Chapter Two - Recent Advances in Transition-Metal-Catalyzed Cross-Coupling Reactions With N-Tosylhydrazones

中文 / Bilingual · English version

Di Qiu**, Fanyang Mo**, Yan Zhang*, Jianbo Wang**,

*Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing, China ${}^{ \dagger }$ College of Chemistry, Tianjin Key Laboratory of Structure and Performance for Functional Molecules, Tianjin Normal University, Tianjin, China

*College of Engineering, Peking University, Beijing, China

${}^{1}$ Corresponding author:

Contents

1. Introduction 1

2. Palladium-Catalyzed Coupling Reaction of N-Tosylhydrazones 2

2.1 Pd-Catalyzed Coupling of N-Tosylhydrazones With Aryl and Alkenyl Halides 4

2.2 Pd-Catalyzed Coupling of N-Tosylhydrazones With Benzyl Halides 19

2.3 Pd-Catalyzed Oxidative Coupling of N-Tosylhydrazones 20

2.4 Pd-Catalyzed Two-Component Cascade Coupling of N-Tosylhydrazones 26

2.5 Pd-Catalyzed Multicomponent Coupling of N-Tosylhydrazones 35

3. Copper-Catalyzed Coupling Reaction of N-Tosylhydrazones

3.1 Cu-Catalyzed Coupling of N-Tosylhydrazones With Alkynes

3.2 Cu-Catalyzed Coupling of N-Tosylhydrazones Involving C-H Activation

3.3 Cu-Catalyzed Oxidative Coupling Reaction of N-Tosylhydrazones

4. Rhodium-Catalyzed Coupling Reaction of N-Tosylhydrazones

5. Nickel- and Cobalt-Catalyzed Coupling Reactions of N-Tosylhydrazones

6. Catalytic Intramolecular Cyclization of N-Tosylhydrazones

7. Summary

Acknowledgments

References

1. INTRODUCTION

The area of transition-metal-catalyzed cross-coupling reactions has experienced considerable growth in the past decades. This strategy has created powerful and indispensable methods for selective constructing carbon-carbon/carbon-heteroatom bond, as well as in synthesizing functional molecules and natural products. ${}^{1}$ To expedite synthetic endeavors, chemists have mainly focused on the development of new catalysts for various coupling reactions. On the other hand, the developments toward novel coupling partners also represent the major challenges in organometallic research area.

$N$ -Tosylhydrazones, easily synthesized through the condensation of carbonyl compounds with $N$ -tosylhydrazine, are useful and common substrates in organic synthesis. Thus, transition-metal-catalyzed cross-coupling reaction of $N$ -tosylhydrazones not only expands the substrate scope of coupling partners but also furnishes novel and practical methodology for the unconventional modification of carbonyl compounds.

Particularly, owing to the reason that the diazo species can be generated in situ via detosylation of $N$ -tosylhydrazones, $N$ -tosylhydrazones have been utilized as the surrogates for unstable diazo compounds or carbene precursors. ${}^{2}$ Conceptually, transition-metal-catalyzed cross-coupling reactions of $N$ -tosylhydrazones introduce diazo component or carbene species into cross-coupling systems, providing novel types of C-C, C=C, and carbon-heteroatom bond formation strategies. Mechanistically, the key feature of these coupling processes involves a migratory insertion of the metal-carbene intermediates, which not only constitutes a fresh and novel reaction type of $N$ -tosylhydrazones but also represents a paradigm shift in understanding metal-carbene chemistry.

Although several reviews related to transition-metal-catalyzed coupling reactions of $N$ -tosylhydrazones have appeared in the literatures in the past years, ${}^{3 - 7}$ in view of the rapid growth of the field a timely and comprehensive summary of this area is still necessary. This chapter will focus on the recent advances in the area, in particular the cascade transformations involving carbene-coupling process. The reactions are classified according to different transition-metal catalysts (Scheme 1). Due to the space limitation, catalytic $\mathrm{C} - \mathrm{H},\mathrm{N} - \mathrm{H}$ , and $\mathrm{O} - \mathrm{H}$ insertion processes of $N$ -tosylhydrazones are not included in this contribution.

2. PALLADIUM-CATALYZED COUPLING REACTION OF N-TOSYLHYDRAZONES

Palladium-catalyzed coupling reaction of $N$ -tosylhydrazones has been extensively developed and demonstrates many applications in organic synthesis. ${}^{{4a} - c}$ The general mechanism is shown in Scheme 2. Initially, the carbon-Pd(II) intermediate1generates either through transmetalation with other metal species or by oxidative addition from organohalide analogues. Subsequently, decomposition of the in situ-generated diazo species from stable $N$ -tosylhydrazone substrates gives rise to the formation of Pd(II)- carbene 2 as the key intermediate. Then, a migratory insertion process, in which an “X” ligand of Pd(II) migrates to carbene center, takes place to generate a new carbon-Pd(II) species 3, followed by sequential $\beta - \mathrm{H},\beta - \mathrm{C}$ elimination or other cascade transformations to afford a variety of functionalized molecules. The Pd-catalyzed cross-coupling reactions of $N$ -tosylhydrazones have established a novel and superior approach toward the selective C-C bond formation, particularly for highly efficient synthesis of polysubstituted alkenes. This content will classify the recent advances according to the various types of the coupling partners.

Scheme 1 Transition-metal-catalyzed cross-coupling reactions of $N$ -tosylhydrazones and typical applications in organic synthesis.

Scheme 2 General reaction pathway of the Pd-catalyzed cross-coupling reaction of $N$ -tosylhydrazones involving migratory insertion.

2.1 Pd-Catalyzed Coupling of N-Tosylhydrazones With Aryl and Alkenyl Halides

In 2007, Barluenga group reported the first example of Pd-catalyzed cross-coupling reactions of $N$ -tosylhydrazones (Scheme 3). ${}^{8}$ They achieved the catalytic coupling of aryl halides with bench-stable $N$ -tosylhydrazones, which provided a novel route for synthesizing polysubstituted olefins with high efficiency. They proposed that the catalytic cycle of this coupling transformation is initiated by the oxidative addition of aryl halide to Pd(0) species 4, giving rise to aryl palladium(II) complex 5. Then, the reaction of 5 with diazo intermediates, which are generated in situ from $N$ -tosylhydrazones in the presence of a base, occurs affording Pd(II)-carbene species 6 . The key feature of this catalytic cycle is the migratory insertion of the aryl group to Pd-carbene center, subsequently delivering the alkyl palladium complex 7. Finally, β-hydrogen elimination of 7 provides the desired arylated olefin along with regeneration of $\mathrm{{Pd}}\left( 0\right)$ species.

In view of the facile condensation of carbonyl compounds with tosylhydrazide into $N$ -tosylhydrazones, this strategy represents a convenient procedure to convert carbonyl compounds into nucleophilic coupling reagents for Pd-catalyzed cross-coupling reactions. This methodology affords a highly efficient way to prepare densely functionalized alkenes with high stereoselectivity and excellent functional group tolerance.

Later, Barluenga and Valdés launched systematic research toward Pd-catalyzed cross-coupling reactions of aryl halides with N-tosylhydrazones derived from divergent carbonyl compounds, proceeding through migratory insertion and $\beta - \mathrm{H}$ elimination to furnish the desired arylated alkenes. ${}^{9 - {18}}$ At the first attempt they have carried out Pd-catalyzed coupling reaction of aryl halides with $N$ -tosylhydrazones derived from 4-piperidones (Scheme 4). ${}^{9}$ The reaction affords 4-aryltetrahydropyridines in good to excellent yields with good functional group tolerance. Furthermore, the catalytic one-pot procedure was also implemented by using 4-piperidone, tosylhydrazide, and aryl halides as the substrates, leading to the formation of functionalized 4-aryltetrahydropyridines in similarly high yields.

Xphos = 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl

Scheme 3 Pd-catalyzed cross-coupling reactions to synthesize substituted alkenes.

Scheme 4 Pd-catalyzed one-pot coupling of 4-piperidone, tosylhydrazide, and aryl halides.

Scheme 5 Pd-catalyzed one-pot synthesis of enol ethers and enamines.

In 2009, the same group carried out the Pd-catalyzed cross-coupling reaction of aryl halides with $\alpha$ -alkoxy- or $\alpha$ -amino-derived $N$ -tosylhydrazones, achieving the facile and efficient synthesis of enol ethers or enamines (Scheme 5). ${}^{10}$ This transformation can be either conducted with the preformed tosylhydrazone substrates or in a one-pot process by using $\alpha$ -functionalized carbonyl compounds and tosylhydrazide. The resulting product of this methodology also demonstrated a potential application in constructing heterocyclic scaffolds.

In 2010, the same group also accomplished a simple and straightforward synthesis of 2-arylacrylates compounds by employing the Pd-catalyzed tosylhydrazide-promoted coupling reaction of aryl halides with pyruvate derivatives 8 (Scheme 6). ${}^{11}$ Taking into account the great importance of 2-arylacrylates as valuable intermediates and direct precursors for the pro-phen family of antiinflammatory drugs, this method demonstrates potential usefulness in organic synthesis and medicinal chemistry. In addition, this coupling reaction from $N$ -tosylhydrazones derived from substituted 2-oxoesters can also afford tri- and tetra-substituted functionalized alkenes in a facile manner.

The transition-metal-catalyzed coupling reaction has provided a novel approach toward the synthesis of conjugated dienes, which demonstrate great importance in organic synthesis, biochemistry, and materials sciences. ${}^{{12}\mathrm{a}}$ In 2010, Barluenga and coworkers reported the synthesis of conjugated dienes through two different pathways: the Pd-catalyzed cross-coupling reaction of $N$ -tosylhydrazones derived from $\alpha ,\beta$ -unsaturated ketone with aryl halides, or using alkenyl halide with nonconjugated $N$ -tosylhydrazones (Scheme 7). ${}^{{12}\mathrm{\;b}}$ In the latter case, the probable pathway rationalizing the formation of product may involve a hydride elimination of $\pi$ -allylpalladium intermediate9. This method provides a novel approach for the synthesis of aryl-substituted conjugated dienes.

Scheme 6 Synthesis of 2-arylacrylates by Pd-catalyzed coupling reaction from pyruvate with aryl halides.

In 2014, Valdés successfully expanded the substrate scope of Pd-catalyzed coupling reaction of aryl halides to 1,1,1-trifluoroacetone tosylhydrazones. ${}^{13}$ Under the optimized conditions, this transformation affords functionalized $\alpha$ -trifluoromethylstyrenes, which serve as valuable trifluoromethylated synthetic intermediates, in high yields and good functional group tolerance (Scheme 8). This contribution not only represents a novel combination of coupling reaction with fluorine chemistry but also demonstrates potential applications in medicinal chemistry and material sciences.

