Synergistic Organoboron/Palladium Catalysis for Regioselective N-Allylation of 2-Pyridones, 4-Pyridones, and Related Ambident Heterocycles

Abstract

The use of a boronic acid co-catalyst along with a palladium complex enables efficient dehydrative couplings of allylic alcohols and tautomerizable heterocycles. The protocol has been applied to achieve N-allylations of 2-pyridones, 4-pyridones, 4-pyrimidinones, and their benzofused derivatives.

Key words

allylation - boronic acids - heterocycles - palladium - regioselectivity

Publication History

Received: 24 August 2023

Accepted after revision: 04 October 2023

Article published online:
15 November 2023

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• 26 General Protocol for N-Allylation: Synthesis of 1-Allylpyridin-4(1H)-one (3a) Under an atmosphere of argon, an oven-dried two-dram vial equipped with a magnetic stir bar and rubber spectrum was charged with 4-pyridone (47.6 mg, 0.500 mmol, 1 equiv), [Pd(allyl)Cl]₂ (1.8 mg, 0.0050 mmol, 1 mol%), Xantphos (5.8 mg, 0.010 mmol, 2 mol %), and 3,5-bis(trifluoromethyl)phenylboronic acid (1a, 25.8 mg, 0.100 mmol, 20 mol%). The vial was evacuated and backfilled with argon, then toluene (2.5 mL) and allyl alcohol (41 mL, 35 mg, 0.60 mmol, 1.2 equiv) were added sequentially by syringe. The vial was sealed with a cap, placed in an oil bath at 50 °C and stirred for 24 h. The mixture was cooled to room temperature, concentrated in vacuo, and purified by flash column chromatography on silica gel (95:5 CH₂Cl₂/MeOH), yielding 3a as a yellow oil in 97% yield (65.5 mg, 0.484 mmol). Characterization Data for 3a ¹H NMR (500 MHz, CDCl₃): δ = 7.25 (d, J = 7.7 Hz, 2 H), 6.30 (d, J = 7.7 Hz, 2 H), 5.87 (ddt, J = 17.0, 10.3, 5.7 Hz, 1 H), 5.37–5.11 (m, 2 H), 4.34 (d, J = 5.7 Hz, 2 H) ppm. ¹³C NMR (126 MHz, CDCl₃): δ = 178.8, 139.9, 131.7, 119.9, 118.6, 58.7 ppm. IR (film): ν = 3082 (w), 1633 (s), 1538 (s), 1399 (m), 1181 (s), 940 (w), 850 (s) cm^–1. HRMS (direct analysis in real time): m/z calcd for C₈H₁₀NO [M + H]⁺: 136.0755; found: 136.0757. Spectroscopic data were in agreement with those reported in the literature.^13b For experimental protocols, characterization data, and copies of NMR spectra of all products shown in Schemes 2 and 3, see the Supporting Information.
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