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. 2020 May 6;142(18):8194-8202.
doi: 10.1021/jacs.9b13165. Epub 2020 Apr 24.

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

Morgan M Walker  1 , Brian Koronkiewicz  1 , Shuming Chen  2 , K N Houk  2 , James M Mayer  1 , Jonathan A Ellman  1
Affiliations

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

Morgan M Walker et al. J Am Chem Soc. .

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).

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
Mechanistic studies (A) Reactions studied by TA and luminescence spectroscopies. (B) TA data collected at 390 nm with 10 mM DCB, 40 μM Ir(ppy)3, and increasing concentrations of 1m. The laser flash leads to rapid oxidation of the Ir(ppy)3+, yielding a large negative absorbance change because the Ir(ppy)3+ species has a smaller ε390 than Ir(ppy)3 (Figure S3). 1m oxidation by Ir(ppy)3+ is observed as a return in the absorbance at 390 nm as Ir(ppy)3+ is reduced to Ir(ppy)3. Residual DCB·− absorbance was observed at higher concentrations of 1m. (C) TA spectroscopy at 346 nm to monitor DCB·− reactivity. (D) Proposed photoredox cycle.
Figure 2.
Figure 2.
Time course studies of the C–H arylation of 1a and follow-up epimerization of 2a.
Figure 3.
Figure 3.
A) Oxidation reactions investigated for stereoisomerically pure 2a diastereomers. B) Plot of observed oxidation rate constant versus 2a concentration, where the slope is kox for the respective diastereomers. kox,anti and kox,syn are within error of each other.
Scheme 1.
Scheme 1.
Photoredox catalyzed α-amino C–H arylation
Scheme 2.
Scheme 2.
Highly diastereoselective two-step synthesis of densely substituted piperidines
Scheme 3.
Scheme 3.
Equilibration of 2m-syn and 2m-anti diastereomersa aYields determined by 1H NMR spectroscopy with 2,6-dimethoxytoluene as the external standard.
See this image and copyright information in PMC

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