In addition to aryl halides, aryl nonaflates as their analogues have been explored as effective electrophilic reaction partners in Pd-catalyzed cross-coupling of $N$ -tosylhydrazones. ${}^{{14} - {17}}$ In 2011, Pd-catalyzed coupling reaction of $N$ -tosylhydrazones with aryl nonaflates was described, affording di-, tri-, and tetra-substituted alkenes with good functional group tolerance (Scheme 9). ${}^{15}$ Notably, the addition of LiCl in the presence of small amounts of water apparently accelerates this transformation. Under optimized reaction conditions, various olefins are obtained with excellent yields and high stereo-selectivity depending on the nature of the coupling partners. Moreover, the success of a single-step synthesis of dihydronaphthalene derivative10, which is the direct precursor of the antidepressant sertraline, demonstrates the practical application of this methodology in organic synthesis.

Scheme 7 Pd-catalyzed coupling reaction for the synthesis of conjugated dienes.

Scheme 8 Pd-catalyzed coupling reaction for the synthesis of $\alpha$ -trifluoromethylstyrenes.

Scheme 9 Pd-catalyzed coupling of $N$ -tosylhydrazones with aryl nonaflates.

Scheme 10 Synthesis of (Z)-N-alkenylazoles and pyrroloisoquinolines.

In 2013, Valdés group reported a one-pot Pd-catalyzed coupling reaction of carbonyl compounds, tosylhydrazine with ortho-substituted aromatic halides or sulfonates (Scheme 10). ${}^{16}$ Taking advantage of ortho-stereo-directing effect in the cross-coupling strategy, this method led to the stereoselective synthesis of $\left( Z\right) - N$ -alkenylazoles with high yields and selectivity. In addition, they also developed a novel and efficient Pd-catalyzed autotandem catalytic system for C-C/C-C bond formation, affording the biologically relevant pyrroloisoquinolines in an efficient manner.

Moreover, Valdés group described the Pd-catalyzed cross-coupling cascade reaction of $\alpha$ -alkoxy $N$ -tosylhydrazones with ortho-substituted aryl non-aflates to give various heterocyclic compounds (Scheme 11). ${}^{17}$ By using sulfonates derived from salicyl aldehydes, the first coupling step leads to protected 1,5-dicarbonyls as the intermediates, followed by the treatment with ammonium hydroxide to generate functionalized isoquinolines in moderate to good yields. Similarly, the employment of ortho-cyanononaflates in the coupling step, followed by subsequent reaction with organolithium reagents, gives rise to 1,2,4-trisubstituted isoquinolines in excellent yields. These two divergent approaches enable a versatile and novel method for the preparation of polysubstituted isoquinolines.

In 2015, a facile and effective synthetic method for various 1,1- heterodiaryl alkenes was reported by Pd-catalyzed cross-coupling reaction of heteroarenols with $N$ -tosylhydrazones (Scheme 12). ${}^{18}$ With the employment of various heteroarenols as the coupling partners, the notable feature of this protocol stands on the mild and viable, economical benign reaction conditions, and the absence of halides or pseudohalides. Proposed mechanism involves in situ C-OH bond activation by using the appropriate phosphonium coupling reagent at first, followed by migratory insertion of the heteroaryl group to Pd(II)-phosphonium-carbene complex 11. Finally, $\beta$ -hydrogen elimination affords the desired 1,1-heterodiaryl alkenes along with the regeneration of $\mathrm{{Pd}}\left( 0\right)$ species.

Scheme 11 Synthesis of polysubstituted isoquinolines through Pd-catalyzed coupling reaction of $\alpha$ -alkoxy $N$ -tosylhydrazones.

Scheme 12 Pd-catalyzed coupling of heteroarenols with $N$ -tosylhydrazones.

In 2015, Pd-catalyzed cross-coupling reaction of α-keto-alkylphosphonate-derived $N$ -tosylhydrazones with aryl bromides was demonstrated by Wang group (Scheme 13). ${}^{19}$ From easily accessible reagents as the substrates, this catalytic route constitutes a novel strategy to synthesize $E$ -trisubstituted alkenylphosphonates bearing versatile functional groups as well as $\alpha$ -substituted vinylphosphonates. Mechanistically, migratory insertion of palladium carbene is proposed as the key step in this coupling reaction. This methodology utilizes $\alpha$ -keto-alkylphosphonate $N$ -tosylhydrazones as the nucleophilic coupling partner.

Furthermore, coupling reaction toward the asymmetric synthesis of chiral functional molecules attracts great attention. In 2010, Barluenga and Valdés attempted Pd-catalyzed cross-coupling reaction of aryl halides with $N$ -tosylhydrazones derived from $\alpha$ -chiral ketones (Scheme 14). ${}^{20}$ As a result, with complete conservation of the stereochemistry at the $\alpha$ -carbon of carbonyl group, a series of aryl-substituted cyclic allylic ethers and allylamines are obtained in high yields. This method not only verifies the cross-coupling reaction of chiral $N$ -tosylhydrazones but also keeps the stability of the $\alpha$ -chiral center of carbonyl compounds.

Scheme 13 Synthesis of alkenylphosphonates via Pd-catalyzed coupling of $\alpha$ -keto-alkylphosphonate-derived N-tosylhydrazones with aryl halides.

Scheme 14 Pd-catalyzed coupling reaction of aryl halides with $N$ -tosylhydrazones derived from $\alpha$ -chiral ketones.

Scheme 15 Pd-catalyzed enantioselective synthesis of axially chiral vinyl arenes.

In 2016, by using chiral pyrrolidine-based phosphoramidite ligand 12, Gu group reported the first asymmetric catalysis in this field, namely, Pd-catalyzed enantioselective synthesis of axially chiral 1-vinylnaphthalen- 2-ylphosphine oxides from achiral substrates of aryl bromides with $N$ -tosylhydrazones derived from cyclic ketones (Scheme 15). ${}^{21}$ This method combines the asymmetric synthesis with Pd-carbene migratory insertion strategy, opening a superior avenue for the construction of axially chiral biaryl compounds with high yields and excellent enantioselectivity. The advantages of this asymmetric coupling approach include good functional group tolerance and mild reaction conditions. Taking into account that desired products are readily reduced to phosphine derivatives, this methodology provides a novel and alternative way to design and synthesize chiral phosphine ligands.

Additionally, Alami and Hamze group have made significant progresses in synthesizing functionalized 1,1-diaryl alkenes by employing the Pd-catalyzed cross-coupling strategy of $N$ -tosylhydrazones with aryl halides or triflates. In particular, they utilized this methodology in the target-oriented synthesis of biochemical active functional molecules. At first, they focused the research topic on the expeditious preparation of 1,1- diarylethylenes derivatives through Pd-catalyzed coupling reaction of poly-oxygenated N-tosylhydrazones with aryl triflates (Scheme 16). ${}^{{22}\mathrm{a}}$ They explored this 1,1-diarylethylene scaffold-constructing strategy in the convergent synthesis of iso-combretastatins A (isoCA-4) analogues, which demonstrate cytotoxic and antimicotic bioactivity. ${}^{{22}\mathrm{\;b},\mathrm{c}}$ This protocol represents a practical application of Pd-catalyzed coupling strategy in biochemistry and medical research. Moreover, by employing this convergent strategy with the coupling of $N$ -tosylhydrazones and aryl iodides under palladium catalysis, they carried out the design and synthesis of an array of benzoxepines derivatives, which served as conformationally restricted iso-combretastatin A-4 analogues. ${}^{22d}$

Scheme 16 Synthesis of polyoxygenated diarylethylenes via Pd-catalyzed coupling reaction with aryl triflates.

In addition, 2- $\alpha$ -styrylpyridines derivatives, exhibiting excellent antip-roliferative and antimitotic activity, were directly obtained in satisfactory to good yields by Pd-catalyzed coupling with 2-halopyridines (Scheme 17). ${}^{23}$ After coupling and subsequent reduction, the desired compound 13, which is found to exhibit excellent antiproliferative and antimitotic activities comparable to isoCA-4, was obtained in simple transformations with good yield.

Scheme 17 Pd(II)-catalyzed coupling of $N$ -tosylhydrazone with heteroaryl halides.

Upon employing the ${\mathrm{{PdCl}}}_{2}{\left( \mathrm{{MeCN}}\right) }_{2}/\mathrm{{dppp}}$ catalytic system, Alami group also reported the synthesis of tetra-substituted 1,1-diarylethylenes from sterically hindered as well as unhindered $N$ -tosylhydrazones with aryl halides under optimized condition. ${}^{{24}\mathrm{a}}$ This procedure provides a chemoselective and general synthetic route to a wide range of tetra-substituted olefins, especially for those having a cycloalkylidene unit. Moreover, the challenge of coupling reactions from sterically hindered $N$ -tosylhydrazones could also be solved by using a newly established ${\mathrm{{PdCl}}}_{2}{\left( \mathrm{{MeCN}}\right) }_{2}/\mathrm{{Xphos}}/t$ -BuONa/fluorobenzene system (Scheme 18). ${}^{{24}\mathrm{\;b}}$ This protocol has been applied successfully to the synthesis of a xanthene scaffold.

Moreover, they developed the one-pot procedure for the $Z$ -selective synthesis of trisubstituted olefins from arylalkynes with ortho-substituted aryl halides. ${}^{{25}\mathrm{a},\mathrm{b}}$ This multistep sequence provided a rapid and versatile protocol for the synthesis of 4-arylchromenes 14, thiochromenes, and related hetero-cycles via a four-step sequence (Scheme 19). In particular, the first three steps involving hydration of alkynes, hydrazone formation, and Pd-catalyzed coupling with ortho-substituted aryl halides furnished $Z$ -trisubstituted olefins stereoselectively without any purification of the intermediates generated in each stage. ${}^{{25}\mathrm{a}}$ In 2012, the same group also described the one-pot three-step synthetic protocol toward $\left( Z\right)$ -trisubstituted olefins from arylalkynes, as well as the sequential cyclization process to access 4-aryl-2H-chromenes and 5-aryl-2,3-dihydrobenzo- $\left\lbrack b\right\rbrack$ oxepine. ${}^{{25}\mathrm{\;b}}$

Scheme ${18}{\mathrm{{PdCl}}}_{2}{\left( \mathrm{{MeCN}}\right) }_{2}$ -catalyzed coupling reaction of sterically hindered and unhindered N-tosylhydrazones.

Scheme 19 One-pot multistep synthesis of 4-arylchromenes through Pd-catalyzed coupling of ortho-substituted aryl halides.

