н, s, ОСН3);
1732 (С=О), 1667 (C=N) 5.71 (1Н, s, Н-4); 7.23-7.44 (4Н, m, H Ar);
9.03 (1Н, br. s, NH); 10.12 (1Н, br. s, NH)
3243 (NH), 2202 (С≡N),
1704 (С=О), 1637 (C=N) 7.04-7.17 (4Н, m, H Ar); 8.89 (1Н, br. s, NH);
9.93 (1Н, br. s, NH)
2.32 (6Н, s, 2СН3); 3.58 (3Н, s, ОСН3); 5.22 (1Н, s, Н-4);
1m
1n
3250 (NH), 2208 (С≡N),
2.31 (3Н, s, СН3); 3.58 (3Н, s, ОСН3); 3.77 (3Н, s, ОСН3);
1717 (С=О), 1634 (C=N) 5.22 (1Н, s, Н-4); 6.82 (2Н, d, J = 8.7, H-2,6 Ar);
7.18 (2Н, d, J = 8.7, H-3,5 Ar); 8.87 (1Н, br. s, NH);
9.92 (1Н, br. s, NH)
1,3-Dibenzyl-2-cyanoimino-5-ethoxycarbonyl-6-methyl-4-(4-methylphenyl)-1,2,3,4-tetrahydropyri-
midine (3a). Cyanoiminopyrimidine 1b (1.49 g, 5 mmol) was dissolved in a mixture of a 1 M solution of
NaOMe in MeOH (5 ml) and of anhydrous DMF (7 ml). The solution was evaporated on a rotary evaporator
617

until the entire methanol was distilled off, and benzyl chloride (1.73 ml, 15 mmol) was added to the remaining
solution. The obtained solution was refluxed for 6 h and after cooling was evaporated on a rotary evaporator.
The residue was treated with petroleum ether (0°C) (5 ml) until a suspension had formed, filtered, and
recrystallized from EtOH. Yield 0.765 g (32%). Colorless crystals; mp 187-188°C. IR spectrum, ν, cm-1: 2202
(С≡N), 1722 (С=О), 1556 (C=N). 1H NMR spectrum, δ, ppm (J, Hz): 1.12 (3H, t, 3J = 7.0, CH3CH2); 2.34 (3H,
3
2
2
s, CH3); 2.36 (3H, s, CH3); 4.05 (2H, q, J = 7.0, СH3CH2); 4.69 (1Н, d, J = 15.4) and 4.88 (1Н, d, J = 15.4,
СН2Ph); 5.30 (1Н, d, 2J = 15.3) and 5.60 (1Н, d, 2J = 15.3, СН2Ph); 5.41 (1Н, s, Н-4); 6.74 (2H, d, 3J = 7.2, H-
2,6 Ar); 6.98 (2H, d, J = 7.2, H-3,5 Ar); 7.03-7.45 (10H, m, H Ph). Found, %: С 75.18; Н 6.39; N 11.70.
3
C30H30N4O2. Calculated, %: С 75.29; Н 6.32; N 11.71.
1,3-Dibenzyl-4-(4-chlorophenyl)-2-cyanoimino-5-ethoxycarbonyl-6-methyl-1,2,3,4-tetrahydro-
pyrimidine (3b). The compound was obtained similarly. Yield 0.724 g (29%); mp 167-168°C. IR spectrum, ν,
1
3
cm-1: 2206 (С≡N), 1711 (С=О), 1568 (C=N). H NMR spectrum, δ, ppm (J, Hz): 1.13 (3H, t, J = 7.0,
CH3CH2); 2.38 (3H, s, CH3); 4.06 (2H, q, 3J = 7.0, СH3CH2); 4.70 (1Н, d, 2J = 15.3) and 4.84 (1Н, d, 2J = 15.3,
СН2Ph); 5.35 (1Н, d, J = 16.3) and 5.58 (1Н, d, J = 16.3, СН2Ph); 5.42 (1Н, s, Н-4); 6.69 (2H, d, J = 7.2,
H-2,6 Ar); 7.02-7.39 (12H, m, H-3,5 Ar, H Ph). Found, %: С 69.88; Н 5.40; N 11.28. C29H27ClN4O2.
