Three-component synthesis of 4-aryl-5-cyano-2-hetarylaminopyrimidines

Article abstract of DOI:10.1007/s11172-006-0382-0

Three-component condensation of benzooxazol-2-yl-, benzothiazol-2-yl-, and 5-ethoxycarbonyl-4-methyl-1,3-thiazol-2-ylguanidines with orthoesters and aroylacetonitriles afforded 4-aryl-5-cyano-2-hetarylaminopyrimidines.

Full text of DOI:10.1007/s11172-006-0382-0

Russian Chemical Bulletin, International Edition, Vol. 55, No. 6, pp. 1089—1090, June, 2006
1089
Threeꢀcomponent synthesis of 4ꢀarylꢀ5ꢀcyanoꢀ2ꢀhetarylaminopyrimidines
Kh. S. Shikhaliev,aꢀ V. I. Kryl´skaya,b and A. Yu. Potapova
aVoronezh State University,
1 Universitetskaya pl., 394006 Voronezh, Russian Federation.
Eꢀmail: chocd261@chem.vsu.ru
bVoronezh State Technological Academy,
19 prosp. Revolyutsii, 394000 Voronezh, Russian Federation
Threeꢀcomponent condensation of benzooxazolꢀ2ꢀylꢀ, benzothiazolꢀ2ꢀylꢀ, and 5ꢀethoxyꢀ
carbonylꢀ4ꢀmethylꢀ1,3ꢀthiazolꢀ2ꢀylguanidines with orthoesters and aroylacetonitriles afforded
4ꢀarylꢀ5ꢀcyanoꢀ2ꢀhetarylaminopyrimidines.
Key words: benzooxazolꢀ2ꢀylguanidine, benzothiazolꢀ2ꢀylguanidine, 5ꢀethoxycarbonylꢀ4ꢀ
methylꢀ1,3ꢀthiazolꢀ2ꢀylguanidine, orthoesters, aroylacetonitriles, 4ꢀarylꢀ5ꢀcyanoꢀ2ꢀhetarylꢀ
aminopyrimidines, threeꢀcomponent condensation.
Earlier,1 we have found that hetarylguanidines 1a—c
(Het — benzooxazolꢀ2ꢀyl (1a), benzothiazolꢀ2ꢀyl (1b),
and 5ꢀethoxycarbonylꢀ4ꢀmethylꢀ1,3ꢀthiazolꢀ2ꢀyl (1c))
enter into a threeꢀcomponent condensation with triethyl
orthoformate and dimedone to give the corresponding
NꢀhetarylꢀNꢀ(oxotetrahydroquinazolyl)amines. Later,2
we have employed linear βꢀdicarbonyl compounds (ethyl
acetoacetate derivatives and acetoacetamides) in this reꢀ
action and obtained pyrimidine derivatives.
Here, we extended this reaction to aroylacetonitriles
2a—c (Scheme 1). Heating of an equimolar mixture of
compounds 2 with guanidines 1a—c in an excess of boilꢀ
Scheme 1
Het =
(1a, 3a),
(1b, 3b,c),
(1c, 3d,e)
2
a
b
c
R
4ꢀCl
H
3
a
b
c
Alk
H
H
R
4ꢀCl
H
Yield (%)
3
d
e
Alk
H
Me
R
Yield (%)
60
66
57
54
4ꢀMeO
H
51
4ꢀMeO
H
4ꢀMeO
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1049—1050, June, 2006.
1066ꢀ5285/06/5506ꢀ1089 © 2006 Springer Science+Business Media, Inc.

