Transition-Metal-Catalyzed Cross-Couplings through Carbene

Review pubs.acs.org/CR

Transition-Metal-Catalyzed Cross-Couplings through Carbene Migratory Insertion Ying Xia, Di Qiu, and Jianbo Wang* Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing 100871, China ABSTRACT: Transition-metal-catalyzed cross-coupling reactions have been wellestablished as indispensable tools in modern organic synthesis. One of the major research goals in cross-coupling area is expanding the scope of the coupling partners. In the past decade, diazo compounds (or their precursors N-tosylhydrazones) have emerged as nucleophilic cross-coupling partners in C−C single bond or CC double bond formations in transition-metal-catalyzed reactions. This type of coupling reaction involves the following general steps. First, the organometallic species is generated by various processes, including oxidative addition, transmetalation, cyclization, C−C bond cleavage, and C−H bond activation. Subsequently, the organometallic species reacts with the diazo substrate to generate metal carbene intermediate, which undergoes rapid migratory insertion to form a C−C bond. The new organometallic species generated from migratory insertion may undergo various transformations. This type of carbenebased coupling has proven to be general: various transition metals including Pd, Cu, Rh, Ni, Co, and Ir are effective catalysts; the scope of the reaction has also been extended to substrates other than diazo compounds; and various cascade processes have also been devised based on the carbene migratory insertion. This review will summarize the achievements made in this field since 2001.

CONTENTS 1. Introduction 1.1. Brief Introduction to Metal Carbene 1.2. Brief Introduction to Metal-Carbene Migratory Insertion 1.3. General Principle of Coupling with Carbene Precursors 2. Pd-Catalyzed Carbene Coupling Reactions 2.1. Coupling with Electrophiles 2.1.1. N-Tosylhydrazones as the Carbene Precursors 2.1.2. N-Tosylhydrazones Bearing Functional Groups as the Carbene Precursors 2.1.3. Diazo Compounds as the Carbene Precursors 2.2. Carbene Coupling with Nucleophiles 2.2.1. Organoboron Compounds as the Nucleophiles 2.2.2. Coupling with Carbon Nucleophiles 2.2.3. Heteroatom Nucleophiles and Amphiphiles 2.3. Cascade Reactions 2.3.1. Cascade Process prior to Carbene Migratory Insertion 2.3.2. Cascade Process of the Coupling Products 2.3.3. Cascade Process Embodied in One Catalytic Cycle 3. Cu-Catalyzed Carbene Coupling Reactions 3.1. Reaction with Terminal Alkynes © 2017 American Chemical Society

3.1.1. Allenes as the Coupling Products 3.1.2. Alkynes as the Coupling Products 3.1.3. Cascade Reactions 3.2. Reaction with Arenes via C−H Bond Functionalization 3.3. Reaction with Other Coupling Partners 4. Rh-Catalyzed Carbene Coupling Reactions 4.1. Carbene Couplings Involving Transmetalation or C−C Bond Cleavage 4.1.1. Transmetalation 4.1.2. C−C Bond Cleavage 4.2. Carbene Couplings Involving C−H Activation without Cyclization 4.2.1. Reactions Terminated by Protonation 4.2.2. Reactions Not Involving Protonation 4.3. Carbene Couplings Involving C−H Activation and Cyclization 4.3.1. Cyclizations Occurred through Reductive Elimination 4.3.2. Cyclizations Occurred through Condensation or 1,2-Addition 5. Other Transition-Metal-Catalyzed Carbene Couplings 5.1. Co- and Ni-Catalyzed Reactions 5.2. Ir- and Ru-Catalyzed Reactions 5.3. Pt- and Ag-Catalyzed Reactions 6. Non-Diazo Compounds as Carbene Precursors

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Received: June 27, 2017 Published: November 1, 2017 13810

DOI: 10.1021/acs.chemrev.7b00382 Chem. Rev. 2017, 117, 13810−13889

Chemical Reviews 6.1. Alkynes, Allenes, and Cyclopropenes as the Carbene Precursors 6.2. Carbene Formation via Nitrogen Extrusion from Nondiazo Compounds 6.3. Other Related Reactions 7. Summary Author Information Corresponding Author ORCID Author Contributions Notes Biographies Acknowledgments Abbreviations References

Review

1.1. Brief Introduction to Metal Carbene 13870

Metal carbene complexes refer to a type of organometallic compounds bearing a neutral divalent carbon ligand. 21 Historically, the synthesis of metal carbene complex can be dated back to the early 20th century. In 1925, Chugaev and coworkers discovered that a platinum(II) isocyanide complex reacted with hydrazine to afford a red platinum salt 1, which reacted with HCl to form a yellow platinum salt 2 (Scheme 2).22

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Scheme 2. Chugaev’s Synthesis of Platinum(II) Complex

1. INTRODUCTION Transition-metal-catalyzed cross-coupling reactions have been well-established as indispensable tools in modern organic synthesis.1−3 In general, a nucleophile (e.g., organometallic regent) and an electrophile (e.g., organic halide) serve as the coupling partners in a cross-coupling reaction, in which the new chemical bond is formed between the two fragments using a transition metal as the catalyst (Scheme 1).1−5 One of the major

However, they could not characterize the structure of these platinum salts 1 and 2, the first synthesized metal-carbene complex, due to the lack of required spectroscopic techniques at that time. The elucidation of these metal diaminocarbene complexes was ultimately realized almost 40 years later by means of NMR and X-ray single crystal diffraction.23−25 In 1964, Fischer and Maasböl found that the treatment of W(CO)6 with phenyl lithium followed by methylation with CH2N2 could result in the formation of a new tungsten complex 3, which was unambiguously characterized and featured the metal carbene structure (Scheme 3).26 The methoxyphenylmethylene tung-

Scheme 1. Transition-Metal-Catalyzed Cross-Coupling Reactions

Scheme 3. Fischer’s Synthesis of Metal Carbene Complex

sten(0) pentacarbonyl synthesized by Fischer and Maasböl is considered as the first recognized metal carbene complex. This method was subsequently applied to the synthesis of chromium(0), iron(0), and manganese(0) carbene complexes bearing different alkoxy- and alkyl-groups.27 This kind of metal carbene complex was later defined as the Fischer-type metal carbene, in which the carbene is in the singlet state and the carbenic carbon has a sp2-hybridized lone pair (σ electron) and an unoccupied p-orbital. The σ lone pair of the carbene donates to the vacant d orbital of the metal, and simultaneously π-back-donation occurs from the metal d-orbital to the unoccupied carbene p-orbital, which collectively constitutes the metal−carbon bond in the Fischer-type metal carbene complex (Scheme 4).21,28 Fischer-type carbene complexes are generally found in middle or late transition metals with low oxidation states, having heteroatom (π-donor) substituents on carbene center such as alkoxy or amino groups. The carbene centers in Fischer-type carbene complexes are

research goals in cross-coupling area is the expanding of the scope of the coupling partners.4−9 For the nucleophilic crosscoupling partners, the substrates have evolved from organometallic reagents, such as Grignard reagents in the early years,5,6 to carboxylic acids (decarboxylative coupling)7,8 and C−H bonds (C−H bond activation)9−15 more recently. While for the electrophilic cross-coupling partners, the substrates have been expanded from halides or pseudohalides5 to the inert ethers or alcohols (C−O bond activation).16−20 Although the field has witnessed remarkable progresses in the past decades,4−20 the exploration of novel cross-coupling partners is still highly demanded, and it remains a dynamic research area until now. In this context, carbene precursors have recently emerged as a new type of cross-coupling partners, which will be the focus of this review.

Scheme 4. Metal−Carbon Bond in Fischer Carbene Complex

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Wanzlick35 and Ö fele.36 The structure of free carbene 9 was unambiguously confirmed by X-ray crystallography, which has remarkable stability both in solution and in the solid state (Scheme 7b). Since then, explosive developments have been witnessed in metal carbene chemistry mainly because NHCs turned out to be excellent ligands that are comparable to phosphine ligands for transition metals.37−42 Metal carbenes nowadays are important reaction intermediates or catalysts for many organic reactions. On the one hand, metal carbenes are generally proposed as active intermediates in carbene-related transformations, such as cyclopropanations, X− H (X = C, Si, O, S, N, etc.) insertions, ylide formations, 1,2migrations, and others. In these reactions, metal carbene intermediates are typically generated from the decomposition of diazo compounds (Scheme 8).43−47

electrophilic in character, which tend to undergo nucleophilic attack (Scheme 4). In 1974, Schrock reported the first synthesis of alkylcarbene complex of tantalum 5 by reaction of trineopentyl tantalum(V) dichloride 4 with two equivalents of neopentyllithium followed by α-hydrogen abstraction (Scheme 5).29 Scheme 5. Synthesis of the Alkylcarbene Complex

This type of alkylcarbene complex was later defined as the Schrock carbene complex.21,28,30,31 The two unpaired electrons interact with the metal d orbital to form a covalent double bond between the metal and the carbenic carbon. Schrock carbene complexes generally exist in early transition metals with high oxidation states. The carbene center is nucleophilic and can react with electrophiles, which resemble an ylide, as compared with phosphine ylides in Wittig reaction, rather than as a carbene (Scheme 6).

Scheme 8. Metal Carbenes as Reactive Intermediates in Carbene-Related Reactions

Scheme 6. Metal−Carbon Bond in Schrock Carbene Complex

On the other hand, there are various stable metal carbene complexes, and few of them are active catalysts in modern organic reactions.37−42 One of the most representative application is the use as type of catalyst for olefin-metathesis. Grubbs’ first- and second-generation catalysts 11a and 11b, Hoveyda−Grubbs II catalyst 11c are now commercially available and widely used in olefin-metathesis (Scheme 9).48,49 In

Although a series of transition metal carbene complexes had been synthesized and characterized, the search of stable free carbenes remained elusive before the 1990’s.32 In 1988, Bertrand and co-workers reported the synthesis of a free carbene, which was stabilized by adjacent phosphorus and silicon substituents.33 By flash thermolysis of diazo compound 6 at 250 °C under vacuum, free carbene 7 can be isolated in good yield as a red oil, which is a thermally stable but kinetically quite reactive compound (Scheme 7a). Three years later, Arduengo and coworkers reported the isolation of a stable N-heterocyclic carbene (NHC) by deprotonation of N,N′-diadamantyl imidazolium salt 8 using sodium hydride (with catalytic amount of DMSO) or tBuOK as the base.34 Interestingly, the first preparations of metal-NHC complexes were actually realized more than 20 years before the first isolation of this free carbene, independently by

Scheme 9. Transition Metal Catalysts Bearing Carbene Ligands

Scheme 7. Early Studies on the Synthesis of Stable Free Carbenes

addition, transition-metals bearing carbene ligands are also used as effective catalysts in cross-coupling reactions.37,50−53 Due to the steric and electronic properties of the carbene ligands,37 this type of catalysts show excellent reactivity for a range of coupling reactions, such as the Negishi, Suzuki−Miyaura, and Buchwald−Hartwig coupling reactions.50−54 One of the most 13812


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complex 15 and 16 to produce the chloromethyl derivative. Another mechanism was also postulated, in which two zwitterion organomercury complexes 17 and 18 were formed, followed by 1,2 shift of chloride to deliver the final product (Scheme 11c). Here the formation of the product from complex 18 can be considered as carbene migratory insertion to mercury chlorine bond. Later, a series of work for which a methylene moiety “inserting” into metal−halogen bonds were reported by the reaction of metal salts with diazomethane.57 In 1966, Mango and Dvoretzky reported that the iridium complex 19 could react with diazomethane to afford a new iridium complex 21 bearing a chloromethyl ligand, most likely involving the 1,2-chloride shift of the proposed iridium carbene complex 20 (Scheme 12).58

widely explored metal-carbene catalysts, known as Pd−PEPPSI− NHC complex 12, is shown in Scheme 9.54 It should be noted that there are generally no heteroatom substituents on the metal carbene intermediates that are shown in Scheme 8.43−47 Compared with the classic Fischer carbene complexes, the carbene center in these nonheteroatom stabilized carbenes 10a is generally more electrophilic due to the lack of the heteroatom substituents that stabilize the carbene vacant porbital. In addition, the π-back-donation from the metal to the carbenic carbon is stronger than that in the case of metal NHC complexes, which to some extent provides stabilization to these very reactive carbene species.21,28 Overall, the chemical properties of these nonheteroatom stabilized metal carbene complexes are significantly different from the above-discussed Fischer-type carbenes, Schrock-type carbenes, or metal NHC complexes.21 The metal carbene intermediates that are proposed in the crosscoupling reactions discussed in this review are generally categorized as this type of nonheteroatom stabilized metal carbenes (vide infra).

