Mechanistic Studies on the SCS‐Pincer Palladium(II)‐Catalyzed Tandem Stannylation/Electrophilic Allylic Substitution of Allyl Chlorides with Hexamethylditin and Benzaldehydes

This paper describes a mechanistic study of the SCS‐pincer Pd^II‐catalyzed auto‐tandem reaction consisting of the stannylation of cinnamyl chloride with hexamethylditin, followed by an electrophilic allylic substitution of the primary tandem‐reaction product with 4‐nitrobenzaldehyde to yield homoallylic alcohols as the secondary tandem products. As it turned out, the anticipated stannylation product, cinnamyl trimethylstannane, is not a substrate for the second part of the tandem reaction. These studies have provided insight in the catalytic behavior of SCS‐pincer Pd^II complexes in the auto‐tandem reaction and on the formation and possible involvement of Pd⁰ species during prolonged reaction times. This has led to optimized reaction conditions in which the overall tandem reaction proceeds through SCS‐pincer Pd^II‐mediated catalysis, that is, true auto‐tandem catalysis. Accordingly, this study has provided the appropriate reaction conditions that allow the pincer catalysts to be recycled and reused.     

Synthesis of Oxacyclic Scaffolds via Dual Ruthenium Hydride/Brønsted Acid‐Catalyzed Isomerization/Cyclization of Allylic Ethers

A ruthenium hydride/Brønsted acid‐catalyzed tandem sequence is reported for the synthesis of 1,3,4,9‐tetrahydropyrano[3,4‐b]indoles (THPIs) and related oxacyclic scaffolds. The process was designed on the premise that readily available allylic ethers would undergo sequential isomerization, first to enol ethers (Ru catalysis), then to oxocarbenium ions (Brønsted acid catalysis) amenable to endo cyclization with tethered nucleophiles. This methodology provides not only an attractive alternative to the traditional oxa‐Pictet–Spengler reaction for the synthesis of THPIs, but also convenient access to THPI congeners and other important oxacycles such as acetals.     

Gold/Acid‐Co‐catalyzed Direct Microwave‐Assisted Synthesis of Fused Azaheterocycles from Propargylic Hydroperoxides

The gold–acid‐co‐catalyzed synthesis of nine series of fused azaheterocycles with structural diversity starting from the same synthons as readily available propargylic hydroperoxides and aromatic amines has been achieved. The overall tandem process consists in a gold‐catalyzed hydroperoxide rearrangement/Michael reaction followed by a final acid‐catalyzed cyclization.     

A General Acid‐Mediated Hydroaminomethylation of Unactivated Alkenes and Alkynes

In comparison to the extensively studied metal‐catalyzed hydroamination reaction, hydroaminomethylation has received significantly less attention despite its considerable potential to streamline amine synthesis. State‐of‐the‐art protocols for hydroaminomethylation of alkenes rely largely on transition‐metal catalysis, enabling this transformation only under highly designed and controlled conditions. Here we report a broadly applicable, acid‐mediated approach to the hydroaminomethylation of unactivated alkenes and alkynes. This methodology employs cheap, readily available, and bench‐stable reactants and affords the desired amines with excellent functional group tolerance and impeccable regioselectivity. The broad scope of this transformation, as well as mechanistic investigations and in situ domino functionalization reactions are reported.     

Silica Sulfuric Acid‐Catalyzed Five‐component Efficient Synthesis of Five‐Substituted Tetrahydropyridines

A highly atom‐economic one‐pot synthesis of five‐substituted tetrahydropyridines via a five‐component condensation of two equivalents of aromatic aldehyde, two equivalents of aromatic aniline, and one equivalent of β‐keto ester catalyzed by silica sulfuric acid is reported. In this reaction, up to five new bonds and one new ring were formed in one pot with water as the only one by‐product.     

Copper‐Catalyzed Cascade Cyclization of Indolyl Homopropargyl Amides: Stereospecific Construction of Bridged Aza‐[n.2.1] Skeletons

Catalytic cycloisomerization‐initiated cascade cyclizations of terminal alkynes have received tremendous interest, and been widely used in the facile synthesis of a diverse array of valuable complex heterocycles. However, these tandem reactions have been mostly limited to noble‐metal catalysis, and are initiated by an exo‐cyclization pathway. Reported herein is an unprecedented copper‐catalyzed endo‐cyclization‐initiated tandem reaction of indolyl homopropargyl amides, where copper catalyzes both the hydroamination and Friedel–Crafts alkylation process. This method allows the practical and atom‐economical synthesis of valuable bridged aza‐[n.2.1] skeletons (n=3–6) with wide substrate scope, and excellent diastereoselectivity and enantioselectivity by a chirality‐transfer strategy. Moreover, the mechanistic rationale for this novel cascade cyclization is also strongly supported by control experiments, and is distinctively different from the related gold catalysis.     

