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The hydrosulfonylation of terminal alkynes employing sulfonohydrazides has been accomplished with copper-catalysis in the presence of BPO (benzoic peroxyanhydride). Generally, excellent yield of the vinyl sulfone products has been acquired by heating the reaction at 70°C in DMSO.

An unprecedented domino reaction involving primary enaminones/enaminoesters and aldehydes has been developed for the synthesis of fully substituted pyridines. The construction of the products has been accomplished via the cascade generation of two C-C and one C-N bond by simply using TfOH as a promoter.

The intramolecular C–N bond forming cross coupling reactions on the enaminones has been achieved for the synthesis of imidazole[1,2-a]pyridines via copper-catalyzed C(sp2)–H amination. This protocol provides a new route for the synthesis of 2-unsubstituted imidazole[1,2-a]pyridines via easily available starting materials.

The Pd-catalyzed C−H arylation of phenylacetamides in the γ position was realized for the first time by means of a domino process consisting of in situ directing group installation and C−H arylation. Unprecedented tunable selectivity between di- and monoactivation of the two identical γ-C−H bonds was achieved by modifying the reaction conditions; this is a distinct feature of this one-pot procedure for the C−H-activation-based synthesis of diverse amides.

The synthesis of polyfunctionalized aminothioalkenes has been realized via the direct C-H sulfenylation of enaminones and analogous enamines. These cross-coupling reactions have been achieved by simple KIO3 catalysis under aerobic conditions without employing any transition metal catalyst or additional oxidant. The employment of bio-based green solvent ethyl lactate as the reaction medium constitutes another sustainable feature of the present work.

The syntheses of β,β-diaryl aryl propiophenones have been realized via palladium-catalyzed domino reactions of dimethyl amino functionalized enaminones and aryl boronic acids. This is the first example of transition metal-catalyzed enaminone C-N bond conversion for the generation of a new C-C(aryl) structure.

The Z-selective halosulfonylation of terminal alkynes has been achieved via the halosulfonylation of terminal alkynes by using sulfonohydrazides and copper(I) halides (CuI, CuBr and CuCl), which enables the generally applicable synthesis of halogenated vinyl sulfones with satisfactory efficiency.

The cascade reactions between enaminones and o-aminothiophenols have been implemented to provide unprecedented vicinal diketones containing benzothiazole structures. The construction of the products has been realized under metal-free conditions via carbonylation on the CC double bond of the enaminone. The tunable synthesis of 2-aroylbenzothiazoles has been achieved by using identical starting materials under modified reaction conditions.

An unprecedented C=C bond cleavage of enaminones has been realized by means of copper catalysis in the presence of hypervalent iodine (PhI(OAc)2). The cascade transformation based on this bond cleavage leads to the synthesis of various α-keto amides. Isotope labeling experiments suggest that water has acted as a source of oxygen atoms during the generation of the new carbonyl group.

The synthesis of heterocyclic products via C–H activation has won impressive advances as a newly emerging synthetic strategy. Herein, the recent research advances in heterocycle synthesis employing 8-aminoquinoline directed C–H activation, either in the form of direct intramolecular C–H elaboration or domino reactions involving the C–H activation and other transformation-based annulation reactions are highlighted.

Domino reactions between N,N-dimethyl enaminones and anilines affording quinolines have been accomplished by using triflic acid. The construction of quinolines proceeds by the cleavage of the branched C=C and C−N bond in the enaminones that provides C2−C3 and C4 fragments, respectively. Two new C−C bonds and a new C−N bond are formed during the product formation.

We developed a copper-catalyzed three component reaction of aryl acetylene, enaminone and sulfonyl azide to construct iminolactone via a cascade process involving copper-catalyzed alkyne–azide cycloaddition (CuAAC), Michael addition of metalated ketenimine followed by elimination and 6π electrocyclization.

