3,5-Dibromopyridine → 3-Bromo-5-(4-methoxyphenoxy)pyridine

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In an alternative approach to the synthesis of pyridine-substituted pyridyl diazabicyclic compounds, 3,5-dibromopyridine can be converted into the corresponding 3-bromo-5-alkoxy- and 3-bromo-5-aryloxypyridines by the action of sodium alkoxides or sodium aryloxides. Procedures such as those described by Comins et al., J. Org. Chem. 55: 69 (1990) and Hertog et al., Recueil Trav. Chim. Pays-Bas 74: 1171 (1955) are used. This is exemplified by the preparation 2-(5-(4-methoxyphenoxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane. Reaction of 3,5-dibromopyridine with sodium 4-methoxyphenoxide in N,N-dimethylformamide gives 3-bromo-5-(4-methoxyphenoxy)pyridine. Coupling of 3-bromo-5-(4-methoxyphenoxy)pyridine with (1S,4S)-N-(tert-butoxycarbonyl)-2,5-diazbicyclo[2.2.1]heptane in the presence of sodium tert-butoxide and a catalytic amount of tris(dibenzylideneacetone)dipalladium(0) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl in toluene provides (1S,4S)-2-(5-(4-methoxyphenoxy)-3-pyridyl)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptane. Removal of the N-tert-butoxycarbonyl group, using trifluoroacetic acid, produces (1S,4S)-2-(5-(4-methoxyphenoxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane.

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