Synthesis of Pyrrolizinone and Pyrrolizino[1,2-a]pyrrolizin-5-one Skeletons Starting From Pyrrole through a Single-Step and Catalyst-Free Approach

Abstract

1H-Pyrrole reacted with lactone-type 2,3-furandione derivatives in anhydrous diethyl ether at room temperature to give a series of derivatives of pyrrolizinone (which is among the most important alkaloid skeletons) in a single step without a catalyst. Pyrrolizinone derivatives with a variety of substituents, such as phenyl, substituted phenyl, thienyl, trifluoromethyl, naphthyl, biphenylyl, ester, or oxalate, were obtained. The reaction of an equimolar amount of pyrrole gave pyrrolizinones, whereas an excess of pyrrole gave pyrrolizino[1,2-a]pyrrolizin-5-ones containing a skeleton that had not previously been reported. The purified molecules were obtained in yields of up to 91%. One cyclization process was carried out on a gram scale, yielding 0.952 g (71%) of the corresponding product.

Keywords

furandiones - alkaloids - Michael addition - decarboxylation - pyrrolizinones - pyrrolizinopyrrolizinones

Publication History

Received: 02 December 2022

Accepted after revision: 03 January 2023

Accepted Manuscript online:
03 January 2023

Article published online:
07 February 2023

• References and Notes

• 1a Morriello GJ, DeVita RJ, Mills SG, Young JR, Lin P, Doss G, Chichi GG, DeMartino J, Kurtz MM, Tsao K.-LC, Carlson E, Townson K, Wheeldon A, Boyce S, Collinson N, Rupniak N, Moore S. Bioorg. Med. Chem. 2008; 16: 2156
• 1b Morriello GJ, Mills SG, Johnson T, Reibarkh M, Chicchi G, DeMartino J, Kurtz M, Davies P, Tsao K.-LC, Townsn K, Tattersall FD, Wheeldon A, Boyce S, Collinson N, Rupniak N, Moore S, DeVita RJ. Bioorg. Med. Chem. Lett. 2010; 20: 2007
• 1c Simic M, Tasic G, Jovanovic P, Petkovic M, Savic V. Org. Biomol. Chem. 2018; 16: 2125
• 2a Mattocks AB, Driver E. Toxicol. Lett. 1987; 38: 315
• 2b Gan C.-Y, Low Y.-Y, Thomas NF, Kam T.-S. J. Nat. Prod. 2013; 76: 957
• 2c Sugimoto K, Toyoshima K, Nonaka S, Kotaki K, Ueda H, Tokuyama H. Angew. Chem. Int. Ed. 2013; 52: 7168
• 2d Álvarez-Micó X, Rocha DD, Guimarães LA, Ambrose A, Chapman E, Costa-Lotufo LV, La Clair JJ, Fenical W. ChemBioChem 2015; 16: 2002
• 3a Sugie Y, Hirai H, Kachi-Tonai H, Kim Y.-J, Kojima Y, Shiomi Y, Sugiura A, Sugiura A, Suzuki Y, Yoshikawa N, Brennan L, Duignan J, Hsiung H, Sutcliffe J, Kojima N. J. Antibiot. 2001; 54: 917
• 3b Robertson J, Stevens KJ. Nat. Prod. Rep. 2014; 31: 1721
• 3c Nicolaou KC, Pulukuri KK, Rigol S, Buchman M, Shah AA, Cen N, McCurry MD, Beabout K, Shamoo Y. J. Am. Chem. Soc. 2017; 139: 15868
• 4a Lewis WJ. M, Shaw DM, Robertson J. Beilstein J. Org. Chem. 2021; 17: 334
• 4b Snider B, Duvall JR. Org. Lett. 2005; 7: 4519
• 4c Duvall JR, Wu F, Snider BB. J. Org. Chem. 2006; 27: 8579
• 5 Ratmanova NK, Andreev IA, Leontiev AV, Momotova D, Novoselov AM, Ivanova OA, Trushkov IV. Tetrahedron 2020; 76: 131031
