An original method for the synthesis of quinazolines

Full text of DOI:10.1007/s10593-010-0480-7

Chemistry of Heterocyclic Compounds, Vol. 46, No. 1, 2010
AN ORIGINAL METHOD FOR THE
SYNTHESIS OF QUINAZOLINES
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A. V. Aksenov **, A. S. Lyakhovnenko , and M. M. Kugutov
Keywords: sodium azide, anisole, PPA, 1,3,5-triazine, phenol, quinazolines, amination.
Quinazolines are a well-known class of heterocyclic compounds, for which quite a few methods of
synthesis have been developed (see, for example, the work of Chilin et al. [1]). Nevertheless, methods involving
the formation of the N(1)–C(8a) and C(4)–C(4a) bonds have not been reported. In the present work, we propose
such a method based on the recently reported NaN /PPA reagent combination [3]*. The reaction of phenol 1a or
3
anisole 1b (1 mmol) and NaN (1.1 mmol) in PPA (2-3 g) at 55-60°C over 3 h monitored by thin-layer
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chromatography with subsequent addition of 1,3,5-triazine (1.5 mmol) and heating for an additional 4 h at
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0-100°C leads to quinazoline 2a in 49% yield or quinazoline 2b in 54% yield.
RO
RO
1
2
) NaN / PPA
3
N
) 1,3,5-triazine
N
1
a,b
2a,b
1
, 2 a R = H, b R = Me
The reaction, evidently procedes trough the following stages sequence:
N
N
NH
+
O
P
O
N
N
NaN3
PPA
– PPA
N2
N
1
a,b
.
..O
N
N
N
OR
+
...O
P
N
N
N
H
OR
–
H
HO
3
OH
4
N
NH2
H
N
RO
+
NH2
N
H
N
N
H
OR
N
2a,b
N
OR
H
– HN=CHNH2
N
N
N
H
5
6
_
*
______
The PPA sample used containing 86% P O was prepared according to Uhlig [2].
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5
*
* To whom correspondence should be addressed, e-mail: k-biochem-org@stavsu.ru.
Stavropol State University, Stavropol 355009, Russia.
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_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 143-145, January, 2010. Original
article submitted November 16, 2009.
009-3122/10/4601-0125©2010 Springer Science+Business Media, Inc.
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The reaction of sodium azide in PPA with the activated arene gives intermediate 3 [3], which reacts with
,3,5-triazine to give compound 4. The decomposition of 4 gives N-(arylamino)triazine 5, which undergoes ring
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opening and subsequent intramolecular electrophilic substitution to give quinazoline derivative 6. The loss of
formamidine from compound 6 gives the desired quinazoline 2.
The NMR spectra were taken on a Bruker WP-200 spectrometer at 200 MHz with TMS as the internal
standard. The reaction course and purity of the products were monitored by thin-layer chromatography on
Silufol UV-254 plates with ethyl acetate as the eluent.
The reaction mixture was treated with 50 ml water and filtered. The filtrate was extracted with three
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0-ml portions of ethyl acetate. The aqueous layer was brought to pH 9-10 by adding ammonium hydroxide.
The precipitate formed or oil was extracted by three 50-ml portions of ethyl acetate. The solvent was evaporated
off and the products obtained were purified by recrystallization.
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-Hydroxyquinazoline (2a) was obtained in 49% yield (0.072 g); mp 237-239°C (water)
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(
mp 239°C [1]). H NMR spectrum in DMSO-d , δ, ppm (J, Hz): 7.61 (1H, dd, J = 9.1, J = 2.5, H-7); 7.99 (1H,
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d, J = 9.1, H-8); 8.14 (1H, d, J = 2.5, H-5); 9.18 (1H, s, H-4); 9.28 (1H, s, H-2). Found, %: C 65.71; H 4.17;
N 19.14. C H N O. Calculated, %: C 65.75; H 4.14; N 19.17.
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6
2
6
-Methoxyquinazoline (2b) was obtained in 54% yield (0.086 g); mp 71-72°C (petroleum ether)
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(
(
mp 71°C [1]). H NMR spectrum in CDCl , δ, ppm (J, Hz): 3.95 (3H, s, OCH ); 7.13 (1H, d, J = 2.5, H-5); 7.56
3
3
1H, dd, J = 9.2, J = 2.5, H-7); 7.94 (1H, d, J = 9.2, H-8); 9.21 (1H, s, H-4); 9.29 (1H, s, H-2). Found, %:
C 67.45; H 5.05; N 17.51. C H N O. Calculated, %: C 67.49; H 5.03; N 17.49.
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2
This work was carried out with the financial support of the Russian Basic Research Fund
Grant No. 10-03-00193a).
(
REFERENCES
1
.
A. Chilin, G. Marzaro, S. Zanatta, V. Barbieri, G. Pastorini, P. Manzinia, and A. Guiottoa, Tetrahedron,
2, 12351 (2006).
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2
3
.
.
F. Uhlig, Angew. Chem., 66, 435 (1954).
A. V. Aksenov, A. S. Lyakhovnenko, and N. Ts. Karaivanov, Khim. Geterotsikl. Soedin., 1091 (2009).
[Chem. Heterocycl. Comp., 45, 871 (2009)].
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