Picolinamide-assisted ortho -C-H functionalization of pyrenylglycine derivatives using aryl iodides.

Chemical transformations involving the pyrenylglycine motif (an unnatural amino acid) and practical methods toward it are seldom known. This work aimed at developing a method for synthesizing novel pyrenylglycine (pyrene-based glycine) unnatural amino acid derivatives. To realize this, initially, a new pyrenylglycine substrate possessing the picolinamide moiety was assembled via the Ugi multicomponent reaction. The picolinamide moiety linked to amine substrates is a well-known bidentate directing group for accomplishing the site-selective γ-C-H functionalization of amines. Subsequently, it was aimed at using a Pd(II)-catalyzed bidentate directing group-aided γ-C-H arylation strategy for generating a wide range of unprecedented examples of C(2)-H arylated pyrenylglycines. Accordingly, pyrenylglycine possessing the picolinamide moiety was subjected to Pd(II)-catalyzed C(2)-H arylation in the non-K-region to afford a library of C(2)-arylated pyrenylglycines (π-extended pyrenes). Additionally, pyrenylglycine-based small peptides were assembled using C(2)-arylated pyrenylglycines. The X-ray structure of a representative compound was obtained, which corroborated the structure of pyrenylglycine and the regioselectivity of C(2)-H arylation of the pyrene in the non-K-region.