Product Selectivity Control in the Brønsted Acid-Mediated Reactions with 2-Alkynylanilines.

Brønsted acid-catalysed/mediated reactions of the 2-alkynylanilines are reported. While metal-catalysed reactions of these valuable building blocks have led to the establishment of robust protocols for the selective, diverse-oriented syntheses of significant heterocyclic derivatives, we here demonstrate the practical advantages of an alternative methodology under metal-free conditions. Our investigation into the key factors influencing the product selectivity in Brønsted acid-catalysed/mediated reactions of 2-alkynylanilines reveals that different reaction pathways can be directed towards the formation of diverse valuable products by simply choosing appropriate reaction conditions. The origins of chemo- and regioselectivity switching have been explored through Density Functional Theory (DFT) calculations.

A [3+3] Aldol-SNAr-Dehydration Approach to 2-Naphthol and 7-Hydroxyquinoline Derivatives.

A one-pot [3+3] aldol-SNAr-dehydration annulation sequence was utilized to fuse hindered phenols onto aromatic substrates. The transformation joins doubly activated 1,3-disubstituted acetone derivatives (dinucleophiles) with C5-activated 2-fluorobenzaldehyde SNAr acceptors (dielectrophiles) in the presence of K2CO3 in DMF at 65-70 °C to form polysubstituted 2-naphthols and 7-hydroxyquinolines. The reaction is regioselective in adding the most stable anionic center to the aldehyde followed by SNAr closure of the less stabilized anion to the electron-deficient aromatic ring. Twenty-seven examples are reported, and a probable mechanism is presented. In two cases where SNAr activation on the acceptor ring was lower (a C5 trifluoromethyl group on the aromatic ring or a 2-fluoropyridine), diethyl 1,3-acetonedicarboxylate initiated an interesting Grob-type fragmentation to give cinnamate esters as the products.

Synthesis of Nitrogen-Containing Heterocyclic Scaffolds through Sequential Reactions of Aminoalkynes with Carbonyls.

Sequential reactions of aminoalkynes represent a powerful tool to easily assembly biologically important polyfunctionalized nitrogen heterocyclic scaffolds. Metal catalysis often plays a key role in terms of selectivity, efficiency, atom economy, and green chemistry of these sequential approaches. This review examines the existing literature on the applications of reactions of aminoalkynes with carbonyls, which are emerging for their synthetic potential. Aspects concerning the features of the starting reagents, the catalytic systems, alternative reaction conditions, pathways and possible intermediates are provided.

Asymmetric Synthesis of N-Substituted 1,2-Amino Alcohols from Simple Aldehydes and Amines by One-Pot Sequential Enzymatic Hydroxymethylation and Asymmetric Reductive Amination.

The chiral N-substituted 1,2-amino alcohol motif is found in many natural and synthetic bioactive compounds. In this study, enzymatic asymmetric reductive amination of α-hydroxymethyl ketones with enantiocomplementary imine reductases (IREDs) enabled the synthesis of chiral N-substituted 1,2-amino alcohols with excellent ee values (91-99 %) in moderate to high yields (41-84 %). Furthermore, a one-pot, two-step enzymatic process involving benzaldehyde lyase-catalyzed hydroxymethylation of aldehydes and subsequent asymmetric reductive amination was developed, offering an environmentally friendly and economical way to produce N-substituted 1,2-amino alcohols from readily available simple aldehydes and amines. This methodology was then applied to rapidly access a key synthetic intermediate of anti-malaria and cytotoxic tetrahydroquinoline alkaloids.

Mimicking natural strategies to create multi-environment enzymatic reactors: From natural cell compartments to artificial polyelectrolyte reactors.

Engineering microenvironments for sequential enzymatic reactions has attracted specific interest within different fields of research as an effective strategy to improve the catalytic performance of enzymes. While in industry most enzymatic reactions occur in a single compartment carrier, living cells are however able to conduct multiple reactions simultaneously within confined sub-compartments, or organelles. Engineering multi-compartments with regulated environments and transformation properties enhances enzyme activity and stability and thus increases the overall yield of final products. In this review, we discuss current and potential methods to fabricate artificial cells for sequential enzymatic reactions, which are inspired by mechanisms and metabolic pathways developed by living cells. We aim to advance the understanding of living cell complexity and its compartmentalization and present solutions to mimic these processes in vitro. Particular attention has been given to layer-by-layer assembly of polyelectrolytes for developing multi-compartments. We hope this review paves the way for the next steps toward engineering of smart artificial multi-compartments with adoptive stimuli-responsive properties, mimicking living cells to improve catalytic properties and efficiency of the enzymes and enhance their stability.

