Synthesis of N-alkyl-N-methyl amino acids. Scope and limitations of base-induced N-alkylation of Cbz-amino acids

The reaction of N-benzyloxycarbonyl derivatives of aliphatic amino acids with NaH/alkyl iodides gave the corresponding N-Cbz-N-alkyl derivatives in good to high yields. The scope and limitations of this simple N-alkylation reaction were investigated as a convenient and flexible attempt to prepare unsymmetrically N,N-diprotected α-amino acids. The procedure is based on the N-alkylation of N-carbamoyl amino acids, a one-pot deprotection/protection sequence without extensive purification of the products. Protection of the carboxyl function is not required while the starting materials are inexpensive and commercially available.

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N-Ethyl-N-methyl-l-alanineC6H13NO2Ee = 100%[α]D19.8=+5.0 (c 0.50, EtOH)Source of chirality: l-alanineAbsolute configuration: (S)

N-Ethyl-N-methyl-l-phenylalanineC12H17NO2Ee = 100%[α]D19.8=+24.7 (c 1.00, EtOH)Source of chirality: l-phenylalanineAbsolute configuration: (S)

N-Ethyl-N-methyl-l-valineC8H17NO2Ee = 100%[α]D18.9=+17.9 (c 0.10, EtOH)Source of chirality: l-valineAbsolute configuration: (S)

N-Methyl-N-propyl-l-alanineC7H15NO2Ee = 99%[α]D20.3=+3.2 (c 0.25, EtOH)Source of chirality: l-alanineAbsolute configuration: (S)

N-Butyl-N-methyl-l-alanineC8H17NO2Ee = 55%[α]D19.8=+3.2 (c 0.50, EtOH)Source of chirality: l-alanineAbsolute configuration: (S)