Exploration of CâH Transformations of Aldehyde Hydrazones: Radical

Article Cite This: Acc. Chem. Res. 2018, 51, 484−495

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Exploration of C−H Transformations of Aldehyde Hydrazones: Radical Strategies and Beyond Pan Xu,† Weipeng Li,† Jin Xie,*,† and Chengjian Zhu*,†,‡ †

State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, P. R. China ‡ State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 200032, P. R. China CONSPECTUS: The chemistry of hydrazones has gained great momentum due to their involvement throughout the evolution of organic synthesis. Herein, we discuss the tremendous developments in both the methodology and application of hydrazones. Hydrazones can be recognized not only as synthetic equivalents to aldehydes and ketones but also as versatile synthetic building blocks. Consequently, they can participate in a range of practical synthetic transformations. Furthermore, hydrazone derivatives display a broad array of biological activities and have been widely applied as pharmaceuticals. Owing to the weak directing group effect of simple aldehydes and ketones in C−H bond functionalizations, the C−H bond functionalizations of hydrazones that have been developed in the past five years represent a significant step forward. These novel transformations open a new door to a broader library of functionalized and complex small molecules. Moreover, a wide range of biologically important N-heterocycles (dihydropyrazoles, pyrazoles, indazoles, cinnolines, etc.) can be efficiently synthesized in an atom- and step-economical manner through single, double, or triple C−H bond functionalizations of hydrazones. Both radical C−H functionalizations and transitionmetal-catalyzed directing-group strategies have enhanced the synthetic utility of hydrazones in the chemical community because these strategies solve the long-standing challenge of C−H functionalizations adjacent to aldehydes and ketones. We began this study based on our ongoing interest in visible-light photoredox catalysis. Visible-light photoredox catalysis has become a powerful tool in contemporary synthetic chemistry due to its remarkable advantages in sustainability and use of radical chemistry. By exploiting a photoredox-catalyzed aminyl radical polar crossover (ARPC) strategy, we successfully achieved visiblelight-induced C(sp2)−H difluoroalkylation, trifluoromethylation, and perfluoroalkylation of aldehyde-derived hydrazones. This intriguing result was later applied in the C(sp2)−H amination of hydrazones and a cascade cyclization reaction for the synthesis of polycyclic compounds. Encouraged by this redox-neutral C−H functionalization of aldehyde hydrazones, we extended the oxidative C−H/P−H cross-coupling method, which represents a novel and efficient method for the synthesis of αiminophosphine oxides. Furthermore, an elegant [3 + 2] cycloaddition of azides and aldehyde hydrazones for the synthesis of functionalized tetrazoles was advantageously developed during our investigation of the oxidative C(sp2)−H azidation of aldehyde hydrazones with TMSN3. The sequential C(sp2)−H/C(sp3)−H bond functionalization of aldehyde-derived hydrazones with simple 2,2-dibromo-1,3-dicarbonyls was achieved by employing relay photoredox catalysis, and it provides a novel method of accessing bioactive fused dihydropyrazole derivatives. The notable feature of this approach was further reflected in the formal [4 + 1] annulation of aldehyde-derived N-tetrahydroisoquinoline hydrazones with 2-bromo-1,3-dicarbonyls. To complement these radical C−H functionalization strategies, we recently applied a directing-group strategy in the Rh-catalyzed C(aldehyde)−H functionalization of aldehyde-derived hydrazones for the synthesis of distinctive and bioactive 1H-indazole scaffolds. In summary, this Account presents recent contributions to the exploration, development, mechanistic insights, and synthetic applications of C−H bond functionalizations of aldehyde hydrazones.

1. INTRODUCTION

chiral N-acylhydrazones have been widely used as versatile imino acceptors in enantioselective amine syntheses.1b In addition, hydrazone derivatives display a broad array of biological activities and pharmacological properties such as antiprotozoal and antitrypanosomal activities.2 Additionally,

Hydrazones are valuable and versatile building blocks in synthetic chemistry.1 Owing to their similarities to carbonyl compounds, hydrazones can participate in a wide range of typical synthetic transformations such as free radical reactions, cycloaddition reactions, and transition-metal-catalyzed reactions (Scheme 1). They are often used as precursors for the synthesis of hydrazines and diazo compounds. For example, © 2018 American Chemical Society

Received: November 12, 2017 Published: January 23, 2018 484

DOI: 10.1021/acs.accounts.7b00565 Acc. Chem. Res. 2018, 51, 484−495

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Accounts of Chemical Research Scheme 1. Synthetic Applications and C−H Transformations of Hydrazones

chlorides,11 N-bromosuccinimide,12 and Vilsmeier-type reagents13 at the azomethine carbon to provide C(sp2)−H functionalization products (Scheme 2).

