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Due to the unique activation modes, the small organic molecule catalysts (organocatalysts) have proved their potential to facilitate the remote functionalizations of the unsaturated acceptors bearing extended conjugation. The organocatalytic 1,6-addition reaction involving the attack of nucleophiles to the δ-carbon of the α,β,γ,δ-unsaturated acceptors has emerged as an excellent strategy to create a stereocenter at the δ-site with high regio- and stereo-control. Organocatalysis has also opened the window for developing the complex domino reactions involving the 1,6-addition step. A tremendous advancement has been accomplished in the organocatalytic asymmetric 1,6-addition and related domino reactions for the stereocontrolled synthesis of complex molecular structures bearing multiple stereocenters. This review article summarizes the significant advancement in stereoselective domino reactions involving 1,6-addition as a critical step.

Herein, we report a novel palladium (Pd)-catalyzed asymmetric domino Heck/carbocyclization/Suzuki reaction of N-(2-bromoaryl)-2-naphthylacrylamides. The reaction involves a novel and enantioselecti...

Herein, we report a new method for synthesis of extended perylenes and terrylenes. The technique is based on the cascade dehydrative π-extensions (DPEX) of aryl aldehydes, in which stepwise annulations activate previously "dormant" substituents. Two- and fourfold cyclizations of 3-aryl-biphenyl-2,2'-dicarbaldehydes offer a rapid path to unsymmetrical perylenes and elusive terrylene derivatives, respectively. DPEX of 3,3''-(phenanthrene-1,8-diyl)bis (([1,1'-biphenyl]-2,2'-dicarbaldehyde)) leads to the biradical structure, which proceeds in situ into oxidative electrocyclization at room temperature. The described domino process complements and expands DPEX approach to a large family of fused acenes and related PAHs.

The field of gold catalysis has been in constant expansion during the last twenty years. Based on the precept of π-activation of unsaturated simple substrates, several new rearrangements have been discovered, implying aryl, alkyne, alkene or keto derivatives as key partners. In this personal account, the main contributions in the field of gold catalysis from our group will be highlighted, emphasizing the recent reports, starting from 1,6- and 1,5-enynes and then moving to keto-ynes derivatives. The gold-catalyzed reactions will be presented starting from classical skeletal rearrangements (cycloisomerization) and then domino processes. In each part, the presentation of asymmetric versions will be highlighted.

A base-catalyzed double annulation of isocyanoacetates with various enynones has been developed for the expeditious synthesis of 4-azafluorene and 4-azafluorenone derivatives. Against the well-known 1,3-dipolar reactivities, the active methylene and isocyano groups of isocyanoacetate serve as nucleophiles in this domino transformation.

Exploring multistep cascade reactions triggered by C–H activation are recognized as appealing, yet challenging. Herein, we disclose a Rh(III)-catalyzed domino C–H coupling of N-carbamoyl indoles an...

A Sc(OTf)3-catalyzed iodocyclization/Ritter-type amidation of N-alkoxypropiolamides for the synthesis of 4-iodoisoxazol-3(2H)-ones bearing an amide group has been developed. This domino protocol allows the construction of a valuable heterocycle, isoxazol-3(2H)-one, as well as the introduction of two functional groups. The reaction has a broad substrate scope and can be carried out on a large scale. Control experiments suggest that Sc(OTf)3 acts as a dual activator for both the iodocyclization and amidation steps. In addition, the N-alkoxy group in the substrate suppresses some of the side reactions.

A novel and mild synthetic route for the preparation of functionalized polycyclic indole skeletons via a gold-mediated cycloisomerization/alkoxylation of 1,6-aldehyde-yne has been developed. This atom-economical catalytic process that associates IPrAu(MeCN)BF4 and an alcohol demonstrated remarkable selectivity in accessing functionalized 3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole derivatives of high synthetic utility (21 examples, yields of ≤96%) and could be optimized under asymmetric conditions with an enantiomeric excess of ≤86%.

Herein, a new mechanism, namely, crystalline phase recognition (CPR), is proposed for the single-crystal-to-single-crystal (SCSC) transition of metal halides. Chiral β-[Bmmim]2 SbCl5 (Bmmim=1-butyl-2,3-methylimidazolium) can recognize achiral α-[Bmmim]2 SbCl5 on the basis of a key-lock feature through intercontact of their single crystals, resulting in a domino phase transition (DPT). The concomitant photoluminescence (PL) switching enables observation of the DPT in situ. The liquid eutectic interface, stress-strain transfer, and feasible thermodynamics are key issues for the CPR. DFT calculations and PL measurements revealed that the optical absorption and emission of the isomers mainly originate from [SbCl5 ]2- anions. The structural effects (e.g., supramolecular interactions and [SbCl5 ]2- distortion) on the optical emission are clarified. As a novel type of stimuli response, the CPR-induced DPT and luminescence switching exhibit potential for application in advanced time-resolved information encryption.

