Synthesis of new 2-sulfanyl- and 2-aminopyrimidines

Article abstract of DOI:10.1134/S1070428012060140

Alkylation of 4,5,6-substituted 2-sulfanylpyrimidines with alkyl and benzyl iodides and chlorides gave the corresponding 2-alkylsulfanyl and 2-benzylsulfanyl derivatives. 2-Methylsulfanylpyrimidines reacted with morpholine, benzylamine, and 4-methoxyanili

Full text of DOI:10.1134/S1070428012060140

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 6, pp. 829–835. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © L.A. Grigoryan, M.A. Kaldrikyan, R.G. Melik-Ogandzhanyan, 2012, published in Zhurnal Organicheskoi Khimii, 2012, Vol. 48,
No. 6, pp. 832–837.
Synthesis of New 2-Sulfanyl- and 2-Aminopyrimidines
L. A. Grigoryan, M. A. Kaldrikyan, and R. G. Melik-Ogandzhanyan
Mndzhoyan Institute of Fine Organic Chemistry, Scientific Technological Center of Organic
and Pharmaceutical Chemistry, National Academy of Sciences of Armenia,
pr. Azatutyan 26, Yerevan, 0014 Armenia
e-mail: melik@cornet.am
Received July 27, 2011
Abstract—Alkylation of 4,5,6-substituted 2-sulfanylpyrimidines with alkyl and benzyl iodides and chlorides
gave the corresponding 2-alkylsulfanyl and 2-benzylsulfanyl derivatives. 2-Methylsulfanylpyrimidines reacted
with morpholine, benzylamine, and 4-methoxyaniline in butanol to produce 2-amino derivatives.
DOI: 10.1134/S1070428012060140
Taking into account high pharmacological activity
of sulfanyl-substituted pyrimidines [1], in continuation
of our previous studies [2] we synthesized a number of
new pyrimidine derivatives with a view to reveal com-
pounds possessing antitumor activity. 2-RS-substituted
pyrimidines were prepared by the most generally used
alkylation method [3] via reaction of 2-sulfanyl-5-al-
kyl(benzyl-, 4-alkoxybenzyl)pyrimidines [3, 4, 5] with
butyl iodide and substituted benzyl chlorides. The
latter were obtained by chloromethylation of the corre-
sponding arenes [6]. The alkylation was carried out in
methanol or ethanol in the presence of potassium hy-
droxide (Scheme 1).
yield to 25% by carrying out the reaction in 20–
25% aqueous acetic acid. 2-(Carboxymethylsulfanyl)-
pyrimidines were synthesized in 57–64% yield using
3 equiv of aqueous alkali.
It is known that alkylsulfanyl group tends to under-
go nucleophilic substitution [7], in particular in reac-
tions with amines. The replacement of alkylsulfanyl
group occurs at a higher rate when a hydroxy group is
present in the pyrimidine ring [8]. 5-Substituted
2-methylsulfanyl-4-hydroxypyrimidines were subject-
ed to amination with morpholine, benzylamine, and
4-methoxyaniline in butan-1-ol (Scheme 2).
2-Aminopyrimidines having a 4-alkoxybenzyl
group on C5 were formed in a lower yield (50–62%).
Structural factors affecting the amination process were
studied in [9]. The presence of ortho- and p-orienting
Chloroacetic acid was also used as alkylating agent.
However, the yield of S-carboxymethyl derivatives
was poor (10–12%). We succeeded in improving the
Scheme 1.
OH
OH
R1
R3
R1
R2X, MeOH, KOH
N
N
HS
N
R2S
N
R3
Ia–Is
IIa–IIs
II, R1 = 4-PrOC6H4CH2, R2 = Bu, R3 = HO (a); R1 = 4-i-BuOC6H4CH2, R2 = Bu, R3 = HO (b); R1 = iso-C5H11, R2 = 3-Br-4-MeO-
C6H3CH2, R3 = Me (c); R1 = C8H17, R2 = 3-Br-4-MeOC6H3CH2, R3 = Me (d); R1 = 4-MeOC6H4CH2, R2 = 3-Br-4-MeOC6H3CH2, R3 =
Me (e); R1 = 4-EtOC6H4CH2, R2 = 3-Br-4-MeOC6H3CH2, R3 = Me (f); R1 = 4-i-PrOC6H4CH2CH2, R2 = 3-Br-4-MeOC6H3CH2, R3 =
Me (g); R1 = PhCH2, R2 = 3-Br-4-MeOC6H3CH2, R3 = HO (h); R1 = 4-EtOC6H4CH2, R2 = 3-Br-4-MeOC6H3CH2, R3 = HO (i); R1 =
C7H15, R2 = 3-O2N-4-MeOC6H3CH2, R3 = Me (j); R1 = C8H17, R2 = 3-O2N-4-MeOC6H3CH2, R3 = Me (k); R1 = C7H15, R2 = 2-MeO-
3-O2NC6H3CH2, R3 = Me (l); R1 = C8H17, R2 = 2-EtO-3-O2NC6H3CH2, R3 = Me (m); R1 = PhCH2, R2 = R2 = 2-EtO-3-O2NC6H3CH2,
R3 = HO (n); R1 = iso-C5H11, R2 = HOC(O)CH2, R3 = Me (o); R1 = C8H17, R2 = HOC(O)CH2, R3 = Me (p); R1 = 4-MeOC6H4CH2,
R2 = HOC(O)CH2, R3 = Me (q); R1 = 4-PrOC6H4CH2, R2 = HOC(O)CH2, R3 = HO (r); R1 = 4-i-BuOC6H4CH2, R2 = HOC(O)CH2,
R3 = HO (s); X = I [R2 = Bu, HOC(O)CH2], Cl (R2 = ArCH2).
829

GRIGORYAN et al.
830
Scheme 2.
