Late-Stage C(sp³)–H Methylation of Drug Molecules

Abstract

Methyl groups are well understood to play a critical role in pharmaceutical molecules, especially those bearing saturated heterocyclic cores. Accordingly, methods that install methyl groups onto complex molecules are highly coveted. Late-stage C–H functionalization is a particularly attractive approach, allowing chemists to bypass lengthy syntheses and facilitating the expedited synthesis of drug analogues. Herein, we disclose the direct introduction of methyl groups via C(sp 3 )–H functionalization of a broad array of saturated heterocycles, enabled by the merger of decatungstate photocatalysis and a unique nickel-mediated SH2 bond formation. To further demonstrate its synthetic utility as a tool for late-stage functionalization, this method was applied to a range of drug molecules en route to an array of methylated drug analogues.

The mechanism of visible light-induced C–C cross-coupling by Csp3–H bond activation

“…101 Using tetrabutylammonium decatungstate (TBADT) as the PC and nickel catalysis based on potassium-tris(3,5-dimethyl-1-pyrazolyl) borate (KTp*) as the source of the Ni ligand, he was able to achieve methylation of α-amino-C sp 3 –H bonds (Scheme 6b). 101…”

The Structure Determination of Organic Molecules by Co-crystallization of Anthracene-Based Crystallization Chaperone

“…However, it could be limited for some other organic molecules, if the solid powder of the crystallization chaperone is difficult to dissolve when the organic molecule acts as the solvent . In addition, thermal crystallization, which is based on direct heating to a high temperature until the crystallization chaperone is soluble with organic guest molecules, is not suitable for molecules with heat resistance and easily degraded structures. − And in addition, the above crystallization chaperones which have relatively small cavities could result in the inaccessibility of larger molecules. On the other hand, in the reported co-crystallization strategies, anthracene rings have received increasing attention as they have been found to be significantly effective co-crystal basic units.…”

A photocatalytic traceless C–N bond formation/cleavage strategy enabling the use of (α-chiral) alkyl aldehydes as deoxygenative (chiral) alkyl radical equivalents

“…4 In the past decade, alkylation strategies involving active alkyl radical species generated from the corresponding alkyl sources via a one-electron transfer process (SET) under visible-light-driven photoredox catalysis 5 conditions have received special attention and have become powerful tools for the incorporation of alkyl groups into organic molecules. 2 c – f ,3,6 In this regard, alkyl aldehydes are ideal alkyl radical precursors due to their advantages of abundant natural stock, convenient preparation, easy commercialization and relatively low toxicity. 7 The typical strategy for the utilization of alkyl aldehydes as alkyl radical equivalents is via decarbonylation reactions (Scheme 1a).…”