By employing the featured amine elimination of tertiary enaminones as a key transformation, cascade reactions of dienals and tertiary enaminones involving [4+2] annulation, Hofmann-like amine elimination and aromatization are devised for benzaldehyde synthesis. This method is of particular interest in providing benzaldehydes containing an electron withdrawing group at the C3 position which are hard to access by previous methods for benzaldehyde synthesis.

An organocatalytic cascade reaction involving the incorporation of alkyl propiolates and primary amines has been realized for the facile synthesis of 1,4-dihydropyridines (1,4-DHPs) bearing a C4 acetate fragment. This method allows rapid and atom economical generation of N -aryl, N -alkyl, and NH 1,4-DHPs with moderate to excellent yields.

The construction of 1,5-disubstituted 1,2,3-triazoles has been effected through the cascade dual C-N bond formation, N-N bond formation and an acyl migration-based C-C bond formation via the three-component reactions of enaminones, tosylhydrazine and primary amines. This metal- and azide-free, regioselective synthetic method proceeds in the presence of only molecular iodine.

An environmentally benign multicomponent synthetic method has been realized for the diastereoselective construction of fused tetrahydropyridines. Structurally diverse products have been acquired with generally good yields via the assembly of simple starting materials, enaminones or nitroenamines, o-aminophenols, and cinnamaldehydes, in the presence of lactic acid in water–ethanol media.

The one-pot reactions of acyl chlorides, Wittig reagents, and o-iodoanilines involving a copper-catalyzed C–C coupling have been realized to provide various indoles. The reactions proceed on the basis of the in situ generation of allenes to incorporate o-iodoanilines via tandem Michael addition, C–C coupling, and tautomerization to afford indoles. This direct one-pot protocol allows the synthesis of indoles with all easily available materials.

The synthesis of diverse 1,4-dihydropyridines have been achieved via the multicomponent reactions of aldehydes, enaminones and amines. The reactions have been smoothly performed in water to provide all products with moderate to excellent yields by using lactic acid as a green catalyst.

The CC double bond cleavage of enaminones has been realized under ambient conditions through visible-light catalysis in the presence of Rose Bengal, which leads to the synthesis of a class of 1,2-diketones without using any metal catalyst. In addition, the one-pot synthesis of quinoxalines has also been achieved under identical photocatalytic conditions by making use of the in situ generated 1,2-diketones as intermediates.

Multicomponent reactions have been successfully applied as a platform for designing the step economical C–H activation-based organic synthesis wherein the in situ installation of directing group (DG) and the subsequent C–H activation-based amide arylation have been achieved in one-step. This multicomponent strategy allows the efficient synthesis of 2,6-biarylated or 6-arylated benzamides with significantly improved sustainability and discloses the potential of designing “ideal” synthesis by combining the concepts of C–H activation and multicomponent reaction.

Transition metal-catalyzed C–H bond functionalization has numerous applications in organic synthesis as a powerful type of bond transformation. In particular, the combination of C–H functionalization with other types of chemical transformations in the manner of multicomponent reactions is an even more beneficial tool in the synthesis of small organic molecules because such reactions provide a platform for the rapid generation of high molecular diversity and complexity by making use of the advantages of both latent C–H bond transformation and the multicomponent reaction. Herein, we provide a review highlighting the research advances in the multicomponent reactions built upon transition metal-catalyzed C–H bond functionalization. The content spans from the reactions featuring the functionalization of C(sp3)–H, C(sp2)–H and C(sp)–H bonds over the last decade.

The tunable three-component reactions of enals, electron deficient alkynes, and primary amines have been achieved for selective synthesis of 1,4- and 1,2-dihydropyridines. The selectivity has been found to be in close relation to the property of the amine component.

2-Vinylbenzofurans have been synthesized via the copper-catalyzed one-pot, three-component reactions of o-iodophenols, in situ generated allenes, and dichloromethane. Cascade transformation of oxa-Michael addition, C-arylation, and sp(3)C-H/sp(3)C-Cl conversion-based vinylation has been involved in realizing the construction of this 2-vinylbenzofuran framework.