In 2015, Alami and Hamze demonstrated the synthetic approach toward benzofulvenes through transition-metal-catalyzed cascade coupling reactions. ${}^{26}$ This sequential transformation involves a site-selective Sonogashira coupling reaction of ${2}^{\prime }$ -iodoacetophenone-derived $N$ -tosylhydrazones, Pd-catalyzed cross-coupling of ortho-ethynyl $N$ -tosylhydrazones, and Pd-catalyzed selective 5-exo-digcycloisomerization (Scheme 20).

Scheme 20 Synthesis of benzofulvenes through Sonogashira and Pd-catalyzed coupling of ortho-ethynyl- $N$ -tosylhydrazones and catalytic cycloisomerization.

In 2014, the same group established a method to access 3-( $\alpha$ -styryl) benzo[b]thiophene library with a high level of molecular diversity. ${}^{27}$ This synthetic sequence is initiated by bromocyclization of methylthio-containing alkynes using $N$ -methylpyrrolidin-2-one hydrotribromide to obtain 3-bromobenzothiophenes intermediates, followed by a Pd-catalyzed coupling reaction with $N$ -tosylhydrazones, furnishing 2-aryl-3-(α-styryl)benzo[ $b$ ]thiophene derivatives (Scheme 21). Among them, the coupling product 15 has demonstrated submicromolar cytotoxic activity against the HCT-116 cell line, inhibiting the polymerization of tubulin at micromolar level comparable to that of CA-4. Additionally, the success in the synthesis of 6-methyl-6-phenyl-6H-benzo[4,5]thieno $\left\lbrack {3,2 - c}\right\rbrack$ chromenes with good yields expand the scope of this synthetic method.

Furthermore, a concise Pd-catalyzed external ligand-free protocol for the synthesis of 1,1-disubstituted alkenes was reported, allowing for the preparation of heterocyclic arylated alkenes under mild conditions (Scheme 22). ${}^{28}$ By using aryl or heteroaryl halides as the substrates, this transformation provides a facile approach to access a variety of heterocyclic compounds, which are difficult to prepare via traditional coupling procedures.

In 2015, the Pd-catalyzed cross-coupling reaction of aryl fluorides with $N$ -tosylhydrazones was described by Wang group, which constituted a straightforward method for synthesizing di- and trisubstituted arylated olefins (Scheme 23). ${}^{29}$ Mechanistically, the reaction is proposed to be initiated by an electron-deficient group-directed ${\mathrm{S}}_{\mathrm{N}}\mathrm{{Ar}}$ -type process to afford aryl-palladium(II) intermediate 16. Notably, this catalytic protocol represents the combination of C-F bond activation and Pd-carbene migratory insertion strategy.

DavePhos = 2-dicyclohexylphosphino-2’-(N, N-dimethylamino)biphenyl

Scheme 21 Synthesis of 3-(α-styryl)benzo[ $b$ ]-thiophene derivatives through Pd-catalyzed coupling of 3-bromobenzothiophenes with $N$ -tosylhydrazones.

Scheme 22 External ligand-free Pd-catalyzed coupling of $N$ -tosylhydrazones with aryl or heteroaryl halides.

Additionally, the Wang group developed a route to 1,3-butadienes through Pd-catalyzed cross-coupling either from cyclopropylmethyl $N$ -tosylhydrazone with aryl halides, or diaryl $N$ -tosylhydrazone with cyclopropyl halides. ${}^{30}$ The key process in this transformation is the migratory insertion of cyclopropylmethyl Pd-carbene species. Subsequent cyclopropyl ring opening through $\beta$ -carbon elimination of 17, which results in the generation of homoallylic species 18, is followed by base-mediated $\beta$ -H elimination of 18 to give rise to the formation of substituted 1,3- butadienes (Scheme 24). These two transformations constitute a novel approach toward the synthesis of arylated 1,3-butadiene derivatives.

Scheme 23 Pd-catalyzed cross-coupling reaction of aryl fluorides with $N$ -tosylhydrazones.

Scheme 24 Synthesis of 1,3-butadienes through Pd-carbene migratory insertion/β-C/ $\beta$ -H elimination.

Subsequently, Yu group reported the synthesis of 1,1-disubstituted 1,3- butadienes through ${\mathrm{{PdCl}}}_{2}{\left( \mathrm{{MeCN}}\right) }_{2}$ -catalyzed cross-coupling reaction by using cyclopropylmethyl $N$ -tosylhydrazones and aryl halides as the substrates. ${}^{31}$ Besides,1,1,4-trisubstituted 1,3-butadienes can also be accessed with moderate to good yields in the presence of an excess of aromatic bromides catalyzed by $\mathrm{{Pd}}{\left( \mathrm{{OAc}}\right) }_{2}$ .

In 2015, the Pd-catalyzed cross-coupling of 2-amino-3-bromo-aromatic and heteroaromatic components with various sulfonylhydrazones was reported. ${}^{32}$ This work has reported on the catalytic system as well as on the electronic nature of hydrazones which are necessary for the success of this series of Pd-catalyzed coupling reaction.

Pd-catalyzed reductive cross-coupling of aryl halides with diazo species has been performed to construct ${\mathrm{{Csp}}}^{3} - {\mathrm{{Csp}}}^{2}$ single bonds. The Wang group utilized diaryl $N$ -tosylhydrazones as coupling partners in the presence of ammonium formate as the reducing agent, accessing the synthesis of functionalized triarylmethanes as well as heterocyclic analogues. ${}^{{33}\mathrm{a}}$ Plausible mechanism involves anion exchange of migrated palladium species 19 and sequential decarboxylation to generate Pd-H intermediate 20, followed by reductive elimination to furnish the desired product along with regeneration of Pd(0) species (Scheme 25). Notably, the addition of ammonium acetate significantly suppresses direct reduction of Ar-Pd-X species before diazo decomposition. This coupling strategy constitutes a novel approach toward the efficient synthesis of various triarylmethanes and the corresponding heteroatom-containing analogues from easily available substrates.

Recently, Wang and coworkers explored this Pd-catalyzed reductive coupling strategy for the synthesis of di- and triarylmethanes. ${}^{{33}\mathrm{\;b}}$ This reaction includes a wide scope of substrates, among which those containing heterocyclic moiety also proceeded well (Scheme 26).

2.2 Pd-Catalyzed Coupling of N-Tosylhydrazones With Benzyl Halides

In 2009, the Wang group demonstrated the first example of Pd-catalyzed cross-coupling reaction of benzyl halides with N-tosylhydrazones (Scheme 27). ${}^{34}$ This catalytic coupling protocol represents an efficient route to di- and trisubstituted olefins in high yields with excellent stereoselectivity. Mechanistically, the key feature of this transformation is the migratory insertion of benzyl group to the carbenic center of21to form intermediate22, from which $\beta - \mathrm{H}$ elimination affords the desired olefins and regenerates the catalyst with the aid of a base.

In 2014, the same group reported the synthesis of a wide range of ${\mathrm{{CF}}}_{3} -$ substituted alkenes and conjugated dienes from Pd-catalyzed coupling reaction of ${\mathrm{{CF}}}_{3}$ -bearing $N$ -tosylhydrazones or diazo compounds with benzyl or aryl halides (Scheme 28). ${}^{35}$ Similarly, Pd-carbene migratory insertion is assumed to play a crucial role in these transformations. With the advantages of mild conditions and good functional group tolerance, this methodology displays the potential to find applications in the synthesis of trifluoromethyl-containing complex molecules.

Scheme 25 Pd-catalyzed reductive coupling for synthesizing triarylmethanes.

Scheme 26 Pd-catalyzed reductive coupling to form di- and triarylmethanes.

2.3 Pd-Catalyzed Oxidative Coupling of N-Tosylhydrazones

In addition to Pd-catalyzed coupling reaction of aryl halides, catalytic oxidative cross-coupling of arylboronic acids with in situ-generated diazo species from $N$ -tosylhydrazones was also developed, involving transmetalation between the Pd(II) intermediate with boronic acid to generate aryl-Pd(II) species. In 2010, the Wang group disclosed an example of Pd-catalyzed oxidative cross-coupling of $N$ -tosylhydrazones with arylboronic acids in the presence of a Cu(I) salt, affording arylated functionalized olefins with high yields (Scheme 29). ${}^{36}$ The success of the selective generation of cross-coupling products indicates that the oxidative homo-coupling of arylboronic acids has been largely suppressed under aerobic conditions. The proposed mechanism involves transmetalation of Pd(II) species 23 with arylboronic acid initially to afford aryl-palladium species 24, which decomposes the in situ-generated diazo substrate to give the Pd-carbene complex 25. Subsequently, migratory insertion of aryl group to the carbenic carbon of 25 results in the generation of intermediates 26. Finally, $\beta$ -H elimination of 26 affords the olefin product with the regeneration of $\mathrm{{Pd}}\left( 0\right)$ species, which is oxidized by $\mathrm{{Cu}}\left( \mathrm{{II}}\right)$ to form $\mathrm{{Pd}}\left( \mathrm{{II}}\right)$ species.

Scheme 27 Pd-catalyzed coupling of benzyl halides with $N$ -tosylhydrazones.

Scheme 28 Pd-catalyzed coupling to access the synthesis of ${\mathrm{{CF}}}_{3}$ -substituted alkenes.

Scheme 29 Pd-catalyzed oxidative cross-coupling of arylboronic acids with N-tosylhydrazones.

Furthermore, Wang group described the alkynyl migratory insertion process of Pd-carbene, providing a new synthetic method for stereo-selective conjugated enynes through Pd-catalyzed oxidative coupling between $N$ -tosylhydrazones or diazo compounds with terminal alkynes (Scheme 30). ${}^{37}$ The key step in this transformation is migratory insertion of the alkynyl group to the metal-carbene center of27, followed by $\beta - \mathrm{H}$ elimination from 28 to afford enynes. Finally, $\mathrm{{Pd}}\left( 0\right)$ is oxidized by BQ (benzoquinone) to regenerate Pd(II) species.

In 2012, Jiang group demonstrated the $\mathrm{C}\left( {\mathrm{{sp}}}^{2}\right) - \mathrm{C}\left( {\mathrm{{sp}}}^{3}\right)$ bond formation via Pd-catalyzed oxidative coupling of allylic alcohols with $N$ -tosylhydrazones derived from ketones. ${}^{{38}\mathrm{a}}$ This reaction is proposed to be initiated by $\beta - \mathrm{H}$ elimination of palladium alkoxide species 29 to generate $\alpha ,\beta$ -unsaturated ketones 30, in which the double bond moiety coordinates to a Pd-H species. Next, olefin insertion into Pd-H bond with sequential diazo decomposition affords alkyl-Pd-carbene intermediate 31. Subsequent migratory insertion of the alkyl group to the Pd-carbene center occurs, facilitated by the coordination of the carbonyl group to Pd species. Finally, $\beta - \mathrm{H}$ elimination of 32 affords the coupling product along with extrusion of $\mathrm{{Pd}}\left( 0\right)$ , which is reoxidized by BQ to regenerate Pd(II) species (Scheme 31).

