Science of Synthesis

DiRocco, D. A.; Schultz, D. M., Science of Synthesis: Photocatalysis in Organic Synthesis, (2018) 1, 612.

Methyl groups are commonly installed to improve the biological activity and physical properties of a molecule and, thus, the ability to install a methyl group at a late stage is of great value.[‌8‌] Consequently, the late-stage methylation of a wide range of biologically relevant hetarenes [e.g., camptothecin (‌2‌), fenarimol (‌4‌), or varenicline (‌5‌)] has been achieved by chemists at MSD using tert-butyl peroxyacetate as a source of methyl radicals under acidic conditions using iridium complex ‌1‌ as photocatalyst with 450-nm light (‌Scheme 1‌).[‌9‌] The reaction proceeds via proton-coupled electron transfer of protonated tert-butyl peroxyacetate with the photoexcited iridium complex, resulting in a fragmentation sequence that generates methyl radicals. The scope of biologically complex hetarenes is wide and the reaction is compatible with aliphatic amines, alcohols, amides, and carbamates. For the majority of the substrates explored, both mono- (e.g., ‌3‌) and difunctionalized products were observed.

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