Practical and General Alcohol Deoxygenation Protocol

Abstract

Herein, we describe a practical protocol for the removal of alcohol functional groups through reductive cleavage of their benzoate ester analogs. This transformation requires a strong single electron transfer (SET) reductant and a means to accelerate slow fragmentation following substrate reduction. To accomplish this, we developed a photocatalytic system that generates a potent reductant from formate salts alongside Brønsted or Lewis acids that promote fragmentation of the reduced intermediate. This deoxygenation procedure is effective across structurally and electronically diverse alcohols and enables a variety of difficult net transformations. This protocol requires no precautions to exclude air or moisture and remains efficient on multigram scale. Finally, the system can be adapted to a one-pot benzoylation-deoxygenation sequence to enable direct alcohol deletion. Mechanistic studies validate that the role of acidic additives is to promote the key C(sp³ )-O bond fragmentation step.

Keywords: Deoxygenation; Formate; Mesolytic Cleavage; Photoredox Catalysis; Reduction.

Figure 1.

(A) Schematic representation of deoxygenation transformations. (B) Representative recent example of using oxygen-based functional groups to build molecular skeletons. (C) Representative recent example of deoxygenation to exploit chiral oxygenated feedstocks to access stereochemically-rich intermediates. (D) Barton-McCombie deoxygenation overview. (E) Proposed deoxygenation strategy based on benzoate ester reduction. (F) Deoxygenation protocol employed in this work. AG = activating group. X = OPh, SMe, or imidazole. AIBN = azobisisobutyronitrile. PC = photocatalyst.

Figure 2.

(A) Targeted system designed to promote deoxygenation via a CO₂^•– chain reaction. (B) Efficient deoxygenation enabled by formate and acid. PTH = N-phenylphenothiazine, mesna = sodium 2-mercaptoethanesulfonate. Reactions run on 0.1 mmol scale in DMSO (0.2 M) for 12 hours under 395 nm irradiation. Calibrated gas chromatography (GC) yields.

Figure 3.

(A) Multi-gram scale deoxygenation. (B) One-pot deoxygenation of alcohols. (C) Reaction components without substrate can be pre-mixed and used after extended storage without activity loss (reaction components = PTH, mesna, formic acid, and zinc formate in DMSO). Deoxygenation = standard conditions from Table 1. ^a4DPAIPN used as photocatalyst, sodium formate as reductant. See Supporting Information for details.

Figure 4.

(A) Gas evolution measurements throughout standard deoxygenation reaction. (B) Cyclization under deoxygenation conditions consistent with generation of a radical intermediate. Deoxygenation = standard conditions from Table 1. See Supporting Information for details. (C) Cyclic voltammograms of 1 with and without acid. (D) Computational study of the impact of acid on the C(sp³)–O bond fragmentation step. Ab initio calculations were carried out using Gaussian 16 at MP2/6–311+G(2d,p)/PCM(DMSO) level of theory. (E) Plausible mechanism for the acid-promoted, reductive C(sp³)–O bond fragmentation.