A general deoxygenation approach for synthesis of ketones from aromatic carboxylic acids and alkenes

Abstract

The construction of an aryl ketone structural unit by means of catalytic carbon-carbon coupling reactions represents the state-of-the-art in organic chemistry. Herein we achieved the direct deoxygenative ketone synthesis in aqueous solution from readily available aromatic carboxylic acids and alkenes, affording structurally diverse ketones in moderate to good yields. Visible-light photoredox catalysis enables the direct deoxygenation of acids as acyl sources with triphenylphosphine and represents a distinct perspective on activation. The synthetic robustness is supported by the late-stage modification of several pharmaceutical compounds and complex molecules. This ketone synthetic strategy is further applied to the synthesis of the drug zolpidem in three steps with 50% total yield and a concise construction of cyclophane-braced 18-20 membered macrocycloketones. It represents not only the advancement for the streamlined synthesis of aromatic ketones from feedstock chemicals, but also a photoredox radical activation mode beyond the redox potential of carboxylic acids.

Fig. 1

Applications of aromatic carboxylic acids in organic synthesis. a The nature choice of aromatic carboxylic acid. b Known ketone synthesis from acids (indirect strategies). c This work: direct deoxygenative C–C coupling by visible light

Fig. 2

Aromatic carboxylic acid scope. Bn benzyl; Boc tert-butoxycarbonyl; Ts para-toluenesulfonyl

Fig. 3

Alkene scope

Fig. 4

Examining functional group compatibility. Reaction conditions: photocatalyst I (1 mol%), 1a (0.1 mmol, 1.0 equiv.), 2a (0.15 mmol, 1.5 equiv.), Ph₃P (0.12 mmol, 1.2 equiv.), biomolecules, pH 7.4 PBS buffer/DCM (1:1, 2.0 mL), blue LEDs, 25 °C

Fig. 5

Synthetic application. a Late-stage application in the complex molecules. b Synthesis of zolpidem

Fig. 6

Deoxygenative macrocyclization in the synthesis of cyclophane-braced cycloketones

Fig. 7

Downstream transformations

Fig. 8

Mechanistic studies. a Control experiments with additives. b Radical cyclization experiment. c Deuterium-labeling experiments. d ¹⁸O-labeling experiments. e Aromatic carboxylate anion as substrate. f Proposed mechanism

Fig. 9

A three-component reductive coupling reaction