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. 2018 Jul 11;9(32):6639-6646.
doi: 10.1039/c8sc02253d. eCollection 2018 Aug 28.

Silyl-mediated photoredox-catalyzed Giese reaction: addition of non-activated alkyl bromides

Abdellatif ElMarrouni  1 , Casey B Ritts  2 , Jaume Balsells  2
Affiliations

Silyl-mediated photoredox-catalyzed Giese reaction: addition of non-activated alkyl bromides

Abdellatif ElMarrouni et al. Chem Sci. .

Abstract

The emergence of photoredox catalysis has enabled the discovery of mild and efficient conditions for the generation of a variety of radical reaction platforms. Herein is disclosed the development of a conjugate addition reaction of non-activated alkyl bromides to Michael acceptors under visible-light photoredox catalysis. Optimization of the reaction was achieved using high-throughput experimentation (HTE) tools to enable the identification of mild, general and practical reaction conditions. A diverse set of alkyl bromides was successfully added to cyclic or acyclic α,β-unsaturated esters and amides. The features of this transformation allowed also access to a key intermediate of Vorinostat®, an HDAC inhibitor used to fight cancer and HIV.

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Figures

Scheme 1
Scheme 1. Synthesis of C–C bonds through photocatalytic Giese reaction.
Fig. 1
Fig. 1. Photocatalyst and solvent screening: N-phenylmetacrylamide (1), (4-bromopiperidin-1-yl)(phenyl)methanone (2), Na2CO3 (2.0 equiv.), (Me3Si)3SiH, photocatalyst (1 mol%), Aldrich® Micro Photochemical Reactor (ring) for 16 h. [a] Assay yields for desired product was determined using standard HPLC techniques.
Fig. 2
Fig. 2. Reactant ratio screening: N-phenylmetacrylamide (1), (4-bromopiperidin-1-yl)(phenyl)methanone (2), Na2CO3 (2.0 equiv.), (Me3Si)3SiH, Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1 mol%) in MeOH, Aldrich® Micro Photochemical Reactor (ring) for 16 h. [a] Assay yields for desired product was determined using standard HPLC techniques.
Fig. 3
Fig. 3. Visible-light source comparison: N-phenylmetacrylamide (1) (1.0 equiv.), (4-bromopiperidin-1-yl)(phenyl)methanone (2) (1.5 equiv.), Na2CO3 (2.0 equiv.), (Me3Si)3SiH, Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1 mol%) in MeOH. [a] Assay yields for desired product was determined using standard HPLC techniques. [b] Ring = Aldrich® Micro Photochemical Reactor. [c] Lamp = Kessil® A160WE Tuna Blue Light. [d] Reactor = 13.2W Merck Photoreactor.
Scheme 2
Scheme 2. Plausible mechanism.
Scheme 3
Scheme 3. Deuterated NMR experiments: (A) control experiment; (B) reaction of amide 1 with t-butyl bromide using deuterated reagents.
Scheme 4
Scheme 4. Versatile approach to Vorinostat® through photocatalytic conjugate addition. [a] 48 (1.0 equiv.), 47 (3.0 equiv.), Na2CO3 (2.0 equiv.), (Me3Si)3SiH (0.75 equiv.) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1 mol%) in MeOH, integrated photoreactor (reactor), 1 h.
See this image and copyright information in PMC

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