Photo- and Metal-Mediated Deconstructive Approaches to Cyclic Aliphatic Amine Diversification

• Authors: Djamaladdin Musaev, Emory University; Alexey Kaledin, Emory University; DM Soro, Berkeley College of Chemistry; JB Roque, Berkeley College of Chemistry; JW Rackl, Berkeley College of Chemistry; B Park, Korea Advanced Institute of Science and Technology; S Payer, Berkeley College of Chemistry; Y Shi, Eli Lilly and Company; JC Ruble, Eli Lilly and Company; MH Baik, Korea Advanced Institute of Science and Technology; R Sarpong, Berkeley College of Chemistry
• Journal Title: Journal of the American Chemical Society
• Volume: Volume 145, Number 20
• Publisher: (publisher) | 2023-05-24, Pages 11245-11257
• Type of Work: Article
• Publisher DOI: http://doi.org/10.1021/jacs.3c01318

Abstract

Described herein are studies toward the core modification of cyclic aliphatic amines using either a riboflavin/photo-irradiation approach or Cu(I) and Ag(I) to mediate the process. Structural remodeling of cyclic amines is explored through oxidative C-N and C-C bond cleavage using peroxydisulfate (persulfate) as an oxidant. Ring-opening reactions to access linear aldehydes or carboxylic acids with flavin-derived photocatalysis or Cu salts, respectively, are demonstrated. A complementary ring-opening process mediated by Ag(I) facilitates decarboxylative Csp3-Csp2 coupling in Minisci-type reactions through a key alkyl radical intermediate. Heterocycle interconversion is demonstrated through the transformation of N-acyl cyclic amines to oxazines using Cu(II) oxidation of the alkyl radical. These transformations are investigated by computation to inform the proposed mechanistic pathways. Computational studies indicate that persulfate mediates oxidation of cyclic amines with concomitant reduction of riboflavin. Persulfate is subsequently reduced by formal hydride transfer from the reduced riboflavin catalyst. Oxidation of the cyclic aliphatic amines with a Cu(I) salt is proposed to be initiated by homolysis of the peroxy bond of persulfate followed by α-HAT from the cyclic amine and radical recombination to form an α-sulfate adduct, which is hydrolyzed to the hemiaminal. Investigation of the pathway to form oxazines indicates a kinetic preference for cyclization over more typical elimination pathways to form olefins through Cu(II) oxidation of alkyl radicals.