Synthesis of 1-Aza-6,7-dehydrotropanes via Copper(I)-Catalyzed Coupling of 5-Chloropentan-2-one with Hydrazines and Terminal Alkynes

Abstract

A one-pot, three-component, Cu(I)-catalyzed coupling of primary hydrazines, 5-chloropentan-2-one, and terminal alkynes was developed. The resulting 1-aza-6,7-dehydrotropanes compose a new class of substances while related 1-azatropanes are scarcely described in literature and closely resemble tropane alkaloids. Hydrogenation of the double bond in 1-aza-6,7-dehydrotropanes triggered a rearrangement, involving a [1,3]-hydride shift, forming cyclic hydrazones.

Key words

multicomponent reactions - alkynes - hydrazines - ketones - copper catalysis - 1-azatropanes

• References and Notes

• 1 Shaaban S. Oh J. Maulide N. Org. Lett. 2016; 18: 345
• 2a Imaizumi T. Yamashita Y. Kobayashi S. J. Am. Chem. Soc. 2012; 134: 20049
• 2b Suzuki Y. Naoe S. Oishi S. Fujii N. Ohno H. Org. Lett. 2012; 14: 326
• 2c Hashimoto T. Takiguchi Y. Maruoka K. J. Am. Chem. Soc. 2013; 135: 11473
• 2d Chen Z. Yang X. Wu J. Chem. Commun. 2009; 3469
• 2e Hashimoto T. Omote M. Maruoka K. Angew. Chem. Int. Ed. 2011; 50: 8952
• 3a Kawai H. Yuan Z. Tokunaga E. Shibata N. Org. Lett. 2012; 14: 5330
• 3b Davies PW. Cremonesi A. Dumitrescu L. Angew. Chem. Int. Ed. 2011; 50: 8931
• 3c Chen Z. Ding Q. Yu X. Wu J. Adv. Synth. Catal. 2009; 351: 1692
• 3d Harju K. Kylänlahti I. Paananen T. Polamo M. Nielsen J. Yli-Kauhaluoma J. J. Comb. Chem. 2006; 8: 344
• 4a Zhang M. Wu F. Wang H. Wua J. Chen W. Adv. Synth. Catal. 2017; 359: 2768
• 4b Yang Z.-W. Wang J.-F. Peng L.-J. You X.-L. Cui H.-L. Tetrahedron Lett. 2016; 57: 5219
• 4c Liu Y. Zhen W. Dai W. Wang F. Li X. Org. Lett. 2013; 15: 874
• 4d Shao C. Zhang Q. Cheng G. Cheng C. Wang X. Hu Y. Eur. J. Org. Chem. 2013; 6443
• 4e Chen X. Jia C. Cao L. Zhang D. Liu S. Zhang Q. Chem. Res. Chin. Univ. 2015; 31: 543
• 4f Arai T. Ogino Y. Sato T. Chem. Commun. 2013; 49: 7776
• 4g Arai T. Ogino Y. Molecules 2012; 17: 6170
• 4h Yoshimura K. Oishi T. Yamaguchi K. Mizuno N. Chem. Eur. J. 2011; 17: 3827
• 4i Shintani R. Fu GC. J. Am. Chem. Soc. 2003; 125: 10778
• 4j Takamichi O. Kazuaki Y. Kazuya Y. Noritaka M. Chem. Lett. 2010; 39: 1086
• 5 Schantl JG. Science of Synthesis . Thieme; Stuttgart: 2004. Vol. 27 731
• 6 Van Beek WE. Van Stappen J. Franck P. Abbaspour Tehrani K. Org. Lett. 2016; 18: 4782
• 7 General Experimental Procedure for the Synthesis of Products 4 In an oven-dried microwave vessel (10 mL) were introduced Cu₂O (36 mg, 0.25 mmol), hydrazine 1 (2.5 mmol), ketone 2a (1 mmol), alkyne 3 (1.2 mmol), and DCM (4 mL). The vessel was flushed with argon for 30 s, sealed, and introduced in a preheated oil bath of 50 °C and stirred during 24 h. Afterwards, the reaction mixture was poured into 0.5 N NaOH solution (20 mL) and extracted with DCM (2 × 20 mL). The organic phases were combined and dried over MgSO₄·3H₂O, filtered, and evaporated in vacuo. The crude product was then purified by automated column chromatography on a 12 g Grace column with heptanes/EtOAc as eluting solvents. 5,8-Dimethyl-7-phenyl-1,8-diazabicyclo[3.2.1]oct-6-ene (4a) ¹H NMR (400 MHz, CDCl₃): δ = 7.64–7.62 (m, 2 H), 7.34–7.26 (m, 3 H), 5.78 (s, 1 H), 3.34–3.26 (m, 1 H), 2.86 (dd, 1 H, J = 13.3, 6.3 Hz), 2.37 (s, 3 H), 1.84–1.79 (m, 2 H), 1.48–1.43 (m, 2 H), 1.22 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 147.0, 132.1, 128.5, 128.3, 126.6, 115.9, 68.8, 47.9, 37.6, 33.7, 20.0, 18.6. HRMS (ESI): m/z calcd for [C₁₄H₁₈N₂ + H]⁺: 215.1543; found: 215.1542. Yellow oil, 119.4 mg (56%) isolated yield of 5,8-dimethyl-7-phenyl-1,8-diazabicyclo[3.2.1]oct-6-ene (4a) after column chromatography; R_f = 0.39 in 1:1 heptanes/EtOAc.
• 8 CCDC-1846488 contains the supplementary crystallographic data for 4g. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac. uk/getstructures.
• 9a Nigst TA. Antipova A. Mayr H. J. Org. Chem. 2012; 77: 8142
• 9b Brotzel F. Chu YC. Mayr H. J. Org. Chem. 2007; 72: 3679
• 10 Mechanism for the de-tert-butylation and rearrangement of 4k into 4k′ (Scheme 7)
• 11 Geffe M. Andernach L. Trapp O. Opatz T. Beilstein J. Org. Chem. 2014; 10: 701
• 12 Grynkiewicz G. Gadzikowska M. Pharmacol. Rep. 2008; 60: 439
• 13 Dennis N. Katritzky AR. Ramaiah M. J. Chem. Soc., Perkin Trans. 1 1976; 2281
• 14 Pirrung FO. H. Rutjes FP. J. T. Hiemstra H. Speckamp WN. Tetrahedron Lett. 1990; 31: 5365
• 15 Meth-Cohn O. Suschitzky H. Adv. Heterocycl. Chem. 1972; 14: 211
• 16a Pigeon P. Mamouni A. Sikoraiova J. Marchalin S. Decroix B. Tetrahedron 2001; 57: 4939
• 16b Mori K. Sueoka S. Akiyama T. J. Am. Chem. Soc. 2011; 133: 2424
• 16c Verboom W. Reinhoudt DN. Visser R. Harkema S. J. Org. Chem. 1984; 49: 269
• 16d Reinhoudt DN. Visser GW. Verboom W. Benders PH. Pennings ML. M. J. Am. Chem. Soc. 1983; 105: 4775
• 16e Boeck BD. Jiang S. Janousek Z. Viehe HG. Tetrahedron 1994; 50: 7075
• 16f Zhang C. De CK. Mal R. Seidel D. J. Am. Chem. Soc. 2008; 130: 416
• 17 Yu X. Xu J. Zhoua Y. Song Q. Org. Chem. Front. 2018; 5: 2463