Scheme 12. Reaction of Iridium Complex with Diazomethane

1.2. Brief Introduction to Metal-Carbene Migratory Insertion

As discussed above, the metal carbene complex has a neutral divalent unsaturated carbon ligand. When a suitable R ligand is coordinated to the metal center (13), there is a tendency that the R ligand migrates to the unsaturated carbenic carbon to form a metal complex (14). This process, as a metal carbene migratory insertion, is energetically favored because stable carbon−carbon bond is generated. As a comparison, it is considered similar to the migratory insertion process that occurs in a metal carbonyl complex (Scheme 10).55

The carbene migratory insertion to metal alkyl bond was proposed by Sharp and Schrock in 1979, during the study of preparation and reactivity of tantalum carbene complexes.59 They prepared a series of tantalum carbene complexes by alkylidene transfer. For example, the reaction of tantalum phosphine complex 22 with phosphorus ylide 23 afforded tantalum carbene complex 24 via formal ligand exchange. The tantalum carbene complex 24 decomposed over 70 °C due to the unsaturation nature of the carbene center, and 25 was isolated in 32% yield as the major product when heated at 75 °C in toluene. The formation of 25 was suggested to produce intermediate 26 via methyl group migration to the carbene ligand, followed by βhydride elimination, although they could not isolate the 16 electron complex 26 (Scheme 13).59 Later, Threlkel and Bercaw studied in detail the migratory insertion of the niobium carbene complex.60 They prepared a series of zirconoxy niobium carbene complexes 29 by the reaction of niobocene carbonyl complex 27 with zirconium hydride complex 28. Treatment of 29 with external ligands resulted in the formation of niobocene hydride complex 31 and zirconium enolate 32, which was proposed to follow a pathway

Scheme 10. Metal Carbene Migratory Insertion versus Metal CO Migratory Insertion

In 1932, Hellerman and Newman found that the addition of one equivalent of diazomethane to a cold mercuric chloride solution can afford quantitative yield of crystalline chloromethylmercuric chloride (Scheme 11a).56 When two equivalents of diazomethane was used, bis(chloromethyl)-mercury was obtained in quantitative yield (Scheme 11b). They proposed a mechanism that involved the formation of organomercuric ionic Scheme 11. Reaction of Mercuric Salt with Diazomethane

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Scheme 13. Reactivity of Tantalum Complex

Scheme 15. Evidence of Migratory Insertion of Tungsten Carbene Complexes

via the carbene migratory insertion to form the intermediate 30, followed by β-hydride elimination. A deuterium labeling experiment using niobium carbene complex 33 supported the carbene migratory insertion process, as niobium carbene complex 35 was observed which was formed via a migratory insertion/α-elimination sequence (Scheme 14). Kinetic experiments revealed that the relative aptitudes of migratory insertion for these niobium carbene complexes followed the order: H ≫ CH3 > CH2Ph, while the Ph group failed to undergo such kind of migratory insertion process. Another evidence for migratory insertion of a methylidene ligand into a transition-metal-methyl bond was reported by Copper and co-workers in 1981 (Scheme 15).61 Tungsten complex 36 was treated with 1-(diphenylmethylidene)-4-trityl2,5-cyclohexadiene (the dimer of the trityl radical) in THF, leading to the formation of the tungsten olefin complex 39, which was then deprotonated with KOH to eventually form Cp2W(C2H4) 42 in 96% yield based on 36. They proposed a mechanism that involved the formation of tungsten carbene complex 37, followed by migratory insertion of the carbene to the metal-methyl bond forming ethyl tungsten complex 38, which would undergo β-hydride elimination to produce 39. When the reaction was carried out in the presence of one equivalent of PMe2Ph, the formation of tungsten complex 40 was observed in 79% yield. This result supported the formation of the transient tungsten carbene complex 37, in which the electrophilic carbene center can react with nucleophilic phosphine to give 40. In addition, tungsten complex 40 could be converted to its isomeric complex 41 and the tungsten olefin complex 39, and full conversion to tungsten complex 41 could be achieved in 86% isolated yield based on 40 when prolonging the reaction time to 12 days. The formation of both 39 and 41 from 40 gave further evidence of the 37 to 38 conversion via a carbene migratory insertion process. Furthermore, a deuterium labeling experiment (using 1:1 ratio of 36 and 36-d6) indicated that the formation of

39 should involve an intramolecular C−C bond forming step to form the olefin moiety, most likely via a carbene migratory insertion process. In 1984, the same group further investigated the reactivity of the phenyl tungsten complex, and they obtained the evidence of tungsten carbene migratory insertion to metal-phenyl bond.62 Further, Green and co-workers carried out kinetic studies of tungsten carbene migratory insertion to the metal-hydride bond.63 Since then, more stoichiometric studies on migratory insertion of metal carbene complex to metal-hydride or metal− carbon bonds have appeared in the literature,55,64−72 which provided understanding for the recently developed transitionmetal-catalyzed cross-coupling process involving carbene process.73−84 1.3. General Principle of Coupling with Carbene Precursors

In 2001, Van Vranken and co-workers reported the first catalytic cross-coupling reaction that used a diazo compound as the carbene precursor.85 In this reaction, benzyl halides 43 reacted with TMSCHN2 44 under the catalysis of palladium complex to furnish the substituted styrene 45 as the coupling products. This reaction is initiated by oxidative addition of benzyl halide 43 to form benzyl palladium(II) intermediate 46, which reacts with diazo compound 44 to generate palladium carbene species 47 with extrusion of N2. The metal carbene migratory insertion process occurs with the palladium carbene intermediate 47, resulting in the formation of a new alkyl palladium species 48.

Scheme 14. Evidence of Migratory Insertion of Niobium Carbene Complexes

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Finally, a β-hydride elimination/olefin reinsertion/β-silyl elimination sequence generates the styrene product 45 with release of the palladium catalyst (Scheme 16, for clarity, all the neutral ligands are omitted in the scheme, the same below).

This is because metal carbene complexes that lack stability from the heteroatoms are generally too reactive to be isolated, although nonheteroatom stabilized palladium carbene complexes with some distinctive ligands can also be synthesized and characterized.96 Overall, although this seminal work suffered from limited substrate scope, the low yields and the lack of detailed mechanistic experiments, the concept that merges the carbene migratory process with a cross-coupling process proposed in this report laid down the foundation for further developments for the catalytic carbene coupling reactions.73−84 In the past decade, the transition-metal-catalyzed carbene coupling reaction has become a fast evolving area, in which the diazo compounds (or their precursors N-tosylhydrazones) have been extensively explored as nucleophilic cross-coupling partners in C−C single bond or CC double bond formations. The transformations so far developed in carbene-based crosscouplings are summarized in the Scheme 17. First, the organometallic species is generated through various typical processes of cross coupling, such as oxidative addition, transmetalation, cyclization, C−C bond cleavage, or C−H bond activation. Subsequently, the organometallic species reacts with diazo substrate or other carbene precursor to generate the metal carbene intermediate, which undergoes rapid migratory insertion to form a C−C bond. The new organometallic species generated from migratory insertion may undergo various transformations, such as β-hydride elimination, protonation, transmetalation/reductive elimination, etc. The carbene-based couplings have proven to be general: the complexes of various transition-metals, including Pd, Cu, Rh, Ni, Co, and Ir, are effective catalysts; the scope of the reaction has also been extended to substrates other than diazo compounds;83,84 and various cascade processes can be devised based on the carbene migratory insertion process (Scheme 17). This review will cover the transition-metal-catalyzed crosscouplings with carbene precursors involving carbene migratory insertion reported in the literature up to April 2017, while those stoichiometric carbene coupling reactions,59−72,86−95 carbenerelated reactions not involving a migratory insertion process,43−47 and carbene polymerization97 are not in the scope of this review. The catalytic carbene coupling reactions using diazo compounds or N-tosylhydrazones as carbene precursors will be

Scheme 16. Pd-Catalyzed Cross-Coupling of Benzyl Halides with TMSCHN2

The difference between this carbene coupling reaction and the traditional coupling reaction (Scheme 1) is the supposed metal carbene migratory insertion process (from 47 to 48), although no direct experimental evidence supports this mechanism in the seminal work. Experimental evidence on palladium carbene migratory insertion has been obtained with some heteroatomstabilized carbene complex, such as some palladium NHC complexes86−88 or palladium carbene complexes obtained from transmetalation with classic Fischer carbene complexes.89−94 However, the migratory insertion process of metal carbene complexes that do not have a heteroatom atom adjacent to the carbene center is very difficult to be confirmed experimentally.95 Scheme 17. Summary of Carbene Coupling Reactions

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Scheme 18. General Process of Palladium-Catalyzed Carbene Coupling Reactions

the olefin product. The generated Pd(II) species 58 undergoes reductive elimination to give Pd(0) catalyst and finish the catalytic cycle. N-Tosylhydrazones derived from both ketones and aldehydes are competent coupling partners, but an elevated reaction temperature is required to achieve decent yields for Ntosylhydrazones derived from aliphatic ketones (Scheme 19).

discussed based on the classification of the transition metal catalysts, which includes palladium, copper, rhodium, and others. Furthermore, catalytic carbene coupling reactions using nondiazo compounds as carbene precursors will also be discussed following the classification of the carbene sources.

2. PD-CATALYZED CARBENE COUPLING REACTIONS As mentioned in section 1.3, the catalytic carbene coupling reaction was first reported for a palladium-catalyzed reaction.85 Since the seminal work, a wide range of palladium-catalyzed carbene coupling reactions have been developed. The general process of these palladium-catalyzed carbene coupling reactions is depicted in Scheme 18. The reaction is initiated by the formation of an organopalladium species 51 from a variety of electrophiles or nucleophiles via oxidative addition, transmetalation, C−H activation, or cascade process. The intermediate 51 then reacts with diazo substrate to generate a palladium carbene species 52, which is followed by migratory insertion to produce an alkyl palladium species 53. The alkyl intermediate 53 has rich downstream transformations, in which the β-hydride elimination process is a major reaction pathway, forming a CC bond to furnish olefin 54 as the coupling product. In addition, 53 can be trapped by an intermolecular or intramolecular nucleophile to give multicomponent coupling product or cyclic product, respectively. Finally, other types of cascade processes, such as the process to form 51 and cascade transformations of the coupling product 54, can be merged with the carbene coupling reactions. A Pd(0)/Pd(II) catalytic cycle is generally involved in the palladium-catalyzed carbene coupling reactions.

Scheme 19. Pd-Catalyzed Carbene Coupling Reaction of Aryl Halides with N-Tosylhydrazones

2.1. Coupling with Electrophiles

2.1.1. N-Tosylhydrazones as the Carbene Precursors. Although diazo compounds have been extensively explored as carbene precursors in transition-metal-catalyzed reactions, the stability and safety issues related to these compounds are obviously obstacles that limit their wide applications. The search of nondiazo carbene precursors have become an attractive research area in recent years. In this context, a major breakthrough was reported by Barluenga and co-workers in 2007, who first utilized N-tosylhydrazones as the precursor of diazo compounds in the carbene coupling reaction.98 The combination of Pd2(dba)3 with XPhos constitutes an excellent catalytic system, in which aryl halide and N-tosylhydrazone are coupled in the presence of base to afford polysubstituted olefins in good to excellent yields with high stereoselectivity. This reaction is initiated by the oxidative addition of aryl halide to Pd(0) species to generate aryl palladium(II) complex, which would react with the in situ generated diazo compound 55 via a Bamford-Steven reaction99 to form palladium carbene intermediate 56. Migratory insertion of the metal carbene to the arylPd bond results in the formation of an alkyl palladium intermediate 57, followed by β-hydride elimination to produce

As N-tosylhydrazones can be easily prepared via the condensation of the corresponding ketones or aldehydes with TsNHNH2, this reaction provides a new mode to perform crosscoupling reaction with carbonyl compounds, a process traditionally achieved through the coupling of enol triflates with organometallic reagents. In the coupling reaction with enol triflates, stoichiometric organometallic reagents are required; while in the new method, N-tosylhydrazones serve as the nucleophilic cross coupling partners. In addition, employing the readily available and easy-to-handle N-tosylhydrazones as the carbene precursors largely enhances the practical applicability of the carbene coupling reactions. 13816


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Alami and co-workers reported a catalytic system for achieving the cross-coupling reaction of sterically hindered N-tosylhydrazones 61 with aryl halides, affording tetra-substituted olefins 62 in good yields.101 The combination of Pd(MeCN)2Cl2 as the precatalyst, bidentate phosphine dppp as the ligand and Cs2CO3 as the base is crucial for the high yielding coupling, in which the formation of byproduct 63 via the decomposition of the in situ generated diazo compound from N-tosylhydrazone 61 can be largely suppressed. In addition, the reaction conditions also worked very well for simple N-tosylhydrazones and could be applied in the synthesis of biologically relevant molecule 66 (a type of CYP17 inhibitor), starting from N-tosylhydrazone 64 and 4-iodopyridine (Scheme 20b). Later, the same group modified this catalytic system to achieve the coupling reaction of extremely sterically encumbered N-tosylhydrazones and/or aryl halides bearing ortho-substituents on the aryl moiety, in which ortho/ ortho’-substituted 1,1-diarylethylenes 68 can be synthesized in high yields (Scheme 20d).102 In 2012, Ojha and Prabhu disclosed that the simple Pd(PPh3)2Cl2 could catalyze the coupling reaction between Ntosylhydrazones and aryl halides in the absence of external ligands (Scheme 20c).103 Furthermore, this coupling reaction can be applied in the synthesis of some biologically active molecules.104−107 As an example shown in Scheme 20e, a 3-(αstyryl)benzo[b]thiophene library 70, which showed the activity of inhibiting tubulin polymerization, could be easily prepared via the Pd-catalyzed carbene coupling reaction of N-tosylhydrazones with 3-bromobenzo[b]thiophenes 69 in excellent yields.107 Apart from aryl halides, oxygen-based aryl electrophiles were also competent substrates to couple with N-tosylhydrazones (Scheme 21).108−111 In 2009, Alami and co-workers reported the cross-coupling reaction of aryl triflates with N-tosylhydrazones to synthesize 1,1-diarylethylenes using a combination of Pd(OAc)2 with XPhos as the catalytic system (Scheme 21a).108 Later, Barluenga and Valdés developed a similar reaction using aryl nonaflates as the coupling partners for the synthesis of polysubstituted olefins.109 In this reaction, water and LiCl were required in order to achieve a high yielding transformation. Interestingly, when aryl nonaflate bearing an ortho-substituent (72) was used as substrate, trisubstituted olefin 73 was obtained as a single stereoisomer in which the alkyl group and the orthosubstituted arene were in a cis configuration. Instead, without this ortho-substituent (74), a similar reaction only afforded a 1:1 mixture of isomeric olefins 75 (Scheme 21b). In 2014, Chikhalia and co-workers reported the carbene crosscoupling of coumarin or quinolinone 4-tosylates 76 with Ntosylhydrazones to furnish the corresponding alkenylated coumarin or quinolinone 77 in good to excellent yields.110 The use of bulky Buchwald ligand tBuBrettPhos is the key to achieve a high yield. In addition, the mesylate analogue (76a) and alkenyl mesylates (76b−d) are also useful substrates for coupling with N-tosylhydrazones under the same reaction conditions (Scheme 21c). Soon after, the same group reported a one-pot, two-step coupling reaction of 4,6-dimethoxy-1,3,5-triazin-2-ol 78 with Ntosylhydrazones under slightly modified reaction conditions, affording 1,1-heterodiaryl olefins 79 in excellent yields.111 The use of PyBroP can convert the heteroarenol to the corresponding phosphonium oxide intermediate, which undergoes facile C−O bond activation in the second step to eventually form the olefin product. Apart from 78, a range of heteroarenols can be used as electrophiles to participate in this Pd-catalyzed PyBroP mediated carbene coupling reaction (Scheme 21d).