1090
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 6, June, 2006
Shikhaliev et al.
C
18H11N5S. Calculated (%): C, 65.64; H, 3.37; N, 21.26.
ing orthoester for 15—20 min gave the corresponding
4ꢀarylꢀ5ꢀcyanoꢀ2ꢀhetarylaminopyrimidines 3a—e. The
most probable reaction pathway involves the formation of
ylidene derivative 4, which reacts with hetarylguanidines
1a—c through replacement of the ethoxy group. Subseꢀ
quent intramolecular cyclization of intermediate 5 closes
a pyrimidine ring.
The IR spectra of compounds 3a—e show a characterꢀ
istic absorption band of the cyano group (2200 cm–1) and
bands due to the vibrations of aromatic rings (1600, 1570,
and 1530 cm–1).
1H NMR, δ: 7.12—7.55 (m, 9 H, H arom.); 8.44 (s, 1 H, H pyriꢀ
midine); 12.04 (s, 1 H, NH). IR, ν/cm–1: 2200 (C≡N); 1600,
1570, 1530 (Ar).
2ꢀ(1,3ꢀBenzothiazolꢀ2ꢀylamino)ꢀ5ꢀcyanoꢀ4ꢀ(4ꢀmethoxypheꢀ
nyl)pyrimidine (3c), m.p. >300 °C. Found (%): C, 63.73; H, 3.61;
N, 19.32. C19H13N5OS. Calculated (%): C, 63.50; H, 3.65;
N, 19.49. 1H NMR, δ: 4.32 (s, 3 H, OMe); 7.25—7.58 (m, 8 H,
H arom.); 8.55 (s, 1 H, H pyrimidine); 12.14 (s, 1 H, NH). IR,
ν/cm–1: 2850 (Me); 2200 (C≡N); 1600, 1570 (Ar).
Ethyl 2ꢀ{[5ꢀcyanoꢀ4ꢀ(4ꢀmethoxyphenyl)pyrimidinꢀ2ꢀyl]amiꢀ
no}ꢀ4ꢀmethylꢀ1,3ꢀthiazoleꢀ5ꢀcarboxylate (3d), m.p. 255—257 °C.
Found (%): C, 57.78; H, 4.41; N, 17.55. C19H17N5O3S. Calcuꢀ
lated (%): C, 57.71; H, 4.33; N, 17.71. 1H NMR, δ: 1.34 (t, 3 H,
OCH2CH3, J = 7.0 Hz); 2.12 (s, 3 H, Me); 4.30 (q, 2 H,
OCH2CH3, J = 7.0 Hz); 4.36 (s, 3 H, OMe); 7.21, 7.65 (both d,
2 H each, H arom., J = 7.6 Hz); 9.10 (s, 1 H, H pyrimidine);
12.11 (br.s, 1 H, NH). IR, ν/cm–1: 2950, 2820 (Me); 2200
(C≡N); 1620, 1570 (Ar).
Experimental
The course of the reactions was monitored and the purity of
the compounds obtained was checked by TLC on Silufol UVꢀ254
1
plates with CHCl3—AcOEt (1 : 2) as an eluent. H NMR specꢀ
Ethyl 2ꢀ[(5ꢀcyanoꢀ6ꢀmethylꢀ4ꢀphenylpyrimidinꢀ2ꢀyl)amino]ꢀ
4ꢀmethylꢀ1,3ꢀthiazoleꢀ5ꢀcarboxylate (3e), m.p. 261—263 °C.
Found (%): C, 60.15; H, 4.40; N, 18.32. C19H17N5O2S. Calcuꢀ
lated (%): C, 60.14; H, 4.52; N, 18.46. 1H NMR, δ: 1.34 (t, 3 H,
OCH2CH3, J = 7.0 Hz); 2.12, 2.71 (both s, 3 H each, Me); 4.30
(q, 2 H, OCH2CH3, J = 7.0 Hz); 7.20—7.52 (m, 5 H, H arom.);
12.11 (br.s, 1 H, NH). IR, ν/cm–1: 2940, 2840 (Me); 2220
(C≡N); 1610, 1570 (Ar).
tra were recorded on a Bruker ACꢀ300 instrument (300 MHz) in
DMSOꢀd6 with Me4Si as the internal standard. IR spectra were
