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

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

Publication History

Received: 14 January 2021

Accepted after revision: 18 January 2021

Accepted Manuscript online:
18 January 2021

Article published online:
02 February 2021

• References and Notes

• 1 Marcote DC, Varela I, Fernández-Casado J, Mascareñas JL, López F. J. Am. Chem. Soc. 2018; 140: 16821
• 2a Krishnasamy SK, Namasivayam V, Mathew S, Eakambaram RS, Ibrahim IA, Natarajan A, Palaniappan S. Arch. Pharm. 2016; 349: 383
• 2b Schlemminger I, Schmidt B, Flockerzi D, Tenor H, Zitt C, Hatzelmann A, Marx D, Braun C, Külzer R, Heuser A, Kley HP, Sterk GJ. WO 2010055083, 2010
• 2c Bao X, Wei S, Qian X, Qu J, Wang B, Zou L, Ge G. Org. Lett. 2018; 20: 3394
• 3a Nourian S, Zilber ZA, Toscano JP. J. Org. Chem. 2016; 81: 9138
• 3b Chauhan P, Mahajan S, Kaya U, Peuronen A, Rissanen K, Enders D. J. Org. Chem. 2017; 82: 7050
• 3c Mondal B, Maity R, Pan SC. J. Org. Chem. 2018; 83: 8645
• 3d Xu J, Hu L, Hu H, Ge S, Liu X, Feng X. Org. Lett. 2019; 21: 1632
• 3e Luo W, Shao B, Li J, Xiao X, Song D, Ling F, Zhong W. Org. Chem. Front. 2020; 7: 1016
• 3f Ao C, Huang J, Xu X, Jia S, Kang Z, Hu W. Org. Biomol. Chem. 2020; 18: 3466
• 3g Chen X.-Y, Jiang Z.-H, Ju W.-Z, Yin H, Qi S.-S, Chu M.-M, Wang Y.-F. Synlett 2020; 31: 1318
• 3h Ji D.-S, Luo Y.-C, Hu X.-Q, Xu P.-F. Org. Lett. 2020; 22: 1028
• 4a Hack D, Dürr AB, Deckers K, Chauhan P, Seling N, Rübenach L, Mertens L, Raabe G, Schoenebeck F, Enders D. Angew. Chem. Int. Ed. 2016; 55: 1797
• 4b Liu J.-Y, Zhao J, Zhang J.-L, Xu P.-F. Org. Lett. 2017; 19: 1846
• 4c Liang J.-Y, Shen S.-J, Chai X.-Q, Lv T. J. Org. Chem. 2018; 83: 12744
• 4d Liu X.-L, Zuo X, Wang J.-X, Chang S.-Q, Wei Q.-D, Zhou Y. Org. Chem. Front. 2019; 6: 1485
• 4e Khairnar PV, Wu C.-Y, Lin Y.-F, Edukondalu A, Chen Y.-R, Lin W. Org. Lett. 2020; 22: 4760
• 4f Mao B, Liu H, Yan Z, Xu Y, Xu J, Wang W, Wu Y, Guo H. Angew. Chem. Int. Ed. 2020; 59: 11316
• 4g Lu D, Liu X, Wu J.-H, Zhang S, Tan J.-P, Yu X, Wang T. Adv. Synth. Catal. 2020; 362: 1966
• 4h Tan C.-Y, Lu H, Zhang J.-L, Liu J.-Y, Xu P.-F. J. Org. Chem. 2020; 85: 594
• 5 Wei S, Bao X, Wang W, Nawaz S, Dai Q, Qu J, Wang B. Chem. Commun. 2020; 56: 10690
• 6a Kimata A, Nakagawa H, Ohyama R, Fukuuchi T, Ohta S, Suzuki T, Miyata N. J. Med. Chem. 2007; 50: 5053
• 6b Huang H, Yu Y, Gao Z, Zhang Y, Li C, Xu X, Jin H, Yan W, Ma R, Zhu J, Shen X, Jiang H, Chen L, Li J. J. Med. Chem. 2012; 55: 7037
• 6c Li X, Chen F.-Y, Kang J.-W, Zhou J, Peng C, Huang W, Zhouiang M.-K, He G, Han B. J. Org. Chem. 2019; 84: 9138
• 6d Wang L, Yang Z, Ni T, Shi W, Guo Y, Li K, Shi A, Wu S, Sheng C. Bioorg. Med. Chem. Lett. 2020; 30: 126662
• 6e Fuse S, Suzuki K, Kuchimaru T, Kadonsono T, Ueda H, Sato S, Kizaka-Kondoh S, Nakamura H. Bioorg. Med. Chem. 2020; 28: 115207
• 7a Deerberg J, Prasad SJ, Sfouggatakis C, Eastgate MD, Fan Y, Chidambaram R, Sharma P, Li L, Schild R, Müslehiddinoğlu J, Chung H.-J, Leung S, Rosso V. Org. Process Res. Dev. 2016; 20: 1949