A Modular and Practical Synthesis of Zwitterionic Hydrogels through Sequential Amine-Epoxy "Click" Chemistry and N-Alkylation Reaction.

In this work, the amine-epoxy "click" reaction is shown to be a valuable general tool in the synthesis of reactive hydrogels. The practicality of this reaction arises due to its catalyst-free nature, its operation in water, and commercial availability of a large variety of amine and epoxide molecules that can serve as hydrophilic network precursors. Therefore, hydrogels can be prepared in a modular fashion through a simple mixing of the precursors in water and used as produced (without requiring any post-synthesis purification step). The gelation behavior and final hydrogel properties depend upon the molecular weight of the precursors and can be changed as per the requirement. A post-synthesis modification through alkylation at the nitrogen atom of the newly formed ß-hydroxyl amine linkages allows for functionalizing the hydrogels. For example, ring-opening reaction of cyclic sulfonic ester gives rise to surfaces with a zwitterionic character. Finally, the established gelation chemistry can be combined with soft lithography techniques such as micromolding in capillaries (MIMIC) to obtain hydrogel microstructures.

Homophtalonitrile for Multicomponent Reactions: Syntheses and Optical Properties of o-Cyanophenyl- or Indol-3-yl-Substituted Chromeno[2,3-c]isoquinolin-5-Amines.

Malononitrile is a useful reagent for multicomponent reactions with hundreds of methods developed. In this paper, we suggest α-(cyano)-o-tolunitrile (homophtalonitrile) to work as a vinylogous malononitrile. Thus, a organocatalytic pseudo-three-component reaction of homopthalonitrile (2 equiv) and o-hydroxybenzaldehyde, leading to the diastereoselective formation of 5-amino-12H-chromeno[2,3-c]isoquinolin-12-yl)(cyano)methyl)benzonitriles, was discovered. The possibility to employ other nucleophiles was demonstrated for indoles, and a sequential three-component reaction of homophtalonitrile, o-hydroxybenzaldehyde, and (aza)indole, giving 12-(1H-Indol-3-yl)-12H-chromeno[2,3-c]isoquinolin-5-amines, was developed. The photophysical properties of the synthesized compounds have been studied, revealing high fluorescence quantum yields (42-70 %) for indol-3-yl substituted 12H-chromeno[2,3-c]isoquinolin-5-amines and reversible fluorescence quenching under acidic conditions.

Microchemical Plant in a Liquid Droplet: Plasmonic Liquid Marble for Sequential Reactions and Attomole Detection of Toxin at Microliter Scale.

Miniaturizing the continuous multistep operations of a factory into a microchemical plant offers a safe and cost-effective approach to promote high-throughput screening in drug development and enforcement of industrial/environmental safety. While particle-assembled microdroplets in the form of liquid marble are ideal as microchemical plant, these platforms are mainly restricted to single-step reactions and limited to ex situ reaction monitoring. Herein, we utilize plasmonic liquid marble (PLM), formed by encapsulating liquid droplet with Ag nanocubes, to address these issues and demonstrate it as an ideal microchemical plant to conduct reaction-and-detection sequences on-demand in a nondisruptive manner. Utilizing a two-step azo-dye formation as our model reaction, our microchemical plant allows rapid and efficient diazotization of nitroaniline to form diazonium nitrobenzene, followed by the azo coupling of this intermediate with target aromatic compound to yield azo-dye. These molecular events are tracked in situ via SERS measurement through the plasmonic shell and further verified with in silico investigation. Furthermore, we apply our microchemical plant for ultrasensitive SERS detection and quantification of bisphenol A (BPA) with detection limit down to 10 amol, which is 50 000-fold lower than the BPA safety limit. Together with the protections offered by plasmonic shell against external environments, these collective advantages empower PLM as a multifunctional microchemical plant to facilitate small-volume testing and optimization of processes relevant in industrial and research contexts.

Synthesis and anti-cancer activities of new sulfonamides 4-substituted-triazolyl nucleosides.

