Highly Diastereoselective Functionalization of Piperidines by Photoredox-Catalyzed α-Amino C–H Arylation and Epimerization

Abstract

We report a photoredox-catalyzed α-amino C–H arylation reaction of highly substituted piperidine derivatives with electron-deficient cyano­(hetero)­arenes. The scope and limitations of the reaction were explored, with piperidines bearing multiple substitution patterns providing the arylated products in good yields and with high diastereoselectivity. To probe the mechanism of the overall transformation, optical and fluorescent spectroscopic methods were used to investigate the reaction. By employing flash-quench transient absorption spectroscopy, we were able to observe electron transfer processes associated with radical formation beyond the initial excited-state Ir­(ppy)3 oxidation. Following the rapid and unselective C–H arylation reaction, a slower epimerization occurs to provide the high diastereomer ratio observed for a majority of the products. Several stereoisomerically pure products were resubjected to the reaction conditions, each of which converged to the experimentally observed diastereomer ratios. The observed distribution of diastereomers corresponds to a thermodynamic ratio of isomers based upon their calculated relative energies using density functional theory (DFT).

Mechanistic Investigations of an α-Aminoarylation Photoredox Reaction

“…A reaction quantum yield of 0.15-0.3 is in good agreement with other studies on non-radical chain propagation reactions, where typical quantum yields of photoredox reactions can range from 0.19 to 0.43. [46][47][48] Ellman and coworkers partly explored the mechanism of a closely related α-amino arylation reaction involving substituted piperidine analogues and observed 0.4-0.6 at early timescales, 44 which is in relatively good agreement with our quantum yields. These results were collected without the use of insoluble sodium acetate, which may explain the higher quantum yield.…”

“…al. 33 and Walker et al 44 of 2.3 x 10 9 M -1 s -1 and 2.9 x 10 9 M -1 s -1 , respectively. By contrast, we did not observe quenching of the excited Ir(ppy) 3 when using NPP as the quencher, which again is in good agreement with McNally and coworkers.…”

“…Despite the importance α-arylamines and related photoredox reactions, the reaction mechanism and kinetics are poorly characterized. Recently, Walker et al 44 examined the coupling of DCB and 2-methyl-1-phenylpiperidine. In that work they determined the rate constant for back electron transfer between DCB •and [Ir(ppy) 3 ] + , as well as the rate constant for the oxidation of the piperidine by [Ir(ppy) 3 ] + , but the rest of the reaction mechanism was left unexplored.…”

Advances in the Synthesis of Imine‐Containing Azaarene Derivatives via Photoredox Catalysis

“…Subsequently, Ellman and collaborators reported the α-amino CÀ H arylation of highly substituted piperidine derivatives 103 with electrondeficient cyanoarenes (entry 4, Scheme 20A). [49] Two transformations using cyanopyridines 100 as the feedstocks were examined; products were obtained in moderate yields and with high diastereoselectivities. Careful studies on the mechanism indicated that the diastereoselectivity of the CÀ H arylation was not good, but the slow epimerization was crucial to the final high diastereomer ratio.…”

Ring-opening functionalizations of unstrained cyclic amines enabled by difluorocarbene transfer

“…iven the ubiquity of cyclic amines in a myriad of natural products and synthetic compounds, a growing emphasis has been placed on how we harness and manipulate such prestigious motifs for the construction of value-added molecules [1][2][3][4] . While significant progress has been made in the development of appending processes for their peripheral variation [5][6][7][8][9][10] , the skeletal diversification by means of ring-opening, -contraction, -expansion or -fusion approaches remains limited (Fig. 1a) 11 .…”