A Convenient Method for the Preparation of 4-Hydroxy-2-methyl-1-oxo-1,2-dihydroisoquinoline-3-carboxylic Acid Derivatives

Abstract

An improved method for the synthesis of 4-hydroxy-2-methyl-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid derivatives is described. The synthetic route involves initial phthalic anhydride aminolysis with alkylaminoacetic acid derivatives, further esterification with diazomethane and final heterocyclization of the phthalamic ester intermediates by alkoxide-induced Dieckmann condensation. The best yields are reached for esters and N,N-disubstituted carboxamides.

Key words

heterocycles - isoquinolinones - cyclization - lactams - enols

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6

Ease of trans-esterification is related to the presence of an electron-withdrawing group at the α-position to the ester (ref. 7) and it was also observed in Dieckmann cyclizations which lead to hydroxy derivatives of related heterocycles (ref. 8).

9

This fact is related to the acid character of aniline hydrogen in phthalamic ester 2c which would allow its deprotonation in basic medium, thus resulting in a less probable formation of the carbanion necessary for the heterocyclization. A similar behavior was observed in the alkoxide promoted cyclization of compounds structurally related to 2c (ref. 3a).

10

Lombardino (ref. 2a) describes the reaction product as a solid, formula: C₁₇H₁₄N₂O₃·0.5H₂O, mp 195-197 °C.

11

The nonresolved multiplicity of the methylene and methyl signals is related to stereochemical features of this type of amides: partial double bond character of CO-N amide bond and/or the diastereotopicity of the methylene hydrogens associated with the presence of a chiral axis (ref. 4a).