Carbene-Catalyzed Tandem Imine Umpolung-Intramolecular Aza-Conjugate Addition-Oxidation to Access N-Substituted Isoindolinones.

Herein, we have described a novel N-heterocyclic carbene (NHC)-catalyzed synthesis of N-substituted isoindolinone acetates. The presented transformation proceeds through NHC-catalyzed tandem imine umpolung-intramolecular aza-Michael addition followed by oxidation, while molecular oxygen in air acts as a sole oxidant. Atom efficiency, operational simplicity, large-scale syntheses, and mild reaction conditions are the salient features of this method. Mechanistic studies were indicative of the necessity of molecular oxygen in air as oxidant for the conversion of imine to amide.

Design and development of intramolecular doubly vinylogous Michael addition to access 3-aryl substituted 2-alkenyl-benzofurans and -indoles.

Herein, we have disclosed a rare example of an intramolecular doubly vinylogous Michael addition (DVMA). The reaction design exploits the innate reactivity of ortho-heteroatom substituted para-quinone methide (p-QM) derivatives. The sequential reaction of p-QMs and activated allyl halides proceeds through heteroatom-allylation, DVMA and oxidation to furnish a diverse range of 2-alkenyl benzofuran and 2-alkenyl indole derivatives in high yields.

Diaryl ether derivative inhibits GPX4 expression levels to induce ferroptosis in thyroid cancer cells.

Papillary thyroid carcinoma contributes to about 80% of the total thyroid cancer cases. BRAFV600E is a frequently occurring mutation in PTCs. Although several BRAF inhibitors are available, many thyroid cancer patients acquire resistance to BRAF inhibitors. Therefore, new targets and drugs need to be identified as therapies. Ferroptosis is a recently discovered type of cell death, and inhibiting glutathione peroxidase 4 (GPX4) using small molecules was found to trigger ferroptosis. But it is unknown whether inhibiting GPX4 renders thyroid cancer cells susceptible to ferroptosis. To identify novel GPX4 inhibitors, we focused on our previously reported cohort of diaryl ether and dibenzoxepine molecules. In this study, we asked whether diaryl ether and dibenzoxepine derivatives trigger ferroptosis in thyroid cancer cells. To answer this question, we screened diaryl ether and dibenzoxepine derivatives in cell-based assays and performed mechanism of action studies. We found that a diaryl ether derivative, 16 decreased thyroid cell proliferation and triggered ferroptosis by inhibiting GPX4 expression levels. Molecular modeling and dynamics simulations showed that 16 binds to the active site of GPX4. Upon deciphering the mode of 16-induced ferroptosis, we found that 16 treatments decrease mitochondrial polarization and reduce mitochondrial respiration similar to a ferroptosis inducer, RSL3. We conclude that the diaryl ether derivative, 16 inhibits GPX4 expression levels to induce ferroptosis in thyroid cancer cells. Based on our observations, we suggest that 16 can be lead-optimized and developed as a ferroptosis-inducing agent to treat thyroid cancers.

Recent advances in the tandem copper-catalyzed Ullmann-Goldberg N-arylation-cyclization strategies.

N-Aryl bond formation under copper catalysis has played a pivotal role and has been extensively used as a key step in the total syntheses of several therapeutic molecules. The construction of fused N-heterocycles remains a flourishing area of research because of their potential importance in drug discovery research and functional materials. On the other hand, tandem reactions provide facile ways to access complex organic molecules by reducing the synthetic steps. This review article provides a detailed overview of the tandem reactions developed in the past two decades, comprising N-arylation-cyclization strategies, including mechanistic aspects, driven by copper catalysts to furnish biologically significant fused N-heterocyclic moieties. The protocols described enlighten the prominence of the copper-catalyzed N-arylation-cyclization tandem strategies; exploration in this direction may open new avenues, inspire the design of new and creative tandem reaction strategies, and may unveil novel transformations with unprecedented reaction mechanisms.

Tandem aza-Michael addition-vinylogous aldol condensation: synthesis of N-bridged pyridine fused quinolones.

Herein, we present a tandem aza-Michael addition-vinylogous aldol condensation strategy for the synthesis of N-bridged pyridine fused quinolone derivatives from quinolones and ynones. The presented tandem transformation features the construction of C-N and CC bonds in a single operation, under transition metal-free conditions. The wide substrate scope and gram scale synthesis of pyridine fused quinolone derivatives expand the synthetic value of the presented protocol.

Tandem copper catalyzed regioselective N-arylation-amidation: synthesis of angularly fused dihydroimidazoquinazolinones and the anticancer agent TIC10/ONC201.

Herein, we present a copper-catalyzed tandem reaction of 2-aminoimidazolines and ortho-halo(hetero)aryl carboxylic acids that causes the regioselective formation of angularly fused tricyclic 1,2-dihydroimidazo[1,2-a]quinazolin-5(4H)-one derivatives. The reaction involved in the construction of the core six-membered pyrimidone moiety proceeded via regioselective N-arylation-condensation. The presented protocol been successfully applied to accomplish the total synthesis of TIC10/ONC201, which is an active angular isomer acting as a tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL): a sought after anticancer clinical agent.

N-Heterocyclic carbene (NHC)-catalyzed intramolecular benzoin condensation-oxidation.

NHC-Catalyzed intramolecular benzoin condensation-oxidation is developed for the expedient synthesis of diverse cyclic 1,2-diketones incorporated in dibenzo-fused seven-membered heterocycles in good to excellent yields, under ambient conditions. The presented carbene-catalyzed transformation appears to proceed through the benzoin intermediate followed by aerobic oxidation.

Tandem Copper-Catalyzed Regioselective N-Arylation-Aza-Michael Addition: Synthesis of Tetracyclic 5H-Benzothiazolo[3,2-a]quinazoline Derivatives.

A copper-catalyzed tandem process integrating regioselective N-arylation, followed by aza-Michael addition, is disclosed using 2-aminobenzothiazoles and ortho-halo cinnamic acid congeners. This process generated diverse tetracyclic 5H-benzothiazolo[3,2-a]quinazoline derivatives in moderate to good yields. The present tandem reaction appears to proceed through concomitant ring opening of 2-aminobenzothiazole and S-arylation to give the ortho-cyanamide-substituted diaryl thioether intermediate. The thus generated intermediate likely undergoes an unprecedented Truce-Smiles-type rearrangement involving S- to N-aryl migration, followed by reformation of the thiazole ring and intramolecular aza-Michael addition to furnish the title products.

The base-free van Leusen reaction of cyclic imines on water: synthesis of N-fused imidazo 6,11-dihydro ß-carboline derivatives.

Construction of imidazoles has been demonstrated on water under base-free conditions. The reaction of dihydro ß-carboline imines and p-toluenesulfonylmethyl isocyanides furnished the corresponding substituted N-fused imidazo 6,11-dihydro ß-carboline derivatives in very good yields under ambient conditions. The use of deuterium oxide (D2O) as a solvent enabled the incorporation of deuterium isotopes in the imidazole ring.

Tandem Aza Michael Addition-Vinylogous Nitroaldol Condensation: Construction of Highly Substituted N-Fused 3-Nitropyrazolopyridines.

A base-mediated tandem aza-Michael addition-vinylogous nitroaldol condensation has been described between 3,5-dialkyl 4-nitropyrazoles and alkynyl ketones/aldehydes. This transition metal-free atom economical transformation occurred via C-N and C═C bond formations in one step with the elimination of water. The construction of a variety of highly substituted N-fused 3-nitropyrazolopyridine derivatives has been demonstrated with good yields. Good to excellent regioselectivities have been achieved with unsymmetrically substituted 4-nitropyrazoles.

Copper-Catalyzed Tandem O-Arylation-Oxidative Cross Coupling: Synthesis of Chromone Fused Pyrazoles.

Intermolecular tandem copper-catalyzed O-arylation-oxidative acylation (cross dehydrogenative coupling-CDC) has been developed under air as an oxidant. The reaction between 2,4-dihydro-3H-pyrazol-3-ones and ortho-halo aryl carboxaldehydes furnished the corresponding chromone fused pyrazoles, in a straightforward manner. The synthetic utility of the presented tandem catalysis has been demonstrated with the synthesis of an A2-subtype selective adenosine receptor antagonist in only two steps.

Ruthenium Phosphine-Pyridone Catalyzed Cross-Coupling of Alcohols To form α-Alkylated Ketones.