• 6 McNab H. J. Org. Chem. 1981; 46: 2809
• 7a Evans DA, Fandrick KR. Org. Lett. 2006; 8: 2249
• 7b Byers JH, DeWitt A, Nasveschuk CG, Swigor JE. Tetrahedron Lett. 2004; 45: 6587
• 7c Unaleroglu C, Tasgin D, Aytac S, Temelli B. Synthesis 2009; 3243
• 7d Unaleroglu C, Tasgin DI. Synthesis 2013; 45: 193
• 8a Manjappa KB, Peng Y.-T, Jhang W.-F, Yang D.-Y. Tetrahedron 2016; 72: 853
• 8b Tang M, Sun R, Li H, Yu X, Wang W. J. Org. Chem. 2017; 82: 8419
• 9 Zhao Y, Yuan Y, Xu M, Zheng Z, Zhang R, Li Y. Org. Biomol. Chem. 2017; 15: 6328
• 10a Şener A, Menges N, Akkurt M, Karaca S, Büyükgüngör O. Tetrahedron Lett. 2008; 49: 2828
• 10b Kuzu B, Menges N. Spectrochim. Acta, Part A 2016; 162: 61
• 10c Şener A, Bildirici İ, Genç H. Turk. J. Chem. 2008; 32: 19
• 10d Uygun MT, Menges N. Org. Biomol. Chem. 2022; 20: 4161
• 10e Çam S, Bildirici İ, Menges N, Tan M, Şener A. J. Heterocycl. Chem. 2013; 50: E211
• 10f Şener A, Bildirici İ, Tozlu İ, Genç H, Arısoy K. J. Heterocycl. Chem. 2007; 44: 1077
• 10g Koca İ, Yıldırım İ, Şahin E. Helv. Chim. Acta 2010; 93: 1336
• 10h Tan M, Bildirici İ, Menges N. J. Serb. Chem. Soc. 2018; 83: 953
• 11 Pyrrolizinones 6a–j; General Method Pyrrole (5, 1 mmol) was added to a solution of the appropriate furandione 4a–j (1 mmol) in dry Et₂O (10 ml) in a round-bottomed flask, and the resulting solution was stirred at rt for 18 h until the reaction should be completed (TLC). The organic layer was extracted with EtOAc (3 × 50 mL), dried (MgSO₄), and concentrated in a low vacuum. The crude product was purified by column chromatography [silica gel, hexane–EtOAc (20:1)]. 2-Benzoyl-1-phenyl-3H-pyrrolizin-3-one (6a) Red viscous liquid; yield: 81%; R_f = 0.80. FTIR (ATR): 3045, 2911, 1725, 1640, 1345, 1215, 685 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.86–7.82 (m, 2 H, Ar-H), 7.53–7.46 (m, 3 H, Ar-H), 7.41–7.35 (m, 2 H, Ar-H), 7.34–7.29 (m, 3 H, Ar-H), 7.13 (dd, J = 0.8, 3.1 Hz, 1 H, Ar-H), 6.41 (dd, J = 0.8, 3.1 Hz, 1 H-Ar-H), 6.21 (t, J = 3.1 Hz, 1 H, Ar-H). ¹³C NMR (100 MHz, CDCl₃): δ = 190.1, 159.2, 153.2, 136.8, 135.2, 133.5, 131.4, 130.3, 129.6, 128.8, 128.7, 128.3, 120.1, 118.7, 116.3, 115.5. HRMS: m/z [M + H]⁺ calcd for C₂₀H₁₄NO₂: 300.1025; found: 300.1018.
• 12a Abe M, Imai T, Ishii N, Usui M, Okuda T, Oki T. Biosci., Biotechnol., Biochem. 2005; 69: 1202
• 12b Zhang Y, Han T, Ming Q, Wu L, Rahman K, Qin L. Nat. Prod. Commun. 2012; 7: 963
• 12c Boussard M.-F, Truche S, Rousseau-Rojas A, Briss S, Descamps S, Droual M, Wierzbicki M, Ferry G, Audinot V, Delagrange P, Boutin JA. Eur. J. Med. Chem. 2006; 41: 306
• 13 Üngören ŞH, Dilekoğlu E, Koca İ. Chin. Chem. Lett. 2013; 24: 1130
• 14a Beigi M, Loschonsky S, Lehwald P, Brecht V, Andrade SL. A, Leeper FJ, Hummel W, Müller M. Org. Biomol. Chem. 2013; 11: 252
• 14b He Z, Qi X, She Z, Li S, Gao G, Lan Y, You J. J. Org. Chem. 2017; 82: 1403