ORGANIC
LETTERS
2009
Vol. 11, No. 6
1421-1424
Synthesis of
3-Substituted-4(3H)-quinazolinones via
HATU-Mediated Coupling of
4-Hydroxyquinazolines with Amines
Zili Xiao, Michael G. Yang,* Peng Li, and Percy H. Carter
Research & DeVelopment, Bristol-Myers Squibb Company,
Princeton, New Jersey 08543
Received January 16, 2009
ABSTRACT
A novel synthesis of 3-substituted 4(3H)-quinazolinones via HATU-mediated coupling of 4-hydroxyquinazolines with primary amines has been
developed. Under mild reaction conditions, the products were achieved in good yield from commercially available starting materials.
3-Substituted 4(3H)-quinazolinones are useful heterocyclic
motifs found in many pharmaceutically active compounds.
One of the most direct ways to access this class of
compounds is N-alkylation of 4-hydroxyquinazolines.1 How-
ever, issues still exist for the synthesis of sterically hindered
3-alkyl 4(3H)-quinazolinones,2 and there are very few studies
on the direct 3-arylation of 4-hydroxyquinazolines.3 In this
paper, we report a novel synthesis of 3-substituted 4(3H)-
quinazolinones via HATU-mediated coupling of 4-hydroxy-
quinazolines with amines. The mechanism of this transfor-
mation is discussed in light of the recently reported
phosphonium-mediated synthesis of 4-aminoquinazolines.4
In a medicinal discovery program directed toward CCR2
antagonism, we were interested in synthesizing quinazoline
2.5 Based on the procedure reported in the literature,6 we
envisioned that 2 could be made through the BOP-mediated
coupling of amine 1 with the 4-hydroxyquinazoline (eq 1,
Scheme 1). When the reaction failed to provide the desired
product, we speculated that HATU could be used to improve
the reaction conditions. To our surprise, the reaction gave
quinazolinone 3 in 34% yield; compound 2 was not detected
(eq 2, Scheme 1).
(1) Some representative examples include: (a) Wee, G. H. A.; Fan, G. J.
Org. Lett. 2008, 10, 386. (b) Michael, J. P.; Koning, C. B. de.; Pienaar,
D. P. Synlett 2006, 3, 383. (c) Testard, A.; Loge, C.; Leger, B.; Robert,
J.-M.; Lozach, O.; Blairvacq, M.; Meijer, L.; Thiery, V.; Besson, T. Bioorg.
Med. Chem. Lett. 2006, 16, 3419. (d) For review articles on the synthesis
of quinazolinones, see: Connolly, D. J.; Cusack, D.; O’Sullivan, T. P.; Guiry,
P. J. Tetrahedron 2005, 61, 10153.
(2) Some representative examples include: (a) Review:Torres, M.; Gil,
S.; Parra, M. Curr. Org. Chem. 2005, 9, 1757,and references cited therein.
(b) Liu, H.; Ko, S. B.; Josien, H.; Curran, D. P. Tetrahedron Lett. 1995,
36, 8917. (c) Bavetsias, V.; Yafai, S. F.; Wilson, M. S. C.; Allan, W. B.;
Jackman, A. L. J. Med. Chem. 2002, 45, 3692. (d) Bowman, W. R.; Bridge,
C. F. Synth. Commun. 1999, 29, 4051. (e) Lanni, E. L.; Bosscher, M. A.;
Ooms, B. D.; Shandro, C. A.; Ellsworth, B. A.; Anderson, C. E. J. Org.
Chem. 2008, 73, 6425.
Following this initial observation, we surveyed a variety
of coupling reagents under the original conditions (MeCN,
DBU). As shown in Table 1, compound 7a was the major
(3) (a) Russell, S. S.; Jahangir, Synth. Commun. 1994, 24, 123. (b)
Filipski, K. J.; Kohrt, J. T.; Casimiro-Garcia, A.; Van Huis, C. A.; Dudley,
D. A.; Cody, W. L.; Bigge, C. F.; Desiraju, S.; Sun, S.; Maiti, S. N.; Jaber,
M. R.; Edmunds, J. J. Tetrahedron Lett. 2006, 47, 7677. (c) Tiwari, S. S.;
Zaidi, S. M. M.; Rajesh, A.; Satsangi, R. K. J. Indian Chem. Soc. 1980,
57, 1039.
(4) Wan, Z.-K.; Wacharasindhu, S.; Levins, C. G.; Lin, M.; Tabei, K.;
Mansour, T. S. J. Org. Chem. 2007, 72, 10194, and references cited therein.
(5) Carter, P. H.; Cherney, R. J.; Batt, D. G.; Brown, G. D.; Duncia,
J. V.; Gardner, D. S.; Yang, M. G. WO Patent 05021500, 2005.
(6) Wan, Z.-K.; Wacharasindhu, S.; Binnun, E; Mansour, T. S. Org.
Lett. 2006, 8, 2425.
10.1021/ol802946p CCC: $40.75
Published on Web 02/25/2009
2009 American Chemical Society