[reaction: see text] New methods for the palladium-catalyzed cyanation of aryl and heteroaryl chlorides have been developed, featuring sterically demanding, electron-rich phosphines. Highly challenging electron-rich aryl chlorides, in addition to electron-neutral and electron-deficient substrates, as well as nitrogen- and sulfur-containing heteroaryl chlorides can all undergo efficient cyanation under relatively mild conditions using readily available materials. In terms of substrate scope and temperature, these methods compare very favorably with the state-of-the-art cyanations of aryl chlorides.
The development of a short and efficient synthesis of a complex 6-azaindole, BMS-663068, is described. Construction of the 6-azaindole core is quickly accomplished starting from a simple pyrrole, via a regioselective Friedel-Crafts acylation, Pictet-Spengler cyclization, and a radical-mediated aromatization. The synthesis leverages an unusual heterocyclic N-oxide α-bromination to functionalize a critical C-H bond, enabling a highly regioselective copper-mediated Ullmann-Goldberg-Buchwald coupling to install a challenging triazole substituent. This strategy resulted in an efficient 11 step linear synthesis of this complex clinical candidate.
The
development of an improved short and efficient commercial synthesis
of the JAK2 inhibitor, a complex pyrrolopyridine, BMS-911543, is described.
During the discovery and development of this synthesis, a Pd-catalyzed
C–H functionalization was invented which enabled the rapid
union of the key pyrrole and imidazole fragments. The synthesis of
this complex, nitrogen-rich heterocycle was accomplished in only six
steps (longest linear sequence) from readily available materials.
Process development of a selective serotonin reuptake inhibitor (1) is described. The synthesis features Nishiyama catalyst-mediated asymmetric cyclopropanation of vinyl indole 2 with ethyldiazoacetate to install the trans-disubstituted cyclopropane. The active pharmaceutical ingredient (1) was prepared in 13 chemical steps with 9 isolations and proceeded in an overall yield of 34%.
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