hydrazone units are attracting increasing attention in supramolecular chemistry,3a dynamic combinatorial chemistry (DCC),3b and hole-transporting optoelectronic devices.3c Organic transformations that directly convert C−H bonds into C−C and C−heteroatom bonds can potentially simplify and shorten synthetic routes, which makes such techniques particularly attractive to organic chemists.4 In this area, the introduction of a coordinating directing-group (DG) is a robust strategy for achieving site-selective C−H bond functionalization. In 2001, the Mino group proved hydrazone moieties are important ligands for a series of Pd-catalyzed cross-coupling reactions.5 However, C−H bond functionalizations using hydrazone units as DGs did not received substantial attention until 2007 when Inamoto and Hiroya developed an efficient protocol for the synthesis of indazole via the Pd-catalyzed intramolecular aromatic C(sp2)−H amination of hydrazones.6 Compared with directing group-enabled C−H functionalizations, radical C−H functionalizations of hydrazones progressed rapidly along with the renaissance of radical chemistry.7 Intramolecular dehydrogenative cyclizations, 8 hydrazonyl amino radical 1,5-H atom transfer (HAT)-enabled C(sp3)−H functionalizations,9 and hydrazone C(aldehyde)−H functionalizations have been developed (Scheme 1). These strategic and novel C−H transformations of hydrazones provide efficient pathways for the synthesis of a great number of functionalized nitrogen-containing molecules. Consequently, structurally diverse N-heterocycles (dihydropyrazoles, pyrazoles, indazoles, cinnolines, etc.) have been concisely constructed through single or multiple C−H bond functionalizations. Both radical and DG strategies have been applied, which has undoubtedly accelerated the utility of hydrazones in contemporary synthetic chemistry. Our group has been actively involved in the development and application of the C−H functionalizations of aldehydederived hydrazones. This is the right time to highlight this topic as a powerful platform that will benefit organic synthesis. The purpose of this Account is to give an overview of the C−H bond transformations of aldehyde-derived hydrazones in synthesis with an emphasis on our recent work.

Scheme 2. Electrophilic C(sp2)−H Functionalization of Aldehyde-Derived N,N-Dialkylhydrazones

In 2013, Bouyssi and Baudoin reported a mild and practical copper-catalyzed C(sp2)−H trifluoromethylation of benzaldehyde-derived N,N-dialkylhydrazones 1 with electrophilic Togni reagent (Scheme 3).14a The radical-trapping experiment with TEMPO suggested a free CF3 radical might be operating, which was in sharp contrast with previous electrophilic C(sp2)−H substitution processes. Later, they further realized the coppercatalyzed trifluoromethylation of conjugated hydrazones14b and aliphatic N-arylhydrazones.14c Despite its numerous applications, hydrazone is rarely explored in photoredox catalysis.15 We began our study in this field based on our ongoing interests in visible-light-induced difluoroalkylations.16 The CF2 group is a valuable motif because it can serve as a lipophilic hydrogenbond donor and act as a bioisostere for an oxygen atom or a carbonyl group. Many contributions toward direct difluoroalkylations of carbon−carbon double bonds have been made,17 but few studies on the difluoroalkylation of carbon− nitrogen π bonds have been reported. We initially tested various aldehyde-derived imine-type substrates including hydrazones, oximes, and imines (Scheme 4).18 Only N,Ndialkylhydrazones and N-alkyl-N-aryl-hydrazones reacted well with BrCF2CO2Et under visible-light photoredox conditions, and they exclusively generated C−H difluoroalkylation products 3. This photoredox-based protocol illustrates the breadth of the substrate scope; both aromatic and aliphatic aldehyde-derived hydrazones could successfully be applied to deliver the corresponding difluoroalkylated hydrazones 3 (Scheme 5).

2. REDOX-NEUTRAL C−H FUNCTIONALIZATIONS OF ALDEHYDE-DERIVED HYDRAZONES One of the most important features of aldehyde-derived N,Ndialkylhydrazones is their ability to act as nucleophilic azaenamine equivalents.10 This impressive umpolung of the imine reactivity is derived from the conjugation between the carbon− nitrogen π bond and the lone electron pair on the terminal nitrogen atom. Consequently, aldehyde-derived N,N-dialkylhydrazones can react with reactive electrophiles such as acyl 485


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Accounts of Chemical Research Scheme 3. Copper-Catalyzed C(sp2)−H Trifluoromethylations of Aldehyde N,N-Dialkylhydrazones

Scheme 5. Visible-Light-Induced C(sp2)−H Difluoroalkylation of Aldehyde Hydrazones

Scheme 4. Visible-Light-Induced Difluoroalkylation of Imine Type Substratesa

Scheme 6. Proposed Mechanism

a

NR = no reaction.

