Synthesis of 8,8-R,R-8,9-dihydro[1,2,4]triazolo[1,5-a]quinazolin-6(7H)-ones

Article abstract of DOI:10.1007/s11172-006-0207-1

Three-component condensation of 3-amino-1,2,4-triazole (or its 5-methyl and 5-methylthio derivatives), dimedone (or cyclohexane-1,3-dione), and dimethylformamide dimethyl acetal afforded 8,8-R, R-8,9-dihydro[1,2,4] triazolo[1,5-a]quinazolin-6(7H)-ones.

Full text of DOI:10.1007/s11172-006-0207-1

Russian Chemical Bulletin, International Edition, Vol. 54, No. 12, pp. 2903—2904, December, 2005
2903
Synthesis of
8,8ꢀR,Rꢀ8,9ꢀdihydro[1,2,4]triazolo[1,5ꢀa]quinazolinꢀ6(7H )ꢀones
Kh. S. Shikhaliev,ꢀ D. V. Kryl´skii, A. Yu. Potapov, and M. Yu. Krysin
Voronezh State University,
1 Universitetskaya pl., 394006 Voronezh, Russian Federation.
Eꢀmail: chocd261@chem.vsu.ru
Threeꢀcomponent condensation of 3ꢀaminoꢀ1,2,4ꢀtriazole (or its 5ꢀmethyl and 5ꢀmethylꢀ
thio derivatives), dimedone (or cyclohexaneꢀ1,3ꢀdione), and dimethylformamide dimethyl
acetal afforded 8,8ꢀR,Rꢀ8,9ꢀdihydro[1,2,4]triazolo[1,5ꢀa]quinazolinꢀ6(7H )ꢀones.
Key words: 3ꢀaminoꢀ1,2,4ꢀtriazole, dimedone, cyclohexaneꢀ1,3ꢀdione, dimethylformamide
dimethyl acetal, 8,8ꢀdimethylꢀ8,9ꢀdihydro[1,2,4]triazolo[1,5ꢀa]quinazolinꢀ6(7H )ꢀone, threeꢀ
component condensation.
Earlier,1 we have found that hetarylguanidines of the
formula HetNHC(=NH)NH2 (Het is benzoxa(thia)zolꢀ
2ꢀyl and 5ꢀethoxycarbonylꢀ4ꢀmethylꢀ1,3ꢀthiazolꢀ2ꢀyl)
enter into threeꢀcomponent condensation with triethyl
orthoformate and dimedone (1a) to give the correspondꢀ
ing NꢀhetarylꢀNꢀtetrahydrooxoquinazolylamines. Later,2
we extended this reaction to 2ꢀaminobenzimidazole,
which also belongs to 1,3ꢀazabinucleophiles; in the latter
case, the tetrahydroquinazoline ring is annelated.
we obtained a multicomponent mixture that was difficult
to separate (TLC). The synthesis was successful when
orthoformate was replaced by dimethylformamide diꢀ
methyl acetal (3) used in such processes.3,4 Apparently,
the reaction proceeds through the in situ formation of
enaminone 4 (Scheme 1). A reaction of the latter with
aminotriazole, which is accompanied by elimination of
the readily leaving dimethylamino group, gives rise to an
intermediate whose intramolecular condensation yields
the final product 5. The reaction was extended to 3ꢀaminoꢀ
5ꢀmethylꢀ and 3ꢀaminoꢀ5ꢀmethylthioꢀ1,2,4ꢀtriazoles and
cyclohexaneꢀ1,3ꢀdione. The best results were obtained
However, an attempt to employ 3ꢀaminoꢀ1,2,4ꢀtriꢀ
azole (2a) failed. Instead of the target product, which
usually precipitates even from the hot reaction mixture,
Scheme 1
R = Me (1a, 5a—c), H (1b, 5d—f); R´ = H (2a, 5a,d), Me (2b, 5b,e), MeS (2c, 5c,f)
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2805—2807, December, 2005.
1066ꢀ5285/05/5412ꢀ2903 © 2005 Springer Science+Business Media, Inc.

