ORGANIC
LETTERS
2006
Vol. 8, No. 3
395-398
A Highly Regioselective Amination of
6-Aryl-2,4-dichloropyrimidine
Zhi-Hui Peng,* Michel Journet, and Guy Humphrey
Department of Process Research, Merck & Co., Inc., P.O. Box 2000,
Rahway, New Jersey 07065
Received October 24, 2005
ABSTRACT
A highly regioselective amination of 6-aryl-2,4-dichloropyrimidine with aliphatic secondary amines and aromatic amines has been developed
which strongly favors the formation of the C4-substituted product. The reactions with aliphatic amines are carried out using LiHMDS as the
base and are catalyzed by Pd, while the aromatic amines require no catalyst.
Pyrimidines are widespread heterocyclic motifs found in
numerous natural products as well as synthetic pharmaco-
phores with antibacterial, antimicrobial, and antimycotic
activities.1 The highly electron-deficient nature of the pyri-
midine ring renders the nucleophilic aromatic substitution
reaction (SNAr) a general approach for the synthesis of a
large number of pyrimidine derivatives, especially from
readily available halopyrimidines.1 This feature also translates
to palladium-catalyzed cross-coupling reactions as even
pyrimidine chlorides are highly reactive substrates.2
The reactivity of each position of the pyrimidine halides
follows the general order C4(6) > C2 . C5. This order has
been observed for both palladium-catalyzed reactions and
SNAr displacements.1,2 In palladium-catalyzed C-C bond
formation reactions, Sonogashira reactions showed little
difference in reactivity between the C2 and C4 positions of
halopyrimidines,3 while a strong preference for the C4
position has been observed in Suzuki4 and Stille5 coupling
reactions such that the sequential introduction of different
substituents has been achieved.
The nucleophilic substitution reactions of 2,4-dichloropyri-
midines are generally only moderately selective toward the
formation of the C4-substituted product. For example, the
nucleophilic displacement of 2,4-dichloropyrimidines with
neutral nitrogen nucleophiles affords only 1:1 to 4:1 ratios
of the C4/C2 isomers (eq 1).6-8 This lack of regioselectivity
(4) (a) Gronowitz, S.; Hornfeldt, A.-B.; Kristjansson, V.; Musil, T. Chem.
Scr. 1986, 26, 305-309. (b) Cocuzza, A. J.; Hobbs, F. W.; Arnold, C. R.;
Chidester, D. R.; Yarem, J. A.; Culp, S.; Fitzgerald, L.; Gilligan, P. J. Bioorg.
Med. Chem. Lett. 1999, 9, 1057-1062. (c) Jiang, B.; Yang, C.-G.
Heterocycles 2000, 53, 1489-1498. (d) Gong, Y.; Pauls, H. W. Synlett
2000, 829-831. (e) Schomaker, J. M.; Delia, T. J. J. Org. Chem. 2001, 66,
7125-7128.
(5) (a) Solberg, J.; Undheim, K. Acta Chem. Scand., Ser. B 1989, 43,
62-68. (b) Benneche, T. Acta Chem. Scand. 1990, 44, 927-931.
(6) For early examples, see: (a) Gabriel, S. Chem. Ber. 1901, 34, 3362-
3366. (b) Bu¨ttner, E. Chem. Ber. 1903, 36, 2227-2235. (c) Winkelmann,
W. J. Prakt. Chem. 1927, 115, 292-296. (d) Boon, W. R. J. Chem. Soc.
1952, 1532-1535.
(7) For recent examples, see: (a) Mossini, F.; Maggiali, C.; Morini, G.;
Impicciatore, M.; Morini, G.; Molina, E. Farmaco, Ed. Sci. 1984, 39, 189-
199. (b) Delia, T. J.; Stark, D.; Glenn, S. K. J. Heterocycl. Chem. 1995,
32, 1177-1180. (c) Schomaker, J. M.; Delia, T. J. J. Heterocycl. Chem.
2000, 37, 1457-1462. (d) Luthin, D. R.; Hong, Y.; Tompkins, E.; Anderes,
K. L.; Paderes, G.; Kraynov, E. A.; Castro, M. A.; Nared-Hood, K. D.;
Castillo, R.; Gregory, M.; Vazir, H.; May, J. M.; Anderson, M. B. Bioorg.
Med. Chem. Lett. 2002, 12, 3635-3640. (e) Montebugnoli, D.; Bravo, P.;
Brenna, E.; Mioskowski, C.; Panzeri, W.; Viani, F.; Volonterio, A.; Wagner,
A.; Zanda, M. Tetrahedron 2003, 59, 7147-7156. (f) Joubran, L.; Jackson,
W. R.; Campi, E. M.; Robinson, A. J.; Wells, B. A.; Godfrey, P. D.;
Callaway, J. K.; Jarrott, B. Aust. J. Chem. 2003, 56, 597-606.
(1) (a) Hurst, D. T. In An Introduction to the Chemistry and Biochemistry
of Pyrimidines, Purines and Pteridines; Wiley: Chichester, 1980. (b) Brown,
D. J. In ComprehensiVe Heterocyclic Chemistry; Katritzky, A. R., Rees, C.
W., Eds.; Pergamon Press: Oxford, 1984; Vol. 3, Chapter 2.13. (c) Brown,
D. J. In The Pyrimidines; Interscience Publishers: New York, 1994.
(2) (a) Undheim, K.; Benneche, T. Heterocycles 1990, 30, 1155-1193.
(b) Undheim, K.; Benneche, T. In AdV. Heterocycl. Chem. 1995, 62, 305-
418. (c) Kalinin, K. N. Synthesis 1992, 413-432. (d) Littke, A. F.; Fu, G.
C. Angew. Chem., Int. Ed. 2002, 41, 4176-4211.
(3) Edo, K.; Yamanaka, H.; Sakamoto, T. Heterocycles 1978, 9, 271-
274.
10.1021/ol052578p CCC: $33.50
© 2006 American Chemical Society
Published on Web 01/12/2006