The salient features of this reaction including facile follow-up transformations and that is it a one-pot, three-component coupling reaction, making this protocol highly attractive. First, the single electron reduction of BrCF2CO2Et by photoexcited *Ir(ppy)3 generates the difluoroalkyl radical. Subsequent electrophilic radical addition to the CN bond gives aminyl radical intermediate A. In a traditional reaction manifold, this aminyl radical would readily undergo H-atom abstraction to form hydrazine as the product. Here, this regular pattern is interrupted by a visible-light-promoted aminyl radical-polar crossover (ARPC) process in which aminyl radical A undergoes a stepwise SET oxidation and subsequent deprotonation to afford C−H difluoroalkylated product 3 (Scheme 6). With a bench-stable dimeric gold complex as the photocatalyst, a conceptually new C(sp2)−H difluoroalkylation and perfluoroalkylation of hydrazones with various RF−Br reagents was developed by the Hashmi group (Scheme 7).19 The coupling partner can be extended to BrCF2PO(OEt)2, BrCF2SO2Ph, BrCF2COPh, and perfluoroalkyl bromides using a dimeric gold complex as the catalyst. Interestingly, under certain reaction conditions, the dimeric gold photocatalyst gave better stereoselectivity than fac-Ir(ppy)3. This may be because

of the fac-Ir(ppy)3-mediated photoisomerization of the Econfiguration product to the less stable Z-configuration product. Importantly, the reaction shows high functional group tolerance, and its synthetic robustness was explored by the late-stage modification of the medically important helicide and vitamin E derivatives. Furthermore, the mild reduction of the products could afford gem-difluoromethylated β-amino acid and β-amino phosphonic acid derivatives. As shown in Scheme 8, the difluoroalkyl radical intermediate was further characterized by an EPR spin trapping experiment, and the results strongly supported a gold-catalyzed radical pathway. By switching from perfluoroalkyl bromides to perfluoroalkyl iodides, we demonstrated a catalyst-free, photoinduced C(sp2)−H fluoroalkylation of aldehyde-derived hydrazones 486


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Accounts of Chemical Research

(Scheme 9).20 According to the results of the mechanistic studies, both the photoexcitation of the hydrazones and an

Scheme 7. Gold-Catalyzed Photoredox C(sp2)−H Difluoroalkylation and Perfluoroalkylation of Aldehyde Hydrazones

Scheme 9. Photosensitizer-Free, Photoinduced C(sp2)−H Fluoroalkylation of Hydrazones

electron donor−acceptor model are likely to be initiated by the generation of a perfluoroalkyl radical. Almost simultaneously, Bouyssi and Monteiro realized a Pdcatalyzed C(sp2)−H difluoroalkylation of aldehyde-derived hydrazones with difluoroalkyl bromides (Scheme 10).21a Scheme 10. Pd-Catalyzed C(sp2)−H Difluoroalkylation of Aldehyde Hydrazones

Scheme 8. EPR Spectruma

Significantly, the substrate scope can be extended to hydrazones bearing strong electron-withdrawing functional groups or heteroaromatic rings. Their method complements the above photoredox protocols. In this case, a single electron transfer (SET) mechanism involving a difluoroalkyl radical was also proposed. As a follow-up to this work, they later disclosed a Cu-catalyzed version with 1,10-phenanthroline as the optimal ligand.21b Inspired by these seminal reports, several similar radical C(sp2)−H fluoroalkylation protocols were recently reported.22 Nitrogen-centered radicals are a class of useful synthetic intermediates that have received increasing attention from the synthetic community. In recent years, visible-light photoredox catalysis has been developed as a green and powerful tool for various transformations involving N-radicals.23 For example, in 2013, the MacMillan group demonstrated that nitrogencentered radicals can be generated from hydroxylamine derivatives via photocatalytic SET reduction processes.24

a

The X-band EPR spectrum (blue line) and simulated EPR spectrum (red line) based on the hyperfine coupling constants of aN = 12.7129, aH = 14.6382, and aF = 1.51504 (g = 2.00649).

