Selective reductions of 1-methyl-4-phenyl-2-pyridone

We have explored the reactions of 1-methyl-4-phenyl-2-pyridone (5) with various reducing agents in an effort to develop synthetic approaches to specifically deuterium-labeled 1,4-disubstituted 1,2,3,6-tetrahydropyridine analogs needed for metabolic and enzyme mechanistic studies. Reactions with NaBH4 in CH3OH or THF, LiAl(O-t-Bu)(3)H in THF, and Al(i-Bu)(2)H(DIBALH) in THF resulted in quantitative recovery of starting material. On the other hand, treatment with BH3 in THF unexpectedly led to the formation of 4-phenylpyridine (7) in 98% yield. LiAIH(4) in THF or Et(2)O and Red-Al in THF gave varying amounts of the 3,6-dihydro-2-pyridone 8 and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (1). In the presence of TiCl3, LiAlH4 in THF at 0 degrees C converted 5 to 1 in 97% yield. LiB(s-Bu)(3)H (L-Selectride) in THF gave exclusively the 1,4-reduction product 8. Base catalyzed isomerization of 8 provided the conjugated 5,6-dihydro-2-pyridone 4. The applications of these reactions with deuterated reagents provide insights into the reaction pathways and several avenues for the regioselective synthesis of the required deuterium-labeled compounds.