Scheme 30 Pd-catalyzed oxidative coupling of $N$ -tosylhydrazones with terminal alkynes.

Moreover, in the same year, the Jiang group established a Pd(II)- catalyzed alternative coupling reactions of electron-deficient terminal alkenes with $N$ -tosylhydrazones. ${}^{{38}\mathrm{\;b}}$ This divergent protocol enables the synthesis of functionalized cyclopropanes from acrylamides, or the chain ketone derivatives from $\alpha ,\beta$ -unsaturated ketones (Scheme 32). The mechanism involves the oxidative cyclometalation of Pd-carbene species 33 with electron-deficient alkene initially to obtain the metallacyclobutane intermediate 34. Sequential $\beta$ -H elimination occurs to produce linear alkyl-Pd species 35, and second $\beta$ -H elimination is suppressed by the strong coordination effect. Amide intermediates undergo an alkene insertion to afford cyclopropane structure 36, followed by reduction elimination or protonolysis to furnish cyclopropanes. On the other hand, weaker coordination effect of the ketone results in the unachievable alkene insertion, instead of the formation of chain products via protonolysis in the presence of water.

To gain insights into the mechanism, the Bi group carried out a theoretical study toward the mechanism of this water-assisted Pd(II)-catalyzed intriguing cross-coupling of alkenes with $N$ -tosylhydrazones. ${}^{{38}\mathrm{c}}$ They have clarified the important roles of water, acetate, and $t - {\mathrm{{BuO}}}^{ - }$ group in the catalytic cycle. The proposed mechanism is as following: (1) migratory insertion to generate stable five-membered metallacyclic intermediate 37; (2) $\beta - \mathrm{H}$ abstraction by $t - {\mathrm{{BuO}}}^{ - }$ , resulting in $\mathrm{C} = \mathrm{C}$ bond formation; (3) oxidative addition; (4) alkene insertion into $\mathrm{{Pd}} - \mathrm{C}\left( {\mathrm{{sp}}}^{2}\right)$ bond; (5) enolization to form Pd-O bond; and (6) hydroxyl hydrogen addition from water to afford final product, along with the generation of Pd-OH species (Scheme 33).

Scheme 31 Pd-catalyzed oxidative coupling of $N$ -tosylhydrazones with allylic alcohols involving alkyl group migratory insertion.

Pd-catalyzed oxidative coupling of two molecules of $N$ -tosylhydrazones provided a new route to branched conjugated dienes. ${}^{39}$ In 2013, Jiang ${}^{{39}\mathrm{a}}$ and Prabhu ${}^{{39}\mathrm{b}}$ reported the Pd-catalyzed oxidative coupling reactions of $N$ -tosylhydrazones under the aerobic condition or using BQ as the oxidant, respectively. These transformations enable the facile, efficient regioselective synthesis of 2,3-substituted-1,3-butadienes from readily available substrates, as well as the preparation of heterocyclic rings. The proposed mechanism involves diazo decomposition by alkenyl-Pd species 38 to generate alkenyl-Pd-carbene intermediate 39. Migratory insertion of alkenyl group with sequential $\beta - \mathrm{H}$ elimination gives rise to the formation of the final product, and Pd(0) is oxidized to regenerate Pd(II) (Scheme 34).

Scheme 32 Pd-catalyzed diverse coupling reaction of N-tosylhydrazones with electron-deficient alkenes.

Scheme 33 Proposed mechanism of water-assisted Pd(II)-catalyzed cross-coupling of alkenes with N-tosylhydrazones.

Scheme 34 Pd-catalyzed oxidative coupling of $N$ -tosylhydrazones to provide branched conjugated dienes.

Moreover, Pd-catalyzed oxidative cross-coupling of N-tosylhydrazones with indoles was carried out, providing an efficient synthetic method for $N$ -vinylindoles ${}^{{40}\mathrm{a}}$ as well as $N$ -vinylazoles ${}^{{40}\mathrm{\;b}}$ with good functional group tolerance (Scheme 35). These transformations are implemented under aerobic conditions or utilized aryl iodide as the oxidant, respectively. Especially, migratory insertion of the indole unit is hypothesized as the key step, followed by $\beta - \mathrm{H}$ elimination to afford $N$ -vinyl-functionalized $N$ -heterocycles.

2.4 Pd-Catalyzed Two-Component Cascade Coupling of N-Tosylhydrazones

Furthermore, Pd-catalyzed two-component cascade reaction involving migratory insertion has also experienced considerable growth. This autotandem catalytic strategy by using diazo compounds establishes a novel and facile approach for synthesizing divergent functional molecules. In 2011, Barluenga and Valdés demonstrated the Pd-catalyzed tandem coupling of $N$ -tosylhydrazones derived from Mannich adducts with 1,2-dihalogenated arenes, proceeding through aryl group migratory insertion with catalytic amination (Scheme 36). ${}^{41}$ This sequential C-C/ intramolecular C-N bond formation protocol provides quinoline derivatives, as well as enantiomerically enriched quinoline scaffold through the combination of organocatalytic Mannich reaction with the Pd-catalyzed coupling reaction. This unprecedented autotandem catalytic transformation opens a new avenue to the development of other appealing coupling cascade transformations.

Scheme 35 Pd-catalyzed oxidative cross-coupling of $N$ -tosylhydrazones with indoles.

Scheme 36 Autotandem Pd-catalyzed C-C/C-N bond formation to obtain quinolines.

Besides, Wang group utilized the autotandem strategy to access the functionalized acridines from coupling reaction of o-dihalobenzenes with $N$ -tosylhydrazones containing amino group. ${}^{42}$ Reaction pathway consists of the aryl group migratory insertion/ $\beta - \mathrm{H}$ elimination sequence followed by catalytic intramolecular amination. In addition, Pd-catalyzed coupling reaction between vinyl iodides and $N$ -tosylhydrazones with intramolecular nucleophilic trapping sequence was performed to afford pyrrolidine and piperidine scaffold (Scheme 37). ${}^{43}$

Scheme 37 Autotandem Pd-catalyzed C-C/C-N bond formation to afford acridines, pyrrolidine, and piperidine scaffold.

Moreover, Pd-catalyzed cross-coupling reaction involving migratory insertion with nucleophilic trapping cascade provided novel and efficient approaches for a wide range of cyclic molecules, including isoindolones 40 (with nitrogen nucleophile), ${}^{44}$ dihydronaphthalene 41 and indene 42 (with carbon nucleophile), ${}^{45}$ 2H-chromenes 43 (with oxygen nucleophile), ${}^{46}$ spiroacetal enol ethers 44 (through intramolecular nucleophilic dearomatization), ${}^{47}$ 1-arylindanes 45 and 1-aryltetralins 46 (with carbon nucleophile), ${}^{48}$ allylic sulfones 47 (using $N$ -tosylhydrazone as a double nucleophile), ${}^{49}$ and chromeno[4,3-b]chromene 48 (with oxygen nucleophile) ${}^{50}$ (Scheme 38). From commercially available aldehydes or ketones and organic halides, these Pd-catalyzed cascade reactions provide facile and straightforward synthesis of divergent building blocks, especially for heterocyclic compounds.

In 2016, Huang group reported the Pd-catalyzed cross-coupling reaction of aminals with vinyl $N$ -sulfonyl hydrazones, in which the C-C and C-S bond was simultaneously constructed in a straightforward manner (Scheme 39). ${}^{51}$ This process affords aminomethyl-substituted allylic sulfones in moderate to good yields. The key step in this reaction is the migratory insertion of aminomethyl group to form the $\pi$ -allylpalladium intermediate 50 generated from electrophilic cyclopalladated complex 49, followed by sequential nucleophilic attack to deliver the final product along with the regeneration of active $\mathrm{{Pd}}\left( 0\right)$ species.

Scheme 38 Synthesis of functional molecules through Pd-catalyzed coupling/nucleophilic trapping cascade synthetic strategy.

Scheme 39 Pd-catalyzed carbene-coupling reaction of aminals to afford allylic sulfones.

In addition, the combination of Pd-catalyzed cross-coupling involving migratory insertion with intramolecular Heck-type reaction has been developed and applied for preparing functional molecules containing C-C double bonds, including spiroamide derivatives 51, ${}^{52}$ 3-vinylindoles and 3-vinylbenzofurans 52, ${}^{53}$ spirocyclic systems 53 (spiro-fluorenes, -dibenzofluorenes, -acridines, and -anthracenes), ${}^{54}$ benzofuran-, dihydrobenzofuran-, and indoline-containing alkenes 54, ${}^{55}$ indanes and 2,3-disubstituted benzofurans 55, ${}^{56}$ polysubstituted indoles 56 and 1,4-dihydroquinolines ${\mathbf{{56}}}^{\prime },{}^{57}$ as well as various naphtho-fused heterocycles ${\mathbf{{57}}}^{58}$ (Scheme 40). Finally, alkenes are obtained through alkyl group migratory insertion followed by $\beta - \mathrm{H}$ elimination. This reaction represents the first example of the reaction involving neopentyl palladium intermediates with carbenes to form alkenes. ${}^{52}$

In 2015, the domino process which converged Pd-carbene migratory insertion with intramolecular Heck reaction was reported, allowing the stereo- and regioselective synthesis of 2-arylidene-3-aryl-1-indanones from readily available $N$ -tosylhydrazones and ${2}^{\prime }$ -iodochalcones (Scheme 41). ${}^{59}$ Moreover, the success of one-pot synthesis as well as gram-scale preparation also demonstrates its practical utility in organic synthesis. Mechanistically, this reaction is assumed to proceed via migratory insertion of aryl group, followed by regioselective 5-exo-trig cyclization and $\beta$ -hydride elimination process.

Yin and Jiang group developed an intriguing Pd-catalyzed cross-coupling reaction of furfural tosylhydrazones with 2-iodo-anilines or -thiophenols, respectively, affording polysubstituted indoles or benzothiophenes. ${}^{60}$ This transformation is proposed to proceed via aryl migratory insertion to generate 2-furylmethylene palladium species 58. Sequential $\beta$ -oxygen elimination with concomitant furan ring-opening procedure affords the allene intermediate 59. Subsequently, intramolecular nucleophilic addition, palladium transfer, and $\beta - \mathrm{H}$ elimination occur, leading to the synthesis of indoles or benzothiophenes as ring closure products (Scheme 42).