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pounds 11 were successfully constructed in a one-pot manner by visible-light photoredox catalysis (Scheme 13).27 The optimization of the reaction conditions indicated dichloromethane was the best solvent for this cascade under the irradiation of a 33 W fluorescent light using fac-Ir(ppy)3 as the photocatalyst. Both 6-6-5- and 6-6-6-tricyclic compounds are easily available by this methodology. With a hydrazone unit as a robust directing group, the resulting cyclohexylidene-hydrazone-fused polycyclic products can be further converted to functionalized isoquinoline 12 by Rh(III)-catalyzed C−H activation reactions. A SET process initially occurs between *IrIII and the α-bromocarbonyls to generate radical D, and radical addition to the triple bond leads to intermediate E. E is then transformed to alkyl radical species F via a 5-exo-trig cyclization. Subsequently, an intramolecular radical addition to the CN bond generates key aminyl radical G, which then undergoes a SET oxidation and deprotonation process, generating desired product 11 (Scheme 14). The success of this cascade transformation largely depends on the different reactivities of the radical intermediates toward the alkyne and hydrazone.

Based on this activation mode, we further utilized the intrinsic reactivity revealed by ARPC in the C(sp2)−H amination of aldehyde hydrazones.25 With N-methyl-N-((phenylsulfonyl)oxy)sulfonamide as the nitrogen-centered radical precursor, the first visible-light-induced C(sp2)−H amidation of aldehyde hydrazones was achieved (Scheme 11), and it represents an Scheme 11. Visible-Light-Induced C(sp2)−H Amidation of Aldehyde Hydrazones

3. OXIDATIVE C−H FUNCTIONALIZATIONS OF ALDEHYDE HYDRAZONE Encouraged by the previous results on photoredox-neural C−H functionalizations of aldehyde-derived hydrazones, we aimed to explore oxidative cross-couplings based on ARPC strategy. Phosphorus-containing compounds are an important class of fine chemicals that are commonly found in synthetic, materials, and agricultural chemistry. A diverse range of heterocycles containing P−C−N units show excellent bioactivity.28 Along with a method for the C−H functionalization of aldehydederived hydrazones, we demonstrated a practical procedure for oxidative C−H phosphonation of aldehyde hydrazones with commercially available diphenylphosphine oxides (Scheme 15).29 This protocol provides a new and efficient method for the synthesis of (E)-α-iminophosphine oxides 13, which remain challenging to prepare by previous methods. The optimized reaction conditions are 2.0 equiv of K2S2O8 and 0.2 equiv of Cu(OAc)2 as an oxidant in CH3CN at 60 °C. Control experiments suggested that K2S2O8 served as the oxidant and radical initiator for the generation of the phosphine-centered radical. As illustrated in Scheme 16, the addition of a reactive phosphine-centered radical to the CN bond gives aminyl radical intermediate I, which is then oxidized by K2S2O8 or copper(II) to generate aminyl cation K or its mesomeric species J. Deprotonation of this species affords α-iminophosphine oxides 3a (Scheme 16). The N3-radical can be formed from azido-I(III) reagents generated in situ from TMSN3 with PhI(OAc)2. Based on the success of the ARPC strategy in the oxidative C−H phosphonation, we next explored the oxidative C−H azidation of aldehyde hydrazones.30 Interestingly, in the presence of PhI(OAc)2/TMSN3 and a catalytic amount of Cu(OAc)2, unexpected tetrazole 14 was generated instead of the C−H azidation product (Scheme 17). In our previous work, we proposed an ARPC mechanism involving an aminyl cation intermediate. In this case, the generated azide radical first attacks the CN bond to give aminyl radical intermediate L. Since a catalytic amount of Cu(OAc)2 obviously improves the yield, radical intermediate L likely undergoes a SET oxidation with a Cu2+ species to produce key aminyl cation M, which is

alternative method for the preparation of benzohydrazonamides 8. The developed reaction shows good functional group tolerance and excellent chemoselectivity. Only monoamidation is observed, and the reaction proceeds smoothly with the generation of hydrazonamides. Notably, the conventional route to benzohydrazonamides from hydrazones usually requires two steps including a prehalogenation and subsequent nucleophilic substitution with an amine (Scheme 12). A similar C(sp2)−H amination using N-acyloxyphthalimides as nitrogen-radical precursors was later achieved by Wang and co-workers.26 Cyclopenta[α]naphthalenes are prevalent units in agrochemicals and materials chemistry because of their unique chemical properties and biological activities. With 2-ethynylbenzaldehyde hydrazones 9 as the radical acceptors and αbromo-carbonyls 10 as the alkyl radical precursors, structurally divergent cyclohexylidene-hydrazone-fused polycyclic comScheme 12. Synthesis of Benzohydrazonamides from Aldehyde Hydrazones

