Pd(II)-Catalyzed, γ-C(sp2)−H Alkoxylation in α-Methylbenzylamine, Phenylglycinol, 3-Amino-3-Phenylpropanol Toward Enantiopure Aryl Alkyl Ethers

Abstract

This paper reports the synthesis of enantiopure aryl alkyl ethers via the Pd(II)-catalyzed picolinamide-aided γ-C(sp2)−H alkoxylation of various enantiopure α-alkylbenzylamine derivatives using alcohols. Enantiopure α-methylbenzylamines and amino alcohol substrates such as 2-amino-2-phenylethanol (phenylglycinol) and 3-amino-3-phenylpropanol were subjected to the γ-C(sp2)−H alkoxylation (etherification) with alcohols using PIDA. α-Alkylbenzylamines and phenylglycinols are valuable building blocks in organic synthesis and medicinal chemistry research areas. Accordingly, this work has enabled the assembling of various enantiopure ortho-alkoxylated α-methylbenzylamine and 2-amino-2-phenylethanol (phenylglycinol) and 3-amino-3-phenylpropanol derivatives containing aryl alkyl ether functionality. We have shown the utility of ortho-alkoxylated α-methylbenzylamine derivatives for assembling enantiopure α-methylbenzylamine-based sulfamoylcarbamates and carboxamides which are structurally related to the bio-active compounds known in the literature. This work demonstrates the substrate scope elaboration in C−H functionalization and etherification through the C−O bond-forming process and synthesis of aryl alkyl ether functionality containing enantiopure α-alkylbenzylamines.