Synlett 2020; 31(07): 723-729
DOI: 10.1055/s-0039-1691577
letter
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Fully Substituted Pyrroles through a Copper-Catalyzed Aza-Michael/Claisen Rearrangement/Cyclization Cascade

Hao Tan
a  Laboratory of Asymmetric Synthesis, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing, 402160, P. R. of China   Email: cuihailei616@163.com
,
Xue-Fei Jiang
a  Laboratory of Asymmetric Synthesis, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing, 402160, P. R. of China   Email: cuihailei616@163.com
,
Lu Jiang
a  Laboratory of Asymmetric Synthesis, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing, 402160, P. R. of China   Email: cuihailei616@163.com
,
Chang Yuan
a  Laboratory of Asymmetric Synthesis, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing, 402160, P. R. of China   Email: cuihailei616@163.com
,
Xue Tang
a  Laboratory of Asymmetric Synthesis, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing, 402160, P. R. of China   Email: cuihailei616@163.com
b  School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, P. R. of China
,
Meng-Fan Li
a  Laboratory of Asymmetric Synthesis, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing, 402160, P. R. of China   Email: cuihailei616@163.com
,
Si-Wei Liu
a  Laboratory of Asymmetric Synthesis, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing, 402160, P. R. of China   Email: cuihailei616@163.com
c  Tonichem Pharmaceutical Technology Co., Ltd, Huizhou, 516008, P. R. of China
,
Si Liu
a  Laboratory of Asymmetric Synthesis, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing, 402160, P. R. of China   Email: cuihailei616@163.com
,
a  Laboratory of Asymmetric Synthesis, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing, 402160, P. R. of China   Email: cuihailei616@163.com
› Author Affiliations
We are grateful for the support provided for this study by the National Natural Science Foundation of China (21502013, 21871035).
Further Information

Publication History

Received: 12 November 2019

Accepted after revision: 23 December 2019

Publication Date:
29 January 2020 (online)


Abstract

We have developed a copper-catalyzed aza-Michael/Claisen rearrangement/cyclization cascade sequence that affords structurally diverse pentasubstituted pyrroles in acceptable to good yields (31–84%).

Supporting Information

 
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  • 24 Pentasubstituted Pyrroles 3ap; General ProcedureAllenoate 2 (0.4 mmol, 2.0 equiv) was added to a mixture of the appropriate propargylic amine 1 (0.2 mmol, 1.0 equiv) and Cu2O (20 mol%) in DCE (2.0 mL), and the mixture was stirred at 50 °C for the time shown in Scheme 2, without exclusion of air. The mixture was then directly purified by flash chromatography (silica gel, hexane–EtOAc).Ethyl 1,5-dibenzyl-4-phenyl-2-(2-phenylethyl)-1H-pyrrole-3-carboxylate (3a)Purified by a flash chromatography [silica gel, hexane–EtOAc (50:1)] as a yellow oil; yield: 382.6 mg (77%). 1H NMR (400 MHz, CDCl3): δ = 7.36–7.11 (m, 14 H), 7.07 (dd, J = 6.8, 1.8 Hz, 2 H), 7.01–6.94 (m, 2 H), 6.81 (dd, J = 6.7, 1.9 Hz, 2 H), 4.54 (s, 2 H), 4.13 (q, J = 7.1 Hz, 2 H), 3.72 (s, 2 H), 3.15 (dd, J = 8.7, 6.6 Hz, 2 H), 2.82 (dd, J = 8.6, 6.6 Hz, 2 H), 1.05 (t, J = 7.1 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 165.6, 141.5, 139.6, 139.5, 137.5, 136.5, 130.5, 128.8, 128.6, 128.5, 128.4, 128.1, 127.8, 127.4, 127.4, 126.2, 126.1, 126.0, 125.5, 125.2, 110.9, 59.2, 46.9, 36.4, 30.3, 28.2, 13.9. ESI-HRMS: m/z [M + H]+ calcd for C35H34NO2: 500.2584; found: 500.2589.Ethyl 5-Benzyl-1-(4-methoxybenzyl)-4-phenyl-2-(2-phenylethyl)-1H-pyrrole-3-carboxylate (3b)Purified by a flash chromatography [silica gel, hexane–EtOAc (25:1)] as a pale-yellow foam solid; yield: 373.5 mg (71%). 1H NMR (400 MHz, CDCl3): δ = 7.30–7.05 (m, 11 H), 7.04–6.97 (m, 2 H), 6.95–6.88 (m, 2 H), 6.79–6.72 (m, 2 H), 6.67 (d, J = 8.5 Hz, 2 H), 4.43 (s, 2 H), 4.06 (q, J = 7.1 Hz, 2 H), 3.72 (s, 3 H), 3.66 (s, 2 H), 3.10 (dd, J = 8.8, 6.6 Hz, 2 H), 2.76 (dd, J = 8.7, 6.6 Hz, 2 H), 0.98 (t, J = 7.1 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 165.6, 158.9, 141.5, 139.5, 139.5, 136.5, 130.5, 129.4, 128.5, 128.4, 128.4, 128.0, 127.8, 127.4, 126.7, 126.2, 126.0, 125.2, 114.4, 114.3, 110.8, 59.2, 55.3, 46.4, 36.4, 30.3, 28.2, 14.0. ESI-HRMS: m/z [M + H]+ calcd for C36H36NO3: 530.2690; found: 530.2690.