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

N-Acyl-alpha-amino acids were efficiently transformed in a two-step procedure into 1-N-(acylamino)alkyltriphenylphosphonium salts, new powerful alpha-amidoalkylating agents. The effect of the alpha-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 alpha-methoxylation of N-acyl-alpha-amino acids (Hofer-Moest reaction) was investigated. For most proteinogenic and all studied unproteinogenic alpha-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 alpha-amino acids to an electrochemical oxidation on the side chain. The methoxy group of N-(1-methoxyallcyl)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.