Following this report, the Pd-catalyzed cross-coupling reactions of aryl halides with N-tosylhydrazones have been extensively explored. The coupling reaction provides an efficient synthesis of arylated olefins, with carbene migratory insertion and β-hydride elimination being the key steps in the reaction mechanism (Scheme 20).100−105 In 2008, Barluenga and coScheme 20. Further Developments on Pd-Catalyzed Carbene Coupling Reaction of Aryl Halides with Simple NTosylhydrazones

workers demonstrated that the one-pot, one-step operation was also very efficient under similar reaction conditions, thus the carbonyl compounds could be directly used as the coupling partners through the in situ formation of N-tosylhydrazones in the presence of tosylhydrazine.100 Using this single operation, a series of polysubstituted olefins, including 4-aryltetrahydropyridines 60 which are important building blocks in medicinal chemistry, can be synthesized from the corresponding ketone or aldehyde in high yields (Scheme 20a). 13817


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Scheme 21. Pd-Catalyzed Carbene Coupling Reaction of Oxygen-Based Aryl Electrophiles with Simple NTosylhydrazones

Scheme 22. Two Reaction Modes of Pd-Catalyzed Carbene Coupling Reaction of Aryl Electrophiles with Simple NTosylhydrazones

intermediate 82, followed by a carbene migratory insertion process to form trityl palladium species 83. Ammonium formate was used as a hydride source to generate the Pd-hydride species 84, which might undergo reductive elimination to give the product 81 with regeneration of the Pd(0) catalyst (Scheme 23a). Scheme 23. Pd-Catalyzed Carbene Coupling Reaction to Form C(sp2)-C(sp3) Bond

Very recently, Wang and co-workers further reported the Pdcatalyzed reductive carbene coupling reaction of N-tosylhydrazones derived from aryl aldehydes with aryl bromides using PCy3 as the ligand and isopropanol as the reductant, affording a range of diarylmethanes in good yields (Scheme 23b).113 It should be mentioned that this type of Pd-catalyzed reductive coupling reaction was only restricted to the N-tosylhydrazones that do not bear α-hydrogen. Thus, the generated alkyl palladium intermediate (e.g., 83) cannot undergo β-hydride elimination. It is meaningful but challenging to broaden this concept to simple N-tosylhydrazones, which should provide a general method to construct C(sp2)−C(sp3) single bond via reductive carbene coupling reaction. The aryl C−F bond can also participate in the cross-coupling with carbene precursors in certain cases. Thus, the ortho-nitro aryl fluorides participated in the carbene coupling reaction with N-tosylhydrazones using simple Pd(PPh3)4 as the catalyst, affording di- and trisubstituted olefins 87 in good yields (Scheme 24).114 However, the aryl fluoride 86 must have a nitro substituent in the position ortho to the fluoride to activate the C−F bond. The formation of trisubstituted olefins was featured

Similar to the above-discussed cross-coupling reactions between aryl electrophiles and N-tosylhydrazones, the benzyl palladium intermediate generated from carbene migratory insertion was terminated with β-hydride elimination to construct CC double bond and furnish the synthesis of arylated olefins. In addition to this reaction mode in which the N-tosylhydrazone serves as an alkenyl metallic reagent, the benzyl palladium intermediate also undergoes reduction to regenerate the Pd(0) catalyst in the presence of a suitable reductant. In this case Ntosylhydrazone can be considered as an alkyl metallic reagent to construct C(sp2)−C(sp3) single bond (Scheme 22). In 2013, Wang and co-workers demonstrated the concept of using N-tosylhydrazone as an alkyl metallic reagent, in which the Pd-catalyzed carbene cross-coupling reaction of N-tosylhydrazones and aryl bromides was able to form C(sp2)−C(sp3) single bonds.112 A series of N-tosylhydrazones derived from diaryl ketones was smoothly converted into the corresponding triarylmethanes in good to excellent yields. This reaction was proposed to proceed via the formation of Pd-carbene 13818


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Scheme 24. Pd-Catalyzed Reaction of Aryl Fluorides with NTosylhydrazones

Scheme 25. Pd-Catalyzed Reaction of Activated Alkyl Electrophiles with N-Tosylhydrazones

by high Z-selectivity of the newly formed double bond due to the ortho-directing effect.109 In addition to aryl electrophiles, activated alkyl electrophiles are also competent coupling partners to participate in the Pdcatalyzed carbene coupling reactions with simple N-tosylhydrazones.115−118 In 2009, Wang and co-workers reported the Pdcatalyzed cross-coupling reaction of benzyl halides with Ntosylhydrazones, which provided di- and trisubstituted olefins in excellent yields.115 This reaction was proposed to involve carbene migratory insertion to the benzyl-metal bond, and the following β-hydride elimination occurred at the benzyl moiety to give the desired olefins. The weakly electron-deficient tri(2furyl)phosphine ligand performed very well for this transformation. A wide range of N-tosylhydrazones, including those derived from aromatic or aliphatic ketones and aldehydes, were all suitable substrates to furnish the corresponding olefins smoothly (Scheme 25a). In 2011, Liang and co-workers used propargylic carbonates 90 as electrophiles to couple with N-tosylhydrazone sodium salts 89, which gave vinyl allenes 91 in moderate to good yields.116 The use of BTAC as the phase transfer catalyst (PTC) was necessary to promote the transformation, otherwise, the propargylic Ntosylhydrazones would be produced predominately via C−N bond formation if dppp were used as the ligand. The reaction may involve the formation of an allenyl palladium carbene intermediate, followed by a carbene migratory insertion to the allenyl-metal bond. This reaction is a facile method to access conjugated vinyl allene compounds which are difficult to synthesize by traditional methods (Scheme 25b). Recently, Wang and co-workers have further achieved the coupling reaction of N-mesylhydrazones 92 with allylic bromides 93 to afford conjugated diene compounds 94.117 The reason for using N-mesylhydrazone in lieu of N-tosylhydrazone is to suppress direct N-allylation of the deprotonated hydrazone with allylic bromide, probably through reducing the nucleophilicity of the nitrogen. However, this reaction was restricted to Nmesylhydrazones derived from diaryl ketones, which limited its application in organic synthesis (Scheme 25c). Furthermore, Wu and co-workers reported the use of allenylphosphine oxides 95 as the electrophiles to participate in the carbene coupling reaction with simple N-tosylhydrazones to furnish phosphinyl[3]dendralenes 96 as the coupling products.118 In this reaction, the oxidative addition to the C(sp2)−O bond in allenylphosphine oxide leads to the formation of a πallyl-palladium species, which reacts with the in situ generated diazo compound to form the key intermediate Pd-carbene 97. The geometry of the newly formed double bond has high Zselectivity (96c, 96d), while the configuration of the double bond originated from the allene moiety is largely dependent on the substrates (96b, 96e). A wide range of phosphinyl[3]dendralenes can be obtained up to 99% yield via this transformation (Scheme 25d).

2.1.2. N-Tosylhydrazones Bearing Functional Groups as the Carbene Precursors. The Pd-catalyzed carbene coupling reaction of functionalized N-tosylhydrazones generates olefin products bearing various substituents, which may serve as useful synthetic building blocks. In 2009, Barluenga and Valdés reported a Pd-catalyzed cross-coupling reaction of α-heteroatom substituted N-tosylhydrazones (directly used or generated in situ from the corresponding carbonyl compounds 98a) with aryl halides, which furnish the synthesis of enol ethers and enamines 99 in good yields.119 The enol ethers can be hydrolyzed smoothly under acidic conditions to afford the corresponding aldehyde 100. They may also undergo acid-promoted cyclization to give indole product 101 in good yields when the aryl halide partners contain ortho-amino moieties (Scheme 26a). The same strategy has been applied in the coupling of α-N-azoleketones 98b with ortho-substituted aryl bromides or nonaflates 102a, affording Nalkenylazoles 103a in good yields with good E-selectivity.120 When 1,2-dibromoarenes 102b were employed as the substrates, a cascade intramolecular C−H arylation occurs, followed by the carbene coupling reaction, affording pyrroloisoquinoline derivatives 103b in good yields (Scheme 26b). Furthermore, when N-tosylhydrazones derived from α-chiral ketones 104 are used as the substrates, the coupling reaction with aryl halides affords the corresponding arylated olefins 105 with complete retention of the stereochemistry of the chiral α13819


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In 2010, Barluenga and Valdés reported an efficient method for the synthesis of conjugated dienes via Pd-catalyzed carbene coupling reaction. 124 The coupling reaction of the Ntosylhydrazones derived from enones 110 with aryl halides afforded polysubstituted dienes 111 in high yields. Alternatively, another type of dienes 113 could be obtained in moderate yields via the cross-coupling reaction of simple N-tosylhydrazones with alkenyl bromides 112 under slightly modified reaction conditions. Notably, carbene migratory insertion to the alkenyl-metal bond was involved as the key step (Scheme 27).

Scheme 26. Pd-Catalyzed Reaction of Aryl Halides with the NTosylhydrazones bearing Functional Groups

Scheme 27. Diene Synthesis via Pd-Catalyzed Carbene Coupling Reactions

Very recently, Valdés and co-workers substantially expanded the substrate scope of the Pd-catalyzed coupling reaction between simple N-tosylhydrazones and alkenyl bromides, which can be used for the stereocontrolled synthesis of highly substituted dienes and polyenes.125 Pd-catalyzed cross-coupling reaction of aryl halides with Ntosylhydrazones 114 derived from cyclopropyl ketones was reported to produce 1,1-disubstituted conjugated dienes 115.126 Similar to the previously introduced carbene coupling reactions, this reaction has been proposed to proceed via the formation of palladium carbene intermediate 116, which undergoes a carbene migratory insertion process to afford the cyclopropylmethyl palladium intermediate 117. Due to the ring strain of this cyclopropyl moiety, β-hydride elimination does not occur even in the case when R is a Me group; instead, a β-carbon elimination occurs leading to the opening of the cyclopropyl ring to form a new alkyl palladium intermediate 118. Finally, β-hydride elimination of 118 gives the desired diene products 115 and regenerates the palladium catalyst. The E/Z selectivity of this reaction is controlled by the steric bulkiness of the substituents R and Ar. When R and Ar have similar steric hindrances, the E/Z selectivity was poor (115a). When aryl halide has an orthosubstituent (115b) or Ar is much larger than R group (115c, 115d), the reaction affords Z-isomer as the major product. In addition, similar palladium intermediate 117 can also be generated in the coupling reaction of diaryl N-tosylhydrazones with cyclopropyl bromide, by which diaryl-substituted dienes 119 is synthesized under modified reaction conditions. Although the yields are only moderate and the substrate scope is limited, this reaction is a good example using an alkyl electrophile to participate in the carbene coupling reactions which probably involve an unusual carbene migratory insertion to the cyclopropyl-metal bond (Scheme 28a). Soon after, Yu and co-workers reported a similar transformation of cyclopropyl N-tosylhydrazones with aryl bromides

carbon.121 A series of aryl-substituted chiral cyclohexenes (105a) and chiral allylamines (105b, 105c) can be readily accessed from the corresponding α-chiral ketones (Scheme 26c). In 2011, Alami and co-workers used N-tosylhydrazones 106 bearing a remote ethyoxyl group as the substrates to participate in the Pd-catalyzed carbene coupling reaction with orthosubstituted aryl halides.122 These N-tosylhydrazones 106 can be synthesized from aryl alkynols 109 in two steps. The coupling products 107 were obtained in high yields and with excellent Zselectivity, again due to the ortho-directing effect.109 When the ortho-substituent in the aryl halide partners was a masked nucleophile, the coupling products undergo further cyclization to produce 4-arylchromenes and related heterocycles (Scheme 26d). The same group later used this one-pot, three-step procedure to achieve the synthesis of a diversity of functionalized trisubstituted Z-olefins, starting from aryl alkynols, TsNHNH2, and ortho-substituted aryl halides, and further cyclization provided a general method for the synthesis of 4-arylchromenes.123 13820


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Scheme 28. Pd-Catalyzed Reactions of Aryl Halides with the N-Tosylhydrazones Bearing Cyclopropyl Moiety

Scheme 29. Pd-Catalyzed Reactions of N-Tosylhydrazones Bearing Electron-Withdrawing Substituent

using Pd(MeCN)2Cl2 as the precatalyst, affording a slightly higher yield of 1,1-disubstituted dienes.127 When two equivalents of aryl bromides are used, the carbene coupling products further undergo cascade Heck reaction to furnish trisubstituted dienes 121 (Scheme 28b). In 2016, Zhou and co-workers applied this reaction to the synthesis of benzoxepines 123 by using N-tosylhydrazones 122 as the substrates.128 It should be mentioned that the β-carbon elimination step (similar to the process from 117 to 118) occurs regioselectively to cleave bond a in this case (Scheme 28c). N-Tosylhydrazones bearing electron-withdrawing substituents are expected to be good cross-coupling partners in this type of reaction. In 2010, Barluenga and Valdés reported the Pdcatalyzed carbene coupling reaction of N-tosylhydrazones derived from 2-ketoesters 124 with aryl halides to synthesize a wide range of 2-aryl-α,β-unsaturated esters 125.129 This reaction proceeded in a one-pot fashion directly using the corresponding ketones as the substrates (Scheme 29a). In 2014, Wang and co-workers reported the use of trifluoromethyl N-tosylhydrazones as substrates to participate in the carbene coupling reaction.130 The reaction of benzyl

bromides with N-tosylhydrazones 126a affords trisubstituted trifluoromethyl olefins 127a in good yields with high Eselectivity. The good E-selectivity may be attributed to the π−π stacking interaction of the two aryl moieties in the transition state of the cis β-hydride elimination process. Besides, trifluoromethyl N-tosylhydrazones 126b with α-hydrogens can couple with aryl bromides to furnish the corresponding trifluoromethyl olefins 127b, in which the E/Z selectivity is poor when R1 ≠ R2 (Scheme 29b). Almost at the same time, Valdés and co-workers reported similar transformations to synthesize trifluoromethyl olefins in slightly higher yields using a low catalyst loading but under elevated reaction temperature (Scheme 29c).131 In 2015, Wang and co-workers further developed the Pdcatalyzed cross-coupling reaction of phosphonate-containing Ntosylhydrazones 128 with aryl bromides, which provided a good method for the synthesis of alkenylphosphonates 129 using simple Pd(PPh3)4 as the catalyst (Scheme 29d).132 In most of the Pd-catalyzed carbene coupling reactions, the CC double bond is formed. Thus, asymmetric catalysis in such type of coupling reaction is not possible to generate chiral centers. However, under certain circumstances, axial chirality may be generated when double bonds are formed. In this context, Gu and co-workers reported an intriguing asymmetric version of the Pd-catalyzed carbene coupling reaction by using tetralone derived N-tosylhydrazones 130 and aryl bromides 131 as the substrates.133 Chiral phosphine ligand 133 was the best choice for the reaction, in which the axially chiral vinyl arenes 132 could be obtained in both high yields and good enantioselectivities under mild conditions. This reaction tolerates a wide range of functional groups and can be successfully carried out in gram13821


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scale. The chiral vinyl arene product 132a can be further reduced to give the (P, olefin) ligand 134, or aromatized to produce binaphthyl phosphine oxide 135 in excellent ee values, thus providing an additional method to design new axially chiral phosphine ligand (Scheme 30).