In 2016, an autotandem Pd-catalyzed coupling reaction of alkyne-based aryl iodides with salicyl $N$ -tosylhydrazones was reported (Scheme 43). This convenient method allows the construction of spiro[benzofuran-3,2’- chromene] scaffold with good yields and excellent selectivity. ${}^{61}$ Mechanistically, this reaction proceeds via initial 5-exo-dig cyclization of 60 to form the vinyl Pd(II) intermediate 61. Then, in situ-generated diazo species reacts with 61 to form Pd-carbene species 62, which undergoes sequential migratory insertion of vinyl group to give benzyl palladium intermediate 63. Finally, intramolecular cyclization of 63 promoted by oxygen as nucleophiles affords the spirocyclic skeleton and regenerate Pd species simultaneously.

Scheme 40 Synthesis of functional molecules through Pd-catalyzed cross-coupling of N-tosylhydrazones via intramolecular Heck-type cascade transformations.

Scheme 41 Synthesis of 2-arylidene-3-aryl-1-indanones through Pd-catalyzed coupling of N-tosylhydrazones with Heck-type cascade reaction.

Scheme 42 Pd-catalyzed coupling of furfural tosylhydrazones with 2-iodoanilines.

Scheme 43 Formation of spiro[benzofuran-3,2’-chromene] derivatives through Pd-catalyzed tandem coupling reaction.

Scheme 44 Synthesis of benzoxepines through Pd-catalyzed coupling reaction involving carbene insertion and C-C bond cleavage.

In 2016, Zhou group achieved the regiospecific synthesis of benzo-xepines derivatives through Pd-catalyzed coupling reaction of aryl halides with oxabicyclo[4.1.0]heptyl $N$ -tosylhydrazones (Scheme 44). ${}^{62}$ Key features of this ring expansion include migratory insertion of the Pd-carbene intermediate to form 64, which undergoes sequential selective C-C bond cleavage to obtain the ring-expanded intermediate 65. Finally, $\beta - \mathrm{H}$ elimination from 65 occurs to deliver benzoxepines containing an aryl group at the 5-position.

Moreover, Liang group established divergent Pd-catalyzed decarboxy-lative coupling of propargylic carbonates with acetophenone-derived $N$ -tosylhydrazones (Scheme 45). ${}^{63}$ Migratory insertion from the allenyl-palladium carbene 66 with subsequently $\beta - \mathrm{H}$ elimination results in the synthesis of multisubstituted conjugated vinylallenes. Alternatively, formation of propargylic $N$ -sulfonylhydrazones comes from direct nucleophilic attack of the propargyl palladium intermediate 67 with hydrazone salt anion, followed by reductive elimination to furnish propargylic substitution product, accompanying with the regeneration of $\operatorname{Pd}\left( 0\right)$ .

Furthermore, except for hydrocarbon groups, migratory insertion processes of other heteroatom groups have also been explored. In 2015, Wang group reported the Pd-catalyzed carbene insertion into Si-Si and Sn-Sn bonds, using $N$ -tosylhydrazones as the carbene precursors (Scheme 46). ${}^{64}$ This protocol affords geminal bis(silane) and geminal bis(stannane) derivatives with high efficiency under mild conditions. Compared with the traditional insertion process, this reaction is proposed to proceed via oxidative addition and migratory insertion of Pd-carbene species as the key steps. This unprecedented reaction shows the generality of metal-carbene migratory insertion process as a new strategy for the construction of carbon-heteroatom bond with high efficiency and good selectivity.

Scheme 45 Pd-catalyzed decarboxylative synthesis of vinylallenes and propargyl N-sulfonylhydrazones.

Scheme 46 Pd-catalyzed carbene insertion into Si-Si and Sn-Sn bonds.

In addition, Huang recently reported the first Pd-catalyzed noncarbene cross-coupling reaction of $\beta ,\gamma$ -unsaturated $N$ -tosylhydrazones with aminals through a catalytic tandem aminomethyl amination/aromatization process (Scheme 47). ${}^{65}$ This Pd-catalyzed coupling strategy constitutes a new approach toward the synthesis of $\beta$ -aminoethylpyrazoles without the need of external oxidant and base. The proposed mechanism is assumed to proceed by C-N bond activation initially to afford electrophilic cyclopalladated complex 68. Then, diene 69 which is in situ generated from tosylhydrazones via imine-enamine tautomerization reacts with 68 to give rise to $\pi$ -allylic palladium complex 70 as the key intermediate. This intermediate then undergoes sequential intramolecular nucleophilic addition to afford 2,3- dihydropyrazole intermediate 71. Subsequently, deprotonation of 71 assisted by aminal results in the formation of the azaallylic anion 72, followed by the capture of 68 and final $\beta - \mathrm{H}$ elimination to afford the desired heterocycle derivatives.

Scheme 47 Pd-catalyzed coupling of $\beta ,\gamma$ -unsaturated $N$ -tosylhydrazones with aminals to synthesize $\beta$ -aminoethylpyrazoles.

2.5 Pd-Catalyzed Multicomponent Coupling of N-Tosylhydrazones

Furthermore, Pd-catalyzed multicomponent cascade transformation involving migratory insertion also attracts great attentions. One typical type of this cascade process is Pd-catalyzed autotandem strategy. Recently, Alami and Hamze have disclosed a series of Pd-catalyzed three-component coupling reactions of $N$ -tosylhydrazones with aryl halides with sequential C-C/C-N bond formation, affording various functionalized aromatic compounds with high efficiency. ${}^{66}$ In 2013 and 2014, Alami and coworkers reported the one-pot autotandem Pd-catalyzed iterative coupling reactions with sequential $\mathrm{C} - \mathrm{X}$ bond amination, producing nitrogen-containing diarylethylenes ${}^{{66}\mathrm{a}}$ and $N$ -vinylindoles ${}^{{66}\mathrm{\;b}}$ (Scheme 48). These three-component reactions of $N$ -tosylhydrazones, amines, and halogen-substituted aromatic compounds provide facile routes to construct C-C double bond and $\mathrm{C} - \mathrm{N}$ bond in one-pot fashion.

Scheme 48 Autotandem Pd-catalyzed C-C/C-N bond formation reactions to access nitrogen-containing diarylethylenes and $N$ -vinylindoles.

In 2015, the same group developed a Pd-catalyzed one-pot coupling reaction of dihalogenated arenes, $N$ -tosylhydrazones with boronic acids or esters, affording a highly functionalized 1,1-diarylethylene skeleton of the natural product ratanhine with good yields and wide substrate scope (Scheme 49). ${}^{{66}\mathrm{c}}$ Notably, this iterative cross-coupling strategy, which constructs two distinct C-C bonds in one-pot fashion, allows the facile synthesis of 73 that exhibits antiproliferative activity in the nanomolar concentration range against HCT116 cancer cell lines.

In 2016, the same group disclosed a convergent synthesis of arylindole derivatives and (1-arylvinyl)carbazoles through one-pot Pd-catalyzed coupling reaction of 2-nitro-haloarenes with $N$ -tosylhydrazones, followed by a Cadogan-Sundberg reductive cyclization to afford indole scaffold. ${}^{66d}$ This methodology not only enables facile construction of C-C/C-N bond formation in a single step but also allows efficient synthesis of functional molecules which exhibits antiproliferative activity in low nM range against colon cancer cell lines. Moreover, they developed a new Pd-catalyzed one-pot coupling process of $N$ -tosylhydrazones, $N$ -(dihalophenyl)-imidates with amines, affording a library of 5-(1-arylvinyl)-1H-benzimidazoles. 66e

SPhos = 2-dicyclohexylphosphino-2’, 6’-dimethoxybiphenyl

Scheme 49 Palladium-catalyzed one-pot coupling reaction of dihalogenated arenes, N-tosylhydrazones with organoborons to form 1,1-diarylethylene derivatives.

N-tosylhydrazones to construct C-C and C-N bonds.

A plausible mechanism involves a Pd-carbene migratory insertion process to give substituted alkenes, followed by Pd-catalyzed N-arylation and sequential intramolecular cyclization to verify the construction of one C-C bond and two C-N bonds in the same catalytic cycle (Scheme 50).

In 2013, Liang group reported a Pd-catalyzed three-component cross-coupling reaction of vinyl iodide, N-tosylhydrazone (derived from benzalde-hydes), and carbon nucleophiles, as well as the one-pot procedure by using the aldehyde compound as the substrate (Scheme 51). ${}^{{67}\mathrm{a}}$ The proposed mechanism involves migratory insertion of vinyl group to Pd-carbene center, followed by the nucleophilic attack of sodium malonate to the ${\eta }^{3}$ -allylpalladium intermediate, resulting in the formation of two distinct C-C bonds.

Scheme 51 Pd-catalyzed carbene insertion of vinyl halides, N-tosylhydrazones with carbon nucleophiles.

Scheme 52 Pd-catalyzed coupling reaction of vinyl iodides, alkyl aldehyde-derived N-tosylhydrazones, with carbon or nitrogen nucleophile.

In 2015, Van Vranken group described the Pd-catalyzed both intra-and intermolecular carbenylative amination and alkylation with vinyl iodides through palladium alkylidene species as the key intermediate (Scheme 52). ${}^{{67}\mathrm{\;b}}$ As a result, vinyl iodides are shown to generate ${\eta }^{3}$ - allylpalladium species, which resists competitive $\beta$ -H elimination process, preserving the $\mathrm{C}\left( {\mathrm{{sp}}}^{3}\right)$ center adjacent to the carbene moiety. This selective multicomponent coupling reaction enables the construction of functionalized alkenes.

Wang group have also focused on the Pd-catalyzed multicomponent coupling reaction of $N$ -tosylhydrazones to access the synthesis of functional molecules. In 2010, they carried out the Pd-catalyzed three-component cross-coupling reaction of aryl halides, N-tosylhydrazones, and terminal alkynes as nucleophiles, constructing two separate C-C bonds on a carbenic carbon atom. ${}^{68}$ Rather than competitive undesirable Sonogashira products, this C(sp)-C(sp ${}^{3}$ ) coupling reaction provides an efficient method for synthesizing benzhydryl acetylene derivatives (Scheme 53). Especially, tran-smetalation between the migrated alkylpalladium key intermediate with various transition-metal species opens a new avenue both for carbene chemistry and for cross-coupling reactions.

Furthermore, Wang group developed the Pd-catalyzed multicomponent reactions of aryl iodides, allenes with $N$ -tosylhydrazones, or diazo species, which is a concise method for synthesizing highly functionalized 1,3- dienes. ${}^{69}$ Mechanistically, the reaction pathway is assumed to proceed via allene carbopalladation to form 74, with sequential allyl group migratory insertion of Pd-carbene 75 as the key step, resulting in the formation of 76 with an $E$ configuration in the formed double bond (Scheme 54).

Scheme 53 Pd-catalyzed three-component coupling of $N$ -tosylhydrazone, terminal alkyne with aryl halide.