Auto‐Tandem Cooperative Catalysis Using Phosphine/Palladium: Reaction of Morita–Baylis–Hillman Carbonates and Allylic Alcohols

Auto‐tandem catalysis (ATC), in which a single catalyst promotes two or more mechanistically different reactions in a cascade pattern, provides a powerful strategy to prepare complex products from simple starting materials. Reported here is an unprecedented auto‐tandem cooperative catalysis (ATCC) for Morita–Baylis–Hillman carbonates from isatins and allylic carbonates using a simple Pd(PPh₃)₄ precursor. Dissociated phosphine generates phosphorus ylides and the Pd leads to π‐allylpalladium complexes, and they undergo a γ‐regioselective allylic–allylic alkylation reaction. Importantly, a cascade intramolecular Heck‐type coupling proceeds to finally furnish spirooxindoles incorporating a 4‐methylene‐2‐cyclopentene motif. Experimental results indicate that both Pd and phosphine play crucial roles in the catalytic Heck reaction. In addition, the asymmetric versions with either a chiral phosphine or chiral auxiliary are explored, and moderate results are obtained.     

Auto‐Tandem Catalysis: A Single Catalyst Activating Mechanistically Distinct Reactions in a Single Reactor

Domino reactions have received great attention as efficient synthetic methodologies for the construction of structurally complex molecules from simple materials in a single operation. Catalysts in domino reactions have also been well studied. In these reactions, a catalyst activates the substrate(s) only once, and the structure of the product is delineated at that time. Recently, the new concept of “tandem catalysis” in domino reactions, in which catalyst(s) sequentially activate more than two mechanistically distinct reactions, has been proposed. Tandem catalysis is categorized into three subclasses: orthogonal‐, auto‐, and assisted‐tandem catalyses. Auto‐tandem catalysis is defined as a process in which one catalyst promotes more than two fundamentally different reactions in a single reactor. An overview of recent and significant achievements in auto‐tandem catalysis is presented in this paper.     

Palladium‐Catalyzed Intramolecular Trost–Oppolzer‐Type Alder–Ene Reaction of Dienyl Acetates to Cyclopentadienes

A new approach to the synthesis of highly substituted cyclopentadienes, indenes, and cyclopentene‐fused heteroarenes by means of the Pd‐catalyzed Trost–Oppolzer‐type intramolecular Alder–ene reaction of 2,4‐pentadienyl acetates is described. This unprecedented transformation combines the electrophilic features of the Tsuji–Trost reaction with the nucleophilic features of the Alder–ene reaction. The overall outcome can be perceived as a hitherto unknown “acid‐free” iso‐Nazarov‐type cyclization. The versatility of this strategy was further demonstrated by the formal synthesis of paucifloral F, a resveratrol‐based natural product.     

Deaminative (Carbonylative) Alkyl‐Heck‐type Reactions Enabled by Photocatalytic C−N Bond Activation

The palladium‐catalyzed Heck reaction is a well‐known, Nobel Prize winning transformation for producing alkenes. Unlike the alkenyl and aryl variants of the Heck reaction, the alkyl‐Heck reaction is still underdeveloped owing to the competitive side reactions of alkyl–palladium species. Herein, we describe the development of a deaminative alkyl‐Heck‐type reaction that proceeds through C?N bond activation by visible‐light photoredox catalysis. A variety of aliphatic primary amines were found to be efficient starting materials for this new process, affording the corresponding alkene products in good yields under mild reaction conditions. Moreover, this strategy was successfully applied to deaminative carbonylative alkyl‐Heck‐type reactions.     

Contemporaneous Dual Catalysis: Aldol Products from Non‐Carbonyl Substrates

The aldol reaction represents an important class of atom‐economic carbon–carbon bond‐forming reactions vital to modern organic synthesis. Despite the attention this reaction has received, issues related to chemo‐ and regioselectivity as well as reactivity of readily enolizable electrophiles remain. To help overcome these limitations, a new direct approach toward aldol products that does not rely upon carbonyl substrates is described. This approach employs room‐temperature contemporaneous lanthanum/vanadium dual catalysis, whereby a vanadium‐catalyzed 1,3‐transposition of allenols is coupled with a lanthanum‐catalyzed Meinwald rearrangement of epoxides in situ to directly form aldol products.     