Scheme 31. Pd-Catalyzed Coupling Reaction of Diazo Compounds with Benzyl Halides

Scheme 30. Pd-Catalyzed Enantioselective Synthesis of Axially Chiral Vinyl Arenes

2.1.3. Diazo Compounds as the Carbene Precursors. In the original work of the Pd-catalyzed carbene coupling reaction, the carbene precursor was limited to TMSCHN2.85 In 2005, the same group revealed that ethyl diazoacetate 136 (EDA) was also a suitable carbene precursor, which reacted with benzyl bromides to afford substituted cinnamates in moderate yields under similar reaction conditions.134 Benzyl bromides bearing electro-withdrawing group on the aryl ring can provide the desired products with decent yields, while electro-neutral or rich ones were sluggish substrates in this reaction (Scheme 31a). In 2009, Yu and co-workers further expanded the diazo substrates to α-aryl α-diazoesters, which are less reactive but more stable diazo compounds than TMSCHN2 and EDA 136.135 In this reaction, α,β-diaryl acrylates 137 can be obtained in moderate to good yields with excellent E-selectivity. A stoichiometric reaction using a well-characterized benzyl palladium complex 138 could afford the coupling product 137a in good yield, which supported the mechanism that benzyl palladium could react with the diazo compound through carbene formation and migratory insertion to generate metal-benzyl bond (Scheme 31b). Wang and co-workers later reported the use of diazo compounds 139 and 141 to couple with benzyl halides, affording trifluoromethyl-containing olefins 140 and alkenylphosphonates 142 in good yields. Both of the two reactions used a combination of Pd2(dba)3 and tri(2-furyl)phosphine, and excellent Eselectivity was achieved similar to Yu’s work (Scheme 31, panels c and d).130,132 Apart from benzyl halides, allylic halides are also suitable electrophiles to couple with diazo compounds. In 2008, Wang and co-workers reported a Pd-catalyzed cross-coupling of αdiazocarbonyl compounds 143 with allylic halides to give polysubstituted conjugated dienes 144 in good yields.136 The reaction conditions were mild and no ligand was required for this transformation. The selectivity of the newly formed double bond in the products was excellent, favoring the E-configuration. The

mechanism of this reaction most likely involves carbene migratory insertion to allyl-metal bond (Scheme 32a). Scheme 32. Pd-Catalyzed Coupling Reaction of Diazo Compounds with Allylic Halides

Wang and co-workers further used the trifluoromethyl diazo compound 139 to couple with allylic halides, affording trifluoromethyl-containing dienes 145.130 Although the reaction yields were excellent in this case, the E/Z selectivity of the products was only moderate (Scheme 32b). In addition, α-diazo phosphonates 141 were also suitable substrates for this type of reaction, which produced phosphonate-containing dienes 146 in good yields with excellent E/Z selectivity (Scheme 32c).132 13822


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Similarly, the coupling of α-diazocarbonyl compounds 147 with aryl iodides could be achieved under the catalysis of Pd(PPh3)4 using DCE as the solvent.137 When α-diazo ketones were used as the substrates, the addition of silver carbonate was required in order to obtain high yields of the enone products 148. The E/Z selectivity of the newly formed double bond was controlled by the diazo substrates. In addition to aryl iodides, aryl bromides were also competent coupling partners for the reaction with α-diazoester 149 using XPhos as the ligand, affording α-aryl acrylates 150 in good yields (Scheme 33a).

to proceed via the formation of palladium carbene intermediate 159, followed by carbene migratory insertion to give intermediate 160. Due to the lack of a β-hydrogen in the intermediate 160, β-hydroxy elimination process occurs to give the palladium complex 161. Finally, the coupling products are released, and the Pd(II) species is reduced to Pd(0) in the presence of diisopropylamine (Scheme 34a). Scheme 34. Reaction of Diazo Compounds with Aryl Iodides with Alternative Terminating Steps

Scheme 33. Pd-Catalyzed Coupling Reaction of Diazo Compounds with Aryl Halides

In 2013, Titanyuk and Beletskaya reported a reductive coupling of ethyl diazoacetate (EDA) 136 with aryl iodides to afford ethyl arylacetates 162 in good yields.142 In this reaction, it was proposed that the benzyl palladium species 164 generated via carbene migratory insertion could convert into the Pdhydride species 165 in the presence of formic acid and triethylamine, followed by a reductive elimination to produce the products and regenerate Pd(0) catalyst (Scheme 34b). 2.2. Carbene Coupling with Nucleophiles

Wang and co-workers subsequently used β-trimethylsiloxy-αdiazoesters 151 as the substrates in the coupling reaction with aryl iodides, and the normal coupling products silyl enol ethers 153 could be readily converted to β-keto-α-aryl esters 152 in a one-pot fashion (Scheme 33b).138 In 2013, Zhai and co-workers reported the coupling reaction of 6-diazo-2-cyclohexenones 154 with aryl iodides under simple reaction conditions, in which the normal coupling products 156 can rapidly isomerize to produce 2-arylphenols 155 via aromatization.139 In addition, when orthohaloiodobenzenes were employed as the electrophiles, the coupling products 155 underwent further Cu-catalyzed intramolecular Ullmann coupling to provide substituted dibenzofurans 157 (Scheme 33c).140 In addition to the coupling reactions that are terminated with β-hydride elimination, catalytic cycles containing other pathways are also possible. In 2011, Wang and co-workers reported a Pdcatalyzed cross-coupling reaction of β-hydroxyl α-diazocarbonyl compounds 158 with aryl iodides.141 This reaction was proposed

2.2.1. Organoboron Compounds as the Nucleophiles. Oxidative coupling between nucleophiles has become attractive in recent years. Since diazo substrates or N-tosylhydrazones are nucleophilic cross-coupling partners, the nucleophiles such as organoboron reagents may be explored in carbene coupling reaction under oxidative conditions. In 2008, Wang and coworkers reported the first example of Pd-catalyzed carbene coupling reaction of diazo compounds with nucleophiles.143 This reaction used arylboronic acids as the nucleophiles to couple with α-diazocarbonyl compounds 147 under the catalysis of Pd(PPh3)4 with diisopropylamine as the base and benzoquinone (BQ) as the oxidant, affording a range of α-aryl-substituted α,βunsaturated carbonyl compounds 148. The reaction tolerates a wide range of functional groups (e.g., Br, CHO) in the nucleophile partners, and different types of α-diazocarbonyl compounds all worked well to afford the electron-deficient olefins in up to 97% yield. When R1 and R2 are not the same, a 13823


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mixture of E/Z isomers is obtained with modest E-selectivity. This reaction is proposed to be initiated by the oxidation of Pd(0) precatalyst to Pd(II) species 166 by BQ, which undergoes transmetalation with arylboronic acid to form an aryl Pd(II) species 167. A carbene formation and a subsequent carbene migratory insertion generate a new Pd(II) species 169, which undergoes β-hydride elimination to furnish the final product (Scheme 35). Notably, this work is also the first example of

Scheme 36. Pd-Catalyzed Oxidative Cross-Coupling of Organoboronic Acids and Diazo Compounds

Scheme 35. Pd-Catalyzed Cross-Coupling of Arylboronic Acids and α-Diazocarbonyl Compounds

bond,143−146 termination with direct protonation in the absence of oxidant resulting in the formation of the C−C single bond is also possible. In 2011, Kitamura and co-workers reported a Pdcatalyzed cross-coupling reaction of 2-diazonaphthoquinones 170 with arylboronic acids, affording 2-arylated 1-naphthols 171 in modest yields.147 The authors have proposed two possible pathways for this transformation. Mechanism A involves the formation of Pd-carbene species 172, followed by carbene migratory insertion and protonation process to give the final products. Alternatively, a general Suzuki−Miyaura coupling mechanism is also possible, in which the reaction of 170 with acetic acid forms aryl diazonium salts 174. A normal sequence of oxidative addition/transmetalation/reductive elimination process produces the coupling product. Given that the Pd(II) precatalysts are more efficient than Pd(0) precatalysts for this reaction, the authors have suggested the carbene mechanism with the Pd(II)-cycle is more reasonable (Scheme 37a). Szabó and co-workers reported the cross-coupling reaction of α-diazoketones 177 and allylboronic acids 178 to realize the construction of C(sp3)−C(sp3) bonds under simple and mild conditions.148 The use of a catalytic amount of copper(I) iodide was very important for the high yielding formation of the γ,δunsaturated ketones 179. The configuration of the allylic double bonds underwent isomerization to some extent when alkylsubstituted allyl boronic acids were used as substrates. The authors have proposed a mechanism that involves the formation of Pd-carbene intermediate 180, which undergoes transmetalation with the allylboronic acids 178 to form a new Pdcarbene species 181. At this point, carbene migratory insertion occurs at the least substituted allylic terminus via the η1-allylic isomer, affording η1-alkylpalladium complex 182. Finally, 182 isomerizes to its Pd-enolate via an oxa-η3-intermediate, followed by protonation process to generate the final products and release the Pd(II) catalyst. This mechanism is different from the previous ones in which transmetalation occurs first followed by carbene formation and migratory insertion.143−146 Supportive evidence for this mechanism is that the stoichiometric reaction of α-diazoketone 177a with allylpalladium complex 183 failed to afford the corresponding product 179a with or without the addition of copper(I) iodide (Scheme 37b).

catalytic oxidative carbene coupling reaction, and the compatibility between the labile diazo compound and the oxidant demonstrated in this reaction suggests more possibilities in such type of reactions. Wang and co-workers further developed the Pd-catalyzed oxidative cross-coupling reaction of N-tosylhydrazones with arylboronic acids, in which the combination of catalytic amount of copper(I) chloride with oxygen was employed as oxidant (Scheme 36a).144 Yu and co-workers also reported a new catalytic system that used a combination of Pd(PPh3)4 with phenanthroline and oxygen as the oxidant to achieve the oxidative coupling of benzyl diazoesters with arylboronic acids.145 The use of B(OH)3 as additive significantly enhances the efficiency of the reaction, and the products α, β-diaryl acrylates can be obtained with excellent E-selectivity (Scheme 36b). This oxidative coupling strategy has been further applied in the convenient synthesis of conjugated dienes by using alkenyl boronic acids as the substrates under reactions conditions similar to that of the original work (Scheme 36c).146 In addition to the oxidative coupling mode that is terminated with β-hydride elimination to form the CC double 13824


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Scheme 38. Pd-Catalyzed Oxidative Coupling of NTosylhydrazones or Diazo Compounds with Terminal Alkynes

Scheme 37. Pd-Catalyzed Cross-Coupling of Organoboronic Acids and Diazo Compounds

Scheme 39. Pd-Catalyzed Oxidative Coupling of NTosylhydrazones with Allylic Alcohols

2.2.2. Coupling with Carbon Nucleophiles. In 2011, Wang and co-workers described a Pd-catalyzed oxidative crosscoupling reaction of N-tosylhydrazones with terminal alkynes, providing a convenient method for the synthesis of conjugated enynes 184.149 This reaction has been proposed to involve the formation of an alkynyl palladium intermediate 185, which reacts with the in situ generated diazo compound to form Pd-carbene intermediate 186. A carbene migratory insertion to the Pdalkynyl bond occurs to give intermediate 187, which undergoes stereoselective β-hydride elimination to furnish the final product 184 with Z-configuration. The Pd(0) species can be oxidized to regenerate the Pd(II) catalyst by BQ. In addition to Ntosylhydrazones, α-diazoesters are also suitable substrates to produce the ester-containing enynes 188 under slightly modified reaction conditions (Scheme 38). Jiang and co-workers developed a Pd-catalyzed oxidative coupling reaction between N-tosylhydrazones and allylic alcohols, which provided γ,δ-unsaturated ketones 190 in good yields with excellent stereoselectivity (Scheme 39).150 The reaction is proposed to be initiated by β-hydride elimination of palladium alkoxide species 191 to form an enone Pd-hydride complex 192, which undergoes olefin insertion to afford an alkyl palladium species 193. The reaction of 193 with the in situ generated diazo compound generates a Pd-carbene intermediate 194, which is followed by a carbene migratory insertion and a βhydride elimination to produce the coupling product 190. The

Pd(II) catalyst is regenerated via the oxidation by BQ. It should be noted that the β-hydride elimination process occurs with high stereoselectivity, presumably due to the formation of a chairlike intermediate 196. In this transformation, the allylic alcohols serve as alkyl nucleophiles to participate in the oxidative carbene coupling reactions. Jiang and co-workers subsequently reported a Pd-catalyzed oxidative homocoupling reaction of N-tosylhydrazones derived from acetophenones, in which the dibranched conjugated dienes 197 could be obtained in good yields.151 This reaction used a combination of catalytic amount of BQ with oxygen as the oxidant. The reaction may proceed via the formation of palladium carbene intermediate 198, which undergoes β-hydride elimination to form a vinyl palladium species 199. The following steps are a general carbene coupling mechanism that involves carbene formation, migratory insertion, and β-hydride elimination to form the diene products. In this reaction, one of the N13825


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tosylhydrazones serves as the alkenyl nucleophiles (Scheme 40a).

