Synthesis and optimization of an original V-shaped collection of 4-7-disubstituted pyrido[3,2-d]pyrimidines as CDK5 and DYRK1A inhibitors.

We here report the synthesis and biological evaluation of an original collection of 4,7-disubstituted pyrido[3,2-d]pyrimidines designed as potential kinase inhibitors. The collection was generated from a single starting material, 4,7-dichloropyrido[3,2-d]pyrimidine, which afforded the final compounds after two steps: a sequential or one-pot sequence including selective cross coupling reactions in C-4, followed by the second cross-coupling in C-7. In position C-4, a Suzuki-Miyaura type reaction led to monosubstituted derivatives whereas in position C-7, synthesis was achieved via a Suzuki or a Buchwald type reaction using commercially available or undescribed boron derivatives.

Couplings of benzylic halides mediated by titanocene chloride: synthesis of bibenzyl derivatives.

Titanocene monochloride catalyzes the homocoupling of benzylic halides and benzylic gem-dibromides to give the corresponding bibenzyl and stilbenyl systems. Exposure of benzylic bromides to Ti(III) in the presence of aldehydes gave rise to the Barbier-type products. Examples of the utility of the herein described processes are included.