Palladium(II)‐Initiated Catellani‐Type Reactions

The Catellani reaction is known as a powerful strategy for the expeditious synthesis of highly substituted arenes and benzo‐fused rings, which are usually difficult to access through traditional cross‐coupling strategies. It utilizes the synergistic interplay of palladium and norbornene catalysis to facilitate sequential ortho C?H functionalization and ipso termination of aryl halides in a single operation. In classical Catellani‐type reactions, aryl halides are mainly used as the substrates, and a Pd⁰ catalyst is required to initiate the reaction. Nevertheless, recent advances showcase that Catellani‐type reactions can also be initiated by a Pd^II catalyst with different starting materials instead of aryl halides via different reaction mechanisms and under different conditions. This emerging concept of Pd^II/norbornene cooperative catalysis has significantly advanced Catellani‐type reactions, thus enabling future developments of this field. In this Minireview, Pd^II‐initiated Catellani‐type reactions and their application in the synthesis of bioactive molecules are summarized.     

Asymmetric Brønsted Acid‐Catalyzed Nazarov Cyclization of Acyclic α‐Alkoxy Dienones

A Brønsted acid‐catalyzed asymmetric Nazarov cyclization of acyclic α‐alkoxy dienones has been developed. The reaction offers access to chiral cyclopentenones in a highly enantioselective manner. The reaction is complementary to our previously reported Brønsted acid‐catalyzed electrocyclization reactions, which provided differently substituted optically active cyclopentenones with a fused tetrahydropyrane ring in good yields and with excellent enantioselectivities.     

A Green Approach for the One‐Pot,Three‐Component Synthesis of 2‐Arylpyrroloacridin‐1(2H)‐Ones using Lactic Acid as a Bio‐based Catalyst under Solvent‐Free Conditions

A facile and benign synthetic strategy is proposed for the synthesis of 2‐arylpyrroloacridin‐1(2H )‐ones via a lactic acid‐catalyzed three‐component reaction of dimedone, various anilines, and isatins under solvent‐free conditions. Avoidance of hazardous organic solvents, the use of a one‐pot multicomponent procedure for the synthesis of 2‐arylpyrroloacridin‐1(2H )‐ones, operational simplicity, no need for column chromatography, lactic acid utilization as a bio‐based organic compound, reusability, homogeneity, and commercial availability of the catalyst, and superior synthetic performance are some important aspects of this methodology to access a series of pyrroloacridine motifs with potentially biological scaffolds.     

Dual Hard/Soft Gold Catalysis: Intermolecular Friedel–Crafts‐Type α‐Amidoalkylation/Alkyne Hydroarylation Sequences by N‐Acyliminium Ion Chemistry

Gold catalysts have been applied in cascade‐type reactions for the synthesis of different nitrogen‐based compounds. The reactions likely proceed by a new gold‐catalyzed cascade intermolecular α‐amidoalkylation/intramolecular carbocyclization cascade process by unifying both the σ‐ and π‐Lewis acid properties of the gold salts. In the first part of this report we show that the σ‐Lewis acidity of gold(I) and gold(III) could be exploited to efficiently catalyze the nucleophilic substitution of various alkoxy‐ and acetoxylactams. The reaction was found to be applicable to a wide range of cyclic N‐acyliminium ion precursors and various nucleophiles, including allyltrimethylsilane, silyl enol ethers, arenes, and active methylene derivatives. As a logical progression of this study, a combined hard/soft binary catalytic gold system was then used to implement an unprecedented tandem intermolecular Friedel–Crafts amidoalkylation/intramolecular hydroarylation sequence allowing an expedient access to new, complex, fused polyheterocyclic structures from trivial materials.     

Lewis Acid‐Assisted Ene Cyclization of 2‐Azetidinone‐Tethered Enals: Synthesis of Enantiopure Carbacepham Derivatives

Diastereocontrolled Lewis acid‐catalyzed preparation of enantiopure carbacepham derivatives have been developed starting from 2‐azetidinone‐tethered enals. The BF₃?Et₂O‐promoted reaction of alkenylaldehydes 1 and 16 is effective as carbocyclization protocol to afford 4‐substituted 5‐hydroxycarbacephams or 3‐substituted 4,5‐dihydroxycarbacephams, respectively, by a type I carbonyl‐ene reaction, while the BF₃?Et₂O or SnCl₄‐mediated type II carbonyl‐ene cyclization of alkenylaldehydes 2 furnishes 3‐methylene 5‐hydroxycarbacephams along with the corresponding 3‐halo 5‐hydroxycarbacepham. The stereochemical outcome of these carbonyl‐ene cyclizations leading to carbacepham derivatives can be explained in terms of six‐membered, cyclic chair‐like transition‐state models. The formation of halocarbacepham derivatives is proposed to proceed by a stepwise mechanism.     

