Oxidative C–N Bond Formation of Isochromans Using an Electronically Tuned Nitroxyl Radical as Catalyst

Abstract

The cross-dehydrogenative coupling between isochromans and nucleophiles using an electronically tuned nitroxyl radical catalyst, which effectively promotes the oxidation of benzylic ethers, has been investigated. Using sulfonamides as a nucleophile, modification of isochromans via oxidative C–N bond formation has been achieved at ambient temperature.

Keywords

isochroman - cross-dehydrogenative coupling - nitroxyl radical - C–N bond formation - organocatalyst - oxidation

Publication History

Received: 31 March 2024

Accepted after revision: 24 April 2024

Article published online:
13 May 2024

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Weak inorganic bases probably neutralize trifluoroacetic acid derived from PIFA slowly in dichloromethane, whereas organic bases are much faster. The differences in solution acidity may affect the reactivity and selectivity of the oxidation catalyzed by 2. For examples of the acidity affecting the reactivity of the oxidation mediated by nitroxyl-radical catalysts or oxoammonium salts, see:
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• 17 The hydride-transfer step has already been proposed as the rate-determining step in the oxidation of isochromans to the corresponding oxocarbenium cations; for details, see ref. 4d.
• 18 General Procedure PIFA (103 mg, 0.240 mmol) was added to a mixture of isochroman (26.8 mg, 200 mmol), 2 (4.6 mg, 20 μmol), K₂CO₃ (111 mg, 0.800 mmol), and sulfonamide (0.400 mmol) in DCM (2.0 mL). The resulting mixture was stirred under N₂ atmosphere for 2 h at room temperature. Then, the reaction was quenched with saturated aq. Na₂S₂O₃ and extracted with CHCl₃. Subsequently, the organic layer was dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography.
• 19 Representative Spectral Data N-(Isochroman-1-yl)-4-methyl­benzenesulfonamide (3)1 The title compound 3 (38.0 mg, 63%) was synthesized from isochroman (26.8 mg, 0.200 mmol) and 4-methylbenzenesulfonamide (68.5 mg, 0.400 mmol). Colorless solid; mp 178–181 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.86 (d, J = 8.5 Hz, 2 H), 7.31 (d, J = 7.9 Hz, 2 H), 7.26–7.18 (m, 3 H), 7.08 (d, J = 7.2 Hz, 1 H), 6.10 (d, J = 8.6 Hz, 1 H), 5.40 (d, J = 8.6 Hz, 1 H), 3.73–3.57 (m, 2 H), 2.85 (ddd, J = 15.9, 9.7, 6.0 Hz, 1 H), 2.61 (dt, J = 16.7, 4.0 Hz, 1 H), 2.44 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 143.40, 138.79, 134.54, 132.82, 129.52, 128.87, 128.47, 127.25, 126.84, 126.76, 79.91, 58.76, 27.58, 21.63. IR (ATR) 3202, 1328, 1157, 748 cm^–1. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₆H₁₇NNaO₃S: 326.0827; found: 326.0829.