Scheme 41. Pd-Catalyzed Oxidative Coupling of Diazo Compounds via Allylic C−H Activation

Scheme 40. Pd-Catalyzed Oxidative Dimerization of NTosylhydrazones

208 and diazo compound 209 in the presence of the base. Thus, the arylsulfinate 208 generated from the sulfonylhydrazone is employed as the nucleophile in this reaction, which reacts with Pd(II) catalyst to form palladium arysulfinate 210. Subsequent carbene formation and extrusion of SO2 leads to the formation of carbene coupling intermediate 211. It should be noted that each part of the sulfonylhydrazones substrate is fully utilized and oxygen can be used as the sole oxidant in this reaction (Scheme 42a). In the same year, Prabhu and co-workers reported a similar transformation using Pd(PPh3)2Cl2 as the precatalyst and bibenzoxazole as the ligand.152 When using diethylphosphite as the ligand and DMF as the solvent, fully substituted dienes 202 can be obtained in good yields. In addition, an intramolecular version of this transformation can occur smoothly for bis-Ntosylhydrazones 201 to furnish the corresponding quinolines 203 via oxidative coupling/aromatization sequence (Scheme 40b). In 2014, Gong and co-workers described the combination of Pd-catalyzed allylic C−H bond activation with the carbene coupling reaction, which achieved the allylic C−H bond olefination with α-diazoesters under a synergistic catalysis of bis-sulfoxide palladium(II) acetate complex 205a and Lewis acid.153 This reaction provides a convenient method for the stereoselective synthesis of polyene derivatives 204. The reaction may involve the formation of an allyl palladium species via allylic C−H bond activation, followed by carbene formation to give the key intermediate 205b. Interestingly, the addition of Lewis acid (R,R)-(salen)CrCl is crucial for this transformation, the role of which may enhance the nucleophilic ability of the diazo compounds to facilitate the formation of π-allylic palladium carbene species. This mechanistic rationale is supported by the stoichiometric reaction of methyl α-diazo-2-phenylacetate with the π-allyl palladium dimer 183, in which the Lewis acid plays the key role for the high yields of the reaction (Scheme 41). The oxidative coupling without external oxidant is desirable in terms of reaction efficiency and functional group tolerance. In this context, Chen and co-workers reported an interesting internal oxidative cross-coupling reaction of sulfonylhydrazones 206, affording olefins 207 in moderate to good yields.154 In this reaction, sulphonylhydrazone 206 is decomposed to arylsulfinate

Scheme 42. Pd-Catalyzed Oxidative Carbene Coupling Reactions Using Arylsulfinates as Nucleophiles

Furthermore, the same group took advantage that the reaction of electron-deficient hydrazones was less efficient in intramolecular fashion as shown in example of 207a, and they could achieve an intermolecular oxidative cross-coupling reaction of sulfonylhydrazones with sodium arylsulfinates under slightly modified reaction conditions.155 The key for the success of this transformation is the use of nitro-containing sulfonylhydrazones 13826


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212, which can avoid the intramolecular coupling that was shown previously (Scheme 42b). 2.2.3. Heteroatom Nucleophiles and Amphiphiles. In 2013, Cui and co-workers reported indole derivatives as nitrogen nucleophiles to participate in the oxidative carbene coupling reactions with N-tosylhydrazones.156 This reaction used oxygen as the oxidant and simple Pd(PPh3)2Cl2 as the catalyst, providing an efficient method for N-alkenylation of indole derivatives. The formation of an indolyl palladium carbene intermediate 216 and the following migratory insertion of nitrogen indolyl moiety may be involved in this transformation. Carbazole was also a competent substrate for this reaction, affording the corresponding alkenylated product 215 in 99% yield (Scheme 43a).

Scheme 44. Pd-Catalyzed Oxidative Coupling of NTosylhydrazones and 2-Arylquinazolinones

When the nucleophile and the electrophile exists in the same molecule, a similar carbene coupling reaction leads to the formation of two bonds at the carbenic carbon (Scheme 45a). In

Scheme 43. Pd-Catalyzed Oxidative Coupling of NTosylhydrazones and Indole Derivatives

Scheme 45. Pd-Catalyzed Carbene Coupling Reaction with Amphiphiles

Almost at the same time, Alami and co-workers reported similar transformations by using iodobenzene as the oxidant.157 In addition to indole derivatives, other nitrogen-containing heteroarenes including carbazoles, benzoimidazoles, imidazoles, and pyrroles were all suitable nucleophiles in this reaction (Scheme 43b). Interestingly, the stereoselectivity of these two reactions was totally opposite that claimed by the two research groups, as shown in the examples of 218 and 219 (Scheme 43c). Very recently, Nagaiah and co-workers reported a Pdcatalyzed oxidative cross-coupling between 2-arylquinazolinones 220 and N-tosylhydrazones, which afforded O-alkenyl quinazolines 221 in good to excellent yields.158 The formation of the phenoxyl palladium carbene intermediate 222 has been proposed to be involved in this reaction, which undergoes carbene migratory insertion into Pd−O bond and β-hydride elimination to produce the O-alkenylated product. The Pd(0) species is oxidized to regenerate the Pd(II) catalyst in the presence of air. This reaction represents a rare example in which the C(sp2)−O bond is constructed via carbene coupling strategy (Scheme 44).

2012, Liang and co-workers used allylic alkynoates 223a as amphiphiles in the Pd-catalyzed carbene coupling reaction, in which two C−C bonds are constructed at the carbene center to furnish the synthesis of 1,5-enynes 224a in good yields.159 This reaction may involve a decarboxylation and a carbene migratory insertion process. When allylic benzoates derivative 223b was used as the substrates, decarboxylation process did not occur. Instead, benzylic ester derivatives 224b containing an Osubstituted quaternary carbon center were obtained in good yields (Scheme 45b). Later, the mechanism of this reaction was comprehensively investigated through DFT calculations, which suggested a [2 + 2] cycloaddition of Pd-carbene with the olefin moiety rather than a carbene migratory insertion process.160 13827


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reductive elimination gives the coupling product and regenerates the Pd(0) catalyst. A similar four-component reaction also occurs by using N-tosylhydrazones as carbene precursors to afford diaryl ketones 235 under slightly modified reaction conditions. In addition, enone products 236 can also be obtained by using an electron-rich phosphine ligand in the absence of triethylsilane. Remarkably, the chemo-selectivity of the two types of reactions is well-controlled by the reaction conditions (Scheme 47a).

Wang and co-workers developed a Pd/C-catalyzed hydrogenation of carbonyl compounds via the N-tosylhydrazone intermediates.161 A carbene migratory insertion to Pd−H bond may be involved in this transformation (Scheme 45c). In 2015, Huang and co-workers developed a Pd-catalyzed cross-coupling reaction of aminals with α-diazoesters.162 This reaction merged the C−N bond activation with carbene coupling reaction, providing an efficient method for the synthesis of α,β-diamino acid esters 225. A migratory insertion of aminomethyl group to the carbenic center may be involved in this reaction. One C−C bond and one C−N bond are constructed at the carbenic carbon to form a quaternary carbon center (Scheme 45d). In 2015, Wang and co-workers reported the first example of Pd-catalyzed carbene insertion into Si−Si bond and Sn−Sn bonds.163 The reaction of N-tosylhydrazones with disilane 226 or distannane 227 would afford geminal bis(silane) 228 and geminal bis(stannane) 229, respectively, in good yields under very mild conditions. This reaction may involve an unusual carbene migratory insertion into a metal-silyl or metal-stannyl bond (Scheme 45e).

Scheme 47. Pd-Catalyzed Carbonylation/Acyl Migratory Insertion Cascade Reactions

2.3. Cascade Reactions

In addition to the simple carbene coupling reactions with electrophiles or nucleophiles, cascade reactions have also been explored recently due to the rich chemistry of both the coupling process and the carbene process. These cascade reactions are roughly divided into three types (Scheme 46). In type I, cascade Scheme 46. General Process of Palladium-Catalyzed Cascade Carbene Coupling Reactions

process occurs before carbene migratory insertion, in which the organopalladium species 51 or diazo compound is generated via the cascade process. Type II cascade reactions involve further transformation of the direct coupling products 54, including either catalytic or noncatalytic transformations, in which the further Pd-catalytic transformations are known as autotandem catalysis.164,165 Additionally, the alkyl palladium species 53 generated by carbene migratory insertion can participate in further coupling process with an intermolecular or intramolecular functional moiety to give multicomponent coupling products or cyclic products, respectively. This type of reaction is classified as type III cascade reactions, which generally involve only one catalytic cycle. 2.3.1. Cascade Process prior to Carbene Migratory Insertion. In 2010, Wang and co-workers developed a Pdcatalyzed carbonylation/acyl migratory insertion cascade reaction, in which a four-component reaction of aryl iodide, carbon monoxide, α-diazoester, and triethylsilane occurs in high efficiency to afford 1,3-dicarbonyl product 230.166 In this reaction, the acylpalladium intermediate 231 generated via carbonylation decomposes the diazo compound to form palladium carbene species 232. A carbene migratory insertion to the Pd-acyl bond may occur to form C-bound palladium enolate 233, which undergoes transmetalation via its O-bound enolate with triethylsilane to generate intermediate 234. Finally,

In 2013, Liang and co-workers employed this strategy to achieve the synthesis of 3-indolone derivatives 238 using orthoamino aryl iodides 237 as the substrates, in which the palladium species generated through acyl migratory insertion could be trapped by the internal amino moiety to form a C−N bond (Scheme 47b).167 In addition to CO insertion, similar cascade reactions are also possible via isonitrile insertion. In 2015, Cheng and co-workers reported a multicomponent reaction of 2-iodoanilines, aryl isonitrile 239, and N-tosylhydrazones, which led to the formation of a variety of highly functionalized indole derivatives 240− 242.168 These reactions may involve the formation of 3iminoindole intermediate 243 via similar process as reported in Liang’s CO insertion cascade reactions, followed by Pd-catalyzed oxidation to give the common indolyl iminium intermediate 244. This highly reactive imine intermediate may react with the solvent amount of H2O or acetone to form 240 or 242, or undergo deprotonation to produce the products 241, respectively. Although only sterically hindered aryl isonitrile can work in these transformation, these multicomponent reactions provide a good method for the rapid construction of these biologically relevant indole frameworks (Scheme 48a). 13828


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Scheme 48. Pd-Catalyzed Cascade Reactions Involving Isonitrile Insertion

Scheme 49. Pd-Catalyzed Intermolecular Carbopalladation/ Carbene Coupling Cascade Reactions

Recently, Jiang, Wu, and co-workers developed a Pd-catalyzed three-component reaction of aryl iodides, alkyl isonitriles, and Ntosylhydrazones, providing an efficient method to access polysubstituted pyrroles (245).169 In this reaction, double isonitrile insertions occur to form an imino palladium intermediate 246, which reacts with the in situ generated diazo compound to give the palladium carbene species 247. Subsequent carbene migratory insertion and β-hydride elimination give the olefin intermediate 248, which undergoes an intramolecular cyclization and aromatization to furnish the final product (Scheme 48b). In 2013, Wang and co-workers reported a Pd-catalyzed threecomponent reaction of aryl iodides, allenes 249, and αdiazoesters, affording polysubstituted dienes 250 in good yields with excellent stereoselectivity.170 This reaction may involve a carbopalladation of an allene to form a π-ally palladium intermediate followed by an allyl migratory insertion process. In addition, ferrocenyl allenes 251 and diphenyl N-tosylhydrazone are also suitable substrates under slightly modified reaction conditions to furnish the corresponding diene products 252 and 253, respectively (Scheme 49a). Later, Wang and co-workers further used norbornene as the unsaturated system to achieve similar carbopalladation/carbene coupling cascade reactions.171 In this reaction, selective olefin insertion forms an alkyl palladium species 255a, which reacts with the in situ generated diazo compounds to generate Pdcarbene intermediate 255b. Carbene migratory insertion to Pdalkyl bond form a benzyl palladium intermediate 257, which may

undergo stereoselective β-hydride elimination to afford the final products 254. The proposed mechanism was also supported by the observed high diastereoselectivity and excellent E/Z selectivity (Scheme 49b). In 2015, Liang, Xu, and co-workers reported a Pd-catalyzed three-component reaction of aryl iodides, norbornene, and Ntosylhydrazones, in which the norbornene ring was opened to afford dienes 258 as the products.172 The substrates and the reaction conditions are very similar to the above-mentioned norbornene-involved reactions. Surprisingly, the intermediate 259 (generated via similar process as 257) undergoes a β-carbon elimination rather than β-hydride elimination to form intermediate 260, which finally undergoes β-hydride elimination to release the ring-opening diene products (Scheme 49c). The cation and the solvent may have a tricky influence on the divergent reaction pathways of the intermediates (257 and 259) generated by carbopalladation/carbene insertion sequence in these two norbornene-involved reactions. 13829


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situ formed N-tosylhydrazones, providing a facile method for the synthesis of 3-vinylindoles and 3-vinylbenzofurans 266.174 This reaction occurred with high stereoselectivity to afford the products with complete E-configuration (Scheme 50b). In 2015, similar cascade reactions of aryl iodides 267 with Ntosylhydrazones via olefin insertion and carbene migratory insertion sequence were reported.175 Two sets of olefins 268 and 269 were obtained in good yields, depending on the Ntosylhydrazones used in the reaction. Furthermore, allene carbopalladation/carbene coupling cascade reactions can occur in an intramolecular fashion, in which the allenyl aryl iodide 270 could react with N-tosylhydrazones to furnish two sets of furyl olefin products 271 and 272. It should be noted that the βhydride elimination process occurred with high site selectivity to form less-substituted olefins when using ketone N-tosylhydrazones as the substrates; for the case of aldehyde Ntosylhydrazones, only one type of β-hydrogen exists and the disubstituted olefins were obtained with high E-selectivity (Scheme 50c). ́ More recently, Garcia-Ló pez and co-workers reported a novel Pd-catalyzed cascade reaction of bromo acrylamides 273 with αdiazoesters, providing an efficient synthesis of spiro-oxoindoles 274.176 This reaction is initiated by the formation of σ-alkyl palladium(II) species 275 via oxidative addition and olefin insertion, which undergoes an intramolecular aromatic C−H activation to form a five-membered palladacycle intermediate 276. The reaction of palladacycle intermediate 277 with αdiazoester gives the Pd-carbene intermediate, which undergoes carbene migratory insertion and reductive elimination to produce the spiro oxoindole product. Two all-carbon stereocenters are constructed in this cascade reaction, although the diastereoselectivity is generally not satisfied (Scheme 50d). In 2015, Zhu, Luo, and co-workers developed an aminopalladation/carbene coupling cascade reaction by using orthoalkynyltrifluoroacetanilides 278 and α-diazoesters as the substrates.177 This reaction can occur in ligand-free and open air conditions, providing a straightforward method for the synthesis of functionalized indole derivatives 279 (Scheme 51).

