A new route for the synthesis of 4,5-diamino-6-arylsulfanylpyrimidine derivatives and also purines on their basis

Article abstract of DOI:10.1007/s10593-011-0786-0

5-Acylamino-4-amino-6-arylsulfanylpyrimidines were formed by the reaction 3-arylsulfanyl-2-acylamino-3-chloroacrylonitriles with benzamidine. The products were converted into new derivatives of 6-arylsulfanyl-substituted purine bases by treatment with pol

Full text of DOI:10.1007/s10593-011-0786-0

Chemistry of Heterocyclic Compounds, Vol. 47, No. 4, July 2011 (Russian original Vol. 47, No. 4, April, 2011)
A NEW ROUTE FOR THE SYNTHESIS OF
4,5-DIAMINO-6-ARYLSULFANYLPYRIMIDINE
DERIVATIVES AND ALSO PURINES ON THEIR BASIS
C. V. Popil’nichenko1, R. N. Solomyannyj1, and V. S. Brovarets1*
5-Acylamino-4-amino-6-arylsulfanylpyrimidines were formed by the reaction 3-arylsulfanyl-2-acylami-
no-3-chloroacrylonitriles with benzamidine. The products were converted into new derivatives of 6-aryl-
sulfanyl-substituted purine bases by treatment with polyphosphoric acid.
Keywords: benzamidine, 4,5-diamino-6-arylsulfanylpyrimidines, purine bases, thiophenols, hetero-
cyclization.
In the last 20 years, interest in 6-arylsulfanylpyrimidine derivatives has increased noticeably in connec-
tion with the search for effective bioregulators, especially after the discovery of preparations of the HEPT type –
6-arylsulfanylthymine based acylnucleosides with high anti-HIV activity [1–4]. In addition, many derivatives of
6-mercaptopyrimidine have a wide spectrum of biological activity. Among them are antioxidants [5], anti-
inflammatories, antimicrobial preparations [6, 7], antitumor substances [8–10], insecticides, and acaricides [11].
The basic method for the synthesis of such compounds is modification of position 6 of the pyrimidine
moiety [6, 8–10]. The most frequently used are 6-hydroxy derivatives of pyrimidine, which are initially
converted into 6-chloro derivatives with subsequent nucleophilic substitution of the chlorine atom by sulfur-
containing groups.
However, this approach is not suitable for hydroxyl groups of pyrimidines, which are containing other
functional groups sensitive to the effects of chlorinating agents. In these cases, acyclic sulfur-containing
reagents are used [12–19].
In the present work with the object of preparing 6-arylsulfanyl derivatives of pyrimidine containing
vicinal amino functions (primary 4-amino groups and 5-acylamine radicals), 2-acylamino-3-arylsulfanyl-3-
chloroacrylonitriles 2 were used, obtained from the accessible products 1 [20] (Scheme).
____________
*To whom correspondence should be addressed; e-mail: brovarets@bpci.kiev.ua.
1 Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, 1 Murman-
ska St., Kyiv 02660, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 597–601, April, 2011. Original
article submitted December 16, 2010.
0009-3122/11/4704-0492©2011 Springer Science+Business Media, Inc.
492

