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

beta-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 beta-ketosulfonamides using Selectfluor in the presence of CsF in DMF at room temperature for 15-60 min provided beta-keto-alpha,alpha-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, beta-ketosulfonamides derived from Val, Leu or Ile gave the expected beta-keto-alpha,alpha-difluorosulfonamides, while beta-ketosulfonarnides derived from Ala, Phe, or hPhe gave the hydrates of the imino beta-keto-alpha,alpha-difluorosulfonamides.