OH
N
OH
N
R1
R1
R3
R2H, BuOH
N
N
MeS
R3
R2
IIIa–IIIq
IVa–IVq
IV, R1 = C8H17, R2 = morpholin-4-yl, R3 = Me (a); R1 = 4-MeOC6H4CH2, R2 = morpholin-4-yl, R3 = Me (b); R1 = 4-EtOC6H4CH2,
R2 = morpholin-4-yl, R3 = Me (c); R1 = PhCH2, R2 = morpholin-4-yl, R3 = HO (d); R1 = 4-EtOC6H4CH2, R2 = morpholin-4-yl, R3 =
HO (e); R1 = 4-PrOC6H4CH2, R2 = morpholin-4-yl, R3 = HO (f); R1 = 4-BuOC6H4CH2, R2 = morpholin-4-yl, R2 = HO (g); R1 =
C7H15, R2 = PhCH2NH, R3 = Me (h); R1 = 4-MeOC6H4CH2, R2 = PhCH2NH, R3 = Me (i); R1 = 4-EtOC6H4CH2O, R2 = PhCH2NH,
R3 = Me (j); R1 = PhCH2, R2 = PhCH2NH, R3 = HO (k); R1 = 4-EtOC6H4CH2O, R2 = PhCH2NH, R3 = HO (l); R1 = 4-BuOC6H4CH2,
R2 = PhCH2NH, R3 = Me (m); R1 = 4-i-BuOC6H4CH2, R2 = PhCH2NH, R3 = HO (n); R1 = C7H15, R2 = 4-MeOC6H4NH, R3 = Me (o);
R1 = 4-EtOC6H4CH2, R2 = 4-MeOC6H4NH, R3 = HO (p); R1 = 4-i-BuOC6H4CH2, R2 = 4-MeOC6H4NH, R3 = HO (q).
substituents in position 5 of the pyrimidine ring
reduces the positive charge on C2 and hampers nucleo-
philic attack by amine.
(benzene–acetone, 2:1). IR spectrum, ν, cm–1: 3300 br
(OH), 3020 s (C–Harom), 1600 (C=Carom), 1125 s
1
[δ(C–OH)], 670 s (C–S). H NMR spectrum, δ, ppm:
0.80 t (3H, OCH2CH2CH3, J = 6.7 Hz), 0.93 t [3H,
(CH2)3CH3, J = 7.0 Hz], 1.30–1.47 m [4H, CH2-
(CH2)2CH3], 1.65 m (2H, OCH2CH2CH3), 1.92 m (2H,
SCH2), 3.45 s (2H, 5-CH2), 3.82 m (2H, OCH2), 6.90–
7.30 m (4H, Harom), 10.60 br.s (2H, OH). Found, %:
N 7.84; S 9.00. C18H24N2O3S. Calculated, %: N 8.04;
S 9.20.
The structure of the newly synthesized compounds
was confirmed by elemental analyses and IR, 1H NMR,
and mass spectra. Preliminary tests of pyrimidines II
and IV for antitumor activity against transplantable
sarcoma showed the highest activity for compound IVa.
EXPERIMENTAL
2-Butylsulfanyl-5-(4-isobutoxybenzyl)pyrimi-
dine-4,6-diol (IIb) was synthesized from compound
Ib and butyl iodide. Yield 54%, mp 248–250°C,
Rf 0.60 (benzene–acetone, 2:1). IR spectrum, ν, cm–1:
3385 br, 3280 br (OH); 3010 s (C–Harom), 1610
Thin-layer chromatography was performed on
Silufol UV-254 plates; spots were visualized under UV
light. The IR spectra were recorded on an NA 330 FT-
IR spectrometer (USA) from samples dispersed in
1
1
(C=Carom), 1120 s [δ(C–OH)], 675 s (C–S). H NMR
mineral oil. The H NMR spectra were measured from
spectrum, δ, ppm: 0.91 t [3H, (CH2)3CH3, J = 7.0 Hz],
1.00 d [6H, OCH2CH2(CH3)2, J = 6.7 Hz], 1.25–
1.41 m [4H, CH2(CH2)2CH3], 1.90 m (2H, SCH2),
2.02 m [1H, CH(CH3)2], 3.63 d (2H, OCH2, J =
6.5 Hz), 3.95 s (2H, 5-CH2), 6.80–7.50 m (4H, Harom),
11.20 br.s (2H, OH). Found, %: N 8.05; S 9.15.
C19H26N2O3S. Calculated, %: N 7.73; S 8.85.
solutions in DMSO-d6 on a Varian Mercury-300 instru-
ment operating at 300 MHz; tetramethylsilane was
used as internal reference. The mass spectra (electron
impact, 60 eV) were obtained on an MKh-1321 mass
spectrometer.
Initial pyrimidines I and III were synthesized as
described in [3, 5].
2-(3-Bromo-4-methoxybenzylsulfanyl)-6-methyl-
5-(3-methylbutyl)pyrimidin-4-ol (IIc) was synthe-
sized from compound Ic and 3-bromo-4-methoxy-
benzyl chloride. Yield 72%, mp 195–196°C, Rf 0.66
(benzene–acetone, 2:1). IR spectrum, ν, cm–1: 3220 br
(OH), 2918 s (CH3), 1455 s, 1385 s [δ(C–CH3)], 670 s
2-Butyl(benzyl)sulfanylpyrimidines IIa–IIn (gen-
eral procedure). The corresponding 2-sulfanylpyrim-
idine, 5 mmol, was added to a solution of 0.28 g
(5 mmol) of potassium hydroxide in 20 ml of methanol
or ethanol. When the mixture turned homogeneous,
5.5 mmol of butyl iodide or substituted benzyl chloride
was added, and the mixture was heated for 30–40 min
under reflux, cooled, and diluted with 60 ml of water.
The precipitate was filtered off, washed with water,
and recrystallized from ethanol.
1
(C–S). H NMR spectrum, δ, ppm: 0.95 d [6H,
CH(CH3)2, J = 6.5 Hz], 1.22 m (2H, 5-CH2CH2),
1.57 m [1H, CH(CH3)2], 2.08 s (3H, CH3), 2.30 m (2H,
5-CH2), 3.84 s (3H, OCH3), 4.35 s (2H, SCH2), 6.82 d
(1H, J = 8.5 Hz), 7.28 d.d (1H, J = 8.5, 2.3 Hz), 7.61 d
(1H, J = 2.3 Hz), 12.18 br.s (1H, OH). Found, %:
N 6.62; S 7.53. C18H23BrN2O2S. Calculated, %:
N 6.81; S 7.79.
