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Synlett 2024; 35(19): 2236-2240
DOI: 10.1055/a-2290-1682
DOI: 10.1055/a-2290-1682
letter
Synthesis of Fused-Ring Pyrrolizine Derivatives via a Copper-Catalyzed Radical Cascade Cyclization
Authors
We gratefully thank the National Natural Science Foundation of China (Project No. 21676088) for financial support.
Abstract
Herein, an atom-economic method for the synthesis of fused-ring pyrrolizine derivatives by a cycloaddition reaction of easily accessible N-substituted pyrrole-2-carboxaldehydes with N-substituted maleimides in the presence of di-tert-butyl peroxide has been successfully developed. A total of 23 compounds were obtained by using this method, with a maximum yield of 72%, providing a practical and efficient method for the synthesis of tricyclic pyrrolizine frameworks.
Key words
N-substituted pyrrole-2-carboxaldehydes - atom-economic reactions - N-substituted maleimides - C–H activation - tricyclic pyrrolizinesSupporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/a-2290-1682.
- Supporting Information (PDF)
Publication History
Received: 21 January 2024
Accepted after revision: 18 March 2024
Accepted Manuscript online:
18 March 2024
Article published online:
03 April 2024
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- 8 Fused-Ring Pyrrolizine Derivatives; General Procedure 1-(2-Oxo-2-phenylethyl)-1H-pyrrole-2-carbaldehyde (0.2 mmol) and N-methylmaleimide (0.4 mmol, 2 equiv) were added sequentially to a sealed tube, followed by the addition of H2O/DMSO (3:1, 2 mL). Cu(OTf)2 (20 mol%) and DTBP (3.0 equiv) were added and the reaction mixture was stirred at 120 °C for 24 h. Upon completion of the reaction (as monitored by TLC), brine (30 mL) and dichloromethane (15 mL) were added to the mixture and the aqueous layer was extracted with dichloromethane (2 × 15 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under vacuum. Purification was performed by column chromatography on silica gel to obtain the product. 4-Benzoyl-2-methyl-1,3-dioxo-1,2,3,3a,4,8b-hexahydropyrrolo[3,4-a]pyrrolizine-6-carbaldehyde (3a): Compound 3a was isolated by column chromatography on silica gel (petroleum ether/ethyl acetate, 25:1). Yield: 46.4 mg (72%); red solid; mp 213.8–214.5 °C. 1H NMR (400 MHz, CDCl3): δ = 9.45 (s, 1 H), 8.35 (d, J = 8.0 Hz, 2 H), 7.73 (t, J = 7.4 Hz, 1 H), 7.63 (t, J = 7.6 Hz, 2 H), 7.11 (d, J = 4.0 Hz, 1 H), 6.82–6.60 (m, 1 H), 6.43 (d, J = 4.0 Hz, 1 H), 4.38 (d, J = 7.9 Hz, 1 H), 4.02 (d, J = 7.9 Hz, 1 H), 3.09 (s, 3 H). 13C NMR (151 MHz, CDCl3): δ = 192.62, 178.71, 175.68, 172.96, 140.03, 134.58, 132.96, 129.28, 129.23, 129.00, 126.28, 104.93, 63.85, 52.19, 43.44, 25.70. HRMS (EI): m/z [M]+ calcd. for C18H14N2O4: 322.0954; found: 322.0953.