The Synthesis of New Spirolactones from Substituted Isatins

Abstract

Abstract. Interaction of N-ethyl isatin 3 with dimethyl acetylenedicarboxylate in the presence triphenylphosphine has led to good selectivity of methyl 1'-ethyl-4-methoxy-2',5-dioxo-5H-spiro[furan-2,3'-indoline]-3-carboxylate 4 formation. Similar yields of spirolactones 6,8 were obtained by addition of dimethyl acetylenedicarboxylate to 5-bromo functionalized isatins 5,7. However, reaction of N-butyl isatin 9 resulted in formation of an inseparable mixture of compounds. Treatment of N-benzyl isatin 10 and dimethyl acetylenedicarboxylate with triphenylphosphine proceeded with reduced selectivity of the spirooxindole 11 formation.Keywords: spirolactones, isatins, triphenylphosphine, dimethyl acetylenedicarboxylate. IntroductionThe widespread distribution of butenolides in naturally occurring [1-3] and synthetic bioactive substances strongly motivate an interest for improving the methodology of the selective synthesis of butenolide functionalized spirooxindoles in high yield [4,5]. Such developments are of interest not only for the possible total synthesis of therapeutically useful spirooxindoles [6][7][8][9][10][11][12][13][14][15], but also for the preparation of synthetic analogs [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] in order to improve our knowledge in structure-activity relationships [12-14, 31, 32]. So-called butenolide functionalized spirooxindoles 1 provide the most interesting subject for synthetic investigations in view of the large and ever increasing number of the members of this family which have furan-2(5H)-one 2 as a building block (Scheme 1).

Natural and Synthetic Spirobutenolides and Spirobutyrolactones

“…In this strategy, treatment of dimethyl acetylenedicarboxylate and N-substituted isatin with triphenylphosphine in the presence of DCM as solvent yielded spirooxindoles (Scheme 44). [94]…”

Synthesis of Highly Functionalized Spirobutenolides via a Nitroalkane-Mediated Ring Contraction of 2-Oxobenzo[h]chromenes through Denitration

“…A three-component condensation reaction of primary amines, dialkyl acetylenedicarboxylates, and 1,3-dimethylalloxan afforded oxaspirobutanolides . N. Sucman et al prepared butenolide-functionalized spirooxindoles by the reaction of N-substituted isatin with dimethyl acetylenedicarboxylate in the presence of triphenylphosphine . A gold-catalyzed approach has been established for constructing spirobutenolides from ( Z )-enynols, having a cyclic substituent at the C-1 position .…”

“…14 N. Sucman et al prepared butenolide-functionalized spirooxindoles by the reaction of N-substituted isatin with dimethyl acetylenedicarboxylate in the presence of triphenylphosphine. 15 A gold-catalyzed approach has been established for constructing spirobutenolides from (Z)-enynols, having a cyclic substituent at the C-1 position. 16 Hejmanowska et al developed a novel approach to construct spirobutanolides via a trienamine-mediated [4+2]cycloaddition reaction of (E)-3-alkylidene-5-arylfuran-2(3H)ones and 2,4-dienals.…”