New synthesis of the dihydroindolizinoquinoline system by intramolecular cyclization of sulfur ylide

Abstract

An efficient method is proposed for obtaining the dihydroindolizinoquinoline system by intramolecular cyclization of keto-stabilized sulfonium ylide obtained from β-alanine and quinoline-2,3-dicarboxylic acid anhydride.Keywords: keto-stabilized sulfur ylide, 6-methylthio-8,9-dihydroindolizino[1,2-b]quinoline-7,11-dione, intramolecular cyclization.The indolizinoquinoline system is a structural fragment of certain natural compounds, such as alkaloid camptothecin and its closest analogs, which possess anticancer activity [1-3]. Previously we discovered a new intramolecular cyclization of sulfur ylides [4-6], synthesized from substituted α-and β-amino acids [7], which opened a convenient route for constructing nitrogen-containing condensed heterocyclic systems. In the present work a method is proposed for the synthesis of 6-methylthio-8,9-dihydroindolizino[1,2-b]quinoline-7,11-dione (1) by the cyclization of sulfur ylide 2 containing quinoline-2,3-dicarboximide fragment.Sulfonium ylide 2 was obtained by the procedure of [7] from quinoline-2,3-dicarboxylic acid anhydride (3) [8] and β-alanine. N-Substituted β-alanine 4 was converted into diazo ketone 5. The yield of diazo ketone 5 synthesized by interacting CH 2 N 2 with acid 4 chloride [7] was 50%. On using the mixed anhydride formed by interacting acid 4 with methyl chloroformate the yield of diazo ketone 5 became practically quantitative and the obtained diazo ketone did not require additional purification. On sequential treatment of diazo ketone with 48% HBr solution and Me 2 S sulfonium salt 6 is formed, the deprotonation of which with a mixture of saturated K 2 CO 3 solution and 12.5 N NaOH gives ylide 2 in 91% yield. Heating ylide 2 in the presence of equimolar quantity of benzoic acid in toluene solution leads to 6-methylthio-8,9-dihydroindolizino[1,2-b]quinoline-7,11-dione (1) in 90% yield (Scheme 1).We investigated the possibility of obtaining compound 1 by the one-pot method directly from diazo ketone 5. Ylide 2 is formed on catalytic decomposition of diazo ketone 5 with rhodium acetate in the presence of Me 2 S at 40°C. The ylide, without isolation from the reaction mixture, becomes involved in an intramolecular cyclization giving product 1 in 60% yield.The intramolecular cyclization of sulfonium ylide 2 proceeds regioselectively with the formation of one isomer of 1. The nucleophilic character of sulfur ylide enables the suggestion that the cyclization comprises interaction of the carbanionic center with the electron-deficient carboximide carbon atom located in the position β to the nitrogen atom of the pyridine ring. In the 13 C NMR spectrum of compound 1 taken in modulation mode at the CH constant the signals from the C (8) and C (9) atoms are defined unequivocally, being displayed as two triplets at 36.90 and 35.95 ppm respectively, and the singlets of the carbonyl carbon atoms were at 190.78 and