A novel method of synthesis of 2,4-diamino-6-arylmethylquinazolines using palladium(0)-catalyzed organozinc chemistry.

Abstract

Palladium-catalyzed cross-coupling reactions offer a powerful approach to the creation of a carbon-carbon bond between an electrophile C-X (e.g., X ) Cl, Br, I, OTf) and an organometallic species C-M (e.g., M ) Li, Mg, Zn, B, Si).1 Organozinc reagents are extremely useful in this context because they can tolerate a wide range of functionality in the electrophilic partner.2 A large number of organozinc reagents are available commercially as standardized solutions in THF or can prepared easily from organic halides and a highly reactive grade of metallic zinc (“Rieke zinc”),3 which is likewise commercially available. Thus, organozinc reagents in combination with palladium reagents are advantageous in the synthesis of complex molecules containing multiple functional groups, such as natural products. Of particular note are that the reaction requires only a catalytic amount of palladium and that, in contrast to the Heck reaction, the saturated carbon-carbon is generated directly, without the need to first reduce a double or triple bond. Thus, palladium-catalyzed cross-coupling reactions using organozinc reagents are expected to enjoy increasing popularity in organic synthesis and medicinal chemistry. Piritrexim (1),4 a lipophilic inhibitor of the key metabolic enzyme dihydrofolate reductase (DHFR), has been studied intensively as an anticancer drug5 and, more recently, was identified as a potent inhibitor of the enzyme from Pneumocystis carinii (Pc) and Toxoplasma gondii (Tg), two opportunistic parasites known to be potentially life-threatening in patients with acquired immunodeficiency syndrome (AIDS).6 A notable structural feature of 1 is the CH2 bridge between the two halves of the molecule. This bridge is also present in trimethoprim (2),7 another lipophilic DHFR inhibitor widely used for anti-Pc and anti-Tg prophylaxis and therapy in AIDS patients, usually in combination with a sulfa drug to enhance the efficacy.8 Two other members of this class that have been used clinically against these infections are pyrimethamine (3),7,9 in which the two halves of the molecule are linked without a CH2 bridge, and trimetrexate (4),10,11 which contains a CH2NH bridge. In addition to the fact that it contains a longer bridge, 4 differs from 1 in being a quinazoline as opposed to a pyrido[2,3-d]pyrimidine. The structures of these four prototypical examples of clinically active lipophilic antifolates are shown in Figure 1. Although there are a number of examples in the literature of lipophilic DHFR inhibitors in which the fused 2,4-diaminopyrimidine ring system and the aryl side chain are separated by a short O or S bridge, as in 5 and 6,12,13 the only quinazoline antifolates described to date in which this bridge is CH2 are the 5,6,7,8-tetrahydro derivatives 7.14 In the present paper, we report a novel and remarkably straightforward method of synthesis of analogues of 7 in which the B-ring is aromatic.