When the unsaturated moieties are present in the electrophilic partners, similar carbopalladation/carbene coupling cascade reactions produce a series of cyclic compounds. In 2013, Gu and co-workers used alkenyl containing aryl halides 261 as the substrates to achieve cascade reaction with N-tosylhydrazones, affording styryl-substituted cyclic products 262 in good yields.173 The carbene migratory insertion to Pd-alkyl bond was proposed to involve in this reaction. Moreover, a double olefin insertion/ carbene coupling cascade reaction can occur smoothly for aryl iodide 263 under the same reaction conditions, in which the spiro cyclic products 264 is obtained as a mixture of diastereoisomers (Scheme 50a). Almost at the same time, Wang and co-workers described a Pdcatalyzed alkyne carbopalladation/carbene coupling cascade reactions of the alkynyl containing aryl iodide 265 with the in Scheme 50. Pd-Catalyzed Intramolecular Carbopalladation/ Carbene Coupling Cascade Reactions

Scheme 51. Pd-Catalyzed Intramolecular Aminopalladation/ Carbene Coupling Cascade Reactions

The reaction has been proposed to proceed via the formation of an indolylpalladium intermediate 280, followed by carbene coupling process. The CF3CO moiety in the indolyl nitrogen can be easily removed during the workup. In another example of cascade transformation, a Pd-catalyzed norbornene-mediated reaction of aryl halides 281 that contained an internal alkyl halide moiety with N-tosylhydrazones was reported. Ring-fused diary olefins 282 could be obtained in good yields.178 The mechanism of this reaction may involve the formation of a ring-fused arylpalladium species 284 from 283 via 13830


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Scheme 53. Pd-Catalyzed C(sp3)−H Bond Activation/ Carbene Coupling Cascade Reactions

a Catellani cyclization process in the assistance of norbornene,179,180 followed by a normal carbene coupling process to afford the desired products. In addition, a double orthoalkylation/carbene coupling cascade reaction occurs by using substrates 286 to furnish tricyclic olefin products 287 (Scheme 52a). Scheme 52. Pd-Catalyzed Norbornene-Mediated Carbene Coupling Cascade Reactions

process. In 2015, Wang and co-workers reported a Pd-catalyzed one-pot two-step cascade reaction of two different aryl iodides with EDA, providing a facile and efficient method for the synthesis of α,α-diaryl esters 297.186 Aryl α-diazoacetates, which are generated via the Pd-catalyzed coupling reaction of aryl iodide with EDA,187 are the key intermediates for this cascade reaction and participated in the subsequent reductive carbene coupling reaction with another aryl iodide. DFT calculation supports the formation of a Pd-carbene intermediate, in which the following carbene migratory process was suggested as a facile process with a low energy barrier of 3.8 kcal/mol (Scheme 54a). Scheme 54. Pd-Catalyzed Cascade Reactions Involving in situ Generated Diazo Compounds

Furthermore, the use of benzyl chlorides as the external alkyl electrophiles produce highly functionalized olefins 289 under similar reaction conditions (Scheme 52b).181 Moreover, the same strategy can achieve the ortho-amination/carbene coupling cascade reaction by using N-benzoyloxyamines 291 as the electrophiles,182 providing ortho-aminated vinylarenes 292 in moderate to good yields (Scheme 52c).183 C(sp3)−H bond coupling with diazo substrate is a challenging problem. In this context, Martin and co-workers have recently disclosed a palladium-catalyzed C(sp3)−H bond activation/ carbene coupling cascade reactions using aryl bromides 293 and diazo compounds as the substrates.184 This reaction has been proposed to proceed with the initial formation of palladacycle 296 via C(sp3)−H bond activation, followed by a carbene coupling process. The reaction provides an alternative approach for the carbene functionalization of unactivated C(sp3)-H bond.185 With regard to the aryl bromide partners, a gemdimethyl moiety or similar structure is necessary for the success of this transformation. Bidentate phosphine ligand 295 was found as the best choice for this reaction, providing a range of polysubstituted indanes 294 in good yields. Notably, two C−C bonds are constructed at the carbenic center to form all-carbon quaternary centers (Scheme 53). Another type of cascade reaction in this category is the case that the diazo compounds are generated in situ via a cascade

Subsequently, Wang and co-workers further developed a palladium-catalyzed three-component reaction of α-halo-Ntosylhydrazones 298, indoles, and aryl iodides for the synthesis of triaryl substituted olefins 299.188 This reaction may involve the formation of azoalkanes 300 from α-halo-N-tosylhydrazones 298 in the presence of the base, which undergoes conjugated addition by indoles to form the diazo compounds 301. Subsequent carbene coupling reaction with aryl iodides gives the olefin product 299 (Scheme 54b). 2.3.2. Cascade Process of the Coupling Products. There are cases that the olefin products generated via carbene coupling reaction can undergo further transformations with or without the catalysis of Pd complex. When these transformations are catalyzed by the same Pd complex, these reactions are also named as autotandem catalysis.164,165 In 2011, Barluenga, Valdés, and co-workers reported a Pd-catalyzed autotandem reaction of N-tosylhydrazones 303 derived from β-aminoketones 304 with ortho-dihaloarenes, affording tetrahydroquinoline derivatives 305 in good yields.189 This reaction may involve the formation 13831


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of intermediate 306 via carbene coupling reaction to generate the necessary C−C bond, followed by an intramolecular C−N bond forming reaction to afford the tetrahydroquinolines. NTosylhydrazones 303 can be either used directly or generated in a one-pot fashion from the corresponding ketones 304. In addition, enantiomerically enriched β-aminoketones are readily accessible via organocatalyzed asymmetric Mannich reactions, thus this autotandem catalysis is expected to be used in the synthesis of optically enriched quinoline skeletons (Scheme 55a).

Scheme 56. Pd-Catalyzed Auto-Tandem Reactions for the Synthesis of Functionalized Olefins

Scheme 55. Pd-Catalyzed Cyclization via Sequential C−C/ C−N Bond Formation

Moreover, Suzuki-Miyaura coupling can also be merged in the Pd-catalyzed autotandem catalysis with carbene coupling reactions by using aryl- or alkenyl-boron compounds as the third component.193 With this reaction, the construction of two C−C bonds can be achieved by a single Pd-catalyst in one-pot, two-step fashion, providing functionalized 1,1-diarylethylene 313 in high efficiency. These products are tested for their cytotoxic activity, and it has been found that product 314 shows remarkable antiproliferative activity at nanomolar concentration against HCT116 cancer cell lines (Scheme 56c). In 2013, Alami, Hamze, and co-workers reported a Pdcatalyzed carbene coupling of alkyne containing N-tosylhydrazones 315 with aryl iodides to synthesize aromatic enynes 316.194 The diaryl aromatic enynes 317 can be obtained from 316 via a two-step sequence of deprotection and Sonogashira coupling. In the presence of a gold catalyst, compound 317 undergoes a 6-endo-dig cyclization to afford diaryl naphthalenes 318 in excellent yields. When treated with a palladium catalyst, 317 can exclusively undergo a 5-exo-dig cyclization to produce substituted benzofulvenes 319 (Scheme 57a). Furthermore, they developed a one-pot, two-step protocol for the synthesis of benzofulvenes starting from N-tosylhydrazones 320 and aryl iodides, which involved a sequence of palladiumcatalyzed carbene coupling and 5-exo-dig cyclization (Scheme 57b).195 In 2014, Valdés and co-workers developed an autotandem reaction between cyclic N-tosylhydrazones 321 and aryl dibromides 322, producing a series of spirocyclic compounds including spirofluorenes, spirodibenzofluorenes, spiroacridines, and spiroanthracenes.196 A carbene coupling reaction and a subsequent intramolecular Heck reaction accounts for these two independent C−C bond forming processes, in which the

In a similar reaction, Wang and co-workers used similar strategy to achieve the synthesis of polysubstituted acridines 308 from ortho-dihaloarenes and ortho-amino N-tosylhydrazones 307.190 This reaction may proceed via Pd-catalyzed sequential CC double bond formation and C−N bond formation, followed by an aromatization process. This autotandem reaction shows a wide scope with regard to both coupling partners, providing an efficient method for the synthesis of functionalized acridine derivatives (Scheme 55b). In 2013, Alami, Hamze, and co-workers reported a Pdcatalyzed three-component reaction of N-tosylhydrazones, dihaloarenes, and amines.191 Primary and secondary anilines as well as aliphatic amines are all competent coupling partners for this three-component reaction. This reaction contains two independent transformations: carbene coupling and C−N bond forming process, in which the olefin 310 is considered as the intermediate product. Both of these two transformations were catalyzed by a single Pd-complex in a one-pot fashion, affording amino substituted 1,1′-diarylethylenes in good yields 309 (Scheme 56a). They further developed a Pd-catalyzed one-pot, two-step, three-component reaction of N-tosylhydrazones, haloindoles 311, and amines.192 Two C(sp2)−N bonds are built in a sequence of oxidative carbene coupling and C−N cross-coupling reaction. This reaction produces a variety of amino-substituted N-vinylindoles 312 in good yields, some of which have shown promising antiproliferative activity (Scheme 56b). 13832


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Scheme 57. Pd-Catalyzed Sequence of Carbene Coupling and Cycloisomerization

monobromo olefin 324 is proposed as the key intermediate. Notably, two separate C(aryl)−C(sp3) bonds are constructed on the carbenic carbon to form a spiro-quaternary carbon center (Scheme 58a). Subsequently, the same group expanded the substrate scope and found that acyclic N-tosylhydrazones were also competent carbene precursors under similar reaction conditions.197 In 2016, Langer and co-workers disclosed an interesting Pd-catalyzed autotandem reaction of aryl dibromide 325 with N-tosylhydrazone derived from aryl methyl ketones.198 Similar to Valdés’ report, the carbene coupling reaction occurred to give olefins 328 or 329, either of which would undergo an intramolecular 5-exotrig cyclization to form the same alkyl palladium species 330. Due to the lack of a syn β-hydrogen, the Pd-alkyl bond undergoes an insertion of the thiophene double bond to generate a cyclopropane intermediate 331. Finally, β-carbon elimination followed by β-hydride elimination regioselectively produces the desired polycyclic aromatic compounds 326. The endo cyclization to form the final products from the carbene coupling intermediates has been ruled out, because such a reaction pathway leads to the formation of a mixture of regioisomers 326 and 327. A range of polycyclic aromatic compounds that contain oxygen, sulfur, and nitrogen atoms can be facilely obtained using simple starting materials, which may have potential applications in material science (Scheme 58b). Very recently, Valdés and co-workers further developed anautotandem reaction of N-tosylhydrazones with dibromides 333, affording 9-methylene-9H-fluorenes and 9-methylene-9Hxanthenes 334 in moderate to excellent yields.199 Again, a carbene coupling of the benzyl bromide with N-tosylhydrazone and a subsequent intramolecular Heck reaction of the olefin intermediate 335 with the aryl bromide is involved in this autotandem reaction, which constructs a C−C single bond and a CC double bond on the same carbon. In addition, a similar Pdcatalyzed autotandem transformation also occurs between aryl bromide and bromo N-tosylhydrazone 336, producing tricyclic compounds 334 with similarly high efficiency (Scheme 58c). Direct coupling of carbenes with carbon monoxide provides ketenes, which are a highly useful intermediate in organic synthesis. In this context, Wang and co-workers developed a Pd-

catalyzed carbene carbonylation reaction for the synthesis of highly reactive ketene intermediates.200 This reaction is initiated with the decomposition of diazo compounds by Pd-carbonyl complex to form the Pd-carbene species 337, followed by CO migratory insertion to give the Pd-ketene intermediate 338. The Pd-ketene intermediate or the free ketene 339 undergoes a range of further transformations (Scheme 59a). In the presence of amines or alcohols, the ketene generated from α-diazocarbonyl compound is converted to the corresponding 1,3-dicarbonyl compounds 340 (Scheme 59b). Similarly, the reaction of amines or alcohols with N-tosylhydrazone sodium salts provides simple amides or esters 341 (Scheme 59c). In addition, the acylketene generated from α-diazocarbonyl compound reacts with imines to produce 1,3-dioxin-4-one derivatives 342 via a formal [4 + 2] cycloaddition transformation (Scheme 59d). Instead, the reaction of aryl or alkenyl Ntosylhydrazone sodium salts with imines produces the β-lactam derivatives 343 with excellent trans diastereoselectivity via a [2 + 2] cycloaddition process. DFT calculations have suggested that the Pd-catalyst is not only involved in the ketene formation process but also plays a role in the [2 + 2] cycloaddition process which may affect the diastereoselectivity of the products (Scheme 59e). Compared with the Co2(CO)8-catalyzed or -mediated carbonylation of EDA with CO involving the formation of ketene intermediate,201−207 the Pd-catalyzed protocol provides a general route to ketene compounds and is expected to be widely used in organic synthesis owing to the broad substrate scope of carbene precursors and the mild reaction conditions (with atmospheric pressure of CO). Later, similar transformations were also achieved under the catalysis of other transition-metal complexes.208−211 Similarly, Cai, Ding, and co-workers reported a Pd-catalyzed reaction of N-tosylhydrazones with isonitriles.212 This reaction may involve a carbene migratory insertion of isonitrile group to generate the ketenimine intermediates, which is trapped by H2O to afford the corresponding amides 344. Both aryl and alkyl isonitriles are suitable substrates under this simple and mild reaction conditions, constituting a facile route to the synthesis of amides. A limitation was that only H2O can be served as the nucleophile to trap the in situ generated ketenimine 13833


