Diastereoselective Synthesis of 3,3-Disubstituted Oxindoles from N-Aryl-3-Chlorooxindoles Bearing C–N Axial Chirality via Nucleo­philic Substitution

Abstract

Diastereoselective synthesis of 3,3-disubstituted oxindoles was examined using racemic N-aryl-3-chlorooxindoles bearing C–N axial chirality. The reaction involved the nucleophilic substitution of 3-chlorooxindoles via an ortho-azaxylylene intermediate in the presence of AgBF₄ and MS 4 Å. High diastereoselectivities (up to >95:<5) were achieved in the formation of 3-alkyl-3-aryloxindole derivatives when electron-rich arenes were used.

Key words

3,3-disubstituted oxindole - C–N axial chirality - ortho-azaxylylene

• References and Notes


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• 10 Racemic 3-chlorooxindoles 2a and 2b were employed in this work because they are easier to prepare than the nonracemic ones.
• 11 All new compounds were fully characterized by ¹H NMR, ¹³C NMR, and IR analyses.
• 12 For details, see the Supporting Information.
• 13 Major regioisomer was found to be 2-thienyl one, which was confirmed by the transformation of 7 into the n-butyl analogue under reductive desulfurization using Raney Ni. For details, see the Supporting Information.
• 14 General Experimental Procedure of Nucleophilic Substitution To a mixture of the 3-chlorooxindole 2a (75.4 mg, 0.173 mmol), MS 4 Å (ca. 70 mg) and anisole (0.19 mL, 1.7 mmol) in dry CH₂Cl₂ (4 mL) was added AgBF₄ (101 mg, 0.519 mmol) at –40 °C under nitrogen. After stirring at –40 °C, the reaction was quenched with H₂O at –40 °C. The resulting mixture was allowed to warm to r.t., and the aqueous layer was extracted with CH₂Cl₂ (2×). The organic layer was washed with brine (1×) and concentrated. The residue was purified by silica gel column chromatography (hexane–EtOAc, 10:1 → 4:1) to afford oxindole 8 (78.0 mg, 89%, a anti/syn = 95:5 mixture of diastereomers, determined by ¹H NMR analysis) as a colorless clear oil. Relative stereochemistry of 8 was confirmed by NOESY analysis using the corresponding phenol after debenzylation of 8. IR (KBr): ν_max = 1717, 1608, 1509, 1496, 1464, 1067, 1029 cm^–1. ESI-HRMS: m/z [M + Na]⁺ calcd for C₃₃H₃₃NO₄Na: 530.23018; found: 530.23050. ¹H NMR (400 MHz, CDCl₃): δ = 1.45 (3 H, s, CH₃), 1.50 (3 H, s, CH₃), 1.86 (3 H, s, CH₃), 3.05 (3 H, s, OCH₃), 3.79 (3 H, s, OCH₃ of methoxyphenyl), 5.12 (2 H, s, CH₂ of Bn), 6.46 (1 H, br d, J = 8 Hz, oxindole H-7), 6.83–6.88 (2 H, m, methoxyphenyl H-3, methoxyphenyl H-5), 6.93–7.00 (2 H, m, aromatic), 7.08 (1 H, ddd, J = 8, 8, 1 Hz, oxindole H-5), 7.20 (1 H, ddd, J = 8, 8, 1 Hz, oxindole H-6), 7.21 (1 H, dd, J = 8, 1 Hz, oxindole H-4), 7.25–7.30 (2 H, m, methoxyphenyl H-2, methoxyphenyl H-6), 7.31–7.50 (6 H, m, aromatic). ¹³C NMR (100 MHz, CDCl₃): δ = 23.3, 28.0, 28.1, 51.0, 51.5, 55.3, 70.3, 77.2, 110.2, 114.0, 115.3, 115.4, 122.8, 124.2, 125.7, 127.6, 127.90, 127.93, 128.1, 128.6, 132.1, 133.3, 134.8, 136.7, 145.2, 146.6, 158.7, 159.3, 179.8.
• 15 Oxindole 10 Mp 95–100 °C. IR (KBr): ν_max = 3429, 1715, 1608, 1517, 1496, 1068, 1018 cm^–1. ESI-HRMS: m/z [M + Na]⁺ calcd for C₃₄H₃₄N₂O₄Na: 557.24108; found: 557.24140. ¹H NMR (400 MHz, CDCl₃): δ = 1.44 (3 H, s, CH₃), 1.49 (3 H, s, CH₃), 1.86 (3 H, s, CH₃), 2.09 (3 H, s, NHCOCH ₃), 3.04 (3 H, s, OCH₃), 5.12 (2 H, s, CH₂ of Bn), 6.46 (1 H, d, J = 8 Hz, oxindole H-7), 6.93–7.01 (2 H, m, amidophenyl H-3, amidophenyl H-5), 7.08 (1 H, dd, J = 8, 8 Hz, oxindole H-5), 7.15–7.50 (12 H, m, amidophenyl H-2, amidophenyl H-6, aryl H-3, aryl H-5, aryl H-6, oxindole H-4, oxindole H-6, Ph of Bn). ¹³C NMR (100 MHz, CDCl₃): δ = 23.0, 24.4, 28.0, 28.1, 51.0, 51.8, 70.3, 77.2, 110.4, 115.3, 115.5, 120.1, 123.0, 124.3, 125.5, 127.4, 127.6, 128.06, 128.12, 128.7, 132.1, 134.5, 136.6, 136.8, 137.0, 145.1, 146.6, 159.3, 168.3, 179.8.