O-Tetrahydropyran-2-yloxy (O-THP) as an ortho-Directing Group in the Lithiation of Pyridines

Abstract

Herein we report regioselective deprotonations of 3- and 4-(tetrahydropyran-2-yloxy)pyridine with n-butyllithium. Trapping the lithiated species with various electrophiles afforded functionalized pyridines in good yields. A one-pot procedure also allowed the double functionalization at C4 and C2 in the case of 3-O-THP-pyridine. The ortho-metallating ability of this group was examined in comparison with other well-known oxygen-based ortho-directing groups.

Key words

acetals - pyridines - metallations - lithium - organometallic reagents

References

• 1 Mongin F. Quéguiner G. Tetrahedron  2001,  57:  4059 
• 2a Schlosser M. In Organometallics in Synthesis   2nd ed.:  Schlosser M. Wiley; Chichester UK: 2002.  p.1-352  
• 2b Clayden J. In The Chemistry of Organolithium Compounds   Rappoport Z. Marek I. Wiley; Chichester UK: 2004.  p.495-646  
• 3 Miah MAJ. Snieckus V. J. Org. Chem.  1985,  50:  5438 
• 4a Stern R. English J. Cassidy HG. J. Am. Chem. Soc.  1957,  79:  5797 
• 4b Harris TD. Oruganti SR. Davis LM. Keehu PM. Green BS. Tetrahedron  1987,  43:  1519 
• 5 Azzouz R. Bischoff L. Fouquet M.-H. Marsais F. Synlett  2005,  2808 
• 6 Whisler MC. MacNeil S. Snieckus V. Beak P. Angew. Chem. Int. Ed.  2004,  43:  2206 
• 7 Winkle MR. Ronald RC. J. Org. Chem.  1982,  47:  2101