A generally applicable multicomponent method has been established for the synthesis of pyridines. In the reactions, thioacetamide is used as a cheap and efficient ammonium source in a multicomponent reaction with aldehydes and electron-deficient enamines or alkynes to give 3,4,5-trisubstituted pyridines in moderate to good yields and with a high product diversity.

The bio-based chemical ethyl lactate (EL) has been discovered to be an excellent medium for the Glaser-type homo- and cross-coupling reactions of terminal alkynes. Good to excellent yields of conjugate diynes have been obtained under ligand-free and mild heating conditions in the presence of CuI and molecular oxygen. Copyright © 2014 John Wiley & Sons, Ltd.

The multicomponent reactions of aldehydes, electron deficient alkynes and amines have been successfully performed to yield a number of symmetrical 2,6-unsubstituted 1,4-dihydropyridines (1,4-DHPs). This method has been found generally applicable for the synthesis of both N-substituted and N-unsubstituted 1,4-DHPs by employing secondary amine to activate the alkyne component via enaminoester intermediates. The present method runs through an enamine type activation, which is different from the known approach employing AcOH as solvent.

Selective bis-sulfenylation reactions of aryl dihalides have been achieved by copper-catalyzed C–S coupling reactions under mild conditions of refluxing EtOH (80 °C). Employment of disulfides as thiolating reagents enables the production of various bis(phenylthio)benzenes with excellent selectivity, and no products from mono C–S coupling are isolated.

The synthesis of cyano acrylates has been achieved via an organocatalytic domino Knoevenagel reaction, hydration and esterification under metal-free conditions without using any additional solvent. During the reaction, the in situ produced water from the Knoevenagel condensation promotes the hydration of the cyano group and initiates the subsequent esterification, which makes up a novel, clean and atom economical route towards the synthesis of cyano acrylates.

The cyclotrimerization reactions of enaminones and electron deficient terminal alkynes have been efficiently performed in water in the presence of only a small amount of lactic acid. The reactions led to the green synthesis of a variety of 1,3,5-triacylbenzenes without using any metal as catalyst. Brief investigation on different elaboration of the triacylbenzene product demonstrated the versatile synthetic application of these 1,3,5-triacylbenzenes.

The domino reactions between NH-based secondary enaminones and tosyl azide have been developed for the synthesis of various N-substituted 1,2,3-triazoles by employing t-BuONa as the base promoter. Through a key Regitz diazo-transfer process with tosyl azide, the reactions proceed efficiently at room temperature with good substrate tolerance.

The Z-selective halosulfonylation of terminal alkynes has been achieved via the halosulfonylation of terminal alkynes by using sulfonohydrazides and copper(I) halides (CuI, CuBr and CuCl), which enables the generally applicable synthesis of halogenated vinyl sulfones with satisfactory efficiency.

An unprecedented domino reaction involving primary enaminones/enaminoesters and aldehydes has been developed for the synthesis of fully substituted pyridines. The construction of the products has been accomplished via the cascade generation of two C–C and one C–N bond by simply using TfOH as a promoter.

Numerousbenefits have been given by the classic synthetic toolbox,however, the fatal restriction within these heavy metal-cata-lyzed syntheses is the contamination by trace metals producedin the work-up, which prevents this transformation from facileapplication in biologically relevant investigations. In thisregard, the metal-free AAC reactions have emerged as anothermilestone. Previously, these metal-free protocols were de-signed based on the employment of alternative reaction part-ners of alkynes to incorporate azides.

The synthesis of aryloxyl acrylates has been achieved through a new three-component synthetic method involving the assembly of phenols, acyl chlorides and Wittig reagents in the presence of a copper catalyst using glucose as a green ligand. β-Aryloxyl acrylates have been prepared with high diversity and in good to excellent yields involving the cascade formation of a new CC bond and a C(sp2)–O bond.