Ligand‐free,copper‐catalyzed,one‐pot,three‐component synthesis of novel 1,2,3‐triazole‐linked indoles in magnetized water

Magnetized water (MW) is used as a green and new solvent‐promoting medium for the one‐pot, three‐component synthesis of novel 1,2,3‐triazole‐linked indoles catalyzed by copper iodide. A broad range of 2‐aryl‐1‐(prop‐2‐ynyl)‐1H‐indole‐3‐carbaldehydes were reacted with alkyl halides and sodium azide via copper‐catalyzed azide–alkyne cycloaddition reactions in MW in the absence of any ligand. This method offers the advantages of short reaction times, green procedure, low cost, simple work‐up, quantitative reaction yields, and no need for any organic solvent.     

Advances in Copper‐Catalyzed C?C Coupling Reactions and Related Domino Reactions Based on Active Methylene Compounds

Active methylene compounds are a major class of reaction partners for C? C bond formation with sp² C? X (X=halide) fragments. As one of the most‐classical versions of the Ullmann‐type coupling reaction, activated‐methylene‐based C? C coupling reactions have been efficiently employed in a large number of syntheses. Although this type of reaction has long relied on noble‐metal catalysis, the renaissance of copper catalysis at the end of last century has led to dramatic developments in Ullmann C? C coupling reactions. Owing to its low cost, abundance, as well as excellent catalytic activity, the exceptional atom economy of copper catalysis is gaining widespread attention in various organic synthesis. This review summarizes the advances in copper‐catalyzed intermolecular and intramolecular C? C coupling reactions that use activated methylene species as well as in tandem reactions that are initiated by this transformation.     

Mechanism of Phosphine‐Catalyzed Allene Coupling Reactions: Advances in Theoretical Investigations

Organocatalysis has emerged as an effective strategy for chemical synthesis. Within this area, phosphine‐catalyzed coupling reactions have attracted considerable attention because of their versatility and wide range of applications in the construction of new C?C bonds. Recently, various experimental studies on the phosphine‐catalyzed coupling reaction of allenes have been reported, and mechanistic and computational studies have also progressed considerably. As a nucleophile, phosphine can react with an allene to form a zwitterionic phosphoniopropenide intermediate. After stepwise cycloaddition and proton transfer, the phosphine catalyst can be regenerated by C?P bond cleavage. Alternatively, the zwitterionic phosphoniopropenide intermediate could also be protonated by a Brønsted acid to generate a phosphonium intermediate, which can be used to construct new C?C bonds by electrophilic addition. In this review, we have summarized details of mechanistic studies of phosphine‐catalyzed allene coupling reactions that follow these two reaction modes. In addition to detailing the reaction pathway, the regioselectivity and diastereoselectivity of the phosphine‐catalyzed allene coupling reaction are also discussed in this review.     

Concurrent Asymmetric Reactions Combining Photocatalysis and Enzyme Catalysis: Direct Enantioselective Synthesis of 2,2‐Disubstituted Indol‐3‐ones from 2‐Arylindoles

The combination of photoredox and enzymatic catalysis for the direct asymmetric one‐pot synthesis of 2,2‐disubstituted indol‐3‐ones from 2‐arylindoles through concurrent oxidization and alkylation reactions is described. 2‐Arylindoles can be photocatalytically oxidized to 2‐arylindol‐3‐one with subsequent enantioselective alkylation with ketones catalyzed by wheat germ lipase (WGL). The chiral quaternary carbon center at C2 of the indoles was directly constructed. This mode of concurrent photobiocatalysis provides a mild and powerful strategy for one‐pot enantioselective synthesis of complex compounds. The experiments proved that other lipases containing structurally analogous catalytic triad in the active site also can catalyze the reaction in the same way. This reaction is the first example of combining the non‐natural catalytic activity of hydrolases with visible‐light catalysis for enantioselective organic synthesis and it does not require any cofactors.