An Efficient Palladium-Catalyzed α-Arylation of Acetone Below its Boiling Point

Abstract

The monoarylation of acetone is a powerful transformation, but is typically performed at temperatures significantly in excess of its boiling point. Conditions described for performing the reaction at ambient temperatures led to significant dehalogenation when applied to a complex aryl halide. We describe our attempts to overcome both issues in the context of our drug-discovery program.

Key words

arylation - cross-coupling - drugs - ketones - medicinal chemistry - palladium

• References and Notes

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• 15 1-Arylacetones 7a–o; General Method A 20 mL vial equipped with a stirrer bar and rubber seal was charged with the appropriate (het)aryl bromide 6 (2.4 mmol), K₃PO₄ (3 equiv), and P7 (2.5 mol%). The vial was sealed and degassed by using three vacuum/N₂ cycles before acetone (10.8 mL) was added and the resulting mixture was heated to 50 °C for the appropriate time (Scheme 2). The mixture was then cooled to rt, diluted with EtOAc, and filtered through Celite, washing with additional EtOAc. The filtrate was evaporated to dryness and purified by chromatography (silica gel). 1-(2-Methylphenyl)propan-2-one (7d) Synthesized according to the general procedure from 2-bromotoluene (286 μL, 2.38 mmol) as a colorless oil; yield: 245 mg (70%). ¹H NMR (400 MHz, CDCl₃): δ = 7.21–7.12 (m, 4 H), 3.72 (s, 2 H), 2.25 (s, 3 H), 2.14 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 19.8, 29.4, 49.3, 126.7, 127.5, 130.5, 130.6, 133.3, 137.0, 206.6.