Calculated, %: С 69.80; Н 5.45; N 11.23.
2
2
3
Ethyl 2-(Carbamoylamino)-4-methyl-6-(4-methylphenyl)pyrimidine-5-carboxylate (4a). A mixture
of cyanoiminopyrimidine 1b (0.120 g, 0.4 mmol) and MnO2 (0.35 g, 4 mmol) in acetone (15 ml) was refluxed
for 20 h and was filtered off after cooling. The precipitate was washed on the filter with acetone (30 ml), and the
combined filtrates were evaporated. The residue was recrystallized from acetone. Yield 0.098 g (78%).
Colorless crystals; mp 201-202°C. IR spectrum, ν, cm-1: 3416 (NH2), 3199 (NH), 1713 (С=О (ester)), 1693
1
(CONH2), 1552 (C=N). H NMR spectrum, δ, ppm (J, Hz): 1.05 (3H, t, J = 7.1, CH3CH2); 2.32 (3H, s,
CH3С6Н4); 2.42 (3H, s, 6-CH3); 4.10 (2H, q, J = 7.1, СH3CH2); 6.89 (1H, br. s) and 8.43 (1H, br. s, NH2); 7.25
(2H, d, J = 8.0, H-2,6 Ar); 7.45 (2H, d, J = 8.0, H-3,5 Ar); 9.11(1H, s, NH). Found, %: С 61.22; Н 5.68;
N 17.83. C16H18N4O3. Calculated, %: С 61.14; Н 5.77; N 17.82.
Ethyl 2-(Carbamoylamino)-6-(4-chlorophenyl)-4-methylpyrimidine-5-carboxylate (4b). The
compound was obtained similarly. Yield 0.094 g (70%); mp 219-220°C. IR spectrum, ν, cm-1: 3348 (NH2), 3258
(NH), 1711 (С=О (ester)), 1694 (CONH2), 1561 (C=N). 1H NMR spectrum, δ, ppm (J, Hz): 1.08 (3H, t, J = 7.1,
CH3CH2); 2.50 (3H, s, CH3); 4.13 (2H, q, J = 7.1, СH3CH2); 6.88 (1H, br. s) and 8.31 (1H, br. s, NH2); 7.47
(2H, d, J = 8.4, H-2,6 Ar); 7.56 (2H, d, J = 8.4, H-3,5 Ar); 9.21 (1H, s, NH). Found, %: С 53.77; Н 4.59;
N 16.70. C15H15ClN4O3. Calculated, %: С 53.82; Н 4.52; N 16.74.
Ethyl 2-Amino-4-methyl-6-(4-methylphenyl)pyrimidine-5-carboxylate (5a). A mixture of cyano-
iminopyrimidine 1b (0.45 g, 1.5 mmol) and MnO2 (1.31 g, 15 mmol) in o-xylene (50 ml) was refluxed for 26 h
and filtered. The precipitate was washed on the filter with hot o-xylene (20 ml), and the combined filtrates were
evaporated. The residue was treated with petroleum ether (10 ml) (at 0°C) until a suspension was formed,
filtered off, and recrystallized from EtOH. Yield 0.130 g (32%). Colorless crystals; mp 135-136°C. IR
spectrum, ν, cm-1: 3458, 3314 (NH2), 1705 (С=О), 1668 (NH2), 1538 (C=N). 1H NMR spectrum, δ, ppm (J, Hz):
0.97 (3H, t, J = 7.1, CH3CH2); 2.38 (3H, s, CH3С6Н4); 2.40 (3H, s, 6-CH3); 3.99 (2H, q, J = 7.1, СH3CH2); 6.41
(2H, s, NH2); 7.16 (2H, d, J = 7.8, H-2,6 Ar); 7.38 (2H, d, J = 7.8, H-3,5 Ar). Found, %: С 66.32; Н 6.27;
N 15.58. C15H17N3O2. Calculated, %: С 66.40; Н 6.32; N 15.49.