recorded on a Specord IRꢀ75 spectrometer (KBr pellets).
Benzooxazolylꢀ and benzothiazolylguanidines 1a,b were preꢀ
pared as described earlier3 for benzooxazolylguanidine by a reꢀ
action of 2ꢀaminophenol or 2ꢀaminobenzenethiol with dicyanꢀ
diamide in a hydrochloric acid solution.
5ꢀEthoxycarbonylꢀ4ꢀmethylꢀ1,3ꢀthiazolꢀ2ꢀylguanidine (1c).
Ethyl 2ꢀchloroacetoacetate (0.01 mol) was added to a mixture
of amidinothiourea (0.01 mol) and anhydrous sodium acetate
(0.012 mol) in anhydrous ethanol (10 mL). The reaction mixꢀ
ture was refluxed for 0.5 h. The precipitate that formed was
filtered off, washed with water and propanꢀ2ꢀol, and recrystalꢀ
lized from DMF. The yield was 75—80%, m.p. >300 °C.
Aroylacetonitriles 2a—c were prepared according to a known
procedure.4
References
1. Kh. S. Shikhaliev, D. V. Kryl´skii, A. V. Falaleev, Yu. A.
Kovygin, and A. Yu. Potapov, in Karbonil´nye soedineniya v
sinteze geterotsiklov [Carbonyl Compounds in the Synthesis of
Heterocycles], Nauchnaya Kniga, Saratov, 2004, 308 (in
Russian).
2. D. V. Kryl´skii, Kh. S. Shikhaliev, and A. Yu. Potapov, Izv.
Vyssh. Uchebn. Zaved., Khim. Khim. Tekhnol., 2005, 48, 61
[Izv. Vuz. Khim. Khim. Tekhnol., 2005, 48 (Engl. Transl.)].
3. Sintezy geterotsiklicheskikh soedinenii [Syntheses of Heterocyꢀ
clic Compounds], Ed. A. L. Mndzhoyan, Izd. Akad. Nauk
Arm. SSR, Yerevan, 1972, Issue 9, 25 (in Russian).
4ꢀArylꢀ5ꢀcyanoꢀ2ꢀhetarylaminopyrimidines 3a—e (general
procedure). Orthoester (5 mL) was added to a pulverized mixture
of hetarylguanidine (0.01 mol) and aroylacetonitrile (0.01 mol).
After refluxing for 15—20 min, the crystallized reaction mixture
was diluted with propanꢀ2ꢀol and the precipitate was filtered off
and recrystallized from DMF.
2ꢀ(1,3ꢀBenzooxazolꢀ2ꢀylamino)ꢀ4ꢀ(4ꢀchlorophenyl)ꢀ5ꢀ
cyanopyrimidine (3a), m.p. 285—287 °C. Found (%): C, 62.28;
H, 2.97; N, 20.34. C18H10ClN5O. Calculated (%): C, 62.17;
4. D. A. Drapkina, V. G. Brudz´, N. I. Doroshina, and N. I.
Sokolova, in Metody polucheniya khimicheskikh reaktivov i
preparatov [Methods for the Synthesis of Chemicals and Prepaꢀ
rations], IREA, Moscow, 1973, Issues 25, 28 (in Russian).
1
H, 2.90; N, 20.14. H NMR, δ: 7.19—7.53 (m, 8 H, H arom.);
8.56 (s, 1 H, H pyrimidine); 11.94 (s, 1 H, NH). IR, ν/cm–1
2200 (C≡N); 1600, 1570 (Ar).
:
2ꢀ(1,3ꢀBenzothiazolꢀ2ꢀylamino)ꢀ5ꢀcyanoꢀ4ꢀphenylpyrimidine
(3b), m.p. 282—284 °C. Found (%): C, 65.46; H, 3.23; N, 21.35.
Received February 13, 2006;
in revised form April 26, 2006