Scheme 54 Pd-catalyzed multicomponent synthesis of 1,3-dienes from aryl iodides, allenes with diazo species.

Moreover, the Pd-catalyzed carbonylation coupling sequence of aryl iodides with diazo compounds was also developed by Wang group.

The reaction involves acyl group migratory insertion to the carbenic carbon atom (Scheme 55). ${}^{{70}\mathrm{a}}$ This multicomponent strategy provides a novel route to access $\alpha$ -aryl carbonyl compounds. More importantly, it demonstrates the possibility of the combination of Pd-carbene transformation and catalytic carbonylation. Such transformation involves migratory insertion of an acyl group to Pd-carbene center.

In 2011, Wang group reported a Pd(0)-catalyzed carbonylation of $N$ -tosylhydrazone salts or $\alpha$ -diazocarbonyl compounds under atmospheric pressure of CO (Scheme 56). ${}^{{70}\mathrm{\;b}}$ Pd-catalyzed carbonylative coupling of in situ-generated diazo species from $N$ -tosylhydrazone salts with various nucleophiles allows the efficient synthesis of esters and amides with high yields. Moreover, Staudinger [2+2] reactions are also successfully implemented through the trapping of ketene intermediate with imines, providing aryl or alkenyl substituted β-lactams with high yields and good diastereo-selectivity. In this case, ketene-mediated transformation demonstrates great importance in synthesizing functional molecules under mild conditions.

Scheme 55 Pd-catalyzed carbonylation sequence of aryl iodides with in situ-generated diazo compounds.

Scheme 56 Pd-catalyzed carbonylation of $N$ -tosylhydrazones under atmospheric pressure.

Scheme 57 Pd-catalyzed coupling of $N$ -tosylhydrazones with isocyanides.

In addition to the catalytic carbonylation of $N$ -tosylhydrazones, Pd-catalyzed homologation of in situ-generated diazo species with iso-cyanides, involving the generation of ketenimine as the key intermediate, has been explored by Cai and coworkers (Scheme 57). ${}^{71}$ In 2011, they performed the Pd(0)-catalyzed coupling reaction of $N$ -tosylhydrazones with isocyanides in the presence of a base. The mechanistic hypothesis involves the generation of Pd-carbene species, followed by migratory insertion to form ketenimine intermediate 77, which undergoes sequential nucleophilic addition of water to afford the desired amides.

Pd-catalyzed norbornene-mediated coupling reaction (Catellani reaction) of $N$ -tosylhydrazones has also been studied within this field. ${}^{72}$ Liang and coworker successfully developed a series of Pd-catalyzed multicomponent norbornene-mediated cascade reactions involving ortho-C-H activation/migratory insertion of aryl group to Pd-carbene center. ${}^{{72a} - c}$ Under similar reaction condition, this strategy is applied for the synthesis of polycyclic vinylarenes as well as ortho-aminated analogues (Scheme 58). In addition, these cascade transformations have, respectively, combined intra- or intermolecular alkylation/amination with Pd-carbene migratory insertion strategy. Alternatively, Wang group carried out the Pd-catalyzed three-component reaction of $N$ -tosylhydrazones, norbornene, and aryl halides to obtain arylated double-functionalized norbornenes, proceeding through intermolecular Heck reaction/alkyl group migratory insertion sequence. ${}^{72d}$

Scheme 58 Pd-catalyzed norbornene-mediated cascade reactions involving C-H bond activation.

Scheme 59 Pd-catalyzed ring opening of norbornene to access methylenecyclopentanes.

In 2015, Liang group developed the Pd-catalyzed three-component domino cascade of aryl iodides, N-tosylhydrazones, and norbornenes (Scheme 59). ${}^{72e}$ Proceeding through the ring-opening sequence of norbornene, methylenecyclopentane derivatives are obtained with high yields and excellent functional group tolerance under mild reaction conditions. Mechanistically, the reaction pathway is assumed to involve oxidative addition/Heck-type carbopalladium/Pd-carbene 78 migratory insertion to form ${79}/\beta - \mathrm{C}$ elimination $/\beta - \mathrm{H}$ elimination sequence to give the desired cyclopentane derivatives.

Scheme 60 Pd-catalyzed three-component cascade reaction of α-halo-N-tosylhydrazones, indoles with aryl iodides.

Furthermore, in 2016 Wang group disclosed a Pd-catalyzed three-component cascade reaction of $\alpha$ -halo- $N$ -tosylhydrazones, indoles, with aryl iodides, affording 3-indolyl di- or trisubstituted alkenes with moderate to high yields and good functional group tolerance (Scheme 60). ${}^{73}$ This intriguing strategy has been designed by employing indoles as the nucleo-philes to react with the azoalkene intermediate80generated in situ from the corresponding $\alpha$ -halo- $N$ -tosylhydrazone in the presence of base, which is further subjected to Pd-catalyzed carbene-mediated C-C bond forming reactions with aryl iodides. Furthermore, they also reported the 1,2-H shift procedure of the diazo intermediate by using copper(I) iodide as the catalyst.

3. COPPER-CATALYZED COUPLING REACTION OF N-TOSYLHYDRAZONES

3.1 Cu-Catalyzed Coupling of N-Tosylhydrazones With Alkynes

In addition to palladium catalysts, copper complexes have also demonstrated high activity in catalyzing cross-coupling reactions involving migratory insertion. However, the coupling partners as well as the type of transformations are different. In 2011, Wang group developed a novel Cu(I)-catalyzed cross-coupling reaction of terminal alkynes with $N$ -tosylhydrazones as diazo analogues by using rac-bis(oxazoline) 81 as the ligand. ${}^{74}$ Highly functionalized trisubstituted allenes were obtained in high yields with good functional group tolerance (Scheme 61). Mechanistic rationale involves the alkynyl migratory insertion to carbenic center of Cu-carbene intermediate 82 to generate alkyl copper complex 83, followed by the regioselective protonation on the triple bond carbon atom of 83.

Scheme 61 Cu(I)-catalyzed coupling reaction of terminal alkynes with N-tosylhydrazones.

Since then, this catalytic system for the synthesis of a variety of allenes has been improved and simplified, which employed inexpensive copper(I) iodide and ligands. Functionalized substituted allenes (including 1,3-disubstituted), ${}^{{75}\mathrm{a}}$ and terminal allenes, ${}^{{75}\mathrm{\;b}}$ can be efficiently accessed by Cu-catalyzed cross-coupling reaction of terminal alkynes with divergent $N$ -tosylhydrazones (Scheme 62). Particularly, ethyne has been explored as a coupling partner in Cu-mediated carbene transformations with $N$ -tosylhydrazones or $\alpha$ -diazoacetates. ${}^{{75}\mathrm{\;b}}$ These reactions represent a set of concise methods for preparing substituted allenes, which are important structure units that find applications in various areas.

On the other hand, Wang group developed a novel and ligand-free $\mathrm{C}\left( \mathrm{{sp}}\right) - \mathrm{C}\left( {\mathrm{{sp}}}^{3}\right)$ bond formation strategy via $\mathrm{{Cu}}\left( \mathrm{I}\right)$ -catalyzed cross-coupling reaction of $N$ -tosylhydrazones with trialkylsilylethynes. ${}^{76}{}^{a}$ Owing to the presence of trialkylsilyl substituents, functionalized alkynes were obtained in high yields under mild reaction conditions. Mechanistically, the protonation step of alkynyl migrated copper(I) species 84 is crucial for the selectivity of the products (Scheme 63). When changing tert-butyl-substituted alkyne as the coupling partner, this transformation affords allene as the product. Theoretical study indicates that the $\mathrm{{Cu}} - \mathrm{C}$ interaction between the tert-butyl-substituted $\mathrm{C}$ atom with the copper center, as well as the back-donation from $\pi$ orbital of the triple bond to ${\sigma }^{ * }$ antibonding orbital of Si-C, determines the chemoselectivity observed in these studies. ${}^{{76}\mathrm{\;b}}$

Scheme 62 Cu-mediated synthesis of substituted allenes from diazo compounds with terminal alkynes.

Scheme 63 Cu(I)-catalyzed cross-coupling reaction of N-tosylhydrazones with trialkylsilylethynes.

Scheme 64 Cu-catalyzed three-component coupling reaction of $N$ -tosylhydrazones, terminal alkynes with allyl halides.

Furthermore, by utilizing the high reactivity of allene moiety, Cu-catalyzed cascade transformations of $N$ -tosylhydrazones with terminal alkynes have been explored for synthesizing a variety of functional molecules. Wang group reported the efficient synthesis of tri- and tetrasubstituted allyl allenes through Cu(I)-catalyzed three-component coupling of $N$ -tosylhydrazones, terminal alkynes with allyl halides (Scheme 64). ${}^{77}$ Beyond protonation process, the propargylic Cu(I) species 85, which is generated from Cu(I) carbene migratory insertion, undergoes nucleophilic substitution with allylic iodides. This strategy demonstrates the possibility of incorporating other electrophiles into Cu-catalyzed coupling partners.

Phenanthrenes derivatives demonstrate great applications in medicinal chemistry and material research. Wang group has explored the Cu-catalyzed cross-coupling of terminal alkynes with $N$ -tosylhydrazones derived from $o$ -formyl biphenyls for the construction of phenanthrene framework, ${}^{{78}\mathrm{a}}$ as well as the coupling reaction of 2-alkynyl biphenyls with tosylhydrazones derived from aromatic aldehydes. ${}^{{78}\mathrm{\;b}}$ Mechanistically, the reaction is proposed to proceed through Cu-catalyzed coupling/allenylation/6π-electron cyclization of 86/aromatization sequence (Scheme 65). These catalytic transformations provide expeditious synthetic methods for phenanthrenes from readily available starting materials.

Moreover, Cu-catalyzed cascade reaction of terminal alkynes with diazo component has been utilized for the construction of a series of heterocyclic scaffolds (Scheme 66). Wang and Zhou reported the efficient synthesis of benzofurans and indoles through Cu(I)-catalyzed ligand-free cross-coupling reaction of terminal alkynes with salicyl $N$ -tosylhydrazones, ${}^{{79}\mathrm{a}}$ or coupling of $N$ -tosylhydrazones with $o$ -hydroxy or $o$ -amino phenylacetylenes. ${}^{{79}\mathrm{\;b}}$ These two catalytic coupling/allenylation/cyclization strategies lead to the facile and economical preparation of heterocycles by employing easily accessible substrates.

Scheme 65 Cu-catalyzed cross-coupling of alkynes with $N$ -tosylhydrazones for synthesizing phenanthrenes.

Scheme 66 Synthesis of benzofurans and indoles from alkynes with $N$ -tosylhydrazones.

