A new method for the synthesis of 2,4-diamino-6-arylpyrimidines

Article abstract of DOI:10.1007/s11172-005-0246-z

A method for the synthesis of 2,4-diamino-6-arylpyrimidines from guanidine and α-chlorocinnamonitriles was developed. The starting nitriles can be easily prepared by catalytic olefination reaction.

Full text of DOI:10.1007/s11172-005-0246-z

Russian Chemical Bulletin, International Edition, Vol. 54, No. 1, pp. 255—256, January, 2005
255
A new method for the synthesis of 2,4ꢀdiaminoꢀ6ꢀarylpyrimidines
a
a
b
a
V. G. Nenajdenko,a I. V. Golubinskii, O. N. Lenkova, A. V. Shastin, and E. S. Balenkova
ꢀ
aDepartment of Chemistry, M. V. Lomonosov Moscow State University,
1 Leninskie Gory, 119992 Moscow, Russian Federation.
Fax: +7 (095) 932 8846. Eꢀmail: nen@acylium.chem.msu.ru
bInstitute of Problems of Chemical Physics, Russian Academy of Sciences,
142432 Chernogolovka, Moscow Region, Russian Federation.
Eꢀmail: shastin@icp.ac.ru
A method for the synthesis of 2,4ꢀdiaminoꢀ6ꢀarylpyrimidines from guanidine and
αꢀchlorocinnamonitriles was developed. The starting nitriles can be easily prepared by cataꢀ
lytic olefination reaction.
Key words: 2,4ꢀdiaminoꢀ6ꢀarylpyrimidines, αꢀchlorocinnamonitriles, guanidine, catalytic
olefination reaction.
Scheme 1
Catalytic olefination, which is essentially copperꢀcataꢀ
lyzed reactions of carbonyl compound hydrazones with
polyhaloalkanes,1 opens up the route to αꢀchlorocinnamoꢀ
nitriles from hydrazones of aromatic aldehydes and
trichloroacetonitrile.2 We assumed that the reactions of
the products obtained with guanidine can afford 2,4ꢀdiꢀ
aminoꢀ6ꢀarylpyrimidines, which are valuable organic reꢀ
agents3 with a potential biological activity.4
Several methods for the synthesis of 2,4ꢀdiaminoꢀ6ꢀ
arylpyrimidines have been documented. For instance,
2,4ꢀdiaminoꢀ6ꢀphenylpyrimidine was obtained by conꢀ
densation reactions of dicyanodiamide with acetopheꢀ
none5 and of guanidine with phenylpropiolonitrile6 or
βꢀbromocinnamonitriles.7 Nucleophilic substitution for
potassium amide in 4ꢀarylpyrimidines gives the correꢀ
sponding products in low yields.8 A series of substituted
diaminopyrimidines were obtained by the Suzuki reaction
from 2,4ꢀdiaminoꢀ6ꢀchloropyrimidine.9
Solvent
Yield (%)
ButOH
67
DMSO
35
DMF
21
The conditions of the reaction with guanidine were opꢀ
timized for a model 2ꢀchloroꢀ3ꢀ(4ꢀchlorophenyl)acryloꢀ
nitrile (1a). We found that guanidine nitrate does not
react with the substrate in boiling ethanol without a base.
In the presence of NaOH, K2CO3, or NaOEt or with
the use of guanidine carbonate, the product obtained
was 3ꢀ(4ꢀchlorophenyl)ꢀ3ꢀethoxyacrylonitrile (2) instead
of the expected pyrimidine; i.e., a nucleophilic ethoxide
anion attacks the βꢀposition of substituted acryloꢀ
nitrile with subsequent elimination of hydrogen chloride
(Scheme 1).
The target 2,4ꢀdiaminoꢀ6ꢀ(4ꢀchlorophenyl)pyrimidine
(3a) can be obtained by carrying out the reaction in DMSO
or DMF; however, its yield is low. With compound 3a as
an example, we demonstrated that tertꢀbutyl alcohol is
the optimum solvent for the synthesis of diaminopyriꢀ
midines.
Under the optimized conditions, a series of diaminoꢀ
pyrimidines 3a—g was synthesized from various nitriles
1a—g in good yields (Table 1). The presence of electronꢀ
donating substituents (Me and OMe) in the aromatic ring
substantially increases the reaction time compared to comꢀ
Table 1. Synthesis of 2,4ꢀdiaminoꢀ6ꢀarylpyrimidines 3a—g
Compound
Ar
Yield (%)
3a
3b
3c
3d
3e
3f
4ꢀClꢀC6H4
4ꢀOMeꢀC6H4
4ꢀNO2ꢀC6H4
3ꢀNO2ꢀC6H4
2ꢀNaphthyl
1ꢀNaphthyl
4ꢀMeꢀC6H4
67
53
55
36
50
55
54
3g
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 249—251, January, 2005.
1066ꢀ5285/05/5401ꢀ0255 © 2005 Springer Science+Business Media, Inc.

