A Concise Synthesis of Sterically Hindered 3-Amino-2-Oxindoles

Abstract

A new method for the synthesis of 3-alkyl-3-amino-2-oxindoles is reported. These compounds are prepared in a 3-step procedure using a base-mediated nucleophilic addition of benz­ylidene-imine protected α-aminoesters to 2-nitrofluorobenzene as the key step. The process provides a variety of 3-alkyl-3-amino-2-oxindole analogs in yields of 1-24%. Yields are highest with alanine, phenylalanine and 2-pyridylalanine as the amino acid starting materials, while 3-pyridylalanine and O-methyltyrosine are less efficiently arylated. Sterically hindered amino acids such as valine and phenylglycine are for all practical purposes, not substrates for the key nucleophilic substitution reaction. The resulting 3-alkyl-3-amino-2-oxindoles are important intermediates for the preparation of drug-like substances. The conversion of alanine ethyl ester to 3-amino-3-methyl-2-oxindole is described.

Key words

alkaloid - amino acid - arylation - nucleophilic aromatic substitution - steric hindrance - oxindole

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3

Upon treatment with a variety of bases (tertiary amine or inorganic), the gray-colored solution turned immediately purple. TLC and HPLC analysis indicated that very little if any 3-amino-2-oxindole remained.