Dual In Situ Generation of Aliphatic Vinyl Ethers and Electron-Deficient ortho-Quinone Methides for Inverse-Electron-Demand [4+2] Cycloaddition: A Selective One-Pot Synthesis of 3-Alkylchromanes

Abstract

An inverse-electron-demand [4+2] cycloaddition of in situ generated aliphatic vinyl ethers and electron-deficient ortho-quinone methides (o-QMs) has been developed. The reaction of in situ generated aliphatic vinyl ethers with o-QMs afforded the corresponding 3-alkylchromanes with high stereo- and regioselectivities. The method provides a versatile access to functionalized 3-alkylchromanes and it constitutes a useful tool for the synthesis of biologically active chromanes.

Key words

catalysis - [4+2] cycloaddition - vinyl ethers - ortho-quinone methides - salicylaldehydes - chromanes

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• 11 3-Substituted Chromanes 3a–m and 4a–c; General Procedure The appropriate salicylaldehyde 1 (0.50 mmol), aliphatic or aryl aldehyde 2 (1.50 mmol), and CH(OMe)₃ (2.00 mmol) were dissolved in dry toluene (5.0 mL) under N₂. TfOH (20 mol%) was added, and the mixture was stirred at 60 °C for 24 h. The reaction was then quenched with 5% aq NaHCO₃, and the organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layer was dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue was purified by column chromatography [silica gel, hexane–EtOAc (30:1)] to afford 3-substituted chromane 3 or 4. 2,4-Dimethoxy-3,3-dimethyl-6-nitrochromane (3a) Prepared by using 5-nitrosalicylaldehyde (83.7 mg, 0.50 mmol), isobutyraldehyde (135 μL, 1.50 mmol), CH(OMe)₃ (219 μL, 2.00 mmol), and anhyd toluene (5.0 mL) to give a yellow solid; yield: 135 mg (quant); mp 97.8–98.2 °C. IR (ATR): 2928, 1588, 1520, 1481, 1253, 1091, 977, 833, 751 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 8.20 (d, J = 2.8 Hz, 1 H), 8.11 (dd, J = 9.1, 2.8 Hz, 1 H), 6.92 (d, J = 8.8 Hz, 1 H), 4.83 (s, 1 H), 4.04 (s, 1 H), 3.62 (s, 3 H), 3.56 (s, 3 H), 1.04 (s, 3 H), 1.00 (s, 3 H). ¹³C{¹H} NMR (126 MHz, CDCl₃): δ = 157.3, 141.4, 125.1, 124.6, 123.9, 117.0, 106.6, 80.6, 60.4, 57.2, 37.0, 20.3, 18.9. HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₃H₁₈NO₅: 268.1180; found: 268.1190.
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