Highly enantioselective and diastereoselective 1,2-diarylation and 1,2-arylalkynylation of trisubstituted alkenes are reported via the palladium-catalyzed Heck/Suzuki or Heck/Sonogashira domino seq...

A strategy for catalyst-free domino reaction of 4-aminopyridin-2(1H)-ones, arylglyoxal hydrates and different 1,3-dicarbonyl compounds in water has been established. The mild and efficient procedure afforded pyrrolo[3,2-c]pyridine derivatives with 76–94% yields after simple crystallization. The present procedure shows promising characteristics, such as readily available starting materials, the use of water as reaction media, simple and efficient one-pot operation, and avoiding the need for any hazardous or expensive catalysts.

Enantioenriched spiro-oxiranes bearing three contiguous stereocenters were synthesized using a rhodium-catalyzed asymmetric addition/aldol/spirocyclization sequence. Starting from a linear substrate, the cascade enabled the formation of a spirocyclic framework in a single step. sp2 - and sp-hybridized carbon nucleophiles were found to be competent initiators for this cascade, giving arylated or alkynylated products, respectively. Derivatization studies demonstrated the synthetic versatility of both the epoxide and the alkyne moieties of the products. DFT calculations were used to reconcile spectroscopic discrepancies observed between the solution- and solid-state structures of the products.

An efficient, one-pot, domino synthesis of quinolines via the coupling of iodoanilines with allylic alcohols facilitated by palladium catalysis is described. The overall synthetic process involves an intermolecular Heck coupling between 2-iodoanilines and allylic alcohols, intramolecular condensation of in situ generated ketones with an internal amine functional group, and a dehydrogenation sequence. Notably, this protocol occurs in water as a green solvent. Significantly, the method exhibits broad substrate scope and is applied for the synthesis of deuterated quinolines through a deuterium-exchange process.

A convenient catalytic protocol for efficiently constructing indoline-fused tetrahydroisoquinolines based on CuCoFe layered double hydroxide (LDH) has been described. Preliminary mechanistic studies show that indoline-fused tetrahydroisoquinolines are produced via domino coupling/cyclization reactions between tetrahydroisoquinolines and active methylene compounds, including malononitrile, malonates, and analogues. CuCoFe-LDH can accelerate the Csp3-Csp3 and Csp3-Csp2 formation reactions in a single step. The research thus presents a unique opportunity to develop a synthetic methodology for N-containing polycyclic compounds.

We describe the synthesis of 1,4-disubstituted 5-triazenyl-1,2,3-triazoles bearing diethoxy arylphosphoryl moieties via a domino reaction between ortho-azidophosphonates and premade copper(I) alkynides involving chelation-assisted [3+2] cycloaddition followed by interception of the copper(I) triazolide generated by the azide. A resulting dicopper(I) triazoletriazenide complex has been characterized through X-ray diffraction.

Hexaarylbenzene (HAB) derivatives are versatile aromatic systems playing a significant role as chromophores, liquid crystalline materials, molecular receptors, molecular‐scale devices, organic light‐emitting diodes and candidates for organic electronics. Statistical synthesis of simple symmetrical HABs is known via cyclotrimerization or Diels–Alder reactions. By contrast, the synthesis of more complex, asymmetrical systems, and without involvement of statistical steps, remains an unsolved problem. Here we present a generally applicable synthetic strategy to access asymmetrical HAB via an atom‐economical and high‐yielding metal‐free four‐step domino reaction using nitrostyrenes and α,α‐dicyanoolefins as easily available starting materials. Resulting domino product—functionalized triarylbenzene (TAB)—can be used as a key starting compound to furnish asymmetrically substituted hexaarylbenzenes in high overall yield and without involvement of statistical steps. This straightforward domino process represents a distinct approach to create diverse and still unexplored HAB scaffolds, containing six different aromatic rings around central benzene core., A high yielding and scalable metal‐free four‐step linear domino reaction results in functionalized triarylbenzene (TAB) and opens the door for making a broad variety of synthetically challenging hexaarylbenzene (HAB) molecules with six different aryl groups.

