Pyridines Negishi cross-coupling reactions

Cyclin-dependent kinases (CDKs) play a key role in regulating cell cycle machinery. This family of kinases requires association with a cyclin regulatory subunit for activity. Different CDK/cyclin pairs are active during each phase of the cell cycle. Negishi cross-coupling reactions were the key steps in the synthesis of [l,3,5]triazine-pyridine biheteroaryls 161 as a novel series of potent cyclin-dependent kinase inhibitors. ... 

Examples of Negishi cross-couplings by this catalyst system are provided in Table 4. The method tolerates cyanides (entries 3 and 4), pyridines (entry 5), amides (entry 7), imides (entry 8), and esters (entry 10). Furthermore, hindered alkenylzincs (geminally or cfs-substituted entries 6-9) are suitable reaction partners. However, the effectiveness of the catalyst is compromised if the electrophile is hindered (e.g., branching in the a or p positions). 

The pyridyl group has also been immobilized on the resin and was able to survive lithiation conditions necessary to prepare the halopyridine [62]. This approach has also been applied to the Sonogashira, Stille, and Negishi reactions vide infra). In the Suzuki example, the resin-bound pyridine 177 can be converted to the haloderivative 178 using standard lithiation chemistry. With 178 in-hand, cross-coupling and cleavage from the resin afforded 179. 

Fu et al. reported Ni-catalyzed alkyl-alkyl cross-couphng reactions of diverse alkylzinc reagents with unactivated secondary alkyl halides under very mild conditions. Ni(cyclooctadiene)2 and sBu-pyridine-bis(oxazohne) (Pybox) catalyzed the Negishi coupling of various functional alkyl bromides and iodides at room... 

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