2-Butylsulfanyl-5-(4-propoxybenzyl)pyrimidine-
4,6-diol (IIa) was synthesized from compound Ia and
butyl iodide. Yield 51%, mp 238–240°C, Rf 0.71
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 6 2012

SYNTHESIS OF NEW 2-SULFANYL- AND 2-AMINOPYRIMIDINES
831
5-Benzyl-2-(3-bromo-4-methoxybenzylsulfanyl)-
pyrimidine-4,6-diol (IIh) was synthesized from com-
pound Ih and 3-bromo-4-methoxybenzyl chloride.
Yield 48%, mp 272–273°C, Rf 0.65 (benzene–acetone,
2-(3-Bromo-4-methoxybenzylsulfanyl)-6-methyl-
5-octylpyrimidin-4-ol (IId) was synthesized from
compound Id and 3-bromo-4-methoxybenzyl chloride.
Yield 85%, mp 140–142°C, Rf 0.61 (benzene–acetone,
2:1). IR spectrum, ν, cm–1: 3225 br (OH), 2920 s
(CH3), 1450 s, 1380 s [δ(C–CH3)], 675 s (C–S).
1H NMR spectrum, δ, ppm: 0.97 t [3H, (CH2)7CH3, J =
6.9 Hz], 1.35–1.43 m [12H, (CH2)6CH3], 2.20 s (3H,
CH3), 2.35 m (2H, 5-CH2), 3.90 s (3H, OCH3), 4.30 s
(2H, SCH2), 6.82 d (1H, J = 8.5 Hz), 7.31 d.d (1H, J =
8.5, 2.2 Hz), 7.63 d (1H, J = 2.2 Hz), 11.7 br.s (1H,
OH). Found, %: N 6.04; S 7.15. C21H29BrN2O2S. Cal-
culated, %: N 6.18; S 7.07.
1
2:1). H NMR spectrum, δ, ppm: 3.60 s (2H, CH2),
3.85 s (3H, OCH3), 4.28 s (2H, SCH2), 6.91 d (1H, J =
8.5 Hz), 7.41 d.d (1H, J = 8.5, 2.3 Hz), 7.59 d (1H, J =
2.3 Hz), 7.05 t.t (1H, p-H, J = 7.1, 1.5 Hz), 7.16 m
(2H, m-H), 7.25 m (2H, o-H), 11.30 br.s (2H, OH).
Found, %: N 6.16; S 7.18. C19H17BrN2O3S. Calculated,
%: N 6.46; S 7.40.
2-(3-Bromo-4-methoxybenzylsulfanyl)-5-
(4-ethoxybenzyl)pyrimidine-4,6-diol (IIi) was syn-
thesized from compound Ii and 3-bromo-4-methoxy-
benzyl chloride. Yield 49%, mp 242–244°C, Rf 0.58
2-(3-Bromo-4-methoxybenzylsulfanyl)-5-(4-me-
thoxybenzyl)-6-methylpyrimidin-4-ol (IIe) was syn-
thesized from compound Ie and 3-bromo-4-methoxy-
benzyl chloride. Yield 88%, mp 191–192°C, Rf 0.63
1
(benzene–acetone, 2:1). H NMR spectrum, δ, ppm:
1.36 t (3H, CH2CH3, J = 7.0 Hz), 3.52 s (2H, CH2),
3.85 s (3H, OCH3), 3.95 q (2H, OCH2, J = 7.0 Hz),
4.28 s (2H, SCH2); 6.67 m (2H), 7.14 m (2H), 6.91 d
(1H, J = 8.5 Hz), 7.40 d.d (1H, J = 8.5, 2.2 Hz), 7.59 d
(1H, J = 2.2 Hz); 11.34 br.s (2H, OH). Found, %:
N 5.63; S 6.88. C21H21BrN2O4S. Calculated, %:
N 5.87; S 6.72.
1
(benzene–acetone, 2:1). H NMR spectrum, δ, ppm:
2.25 s (3H, CH3), 3.67 s (2H, CH2), 3.73 s (3H,
OCH3), 3.85 s (3H, OCH3), 4.25 s (2H, SCH2), 6.72 m
(2H), 7.07 m (2H), 6.89 d (1H, J = 8.5 Hz), 7.31 d.d
(2H, J = 8.5, 2.2 Hz), 7.57 d (1H, J = 2.2 Hz),
12.32 br.s (1H, OH). Found, %: N 6.51; S 7.05.
C21H21BrN2O3S. Calculated, %: N 6.07; S 6.95.
5-Heptyl-2-(4-methoxy-3-nitrobenzylsulfanyl)-
6-methylpyrimidin-4-ol (IIj) was synthesized from
compound Ij and 4-methoxy-3-nitrobenzyl chloride.
Yield 81%, mp 132–133°C, Rf 0.85 (benzene–acetone,
2-(3-Bromo-4-methoxybenzylsulfanyl)-5-
(4-ethoxybenzyl)-6-methylpyrimidin-4-ol (IIf) was
synthesized from compound If and 3-bromo-4-
methoxybenzyl chloride. Yield 80%, mp 148–150°C,
1
2 : 1). H NMR spectrum, δ, ppm: 0.90 t [3H,
1
(CH2)6CH3, J = 6.9 Hz], 1.27–1.43 m [10H,
(CH2)5CH3], 2.34 m (2H, 5-CH2), 2.26 s (3H, CH3),
3.94 s (3H, OCH3), 4.30 s (2H, SCH2), 7.16 d (1H, J =
8.7 Hz), 7.64 d.d (1H, J = 8.7, 2.3 Hz), 7.92 d (1H, J =
2.3 Hz), 12.28 br.s (1H, OH). Found, %: N 10.25;
S 7.94. C20H27N3O4S. Calculated, %: N 10.36; S 7.91.
Rf 0.64 (benzene–acetone, 2:1). H NMR spectrum, δ,
ppm: 1.37 t (3H, CH2CH3, J = 7.0 Hz), 2.25 s (3H,
CH3), 3.66 s (2H, CH2), 3.85 s (3H, OCH3), 3.96 q
(2H, OCH2, J = 7.0 Hz), 4.25 s (2H, SCH2), 6.70 m
(2H), 7.05 m (2H), 6.89 d (1H, J = 8.5 Hz), 7.31 d.d
(1H, J = 8.5, 2.2 Hz), 7.57 d (1H, J = 2.2 Hz),
12.39 br.s (1H, OH). Found, %: N 6.00; S 6.54.
C22H23BrN2O3S. Calculated, %: N 5.89; S 6.74.
2-(4-Methoxy-3-nitrobenzylsulfanyl)-6-methyl-
5-octylpyrimidin-4-ol (IIk) was synthesized from
compound Ik and 4-methoxy-3-nitrobenzyl chloride.
Yield 78%, mp 122–123°C, Rf 0.71 (benzene–acetone,
2:4). IR spectrum, ν, cm–1: 3210 br (OH), 2905 s
(CH3), 1550 s (νasNO2), 1340 s (νsNO2), 670 s (C–S).
1H NMR spectrum, δ, ppm: 0.95 t [3H, (CH2)7CH3, J =
6.8 Hz], 1.32–1.40 m [12H, (CH2)6CH3], 2.10 s (3H,
CH3), 2.32 m (2H, 5-CH2), 3.95 s (3H, OCH3), 4.28 s
(2H, SCH2), 7.16 d (1H, J = 8.7 Hz), 7.64 d.d (1H, J =
8.7, 2.3 Hz), 7.92 d (1H, J = 2.3 Hz), 12.24 br.s (1H,
OH). Found, %: N 10.16; S 7.53. C21H29N3O4S. Cal-
culated, %: N 10.02; S 7.64.
2-(3-Bromo-4-methoxybenzylsulfanyl)-5-(4-iso-
propoxybenzyl)-6-methylpyrimidin-4-ol (IIg) was
synthesized from compound Ig and 3-bromo-4-
methoxybenzyl chloride. Yield 50%, mp 168–170°C,
Rf 0.62 (benzene–acetone, 2:1). IR spectrum, ν, cm–1:
3200 br (OH), 2930 s (CH3), 1450 s, 1380 s
1
[δ(C–CH3)], 677 s (C–S). H NMR spectrum, δ, ppm:
1.32 s [6H, OCH(CH3)2, J = 6.7 Hz], 2.30 s (3H, CH3),
3.48 s (2H, CH2), 3.85 s (3H, OCH3), 4.20 s (2H,
SCH2), 4.42 m [1H, OCH(CH3)2], 6.67–7.14 m (4H,
Harom), 6.91 d (1H, J = 8.6 Hz), 7.40 d.d (1H, J = 8.6,
2.2 Hz), 7.59 d (1H, J = 2.2 Hz), 11.34 br.s (1H, OH).
Found, %: N 5.92; S 6.35. C23H25BrN2O3S. Calculated,
%: N 5.72; S 6.55.
5-Heptyl-2-(2-methoxy-3-nitrobenzylsulfanyl)-
6-methylpyrimidin-4-ol (IIl) was synthesized from
compound Il and 2-methoxy-3-nitrobenzyl chloride.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 6 2012

GRIGORYAN et al.
832
Yield 83%, mp 145–147°C, Rf 0.52 (benzene–acetone,
2:1). IR spectrum, ν, cm–1: 3190 br (OH), 2915 s
(CH3), 1546 s (νasNO2), 1345 s (νsNO2), 675 s (C–S).
1H NMR spectrum, δ, ppm: 0.90 t [3H, (CH2)6CH3, J =
6.9 Hz], 1.27–1.43 m [10H, (CH2)5CH3], 2.26 s (3H,
CH3), 2.34 m (2H, 5-CH2), 3.94 s (3H, OCH3), 4.30 s
(2H, SCH2), 7.07 d (1H, J = 9.1 Hz), 8.11 d.d (1H, J =
9.1, 2.9 Hz), 8.44 d (1H, J = 2.9 Hz), 12.6 br.s (1H,
OH). Found, %: N 10.12; S 7.43. C20H27N3O4S. Cal-
culated, %: N 10.36; S 7.91.
mp 162–163°C, Rf 0.61 (benzene–acetone–ethanol,
3:3:0.5). H NMR spectrum, δ, ppm: 0.92 d (6H, CH3,
1
J = 6.6 Hz), 1.28 m (2H, CH2), 1.60 m (1H, CH),
2.20 s (3H, CH3), 2.34 m (2H, CH2), 3.80 s (2H,
SCH2), 12.33 br.s (2H, OH, COOH). Found, %:
N 10.16; S 12.0. C12H18N2O3S. Calculated, %:
N 10.36; S 11.86.
(4-Hydroxy-6-methyl-5-octylpyrimidin-2-ylsul-
fanyl)acetic acid (IIp) was synthesized from com-
pound Ip and chloroacetic acid. Yield 71%, mp 137–
138°C, Rf 0.67 (benzene–acetone–ethanol, 3:3:0.5).
IR spectrum, ν, cm–1: 3340 br (OH), 2924 s (C–H,
CH3), 2439 br (COOH, assoc.), 1455 s, 1387
2-(2-Ethoxy-3-nitrobenzylsulfanyl)-6-methyl-
5-octylpyrimidin-4-ol (IIm) was synthesized from
compound Im and 2-ethoxy-3-nitrobenzyl chloride.
Yield 85%, mp 158–159°C, Rf 0.57 (benzene–acetone,
2:4). IR spectrum, ν, cm–1: 3350 br (OH), 2930 s
(CH3), 1538 s (νasNO2), 1340 s (νsNO2), 1125 s
1
[δ(C–CH3)], 660 s (C–S). H NMR spectrum, δ, ppm:
0.92 t [3H, (CH2)7CH3, J = 6.9 Hz], 1.35–1.45 m [12H,
(CH2)6CH3], 2.20 s (3H, CH3), 2.35 m (2H, 5-CH2),
3.70 s (2H, SCH2), 11.04 br.s (1H, OH), 12.60 br.s
(1H, COOH). Found, %: N 9. 04; S 10. 12.
