Conversion of 4-Oxoproline Esters to 4-Substituted Pyrrole-2-carboxylic Acid Esters

Abstract

167During our study of the synthesis of several compounds using 4-hydroxyproline (1) as a starting material, 1) when a ptoluenesulfonyl (Ts, tosyl) group was introduced to the nitrogen atom of 1 by the Schotten-Baumann method employing TsCl and aqueous NaOH according to Portoghese's method 2) in order to obtain compound 2, thereby prolonging the reaction, we encountered a side reaction that caused the elimination of sulfinic acid and aromatization, giving pyrrole-2-carboxylic acid (3) (Chart 1). We therefore considered that the aromatization could be utilized for the synthesis of pyrrole-2-carboxylic acid derivatives such as methyl 4-methylpyrrole-2-carboxylate (4), which is a trail pheromone of Atta texana. [3][4][5][6] Although aromatizations of the N-tosylproline derivatives giving pyrrole-2-carboxylic acid derivatives, [7][8][9] as well as other syntheses of the pyrrole-2-carboxylic acid derivatives, [10][11][12] have been reported by many workers, synthesis of the pyrrole-2-carboxylic acid derivatives using 4-oxoproline derivatives has not been reported. Therefore, we performed alkylation and alkylidenaion of N-tosyl-4-oxoproline ester, followed by aromatization of the products to give 4-substituted proline-2-carboxylic acid esters 7 (Chart 2). This method made it possible to introduce not only a simple alkyl group but also an alkyl possessing a functional group into 4-position of the pyrrole-2-carboxylic acid derivatives.Thus we report here the conversion of 4-oxoproline esters 5 and 6 to the 4-substituted proline-2-carboxylic acid esters 7.Base Treatments of N-Tosyl-4-oxoproline Esters We chose the methyl and/or tert-butyl esters of N-tosyl-4-oxoproline 5 13) and 6 14) as substrates for the ketone reactions, and synthesized them from 1 according to the previously reported methods.2) Next, we attempted the base treatments of 5 and 6 using appropriate bases to cause enolization and aromatization. As a result, 4-hydroxypyrrole-2-carboxylic acid esters 8 and 9 were successfully obtained in 76% and 60% yields, respectively. Only the benzyl ester of 4-hydroxypyrrole-2-carboxylic acid 15) has been reported previously; 8 and 9 are new compounds (Chart 3). The Grignard Reactions of N-Tosyl-4-oxoproline Ester and Conversion into the Pyrrole DerivativesGrignard reactions were attempted with the tert-butyl ester of N-tosyl-4-oxoproline 6, in order to prevent the reaction at the ester moiety. When the Grignard reagent was employed without addition of other reagent, the by-products were remarkably formed and yields of the desired products were much lower (mixture of epimers Ͻ70%). In order to prevent the aldol reaction and the aromatization of 6, which seemed to be the side reactions, additions of CeCl 3 16,17) into the reaction systems were examined. Consequently, the numbers of the com- Conversion of 4-Oxoproline Esters to 4-Substituted Pyrrole-2-carboxylic Acid EstersYasushi ARAKAWA,* Naomi YAGI, Yukimi ARAKAWA, Ken-ichi TANAKA, and Shigeyuki YOSHIFUJI Faculty of Pharmaceutical Sciences, Hokuriku University; Kanagaw...