Copper-Catalyzed [4+1] and [4+2] Reactions through Tandem ­Remote Propargylation/Cyclization/Isomerization with an Amine or a Hydrazine

Yu-Ze Sun; Guo-Qiang Lin; Zhi-Tao He

doi:10.1055/a-2294-5395

Synlett, Inhaltsverzeichnis

Synlett 2025; 36(01): 82-86
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

Yu-Ze Sun

^aDepartment of Chemistry, Shanghai Normal University, Shanghai 200234, P. R. of China

^bState Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Shanghai, 200032, P. R. of China

^cState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Shanghai, 200032, P. R. of China

,

Guo-Qiang Lin

^aDepartment of Chemistry, Shanghai Normal University, Shanghai 200234, P. R. of China

^bState Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Shanghai, 200032, P. R. of China

,

Zhi-Tao He ∗

^cState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Shanghai, 200032, P. R. of China

^dSchool of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, P. R. of China

^eNingbo Zhongke Creation Center of New Materials, Ningbo, 315899, P. R. of China

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Abstract

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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 - amines

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References and Notes
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19 CCDC 2334156 contains the supplementary crystallographic data for compound 5b. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.
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.

Zusatzmaterial

Supporting Information

Copper-Catalyzed [4+1] and [4+2] Reactions through Tandem ­Remote Propargylation/Cyclization/Isomerization with an Amine or a Hydrazine

Copper-Catalyzed [4+1] and [4+2] Reactions through Tandem Remote Propargylation/Cyclization/Isomerization with an Amine or a Hydrazine