A Novel Pseudo-Three-Component Synthetic Strategy for the Synthesis of 1,6-Dihydroazaazulenes via Cyclization of Pyrrolyl-enones

Abstract

A synthetic novel strategy involving a pseudo-three-component reaction to obtain 1,6-dihydroazaazulenes derivates via cyclization of pyrrolyl-enones was developed. This reaction is carried out under mild conditions from simple starting materials and catalyzed with ionic liquid. Notably, three new C–C bonds are formed in the one-pot process. The target molecules are of interest in medicinal chemistry as they contain a privileged scaffold and are considered indole homologues.

Key words

1,6-dihydroazaazulenes - pyrrole - pyrrolyl-enones - butanone - Michael addition - electrophilic aromatic substitution - metal-free catalyst

Publication History

Received: 11 May 2021

Accepted after revision: 24 June 2021

Accepted Manuscript online:
24 June 2021

Article published online:
15 July 2021

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• 13 Synthesis of 1,6-Dihydroazaazulenes by Cyclization of Pyrrolyl-enones; General Procedure In a vial with a stir bar, a solution of butenone (2.5 equiv) and methanesulfonic acid (1.5 equiv) in DCM (0.1 M) was added. Taken the reaction to ice-bath, the N-benzyl- and N-methyl-enones were then added dropwise. The reaction mixture was stirred at room temperature until starting material was consumed. The reaction was diluted with distilled water and neutralized with saturated solution of NaHCO₃. Next, the organic phase was extracted with DCM (30 mL) and washed with distilled water (3 × 10 mL). The product was obtained by column chromatography on silica gel using a mixture of hexane/ethyl acetate, 9:1 (v/v) as eluent. 4-(7-Acetyl-1-benzyl-4-methyl-1,6-dihydrocyclohepta[b]pyrrol-2-yl)butan-2-one (5a) Yellow oil; yield 40%. ¹H NMR (400 MHz, CDCl₃): δ = 7.33–7.28 (m, 3 H), 7.25 (s, 1 H), 6.95 (d, J = 6.8 Hz, 2 H), 6.21 (s, 1 H), 5.27–5.25 (m, 3 H), 2.86–2.79 (m, 4 H), 2.68 (d, J = 7.5 Hz, 2 H), 2.25 (s, 3 H), 2.14 (s, 3 H), 2.08 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 207.0, 196.7, 137.1, 136.9, 131.6, 130.5, 129.8, 129.0, 129.0, 127.6, 126.7, 125.8, 125.7, 124.8, 115.5, 105.6, 47.3, 41.9, 30.0, 25.6, 24.4, 21.4, 20.4. HRMS (ESI⁺): m/z calcd for C₂₃H₂₆NO₂ [M + H]⁺: 348.1964; found: 348.1959.