SolutionsThe Buchwald-Hartwig amination
Exercise 1
Propose two syntheses of N-phenylpiperidine: a classical one, without metals, and one by Buchwald–Hartwig coupling. Why does the direct reaction of chlorobenzene with piperidine not work?
Classical: dialkylation of aniline with 1,5-dibromopentane (or a reductive amination with glutaraldehyde). Buchwald–Hartwig: bromobenzene or chlorobenzene + piperidine, Pd2(dba)3 with a bulky phosphine and NaOtBu. Chlorobenzene does not react directly because aryl halides do not undergo SN2 and, without electron-withdrawing groups in the ortho or para positions, not SNAr either.
Exercise 2
In a Buchwald–Hartwig amination of 4-bromotoluene with diethylamine, toluene is isolated as a by-product. Where does it come from? How can its formation be reduced?
From the palladium amido Ar–Pd–NEt2: instead of reductive elimination, it undergoes β-hydride elimination (an H from the ethyl CH2), giving the imine and Ar–Pd–H; reductive elimination from this hydride gives toluene. It is reduced by using bulky, electron-rich ligands, which accelerate C–N reductive elimination relative to β-elimination.