• 7b Narczyk A, Mrozowicza M, Stecko S. Org. Biomol. Chem. 2019; 17: 2770
• 7c Fan W, Li X, Huang L, He S, Xie Z, Fu Y, Fang W, Li Y. Neurochem. Int. 2018; 115: 50
• 7d Sun S, Wu Y, Yao X, Yang S, Liu Y. J. Chem. Eng. Data 2020; 65: 2694
• 8 Taylor RD, MacCoss M, Lawson AD. G. J. Med. Chem. 2014; 57: 5845
• 9a Morphy R, Kay C, Rankovic Z. Drug Discov. Today 2004; 9: 641
• 9b Duarte CD, Barreiro EJ, Fraga CA. M. Mini-Rev. Med. Chem. 2007; 7: 1108
• 9c Talevi A. Front. Pharmacol. 2015; 6: 205
• 9d Pagliero RJ, Kaiser M, Brun R, Nieto MJ, Mazzieri MR. Bioorg. Med. Chem. Lett. 2017; 27: 3945
• 9e Svensson F, Bende A, Bailey D. J. Med. Chem. 2018; 61: 1415
• 9f Zhang W.-H, Chen S, Liu X.-L, Feng T.-T, Yang W.-D, Zhou Y. Bioorg. Med. Chem. 2019; 27: 115109
• 10a Chen L, Wu Z.-J, Zhang M.-L, Yue D.-F, Zhang X.-M, Xu X.-Y, Yuan W.-C. J. Org. Chem. 2015; 80: 12668
• 10b Kowalczyk D, Albrecht Ł. J. Org. Chem. 2016; 81: 6800
• 10c Laina-Martín V, del Río-Rodríguez R, Díaz-Tendero S, Fernández-Salas JA, Alemán J. Chem. Commun. 2018; 54: 13941
• 10d Kowalczyk D, Albrecht Ł. Tetrahedron Lett. 2018; 59: 2636
• 10e He J, Sun R.-G, Fan L, Tian S.-Y, Huang T.-P, Chen Z, Chen L. Synthesis 2019; 5: 1353
• 10f Chen L, He J. J. Org. Chem. 2020; 85: 5203
• 11a Fukui K, Yonezawa T, Shingu H. J. Chem. Phys. 1952; 20: 722
• 11b Fukui K, Yonezawa T, Nagata C, Shingu H. J. Chem. Phys. 1954; 22: 1433
• 12 Zhou Y, Wang J, Gu Z, Wang S, Zhu W, Aceña JL, Soloshonok VA, Izawa K, Liu H. Chem. Rev. 2016; 116: 422
• 13 CCDC 1988619 contains the supplementary crystallographic data of compound 3v for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures .
• 14a Thompson AM, O’Connor PD, Marshall AJ, Blaser A, Yardley V, Maes L, Gupta S, Launay D, Braillard S, Chatelain E, Wan B, Franzblau SG, Ma Z, Cooper CB, Denny WA. J. Med. Chem. 2018; 61: 2329
• 14b Ghosh AK, Williams JN, Ho RY, Simpson HM, Hattori S.-I, Hayashi H, Agniswamy J, Wang Y.-F, Weber IT, Mitsuya H. J. Med. Chem. 2018; 61: 9722
• 14c Li S, Qin C, Cui S, Xu H, Wu F, Wang J, Su M, Fang X, Li D, Jiao Qi, Zhang M, Xia C, Zhu L, Wang R, Li J, Jiang H, Zhao Z, Li J, Li H. J. Med. Chem. 2019; 62: 2348
• 14d Shi C, Zhang Y, Wang T, Lu W, Zhang S, Guo B, Chen Q, Luo C, Zhou X, Yang Y. J. Med. Chem. 2019; 62: 2950
• 14e Bogart JW, Kramer NJ, Turlik A, Bleich RM, Catlin DS, Schroeder FC, Nair SK, Williamson RT, Houk KN, Bowers AA. J. Am. Chem. Soc. 2020; 142: 13170
• 15a Cui B.-D, Zuo J, Zhao J.-Q, Zhou M.-Q, Wu Z.-J, Zhang X.-M, Yuan W.-C. J. Org. Chem. 2014; 79: 5305
• 15b Yang P, Wang X, Chen F, Zhang Z.-B, Chen C, Peng L, Wang L.-X. J. Org. Chem. 2017; 82: 3908
• 15c Lin Y, Zhao B.-L, Du D.-M. J. Org. Chem. 2018; 83: 7741
• 15d Lei C.-W, Zhang C.-B, Wang Z.-H, Xie K.-X, Zhao J.-Q, Zhou M.-Q, Zhang X.-M, Xu X.-Y, Yuan W.-C. Org. Chem. Front. 2020; 7: 499
• 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.