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Synlett 2021; 32(09): 923-929
DOI: 10.1055/a-1362-0296
letter

Syntheses of Spiro(2-oxopyrrolidinyl)-5,4′-pyrazolones via Organocatalyzed Michael/Ammonolysis Cascade Reaction of 4-Aminopyrazolones and α,β-Unsaturated Acyl Phosphates

You-Fen Li
,
Zheng-Jun Chen
,
Wen-Ya Jiao
,
Zhi-Jiao Chen
,
Lin Chen  ∗
We are grateful for the grants from the National Natural Science Foundation of China (21762013), the Science and Technology Project of Guizhou Province (Qian Ke He Ji Chu [2020] 1Y029), and the Science and Technology Development Project of Education Department of Guizhou Province for Young Talents (Qian Jiao He KY Zi [2016] 133).
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Abstract

The efficient organocatalyzed Michael/ammonolysis cascade reaction of N-protected 4-aminopyrazolones and α,β-unsaturated acyl phosphates has been developed. This tactic gives rise to architecturally multifarious spiro(2-oxopyrrolidinyl)-5,4′-pyrazolones in good productiveness (up to 88% yield) and with moderate to good diastereoselectivities (up to 20:1 dr). These novel hybrid heterocycles would be promising candidates for drug-discovery programs and chemical biology.

Key words

spiro(2-oxopyrrolidinyl)-5,4′-pyrazolones - N-protected 4-aminopyrazolones - α,β-unsaturated acyl phosphates - organocatalysis - drug discovery - pharmacophores - medicinal chemistry - Michael/ammonolysis cascade reaction

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-1362-0296.
  • Supporting Information


Publication History

Received: 14 January 2021

Accepted after revision: 18 January 2021

Accepted Manuscript online:
18 January 2021

Article published online:
02 February 2021

© 2021. Thieme. All rights reserved

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  • 16 Typical Procedure and Characterization Data for 3s To a solution of N-protected 4-aminopyrazolone 1a (64.7 mg, 0.2 mmol), α,β-unsaturated acyl phosphonate 2j (119.3 mg, 0.4 mmol), NaHCO3 (50.4 mg, 0.6 mmol), and 4 Å MS (200.0 mg) in MeCN (2.0 mL) was added DMAP (2.4 mg, 10 mol%). The reaction mixture was stirred at room temperature for 8 h. Then, the reaction slurry was diluted with DCM and filtered through a thin pad of silica gel. The filtrate was concentrated under reduced pressure, and the purification of the residue by column chromatography on silica gel (using petroleum ether/ethyl acetate = 4:1 as eluent) afforded the pure spiro(2-oxopyrrolidinyl)-5,4′-pyrazolone 3s as a white solid; 31.9 mg, 33% yield; 20:1 dr; mp 215.5–216.2 ℃. 1H NMR (400 MHz, CDCl3): δ = 7.96–7.98 (m, 2 H), 7.49–7.50 (m, 3 H), 7.43–7.45 (m, 3 H), 7.29 (t, J = 7.9 Hz, 2 H), 7.12–7.17 (m, 2 H), 6.89 (td, J = 7.5, 0.6 Hz, 1 H), 6.68 (d, J = 7.8 Hz, 1 H), 4.75 (q, J = 7.3 Hz, 1 H), 4.15 (dd, J = 7.2, 21.4 Hz, 2 H), 3.68 (dd, J = 16.9, 16.9 Hz, 1 H), 3.19 (s, 3 H), 2.79 (q, J = 8.3 Hz, 1 H), 1.08 (t, J = 7.1 Hz, 3 H). 13C{1H} NMR (100 MHz, CDCl3): δ = 172.0, 170.4, 157.8, 154.6, 149.9, 137.0, 130.5, 130.1, 129.8, 128.9, 128.7, 127.9, 125.8, 125.5, 120.4, 119.7, 119.7, 110.2, 74.3, 63.9, 54.5, 37.1, 34.3, 13.8. HRMS (ESI-TOF): m/z [M + H]+ calcd for C28H26N3O5: 484.1867; found: 484.1877.