Synthesis of β‑Ketosulfonamides Derived from Amino Acids and Their Conversion to β‑Keto-α,α-difluorosulfonamides via Electrophilic Fluorination

β-Ketosulfonamides
derived from Boc or Cbz-protected amino
acids bearing hydrophobic side chains were prepared in good to excellent
yield by treating N-allyl, N-alkyl
methanesulfonamides with n-BuLi, followed by reaction
of the resulting carbanion with methyl esters of N-protected l-amino acids. The analogous reaction using the
dianion derived from an N-alkyl methanesulfonamide
proceeded in much lower yield. Electrophilic fluorination of the β-ketosulfonamides
using Selectfluor in the presence of CsF in DMF at room temperature
for 15–60 min provided β-keto-α,α-difluorosulfonamides
in good to excellent yields. The allyl protecting group could be removed
in good yield using cat. Pd­(PPh)3)4 and dimethyl
barbituric acid. When the fluorination reaction was performed with
Cs2CO3 as base, β-ketosulfonamides derived
from Val, Leu or Ile gave the expected β-keto-α,α-difluorosulfonamides,
while β-ketosulfonamides derived from Ala, Phe, or hPhe gave
the hydrates of the imino β-keto-α,α-difluorosulfonamides.