Regioselective Aldehyde Decarbonylation through Palladium-Catalyzed Nitrile Boronic Acid Cross-Coupling

Abstract

Aldehyde decarbonylation is a vital chemical transformation in the synthesis of natural products. Nature accomplishes this process through a family of decarbonylase enzymes, while in the laboratory, harsh transition metals and elevated temperatures are required. Herein, we report a mild aldehyde decarbonylation reaction that exhibits exclusive selectivity for ortho-aldehydes during a tandem nitrile boronic acid cross-coupling reaction. A wide substrate scope is displayed that includes regioselective removal of the ortho-aldehyde from phenyl boronic acids in the presence of meta- or para-aldehydes. A mechanistic investigation of the observed regioselectivity for ortho-aldehydes by density functional theory (DFT) calculations shows that the CO ligand extrusion is energetically more favorable for the ortho position as compared to the para position.

Key words

decarbonylation - aldehydes - boronic acids - nitriles - palladium

Publication History

Received: 15 November 2023

Accepted after revision: 01 February 2024

Article published online:
14 February 2024

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• 22 Aldehyde Decarbonylation; General Procedure To a mixture of THF:H₂O (5:1) in a 35 mL high-pressure tube, TFA (10 equiv.) was added followed by the addition of nitrile 1 (1 equiv.), formyl phenyl boronic acid 2 (4 equiv.), and 2,2′-bipyridyl ligand (40 mol%). The mixture was left to stir until all compounds had dissolved, after which N₂ was bubbled for 5 minutes. Finally, Pd(OAc)₂ (20 mol%) was transferred to the reaction vessel (order of addition reduces oxidative homocoupling of boronic acid). The high-pressure tube was again flushed with N₂ and the contents left to stir for 24 hours at 80 °C. The reaction progress was monitored by TLC. After completion of the reaction, the mixture was diluted with EtOAc (10 mL), extracted with brine (3 × 15 mL), dried over Na₂SO₄, and evaporated. The crude reaction mixture was then purified by silica gel column chromatography (EtOAc/hexane gradient), and the resulting products were characterized by NMR.