Synthesis of Fused-Ring Pyrrolizine Derivatives via a Copper-Catalyzed Radical Cascade Cyclization

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 pyrrolizines

Publication History

Received: 21 January 2024

Accepted after revision: 18 March 2024

Accepted Manuscript online:
18 March 2024

Article published online:
03 April 2024

• References and Notes

• 1a Gouda AM, Abdelazeem AH. Eur. J. Med. Chem. 2016; 114: 257
• 1b Hao F, Reddy AR, Zhou CY, Che CM. Adv. Synth. Catal. 2018; 360: 1433
• 1c Guzman A, Yuste F, Toscano RA, Young JM, Van Horn AR, Muchowski JM. J. Med. Chem. 1986; 29: 589
• 1d Sugimoto K, Yamamoto N, Tominaga D, Matsuya Y. Org. Lett. 2015; 17: 1320
• 2a Olsen JA, Banner DW, Seiler P, Sander UO, D’Arcy A, Stihle M, Muller K, Diederich F. Angew. Chem. Int. Ed. 2003; 42: 2507
• 2b Olsen J, Seiler P, Wagner B, Fischer H, Tschopp T, Obst-Sander U, Banner DW, Kansy M, Mueller K, Diederich F. Org. Biomol. Chem. 2004; 2: 1339
• 2c Schweizer E, Hoffmann-Roder A, Scharer K, Olsen JA, Fah C, Seiler P, Obst-Sander U, Wagner B, Kansy M, Diederich F. ChemMedChem 2006; 1: 611
• 2d Selva V, Selva E, Merino P, Najera C, Sansano JM. Org. Lett. 2018; 20: 3522
• 3 Belabbes A, Retamosa MG, Foubelo F, Sirvent A, Najera C, Yus M, Sansano JM. Org. Biomol. Chem. 2023; 21: 1927
• 4a Chen L, Sun J, Xie J, Yan CG. Org. Biomol. Chem. 2016; 14: 6497
• 4b Reddy CN, Sathish M, Adhikary S, Nanubolu JB, Alarifi A, Maurya RA, Kamal A. Org. Biomol. Chem. 2017; 15: 2730
• 4c Mali PR, Khomane NB, Sridhar B, Meshram HM, Likhar PR. New J. Chem. 2018; 42: 13819
• 4d Shen P, Guo YT, Wei J, Zhao H, Zhai HB, Zhao YF. Synthesis 2021; 53: 1262
• 4e Coldham I, Jana S, Watson L, Pilgram CD. Tetrahedron Lett. 2008; 49: 5408
• 4f Gorman RM, Little MA, Morris JA, Sridharan V. Chem. Commun. 2012; 48: 9537
• 4g Windle J, Allison M, Shepherd H, Sridharan V. RSC Adv. 2014; 4: 2624
• 4h Pearson WH, Stoy P, Mi Y. J. Org. Chem. 2004; 69: 1919
• 4i Pearson WH, Dietz A, Stoy P. Org. Lett. 2004; 6: 1005
• 5a Wu K, Du YL, Wei Z, Wang T. Chem. Commun. 2018; 54: 7443
• 5b Su YP, Zhang R, Xue WX, Liu X, Zhao YN, Wang KH, Huang DF, Huo CD, Hu YL. Org. Biomol. Chem. 2020; 18: 1940
• 5c Ren LL, Wang YG, Huo YM, Tong XG, Xia CF. Chem. Commun. 2022; 58: 13935
• 5d Muthengi A, Erickson J, Muriph RE, Zhang W. J. Org. Chem. 2019; 84: 5927
• 6a Hao LQ, Wu GR, Wang YY, Xu XB, Ji YF. Adv. Synth. Catal. 2023; 365: 2159
• 6b Hao LQ, Wang ZC, Wang YY, Yang ZZ. Y, Liu X, Xu XB, Ji YF. Org. Biomol. Chem. 2023; 21: 7611
• 7a Jiang HM, Sun Q, Jiang JP, Qin JH, Ouyang XH, Song RJ. Adv. Synth. Catal. 2022; 364: 2772
• 7b Xu CH, Xiong ZQ, Li Y, Zhu YP, Li JH. Org. Chem. Front. 2022; 9: 476
• 7c Xie D, Tian RG, Zhang XT, Tian SK. Org. Biomol. Chem. 2022; 20: 4518
• 7d Kwon Y, Wang Q. Org. Lett. 2020; 22: 4141
• 7e Hemric BN, Shen K, Wang Q. J. Am. Chem. Soc. 2016; 138: 5813
• 7f Sun K, Chen XL, Zhang YL, Li K, Huang XQ, Peng YY, Qu LB, Yu B. Chem. Commun. 2019; 55: 12615
• 7g Wei WT, Teng F, Li Y, Song RJ, Li JH. Org. Lett. 2019; 21: 6285
• 7h Ji JJ, Zhu ZQ, Xie ZB, Tang J, Yuan E, Le ZG. Synthesis 2021; 53: 2277
• 7i Segundo MS, Correa A. ChemSusChem 2018; 11: 3893
• 7j Song Y, Zhang H, Guo JB, Shao Y. f, Ding YZ, Zhu L, Yao XQ. Eur. J. Org. Chem. 2021; 5914
• 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.