NH2
NH
H
N
R
H
Ph
2
ArS
Cl
R
Cl
Cl
N
ArSH, Et3N
O
O
C
C
N
N
2a–e
1a–c
H
N
R
ArS
O
NH2
NH
C
NH
_
.
Ph
HCl
N
NH2
Ph
3
H
R
N
ArS
O
NH2
Cl
HN
NH2
_
.
Ph
N
HCl
NH
4
Ph
SAr
N
SAr
H
N
R
N
Polyphosphoric acid
N
N
O
Ph
NH2
Ph
N
R
N
H
6a–e
5a–e
1 а R = Ph, b R = 4-MeC6H4, c R = 4-ClC6H4; 2, 5, 6 а R = Ph, Ar = 4-MeC6H4,
b R = Ph, Ar = 4-ClC6H4, c R = 4-MeC6H4, Ar = 4-ClC6H4, d R = 4-ClC6H4,
Ar = 4-MeC6H4, е R = Ar = 4-ClC6H4
Cyclocondensation products 5 (trifunctionalized pyrimidines) were formed by reaction of reagents 2 with
benzamidine, which is in agreement with cyanovinylation and subsequent cyclization 2 → 3 → 5. However, one
cannot exclude the alternative route 2 → 4 → 5 which involves initial addition of the amine to the nitrile group,
although the electrophilicity of the latter in the acrylonitrile unit of compound 2 is decreased in consequence of the
..
..
ArS
C
C
C
N
(cf, the interaction of
electron donor influence of the sulfur atom in the conjugated system
H
C
C
C
N
with benzamidine [21] which leads to the synthesis of imidazole derivatives).
New derivatives of purine 6 are formed in reasonable yield (Table 1) on heating compounds 5 with
polyphosphoric acid. The structures of compounds 5 and 6 were confirmed by complex spectroscopic studies.
Thus, in the IR spectra of compounds 5 bands νC=O of the acylamine residues were observed (1637–1639 cm–1),
1
bands of the nitrile groups at ν 2215–2225 cm–1 were absent, and in the H NMR spectra there were signals of
the primary amino groups (δNH2 6.92–7.06 ppm). Formation of the imidazole ring during the conversion 5→6 is
in agreement with the IR, 1H NMR, and mass spectrometric data (Table 2).
We note in conclusion that data on the synthesis of derivatives of 2-aryl-6-arylsulfanyl-7(9)H-purine of
type 6 and 2-aryl-6-arylsulfanylpyrimidine 5 are absent from the literature.
Our proposed route to the synthesis of purine bases permits the regioselective introduction of aryl substitu-
ents in positions 2 and 8, and also arylsulfanyl groups into position 6 of the purine bases, which makes possible the
synthesis of a large series of compounds for the development of new biologically active substances ( see [22–24]).
493

TABLE 1. Characteristics of the Compounds Synthesized
Found, %
Calculated, %
Com-
pound
Empirical
formula
mp, °C*
С
Н
Сl
N
S
2d
2e
5а
5b
5c
5d
5e
6a
6b
6c
6d
6e
C17H12Cl2N2OS
C16H9Cl3N2OS
C24H20N4OS
56.51
56.21
3.45
3.33
19.75
19.52
7.92
7.71
8.56
8.83
197–199
222–224
239–241
245–247
246–248
234–236
249–251
221–223
262–264
253–255
261–263
268–270
75
81
56
61
60
66
71
57
59
54
58
61
50.29
50.09
2.16
2.36
27.93
27.72
7.44
7.30
8.31
8.36
69.05
69.88
4.58
4.89
–
13.24
13.58
7.61
7.77
C23H17ClN4OS
C24H19ClN4OS
C24H19ClN4OS
C23H16Cl2N4OS
C24H18N4S
63.48
63.81
3.73
3.96
8.05
8.19
12.81
12.94
7.35
7.41
64.19
64.49
4.03
4.28
7.98
7.93
12.94
12.54
7.32
7.17
64.25
64.49
4.09
4.28
7.88
7.93
12.88
12.54
7.44
7.17
59.03
59.11
3.12
3.45
15.09
15.17
12.19
11.99
6.74
6.86
73.25
73.07
4.43
4.60
–
14.44
14.20
8.31
8.13
C23H15ClN4S
C24H17ClN4S
C24H17ClN4S
C23H14Cl2N4S
66.37
66.58
3.23
3.64
8.72
8.54
13.88
13.50
7.33
7.72
67.13
67.20
3.65
3.99
8.13
8.27
13.85
13.06
7.66
7.48
67.01
67.20
3.54
3.99
8.21
8.27
12.81
13.06
7.82
7.48
61.33
61.48
3.43
3.14
15.09
15.78
12.82
12.47
7.05
7.14
_________
* Solvents for recrystallization: ethanol (compounds 2–5), acetonitrile
(compounds 6).
EXPERIMENTAL
IR spectra of KBr disks were recorded on a Vertex 70 spectrometer, 1H NMR spectra of DMSO-d6 solu-
tions with TMS as internal standard were measured on a Bruker Avance DRX-500 (500 MHz) instrument. Mass
spectra were recorded on an Agilent 1100/DAD/MSD VL G1965 instrument. Melting points were measured
with a Fisher-Johns apparatus.
2-Acylamino-3-arylsulfanyl-3-chloroacrylonitriles 2a–c were prepared by a known method [20], the
previously unknown compounds 2d,e were prepared analogously.
6-Amino-5-arylamino-4-arylsulfanyl-2-phenylpyrimidines 5a–e. Benzamidine (2.64 g, 22 mmol)
was added to a solution of one of the compounds 2a–d (10 mmol) in tetrahydrofuran (50 ml). The mixture was
stirred for 20 h at 40°C, the residue was filtered off, washed with water, added to the product obtained after
evaporation of the solvent, and compounds 5a–e were purified by recrystallization.
8-Aryl-6-arylsulfanyl-2-phenyl-7(9)H-purines 6a–e. A mixture of one of the compounds 5a–e
(5 mmol) and polyphosphoric acid (10 g) was heated on an oil bath for 6 h at 160°C, the viscous mass formed
was cooled, cold water (50 ml) was added, stirred, the precipitate was filtered off, washed with 25% aqueous
ammonia, and purified by recrystallization.
494