Recently, Cu(I)-catalyzed cross-coupling cascade of $N$ -tosylhydrazones with 3-butyn-1-ol has been reported by Wang group. ${}^{80}$ This methodology constitutes a new approach toward the synthesis of 2-(diarylmethylene) tetrahydrofurans with moderate to good yields. The proposed mechanism involves the intramolecular cyclization of hydroxy-tethered allenes, which are generated via migratory insertion of alkynyl Cu-carbene species.

In 2015, Wang group reported a Cu-catalyzed three-component coupling reaction of $N$ -tosylhydrazones, alkynes, and azides, which constitutes a convenient synthetic route to 1,4,5-trisubstituted 1,2,3-triazoles in an efficient and regioselective manner (Scheme 67). ${}^{81}$ Mechanistically, this reaction proceeds through the generation of copper(I) triazolide intermediate 87 initially via Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC). Subsequently, migratory insertion of the triazole group from Cu(I)-carbene 88 occurs to afford alkyl copper complex 89. Finally, sequential protonation of 89 by HO- $t$ -Bu results in the formation of the product along with regeneration of $\mathrm{{Cu}}\left( \mathrm{I}\right)$ catalyst. This efficient catalytic strategy shows the combination of click chemistry with a metal-carbene migratory insertion process.

Scheme 67 Cu-catalyzed three-component reaction of $N$ -tosylhydrazones, alkynes, and azides.

Moreover, the synthesis of fluorinated 1,3-enynes, which serve as important building blocks in organic synthesis and medicinal research, attracts great attention. Wang group demonstrated the feasibility of the Cu(I)-catalyzed cross-coupling reaction of terminal alkynes with $N$ -tosylhydrazones derived from trifluoromethyl ketones, furnishing functionalized 1,1-dif-luoro-1,3-enyne derivatives with high efficiency. ${}^{82}$ This convenient and facile protocol has combined the Cu-carbene 90 migratory insertion with $\beta$ -fluoride elimination through a cascade Cu-catalytic cycle (Scheme 68).

Scheme 68 Cu-catalyzed synthesis of 1,1-difluoro-1,3-enynes from terminal alkynes with trifluoromethyl ketone N-tosylhydrazones.

3.2 Cu-Catalyzed Coupling of N-Tosylhydrazones Involving C-H Activation

Except for terminal alkynes, heterocycles as well as substituted aromatics have also been employed as the nucleophilic coupling partners, proceeding through a C-H bond activation process. In 2011, Wang group reported Cu-catalyzed cross-coupling of N-tosylhydrazones with 1,3-azoles, directly affording 2-benzylated or 2-allylation products. ${}^{83}$ Compared with other methods, this strategy provides an efficient avenue for the synthesis of 2-alkylated heterocycles through C-H bond functionalization. For the reaction mechanism, Cu-carbene 91 migratory insertion seems more reasonable rather than the direct carbene C-H insertion (Scheme 69).

In 2013, this Cu-catalyzed reaction strategy was expanded to 1,3,4- oxadiazoles as the nucleophilic coupling partners, providing an efficient and concise benzylation through direct $\mathrm{C} - \mathrm{H}$ bond functionalization. ${}^{84}$ A series of 2-substituted oxadiazoles could be obtained in high yields (17 examples, 80%-89% yields). Migration of the heteroaryl group to the Cu-carbene center is proposed as the key step.

In 2013, Wang group further demonstrated the $\mathrm{C} - \mathrm{H}$ alkylation of pyridine derivatives through Cu-catalyzed cross-coupling of $N$ -tosylhydrazones with N-iminopyridinium ylides (Scheme 70). ${}^{85}$ Using inexpensive CuI catalyst under ligand-free conditions, various ortho-alkylated pyridines were obtained in good yields. The reaction is assumed to proceed via a copper carbene 92 migratory insertion of the pyridyl group, a proposal supported by DFT calculations.

Scheme 69 Cu-catalyzed cross-coupling of $N$ -tosylhydrazones with 1,3-azoles.

Scheme 70 Cu-catalyzed coupling of $N$ -iminopyridnium ylides with $N$ -tosylhydrazones.

Transition-metal-catalyzed C-H alkylation of polyfluoroarenes still remains a challenging problem. Toward this end, Wang group carried out the Cu-catalyzed alkylation of electron-deficient polyfluoroarenes through cross-coupling with $N$ -tosylhydrazones or diazo compounds (Scheme 71). ${}^{86}$ This process represents an efficient construction of a $\mathrm{C}\left( {\mathrm{{sp}}}^{2}\right) - \mathrm{C}\left( {\mathrm{{sp}}}^{3}\right)$ bond of polyfluoroarenes via direct $\mathrm{C} - \mathrm{H}$ bond alkylation. Mechanistically, migratory insertion of polyfluoroaryl copper carbene species is the key step in the catalytic cycle.

In 2014, the Cu(I)-catalyzed cross-coupling of 1,3-azoles with $N$ -tosylhydrazones derived from ferrocenyl ketones was reported, affording secondary alkylated products. ${}^{87}$ This method may be used for the synthesis of substituted ferrocenyl-based ligands, as well as $1,{1}^{\prime }$ -disubstituted ferro-cenyl bidentate derivatives (Scheme 72).

Scheme 71 Cu(I)-catalyzed alkylation of polyfluoroarenes via C-H functionalization.

Scheme 72 Cu-catalyzed direct alkylation of 1,3-azoles with N-tosylhydrazones bearing ferrocenyl group.

Recently, the Cu(I)-catalyzed regioselective C-H functionalization of azine $N$ -oxides with $N$ -tosylhydrazones was achieved under microwave conditions, giving rise to ortho-alkylated heterocyclic compounds (Scheme 73). ${}^{88}$ With readily available substrates and inexpensive copper(I) iodide, a series of 2-alkyl-substituted pyridine, quinoline, and isoquinoline derivatives are easily obtained.

3.3 Cu-Catalyzed Oxidative Coupling Reaction of N-Tosylhydrazones

In 2016, Jiang and Wu reported a copper-mediated oxidative coupling reaction of $\beta$ -ketoesters by using $N$ -tosylhydrazones as two-carbon synthons, affording 2,3,5-trisubstituted furans in moderate to good yields and excellent regioselectivity. ${}^{89}$ The proposed mechanism is illustrated in Scheme 74, which involves the oxidation of Cu-carbene 93 under aerobic conditions to give the vinyl copper(II) complex 94. Then, accelerated by the Lewis acidic nature of the Zn(II) complex, the regioselective radical addition of the dicarbonyl free radical 95 with 94 occurs to generate the radical intermediate 96. Finally, the products are formed through divergent oxidative sequence. This oxidative cyclization strategy represents a unique type of $N$ -tosylhydrazone transformations.

Scheme 73 Cu(I)-catalyzed coupling of azine $N$ -oxides with $N$ -tosylhydrazones.

Scheme 74 Cu/Zn-mediated oxidative coupling of $N$ -tosylhydrazones and $\beta$ -ketoesters.

Moreover, Jiang group reported the Cu-catalyzed oxidative transformations of ketone-derived $N$ -tosylhydrazones under aerobic conditions, including Glaser homo-coupling, the cross-coupling reaction with an array of halides and terminal alkynes (Scheme 75). ${}^{90}$ This protocol affords functionalized internal alkynes and diynes, featured by the use of inexpensive catalytic system, wide substrate scope, and high regioselectivity. Reaction mechanism involves the oxidation and dehydrogenation of in situ-generated Cu-carbene species 97 as the key step, affording the internal (99) or terminal alkyne 98 intermediates. Subsequently, deprotonation of the terminal alkyne 98 assisted by copper coordination gives rise to an alkyne-coordinated copper species 100, which allows the sequential Glaser reaction as well as cross-coupling processes. This method enables the utilization of ketone-derived hydrazones as effective terminal alkyne synthons, providing a new type of alkyne synthetic strategies.

Scheme 75 Cu-catalyzed aerobic oxidative reactions of $N$ -tosylhydrazones to afford various alkynes.

In 2016, a Cu-catalyzed oxidative cross-coupling reaction of two different $N$ -tosylhydrazones with elemental sulfur was reported. ${}^{91}$ Under aerobic conditions, a series of unsymmetric 2,5-disubstituted 1,3,4-thiadiazoles are obtained in moderate to good yields (Scheme 76). A tentative mechanism proposed the involvement of carbene species and elemental sulfur to afford benzothialdehyde intermediate 101. Thus, nucleophilic attack of $N$ -tosylhydrazone anion with 101 provides the intermediate 102, followed by sequential intramolecular nucleophilic attack to give 103. Final oxidative aromatization by air results in the generation of the desired heterocyclic scaffold.

M

4. RHODIUM-CATALYZED COUPLING REACTION OF N-TOSYLHYDRAZONES

In 2016, Wang group reported a Rh(I)-catalyzed chemoslective cross-coupling reaction of trifluoromethylketone-derived $N$ -tosylhydrazones with arylboronates, affording 1,1-difluoro-2,2-diarylalkenes with moderate to good yields or 2,2-diaryltrifluoroethanes (Scheme 77). ${}^{92}$ Proposed mechanism involves the generation of aryl rhodium species at first through transmetala-tion with arylboronic acid esters in the presence of a base. This aryl rhodium species then reacts with the in situ-generated diazo compounds to afford the Rh(I)-carbene intermediate, followed by migratory insertion to generate a ${\mathrm{{CF}}}_{3}$ -substituted alkyl rhodium(I) intermediate. This intermediate can either experience $\beta$ -fluoride elimination to obtain desired 1,1-difluoroolefin product, or experience protonation of carbon-rhodium bond to afford ${\mathrm{{CF}}}_{3} -$ substituted alkane as a by-product. This transformation illustrates the practical application of trifluoromethylketone-derived $N$ -tosylhydrazones in the concise synthesis of fluorine-containing functional molecules.

Scheme 76 Cu-catalyzed multicomponent coupling reaction of two different N-tosylhydrazones with elemental sulfur.

Apart from the transmetalation process, selective C-C bond cleavage was implemented to efficiently generate carbon-rhodium species, which experienced sequential migratory insertion to perform carbene species func-tionalization. In 2014, Murakami group reported the Rh-catalyzed asymmetric carbene insertion to $\mathrm{C}\left( {\mathrm{{sp}}}^{3}\right) - \mathrm{C}\left( {\mathrm{{sp}}}^{3}\right)$ bond of cyclobutanols with $N$ -tosylhydrazones as diazo analogues (Scheme 78). ${}^{93}$ With the employment of chiral phosphine ligands, cyclopentanol derivatives are furnished by ring expansion of cyclobutanols with moderate to good yields (up to 77% yield) and excellent enantioselectivities (up to 99% ee). In the reaction mechanism, initially the rhodium alkoxide is formed through the ligand exchange with the substrate. Through $\beta$ -carbon elimination the four-membered ring rhodium alkoxide is cleaved, affording a $\gamma$ -keto alkylrhodium intermediate. Then, the reaction of in situ-generated diazo species with alkylrhodium species occurs, giving rise to (alkyl)(carbene)rhodium complex. Migratory insertion of ring-opened alkyl group onto prochiral carbene carbon is proposed as the key step. This Rh-catalyzed enantioselective carbene ring-expansion reaction has created two new chiral centers through the facile selective C-C bond cleavage.