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Scheme 58. Pd-Catalyzed Sequence of Carbene Coupling and Olefin Insertion

Scheme 59. Pd-Catalyzed Ketene Formation and Further Transformations

Scheme 60. Pd-Catalyzed Ketenimine Formation and Further Transformations

without further isolation, can be converted to isoquinolines 349 or 350 in the presence of ammonium hydroxide (FG = CHO) or organolithum reagents (FG = CN), respectively (Scheme 61a). In 2016, Alami and co-workers reported that the carbene coupling product 353 bearing an ortho-nitro group can undergo a triphenylphosphine mediated reductive C−N bond forming reaction in a one-pot fashion, providing an efficient route to poly substituted indoles 352.215 Besides, (1-arylvinyl)carbazole derivatives 355 can be synthesized smoothly from bromonitrobiphenyl derivatives 354 and N-tosylhydrazones under the same reaction conditions. The authors demonstrated that one of these carbazole products had excellent antiproliferative activity against colon cancer cell lines (Scheme 61b). In the same year, Cheng and co-workers disclosed that a free amino group in the carbene coupling product (358) can trigger a base promoted cyclization with carbon dioxide, providing a general method to quinolinone derivatives 357.216 Mechanistic studies support the conclusion that the palladium catalyst only

intermediates under the current reaction conditions (Scheme 60a). In 2015, Cheng and co-workers successfully realized the use of amines as nucleophiles to trap the in situ generated ketenimines, providing a straightforward method for the synthesis of amidines 345 (Scheme 60b).213 In addition to the reactions involving subsequent transformations catalyzed by the same palladium complex, the products generated via carbene coupling process can also undergo noncatalytic transformations in a one-pot fashion to produce the corresponding downstream products. Valdés and co-workers developed a general route to the synthesis of polysubstituted isoquinolines starting from ortho-functionalized aryl nonaflates 346 and α-methoxyl N-tosylhydrazones 347.214 The first step of this transformation is the formation of enol ether 348 via carbene coupling reaction. The intermediate 348, 13834


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This type of cascade reaction was first realized in 2007 by Devine and Van Vranken in their Pd-catalyzed three-component reaction of vinyl iodides, amines, and TMSCHN2.217 In this reaction, the π-allyl palladium species generated via carbene migratory insertion process can be trapped by external amino nucleophiles, providing TMS-substituted allylamines 361 in moderate to excellent yields. The nucleophilic substitution of amines to the π-allyl palladium intermediates occurred regioselectively at the distal position of TMS moiety, leading to the formation of the products with vinylsilane structures (Scheme 63a).

Scheme 61. Carbene Coupling Products Followed by NonCatalytic Transformations

Scheme 63. π-Allyl Palladium Species Trapped by External Heteroatom Nucleophiles

plays a role in the carbene coupling process and is not involved in the cyclization step (Scheme 61c). 2.3.3. Cascade Process Embodied in One Catalytic Cycle. When the electrophile or the carbene precursor contains an alkenyl group, the carbene formation and migratory insertion will lead to the formation of π-allyl palladium species 360, which can be trapped by an internal or an external nucleophile, providing cyclic compounds or three-component coupling products, respectively (Scheme 62).

Subsequently, they expanded the carbene precursors to αdiazoesters under similar reaction conditions, providing a general method for the synthesis of α,β-unsaturated γ-amino esters 362 (Scheme 63b).218 In addition, they could also achieve the use of N-tosylhydrazones 363 as carbene precursors in a threecomponent reaction by using benzyltriethylammonium chloride as the phase transfer catalyst (PTC) and lithium tert-butoxide as the base, giving simple allylamine 364 as the product.219 Again, the nucleophilic substitution process occurred in high regioselectivity, which was presumably controlled by the steric hindrance of the carbene moiety. The vinyl iodides in the Zconfiguration worked better in these transformations than those in the E-configuration (Scheme 63c). In 2014, Liang, Xu, and co-workers developed a Pd-catalyzed reaction of aryl iodides with cinnamaldehyde derived N-sulfonyl hydrazones 365, providing an efficient route to allylic sulfones

Scheme 62. π-Allyl Palladium Species Generated by Carbene Migratory Insertion and Their Transformations

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366.220 Interestingly, both alkenyl carbene precursors and the sulfinate nucleophiles were generated from base-mediated decomposition of N-sulfonyl hydrazones 365. Thus, for this reaction the aryl moiety in aryl iodides and N-sulfonyl hydrazones should be the same, otherwise two regioisomeric allylic sulfones would be produced due to poor differentiation of these two allylic positions in the π-allyl palladium intermediate (Scheme 63d). In 2016, Huang and co-workers reported a Pd-catalyzed coupling reaction of aminals with N-sulfonyl hydrazones 365 to synthesize amino-substituted allylic sulfones 367.221 The oxidative addition of the aminals to the palladium catalyst forms amino anions, which can serve as the bases that are required for the generation of the diazo compounds and the sulfinate nucleophiles from the decomposition of N-sulfonyl hydrazones. As a result, no external base is required for this transformation. The nucleophilic substitution process occurs in a regioselective manner to afford the products bearing styrene-type structures (Scheme 63e). In addition to the heteroatom nucleophiles, carbon nucleophiles can also be employed as the external trapping reagents to furnish similar three-component reactions. In 2008, Van Vranken and co-workers reported a Pd-catalyzed threecomponent reaction of vinyl halides, stabilized carbon nucleophiles 368 and TMSCHN2, producing substituted vinylsilanes 369 in good yields (Scheme 64a).222 Subsequently, Liang and co-workers employed aryl aldehyde derived N-tosylhydrazones as carbene precursors and sodium malonates 370 as nucleophiles to achieve similar transformations (Scheme 64b).223 Van Vranken and co-workers further demonstrated that aliphatic aldehyde derived N-tosylhydrazones were also suitable carbene precursors, which afforded the

corresponding products 372 in good yield with high regioselectivity (Scheme 64c).219 In 2013, Liang and co-workers found that the π-allyl palladium species generated from the combination of aryl iodides with α,βunsaturated aldehyde derived N-tosylhydrazones could also be trapped by carbon nucleophiles, affording the three-component coupling products 373 in moderate to good yields.224 In this reaction, the nucleophilic attack occurs regioselectively at the distal position of the aryl group in the case of (E)-but-2-enalderived N-tosylhydrazones (R = Me), providing the products bearing styrene-type structures. In the cases of cinnamaldehyde derived N-tosylhydrazones (R = Aŕ), two regioisomeric products were obtained in poor regioselectivity if the π-allyl palladium intermediates were unsymmetrical (Ar ≠ Aŕ) (Scheme 64d). When nitrogen nucleophiles are linked in the organohalide substrates, the intramolecular trapping of the π-allyl palladium species leads to the formation of various nitrogen-containing cyclic compounds (Scheme 65). In 2012, Van Vranken and coScheme 65. π-Allyl Palladium Species Trapped by Internal Nitrogen Nucleophiles

Scheme 64. π-Allyl Palladium Species Trapped by External Carbon Nucleophiles

workers reported a Pd-catalyzed reaction of amino-containing vinyl iodides 374 with aryl aldehyde derived N-tosylhydrazones, affording alkenyl substituted pyrrolidines and piperidines 375 in moderate to good yields.225 The efficiency of this reaction was demonstrated in a concise synthesis of alkaloid caulophyllumine B (Scheme 65a). Later on, the same group realized the use of aliphatic aldehyde hydrazones 379 in similar cascade reaction to access alkenylsubstituted pyrrolidines 380.219 Notably, the key for the success 13836


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of this transformation is the use of bulky N-trisylhydrazones, presumably due to their good solubility. The products were generally a mixture of diastereomers, and the configuration of the double bond was reliant on the substrates (Scheme 65b). In 2013, Liang and co-workers reported a Pd-catalyzed reaction of N-substituted-2-iodoanilines with arylvinyldiazoacetates to synthesize poly-substituted 1,2-dihydroquinolines 381 (Scheme 65c).167 In addition, similar transformation can also be used in the construction of isoindoline derivatives 382 (Scheme 65d).226 Liang and co-workers developed a Pd-catalyzed cascade reaction that involved intramolecular trapping of π-allyl palladium species with carbon nucleophiles.224 The reaction of aryl iodides 383 or 384 with α,β-unsaturated N-tosylhydrazones produced polysubstituted 1,2-dihydronaphthalenes 385 or alkenyl-substituted indanes 386 via 6-endo or 5-exo cyclization, respectively (Scheme 66a).

facilitating the formation of the key intermediate 392. The mechanism was supported by the control experiments in which the use of aliphatic aldehyde derived N-tosylhydrazone failed to produce a similar product (Scheme 66c). Oxygen-centered nucleophiles are also explored. Wang and co-workers reported a Pd-catalyzed reaction of salicylaldehyde derived N-tosylhydrazones 393 and β-bromostyrenes 394, providing an efficient synthesis of 2-aryl substituted chromenes 395.228 In this reaction the π-allyl palladium species is attacked by the internal oxygen nucleophiles which are linked in the Ntosylhydrazone partners (Scheme 67a). Scheme 67. π-Allyl Palladium Species Trapped by Internal Oxygen Nucleophiles

Scheme 66. π-Allyl Palladium Species Trapped by Internal Carbon Nucleophiles

Subsequently, Liu and co-workers reported a similar transformation using chromene-based cyclic vinyl iodides 396 as the substrates to access the synthesis of chromeno[4,3-b]chromene derivatives 397.229 The products contain two fused chromene moieties and such a skeleton exists in various pharmaceuticals and biologically active compounds (Scheme 67b). In addition to the π-allyl palladium species, the benzyl palladium species (398) generated via carbene migratory insertion process may also participate in cascade reactions. In the case when β-hydride elimination pathway was turned off due to the substrate restriction, 398 can undergo a series of cascade processes, including olefin insertion (carbopalladation), transmetalation, and C−H activation, affording the products with two separate C−C bonds formed at the carbenic center (Scheme 68). Scheme 68. Benzyl Palladium Species Generated by Carbene Migratory Insertion and Their Transformations

In 2015, Van Vranken and co-workers also reported an example of intramolecular trapping with carbon nucleophile by using vinyl iodide 387 and N-trisylhydrazone 388 as substrates, providing alkenyl substituted cyclopentanes 389 in good yield (Scheme 66b).219 Furthermore, Van Vranken and co-workers disclosed a Pd-catalyzed cascade reaction of aryl iodides 390 with simple aryl aldehyde derived N-tosylhydrazones, providing 1arylindanes and 1-aryltetralins 391 in moderate to excellent yields.227 The authors have proposed a mechanism that involves the formation of the η3-benzylpalladium intermediate 392, which is very similar to the above-discussed π-allyl palladium species. This intermediate undergoes 5- or 6-exo cyclizations triggered by the internal carbon nucleophiles. Thus, the aryl moiety in Ntosylhydrazone substrates is crucial for this transformation by

In 2008, Kudirka and Van Vranken reported a Pd-catalyzed cascade reaction of α,β-unsaturated ester containing aryl bromide 399 with TMSCHN2, affording three cyclic products 400, 401, and 402 in 41%, 18%, and 20% yields, respectively.230 The reaction mechanism has been proposed to be initiated with the oxidative addition to form an aryl palladium species 403, followed by a carbene formation and migratory insertion process to generate a benzyl palladium intermediate 404. An intramolecular olefin insertion to the benzyl-palladium bond generates an alkyl palladium species 405, which undergoes another carbene insertion to produce 406. Finally, a β-hydride elimination forms a palladium-hydride complex 407, and the product 400 is released as a 1:1 mixture of E/Z isomers in the 13837


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general principle of cascade reactions involving sequence of carbene migratory/carbopalladation. N-Tosylhydrazones are also explored as carbene precursors in this type of cascade reaction. Valdés and co-workers reported the use of aldehyde-derived N-tosylhydrazones as carbene precursors to participate in the Pd-catalyzed carbene migratory insertion/carbopalladation cascade reactions with a series of alkenyl substituted aryl halides.231 The reaction of aryl halides 416, 417, and 418 with N-tosylhydrazones afford the corresponding benzo-fused ring systems 419−421, respectively. In these reactions, the olefin insertion processes occur regioselectively in 5-exo-trig fashion to form five-membered ring. In the case of oxygen-linked substrates, spontaneous aromatization occurs to produce benzofuran products 420. It should be noted that only pivalaldehyde or aryl aldehyde derived N-tosylhydrazones, which does not have α-hydrogen and the generated benzyl palladium species cannot undergo β-hydride elimination, can successfully participate in such kind of cascade reactions (Scheme 70a). Almost at the same time, Sekar and co-workers reported similar transformations to convert 2′-iodochalcones 422 to the corresponding indanone products 423.232 The reaction gave the products in high yields with completely E-configuration. This reaction can be successfully carried out in gram-scale, and both of

presence of the base with regeneration of the Pd(0) catalyst. Meanwhile, the alkyl palladium intermediate 405 can directly undergo a β-hydride elimination to form another palladiumhydride complex 408. Through an intramolecular transmetalation of Pd(II) with an allylsilane moiety would generate an allyl palladium-hydride species 409. At this point, 409 can either undergo direct reductive elimination to produce the product 402 or undergo another carbene insertion followed by reductive elimination to finish the product 401 (Scheme 69a). The authors have found that the ligand affects the product distribution. The bulky ligand favors the formation of product 402. Scheme 69. Carbopalladation of Benzyl Palladium Species