2904
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 12, December, 2005
Shikhaliev et al.
8,9ꢀDihydro[1,2,4]triazolo[1,5ꢀa]quinazolinꢀ6(7H )ꢀone
(5d). The yield was 73%, m.p. 211—213 °C. Found (%): C, 57.46;
H, 4.29; N, 29.62. C9H8N4O. Calculated (%): C, 57.44; H, 4.28;
N, 29.77. 1H NMR, δ: 2.32 (m, 2 H, C(8)H2); 2.76 (t, 2 H,
upon mixing of DMF dimethyl acetal with a dicarbonyl
compound followed by addition of aminotriazole. This
prevented possible side reactions of the latter with diꢀ
methyl acetal.
3
3
C(9)H2, J = 8.4 Hz); 3.51 (t, 2 H, C(7)H2, J = 8.4 Hz); 8.61
(s, 1 H, CH of triazole); 9.16 (s, 1 H, CH of quinazoline).
2ꢀMethylꢀ8,9ꢀdihydro[1,2,4]triazolo[1,5ꢀa]quinazolinꢀ
6(7H )ꢀone (5e). The yield was 75%, m.p. 280—282 °C.
Found (%): C, 59.48; H, 4.79; N, 27.67. C10H10N4O. Calcuꢀ
lated (%): C, 59.40; H, 4.98; N, 27.71. 1H NMR, δ: 2.32 (m,
Experimental
The course of the reactions was monitored and the purity of
the products was checked by TLC on Silufol UVꢀ254 plates with
3
1
2 H, C(8)H2); 2.72 (t, 2 H, C(9)H2, J = 8.4 Hz); 2.89 (s, 3 H,
chloroform—ethyl acetate (1 : 2) as an eluent. H NMR spectra
Me); 3.46 (t, 2 H, C(7)H2, 3J = 8.4 Hz); 9.08 (s, 1 H, CH of
quinazoline).
were recorded on a Bruker ACꢀ300 instrument (300 MHz) in
DMSOꢀd6 with Me4Si as the internal standard.
2ꢀMethylthioꢀ8,9ꢀdihydro[1,2,4]triazolo[1,5ꢀa]quinazolinꢀ
6(7H )ꢀone (5f). The yield was 70%, m.p. 170—172 °C.
Found (%): C, 51.24; H, 4.29; N, 23.97. C10H10N4OS. Calcuꢀ
lated (%): C, 51.27; H, 4.30; N, 23.91. 1H NMR, δ: 2.32 (m,
8,8ꢀDimethylꢀ8,9ꢀdihydro[1,2,4]triazolo[1,5ꢀa]quinazolinꢀ
6(7H )ꢀone (5a). Dimedone 1 (1.4 g, 10 mmol) was added to
dimethyl acetal 3 (1.44 g, 12 mmol) and the mixture was heated
at 60 °C to complete homogenization, whereupon aminotriazole
2 (0.84 g, 10 mmol) was added. The reaction mixture was reꢀ
fluxed for 30 min. After cooling, it solidified and was diluted
with propanꢀ2ꢀol. The precipitate was filtered off and recrystalꢀ
lized from DMF. The yield of compound 5a was 1.88 g (87%),
m.p. 172—174 °C. Found (%): C, 61.26; H, 5.45; N, 25.74.
3
2 H, C(8)H2); 2.70 (t, 2 H, C(9)H2, J = 8.4 Hz); 2.78 (s, 3 H,
3
MeS); 3.42 (t, 2 H, C(7)H2, J = 8.4 Hz); 9.03 (s, 1 H, CH of
quinazoline).
References
C
11H12N4O. Calculated (%): C, 61.10; H, 5.59; N, 25.91.
1H NMR, δ: 1.21 (s, 6 H, 2 Me); 2.65, 3.41 (both s, 2 H each,
CH2); 8.61 (s, 1 H, CH of triazole); 9.14 (s, 1 H, CH of
quinazoline).
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 Heterocyclic Synꢀ
thesis], Nauchnaya Kniga, Saratov, 2004, 308 (in Russian).
2. Kh. S. Shikhaliev, D. V. Kryl´skii, A. Yu. Potapov, M. Yu.
Krysin, and I. N. Trefilova, Izv. Vyssh. Uchebn. Zaved., Khim.
Khim. Tekhnol. [Bulletin of Higher Schools, Chemistry and
Chemical Technology], 2004, 47, No. 3, 149 (in Russian).
3. V. Molteni, M. M. Hamilton, L. Mao, C. M. Crane, A. P.
Termin, and D. M. Wilson, Synthesis, 2002, 1669.
Compounds 5b—f were obtained analogously.
2,8,8ꢀTrimethylꢀ8,9ꢀdihydro[1,2,4]triazolo[1,5ꢀa]quinazoꢀ
linꢀ6(7H )ꢀone (5b). The yield was 84%, m.p. 164—166 °C.
Found (%): C, 62.61; H, 6.09; N, 24.42. C12H14N4O. Calcuꢀ
lated (%): C, 62.59; H, 6.13; N, 24.33. 1H NMR, δ: 1.21 (s, 6 H,
2 Me); 2.60, 3.38 (both s, 2 H each, CH2); 2.76 (s, 3 H, Me);
9.08 (s, 1 H, CH of quinazoline).
8,8ꢀDimethylꢀ2ꢀmethylthioꢀ8,9ꢀdihydro[1,2,4]triazoꢀ
lo[1,5ꢀa]quinazolinꢀ6(7H )ꢀone (5c). The yield was 78%, m.p.
157—159 °C. Found (%): C, 60.11; H, 5.29; N, 21.44.
C12H14N4OS. Calculated (%): C, 54.94; H, 5.38; N, 21.36.
1H NMR, δ: 1.20 (s, 6 H, 2 Me); 2.60, 3.32 (both s, 2 H each,
CH2); 2.71 (s, 3 H, MeS); 9.01 (s, 1 H, CH of quinazoline).
4. E. Bejan, H. A. Haddou, J. C. Daran, and G. G. A. Balavoine,
Synthesis, 1996, 1012.
Received June 6, 2005;
in revised form October 25, 2005