Novel, efficient and environmentally friendly approaches have been developed for the synthesis of 1,5-benzodiazepine-2,3-dicarboxylates by one-pot three-component domino reactions in the presence of a catalytic amount of γ-Fe2O3@SiO2/Ce(OTf)3 in EtOH at ambient temperature. A total of 32 2,5-dihydro-1H-1,5-benzodiazepine-2,3-dicarboxylates and 2-methyl-2,3-dihydro-1H-1,5-benzodiazepine-2,3-dicarboxylates with enamine or imine structure of the heterocycle, respectively, were obtained in good yields by reacting substituted 1,2-phenylenediamine, β-carbonyl esters, and ethyl glyoxylate or ethyl pyruvate. One-pot reactions were successfully realized to form one new cycle and four new bonds (one C–C, two C–N, one C=C or two C–C, one C–N, one C=N). Furthermore, plausible mechanisms for the formation of 1,5-benzodiazepine-2,3-dicarboxylates have been proposed. The salient features of this reaction include short reaction time, mild reaction conditions, moderate to excellent yields, recyclability of the catalyst, and wide substrate scope.

A regio- and diastereoselective ring-expansion reaction of N-acylaziridines is described for the synthesis of 4-carboxamide oxazolines using InCl3. A domino Ugi–Joullié/ring-expansion reaction of arylphenylazirines, isocyanides, and carboxylic acids leads to the target products through the N-acylaziridine intermediates in the presence of the indium catalyst. The oxazolines were synthesized in moderate to excellent yields with high atom economy and high bond-forming efficiency under mild reaction conditions.

We described a novel palladium-catalyzed domino procedure for the preparation of (hetero)aryl thio/selenoglycosides. Readily available (hetero)aryl iodides and easily accessible 1-thiosugars/1-selenosugars are utilized as the substrates. Meanwhile, 10 types of sugars are quite compatible with this reaction with good regio- and stereoselectivity, high efficiency, and broad applicability (up to 89%, 53 examples). This method enables the straightforward formation of the C(sp2)-S/Se bond of (hetero)aryl thio/selenoglycosides.

A palladium-catalyzed domino Heck cyclization/Hiyama cross-coupling has been achieved for the synthesis of (hetero)aryl-functionalized azaindoline derivatives bearing all-carbon quaternary centers in 46–85% yields. The synthetic versatility of this protocol has been highlighted by the gram-scale synthesis and modification of aryl-containing complex bioactive molecules.

This review highlights methods for the synthesis of five- and six-membered heterocycles and their annulated analogues. These methods are based on anionic domino reactions that have a common step: an SN2/Thorpe–Ziegler reaction. In addition, data on the biological activity of these heterocycles are summarized.1 Introduction2 Synthesis of Thiophenes, Pyrroles, Furans and Other Heterocycles2.1 Synthesis of 3-Aminothiophenes2.2 Synthesis of 3-Aminopyrroles2.3 Synthesis of 3-Aminofurans3 Synthesis of Bicyclic Heterocyclic Systems3.1 Thiophenes, Pyrroles and Furans Fused with Five-Membered Heterocycles3.2 Thiophenes, Pyrroles and Furans Fused with Six-Membered Heterocycles4 Synthesis of Heterocyclic Compounds Using Three-Step Domino Reactions5 Synthesis of Heterocyclic Compounds Based on a Combination of Two Domino Reactions6 Miscellaneous7 Conclusion

Virtually inert sulfur hexafluoride becomes a precious pentafluorosulfanylation agent, if properly activated by photoredox catalysis, to access α-fluoro and α-alkoxy SF5-compounds. This advanced protocol converts SF6 in the presence of alkynols as bifunctional C−C- and C−O-bond forming reagents directly into pentafluorosulfanylated oxygen-containing heterocycles in a single step from α-substituted alkenes. The proposed mechanism is supported by theoretical calculations and gives insights not only in the pentafluorosulfanylation step but also into formation of the carbon-carbon bond and is in full agreement with Baldwin's cyclization rules. The key step is a radical type 5-, 6- respectively 7-exo-dig-cyclization. The synthesized oxaheterocycles cannot be simply prepared by other synthetic methods, show a high level of structural complexity and significantly expand the scope of pentafluorosulfanylated building blocks valuable for medicinal and material chemistry. ISSN:0947-6539 ISSN:1521-3765