256
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 1, January, 2005
Nenajdenko et al.
Scheme 2
2,4ꢀDiaminoꢀ6ꢀ(3ꢀnitrophenyl)pyrimidine (3d) was obtained
in 36% yield, yellow crystals, m.p. 212—216 °C (cf. Ref. 9:
213—216 °C), Rf 0.33 (ethyl acetate). 1H NMR (DMSOꢀd6), δ:
8.74 (s, 1 H, Harom); 8.29—8.25 (m, 2 H, Harom); 7.74 (t, 1 H,
Harom, J = 8.0 Hz); 6.49 (br.s, 2 H, NH2); 6.33 (s, 1 H, CH);
6.13 (br.s, 2 H, NH2).
2,4ꢀDiaminoꢀ6ꢀ(2ꢀnaphthyl)pyrimidine (3e) was obtained in
50% yield, yellow crystals, m.p. 108—110 °C, Rf 0.1 (ethyl
acetate). 1H NMR (DMSOꢀd6), δ: 8.47 (s, 1 H, Harom);
8.03—7.90 (m, 4 H, Harom); 7.55—7.51 (m, 2 H, Harom); 6.44
(br.s, 2 H, NH2); 6.38 (s, 1 H, CH); 6.07 (br.s, 2 H, NH2).
13C NMR (DMSOꢀd6), δ: 165.25, 163.59, 161.87, 135.62,
133.52, 132.77, 128.57, 127.85, 127.50, 126.68, 126.39, 125.60,
124.03, 91.14 (CH, pyrimidine). Found (%): C, 71.58; H, 5.31.
C14H8N4. Calculated (%): C 71.17; H 5.12.
pounds bearing electronꢀwithdrawing substituents (NO2);
this can be associated with the effect of the substituent on
the increase or decrease in the electron density at the
C(3) atom of the nitrile.
Thus, we developed the novel method for the syntheꢀ
sis of 2,4ꢀdiaminoꢀ6ꢀarylpyrimidines, which can be a conꢀ
venient alternative for their preparation because of the
simple procedure, good yields, and accessible starting reꢀ
agents.
2,4ꢀDiaminoꢀ6ꢀ(1ꢀnaphthyl)pyrimidine (3f) was obtained in
55% yield, yellow crystals, m.p. 123—125 °C, Rf 0.1 (ethyl
1
acetate). H NMR (DMSOꢀd6), δ: 8.19—8.16 (m, 1 H, Harom);
7.95—7.92 (m, 2 H, Harom): 7.56—7.48 (m, 4 H, Harom); 6.41,
6.01 (both br.s, 2 H each, NH2); 5.92 (s, 1 H, CH). 13C NMR
(DMSOꢀd6), δ: 164.72, 164.44, 163.13, 143.84, 137.78, 133.31,
130.33, 128.55, 128.16, 126.08, 125.86, 125.75, 125.31, 95.72
(CH, pyrimidine). Found (%): C, 71.45; H, 5.34. C14H8N4.
Calculated (%): C, 71.17; H, 5.12.
2,4ꢀDiaminoꢀ6ꢀ(4ꢀmethylphenyl)pyrimidine (3g) was obtained
in 54% yield, yellow crystals, m.p. 117—120 °C (cf. Ref. 9:
118—120 °C), Rf 0.12 (ethyl acetate). 1H NMR (DMSOꢀd6), δ:
7.78, 7.23 (both d, 2 H each, Harom, J = 8.0 Hz); 6.30 (br.s,
2 H, NH2); 6.17 (s, 1 H, CH); 5.91 (br.s, 2 H, NH2); 2.32
(s, 3 H, Me).
Experimental
IR spectra were recorded on a URꢀ20 spectrophotometer
(Nujol). 1H and 13C NMR spectra were recorded on a Varian
VXRꢀ400 spectrometer (400 (1H) and 100 MHz (13C), respecꢀ
