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. 2021 Mar 5;11(5):3153-3158.
doi: 10.1021/acscatal.1c00099. Epub 2021 Feb 24.

β-Functionalization of Saturated Aza-Heterocycles Enabled by Organic Photoredox Catalysis

Natalie Holmberg-Douglas  1 , Younggi Choi  2 , Brian Aquila  2 , Hoan Huynh  2 , David A Nicewicz  1
Affiliations

β-Functionalization of Saturated Aza-Heterocycles Enabled by Organic Photoredox Catalysis

Natalie Holmberg-Douglas et al. ACS Catal. .

Abstract

The direct β-functionalization of saturated aza-heterocycles has remained a synthetic challenge because of the remote and unactivated nature of β-C-H bonds in these motifs. Herein, we demonstrate the β-functionalization of saturated aza-heterocycles enabled by a two-step organic photoredox catalysis approach. Initially, a photoredox-catalyzed copper-mediated dehydrogenation of saturated aza-heterocycles produces ene-carbamates. This is followed by an anti-Markovnikov hydrofunctionalization of the ene-carbamates with a range of heteroatom-containing nucleophiles furnishing an array of C-C, C-O, and C-N aza-heterocycles at the β-position.

Keywords: anti-Markovnikov; catalysis; dehydrogenation; heterocycle; organic; photoredox.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1.
Scheme 1.
Examples of Bioactive C-3-Substituted Aza-Heterocycles and Methods for C–H Functionalization at C-3 through (a) Ruthenium Catalysis,– (b) Electrochemical Methods, or (c) Organic Photoredox Catalysis
Chart 1.
Chart 1.
Dehydrogenation Scope‡ ‡Average isolated yields are reported (0.200 mmol, n = 2). aYield determined by 1H NMR using (Me3Si)2O as an internal standard.
Chart 2.
Chart 2.
Aza-Heterocycle β-Functionalization via anti-Markovnikov Hydrofunctionalization: (a) Substrate Scope, (b) Nucleophile Scope, (c) Application to Pharmaceuticals and (d) Synthesis of Orexin Antagonists aPhenylmalononitrile instead of thiophenol. bWithout NaOAc. c5.0 equiv of nucleophile. dAverage isolated yields are reported (0.200 mmol, n = 2).
See this image and copyright information in PMC

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