One-Pot Expeditious Synthesis of Pyrazoloindolones via Base-Promoted Electrocyclization, C–N Coupling and Intramolecular Oxidative Cyclization

Abstract

Pyrazoloindolones are synthesized from N-tosylhydrazones in a one-pot multistep process which include base-promoted (i) electrocyclization reaction of N-tosylhydrazones derived from α,β-unsaturated aldehydes, (ii) aromatic nucleophilic substitution, and (iii) a domino cyclization–oxidation process under aerobic conditions.

Key words

N-tosylhydrazone - electrocyclization - aromatic nucleophilic substitution - oxidative cyclization - pyrazoloindolones

Publication History

Received: 28 March 2024

Accepted after revision: 29 April 2024

Accepted Manuscript online:
29 April 2024

Article published online:
14 May 2024

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• 15 Experimental Procedure for the One-Pot Synthesis of Pyrazoloindolone 5a A round-bottomed flask (10 mL) fitted with a magnetic stir bar and nitrogen inlet was charged with cinnamaldehyDe (26.2 mg, 0.20 mmol) and MeOH (0.40 mL) at rt. Then TsNHNH₂ (37.2 mg, 0.20 mmol) was added, and the mixture was stirred at rt for 3 h. During this time TLC analysis indicated complete conversion. Then, MeOH was evaporated, the residue was dissolved in dry DMSO (0.40 mL), and Cs₂CO₃ (81.5 mg, 0.25 mmol) was added under nitrogen atmosphere. The resulting mixture was placed in a pre-heated oil bath at 110 °C and stirred for 15 min. Then, 2-fluorobenzaldehyde 3a (24.8 mg, 0.20 mmol) and Cs₂CO₃ (146.6 mg, 0.45 mmol) were added, and the reaction mixture was stirred at 110 °C for 5 h. Then, the reaction mixture was purged with oxygen and heated at 130 °C under oxygen atmosphere (balloon) for 10 h. After cooling to rt, the reaction mixture was diluted with ethyl acetate (25 mL), extracted with brine (3 × 10 mL), dried over Na₂SO₄, and evaporated. The crude product was purified by silica gel column chromatography using 5% ethyl acetate in hexanes as eluent to obtain pyrazoloindolone 5a (32.1 mg, 65% yield) as a yellow-brown solid; mp 150–152 °C; R_f = 0.75 (0.5:9.5 ethyl acetate/hexane); purified using 2% ethyl acetate in hexanes as eluent. ¹H NMR (500 MHz, CDCl₃): δ = 7.76 (d, J = 6.5 Hz, 2 H), 7.53 (d, J = 6.5 Hz, 1 H), 7.45 (apt, J = 7.5 Hz, 1 H), 7.40–7.34 (m, 3 H), 7.29 (apt, J = 8.0 Hz, 1 H), 7.12 (apt, J = 8.0 Hz, 1 H), 6.86 (s, 1 H). ¹³C{¹H} NMR (126 MHz, CDCl₃): δ = 179.5, 157.9, 144.0, 139.7, 135.6, 132.0, 128.8, 128.7, 128.0, 126.3, 125.6, 124.9, 110.7, 103.3. HRMS (ESI-TOF): m/z calcd for C₁₆H₁₁N₂O [M + H]⁺: 247.0871; found: 247.0842.