tively) in CDCl3 and DMSO with Me4Si as the internal stanꢀ
dard. TLC was carried out with Merck 60 F254 plates; Merck
silica gel (63—200 mesh) was used for column chromatography.
Compounds 1a—g were prepared according to the previꢀ
ously described procedures.2
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 03ꢀ03ꢀ
32052a).
Synthesis of diaminopyrimidines 3a—g (general procedure).
A stirred solution of an αꢀchlorocinnamonitrile 1a—g (1 mmol)
and guanidine carbonate (0.36 g, 2 mmol) was refluxed in 2 mL
of tertꢀbutyl alcohol for 4 to 20 h (TLC monitoring). The preꢀ
cipitate that formed was filtered off and washed with ethanol
(2 mL). The solvent was removed in a rotary evaporator and the
product was purified on a thin layer of silica gel with ethyl
acetate as the eluent. Compound 3a was identified as hydroꢀ
chloride.
References
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Lenkova, and E. S. Balenkova, Izv. Akad. Nauk, Ser. Khim.,
2004, 218 [Russ. Chem. Bull., Int. Ed., 2004, 53, 228].
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The IR spectra of all products contained the absorption
bands of amino groups at 3470 to 3280 and 1630 cm–1
.
2,4ꢀDiaminoꢀ6ꢀ(4ꢀchlorophenyl)pyrimidine hydrochloride
(3a•HCl) was obtained in 67% yield, slightly yellowish crystals,
m.p. 288—289 °C (cf. Ref. 10: 291—292 °C), Rf 0.15 (ethyl
acetate). 1H NMR (DMSOꢀd6), δ: 8.42, 8.20 (both br.s,
1 H each, NH); 7.90, 7.64 (both d, 2 H each, Harom, J = 8.7 Hz);
6.44 (s, 1 H, CH); 3.83 (br.s, 3 H, NH3+).
2,4ꢀDiaminoꢀ6ꢀ(4ꢀmethoxyphenyl)pyrimidine (3b) was obꢀ
tained in 53% yield, yellow crystals, m.p. 210—212 °C (cf. Ref. 9:
1
212—215 °C), Rf 0.12 (ethyl acetate). H NMR (DMSOꢀd6), δ:
7.84, 6.98 (both d, 2 H each, Harom, J = 8.7 Hz); 6.36 (br.s, 2 H,
NH2); 6.15 (s, 1 H, CH); 6.02 (br.s, 2 H, NH2); 3.78 (s, 3 H, Me).
2,4ꢀDiaminoꢀ6ꢀ(4ꢀnitrophenyl)pyrimidine (3c) was obtained
in 55% yield, yellow crystals, m.p. 210—215 °C, Rf 0.30 (ethyl
acetate). 1H NMR (DMSOꢀd6), δ: 8.28, 8.11 (both d, 2 H each,
H
arom, J = 8.9 Hz); 6.57 (br.s, 2 H, NH2); 6.32 (s, 1 H, CH);
6.17 (br.s, 2 H, NH2). 13C NMR (DMSOꢀd6), δ: 165.32, 163.76,
159.89, 147.88, 144.53, 127.39, 123.68, 92.05 (CH, pyrimidine).
Found (%): C, 51.86; H, 3.88. C10H9N5O2. Calculated (%):
C, 51.95; H, 3.92.
Received June 30, 2004;
in revised form August 2, 2004