An Organocatalytic Cascade Spirocycloaddition Reaction for the Construction of Spiro[indoline-3,3′-piperidin]-6′-ones

Abstract

A cascade intramolecular spirocycloaddition reaction of TBS-O-protected indole-alkynamides in the presence of a chiral bifunctional thiourea, which involves in situ deprotection, dearomatization, and intramolecular spirocycloaddition under mild conditions, is developed. This approach enables the efficient construction of a wide range of polycyclic spiro[indoline-3,3′-piperidin]-6′-one scaffolds in excellent yields (up to 98%) and with good enantioselectivities (up to 94:6 er).

Keyword

organocatalysis - spiroindolines - dearomatization - spirocycloaddition - cascade reaction

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• 17 See the Supporting Information for details.
• 18 Spirocycloadduct 2a; General Procedure The reaction was carried out in a 25 mL tube by adding 1a (24.1 mg, 0.05 mmol, 1.0 equiv), AcOH (100 μL, 1 M in CH₂Cl₂, 0.10 mmol, 2.0 equiv), TBAI (3.7 mg, 0.01 mmol, 20 mol%), and C2 (10 μL, 0.5 M in CH₂Cl₂, 0.005 mmol, 10 mol%) in CH₂Cl₂ (2.0 mL) at room temperature, followed by the addition of KF (5.8 mg, 0.10 mmol, 1.0 equiv). The mixture was vigorously stirred at rt under air for 12 h. The mixture was then filtered through a pad of silica gel, washed with EtOAc twice, and the filtrate evaporated under reduced pressure. The residue was purified by column chromatography on silica gel with PE/EtOAc/DCM (3:1:1) as the eluent to give the enantioenriched product 2a. Yield: 16.2 mg (88%); white solid; [α]_D ²⁰ +218.8 (c 0.022, THF). ¹H NMR (600 MHz, CDCl₃): δ = 8.23 (d, J = 8.4 Hz, 1 H), 7.73–7.70 (m, 2 H), 7.44 (t, J = 8.4 Hz, 1 H), 7.34 (t, J = 9.6 Hz, 1 H), 7.28–7.25 (m, 1 H), 7.12 (d, J = 8.4 Hz, 1 H), 6.96 (t, J = 8.4 Hz, 1 H), 6.64 (t, J = 6.6 Hz, 1 H), 6.51 (s, 1 H), 6.45 (d, J = 7.2 Hz, 1 H), 5.75 (s, 1 H), 4.84 (s, 1 H), 4.10 (d, J = 12.0 Hz, 1 H), 3.74 (d, J = 12.0 Hz, 1 H), 3.59 (q, J = 7.8 Hz, 2 H), 3.50 (d, J = 11.4 Hz, 1 H), 1.17 (t, J = 7.2 Hz, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 165.2, 152.8, 148.0, 141.9, 131.9, 130.9, 130.7, 129.4, 128.7, 128.3, 127.8, 124.7, 124.3, 124.2, 119.8, 119.7, 119.2, 117.2, 108.6, 93.0, 55.6, 52.7, 41.6, 12.6. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₄H₂₀N₂NaO₂: 391.1417; found: 391.1418. Enantiomeric ratio: 88.5:11.5, determined by HPLC (Daicel Chiralpak IA, i-PrOH/n-hexane = 30:70, flow rate = 1.0 mL/min, T = 30 °C, λ = 254 nm): t _R = 9.34 min (minor), t _R = 18.10 min (major).
• 19 The absolute configuration of compound 3 was confirmed based on our prior work (see ref. 15 above).
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