C15H24N2O3S. Calculated, %: N 8.97; S 10.26.
1
(C–OH), 670 s (C–S). H NMR spectrum, δ, ppm:
0.89 t [3H, (CH2)7CH3], 1.25–1.42 m [12H,
(CH2)6CH3], 2.34 m (2H, 5-CH2), 1.49 t (3H,
OCH2CH3, J = 7.0 Hz), 2.32 s (3H, CH3), 4.25 q (2H,
OCH2, J = 7.0 Hz), 4.32 s (2H, SCH2), 7.07 d (1H, J =
9.15 Hz), 8.11 d.d (1H, J = 9.1, 2.9 Hz), 8.44 d (1H,
J = 2.9 Hz), 12.24 br.s (1H, OH). Found, %: N 9.47;
S 7.18. C22H31N3O4S. Calculated, %: N 9.69; S 7.40.
[4-Hydroxy-5-(4-methoxybenzyl)-6-methylpy-
rimidin-2-ylsulfanyl]acetic acid (IIq) was synthe-
sized from compound Iq and chloroacetic acid. Yield
75%, mp 259–260°C, Rf 0.60 (benzene–acetone–
ethanol, 3:3:0.5). IR spectrum, ν, cm–1: 3220 br (OH),
2920 s (C–H, CH3), 2440 br (COOH, assoc.), 1610 s
(C=C), 1450 s, 1370 [δ(C–CH3)], 659 s (C–S).
1H NMR spectrum, δ, ppm: 2.06 s (3H, CH3), 3.62 s
(2H, CH2), 3.72 s (3H, OCH3), 4.02 s (2H, SCH2),
6.70–7.05 m (4H, Harom), 11.3 br.s (1H, OH), 12.2 br.s
(1H, COOH). Found, %: N 8. 47; S 10. 33.
C15H16N2O4S. Calculated, %: N 8.74; S 10.01.
5-Benzyl-2-(2-ethoxy-3-nitrobenzylsulfanyl)py-
rimidine-4,6-diol (IIn) was synthesized from com-
pound In and 2-ethoxy-3-nitrobenzyl chloride. Yield
40%, mp 220–222°C, Rf 0.58 (benzene–acetone, 2:4).
IR spectrum, ν, cm–1: 3650, 3340 br (OH), 2925 s
(CH3), 1530 s (νasNO2), 1335 s (νsNO2), 1120 s
1
(C–OH), 670 s (C–S). H NMR spectrum, δ, ppm:
1.49 t (3H, CH2CH3, J = 7.0 Hz), 3.38 s (2H, CH2),
3.70 s (2H, SCH2), 4.25 q (2H, OCH2, J = 7.0 Hz),
7.10 t.t (1H, p-H, J = 7.1, 1.5 Hz), 7.18 m (2H, m-H),
7.25 m (2H, o-H), 7.01 d (1H, J = 9.0 Hz), 8.10 d.d
(1H, J = 9.0, 2.8 Hz), 8.40 d (1H, J = 2.8 Hz),
11.30 br.s (2H, OH). Found, %: N 10.00; S 7.96.
C20H19N3O5S. Calculated, %: N 10.16; S 7.76.
[4,6-Dihydroxy-5-(4-propoxybenzyl)pyrimidin-
2-ylsulfanyl]acetic acid (IIr) was synthesized from
compound Ir and chloroacetic acid. Yield 57%,
mp 193–194°C, Rf 0.68 (benzene–acetone–ethanol,
3:3:0.5). IR spectrum, ν, cm–1: 3210 br (OH), 2900 s
(C–H, CH3), 2445 br (COOH, assoc.), 1600 s (C=C),
1450 s, 1380 [δ(C–CH3)], 670 s (C–S). 1H NMR spec-
trum, δ, ppm: 0.85 t (3H, OCH2CH2CH3, J = 6.6 Hz),
1.60 m (2H, OCH2CH2CH3), 3.47 s (2H, CH2), 3.82 m
(2H, OCH2), 4.02 s (2H, SCH2), 6.80–7.50 m (4H,
Pyrimidin-2-ylsulfanylacetic acids IIo–IIs (gen-
eral procedure). A mixture of 0.34 g (6 mmol) of
potassium hydroxide, 30 ml of water, 2 mmol of the
corresponding 2-sulfanylpyrimidine, and 0.19 g
(2 mmol) of chloroacetic acid was heated for 2 h under
reflux. The mixture was filtered, glacial acetic acid
was added to the filtrate, and the precipitate was
filtered off, washed with water, and recrystallized from
ethanol.
H
arom), 10.6 br.s (2H, OH), 12.21 br.s (1H, COOH).
Found, %: N 7.76; S 9.07. C17H20N2O4S. Calculated,
%: N 8.04; S 9.20.
[4,6-Dihydroxy-5-(4-isobutoxybenzyl)pyrimidin-
2-ylsulfanyl]acetic acid (IIs) was synthesized from
compound Is and chloroacetic acid. Yield 64%,
mp 197–199°C, Rf 0.64 (benzene–acetone–ethanol,
3:3:0.5). IR spectrum, ν, cm–1: 3600 br, 3310 br (OH),
2920 s (C–H, CH3), 2450 br (COOH, assoc.), 1620 s
[4-Hydroxy-6-methyl-5-(3-methylbutyl)pyrimi-
din-2-ylsulfanyl]acetic acid (IIo) was synthesized
from compound Io and chloroacetic acid. Yield 63%,
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SYNTHESIS OF NEW 2-SULFANYL- AND 2-AMINOPYRIMIDINES
833
(C=C), 672 s (C–S). 1H NMR spectrum, δ, ppm: 1.02 d
[6H, CH(CH3)2, J = 6.8 Hz], 2.05 m [1H, CH(CH3)2],
3.65 d (2H, OCH2, J = 6.5 Hz), 3.91 s (2H, CH2),
4.20 s (2H, SCH2), 6.90–7.40 m (4H, Harom), 11.4 br.s
(2H, OH), 12.5 br.s (1H, COOH). Found, %: N 7.47;
S 8.82. C17H20N2O5S. Calculated, %: N 7.69; S 8.80.
