Indium(III)‐catalyzed Aza‐Conia‐Ene Reaction for the Synthesis of Indolizines

Abstract

An ew indium(III)-catalyzed reaction fort he synthesis of as eries of indolizines caffolds has been developed. This methodologyw as highlye fficient, allowing al ow catalystl oading of 2mol %( down to 0.5 mol %) and rendering the products in high yields througha5-exo-dig aza-Conia-ene reaction.F urthermore, the possibility of incorporating an electrophile into the generatedpyrrolidone ring in aone-pot synergistic fashion was demonstrated. Finally,b ased on experimental observations, am echanism proposal was outlined.Indolizines represent the core structures of manyn atural products and pharmacologically activec ompounds such as anticancer,a ntibacterial, antifungal, anticholinergic, antihistaminic, antitubercular,c alcium-entry blockers, anda ntinflammatory agents. Indolizines also have applicationsi nm aterials cience as organic light-emitting devices,b iologicalm arkers,a nd dyes. [1] Thus, the development of synthetic methodologies to access these valuables caffolds hasattracted alot of attention.Various methodologiesh ave been reported starting from pyridine or pyrrole frameworks. [2] The classical synthesis is based on the venerable Scholtza nd Chichibabin reactions. [3] More recently,n ew methodologies basedo nd ipolar cycloadditions of pyridiniumy lides and cyclization with alkenyldiazoacetates have been reported. [3] Another approach to synthesize indolizines is through cycloisomerization reactions,b ased on the activation of an alkyne by am etal. Theser eactions require the use of transition metals such as Cu, Ag, Pd, Pt, or Au as catalysts, and sometimes the combinationo fm ore than one metal. [4] Thel oading of the metal varies from 1equiv to 4mol %, andi no nly two methodologies employing Au [5] was the loading decreased to 1-2 mol %, providingt he final products in good-to-moderate yields.The aforementioned metal-catalyzedc ycloisomerizations proceedt hrough a5 -endo-dig cyclization,i nw hich the nucleophilic pyridine attacks the alkyne coordinated to the metal. Surprisingly,t here are, to the best of our knowledge,n om etalcatalyzed 5-exo-dig cycloisomerization reactions for the synthesis of indolizines and pyrrolo-quinolines. Inspired by the success of 5-exo-dig cyclizations such as the Conia-ene reaction, [6] we envisioned an ew approach for the synthesis of indolizines and related/fused heterocycles through an aza-Conia-ene type reactiont hat would be complementary to the previousm ethodologies (Scheme 1, top).In the following, we present ar eaction concept fort he formationo fi ndolizines and pyrrolo-quinolinesb ased on an 5-exo-dig indium(III)-catalyzed aza-Conia-ene cyclizationr eaction (Scheme 1, bottom). [7] Initially,w etested the cycloisomerization of 2-(but-3-yn-1-yl)-quinoline 1a under InCl 3 catalysis in the presence of 0.5 equiv benzoica cid (BA) in dichloroethane, and to our delight product 2a was obtained in 66 %y ield after 3d (Table 1, entry 1). When the loading of BA was increased to 1equiv,p roduct 2a was obtainedi n9 2% yield in 2h (entry 2). The use of CH 3 CN a...

Hemoglobin‐Catalyzed Synthesis of Indolizines Under Mild Conditions

“…Traditional synthetic routes to indolizines mainly comprise the Scholtz or Chichibabin reactions. More recently, cycloaddition reactions (1,3‐dipolar cycloadditions), intramolecular cyclizations using acetic anhydride, formation of C3–C4 bond, formation of C1–C9 bond, and formation of C8–C9 bond have been reported . However, most of these methods suffer from some drawbacks, such as the formation of conjugate‐acid waste, narrow substrate scope, harsh reaction conditions, need for toxic transition‐metal catalysts and harmful organic solvents.…”

Recent Developments in the Cyclization of Alkynes and Nitrogen Compounds for the Synthesis of Indole Derivatives

“…In an example, indium(III) salts have been used as catalysts for the synthesis of fused indolizines 101 via Aza‐Conia‐Ene reactions using homopropargyl pyridines as substrates (Scheme 72). [151] The indolizines were obtained with a low In(OAc) 3 loading of 2 mol% in the presence of benzoic acid in DCE as a solvent at 60 °C. The reaction mechanism, proposed by the authors, involved the activation of alkyne by indium(III) catalyst followed by the nucleophilic nitrogen attack to give the vinylindium intermediate, which after deprotonation, protodemetalation, and aromatization gives the product (Scheme 72).…”

In(OTf)3-Catalyzed One-Pot Tandem Mannich and Conia-Ene Cyclization Reaction of N-Propargyl Amido Alcohols with 1,3-Dicarbonyl Compounds: An Approach To Construct Tetrahydro-1H-pyrrolo[2,1-a]isoindolone-1,1-dicarboxylate and Its Application

“…Zhang and co-workers have reported the synthesis of fused bicyclic scaffolds from acyclic β-ketoesters and alkynyl aldehydes via Nazarov and Conia-ene cyclization reaction . Aza-Conia-ene cyclization has also been used for the synthesis of indolizines . Cyclic N -acyliminium ions are versatile reaction intermediates for the synthesis of azabicyclic compounds .…”