Ethyl 2-Amino-6-(4-chlorophenyl)-4-methylpyrimidine-5-carboxylate (5b). The compound was
obtained similarly. Yield 0.131 g (30%). Colorless crystals; mp 160°C. IR spectrum, ν, cm-1: 3424, 3312 (NH2),
1700 (С=О), 1643 (NH2), 1531 (C=N). 1H NMR spectrum, δ, ppm (J, Hz): 1.01 (3H, t, J = 6.9, CH3CH2); 2.39
(3H, s, 6-CH3); 4.01 (2H, q, J = 6.9, СH3CH2); 6.61 (2H, s, NH2); 7.39 (2H, d, J = 7.9, H-2,6 Ar); 7.47 (2H, d,
J = 7.9, H-3,5 Ar). Found, %: С 57.67; Н 4.92; N 14.31. C14H14ClN3O2. Calculated, %: С 57.64; Н 4.84;
N 14.40.
618

The work was carried out with financial support from the Federal Target Program of the Ministry of
Education and Science of the Russian Federation "Scientific and Scientific-pedagogical Personnel of Innovative
Russia" in 2009-2013 (State contract No. 14.740.11.0368) and the Ministry of Education and Science of the
Russian Federation Analytical Target Program "Development of the Higher School Scientific Potential (2009-
2011)" (Project No. 2.11/11994).
REFERENCES
1.
M. Berthelot, M. Helbert, C. Laurence, J.-Y. LeQuestel, F. Anvia, and R. W. Taft, J. Chem. Soc., Perkin
Trans. 2, 625 (1993).
2.
3.
4.
5.
6.
7.
8.
9.
D. D. Nekrasov, Khim. Geterotsikl. Soedin., 963 (2005). [Chem. Heterocycl. Compd., 41, 809 (2005).]
A. Kreutzberger and M. Sellheim, J. Heterocycl. Chem., 22, 721 (1985).
F. Ishikawa, A. Kosasayama, S. Nakamura, and T. Konno, Chem. Pharm. Bull., 26, 3658 (1978).
A. Kosasayama, T. Konno, K. Higashi, and F. Ishikawa, Chem. Pharm. Bull., 27, 841 (1979).
A. Buschauer, H.-J. Sattler, and W. Schunack, Chem. Ber., 117, 2597 (1984).
A. Borchers and W. Schunack, Arch. Pharm., 317, 455 (1984).
G. Walther, H. Daniel, W. D. Bechtel, and K. Brandt, Arzneim. Forsch., 40, 440 (1990).
P. J. Garratt, C. J. Hobbs, C. S. J. Walpole, and R. Wrigglesworth, J. Chem. Soc., Chem. Commun., 568
(1987).
10.
11.
P. Aleksandrowicz, M. Bukowska, M. Maciejewski, and J. Prejzner, Can. J. Chem., 57, 2593 (1979).
A. D. Shutalev, in: The Fourth International Electronic Conference on Synthetic Organic Chemistry
ECSOC-4, 2000, p. 1.
12.
13.
P. A. Solov'ev and A. D. Shutalev, Khim. Geterotsikl. Soedin., 1023 (2009). [Chem. Heterocycl.
Compd., 45, 809 (2009).]
R. Hulme, O. D. P. Zamora, E. J. Mota, M. A. Pasten, R. Conteras-Rojas, R. Miranda, I. Valencia-
Hernandez, J. Correa-Basurto, J. Trujillo-Ferrara, and F. Delgado, Tetrahedron, 64, 3372 (2008).
S. V. Vdovina and V. A. Mamedov, Usp. Khim., 77, 1091 (2008). [Russ. Chem. Rev., 77, 1017 (2008).]
A. Miller, J. Org. Chem., 49, 4072 (1984).
14.
15.
619