Microwave enhanced synthesis of 4-aminoquinazolines

Article abstract of DOI:10.1016/S0040-4039(00)00090-3

Cyanoaromatic compounds react with anthranilonitrile in a domestic microwave oven affording good yields of the corresponding 4-aminoquinazolines in a very short irradiation time. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00090-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2215–2217
Microwave enhanced synthesis of 4-aminoquinazolines
Julio A. Seijas,∗ M. Pilar Vázquez-Tato ∗ and M. Montserrat Martínez
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Santiago de Compostela, Aptdo. 280,
27080-Lugo, Spain
Received 2 December 1999; accepted 11 January 2000
Abstract
Cyanoaromatic compounds react with anthranilonitrile in a domestic microwave oven affording good yields of
the corresponding 4-aminoquinazolines in a very short irradiation time. © 2000 Elsevier Science Ltd. All rights
reserved.
Keywords: quinazolines; amino nitriles; microwave heating.
Quinazolines are a wide family of compounds with well-known pharmacological properties:1–5 anal-
gesic, narcotic, anti-malarial, sedative or hypoglycaemic. Among the different substitution patterns that
are known, 4-aminoquinazolines are useful as fungicides6,7 and as anti-inflammatory,8,9 anti-cancer,10
anti-microbial and anti-hypertensive agents.11,12
Quinazolines have not been the object of new synthetic developments in the last few years and recent
reports on their preparation use only classical methods.13 This fact joined to the circumstance that the
main part of the literature on 4-aminoquinazolines is covered by patents, led us to carry out studies to
improve the synthesis of these compounds bearing in mind new synthetic methodologies. In later years,
microwaves have become popular among synthetic organic chemists both to improve classical organic
reactions14–20 shortening reaction times and/or improving yields, as well as to promote new reactions.
Our previous experience in the use of microwaves,21,22 led us to check if there was any possibility
for improvement in methods used for the synthesis of 4-aminoquinazolines. Most of them start from
cyanophenyltriazenes,23 o-azidobenzonitriles and nitriles,24 o-aminonitriles and nitriles.25 These proce-
dures employ high temperatures and various solvents. Often when carrying out a reaction in a microwave
oven, the use of a solvent can be avoided which is important in order to make the synthesis more
environmentally friendly (‘green chemistry’).
We performed our first experiment by heating anthranilonitrile (1a) in the presence of t-BuOK and
after 1 min we obtained 4-amino-2-(2-aminophenyl)quinazoline 2a (Scheme 1). We assayed different
ratios of alkoxide, obtaining our best yield (82%) using 10% of t-BuOK; other bases such as: NaH,
MeONa and lithium bis(trimethylsilyl)amide were unsuitable for our experiments.
Once we realised the viability of the use of a microwave oven for this reaction, we studied the pos-
sibility of mixed couplings. Anthranilonitrile was reacted with several aromatic nitriles (Table 1, entries
∗
Corresponding authors. E-mail: qoseijas@lugo.usc.es (J. A. Seijas), pilarvt@lugo.usc.es (M. P. Vázquez-Tato)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00090-3
tetl 16365

2216
Scheme 1. Synthesis of 4-aminoquinazolines
2–10). Benzonitrile (1b) gave 2b in a very good yield (93%) using a ratio of anthranilonitrile:benzonitrile
1:1, without any self condensation product 2a. A synthesis of 2b has been described25 in 39% yield, by
heating anthranilonitrile with a slight molar excess of benzonitrile in methanolic ammonia in a sealed
tube (20 h at 200°C); no reaction occurred in refluxing methanol in the presence of sodium methoxide.
These authors also reported the absence of a reaction between anthranilonitrile and nitrile 1c. Meanwhile,
we obtained quinazoline 2c (76% yield) from 4-methoxybenzonitrile (1c) under microwave irradiation
for 1 min.
Table 1
Synthesis of 4-aminoquinazolines
In these reactions we had to define the amount of base and, after several experiments, we fixed the
ratio of t-BuOK as 10% with respect to the molar amount of 1a.
When 1,3-dicyanobenzene (1d) was treated with anthranilonitrile in a ratio of 1:1, it gave an 85% yield
of 4-amino-2-(3-cyanophenyl)quinazoline (2d).† The yields were also very good with 2-thiophenenitrile
(1e) and with 2-furanonitrile (1f) yielding 2e‡ and 2f, respectively. In the series of 2-pyridinoquinazolines,
†
1
4-Amino-2-(3-cyanophenyl)-quinazoline (2d). H NMR (Cl3CD, 300 MHz): δ 8.84 (s, 1H), 8.78 (d, 1H), 7.95 (d, 1H),
7.82–7.72 (m, 3H), 7.61–7.52 (m, 2H), 5.81 (br s, 2H). 13C NMR (Cl3CD, 75 MHz): δ (selected C_N signals) 161.5, 150.8.
MS: m/z 246 (M+, 24%).
‡
General procedure. A mixture of anthranilic acid (1) (100 mg, 0.846 mmol), 2-thiophenenitrile (1e) (92 mg, 0.843 mmol)
and potassium tert-butoxide (10 mg, 0.089 mmol) in a test tube was heated in a domestic microwave oven (1000 W, 70% of
total power) until no starting materials were observed by TLC (1.5 min). The crude reaction was purified by crystallization from
methanol to afford 4-amino-2-(2-thiophenyl)-quinazoline (2e) (173 mg, 90%). 1H NMR (CD3OD, 300 MHz): δ 8.19 (d, 1H),
8.14 (d, 1H), 7.89 (s, 2H), 7.68 (d, 1H), 7.55 (m, 1H), 7.28 (t, 1H). 13C NMR (CD3OD, 75 MHz): δ (selected C_N signals)
164.8, 160.0. MS: m/z 227 (M+, 100%).

