ORGANIC
LETTERS
2004
Vol. 6, No. 25
4775-4778
Efficient Synthesis of
4-Aminoquinazoline and
Thieno[3,2-d]pyrimidin-4-ylamine
Derivatives by Microwave Irradiation
David S. Yoon, Ying Han,* Todd M. Stark, James C. Haber, Brian T. Gregg, and
Sara B. Stankovich
Albany Molecular Research, Inc., 21 Corporate Circle, P.O. Box 15098,
Albany, New York 12212-5098
Received October 8, 2004
ABSTRACT
A simple, efficient, and high-yielding synthesis of quinazolin-4-ylamine and thieno[3,2-d]pyrimidin-4-ylamine derivatives is reported under
microwave irradiation conditions. Reaction conditions including temperature, solvent, and reaction time have been studied. An efficient parallel
workup procedure was developed to generate a small library (23 compounds) in a short time period.
4-Aminoquinazoline and its derivatives are useful as fungi-
cides and as antiinflammatory, antimicrobial, and antihy-
pertensive agents.1 In particular, they are potent and highly
selective inhibitors of tyrosine kinase.2 Therefore, in recent
years, the synthesis of 4-aminoquinazolines has attracted
much attention.3
Traditional preparation of 4-aminoquinazolines involves
the reaction of amines and 4-chloroquinazolines. The 4-chlo-
roquinazolines were synthesized by chlorination of the
corresponding quinazolinones that were in turn prepared by
heating anthranilamides with formic acid, triethyl orthofor-
mate, or formamide.
Microwave-assisted organic synthesis has had a significant
impact on synthetic organic chemistry since 1986, with the
introduction of controlled, precise microwave reactors.4 The
advantages of microwave irradiation include not only im-
proving classical reactions, shortening reaction times, im-
proving yields, and suppressing byproduct formation as com-
pared with conventional thermal heating but also promoting
new reaction types for drug discovery and process chemistry.5
In a search for novel compounds with pharmaceutical
value and expanding application of formamidines in organic
synthesis,6 we wish to report herein a straightforward and
high-yielding synthesis of 4-aminoquinazoline and thieno-
(2) For recent review, see: (a) Fry, D. W.; Kraker, A. J.; McMichael,
A.; Ambroso, L. A.; Nelson, J. M.; Leopold, W. R.; Connors, R. W.;
Bridges, A. J. Science 1994, 265, 1093-1095. (b) Bridges, A. J. Chem.
ReV. 2001, 101, 2541-2572. (c) Tsou, H. R.; Mamuya, N.; Johnson, B.
D.; Reich, M. F.; Gruber, B. C.; Ye, F.; Nilakantan, R.; Shen, R.; Discafani,
C.; DeBlanc, R.; Davis, R.; Koehn, R. E.; Greenberger, L. M.; Wang, Y.
F.; Wissner, A. J. Med. Chem. 2001, 44, 2719-2734. (d) Berger, M.;
Albrecht, B.,; Berces, A, Ettmayer, P.; Neruda, W.; Woisetschla¨ger, M. J.
Med. Chem. 2001, 44, 3031-3038.
(3) (a) Reference 2c. (b) Rocco, S. A.; Barbarini, J. E.; Rittner, R.
Synthesis 2004, 3, 429-435 and references cited therein.
(4) Gedye, R.; Smith, F.; Westaway, K.; Ali, H.; Baldisera, L. Tetra-
hedron Lett. 1986, 27, 279-282.
(5) For recent reviews on microwave-assisted chemistry, see: (a) Perio,
B.; Dozias, M.; Hamelin, J. Org. Process Res. DeV. 1998, 2, 428-430. (b)
Cleophax, J.; Liagre, M.; Loupy, A.; Petit, A. Org. Process Res. DeV. 2000,
4, 498-504. (c) Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199-9223.
(d) Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001,
57, 9225-9283. (e) Lew, A.; Krutzik, P. O.; Hart, M. E.; Chamberlin, A.
R. J. Comb. Chem. 2002, 4, 95-105. (f) Santagada, V.; Perissutti, E.;
Caliendo, G. Curr. Med. Chem. 2002, 9, 1251-1283. (g) Mavandadi, F.;
Lidstrom, P. Curr. Top. Med. Chem. 2004, 4, 773-792.
(1) Johne, S. The Alkaloids, Chemistry and Pharmacology; Brossi, A.,
Ed.; 1986; Vol. 29, pp 99-140.
(6) Cai, L.; Han, Y.; Ren, S. M.; Huang, L. F. Tetrahedron 2000, 56,
8253-8262.
10.1021/ol047919y CCC: $27.50
© 2004 American Chemical Society
Published on Web 11/11/2004