Nucleoside analogues are among the most known drugs commonly used in antiviral and anticancer chemotherapies. Among them, those featuring a five-membered ring nucleobase are of utmost interest such as the anti-cancer agent AICAR or the anti-viral drug ribavirin. Despite its low activity in vitro in different cell lines, AICAR is under clinical development for several pathologies, thanks to its original mode of action. Indeed, AICAR induced autophagy cell death and is able, following this mechanism, to circumvent resistance to apoptotic drugs including kinase inhibitors currently on the market. To improve the activity of AICAR, we report herein an efficient synthesis of new series of sulfonamide-4-substituted-1,2,3-triazolyl nucleosides using a Cu-catalyzed 1,3-dipolar cycloaddition. All these molecules have been fully characterized and evaluated against two aggressive tumor cell lines, RCC4 and MDA-MB-231. Among them, nucleoside analogue 5i belonging to the ribose series was found to be 19 to 66-fold more active than AICAR. Western blot analyses on RCC4 cells showed that 5i displayed an interesting mode of action by inducing both apoptosis and autophagy cell death, making therefore this class of molecules highly promising for further hit-to-lead optimization.

Comparative Study of Eis-like Enzymes from Pathogenic and Nonpathogenic Bacteria.

Antibiotic resistance is a growing problem worldwide. Of particular importance is the resistance of Mycobacterium tuberculosis (Mtb) to currently available antibiotics used in the treatment of infected patients. Up-regulation of an aminoglycoside (AG) acetyltransferase, the enhanced intracellular survival (Eis) protein of Mtb (Eis_Mtb), is responsible for resistance to the second-line injectable drug kanamycin A in a number of Mtb clinical isolates. This acetyltransferase is known to modify AGs, not at a single position, as usual for this type of enzyme, but at multiple amine sites. We identified, using in silico techniques, 22 homologues from a wide variety of bacteria, that we then cloned, purified, and biochemically studied. From the selected Eis homologues, 7 showed the ability to modify AGs to various degrees and displayed both similarities and differences when compared to Eis_Mtb. In addition, an inhibitor proved to be active against all homologues tested. Our findings show that this family of acetyltransferase enzymes exists in both mycobacteria and non-mycobacteria and in both pathogenic and nonpathogenic species. The bacterial strains described herein should be monitored for rising resistance rates to AGs.

Chemoselective reductive nucleophilic addition to tertiary amides, secondary amides, and N-methoxyamides.

As the complexity of targeted molecules increases in modern organic synthesis, chemoselectivity is recognized as an important factor in the development of new methodologies. Chemoselective nucleophilic addition to amide carbonyl centers is a challenge because classical methods require harsh reaction conditions to overcome the poor electrophilicity of the amide carbonyl group. We have successfully developed a reductive nucleophilic addition of mild nucleophiles to tertiary amides, secondary amides, and N-methoxyamides that uses the Schwartz reagent [Cp2 ZrHCl]. The reaction took place in a highly chemoselective fashion in the presence of a variety of sensitive functional groups, such as methyl esters, which conventionally require protection prior to nucleophilic addition. The reaction will be applicable to the concise synthesis of complex natural alkaloids from readily available amide groups.

Sequential one-pot addition of excess aryl-Grignard reagents and electrophiles to O-alkyl thioformates.

The sequential addition of aromatic Grignard reagents to O-alkyl thioformates proceeded to completion within 30 s to give aryl benzylic sulfanes in good yields. This reaction may begin with the nucleophilic attack of the Grignard reagent onto the carbon atom of the O-alkyl thioformates, followed by the elimination of ROMgBr to generate aromatic thioaldehydes, which then react with a second molecule of the Grignard reagent at the sulfur atom to form arylsulfanyl benzylic Grignard reagents. To confirm the generation of aromatic thioaldehydes, the reaction between O-alkyl thioformates and phenyl Grignard reagent was carried out in the presence of cyclopentadiene. As a result, hetero-Diels-Alder adducts of the thioaldehyde and the diene were formed. The treatment of a mixture of the thioformate and phenyl Grignard reagent with iodine gave 1,2-bis(phenylsulfanyl)-1,2-diphenyl ethane as a product, which indicated the formation of arylsulfanyl benzylic Grignard reagents in the reaction mixture. When electrophiles were added to the Grignard reagents that were generated in situ, four-component coupling products, that is, O-alkyl thioformates, two molecules of Grignard reagents, and electrophiles, were obtained in moderate-to-good yields. The use of silyl chloride or allylic bromides gave the adducts within 5 min, whereas the reaction with benzylic halides required more than 30 min. The addition to carbonyl compounds was complete within 1 min and the use of lithium bromide as an additive enhanced the yields of the four-component coupling products. Finally, oxiranes and imines also participated in the coupling reaction.