Acrylamides are versatile building blocks that are easily obtained from readily available starting materials. During the last 20 years, these valuable substrates bearing a nucleophilic nitrogen atom and an electrophilic double bond have proven to be efficient domino partners, leading to a wide variety of complex aza-heterocycles of synthetic relevance. In this non-exhaustive review, metal-free and metal-triggered reactions followed by an annulation will be presented; these two approaches allow good modulation of the reactivity of the polyvalent acrylamides.1 Introduction2 Metal-Free Annulations2.1 Domino Reactions Triggered by a Michael Addition2.2 Domino Reactions Triggered by an Aza-Michael Addition2.3 Domino Processes Triggered by an Acylation Reaction2.4 Domino Reactions Triggered by a Baylis–Hillman Reaction2.5 Cycloadditions and Domino Reactions2.6 Miscellaneous Domino Reactions3 Metal-Triggered/Mediated Annulations3.1 Zinc-Promoted Transformations3.2 Rhodium-Catalyzed Functionalization/Annulation Cascades3.3 Cobalt-Catalyzed Functionalization/Annulation Cascades3.4 Ruthenium-Catalyzed Functionalization/Annulation Cascades3.5 Iron-Catalyzed Functionalization/Annulation Cascades3.6 Palladium-Catalyzed Functionalization/Annulation Cascades3.7 Copper-Catalyzed Transformations3.8 Transition Metals Acting in Tandem in Domino Processes4 Radical Cascade Reactions5 Conclusion

A simple InBr3-catalyzed domino reaction of indoles, phenylacetylenes, and various 3-methyleneoxindolines in toluene is described. This reaction not only provided a convenient synthetic protocol fo...

An efficient method for the synthesis of highly substituted bicyclic pyridone derivatives containing the dithiocarbamate group is reported via a one-pot three-component reaction of 2-(alkylthio)thio­azlactones, diamines, and nitroketene dithioacetal in EtOH under catalyst-free conditions. The reaction proceeds via a domino amidation–­intramolecular 1,4-addition-type Friedel–Crafts alkylation reaction to afford the corresponding fused bicyclic pyridones with high yields and diastereoselectivity.

We disclose herein a Au(I)-catalyzed domino cyclization of 1,6-diynes incorporated with indole. This protocol enabled the diastereoselective buildup of indole-fused azabicyclo[3.3.1]nonanes from linear precursors. Density functional theory calculations showed that the reaction proceeded via an unprecedented cascade dearomatization/rearomatization/dearomatization process. Independent gradient model analysis revealed that a noncovalent attractive interaction between the distal alkyne and the Au/proximal complex was responsible for the chemoselectivity of the first spirocyclization step.

Domino reactions involving nickel‐catalyzed additions of (hetero)arylboronic acids to alkynes, followed by cyclization of the alkenylnickel intermediates onto tethered acyclic ketones to give chiral tertiary‐alcohol‐containing products in high enantioselectivities, are described. The reversible E/Z isomerization of the alkenylnickel intermediates enables overall anti‐arylmetallative cyclization to occur. The ring system of the products are substructures of certain diarylindolizidine alkaloids.

The base-catalyzed reaction of diethyl 1,3-acetonedicarboxylate with 2-hydroxybenzylidene indenediones was studied. The reaction provides a facile and expeditious protocol for the synthesis of natural product inspired fluorenone-fused coumarins in good to very good yields. This process resembles a combination of domino Michael–intramolecular Knoevenagel–aromatization–lactonization reactions in a single step. Although this reaction operates with many bases, the best yields were obtained with DMAP as a catalyst. This protocol could open new potential avenues for the synthesis of fused coumarins by the reaction of substituted β-keto esters with different 2-(2-hydroxybenzylidenes) of 1,3-dicarbonyl compounds.

In this study, the domino Knoevenagel-Michael and cyclization reaction between 5,5-dimethyl-1,3-cyclohexanedione (dimedone) and aryl aldehydes was performed in the presence of sulfacetamide as an o...

The electrochemical three‐component assembly of isoquinolines has been accomplished by ruthenaelectro‐catalyzed C−H/N−H functionalization. The robustness of the electrocatalysis was reflected by an ample substrate scope, an efficient electrooxidation, and an operationally friendly procedure. The isolation of key intermediates and detailed mechanistic studies, including unprecedented cyclovoltammetric analysis of a seven‐membered ruthenacycle, provided support for an unusual ruthenium(II/III/I) regime., Ruthenium‐catalyzed electrooxidative three‐component syntheses of isoquinolines proved viable with ample scope. The isolation of key intermediates, along with DFT calculations revealed an unusual ruthenium(II/III/I) catalytic cycle.

An unprecedented nickel-catalyzed domino reductive cyclization of alkynes and o-bromoaryl aldehydes is described. The reaction features broad substrate scope and is tolerant of a variety of functional groups, providing a straightforward access to biologically significant indanones and spiro-indanone pyrrolidine derivatives in good yields with excellent regio- and diastereoselectivity. Preliminary mechanistic studies have shown that indanones are formed by the cyclization of o-bromoaryl aldehydes and alkynes to form indenol intermediates, followed by hydrogen autotransfer.