Scheme 77 Rh(I)-catalyzed cross-coupling of trifluoromethylketone-derived N-tosylhydrazones with arylboronates.

Differing from the previous Pd- and Cu-catalyzed N-tosylhydrazones transformations, a typical feature of Rh-catalyzed cross-coupling reaction involving migratory insertion is the combination with the directing-group-assisted C-H activation strategy. Thus, these transformations demonstrate complementary strategy for classic ${\mathrm{{sp}}}^{2}\mathrm{C} - \mathrm{H}$ bond insertion pathway. In contrast to the Rh-catalytic transformations, which are also typically terminated by protonation in the cyclic cycle, the copper-catalyzed reactions also show diverse reaction type. In 2014, Wang group disclosed an efficient synthetic method for ortho-alkenyl phenols through $\mathrm{{Rh}}\left( \mathrm{{III}}\right)$ -catalyzed $\mathrm{C} - \mathrm{H}$ activation of $N$ -phenoxyacetamides with $N$ -tosylhydrazones or $\alpha$ -dia-zoesters. ${}^{{94}\mathrm{a}}$ By employing oxidizing $N$ -oxyacetamide as the directing group, this transformation allows the direct preparation of ortho-alkenyl phenols with high yields and excellent regio- and stereoselectivity. Besides, these reactions proceed under mild conditions and do not need any external oxidants. Mechanistic hypothesis involves the sequence of Rh-carbene 104 migratory insertion to form $\mathbf{{105}},\beta - \mathrm{H}$ elimination, reductive elimination, oxidative addition to regenerate active Rh(III) species, instead of direct protonation process (Scheme 79). This methodology has integrated with the $\mathrm{C} - \mathrm{H}$ bond activation with transition-metal-catalyzed coupling reaction of $N$ -tosylhydrazones.

Scheme 78 Rh-catalyzed enantioselective carbenoid insertion of cyclobutanols with N-tosylhydrazones.

Scheme 79 Rh-catalyzed C-H bond activation of N-phenoxyacetamides with $N$ -tosylhydrazones or $\alpha$ -diazoesters.

In 2016, Liao and Li implemented a DFT study to examine the mechanism of the above rhodium(III)-catalyzed alkenylation of $N$ -phenoxyacetamide with $N$ -tosylhydrazones. ${}^{{94}\mathrm{\;b}}$ The results indicate that the most favorable pathway for the Rh-catalyzed coupling of $N$ -tosylhydrazones involves sequential $\mathrm{N} - \mathrm{H}$ deprotonation, $\mathrm{C} - \mathrm{H}$ activation through concerted-metalation-deprotonation process, nitrogen extrusion, Rh(III)-carbene migratory insertion of aryl group, O-N bond cleavage to give a Rh(V) nitrene species, tautomerization, hydrogen migration from the $\beta - \mathrm{C}$ atom to the $\mathrm{N}$ atom of the internal oxidant, and acetic-acid-assisted protonation steps (Scheme 80).

Alternatively, Rh(I) complexes also emerged as efficient catalysis for C-C double bond formation through coupling reaction of (quinolin- 8-yl)methanone with $N$ -tosylhydrazones, representing a rare case of $\mathrm{C}\left( {\mathrm{{sp}}}^{3}\right) - \mathrm{H}$ activation case in this research area. ${}^{95}$ In the presence of a base and ${\mathrm{{Ag}}}_{2}\mathrm{O}$ ,3-aryl-1-(quinolin-8-yl)prop-2-en-1-one derivatives are obtained in good yields (Scheme 81). A plausible mechanism involves directing-group-assisted $\mathrm{C} - \mathrm{H}$ metalation at first, followed by migratory insertion as the key step to generate seven-membered rhodacycle 106. This key intermediate experiences sequential $\beta$ -H elimination to release desired alkenes, accompanying with the regeneration of Rh species. This methodology provides an alternative route for the direct arylvinylation of (quinolin- 8-yl)methanone by using $N$ -tosylhydrazones.

Scheme 80 Probable intermediates for rhodium(III)-catalyzed alkenylation of N-phenoxyacetamide with N-tosylhydrazones.

Scheme 81 Rh(I)-catalyzed C-H bond activation of (quinolin-8-yl)methanone with N-tosylhydrazones.

5. NICKEL- AND COBALT-CATALYZED COUPLING REACTIONS OF N-TOSYLHYDRAZONES

In 2012, Miura and coworkers disclosed the direct 2-alkylation process of azoles with $N$ -tosylhydrazones containing unactivated alkyl sub-stituents by employing nickel(II) and cobalt(II) catalysts (Scheme 82). In the presence of a base, nickel complexes have emerged as efficient catalysts for the introduction of secondary alkyl groups into benzoxazole scaffolds. Moreover, straightforward alkylation of 5-aryloxazoles and benzothiazole can be achieved catalyzed by cobalt(II) bromide. The plausible mechanism involves the base-mediated $\mathrm{C} - \mathrm{H}$ bond metalation process initially, followed by metal-carbene migratory insertion as the key steps. Finally, protonation or ligand exchange with the C-H bond of the starting heteroarene gives rise to the desired heterocycles bearing secondary alkyl side chain. This methodology enables a concise access to azole cores containing unactivated secondary alkyl side chains, which are generally difficult to achieve by using the precedent C-H alkylation strategy.

Scheme 82 Ni- and Co-catalyzed alkylation of azoles with N-tosylhydrazones.

In 2013, Zhang and de Bruin reported a radical-type Co(II)Por (Por=porphyrin)-catalyzed carbene carbonylation with sequential ketene-trapping process by diverse nucleophiles and imines, affording esters, amides, or good diastereoselective trans-β-lactams with high yields in one-pot cascade procedure. ${}^{97}$ Consequently, the metalloradical [Co(II) TPP] complex has emerged as an efficient catalyst for the homologation of both $N$ -tosylhydrazone sodium salts and $\alpha$ -diazocarbonyl compounds (Scheme 83).

Scheme 83 Co(II)Por-catalyzed carbene carbonylation of N-tosylhydrazone sodium salt with nucleophiles for the synthesis of esters, amides, and β-lactams.

6. CATALYTIC INTRAMOLECULAR CYCLIZATION OF N-TOSYLHYDRAZONES

In the past few decades, transition-metal-catalyzed ring-closing metathesis has evolved into a highly efficient and versatile strategy for the intramolecular $\mathrm{C} = \mathrm{C}$ bond formation. In particular, by employing $N$ -tosylhydrazones or diazo compounds as the carbene precursors, the catalytic carbene dimerization process provides an alternative way to form $\mathrm{C} = \mathrm{C}$ bonds. However, owing to the instability of diazo species and poor selectivity, this method suffers significant limitation for its use in organic synthesis. In 2012, Wang group successfully disclosed a novel Rh(II)-catalyzed intramolecular carbene dimerization of bis(N-tosylhydrazone)s. ${}^{98}$ This catalytic cyclization process, as well as the one-pot procedure from corresponding readily available dicarbonyl substrates, provides a general and highly efficient synthetic method for polycyclic aromatic compounds, including chrysene, helicene, picene, and pent-aphenes (Scheme 84). This method is operationally simple and can be served as a general and practical approach to polycyclic aromatic compounds.

In addition to the rhodium catalysts, gold complexes have been explored in intramolecular coupling reaction of bis- $N$ -tosylhydrazones. In 2015, Sun group developed a selective and controllable divergent synthetic approach of decomposition of bis- $N$ -tosylhydrazones (Scheme 85). ${}^{99}$ Thus, in the presence of gold(I) catalyst and strong base, polysubstituted cyclic olefins are effectively accessed through this Au-catalyzed intramolecular coupling reaction of bis- $N$ -tosylhydrazones. Moreover, the one-pot procedure by using bis-carbonyl compounds as substrates is also employed to access poly-aromatic scaffold in a facile and efficient manner. This gold-catalyzed effective approach demonstrates practical applications in synthesizing polycyclic aromatic compounds with good yields.

Scheme 84 Rh(II)-catalyzed intramolecular carbene cyclization of bis(N-tosylhydrazone)s.

Scheme 85 Au-catalyzed intramolecular coupling of bis- $N$ -tosylhydrazones.

OF

7. SUMMARY

As described in this chapter, the incorporation of transition-metal-catalyzed coupling strategy with $N$ -tosylhydrazones allows toward various novel transformations for C-C bond construction. Serving as readily available substrates, $N$ -tosylhydrazones are widely used in traditional organic transformations, including Bamford-Stevens-Shapiro reaction, Barton-Kellogg reaction, or Julia-type olefination, which have already demonstrated great applications in organic synthesis. Furthermore, the introduction of $N$ -tosylhydrazones in transition-metal-catalyzed cross-coupling reactions not only expands the substrate scope of coupling partners but also makes this coupling strategy practically useful in organic synthesis and other fields. This type of transformation constitutes an unprecedented avenue to construct C-C, C=C, C-X bonds in a selective and efficient manner. Otherwise, various functionalized molecules such as polysubstituted alkenes, allenes, alkynes, aromatic and heterocyclic compounds, can be expeditiously and facilely accessed from N-tosylhydrazones or corresponding carbonyl substrates.

Mechanistically, most of these catalytic transformations involve the formation of metal-carbene and subsequent migratory insertion as the key steps. The migratory insertion of metal-carbene has been proved to be general in terms of migrating groups, which include aryl, vinyl, benzyl, acyl, allyl, allenyl, alkynyl, propargyl, and cyclopropyl groups.

Although significant achievements have been made in this field, some difficult problems still remain. For example, $\mathrm{C}\left( {\mathrm{{sp}}}^{3}\right) - \mathrm{H}$ activation combined with migratory insertion, decarboxylative coupling with N-tosylhydrazones, asymmetric carbene transformation, and the coupling catalyzed by early transition-metal are yet challenging goals. With the significant achievements mostly made only in the last 10 years, it would be confident to say that this area is still far from mature and further developments can be expected.

ACKNOWLEDGMENTS

The project is supported by the National Basic Research Program of China (973 Program, No. 2015CB856600) and the Natural Science Foundation of China (Grant 21332002, 21472004).

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