Fe‐Catalyzed Aliphatic C−H Methylation of Glycine Derivatives and Peptides

• Published in: Chemistry : a European journal Vol. 29; no. 17; pp. e202203404 - n/a
• Main Authors: Song, Silin, Cheng, Xiuliang, Cheng, Shiyan, Lin, Yu‐Mei, Gong, Lei
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 22.03.2023; Wiley Subscription Services, Inc
• Subjects: Biomolecules; Catalysis; Catalysts; Chelation; Chemistry; Chemistry, Multidisciplinary; C−H methylation; Glycine; Intermediates; Iron; Iron - chemistry; Lewis acid; Methyl radicals; Methylation; Natural products; Organic chemistry; Oxidation; Peptides; peroxides; Physical Sciences; Reagents; Science & Technology; Selectivity; ANTAGONIST; ALKYLATION; peptides; C-H methylation; peroxides; TERT-BUTYL PEROXIDE; DISCOVERY; FUNCTIONALIZATION; POTENT; HETEROCYCLES; glycine; BONDS; NITROGEN; iron; AMIDES; C−H methylation
• ISSN: 0947-6539; 1521-3765; 1521-3765
• DOI: 10.1002/chem.202203404

Direct and selective C−H methylation is a powerful tool with which to install methyl groups into organic molecules, and is particularly useful in pharmaceutical chemistry. However, practical methods for such modification of biologically interesting targets have been rarely developed. We here report an iron‐catalyzed C(sp3)−H methylation reaction of glycine derivatives, peptides and drug‐like molecules in an alcohol in the presence of di‐tert‐butyl peroxide. A readily available iron catalyst plays multiple roles in the transformation, which accelerates oxidation of C−N bonds to C=N double bonds, activates imine intermediates as Lewis acids by bidentate chelation, and at the same time facilitates cleavage of the peroxide to generate methyl radicals. A variety of methylated N‐aryl glycine derivatives and peptides were obtained in good yield and with excellent chemo‐ and site‐selectivity. This reaction is scalable, easily managed, and can be completed within 1–2 h. It features an economic, bio‐friendly catalyst, a green solvent and low toxic reagents, and will provide effective access to precise C−H modification of biomolecules and natural products. A concise strategy relying on multifunctional iron catalysis in the presence of di‐tert‐butyl peroxide has been reported, allowing rapid and highly selective C(sp3)−H methylation of various glycine derivatives and peptides.