Multi-Component Reaction of Amines, Alkyl Propiolates, and Ninhydrin: An Efficient Protocol for the Synthesis of Tetrahydro-dihydroxy-oxoindeno[1,2-b]pyrrole Derivatives

Abstract

t h e s i s o f T e t r a h y d r o -d i h y d r o x y -o x o i n d e n o [ 1 , 2 -b ] p y r r o l e D e r i v a t i v e sAbstract: A new protocol for the synthesis of a series of tetrahydrodihydroxy-oxoindeno[1,2-b]pyrrole from simple primary amines, alkyl propiolates, and ninhydrin was developed. The key step in the synthesis is an efficient three-component reaction of an amine with an alkyl propiolate to give a 3-amino acrylate derivative, which then reacts with ninhydrin.Despite recent advances in molecular biology and the progress in combinatorial synthetic methodology, the rate of introduction of new pharmaceuticals has decreased markedly over the past two decades. 1a Structural diversity in a focused collection of potential therapeutics is believed to increase the positive hit rate. Most pharmaceuticals in use are still small synthetic organic molecules that often contain a heterocyclic ring. 1a-c However, the range of easily accessible and suitably functionalized heterocyclic building blocks for the synthesis of structurally diverse libraries is rather limited. The development of new, rapid, and clean synthetic routes toward focused libraries of such compounds is therefore of great importance to both medicinal and synthetic chemists. 1 Undoubtedly, the most efficient strategies involve multicomponent reactions (MCRs), which have become a powerful tool for the rapid introduction of molecular diversity. 2 Consequently, the design and development of MCRs for the generation of heterocycles have received increased interest. 2aPolyhydroxylated alkaloids are interesting heterocycles that can act as powerful and selective inhibitors of glycosidases and exhibit bactericidal, antidiabetic, and antiviral activities, 3,4 making these compounds good lead compounds for the development of new drugs for the treatment of viral infections, cancer, and diabetes. 3,4 Consequently, the development of general and facile methods for the synthesis of such compounds is an active field of research. 4-7 For example the tetrahydro-dihydroxy-oxoindeno[1,2-b]pyrrole system is of interest in connection with the search for potential oral hypoglycemic agents. 8As part of our general interest in MCRs, 9 our ongoing research programs in the area of heterocyclic compounds containing nitrogen, 9,10 and due to the resultant pharmacological interest in polyhydroxylated alkaloids, herein we report an efficient three-component method for the construction of new tetrahydro-dihydroxy-oxoindeno[1,2-b]pyrroles, via condensation of amines, alkyl propiolates, and ninhydrin (Scheme 1).In order to prove that b-aminoacrylates 5 exist as intermediates in this reaction, compound 5e (Z/E, 6:4) was synthesized separately by the condensation of benzyl amine and methyl propiolate, and then reacted with 3. The resulting product was identical to that formed in the three-component procedure.The reaction was carried out by the simple addition of one equivalent of primary amine to one equivalent of alkyl propiolate in water, followed by the addition of one equivale...

One-pot diastereoselective synthesis of new spiro indenoquinoxaline derivatives containing cyclopropane ring

“…The chalcones 1a-e were prepared by the reaction of indenoquinoxaline with acetophenones in a solvent free condition catalyzed by dimethylamine and then glacial acetic acid and HCl. 10,14 These chalcones reacted with hydrazine hydrate in toluene and then in situ with lead(IV) acetate (LTA or Pb(OAc) 4 ) to afford new spiro indenoquinoxaline-cyclopropane derivatives 2a-e and 3a-e (Scheme 3).…”

“…7 Many synthetic methods have been reported for the preparation of cyclopropanes such as intramolecular cyclization, addition of carbenes to olefins and Michael initiated ring closure (MIRC). 1,8 In this study along our pervious works on the synthesis of spiro indenoquinoxalines and other biologically active compounds, 9,10 we report a novel one-pot facile procedure for the synthesis of some spiro indenoquinoxaline-cyclopropane derivatives which directly prepared from chalcones of indenoquinoxaline.…”

One-Pot Synthesis of 1,8-Dioxo-octahydroxanthene Derivatives Using Zn(NO3)2 under Solvent-free Conditions

“…Recently, several improved methodologies have been developed that use triethylbenzyl ammonium chloride 10 , p-dodecyl benzenesulfonic acid 11 , phosphomolybdic acid supported on silica gel 12 , sulfonic acid on silica gel 13 , HClO 4 -SiO 2 14 and ZnO 15 among others. Previously, we have synthesized a number of heterocyclic compounds [16][17][18][19][20][21][22][23][24][25][26] .…”

Glutamic acid as an Efficient Catalyst for Synthesis of Dihydropyrimidinones

“…Glutamic acid has been used previously as a catalyst for synthesis of organic compound 17 , Previously, we have synthesized a number of heterocyclic compounds [18][19][20][21][22][23][24][25][26][27] . Herein we report glutamic acid a new catalyst for the synthesis of DHPMs at one pot reaction, environmentally friendly with high yields and easy separation (Scheme 1).…”