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Synlett 2025; 36(01): 82-86
DOI: 10.1055/a-2294-5395
DOI: 10.1055/a-2294-5395
letter
Copper-Catalyzed [4+1] and [4+2] Reactions through Tandem Remote Propargylation/Cyclization/Isomerization with an Amine or a Hydrazine
We acknowledge financial support from the National Natural Science Foundation of China (22371292 and 22071262), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB0610000), Natural Science Foundation of Ningbo (2023J036), Shanghai Municipal Committee of Science and Technology (22ZR1475200), the State Key Laboratory of Organometallic Chemistry, and Shanghai Institute of Organic Chemistry.
Abstract
Two novel copper-catalyzed cyclization reactions involving a remote propargylic substitution/cyclization/isomerization cascade are disclosed. Derivatives of the seldomly studied heterocycles thieno[2,3-c]pyrrole and thieno[2,3-d]pyridazine are conveniently synthesized in moderate to good yields from primary amines or arylhydrazines through [4+1] and [4+2] reactions, respectively. Preliminary mechanistic experiments corroborated the occurrence of the designed cascade reactions.
Key words
copper catalysis - propargylic substitution - [4+1] cyclization - [4+2] cyclization - arylhydrazines - aminesSupporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/a-2294-5395.
- Supporting Information
Publication History
Received: 29 February 2024
Accepted after revision: 25 March 2024
Accepted Manuscript online:
25 March 2024
Article published online:
15 April 2024
© 2024. Thieme. All rights reserved
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- 20 [4+1] Reaction with Amines; General ProcedureIn a N2-filled glovebox, a 4 mL vial was charged sequentially with Cu(MeCN)4PF6 (1.9 mg, 0.0050 mmol), ligand L1 (1.3 mg, 0.0060 mmol), the appropriate alkyne 1 (0.10 mmol), Et3N (28 μL, 0.20 mmol), the appropriate amine 2 (0.12 mmol), and anhyd MeOH (0.10 mL). The resulting mixture was stirred at 60 °C for 4 h, then diluted with hexane and filtered through Celite. The filtrate was concentrated and purified by flash column chromatography. 4-Methyl-5,6-diphenyl-5H-thieno[2,3-c]pyrrole (3a) Yellow oil; yield: 23.7 mg (82%). 1H NMR (400 MHz, CDCl3): δ = 7.45–7.39 (m, 3 H), 7.26–7.23 (m, 2 H), 7.18–7.14 (m, 2 H), 7.09–6.95 (m, 5 H), 2.33 (s, 3 H). 13C NMR (101 MHz, CDCl3): δ = 139.7, 132.8, 130.9, 129.3, 128.7, 128.3, 128.1, 126.7, 124.99, 124.96, 123.7, 121.5, 120.8, 116.2, 12.5. HRMS (EI): m/z [M+] calcd for C19H15NS: 289.0920; found: 289.0926.
- 21 [4+2] Reaction with Hydrazines; General ProcedureIn a N2-filled glovebox, a 4 mL vial was charged sequentially with Cu(MeCN)4PF6 (3.7 mg, 0.010 mmol), ligand L1 (2.6 mg, 0.012 mmol), the appropriate alkyne 1 (0.10 mmol), Et3N (28 μL, 0.20 mmol), the appropriate arylhydrazine 4 (0.20 mmol), and anhyd MeOH (0.10 mL). The resulting mixture was stirred at 60 °C for 4 h, then diluted with hexane and filtered through Celite. The filtrate was concentrated and purified by flash column chromatography. 4-Methyl-6,7-diphenyl-6,7-dihydrothieno[2,3-d]pyridazine (5a) Green oil; yield: 25.3 mg (83%). 1H NMR (400 MHz, CDCl3): δ = 7.32–7.19 (m, 9 H), 7.16 (d, J = 5.2 Hz, 1 H), 6.99 (d, J = 5.2 Hz, 1 H), 6.90–6.86 (m, 1 H), 6.57 (s, 1 H), 2.38 (s, 3 H). 13C NMR (101 MHz, CDCl3): δ = 146.5, 141.2, 138.8, 136.7, 128.99, 128.97, 127.78, 127.76, 125.8, 124.0, 122.7, 120.4, 115.1, 58.7, 19.8. HRMS (EI): m/z [M+] calcd for C19H16N2S: 304.1029; found: 304.1033.