Construction of Spiropyrroloindolines by Dearomative [3+2]-Cycloaddition of Indoles with Oxindole-Embedded Azaoxyallyl ­Cations

Abstract

A dearomative [3+2]-cycloaddition reaction of oxindole-embedded azaoxyallyl cations with indoles at the C3 position has been developed. The use of this new class of azaoxyallyl cation species in the reaction permits access to more-elaborate hexahydropyrrolo[2,3-b]indole moieties that contain a spiro-oxindole ring. The transformation displays a broad substrate scope and good regio- and stereoselectivity for the cycloaddition step. Several observations suggested that this class of azaoxyallyl cations can display a different reactivity pattern from those of commonly employed azaoxyallyl cation systems.

Key words

indoles - dearomatization - azaoxyallyl cations - oxindoles - cycloaddition - indolines

• References and Notes


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• 9 [3+2]-Cycloaddition: General ProcedureEt₃N (1.5 equiv) was added to a solution of the appropriate indole derivative 1 (1.0 equiv) and α-halohydroxamate (oxindole) 2 (1.5 equiv) in PhCF₃ (0.1 M) under argon. The mixture was stirred at rt until the starting material was consumed (TLC; ~60–90 min). The solvent was then removed under the reduced pressure, and the crude product was purified by column chromatography (silica gel, EtOAc–hexane).1′-(Benzyloxy)-1,3a′,8′-trimethyl-1′,3a′,8′,8a′-tetrahydro-2′H-spiro[indole-3,3′-pyrrolo[2,3-b]indole]-2,2′(1H)-dione (3)Prepared by the general procedure from 1,3-dimethyl-1H-indole (1b; 0.02 g, 0.137 mmol) and α-chlorohydroxamate 2a (0.067 g, 0.205 mmol), and purified by chromatography [silica gel, EtOAc–hexanes (1:4)] as a white foam; yield: 0.055 g (91%; dr 4.5:1); R_f = 0.4 (EtOAc–hexanes, 1:4).¹H NMR (400 MHz, CDCl₃): δ = 7.59 (d, J = 6.5 Hz, 2 H), 7.45–7.39 (m, 3 H), 7.33 (app t, J = 7.5 Hz, 1 H), 7.13 (app t, J = 7.4 Hz, 1 H), 6.96 (app t, J = 7.5 Hz, 1 H), 6.88 (d, J = 7.8 Hz, 1 H), 6.81 (d, J = 7.4 Hz, 1 H), 6.55 (app t, J = 7.4 Hz, 1 H), 6.44 (app t, J = 7.9 Hz, 2 H), 5.13 (d, J = 10.0 Hz, 1 H), 5.11 (d, J = 12.0 Hz, 1 H), 5.05 (s, 1 H), 3.28 (s, 3 H), 3.03 (s, 3 H), 1.31 (s, 3 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 173.8, 165.1, 148.9, 145.4, 135.1, 130.2, 130.1, 129.6, 129.3, 129.1, 128.7, 128.6, 126.6, 124.7, 122.2, 117.4, 108.3, 107.0, 85.1, 77.5, 62.7, 52.3, 33.5, 26.8, 22.3. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₇H₂₆N₃O₃: 440.1974; found: 440.1970.1-Benzyl-1′-(benzyloxy)-5-methoxy-3a′,8′-dimethyl-1′,3a′,8′,8a′-tetrahydro-2′H-spiro[indole-3,3′-pyrrolo[2,3-b]indole]-2,2′(1H)-dione (4)Prepared by the general procedure from 1,3-dimethyl-1H-indole (1b; 0.02 g, 0.137 mmol) and α-chlorohydroxamate 2b (0.089 g, 0.205 mmol), and purified by chromatography [silica gel, EtOAc–hexanes (1:4)] as a white foam; yield: 0.073 g (92%; dr 6:1); R_f = 0.4 (EtOAc–hexanes, 1:4).¹H NMR (400 MHz, CDCl₃): δ = 7.61 (d, 2 H), 7.46–7.40 (m, 3 H), 7.36–7.33 (m, 4 H), 7.30–7.28 (m, 1 H), 7.14 (app t, J = 7.6 Hz, 1 H), 6.75 (dd, J = 8.6, 2.5 Hz, 1 H), 6.64 (d, J = 8.6 Hz, 1 H), 6.56 (app t, J = 7.4 Hz, 1 H), 6.48 (app t, J = 7.1 Hz, 2 H), 6.41 (d, J = 2.5 Hz, 1 H), 5.20–5.13 (m, 3 H), 5.08 (s, 1 H), 4.79 (d, J = 15.8 Hz, 1 H), 3.57 (s, 3 H), 3.05 (s, 3 H), 1.39 (s, 3 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 173.6, 165.2, 155.3, 149.0, 137.9, 135.6, 135.1, 130.1, 129.9, 129.5, 129.2, 129.0, 128.8, 127.8, 127.2, 126.8, 125.8, 117.3, 115.8, 114.6, 109.8, 107.1, 85.2, 77.5, 63.0, 55.7, 52.4, 44.4, 33.6, 22.6. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₃₄H₃₂N₃O₄: 546.2393; found: 546.2391

For compound 16, we determined the relative orientation of the spiro oxindole carbonyl and the C–H bond at the ring fusion from the ³J_C1,_H3 value. The experimental value of ³J_C1,_H3 was ~3.0 Hz, which suggested a syn orientation between the indicated C–H bond and the carbonyl group (see Supporting Information for details). Based on reactive similarities, the relative orientation of this C–H bond and spiro-oxindole carbonyl is shown in Scheme [1]. A similar exercise is performed to determine the anomeric configurations of Kdo glycosides; for selected references, see:
• 10a Zhang Z, Xu Z, Liu X, Luo S, Li T. Org. Lett. 2021; 23: 6090
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• 12 CCDC 2182551 contains the supplementary crystallographic data for compound 20. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures