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.

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.

Sequential One-Pot Carbene-Catalyzed Intramolecular Stetter Reaction and Acid-Mediated Condensation: Access to Heteroatom Analogues of π-Extended Polyaromatic Hydrocarbons.

In this Letter, we disclose a simple and effective method to access a variety of phenanthro[9,10-b]furan and 1H-dibenzo[e,g]indole derivatives based on the design of a carbene-catalyzed intramolecular Stetter reaction followed by a Paal-Knorr reaction in one-pot. These compounds are a class of π-extended polycyclic aromatic hydrocarbon (PAH) derivatives containing an oxygen/nitrogen atom. The practical utility of the developed transformation was demonstrated on the gram scales and postsynthetic transformations thereof.

N-Heterocyclic carbene (NHC)-catalyzed oxidation of unactivated aldimines to amides via imine umpolung under aerobic conditions.

Herein, we disclose an NHC-catalyzed aerobic oxidation of unactivated aldimines for the synthesis of amides via umpolung of imines proceeding through an aza-Breslow intermediate. We have developed an eco-friendly method for the conversion of imines to amides by using molecular oxygen in air as the sole oxidant and dimethyl carbonate (DMC) as a green solvent under mild reaction conditions. Broad substrate scope, high yields and gram scale syntheses expand the practicality of the developed method.

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.

Design and application of intramolecular vinylogous Michael reaction for the construction of 2-alkenyl indoles.

A base-mediated transformation based on a designed intramolecular vinylogous Michael addition (intra-VMA) is presented to access 3-substituted 2-alkenyl indole derivatives. The reaction represents the first example of the intra-VMA for the construction of indoles. A one-pot N-allylation of ortho-tosylamidocinnamates/congeners with γ-bromocrotonates followed by intra-VMA has been described to provide access to a diverse range of 2-alkenyl indole derivatives in reasonable to high yields. The synthetic value of the developed intra-VMA has been demonstrated by gram-scale synthesis of a representative indole derivative and also by the formal synthesis of MK-7246: a Merck's clinical CRTH2 antagonist.

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.

N-Heterocyclic carbene (NHC)-catalyzed tandem imine umpolung-aza-Michael addition-oxidation of ß-carboline cyclic imines.

Herein we describe an NHC-catalyzed umpolung of ß-carboline-based cyclic imines for their conversion to the corresponding N-substituted cyclic amides. The key to the success of this transformation appears to be that NHC upon reaction with the imine concomitantly goes through the generation of an aza-Breslow intermediate and aza-Michael addition followed by oxidation with molecular oxygen to deliver the N-substituted amide products. The developed method has enabled the synthesis of various biologically relevant ß-carboline-1-one derivatives in good yields.

Substrate controlled, regioselective carbopalladation for the one-pot synthesis of C4-substituted tetrahydroisoquinoline analogues.

6-Exo-trig cyclization reaction through regioselective carbopalladation was demonstrated with N-(2-halobenzyl)-N-allylamines to furnish the corresponding C4-substituted tetrahydroisoquinoline derivatives. The scope of the reaction was extended to the synthesis of C4-quaternary tetrahydroisoquinoline derivatives also. The nature of the substituent on the olefin moiety dictates the course of the carbopalladation sequence. Regioselective carbopalladation is substantiated by performing the reaction with unsymmetrical diallylated amine substrates.

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.

One-Pot Allylation-Intramolecular Vinylogous Michael Addition-Isomerization Cascade of o-Hydroxycinnamates and Congeners: Synthesis of Substituted Benzofuran Derivatives.

A unique intramolecular vinylogous Michael addition leading to the synthesis of heterocycles has been disclosed. Base-promoted one-pot sequential O-allylation of o-hydroxy-cinnamates or -cinnamonitrile or -chalcones with γ-bromocrotonates followed by an intramolecular conjugate addition of vinylogous Michael donors resulted in the formation of highly substituted benzofuran derivatives in good to excellent yields. The intramolecular event followed by two [1,3]-H shifts leading to aromatization appears to be the key to the success of this unprecedented transformation.

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.

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.

Ruthenium catalyzed ß-C(sp3)-H functionalization on the 'privileged' piperazine nucleus.

ß-C(sp3)-H functionalization on the 'privileged' piperazine nucleus has been disclosed using ruthenium catalysis. The ruthenium catalyzed synthesis of a variety of piperazine fused indoles from ortho-piperazinyl (hetero)aryl aldehydes is presented. This transformation takes place via the dehydrogenation of piperazine followed by an intramolecular nucleophilic addition of the transient enamine moiety onto the carbonyl group and aromatization cascade.

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.