(1H, p-H), 7.14 m (2H, m-H), 7.23 m (2H, o-H),
10.50 br.s (2H, OH). Found, %: C 62.64; H 6.03;
N 14.49. C15H17N3O3. Calculated, %: C 62.71; H 5.96;
N 14.62.
5-(4-Ethoxybenzyl)-2-(morpholin-4-yl)pyrimi-
dine-4,6-diol (IVe) was synthesized from compound
IIIe and morpholine. Yield 59%, mp 300–301°C,
Rf 0.63 (benzene–acetone, 1:1). IR spectrum, ν, cm–1:
3465 br (OH, assoc.), 1725 s (C=O), 1455 s [δ(OH)],
2-Aminopyrimidines IVa–IVq (general proce-
dure). A mixture of 5 mmol of 2-methylsulfanylpy-
rimidine IIIa–IIIq, 5.5 mmol of morpholine, benzyl-
amine, or 4-methoxyaniline, and 10 ml of butan-1-ol
was heated for 15–20 h under reflux. The solvent was
distilled off, 5 ml of ethanol was added to the residue,
and the precipitate was filtered off, washed with cold
ethanol, and recrystallized from 80% ethanol.
1
1385 s (C–N). H NMR spectrum, δ, ppm: 1.36 t (3H,
CH2CH3, J = 7.0 Hz), 3.55 m (4H, NCH2), 3.59 s (2H,
CH2), 3.61 m (4H, OCH2), 3.95 q (2H, OCH2CH3,
J = 7.0 Hz); 6.68 m (2H), 7.03 m (2H), 10.05 br.s
(2H, OH). Found, %: C 61.58; H 6.17; N 12.87.
C17H21N3O4. Calculated, %: C 61.62; H 6.39; N 12.68.
6-Methyl-2-(morpholin-4-yl)-5-octylpyrimidin-
4-ol (IVa) was synthesized from compound IIIa and
morpholine. Yield 77%, mp 142–143°C, Rf 0.59 (ben-
zene–acetone, 1:1). IR spectrum, ν, cm–1: 3460 br
(OH, assoc.), 1720 s (C=O), 1620 (C–N), 1570 s
2-(Morpholin-4-yl)-5-(4-propoxybenzyl)pyrimi-
dine-4,6-diol (IVf) was synthesized from compound
IIIf and morpholine. Yield 61%, mp 350–352°C,
Rf 0.62 (benzene–acetone, 1:1). IR spectrum, ν, cm–1:
3460 br (OH, assoc.), 1720 s (C=O), 1450 s [δ(OH)],
1
(C=Carom), 1450 s [δ(OH)], 1385 s (C–N). H NMR
1
1380 s (C–N). H NMR spectrum, δ, ppm: 0.95 t (3H,
spectrum, δ, ppm: 0.92 t [3H, (CH2)7CH3, J = 6.8 Hz],
1.32–1.41 m [12H, (CH2)6CH3], 2.40 s (3H, CH3),
2.45 m (2H, 5-CH2), 3.50 m (4H, NCH2), 3.62 m (4H,
OCH2), 11.31 br.s (1H, OH). Found, %: C 66.41;
H 9.74; N 13.76. C17H29N3O2. Calculated, %: C 66.42;
H 9.51; N 13.67.
CH2CH3, J = 6.7 Hz), 1.65 m (2H, OCH2CH2), 3.52 m
(4H, NCH2), 3.65 m (4H, OCH2), 3.82 m (2H,
OCH2CH2), 4.13 s (2H, 5-CH2), 6.85 m (2H), 7.15 m
(2H), 11.22 br.s (2H, OH). Found, %: C 62.30; H 6.92;
N 11.90. C18H23N3O4. Calculated, %: C 62.59; H 6.71;
N 12.17.
5-(4-Methoxybenzyl)-6-methyl-2-(morpholin-
4-yl)pyrimidin-4-ol (IVb) was synthesized from com-
pound IIIb and morpholine. Yield 66%, mp 264–
5-(4-Butoxybenzyl)-2-(morpholin-4-yl)pyrimi-
dine-4,6-diol (IVg) was synthesized from compound
IIIg and morpholine. Yield 58%, mp 320–322°C,
Rf 0.55 (benzene–acetone, 1:1). IR spectrum, ν, cm–1:
3465 br (OH, assoc.), 1730 s (C=O), 1455 s [δ(OH)],
1
265°C, Rf 0.67 (benzene–acetone, 1:1). H NMR spec-
trum, δ, ppm: 2.06 s (3H, CH3), 3.56 m (4H, NCH2),
3.62 s (2H, CH2), 3.63 m (4H, OCH2), 3.72 s (3H,
OCH3), 6.70 m (2H), 7.05 m (2H), 11.04 br.s (1H,
OH). Found, %: C 65.00; H 6.44; N 13.09.
C17H21N3O3. Calculated, %: C 64.74; H 6.71; N 13.32.
1
1380 s (C–N). H NMR spectrum, δ, ppm: 0.98 t [3H,
(CH2)3CH3, J = 7.3 Hz], 1.45 m (2H, CH2CH3], 1.71 m
(2H, OCH2CH2), 3.43 s (2H, 5-CH2), 3.50 m (4H,
NCH2), 3.66 m (4H, OCH2), 3.87 t (2H, OCH2CH2,
J = 6.4 Hz), 6.46 m (2H), 7.22 m (2H), 11.02 br.s
(2H, OH). Found, %: C 63.66; H 7.25; N 11.45.
C19H25N3O4. Calculated, %: C 63.49; H 7.01; N 11.69.
