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…”

“…100 The first report of a-amino-C sp 3-H cross coupling using the PC-HAT/ TM dual catalysis strategy was recently published by MacMillan using decatungstate W 10 O 32 4À (DT) as the photocatalyst. 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 a-amino-C sp 3-H bonds (Scheme 6b). 101 As for the activation of unfunctionalized C sp 3-H bonds, MacMillan reported the arylation of alkane-C sp 3-H bonds in the presence of sodium decatungstate (NaDT) as the photocatalyst (Scheme 6c).…”

“…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 a-amino-C sp 3-H bonds (Scheme 6b). 101 As for the activation of unfunctionalized C sp 3-H bonds, MacMillan reported the arylation of alkane-C sp 3-H bonds in the presence of sodium decatungstate (NaDT) as the photocatalyst (Scheme 6c). 102 Replacing the Ni catalyst by a Cu based catalyst allowed expanding the scope to the NaDT/Cu promoted trifluoro methylation of aliphatic-C sp 3-H bonds.…”

Oxidative Cross Dehydrogenative Coupling of N-Heterocycles with Aldehydes through C(sp3)–H Functionalization

“…In the realm of cross-couplings that involve a single functionalized reaction partner, key contributions have come from many investigators, including initial findings from Doyle and MacMillan, across a range of reactions and catalyst types (Scheme A). The fields of photoredox catalysis and hydrogen atom transfer (HAT) have subsequently experienced rapid growth with broad scope being demonstrated in α-amino C­( sp 3 )–H functionalization with different coupling partners, including halides, activated acids, acrylates, azoliums, and amides . Of these and related reports, work from Doyle, Scheidt, Hong, Huo, Xu, Ohmiya, and Chi describe acylation processes using an array of electrophile classes.…”

“…The fields of photoredox catalysis and hydrogen atom transfer (HAT) have subsequently experienced rapid growth with broad scope being demonstrated in α-amino C­( sp 3 )–H functionalization with different coupling partners, including halides, activated acids, acrylates, azoliums, and amides . Of these and related reports, work from Doyle, Scheidt, Hong, Huo, Xu, Ohmiya, and Chi describe acylation processes using an array of electrophile classes. Among various HAT agents explored, peroxide oxidants have been demonstrated by Lei as effective in nickel-catalyzed C–H activation processes of heterocyclic C­( sp 3 )–H bonds .…”