2217
we prepared 4-amino-2-(4-pyridyl)quinazoline (2g), 4-amino-2-(3-pyridyl)quinazoline (2h) and 4-
amino-2-(2-pyridyl)quinazoline (2i) in good yields.
We also prepared 4-amino-2-benzylquinazoline (2j) using an equimolar ratio of 1a and benzyl cyanide.
We wanted to check the performance of the classical methods for the preparation of this quinazoline. Thus
we refluxed 1a with an excessive amount of 1j (400% molar) and t-BuOK (100% molar) in isopropanol;
after 48 h we isolated only a 40% yield§ of quinazoline 2j.
We have established the advantages of using a domestic microwave oven as a heating device in the
synthesis of 4-aminoquinazolines as: the absence of solvent, a radical decrease in reaction time, the use
of a catalytic amount of base, and an improvement over precedent synthesis using conventional heating.
Acknowledgements
We thank DGES (PB96-0932) for their financial support.
References
1. Petersen, S.; Herlinger, H.; Tietze, E.; Siefken, W. Angew. Chem. 1962, 74, 855–861.
2. Bogentoft, C.; Kronenberg, L.; Danielsson, C. Acta Pharm. Suec. 1969, 6, 489–500.
3. Johne, S.; Jung, B. Pharmazie 1978, 33, 299.
4. Johne, S. Pharmazie 1981, 36, 583–596.
5. Shaban, M. A. E.; Taha, M. A. M.; Sharahira, E. M. Adv. Heterocycl. Chem. 1991, 52, 1–153.
6. Nakagami, K.; Yokoi, S.; Nishimura, K.; Nagai, S.; Honda, T.; Oda, K.; Fujii, K.; Kobayashi, R.; Kojima, M. US Pat. 1982,
4323680.
7. Haley, G. J. US Pat. 1994, 5373011.
8. Palanki, M. S. S.; Suto, M. J. US Pat. 1999, 5939421.
9. Myers, M. R.; Spada, A. P.; Maguire, M. P.; Persons, P. E.; Zilberstein, A.; Hsu, C.-Y.-J.; Johnson, S. E. US Pat. 1998,
5714493.
10. Barker, A. J. US Pat. 1999, 5942514 and 1999, 5932574.
11. Nauta, W. T. US Pat. 1976, 3980650.
12. Mizogami, S.; Hiranuma, H.; Sekiya, T.; Hanazuka, M. US Pat. 1986, 4607034.
13. Comprehensive Heterocyclic Chemistry II; Katrizky, A. R.; Rees, C. W., Eds.; Pergamon Press: Oxford, 1996.
14. Varma, R. S. Green Chemistry 1999, 43–55.
15. Loupy, A.; Petit, A.; Hamelin, J.; Texier-Boullet, F.; Francoise, P.; Mathe, D. Synthesis 1998, 1213–1234.
16. Bose, A. K.; Banik, B. K.; Lavlinskaia, N.; Jayaraman, M.; Manhas, M. S. Chemtech. 1997, 27, 18–24.
17. Galema, S. A. Chem. Soc. Rev. 1997, 26, 233–238.
18. Majetich, G.; Hicks, R. Radiat. Phys. Chem. 1995, 45, 567–579.
19. Caddick, S. Tetrahedron 1995, 51, 10403–10432.
20. Strauss, C. R.; Trainor, R. W. Aust. J. Chem. 1995, 48, 1665–1692.
21. Seijas, J. A.; Vázquez-Tato, M. P.; Martínez, M. M.; Nuñez-Corredoira, G. J. Chem Res. (S) 1999, 420–421.
22. Vázquez-Tato, M. P. Synlett 1993, 506.
23. Stevens, M. F. G. J. Chem. Soc. (C) 1967, 1096–1098.
24. Sutherland, D. R.; Tennant, G. J. Chem. Soc. Perkin Trans. 1 1974, 534–540.
25. Taylor, E. C.; Borror, A. L. J. Org. Chem. 1961, 26, 4967–4974.
26. Partridge, M. W.; Stevens, M. F. G. J. Chem. Soc. 1964, 3663–3669.
27. Korbonits, D.; Kiss, P.; Simon, K.; Kolonits, P. Chem. Ber. 1984, 117, 3183–3193.
§
If the reaction is carried out using equimolar amounts of 1a and 1j, no formation of the 4-aminoquinazoline 2j is observed.