Lewis Acid Catalyzed [4+1] Cycloaddition of o-Quinone Methides and Isocyanides: Mild and Efficient Synthesis of 3-Aryl-2-aminobenzofurans

Dedicated to the 100^th anniversary of Shanghai University

Abstract

We herein report a mild and efficient synthesis of 3-aryl-2-aminobenzofurans by Lewis acid catalyzed [4+1] cycloaddition of in situ generated o-quinone methides and isocyanides. Compared with the well-known methods, the current reactions are carried out under mild conditions and feature wide substrate scope in high yields at ambient temperature at catalyst loadings as low as 1 mol%. DFT calculations show dehydration as the rate-determining step, a stepwise [4+1] cycloaddition process, and the Lewis acid as dual roles in accelerating dehydration and cycloaddition reaction.

Key words

Lewis acid - [4+1] cycloaddition - o-quinone methides - isocyanides - benzofurans

Publication History

Received: 29 November 2022

Accepted after revision: 08 February 2023

Accepted Manuscript online:
08 February 2023

Article published online:
02 March 2023

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• 21 CCDC 2225353 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.
• 22 N-(tert-Butyl)-3-(4-methoxyphenyl)benzofuran-2-amine; Typical Procedure To a flame-dried Schlenk tube were added 1a (46 mg, 0.2 mmol), Sc(OTf)₃ (5.0 mg, 0.01 mmol), 3 Å MS (100 mg), anhydrous toluene (2.0 mL), and 2a (33 mg, 0.4 mmol). The resulting reaction mixture was stirred at RT for 3 h. Then the solution was concentrated under vacuum, and the residue was purified by chromatography (silica gel, EtOAc–PE = 1:100) to give a light-yellow oil; yield 56 mg (95%). ¹H NMR (500 MHz, CDCl₃): δ = 7.47‒7.40 (m, 3 H), 7.35 (dt, J = 8.0, 0.9 Hz, 1 H), 7.16 (td, J = 7.5, 1.1 Hz, 1 H), 7.12‒7.06 (m, 1 H), 7.05–7.00 (m, 2 H), 4.20 (s, 1 H), 3.87 (s, 3 H), 1.40 (s, 9 H). ¹³C NMR (126 MHz, CDCl₃): δ = 158.1, 155.0, 150.6, 130.0, 129.4, 125.9, 122.8, 120.8, 117.1, 114.8, 110.1, 97.6, 55.5, 53.6, 30.7. HRMS (ESI): m/z [C₁₉H₂₁NO₂ + H]⁺ calcd: 296.1645; found: 296.1643.§
• 23a All of the DFT calculations were performed with the Gaussian 09 program package at the B3LYP-D3(BJ) level of theory with the 6-31G
• 23b basis set (keyword 5D) using the SMD solvation model with toluene solvent. Single-point solvent calculations were performed at the M06-2X-D3 level of theory with 6-311+G(d,p) basis set at the optimized geometries. All of the energies discussed in the paper are in toluene solution (ΔG _tol). Computational details and references are given in the Supporting Information.