α-Amidoalkylating Agents from N-Acyl-α-amino Acids: 1-(N-Acylamino)alkyltriphenylphosphonium Salts

N-Acyl-α-amino acids were efficiently transformed in a two-step procedure into 1-N-(acylamino)­alkyltriphenylphosphonium salts, new powerful α-amidoalkylating agents. The effect of the α-amino acid structure, the base used [MeONa or a silica gel-supported piperidine (SiO2–Pip)], and the main electrolysis parameters (current density, charge consumption) on the yield and selectivity of the electrochemical decarboxylative α-methoxylation of N-acyl-α-amino acids (Hofer–Moest reaction) was investigated. For most proteinogenic and all studied unproteinogenic α-amino acids, very good results were obtained using a substoichiometric amount of SiO2–Pip as the base. Only in the cases of N-acylated cysteine, methionine, and tryptophan, attempts to carry out the Hofer–Moest reaction in the applied conditions failed, probably because of the susceptibility of these α-amino acids to an electrochemical oxidation on the side chain. The methoxy group of N-(1-methoxyalkyl)­amides was effectively displaced with the triphenylphosphonium group by dissolving an equimolar amount of N-(1-methoxyalkyl)­amide and triphenylphosphonium tetrafluoroborate in CH2Cl2 at room temperature for 30 min, followed by the precipitation of 1-N-(acylamino)­alkyltriphenylphosphonium salt with Et2O.