Scheme 70. Pd-Catalyzed Carbene Migratory Insertion/ Olefin Insertion Cascade Reactions

The same group also reported a Pd-catalyzed threecomponent reaction of allene containing aryl iodide 410, TMSCHN2, and piperidine, affording amino-substituted indene product 415 in moderate yield.230 This transformation also involves multiple cascade processes. After oxidative addition, carbene formation, and migratory insertion, a benzyl palladium species 412 is generated, which undergoes an allene double bond insertion to form a π-allyl palladium species 413. Intermolecular trapping of 413 by piperidine generates intermediate 414, in which the allylsilane moiety is labile and undergoes in situ protodesilylation to finish the final product (Scheme 69b). Although the work only showed very limited examples with low yield and poor selectivity, this reaction was a good demonstration of the 13838


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natively, C(sp2)−H bond activation may occur first to generate a palladacyclic intermediate 434, followed by a sequence of carbene insertion and reductive elimination. The TMS moiety is removed in situ under the standard reaction conditions. This transformation can be regarded as a formal [4 + 1] annulation reaction, providing a concise synthetic route to fluorene derivatives 432 (Scheme 72a).

these two reaction partners can be formed in situ to enable a onepot manipulation (Scheme 70b). Moreover, Valdés and co-workers reported a Pd-catalyzed reaction of nitrogen-linked alkenyl aryl iodides 424 with Ntosylhydrazones, affording poly-substituted indoles 425 in good yields.233 When the alkene moiety is adjacent to a ketone carbonyl group (426), a formal 6-endo-trig cyclization occurs from the benzyl intermediate, leading to the formation of poly substituted 1,4-dihydroquinolines 427 (Scheme 70c). Although many carbene migratory insertion/intramolecular olefin insertion cascade reactions have been developed to access a range of cyclic compounds, the intermolecular olefin insertion of the benzyl palladium species has not been achieved yet. The cascade reactions involving intermolecular transmetalation of the benzyl palladium species are synthetically very useful because such reactions can incorporate two different fragments to the carbene moiety, leading to the construction of two separate C−C bonds at the carbenic center in a single catalytic cycle. However, this kind of cascade reactions are challenging due to the obvious competing reaction between the electrophiles and the organometallic reagents. Actually, Van Vranken and coworkers have attempted this kind of cascade reactions in their early report on carbene coupling reactions.85 They found that the Pd-catalyzed three-component reaction of aryl iodides, TMSCHN2, and phenyl tin reagent 428 could indeed afford the desired products 429. However, only two examples were shown with very low yields (Scheme 71a).

Scheme 72. Pd-Catalyzed Carbene Migratory Insertion/C−H Activation Cascade Reactions

Scheme 71. Pd-Catalyzed Carbene Migratory Insertion/ Transmetalation Cascade Reactions

Furthermore, the same reaction conditions can be successfully applied in the substrates 435 and 437, producing nitrogencontaining polycyclic aromatic compounds 436 and 1H-indenes 438, respectively (Scheme 72, panels b and c). In the reaction of substrates 437, the first occurrence of a vinyl C(sp2)−H bond activation via CMD mechanism to form a palladacyclic intermediate 439 has been proposed as the major reaction pathway on the basis of the mechanistic experiments. In 2014, Yin and co-workers reported a Pd-catalyzed cascade reaction of distal hydroxyl-substituted furfural N-tosylhydrazones 440 with aryl bromides, affording spiroacetal enol ethers 441 in moderate to good yields.236 In the reaction mechanism, the formation of benzyl palladium intermediate 442 has also been proposed. The intermediate 442 isomerizes to a η3furylmethyl palladium species 443, which is followed by an intramolecular nucleophilic dearomatization triggered by the internal hydroxyl group to finish the final products. The configuration of the newly formed double bond is largely dependent on the aryl bromides (Scheme 73a). Subsequently, they reported another Pd-catalyzed reactions of 2-iodoanilines or 2-iodothiophenols 444 with furfural Ntosylhydrazones 445, affording 2-alkenyl indoles or benzothiophenes 446 via furan ring opening followed by ring closure.237 The authors have proposed a mechanism that involves the formation of benzyl palladium intermediate 447, which would undergo an unusual β-oxygen elimination to open the furan ring forming allene intermediate 448. An intramolecular nucleophilic attack on the allene moiety forms the new five member ring to

In 2010, Wang and co-workers reported a successful example of carbene migratory insertion/transmetalation cascade reaction among aryl bromides, aryl aldehyde-derived N-tosylhydrazones, and terminal alkynes, providing a facile synthetic route to benzhydryl acetylene derivatives (430).234 The direct Sonogashira coupling reaction between aryl electrophiles and terminal alkynes was successfully suppressed by careful condition optimizations. Copper(I) iodide was used as a cocatalyst to in situ generate the organometallic reagent copper acetylide, which was kept in a catalytic amount and might be helpful for the occurrence of carbene insertion prior to transmetalation process to facilitate this cascade reaction (Scheme 71b). More recently, Wang and co-workers reported a Pd-catalyzed cascade reaction of biaryl bromides 431 with TMSCH2, which involved a combination of carbene migratory insertion and C(sp2)−H bond activation process.235 One of the possible mechanism involves the formation of a benzyl palladium species 433 via carbene migratory insertion, followed by a sequence of C(sp2)−H bond activation and reductive elimination. Alter13839


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3.1. Reaction with Terminal Alkynes

Scheme 73. Pd-Catalyzed Cascade Reactions of Benzyl Palladium Species with Furan Moiety

3.1.1. Allenes as the Coupling Products. In 2011, Wang and co-workers reported the first Cu-catalyzed carbene coupling reactions for the synthesis of allenes (Scheme 75).245 The Scheme 75. Cu-Catalyzed Coupling Reactions NTosylhydrazones with Terminal Alkynes for Allene Synthesis

give 449, followed by a β-hydride elimination to produce the desired products with high E-selectivity (Scheme 73b).

3. CU-CATALYZED CARBENE COUPLING REACTIONS Being analogous to the palladium-catalyzed carbene coupling reactions, organocopper species 450 generated from terminal alkynes, arenes, and others can also react with diazo compounds to form copper carbene intermediate 451.238−241 Similar to the reaction of palladium carbene, copper(I) carbene migratory insertion process occurs to give a new organocopper intermediate 452, which can undergo protonation to give products 453−455, or react with electrophiles to produce 456 with the formation of two C−C bonds. Meanwhile, the generated allene 453 or alkyne 454 is a reactive compound, which can undergo further transformations to afford a series of downstream products (Scheme 74).242−244 It should be noted that Cu-

combination of Cu(MeCN)4PF6 and bisoxazoline ligand 457 was proven to be the optimized catalytic system, which could convert N-tosylhydrazone and terminal alkyne to the corresponding allene 458 in excellent yield. Synthetically, this reaction provides a straightforward and highly efficient approach to the synthesis of trisubstituted allenes. The combination of aromatic ketone derived N-tosylhydrazones with aryl alkynes to give trisubstituted allenes was generally highly efficient, while other types of combinations produced the corresponding allenes in decreased yields. Such limitations, as well as the necessity of the complex ligand 457, were resolved in the following work. Mechanistically, the formation of an alkynyl copper-carbene species 460 and a following alkynyl migratory insertion to give 461 has been proposed. A regioselective protonation occurs at the triple bond carbon to deliver the allene product 458 and regenerate the copper catalyst. Alternatively, an ipso protonation of 461 followed by based mediated arrangement also affords the allene product via alkyne intermediate 462. To differentiate these two reaction pathways, alkyne 462 was independently prepared and subjected to the same reaction conditions for 18 h. However, the rearrangement was much slower and the allene product 458 could only be obtained in 39% yield. In contrast, the reaction under standard reaction conditions could produce allene product 458 in 87% yield and the alkyne 462 was not detected. Taking together, the ipso protonation/arrangement is not considered as the major reaction pathway for the allene formation. Following this report, Wang and co-workers made a series of improvements on the allene synthesis via Cu-catalyzed coupling of N-tosylhydrazones and terminal alkynes, especially to expand the substrate scope and simplify the catalytic system (Scheme

Scheme 74. General Process of Copper-Catalyzed Carbene Coupling Reactions

catalyzed carbene coupling reactions are generally carried out in redox neutral conditions, and the valence of copper remained unchanged in the whole catalytic cycle, which is remarkably different from the Pd-catalyzed carbene coupling reactions that generally involves a Pd(0)/Pd(II) catalytic cycle. 13840


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synthesis of mono- or 1,1-disubstituted allenes 466, although the use of stoichiometric catalyst and ligand was required for achieving high yields.248 When increasing the amount of LiOtBu and prolonging the reaction time, the isomerization of the allene products was observed in the case of aldehyde derived Ntosylhydrazones, affording the corresponding 1-methyl-2arylacetylene derivatives 467 as the major products (Scheme 76c). It is noteworthy to mention that all of these coupling reactions described in Scheme 76 can be successfully conducted in gramscale, which further demonstrates the robustness and the versatility of this methodology (Scheme 76d). In addition to N-tosylhydrazones, diazo compounds are also competent substrates to participate in the Cu-catalyzed crosscoupling of terminal alkynes for the synthesis of allenes. In 2011, Fox and co-workers reported the Cu-catalyzed cross-coupling of α-diazoesters with terminal alkynes to synthesize allenoates 470.249 The use of Cu(II)(trifluoroacetylacetonate)2 468 as the catalyst and 469 as the ligand was the key to give high selectivity for allenoates 470 over the corresponding alkynoates 471. The authors have proposed that the Cu-carbene intermediate is first formed, which reacts with terminal alkynes to produce alkynoates 471. The allenoates 470 can be obtained via complete isomerization under the reaction conditions (Scheme 77a). In the same year, Wang and co-workers reported the same transformation for the synthesis of allenoates 470 by using a simple combination of copper iodide and phenanthroline under base-free conditions (Scheme 77b).250,251 Subsequently, Sun and co-workers developed a Cu-catalyzed cross coupling of diazoacetamides 472 with terminal alkynes, in which the corresponding allenamides 473 could be obtained in good yields using Na2CO3 as the base (Scheme 77c).252 In 2015, Wang and co-workers disclosed that simple ethyne was also a suitable substrate to react with α-diazoesters in the presence of stoichiometric catalyst and ligand, providing a good method for the synthesis of 1,1-disubstituted allenes 474 (Scheme 77d).248 They also achieved a Cu-catalyzed crosscoupling reaction of diaryldiazomethanes with terminal alkynes, affording di- or triaryl substituted allenes 475 in good to excellent yields.253 The coupling of such types of substrates was sluggish in the original report on allene formation.245 In this reaction, diisopropylamine was used as the base and no additional ligand was required (Scheme 77e). In 2015, Ley and co-workers developed an efficient and robust method for the synthesis of di- and trisubstituted allenes using flow technology.254 Thus, the highly reactive diazo compounds 477 were first generated in situ from hydrazone 476 via flow chemistry. Subsequently, the coupling reaction could be completed at room temperature in 10 min under very simple conditions, and the products 478 were obtained generally in excellent yields. This reaction could be successfully carried out on a gram scale. When deuterated methanol was used as an additive under the standard reaction conditions, allene 480 could be obtained in 93% yield with 37% deuterium incorporation at the C3 position (Scheme 77f). This experiment indicates that the protonation occurs regioselectively at the triple bond carbon atom, which is in accordance with the observation made in previous work.245 To achieve asymmetric catalysis in these coupling reactions is challenging but highly desirable since it will provide methods to construct axial chirality directly. In 2015, Feng and co-workers made a breakthrough in the asymmetric version of Cu-catalyzed cross-coupling reaction between α-diazoesters with terminal

76). In 2013, Wang and co-workers disclosed that the synthesis of 1,3-disubstituted allenes 463 could be achieved in a ligand-free Scheme 76. Allene Synthesis from N-Tosylhydrazones and Terminal Alkynes

conditions using simple CuI as the catalyst.246 In addition, the formation of aldehyde N-tosylhydrazones and the Cu-catalyzed carbene coupling can be carried out in a one-pot, two-step fashion, which has largely simplified the allene synthesis (Scheme 76a). When an electrophile is introduced to this reaction system, the organocopper intermediate (similar to 461 in Scheme 75) generated from carbene migratory insertion can be trapped by the electrophile instead of proton, giving allyl-substituted allene as the three-component coupling products.247 Both aldehyde and ketone derived N-tosylhydrazones are suitable coupling partners, affording the corresponding tri- and fully substituted allenes 464 and 465 in good yields (Scheme 76b). Furthermore, simple ethyne was also competent coupling component to react with N-tosylhydrazones to furnish the 13841


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Scheme 77. Allene Synthesis from Diazo Compounds and Terminal Alkynes

Scheme 78. Asymmetric Synthesis of Allenes via Cu(I)Catalyzed Coupling of Diazo Compounds with Terminal Alkynes

aldehydes with propargyl amines by using pyridine bis(imidazoline) 487 as the chiral ligand.257 Again, the highly reactive diazo compounds were generated in situ via flow chemistry from the corresponding hydrazones. Although the yields of the disubstituted allenes 485 were only moderate, excellent enantioselectivities were achieved for all the cases. Alkynes 486 were also generated in significant amount in this reaction, which attributed to the low yields of the corresponding allenes 485 (Scheme 78c). 3.1.2. Alkynes as the Coupling Products. In addition to allenes, the Cu-catalyzed carbene coupling with terminal alkynes can afford internal alkynes as the coupling products, in which C(sp3)−C(sp) bond is constructed in the transformation. The first example of such reaction was actually reported prior to the parallel allene formation reactions as discussed above.245 In 2004, Fu and co-workers reported a Cu-catalyzed cross-coupling of αdiazoacetate or diazoamide with terminal alkynes, affording 3alkynoates 488 or 3-alkynamides 489 in good to excellent yields.258 A wide range of terminal alkynes can be smoothly coupled with diazo compounds under base and ligand free conditions at room temperature. A small quantity of the allene isomers (

Transition-Metal-Catalyzed Cross-Couplings through Carbene

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