Sultines as o-Quinodimethane Precursors in an Oxa-Diels–Alder Reaction: Synthesis of Functionalized Isochromans

Abstract

The development of an oxa-Diels–Alder reaction between sultines and carbonyl compounds is reported. o-Quinodimethanes, generated from sultines, undergo a [4+2]-cycloaddition with activated aldehydes or ketones in the presence of Cu(OTf)₂ to provide a variety of functionalized isochromans, including spiroisochromans, in up to 99% yield. The developed protocol demonstrates broad functional-group compatibility and tolerates unprotected isatins bearing free NH-functionalities.

Key words

quinodimethanes - oxa-Diels–Alder reaction - cycloaddition - sultines - isochromans

Publication History

Received: 21 November 2023

Accepted after revision: 02 January 2024

Accepted Manuscript online:
02 January 2024

Article published online:
31 January 2024

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• 25 Isochromans 5aa–5am; General Procedure A flame-dried 25-mL round-bottomed flask equipped with a magnetic stirrer bar was charged with the appropriate sultine (0.4 mmol, 2 equiv) and Cu(OTf)₂ (0.01 mmol, 5 mol %). The flask was sealed with a septum then evacuated and backfilled with argon for three cycles. The appropriate aldehyde or ketone (0.2 mmol, 1 equiv) and DCE (2 mL) were added, and the septum was replaced with a Findenser equipped with an Ar balloon at the top. The mixture was stirred at 90 °C (preheated oil bath) for 18 h, then cooled to r.t., and filtered through a silica plug that was subsequently rinsed with EtOAc. The organic phase was then concentrated in vacuo, and the crude product was purified by column chromatography (silica gel; EtOAc–hexanes). Ethyl Isochroman-3-carboxylate (5aa) Prepared from sultine 3a (67.3 mg, 0.4 mmol) and a 47% solution of ethyl glyoxylate (polymer form) in toluene (42 μL, 0.2 mmol) by the general procedure, and purified by column chromatography (silica gel, 10% EtOAc/hexanes) as a pale-yellow oil; yield: 37.9 mg (92%). ¹H NMR (400 MHz, CDCl₃): δ = 7.22–7.17 (m, 2 H), 7.16–7.12 (m, 1 H), 7.04–6.98 (m, 1 H), 5.01 (d, J = 15.0 Hz, 1 H), 4.87 (d, J = 15.1 Hz, 1 H), 4.37 (dd, J = 8.8, 5.7 Hz, 1 H), 4.29 (q, J = 7.1 Hz, 2 H), 3.16–2.99 (m, 2 H), 1.33 (t, J = 7.1 Hz, 3 H). Ethyl 6,7-Dimethylisochroman-3-carboxylate (5ab) Prepared from sultine 3b and a 47% solution of ethyl glyoxylate (polymer form) in toluene (42 μL, 0.2 mmol) by the general procedure, and purified by column chromatography (silica gel, 10% EtOAc/hexanes) as a yellow oil; yield: 43.7 mg (93%). IR (UATR): 2924, 1734, 1451, 1186, 1117 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 6.91 (s, 1 H), 6.78 (s, 1 H), 4.95 (d, J = 14.8 Hz, 1 H), 4.81 (d, J = 14.8 Hz, 1 H), 4.36–4.31 (m, 1 H), 4.28 (q, J = 7.6 Hz, 2 H), 3.05–2.93 (m, 2 H), 2.22 (s, 3 H), 2.22 (s, 3 H), 1.32 (t, J = 7.1 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 171.4, 135.2, 135.0, 131.1, 129.9, 129.0, 125.3, 73.7, 67.9, 61.4, 30.6, 19.6, 14.5. HRMS (ESI-TOF); m/z [M + H]⁺ calcd for C₁₄H₁₉O₃: 235.1329; found: 235.1329.