An efficient and green route to access diverse functionalized ketones via dehydrogenative-dehydrative cross-coupling of primary and secondary alcohols is demonstrated. Selective and tunable formation of ketones or alcohols is catalyzed by a recently developed proton responsive ruthenium phosphine-pyridone complex. Light alcohols such as ethanol could be used as alkylating agents in this methodology. Moreover, selective tandem double alkylation of isopropanol is achieved by sequential addition of different alcohols.

Gold(iii)-catalyzed synthesis of aroylbenzo[b]oxepin-3-ones from ortho-O-propargyl-1-one substituted arylaldehydes.

An efficient gold-catalyzed intramolecular cyclization of ortho-O-propargyl-1-one substituted arylaldehydes has been achieved for the generation of substituted aroylbenzo[b]oxepin-3-one derivatives in moderate to good yields. This synthetic transformation proceeds via gold-catalysed oxidation of the internal alkyne moiety followed by an intramolecular condensation leading to seven-membered oxacycles.

Gold-Catalyzed Intramolecular Cyclization of N-Propargylic ß-Enaminones for the Synthesis of 1,4-Oxazepine Derivatives.

An efficient and mild one-pot, gold-catalyzed intramolecular cyclization of N-propargylic ß-enaminones has been achieved for the generation of 1,4-oxazepine derivatives. This synthetic transformation tolerates a range of substituted N-propargylic ß-enaminones in moderate to good yields.

Tandem copper (Cu) catalysed N-arylation-vinylogous nitroaldol condensation of 3,5-disubstituted 4-nitropyrazoles.

A tandem process involving copper catalysed N-arylation and vinylogous nitroaldol condensation is described. The reaction of 3,5-dialkyl substituted 4-nitropyrazoles and ortho-halo substituted (hetero)aryl aldehydes or ketones furnished 3-nitropyrazolo[1,5-a]quinoline and heteroaryl-fused 3-nitropyrazolo[1,5-a]pyridine derivatives in moderate to high yields.

Catalytic enantioselective addition of isocyanoacetate to 3-methyl-4-nitro-5-styrylisoxazoles under phase transfer catalysis conditions.

The reaction between 3-methyl-4-nitro-5-styrylisoxazoles and ethyl isocyanoacetate proceeded under phase transfer catalysis to give enantioenriched monoadducts in high enantiomeric excess (up to 99% ee). The resulting adducts were subsequently cyclised to give 2,3-dihydropyrroles and substituted pyrrolidines in identical high ees and as a single diastereoisomer.

Reaction of ß-enaminones and acetylene dicarboxylates: synthesis of substituted 1,2-dihydropyridinones.

Synthesis of substituted 1,2-dihydropyridinones is described in a one pot reaction of ß-enaminones and acetylene dicarboxylates where new C-C and C-N bonds were formed. The title compounds were obtained in moderate to good yields.

Gold-catalysed cyclisation of N-propargylic ß-enaminones to form 3-methylene-1-pyrroline derivatives.

A gold(I) catalysed reaction between N-propargylic ß-enaminones and arynes was developed to access 3-methylene-1-pyrrolines. The title compounds were obtained in 57-78% yields. This reaction is useful for the generation of substituted 1-pyrrolines exhibiting significant molecular complexity.

NHC-Catalyzed Formal [4 + 2] Annulation of o-Formyl-Tethered Michael Acceptors and Ynones to Access Highly Functionalized Naphthalene Derivatives.

Herein we demonstrate a novel organocatalytic method to access multifunctionalized naphthalenes via an NHC-catalyzed reaction of ynones and o-formyl-tethered Michael acceptors. The presented method proceeds through an intermolecular Stetter reaction-cyclization-aromatization cascade and represents a rare example of organocatalytic benzannulation for the synthesis of substituted arenes by using ynone as a two-carbon synthon. The current method has broad substrate scope; postsynthetic transformations and gram-scale syntheses highlight the practicality of the displayed methodology.

Convenient methods for the synthesis of chiral amino alcohols and amines.

Simple, convenient methods have been developed using readily available, easy-to-handle reagents to access a variety of chiral amino alcohols and amines, which have considerable potential for applications in asymmetric organic transformations. Scholars from this laboratory in India have made significant contributions to this field, which is the subject of the current review.