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Accounts of Chemical Research Scheme 13. Visible-Light-Induced Cascade Annulation of Hydrazones with Alkenyl α-Bromocarbonyls


then captured by a “nucleophilic” N3 group in a concerted deprotonation/cyclization process (Scheme 18). This novel [3 + 2] cycloaddition of azides with aldehyde-derived hydrazones represents a rare route for the synthesis of functionalized tetrazoles.

to be a key unit that enables the successful transformation of the C(sp2)−H bond in aldehyde-derived hydrazones. A close consideration of the formulas inspired us to explore the feasibility of the functionalization of both sp2 and sp3 C−H bonds. With 2,2-dibromo-1,3-dicarbonyl 15 as a radical precursor, we recently achieved a visible-light photoredoxcatalyzed cascade of the C(sp2)−H/C(sp3)−H bond functionalization of aldehyde hydrazones in one step (Scheme 19).32 This reaction provides a simple and efficient pathway for the synthesis of complex fused dihydropyrazoles 16, which are widely found in medicinal and biocidal compounds. Two major

4. MULTIPLE C−H FUNCTIONALIZATIONS OF ALDEHYDE HYDRAZONE Since early 2010, visible-light photoredox catalysis has become a powerful tool for the α-C(sp3)−H functionalization of tertiary amines.31 In our recent work, the N-alkyl substituent was found 489


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Accounts of Chemical Research Scheme 15. Oxidative C(sp2)−H Phosphonation of Aldehyde Hydrazones

Scheme 17. [3 + 2] Cycloaddition of Azides to Aldehyde Hydrazones



Scheme 19. Visible-Light-Induced Cascade C(sp2)−H/ C(sp3)−H Functionalization of Aldehyde Hydrazones

events are involved in this transformation, namely, (1) a photoredox-catalyzed C(sp2)−H alkylation through an ARPC process and (2) a photoredox-catalyzed intramolecular αC(sp3)−H alkylation adjacent to a nitrogen atom (Scheme 20). Two possible pathways were proposed for the second event. In path 1, radical precursor Q undergoes a SET reduction by *Ir(ppy)3 to give radical intermediate S. Then, a 1,5-HAT process occurs to generate α-aminoalkyl radical intermediate T, which is further oxidized by Ir(IV). Ultimately, an intramolecular Mannich-type reaction gives dihydropyrazoles 16. In path 2, carbon radical S may be in resonance with aminyl radical R, which can undergo a second ARPC process, to generate diazenium species V. Then, intermediate W proceeds through a sequential deprotonation and 6π electrocyclic process to give final product 16. Concurrently, the Bouyssi and Monteiro group disclosed a conceptually new copper-catalyzed double C−H alkylation of aldehyde N,N-dialkylhydrazones with polyhalomethane derivatives, thus providing a practical and flexible approach to the preparation of various 4-functionalized pyrazoles 18 (Scheme

21).33a More recently, they further applied their C−H functionalization strategy to a novel Ru-catalyzed synthesis of 4-fluoropyrazoles 19.33b Both reactions were proposed to 490


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Accounts of Chemical Research Scheme 20. Proposed Mechanism

Scheme 21. Copper-Catalyzed Double C−H Alkylation of Aldehyde-Derived N,N-Dialkylhydrazones

Scheme 22. Copper-Catalyzed Dehydrogenative Cyclization of N,N-Dialkylhydrazones

[4 + 1] annulation of aldehyde-derived hydrazones with diethyl 2-bromomalonate by exploiting a relay photoredox catalysis strategy, thus offering a convenient method for accessing biologically important pyrazoloisoquinolines 20 (Scheme 23).35 Scheme 23. Visible-Light-Induced [4 + 1] Annulation of Aldehyde Hydrazones with Diethyl 2-Bromomalonates

undergo a cascade radical C(sp2)−H haloalkylation/C(sp3)−H cyclization/aromatization sequence. Similarly, Nenajdenko and co-workers recently disclosed a Cu-catalyzed polyhalomethyl radical addition to aldehyde hydrazones for the synthesis of a wide range of useful halogenated azabutadiene building blocks.34 Indeed, hydrazones have already been recognized as versatile precursors for the synthesis of a broad range of functionalized pyrazoles. Ge et al. made great advances in intramolecular dehydrogenative cyclization reactions of hydrazones.8 For example, in 2013, they reported an elegant copper-catalyzed C(sp3)−H dehydrogenative cyclization of N,N-dialkylhydrazones with O2 as the sole oxidant (Scheme 22).8b This novel transformation constitutes a practical and environmentally friendly approach to the construction of pyrazole derivatives. Inspired by these seminal works, we recently developed a novel