TABLE 2, IR, 1H NMR, and Mass Spectra of the Compounds
Synthesized
Mass
Com-
pound
IR spectra,
1Н NMR spectra, δ, ppm
spectra,
ν, cm–1
m/z [M]+
2d
2e
5a
5b
5c
5d
5e
6a
1662 (NС=О),
2215 (C≡N),
3268 (NH as.)
2.36 (3H, s, CH3); 7.46–7.97 (8H, m, Н arom.);
10.68 (1H, s, NH)
364
385
413
433
447
447
467
395
1666 (NС=О),
2220 (C≡N),
3267 (NH as.)
7.59–7.96 (8Н, m, Н arom.);
10.76 (1H, s, NH)
1637* (NС=О),
3283 (NH as.),
3422, 3473 (NH2)
2.39 (3H, s, CH3); 6.92 (2H, s, NH2);
7.31–8.07 (14H, m, Н arom.);
9.78 (1H, s, NH)
1637* (NС=О),
3286 (NH as.),
3404, 3475 (NH2)
7.00 (2H, s, NH2); 7.39–8.13 (14H, m, Н
arom.); 9.80 (1H, s, NH)
1639* (NС=О),
3229 (NH as.),
3410, 3469 (NH2)
2.41 (3H, s, CH3); 6.97 (2H, s, NH2);
7.34–8.02 (13H, m, Н arom.); 9.73 (1H, s,
NH)
1638* (NС=О),
3287 (NH as.),
3405, 3472 (NH2)
2.39 (3H, s, CH3); 6.97 (2H, s, NH2);
7.29–8.08 (13H, m, Н arom.); 9.86 (1H, s,
NH)
1637* (NС=О),
3268 (NH as.),
3421, 3479 (NH2)
3058 (NH as.)*2
7.06 (2H, s, NH2); 7.39–8.10 (13H, m, Н arom.);
9.90 (1H, s, NH)
2.46 (3H, s, CH3);
7.41–8.28 (14H, m, Н arom.)*3
6b
6c
3054 (NH as.)*2
3052 (NH as.)*2
7.44–8.26 (14H, m, Н arom.)*3
415
429
2.42 (3H, s, CH3);
7.43–8.14 (13H, m, Н arom.)*3
6d
3054 (NH as.)*2
3101 (NH as.)*2
2.45 (3H, s, CH3);
429
449
7.40–8.26 (13H, m, Н arom.)*3
6e
7.43–8.23 (13H, m, Н arom.)*3
__________
* Band with a shoulder.
*2 No band in the 1600–1700 cm–1 region.
*3 N–H in exchange.
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