Chemodivergent Transformations of Alkynyl Imines

Abstract

The investigation of cycloisomerization cascades of alkynyl imines towards pyrroles unexpectedly led to the development of chemodivergent routes towards quinolines and fused pyrrolines. It was found that, depending on the nature of the nitrogen substituent and choice of reagents, up to three different heterocyclic cores can be accessed from a common structural precursor.

Key words

alkynyl imines - cycloaddition - electrophilic cyclization - heterocycles - quinoline

References and Notes

• For recent examples, see:
• 1a Pandey S. Takashima W. Kaneto K. React. Funct. Polym.  2004,  58:  103 
• 1b Georgiadis R. Peterlinz KA. Rahn JR. Peterson AW. Grassi JH. Langmuir  2000,  16:  6759 
• 1c Czerwinski W. Wrzeszcz G. Kania K. Rabek JF. Linden LA. J. Mater. Sci.  2000,  35:  2305 
• For recent reviews on heterocycle synthesis, see:
• 2a Nakamura I. Yamamoto Y. Chem. Rev.  2004,  104:  2127 
• 2b Zeni G. Larock RC. Chem. Rev.  2004,  104:  2285 
• 2c Alonso F. Beletskaya IP. Yus M. Chem. Rev.  2004,  104:  3079 
• 2d Black DStC. In Science of Synthesis   5th Ed., Vol. 9:  Maas G. Thieme; Stuttgart: 2000.  p.543-552  
• 3 Kel’in AV. Sromek AW. Gevorgyan V. J. Am. Chem. Soc.  2001,  123:  2074 
• 4 Kel’in AV. Gevorgyan V. J. Org. Chem.  2002,  67:  95 
• 5 Sromek AW. Rubina M. Gevorgyan V. J. Am. Chem. Soc.  2005,  127:  10500 
• 6 Kim JT. Kel’in AV. Gevorgyan V. Angew. Chem. Int. Ed.  2003,  42:  98 
• 7 Sromek AW. Kel’in AV. Gevorgyan V. Angew. Chem. Int. Ed.  2004,  43:  2280 
• 8 Lin S. Sheng H. Huang Y. Synthesis  1991,  235 
• 9a Ried W. Winkler H. Chem. Ber.  1979,  112:  384 
• 9b Ried W. Weidemann P. Chem. Ber.  1971,  104:  3329 
• 9c Himbert G. Schwickerath W. Liebigs Ann. Chem.  1984,  85 
• 10 Strained cyclic cumulenes have been proposed as intermediates in benzannulation reactions, see: Danheiser RL. Gould AE. Fernández de la Pradilla RF. Helgason AL. J. Org. Chem.  1994,  59:  5514 
• For recent reports of transition-metal-catalyzed cyclization of alkynyl imines into quinolines, see:
• 11a Movassaghi M. Hill MD. J. Am. Chem. Soc.  2006,  128:  4592 
• 11b Sangu K. Fuchibe K. Akiyama T. Org. Lett.  2004,  6:  353 
• For selected examples of metal-catalyzed [2+2]-cyclo-additions, see:
• 14a Mango FD. Schachtschneider JH. J. Am. Chem. Soc.  1971,  93:  1123 
• 14b Fraser AR. Bird PH. Bezman SA. Shapley JR. White R. Osborn JA. J. Am. Chem. Soc.  1973,  95:  597 
• 14c Baik T.-G. Luis AL. Wang LC. Krische MJ. J. Am. Chem. Soc.  2001,  123:  6716 
• For the thermal cyclization of allenyl thioimine into bicyclic pyrroline derivatives, see:
• 15a Brandsma L. Nedolya NA. Heerma V. Van der Kerk ASHTM. Lutz ETHG. de Lang R.-J. Afonin AV. Trofimov BA. Chem. Heterocycl. Compd. (Engl. Transl.)  1997,  33:  493 
• 15b Brandsma L. Nedolya NA. Verkruijsse HD. Owen NL. Li D. Trofimov BA. Tetrahedron Lett.  1997,  38:  6905 
• 15c Trofimov BA. Nedolya NA. Brandsma L. Frolov YuL. Larionova EYu. Toryashinova DD. Kobychev VB. Vitkovskaya NM. Sulfur Lett.  1999,  22:  249 

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CCDC-605793 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge at www.ccdc.cam.uk/conts/retrieving.html [or from the Cambridge Crystallographic Data Center, 12 Union Road, Cambridge, CB2 1EZ, UK; fax: [phone]; email: [e-mail]].

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A base-assisted formal [1,3]-H shift in alkynyl imines 1 into allenyl imines has been proposed as the first step of the cycloisomerization cascade towards pyrroles 2; see ref. 3 for a detailed discussion.

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Quinolines 3; General Procedure. A 3-mL Wheaton microreactor equipped with a Teflon spin vane and Mininert valve under an argon atmosphere was employed. CuI (23 mg, 0.12 mmol), anhyd DMA (1.80 mL), Et₃N·HCl (55 mg, 0.40 mmol), and alkynyl imine 1 (88 mg, 0.40 mmol) were added successively. The microreactor was then placed in an aluminum block, which was preheated to 110 °C. The mixture was stirred at 110 °C with protection from light for 24 h. The progress of the reaction was monitored by GC-MS. When the reaction was complete the mixture was cooled to r.t. and poured into H₂O (15 mL). After shaking with hexanes-Et₂O (1:1, 5 mL) a three-layer system usually formed. The lower(aqueous) phase and upper(organic) phase were thoroughly separated from the middle layer, which contained an emulsion of Cu⁺ complexes. The emulsion and water phases were separately extracted with hexanes-Et₂O (1:1; 3 × 2 mL and 1 × 2 mL, respectively). The combined extracts were dried over anhyd Na₂CO₃, the solvent was evaporated under reduced pressure, and the residue was purified over a short column of silica gel(benzene) to afford 2-phenyl-4-methylquinoline 3 in 93% isolated yield.
Fused Pyrrolines 4; General Procedure. A 3-mL Wheaton microreactor equipped with a Teflon spin vane and Mininert valve under an argon atmosphere was employed. CuI (23 mg, 0.12 mmol), anhyd DMA (1.80 mL), and imine 1 (0.40 mmol) were added successively. After the CuI had dissolved, anhyd Et₃N (0.25 mL) was added, and the microreactor was placed in an aluminum heating block, preheated to 110 °C. The mixture was stirred at 110 °C with protection from light. The reaction was monitored by GC-MS. When the reaction was complete, the mixture was cooled to r.t., and poured into H₂O (15 mL). After shaking with hexanes (5 mL) a three-layer system usually formed. The lower(aqueous) phase and upper(organic) phase were thoroughly separated from the middle layer, which contained an emulsion of Cu⁺ complexes. The emulsion and water phases were separately extracted with hexanes (3 × 2 mL and 1 × 2 mL, respectively). The combined hexanes extracts were dried over anhyd Na₂CO₃, the solvent was evaporated under reduced pressure, and the residue was purified over a short column of silica gel (hexanes or hexanes-EtOAc) to afford the pure fused pyrroline 4.