The cascade functionalization of multiple C−H bonds can be efficiently accomplished in a step-economic manner under mild reaction conditions. Based on control experiments and previous studies, we reasoned that the reaction involved three successive photoredox quenching cycles (Scheme 24). In the first quenching cycle, hydrazone AA is generated through a photoredox-catalyzed ARPC process. In the second quenching cycle, hydrazone AA undergoes a SET oxidation with photoexcited *IrIII and C−H atom abstraction, producing reactive iminium ion BB or equilibrium species CC. Aldehyde EE was isolated in mechanistic experiments, which further confirmed the existence of possible intermediate DD. The intramolecular Mannich reaction of BB delivers key dihydropyrazole FF. Notably, both hydrazone AA and dihydropyrazole FF can be detected by high-resolution mass spectrometry. 491


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Accounts of Chemical Research Scheme 24. Proposed Mechanism

Scheme 25. 1H-Indazole Synthesis via C−H Activation

indazoles were efficiently synthesized by this protocol, which shows excellent functional-group tolerance (Scheme 26). Compared with previous methods for the synthesis of 1Hindazoles, which all focused on C−N bond construction,38 the Rh-catalyzed C−C bond forming has the advantage of allowing the rapid synthesis of certain distinctive and bioactive 1H-

Dihydropyrazole FF then undergoes decarboxylation to give intermediate GG, which acts as the reductive quencher in the third quenching cycle. Dihydropyrazole GG undergoes a SET oxidation and sequential deprotonation/aromatization to form final product 20a. More than 2 equiv of the alkyl bromides were used as they serve not only as the alkylation reagents but also as the oxidant in this reaction. On the other hand, with the N−N bond as a Lewis basic unit, hydrazones can be utilized as directing groups in transition-metal-catalyzed C−H activations. In this context, Inamoto and Hiroya developed an efficient protocol for the synthesis of indazoles via a Pd-catalyzed intramolecular aromatic C(sp2)−H amination of hydrazones.6 Rao and coworkers realized the synthesis of tri- and tetrasubstituted pyrazoles by Ru(II)-catalyzed, intramolecular aerobic oxidative C−H/N−H couplings of conjugated hydrazones.36a Fernández and Lassaletta reported an elegant Ir-catalyzed aromatic C(sp2)−H diborylation of N,N-dimethylhydrazones.36b Hua developed a novel Rh-catalyzed C−H activation and alkyne annulation strategy for the synthesis of indoles in which the generated hydrazone serves not only as a directing group but also as an internal oxidant.36c Recently, Dong reported a hydrazone-based directing-group strategy for the β-C(sp3)−H oxidation of aliphatic amines.36d Guided by these works and to complement the radical-type strategies, we attempted to exploit the DG strategy for the C−H bond functionalization of aldehyde-derived hydrazones. With readily available aldehyde phenylhydrazones as substrates, we successfully developed a Rh-catalyzed cascade involving a double C−H activation and an oxidative C−C coupling (Scheme 25).37 A series of 1H-

Scheme 26. Rh-Catalyzed Intramolecular C−H/C−H CrossCoupling of Aldehyde Hydrazones

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Accounts of Chemical Research Scheme 27. Deuterium Labeling Experiment

transition-metal catalysis (Cu, Pd, Ru, etc.) and photoredox catalysis, have emerged as a powerful tool for the C−H functionalization (trifluoromethylation, difluoroalkylation, amidation, and phosphonation) of aldehyde-derived hydrazones as these methods allow efficient access to various functionalized hydrazones. These novel C−H transformations are highly compatible with both redox-neutral and oxidative reaction conditions. Importantly, a wide range of valuable N-heterocycles such as dihydropyrazoles and pyrazoles can be concisely synthesized from easily accessible hydrazones by multiple C−H functionalization protocols. In addition, the new mode of intrinsic reactivity was further extended to other types of reactions including cascade cyclization and cycloaddition reactions. Furthermore, a transition-metal-catalyzed directinggroup strategy can be successfully applied in this field, which makes it complementary to the radical C−H functionalization strategies. We believe the C−H bond functionalization of hydrazones will attract considerable attention in the near future and stimulate the broad application of hydrazones in contemporary chemistry.

indazole scaffolds. For instance, product 21h shows 5-HT4/5HT3 receptor antagonist activity. The deuterium labeling experiment showed that the process involved an initial reversible C−H bond metalation (Scheme 27), which is consistent with the results of DFT calculations (endothermic by 5.4 kcal/mol). In addition, the C−H bond deuteration at the ortho-position of the C-aryl ring indicated there were two competing coordination sites during the initial step. Both coordination modes can be clearly illustrated by the reported examples. Two paths were proposed for the second C−H activation event (Scheme 28). Five-membered rhodacyScheme 28. Proposed Mechanism

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (J. X.). *E-mail: [email protected] (C. Z.). ORCID

Jin Xie: 0000-0003-2600-6139 Chengjian Zhu: 0000-0003-4465-9408 Funding

This work was funded by National Natural Science Foundation of China (21732003, 21702098, 21372114, and 21672099) and Nanjing University Dengfeng Talent Plan. Notes

clic complex II may undergo a C(aldehyde)−H bond insertion and sequential reductive elimination of JJ to furnish the desired 1H-indazole. Another pathway involves a nucleophilic addition of the C(aryl)−Rh bond to the CN bond to form N−Rh species KK. This species undergoes β-H elimination to generate product 21a. However, the DFT calculations suggest that the sequential C−H insertions are more responsible for the Rh(III)-catalyzed dual C−H bond cross-coupling reaction. This Account has summarized the recent achievements in the C−H transformations of aldehyde-derived hydrazones with an emphasis on our own contributions. Radical strategies, such as

The authors declare no competing financial interest. Biographies Pan Xu was born in Yancheng, China, in 1990. He received his Bachelor’s degree from Soochow University in 2012. Subsequently, he began his Ph.D. studies under the supervision of Professor Chengjian Zhu at Nanjing University. While earning his Ph.D., he studied as a joint Ph.D. student in the group of Prof. Armido Studer at the University of Münster from 2016 to 2017. His current research focuses on the development of novel C−H transformations of hydrazones. 493


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Heterocycles 2001, 55, 453−456. (b) Mino, T.; Shiotsuki, M.; Yamamoto, N.; Suenaga, T.; Sakamoto, M.; Fujita, T.; Yamashita, M. Palladium-Catalyzed Allylic Alkylation Using Chiral Hydrazones as Ligands. J. Org. Chem. 2001, 66, 1795−1797. (c) Mino, T.; Komatsumoto, E.; Nakadai, S.; Toyoda, H.; Sakamoto, M.; Fujita, T. Facile Preparation of Chiral P, N-Hydrazone Ligands and Their PdCatalyzed Asymmetric Allylic Alkylations. J. Mol. Catal. A: Chem. 2003, 196, 13−20. (6) Inamoto, K.; Saito, T.; Katsuno, M.; Sakamoto, T.; Hiroya, K. Palladium-Catalyzed C-H Activation/Intramolecular Amination Reaction: A New Route to 3-Aryl/Alkylindazoles. Org. Lett. 2007, 9, 2931−2934. (7) (a) Studer, A.; Curran, D. P. Catalysis of Radical Reactions: A Radical Chemistry Perspective. Angew. Chem., Int. Ed. 2016, 55, 58− 102. (b) Li, W.; Xu, W.; Xie, J.; Yu, S.; Zhu, C. Distal Radical Migration Strategy: An Emerging Synthetic Means. Chem. Soc. Rev. 2018, DOI: 10.1039/C7CS00507E. (8) (a) Zhang, G.; Miao, J.; Zhao, Y.; Ge, H. Copper-catalyzed Aerobic Dehydrogenative Cyclization of N-Methyl-N-phenylhydrazones: Synthesis of Cinnolines. Angew. Chem., Int. Ed. 2012, 51, 8318− 8321. (b) Zhang, G.; Zhao, Y.; Ge, H. Copper-Catalyzed Aerobic Intramolecular Dehydrogenative Cyclization of N,N-Disubstituted Hydrazones through Csp3-H Functionalization. Angew. Chem., Int. Ed. 2013, 52, 2559−2563. (9) Zhu, X.; Wang, Y.; Ren, W.; Zhang, F. L.; Chiba, S. TEMPOmediated Aliphatic C-H Oxidation with Oximes and Hydrazones. Org. Lett. 2013, 15, 3214−3217. (10) (a) Brehme, R.; Nikolajewski, H. E. Aza-Enamine-II, Reaktionen von benzaldehyd-N,N-tetaamethylen-Hydrazonen mit sulfonuylsocyanaten. Tetrahedron 1969, 25, 1159−1163. (b) Brehme, R.; Enders, D.; Fernandez, R.; Lassaletta, J. M. Aldehyde N,N-Dialkylhydrazones as Neutral Acyl Anion Equivalents: Umpolung of the Imine Reactivity. Eur. J. Org. Chem. 2007, 2007, 5629−5660. (11) Kamitori, Y.; Hojo, M.; Msuda, R.; Yoshida, T.; Ohara, S.; Yamada, K.; Yoshikawa, N. Electrophilic Substitution Reaction at An Azomethine Carbon Atom. Acylation of Aliphatic Aldehyde Hydrazones. J. Org. Chem. 1988, 53, 519−526. (12) Prieto, A.; Uzel, A.; Bouyssi, D.; Monteiro, N. Thiocyanation of N,N-Dialkylhydrazonoyl Bromides: An Entry to Sulfur-Containing 1,2,4-Triazole Derivatives. Eur. J. Org. Chem. 2017, 2017, 4201−4204. (13) Brehme, R. H.; Nikolajewski, E. Enamin-Analogue Reaktionen von Aldehyd-N,N-Dimethylhydrazonen. Tetrahedron Lett. 1982, 23, 1131−1134. (14) (a) Pair, E.; Monteiro, N.; Bouyssi, D.; Baudoin, O. CopperCatalyzed Trifluoromethylation of N,N-Dialkylhydrazones. Angew. Chem., Int. Ed. 2013, 52, 5346−5449. (b) Prieto, A.; Jeamet, E.; Monteiro, N.; Bouyssi, D.; Baudoin, O. Copper-Catalyzed βTrifluoromethylation of Conjugated Hydrazones. Org. Lett. 2014, 16, 4770−4773. (c) Prieto, A.; Landart, M.; Baudoin, O.; Monteiro, N.; Bouyssi, D. Copper-Catalyzed Trifluoromethylation of Aliphatic NArylhydrazones: A Concise Synthetic Entry to 2-Trifluoromethylindoles from Simple Aldehydes. Adv. Synth. Catal. 2015, 357, 2939− 2943. (15) Rono, L. J.; Yayla, H. G.; Wang, D. Y.; Armstrong, M. F.; Knowles, R. R. Enantioselective Photoredox Catalysis Enabled by Proton-Coupled Electron Transfer: Development of An Asymmetric Aza-Pinacol Cyclization. J. Am. Chem. Soc. 2013, 135, 17735−17738. (16) (a) Xu, P.; Hu, K.; Gu, Z.; Cheng, Y.; Zhu, C. Visible Light Promoted Carbodifluoroalkylation of Allylic Alcohols via Concomitant 1,2-Aryl Migration. Chem. Commun. 2015, 51, 7222−7225. (b) Qu, C.; Xu, P.; Ma, W.; Cheng, Y.; Zhu, C. A Novel Visible Light Mediated Radical Cyclization of Enol Lactones: A Concise Method for Fluorinated Polycyclic Lactone Scaffolds. Chem. Commun. 2015, 51, 13508−13510. (17) Belhomme, M. C.; Besset, T.; Poisson, T.; Pannecoucke, X. Recent Progress toward the Introduction of Functionalized Difluoromethylated Building Blocks onto C(sp2) and C(sp) Centers. Chem. Eur. J. 2015, 21, 12836−12865.

Weipeng Li was born in Henan, China, in 1989. He received his Bachelor’s degree from Henan Normal University in 2011 and his Ph.D. from Nanjing University in 2016 under the supervision of Prof. Chengjian Zhu. Currently, he works as a postdoctoral fellow with Prof. Chengjian Zhu at Nanjing University. His current research interests are focused on visible-light-induced organic transformations and goldcatalyzed oxidative couplings. Jin Xie was born in Chongqing, China, in 1985. He received his Bachelor’s degree from Northeast Forestry University in 2008 and a Ph.D. in 2013 from Nanjing University working under the direction of Prof. Chengjian Zhu. From 2014 to 2017, he was a postdoctoral research associate in the group of Prof. A. S. K. Hashmi at Heidelberg University. In 2017, he returned to Nanjing University to start his independent career as an associate professor. His current research interests lie in organometallic chemistry and biomimetic radical transformations. Chengjian Zhu was born in Henan, China, in 1966. He obtained his Ph.D. from Shanghai Institute of Organic Chemistry (CAS) in 1996 under the supervision of Professor Changtao Qian. Then, he worked as a postdoctoral fellow at the Universite de Bourgogne, the University of Oklahoma, and then the University of Houston from 1997 to 2000. He joined Nanjing University as an associate professor in 2000. Since 2003, he has been a professor at Nanjing University. His present research interests lie in organometallic chemistry and asymmetric catalysis.

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ACKNOWLEDGMENTS We gratefully acknowledge all co-workers who have contributed to this project. Prof. A. Stephen K. Hashmi at Heidelberg University is greatly acknowledged for his generous support on this Account.

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