A three-component synthetic method involving the assembly of enals, N,N-disubstituted enaminones and 2-aminopyridines has been designed, which leads to the facile and regioselective synthesis of 1,2-dihydropyridines (1,2-DHPs) with broad scope and generally good yields in the presence of simple acid catalysts.

Selective single arylsulfanylation reactions of aryl diiodides with aryl or hetaryl thiols to give a broad array of iodine-functionalized sulfides were developed. Further elaboration of the iodine-containing products to provide a variety of aryl and hetaryl sulfides through coupling reactions was also demonstrated.

Highly stereoselective synthesis of Z-enaminones bearing reactive secondary amino group has been successfully performed in water using tertiary amino group functionalized enaminones under ambient conditions. An interesting promotion effect of water on the reaction via hydrolysis–dehydration condensation has been observed through a designed isotope labeling experiment. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.

Isatins are well-known carbonyl electrophiles which allow a vast number of reactions initiated by nucleophilic attack on the C3 carbonyl group when used as starting materials. The most notable feature of isatins is that they serve as donors of oxindole fragments and furnish spirocyclic products in most cases. Because of their high reactivity and easy availability, isatins have been broadly used as building blocks in the synthesis of structurally complex and diverse heterocyclic compounds in multicomponent reactions (MCRs). Recent advances in diversity oriented synthesis with isatin-based MCRs are discussed in this Focus Review and are classified into different sections based on the key transformation involved in the reactions, such as 1,3-dipolar cycloaddition, Knoevenagel reaction, ring-opening of isatins and so on.

Hydroxychloroquine (HCQ) is known as one of the most fascinating synthetic antimalarial drugs during the last 50 years. It is currently among the most commonly employed medicines for the clinical treatment of rheumatic diseases, especially systemic lupus erythematosus and rheumatoid arthritis. In related mechanism studies, it has been found that HCQ possesses various immunomodulatory and anti-inflammatory activities. In addition, the effects of HCQ on anti-platelet, metabolic pathways, and antineoplasticity have also been disclosed in more recent studies. These significant findings on HCQ suggest the potential therapeutic applications of HCQ for treatment of many diseases, such as cancers, skin disease, antiphospholipid syndrome, etc. This review focuses on recent in vitro and clinical trials on its pharmacological mechanisms, therapeutic activities, and potential adverse effects.

The syntheses of β,β-diaryl aryl propiophenones have been realized via palladium-catalyzed domino reactions of dimethyl amino functionalized enaminones and aryl boronic acids. This is the first example of transition metal-catalyzed enaminone C–N bond conversion for the generation of a new C–C(aryl) structure.

The intramolecular C–N bond forming cross coupling reactions on the enaminones has been achieved for the synthesis of imidazole[1,2-a]pyridines via copper-catalyzed C(sp2)–H amination. This protocol provides a new route for the synthesis of 2-unsubstituted imidazole[1,2-a]pyridines via easily available starting materials.

Carbonyl-forming reactions are a class of fundamental transformations in organic chemistry. Guided by the current importance of environmentally benign metal-free catalysis and synthesis, herein we review recent advances in carbonyl-generation reactions based on alkene C=C double oxygenation as well as related cascade reactions in the synthesis of diverse organic products. The content of this focus review consists of two important but different reaction models: oxygenation based on full C=C double-bond cleavage and oxygenation based on partial C=C double-bond cleavage.

The Pd-catalyzed C−H arylation of phenylacetamides in the γ position was realized for the first time by means of a domino process consisting of in situ directing group installation and C−H arylation. Unprecedented tunable selectivity between di- and monoactivation of the two identical γ-C−H bonds was achieved by modifying the reaction conditions; this is a distinct feature of this one-pot procedure for the C−H-activation-based synthesis of diverse amides.