BF₃-Mediated Oxidative Cross-Coupling of Pyridines with Alkynyllithium Reagents and Further Reductive Functionalizations of the Pyridine Scaffold

Abstract

A set of functionalized alkynylpyridines can be readily obtained using Et₂O·BF₃ as promoter. Alkynyllithium reagents undergo an addition reaction at position C-2 of pyridines that are rearomatized by oxidative treatment with chloranil. These substituted pyridines can be easily converted into more valuable intermediates. Examples of applications are given as well. Finally, the synthesis of piperidines and lactams via first an oxidative BF₃-mediated addition reaction followed by a NaBH₄ reduction or acidic workup is also described.

Key words

cross-coupling - pyridines - alkynyllithiums - BF₃ - piperidines - lactams

• References

• 1a Glorius F, Spielkamp N, Holle S, Goddard R, Lehmann CW. Angew. Chem. Int. Ed. 2004; 43: 2850
• 1b Modern Heterocyclic Chemistry . Alvarez-Builla J, Vaquero JJ, Barluenga J. Wiley-VCH; Weinheim: 2011
• 1c Hardin Narayan AR, Sarpong R. Org. Biomol. Chem. 2012; 10: 70
• 2a Organotransition Metal Chemistry . Hartwig JF. University Science Books; Sausalito (CA, USA): 2010
• 2b Metal-Catalyzed Cross-Coupling Reactions . Diederich F, de Meijere A. Wiley-VCH; Weinheim: 2004

For few examples, see:
• 3a Carvalho JF. S, Louvel J, Doornbos ML. J, Klaasse E, Yu Z, Brussee J, Ijzerman AP. J. Med. Chem. 2013; 56: 2828
• 3b Moulton BE, Whitwood AC, Duhme-Klair AK, Lynam JM, Fairlamb IJ. S. J. Org. Chem. 2011; 76: 5320
• 4 Chen Q, Mollat du Jourdin X, Knochel P. J. Am. Chem. Soc. 2013; 135: 4958
• 5 Chen Q, León T, Knochel P. Angew. Chem. Int. Ed. 2014; 53 in press; DOI: 10.1002/anie.201400750
• 6a For a recent review of Pauson–Khand reaction, see: The Pauson–Khand Reaction: Scope, Variations and Applications. Ríos Torres R. Wiley-VCH; Weinheim: 2012

For examples of application, see:
• 6b Vázquez-Romero A, Cárdenas L, Blasi E, Verdaguer X, Riera A. Org. Lett. 2009; 11: 3104
• 6c Kizirian J.-C, Aiguabella N, Pesquer A, Fustero S, Bello P, Verdaguer X, Riera A. Org. Lett. 2010; 12: 5620
• 7 Only one regioisomer was detected by GC analysis. For a study of regioselectivities in cobalt-mediated intermolecular Pauson–Khand reaction, see ref. 3b.
• 8a Bull JA, Mousseau JJ, Pelletier G, Charette AB. Chem. Rev. 2012; 112: 2642
• 8b Legault C, Charette AB. J. Am. Chem. Soc. 2003; 125: 6360
• 9 Hussain M, Sainte-LuceBanchelin T, Andersson H, Olsson R, Almqvist F. Org. Lett. 2013; 15: 54
• 10 Comins DL, Brown JD. Tetrahedron Lett. 1986; 27: 4549