A novel divergent domino annulation reaction of prop-2-ynylsulfonium salts with sulfonyl-protected β-amino ketones has been developed, affording various epoxide-fused 2-methylenepyrrolidines and S-containing pyrroles in moderate to excellent yields. Prop-2-ynylsulfonium salts act as C2 synthons in the reactions providing a promising epoxide-fused skeleton in a single operation with readily accessible starting materials.

The Cu-catalyzed domino synthesis of multi-substituted benzo[b]thiophene through radical cyclization of 2-iodophenyl ketones was developed using xanthate as a sulfur surrogate. This method was extended to obtain tetracyclic Lupinalbin analogues through double C-S/C-O bond formation by changing the substituents. The products were converted to a HTI photoswitch, benzothiophene-fused flavone.

One-pot reactions elaborated around transition metal-catalyzed isomerization of alkenes not only offer the inherent advantages of atom-, step- and redox-economy but also enable the preparation of value-added products that would be difficult to access by conventional methods. In this Review, we cover seminal and recent examples of tandem, sequential and domino processes, which incorporate the most attractive features of olefin isomerization.

The acetic acid promoted reaction of 3-hydroxy-3-(indol-3-yl)indolin-2-ones and mercapto-substituted β-enamino esters showed very interesting molecular diversity. The reaction in ethanol at room temperature in the presence of acetic acid resulted in two diastereoisomeric 3,3-disubstituted oxindoles in high yields. When the reaction was carried out in refluxing ethanol, the reaction with 3-hydroxy-3-(indol-3-yl)indolin-2-ones with N-alkyl groups gave polycyclic spirooxindoles in satisfactory yields. However, a similar reaction with 3-hydroxy-3-(indol-3-yl)indolin-2-ones with NH groups afforded functionalized dihydroindolo[3,2-c]phenothiazines with sequential ring-opening of oxindole. A plausible domino annulation mechanism was rationally proposed for the formation of different kinds of polycyclic compounds.

A palladium-catalyzed domino Heck/intermolecular direct hetero arylation sequence of unactivated alkenes was developed, providing 1,2,3-triazole containing bisheterocycles bearing all-carbon quaternary centers with yields of 25-90%. The protocol was extended to 1,3,4-oxadiazoles as well. The installed triazole was further exploited for late-stage functionalizations, and the mechanistic studies indicate the involvement of C-H activation.

A cobalt-catalyzed domino Pauson–Khand and [4 + 2] cycloaddition of substituted diynes has been developed for the rapid construction of complexed polycyclic ring systems. Using benzene-1,3,5-triyl triformate (TFBen) as the CO source, the reaction proceeded well to give various tetracyclic compounds bearing two new quaternary carbon cores in high yields with excellent regioselectivity and diastereoselectivity. Control experiments were performed to gain a better understanding of the reaction mechanism.

Efficient C4-arylation and domino C4-arylation/3,2-carbonyl migration of indoles have been developed. The former route enables C4-arylation in a highly efficient and mild manner and the latter route provides an alternative straightforward protocol for synthesis of C2/C4 disubstituted indoles. The mechanism studies imply that the different reaction pathways were tuned by the distinct acid additives, which led to either the Pd(I)–Pd(II) pathway or Pd(II) catalysis.

A tartaric acid-catalyzed three-component reaction of para-quinols, organoboronic acids, and alcohols is reported, leading to meta-alkenylated aryl alkyl ether in a single step. Moreover, meta-functionalized phenols could also be obtained in the absence of alcohols. Initial mechanistic studies indicated that the free hydroxy group of p-quinol plays a vital role in initiating the conjugate addition.

The design and development of a TfOH catalysed domino strategy for the double annulation of arenes with propargylic alcohols for the rapid generation of indene based polycyclic systems is reported. The dehydration, intramolecular 6-endo-dig hydroarylation, and cationic cyclization were consecutively promoted by TfOH. The key features of this strategy are the formation of two C–C bonds, unified access to indene polycyclic systems, excellent yields (up to 95%), high atom economy (>90%), an operationally simple procedure, and water being the only byproduct. By extending this strategy, a two-step synthesis of the pentacyclic systems of hypoxylonol A (43% overall yield from α-tetralone), daldinone A (63% overall yield from β-tetralone) and spiro-tetracyclic framework of incarviatone A has also been achieved.