5-(4-Ethoxybenzyl)-6-methyl-2-(morpholin-4-yl)-
pyrimidin-4-ol (IVc) was synthesized from compound
IIIc and morpholine. Yield 75%, mp 241–242°C,
1
Rf 0.70 (benzene–acetone, 1:1). H NMR spectrum, δ,
2-Benzylamino-5-heptyl-6-methylpyrimidin-4-ol
(IVh) was synthesized from compound IIIh and
benzylamine. Yield 67%, mp 149–150°C, Rf 0.64
(benzene–acetone, 1:1). IR spectrum, ν, cm–1: 3465 br,
3360 br, 3245 br (NH, OH assoc.), 1725 s (C=O),
ppm: 1.36 t (3H, CH2CH3, J = 7.0 Hz), 2.06 s (3H,
CH3), 3.56 m (4H, NCH2), 3.61 s (2H, CH2), 3.63 m
(4H, OCH2), 3.95 q (2H, OCH2CH3, J = 7.0 Hz),
6.68 m (2H), 7.03 m (2H), 11.01 br.s (1H, OH). Found,
%: C 65.81; H 6.91; N 13.00. C18H23N3O3. Calculated,
%: C 65.63; H 7.04; N 12.76.
1
1630 s (C=N), 460 s [δ(OH)]. H NMR spectrum, δ,
ppm: 0.90 t [3H, (CH2)6CH3], 1.30 m [10H,
(CH2)5CH3], 2.05 s (3H, CH3), 2.30 m (2H, 5-CH2),
4.50 d (2H, PhCH2), 6.55 t (1H, NH), 7.20–7.30 m
(5H, C6H5), 10.72 br.s (1H, OH). Found, %: C 73.60;
H 8.48; N 12.41. C19H27N3O. Calculated, %: C 72.81;
H 8.68; N 13.41.
5-Benzyl-2-(morpholin-4-yl)pyrimidine-4,6-diol
(IVd) was synthesized from compound IIId and mor-
pholine. Yield 60%, mp 337–338°C, Rf 0.61 (benzene–
1
acetone, 1:1). H NMR spectrum, δ, ppm: 3.55 s (2H,
CH2), 3.56 m (4H, NCH2), 3.62 m (4H, OCH2), 7.03 m
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GRIGORYAN et al.
834
2-Benzylamino-5-(4-methoxybenzyl)-6-methyl-
IIIm and benzylamine. Yield 50%, mp 308–309°C,
Rf 0.67 (benzene–acetone, 1:1). H NMR spectrum, δ,
1
pyrimidin-4-ol (IVi) was synthesized from compound
IIIi and benzylamine. Yield 62%, mp 204–205°C,
Rf 0.59 (benzene–acetone, 1:1). IR spectrum, ν, cm–1:
3460 br, 3350 br (NH, OH assoc.), 1720 s (C=O),
1630 s (C=N), 1600 s (C=Carom), 1385 s (C–N).
1H NMR spectrum, δ, ppm: 2.06 s (3H, CH3), 3.61 s
(2H, CH2), 3.72 s (3H, OCH3), 4.40 d (2H, NHCH2),
6.45 t (1H, NH, J = 5.8 Hz), 6.50 m (2H), 6.70 m (2H),
7.21 m (1H), 7.27–7.33 m (4H), 10.45 br.s (1H, OH).
Found, %: C 71.45; H 6.52; N 12.74. C20H21N3O2. Cal-
culated, %: C 71.62; H 6.31; N 12.53.
ppm: 0.98 t [3H, (CH2)3CH3], 1.48 m (2H, CH2CH3),
1.71 m (2H, OCH2CH2), 3.45 s (2H, 5-CH2), 3.87 t
(2H, OCH2, J = 6.4 Hz), 4.49 d (2H, NHCH2,
J = 5.8 Hz), 6.50 t (1H, NH, J = 5.8 Hz), 6.64 m
(2H), 7.12 m (2H), 7.21 m (1H), 7.27–7.33 m (4H),
10.05 br.s (2H, OH). Found, %: C 69.43; H 6.39;
N 10.96. C23H27N3O2. Calculated, %: C 73.18;
H 7.21; N 11.13.
2-Benzylamino-5-(4-isobutoxybenzyl)pyrimi-
dine-4,6-diol (IVn) was synthesized from compound
IIIn and benzylamine. Yield 49%, mp 304–306°C,
Rf 0.62 (benzene–acetone, 1:1). IR spectrum, ν, cm–1:
3465 br, 3360 br, 3255 br (NH, OH assoc.), 1720 s
(C=O), 1610 s (C=Carom), 1460 s [δ(OH)], 1385 s
2-Benzylamino-5-(4-ethoxybenzyl)-6-methylpy-
rimidin-4-ol (IVj) was synthesized from compound
IIIj and benzylamine. Yield 60%, mp 200–201°C,
1
Rf 0.58 (benzene–acetone, 1:1). H NMR spectrum, δ,
1
(C–N). H NMR spectrum, δ, ppm: 1.01 d [6H,
ppm: 1.37 t (3H, CH2CH3, J = 7.0 Hz), 2.07 s (3H,
CH3), 3.58 s (2H, CH2), 3.95 q (2H, OCH2, J =
7.0 Hz), 4.43 d (2H, NHCH2, J = 5.6 Hz), 6.34 t (1H,
NH, J = 5.6 Hz), 6.68 m (2H), 7.04 m (2H), 7.21 m
(1H), 7.26–7.32 m (4H), 10.45 br.s (1H, OH). Found,
%: C 71.89; H 6.44; N 11.96. C21H23N3O2. Calculated,
%: C 72.18; H 6.63; N 12.03.
CH(CH3)2, J = 6.7 Hz], 2.03 m [1H, CH(CH3)2],
3.63 d (2H, OCH2, J = 6.5 Hz), 3.93 s (2H, 5-CH2),
6.35 t (1H, NH), 6.72 m (2H), 7.13 m (2H), 7.13–
7.25 m (5H, C6H5), 11.84 br.s (2H, OH). Found, %:
C 69.78; H 6.59; N 11.28. C22H25N3O3. Calculated, %:
C 69.64; H 6.64; N 11.07.
5-Heptyl-2-(4-methoxyphenylamino)-6-methyl-
pyrimidin-4-ol (IVo) was synthesized from compound
IIIo and 4-methoxyaniline. Yield 63%, mp 168–
169°C, Rf 0.66 (benzene–acetone, 1:1). IR spectrum,
ν, cm–1: 3460 br, 3360 br, 3250 br (NH, OH assoc.),
1710 s (C=O), 1460 s [δ(OH)], 1390 s (C–N). 1H NMR
spectrum, δ, ppm: 0.85 t [3H, (CH2)6CH3, J = 6.8 Hz],
1.25–1.45 m [10H, (CH2)5CH3], 2.25 s (3H, CH3),
2.31 m (2H, 5-CH2), 3.84 s (3H, OCH3), 6.60 m (2H),
7.15 m (2H), 8.20 br.s (1H, NH), 10.26 br.s (1H, OH).
Found, %: C 69.63; H 8.49; N 12.34. C19H27N3O2. Cal-
culated, %: C 69.27; H 8.26; N 12.75.
5-Benzyl-2-benzylaminopyrimidine-4,6-diol
(IVk) was synthesized from compound IIIk and
benzylamine. Yield 78%, mp 324–325°C, Rf 0.57
(benzene–acetone, 1:1). IR spectrum, ν, cm–1: 3465 br,
3360 br, 3250 br (NH, OH, assoc.), 1720 s (C=O),
1610 s (C=Carom), 1390 s (C–N). 1H NMR spectrum, δ,
ppm: 3.60 s (2H, CH2), 4.50 d (2H, NHCH2, J =
5.7 Hz), 6.32 t (1H, NH, J = 5.7 Hz), 7.02–7.25 m (5H,
C6H5), 7.30–7.41 m (5H, CH2C6H5), 11.42 br.s (2H,
OH). Found, %: C 65.59; H 5.50; N 13.49.
C18H17N3O2. Calculated, %: C 70.34; H 5.58; N 13.67.
2-Benzylamino-5-(4-ethoxybenzyl)pyrimidine-
4,6-diol (IVl) was synthesized from compound IIIl
and benzylamine. Yield 57%, mp 310–311°C, Rf 0.60
(benzene–acetone, 1:1). IR spectrum, ν, cm–1: 3460 br,
3365 br, 3250 br (NH, OH assoc.), 1715 s (C=O),
1610 s (C=Carom), 1465 s [δ(OH)], 1385 s (C–N).
1H NMR spectrum, δ, ppm: 1.43 t (3H, CH2CH3, J =
7.0 Hz), 3.60 s (2H, CH2), 4.05 q (2H, OCH2, J =
7.0 Hz), 4.45 d (2H, NHCH2), 6.34 t (1H, NH, J =
5.6 Hz), 6.67–7.05 m (4H, C6H4), 7.20–7.30 m (5H,
C6H5), 12.01 br.s (2H, OH). Found, %: C 68.49;
H 5.93; N 11.72. C20H21N3O3. Calculated, %: C 68.36;
H 6.02; N 11.96.
5-(4-Ethoxybenzyl)-2-(4-methoxyphenylamino)-
pyrimidine-4,6-diol (IVp) was synthesized from
compound IIIp and 4-methoxyaniline. Yield 54%,
mp 122–123°C, Rf 0.60 (benzene–acetone, 1:1). IR
spectrum, ν, cm–1: 3460 br, 3365 br, 3250 br (NH,
OH assoc.), 1710 s (C=O), 1600 s (C=Carom), 1385 s
1
(C–N). H NMR spectrum, δ, ppm: 1.50 t (3H,
CH2CH3, J = 7.0 Hz), 3.48 s (2H, 5-CH2), 3.77 s (3H,
OCH3), 4.30 q (2H, OCH2, J = 7.0 Hz), 6.66 m (2H),
7.16 m (2H), 6.80 m (2H), 7.47 m (2H), 8.25 br.s
(1H, NH), 10.76 br.s (2H, OH). Found, %: C 65.18;
H 5.49; N 11.23. C20H21N3O4. Calculated, %: C 65.38;
H 5.76; N 11.44.
2-Benzylamino-5-(4-butoxybenzyl)-6-methylpy-
5-(4-Isobutoxybenzyl)-2-(4-methoxyphenyl-
amino)pyrimidine-4,6-diol (IVq) was synthesized
rimidin-4-ol (IVm) was synthesized from compound
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SYNTHESIS OF NEW 2-SULFANYL- AND 2-AMINOPYRIMIDINES
835
3. Grigoryan, L.A., Aroyan, A.A., and Kaldrikyan, M.A.,
Arm. Khim. Zh., 1969, vol. 22, no. 4, p. 341; ibid., 1975,
vol. 28, no. 2, p. 155.
from compound IIIq and 4-methoxyaniline. Yield
52%, mp 242–244°C, Rf 0.70 (benzene–acetone, 1:1).
1H NMR spectrum, δ, ppm: 1.01 s [6H, CH(CH3)2, J =
6.7 Hz], 2.02 m [1H, CH(CH3)2], 3.47 s (2H, 5-CH2),
3.64 d (2H, OCH2, J = 6.5 Hz), 3.76 s (3H, OCH3),
6.66 m (2H), 7.13 m (2H), 6.80 m (2H), 7.47 m (2H),
8.23 br.s (1H, NH), 10.16 br.s (2H, OH). Found, %:
C 66.86; H 6.15; N 10.41. C22H25N3O4. Calculated, %:
C 66.82; H 6.37; N 10.63.
4. Stimpson, A. and Reater, R., J. Am. Chem. Soc., 1945,
vol. 67, p. 2191.
5. Aroyan, A.A. and Kramer, M.S., Arm. Khim. Zh., 1967,
vol. 20, no. 3, p. 218.
6. Hromatka, O., Chem. Ber., 1942, vol. 75, p. 123.
7. Spraque, J.M. and Johnson, T.B., J. Am. Chem. Soc.,
1954, vol. 76, p. 2441; Cuse, F.H. and Hill, A.J., J. Am.
Chem. Soc., 1929, vol. 51, p. 1590.
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1. Hull, R., Lovele, B.J., Openshaw, H.T., and Todd, R.,
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2. Grigoryan, L.A., Kaldrikyan, M.A., Melik-Ogandzha-
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