Selective Hydrogenation of Indolizines: An Expeditious Approach To Derive Tetrahydroindolizines and Indolizidines from Morita–Baylis–Hillman Adducts

In this study, we describe the hydrogenation of indolizines derived from Morita–Baylis–Hillman adducts. We demonstrate that functionalized tetrahydroindolizines and indolizidines can be prepared selectively, at low pressure, by simply adjusting the acidity of the medium. Using this simple and straightforward strategy, substituted tetrahydroindolizines and indolizidines were obtained diastereoselectively in high yield

Aqueous Morita–Baylis–Hillman Reaction of Unprotected Isatins with Cyclic Enones

The readily available bicyclic imidazolyl alcohol <b>1</b> is a unique catalyst for the aqueous Morita–Baylis–Hillman (MBH) reaction between unprotected isatins and cyclic enones that gives access to a variety of potentially very useful 3-substituted 3-hydroxy-2-oxindoles in an operationally simple, efficient, and environmentally friendly way. The hydroxyl group of the catalyst is believed to stabilize the betaine intermediate formed in the first step of the MBH reaction

Effects of novel acylhydrazones derived from 4-quinolone on the acetylcholinesterase activity and A<b>β</b>42 peptide fibrils formation

<p>Acetylcholinesterase inhibitors and compounds that trigger Aβ amyloid oligomerization and fibrillization represent an opportunity to discover new drug candidates to treat Alzheimer’s disease. In this work, we synthesized nine new acylhydrazones and a known one, both employing 3-carboethoxy-4-quinolone derivatives as starting materials with chemical yields ranging from 63% to 90%. We evaluated the effect of these compounds on the acetylcholinesterase (AChE) activity and the fibrillization of Aβ₄₂ peptide. Except for one acylhydrazone, the compounds exhibited good inhibitory effect on AChE (1.2 μM < IC₅₀ values < 17 μM). They also showed a significant decrease in the thioflavin-T fluorescence emission, suggesting an inhibitory effect on the Aβ₄₂ fibril formation.</p

Charge Tags for Most Comprehensive ESI-MS Monitoring of Morita–Baylis–Hillman (MBH)/<i>aza</i>-MBH Reactions: Solid Mechanistic View and the Dualistic Role of the Charge Tagged Acrylate

Neutral and charge tagged reagents were used to investigate the mechanism of the classical Morita–Baylis–Hillman (MBH) reaction as well as its <i>aza</i>-version using mass spectrometry with electrospray ionization (ESI-MS). The use of an acrylate (activated alkene) with a methylimidazolium ion as a charge tag eliminates the requirement for adding acids as ESI­(+) additives, which are normally used to favor protonation and therefore detection of reaction partners (reagents, intermediates, and products) by ESI­(+)-MS. For both charge tagged reactions (MBH/<i>aza</i>-MBH), most reactants, intermediates, and the final adducts were efficiently detected in the form of abundant doubly and singly charged ions. Characterization of the reactions partners was performed via both tandem mass spectrometry (ESI­(+)-MS/MS) and accurate <i>m</i>/<i>z</i> measurements. The charge tagged reactions also showed faster conversion rates when compare to the neutral reaction, indicating a dualistic role for the charge tagged acrylate. It acts as both the reagent and a cocatalyst due to the inherent ionic-coordination nature of the methylimidazolium ion, which stabilizes the zwitterionic intermediates and reagents through different types of coordination ion pairs. Hemiacetal intermediates for the rate-limiting proton transfer step were also intercepted and characterized for both classical and <i>aza</i>-MBH charge tagged reactions

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Morita–Baylis–Hillman Reaction: ESI-MS(/MS) Investigation with Charge Tags and Ionic Liquid Effect Origin Revealed by DFT Calculations

The use of a charge-tagged acrylate derivative bearing an imidazolium tag to study the Morita–Baylis–Hillman reaction via ESI-MS­(/MS) monitoring and the effect of such tag (imidazolium cations and ion pairs) over TSs is described. The ionic nature of the substrate was meant to facilitate ESI transfer to the gas phase for direct mass spectrometric analysis. The detection and characterization of charged intermediates has suggested major reaction pathways. DFT calculations considering the effect of a polar and protic solvent (methanol), of a polar and aprotic solvent (acetonitrile), and of no solvent (gas phase) were used to predict possible TSs through a common accepted intermediate. The controversial proton transfer step, which may proceed via Aggarwal’s or McQuade’s proposals, was evaluated. Calculations predicted the formation of electrostatic intermediate complexes with both the cation and anion when charge-tagged reagents are used. These complexes contribute to the positive ionic liquid effect, and based on the formation of these unique complexes, a rationale for the ionic liquid effect is proposed. These complexes also pointed to a plausible explanation for the positive ionic liquid effect observed in several reactions that are difficult to be carried out in organic solvents but have shown a beneficial effect when performed in ionic liquids

Morita–Baylis–Hillman Reaction: ESI-MS(/MS) Investigation with Charge Tags and Ionic Liquid Effect Origin Revealed by DFT Calculations

The use of a charge-tagged acrylate derivative bearing an imidazolium tag to study the Morita–Baylis–Hillman reaction via ESI-MS­(/MS) monitoring and the effect of such tag (imidazolium cations and ion pairs) over TSs is described. The ionic nature of the substrate was meant to facilitate ESI transfer to the gas phase for direct mass spectrometric analysis. The detection and characterization of charged intermediates has suggested major reaction pathways. DFT calculations considering the effect of a polar and protic solvent (methanol), of a polar and aprotic solvent (acetonitrile), and of no solvent (gas phase) were used to predict possible TSs through a common accepted intermediate. The controversial proton transfer step, which may proceed via Aggarwal’s or McQuade’s proposals, was evaluated. Calculations predicted the formation of electrostatic intermediate complexes with both the cation and anion when charge-tagged reagents are used. These complexes contribute to the positive ionic liquid effect, and based on the formation of these unique complexes, a rationale for the ionic liquid effect is proposed. These complexes also pointed to a plausible explanation for the positive ionic liquid effect observed in several reactions that are difficult to be carried out in organic solvents but have shown a beneficial effect when performed in ionic liquids

Diastereoselective Synthesis of Biologically Active Cyclopenta[<i>b</i>]indoles

The cyclopenta­[<i>b</i>]­indole motif is present in several natural and synthetic biologically active compounds, being directly responsible for the biological effects some of them present. We described herein a three step sequence for the synthesis of cyclopenta­[<i>b</i>]­indoles with a great structural diversity. The method is based on an oxidative Michael addition of suitable indoles on the double bond of Morita–Baylis–Hillman adducts mediated by a hypervalent iodine reagent (IBX) to form β-ketoesters, which were chemoselectively reduced with NaBH₄ in THF to give the corresponding β-hydroxy-esters. The diastereoisomeric mixture was then treated with a catalytic amount of triflic acid (20 mol %) to give cyclopenta­[<i>b</i>]­indoles with overall yields ranging from 8 to 73% (for 2 steps). The acid-catalyzed cyclization step gave the required heterocycles, via an intramolecular Friedel–Crafts reaction, with high diastereoselectivity, where only the <i>trans</i> product was observed. A mechanistic study monitored by ESI-(+)-MS was also conducted to collect evidence about the mechanism of this reaction. The new molecules herein synthesized were also evaluated against a panel of human cancer cells demonstrating a promising antitumoral profile