One-Pot Synthesis of Spiro-2H-pyrroles from N-Propargylic β-Enaminones

Abstract

A simple and general one-pot method for the synthesis of spiro-2H-pyrroles has been developed. Initially, cyclohexane-embedded β-enaminones with internal alkyne functionality were synthesized by conjugate addition of 1-ethynylcyclohexylamine to α,β-alkynic ketones, followed by palladium-catalyzed coupling of the resulting N-propargylic β-enaminones with aryl iodides. When subjected to basic conditions, the cyclohexane-embedded β-enaminones with internal alkyne functionality underwent tandem nucleophilic cyclization and benzylic C–H oxidation to furnish 3,4-diaryloyl-1-azaspiro[4.5]deca-1,3-diene derivatives in good yields.

Key words

pyrrole - 2H-pyrrole - N-propargylic β-enaminones - spiro compound - nucleophilic cyclization - benzylic C–H oxidation

• References and Notes

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• 18 (2-Phenyl-1-azaspiro[4.5]deca-1,3-diene-3,4-diyl)bis(phenylmethanone) (5a); Typical Procedure: To a stirred solution of 1,3-diphenyl-3-((1-(phenylethynyl)cyclohexyl)amino)prop-2-en-1-one (3a; 106.5 mg, 0.263 mmol) in DMSO (3 mL) under air, was added Cs₂CO₃ (256.7 mg, 0.788 mmol) and the resulting solution was allowed to stir at 80 °C until all starting material was consumed as monitored by TLC (ca. 30 min). When the reaction was complete, the mixture was cooled to room temperature and diluted with chloroform (30 mL). To the diluted reaction mixture, an equal volume of ice was added, the mixture stirred for 10 minutes and the organic layer was separated from the aqueous layer. The aqueous layer was extracted with chloroform (2 × 15 mL) and the combined organic layers were dried over MgSO₄, filtered and evaporated on a rotary evaporator to give the crude product, which was purified by flash chromatography on silica gel eluting with hexane/ethyl acetate (9:1 followed by 4:1) to afford spiro-2H-pyrrole 5a (76.1 mg, 69%) as a yellow solid (R_f = 0.44 in 4:1 hexane/ethyl acetate; mp 172.4–174.6 °C). ¹H NMR (400 MHz, CDCl₃): δ = 7.56–7.52 (m, 2 H), 7.49 (m, 2 H), 7.45–7.42 (m, 2 H), 7.41–7.34 (m, 2 H), 7.30–7.15 (m, 7 H), 2.13–1.97 (m, 4 H), 1.83 (d, J = 13.2 Hz, 1 H), 1.78–1.67 (m, 2 H), 1.56 (d, J = 11.0 Hz, 2 H), 1.35–1.24 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 194.5 (CO), 192.9 (CO), 170.9 (C), 166.7 (C), 137.8 (C), 137.2 (C), 137.1 (C), 134.0 (CH), 133.9 (CH), 133.7 (C), 130.1 (CH), 129.5 (CH), 129.3 (CH), 128.7 (CH), 128.6 (CH), 128.5 (CH), 128.5 (CH), 85.3 (C), 33.8 (CH₂), 25.6 (CH₂), 23.8 (CH₂). IR (neat): 3057, 2913, 2857, 1657, 1597, 1578, 1445, 1337, 1315, 1296, 1258, 1154, 1071, 866, 744, 720, 688 cm^–1. MS (ESI): m/z 420.20 [M + H]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆NO₂: 420.1958; found: 420.1968.
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