Advances in CâCN Bond Formation via CâH Bond Activation - ACS

Review pubs.acs.org/acscatalysis

Advances in C−CN Bond Formation via C−H Bond Activation Yuanyuan Ping, Qiuping Ding,* and Yiyuan Peng* Key Laboratory of Small Functional Organic Molecule, Ministry of Education and Jiangxi’s Key Laboratory of Green Chemistry, Jiangxi Normal University, Nanchang, Jiangxi 330022, People’s Republic of China ABSTRACT: The cyano group is well known as a versatile intermediate for transformations into a multitude of useful functional groups such as carboxyl, carbamoyl, aminomethyl, carbonyl, and heterocycles. Moreover, benzonitriles and α-aminonitriles are practical synthetic and natural scaffolds. This paper reviews catalytic methodologies for direct cyanation reactions of C−H bonds. These are classified by the cyano-group sources and are sorted into three categories: (i) organic cyano-group sources, (ii) metallic cyanogroup sources, and (iii) combined cyano-group sources. This review includes all the reported methods in the literature until the beginning of 2016. KEYWORDS: cyanation, benzonitriles, α-aminonitriles, arenes, and cyano-group sources

1. INTRODUCTION Benzonitriles are important structural motifs that are an integral part of dyes, natural products, and some biologically active molecules such as herbicides, agrochemicals, and pharmaceuticals.1 For instance, etravirine, periciazine, fadrozole, and citalopram are well-known drugs containing an aromatic nitrile scaffold (Figure 1).2 Furthermore, aryl nitriles are versatile

transition-metal-catalyzed cyanation of aryl halides, arenes, and arylboronic acids using CuCN, KCN, NaCN, Zn(CN)2, TMSCN, K4[Fe(CN)6], and some other metal- or metalloidbound cyanide sources. Recently, “non-metallic” organic cyanogroup sources have become attractive, including acetonitrile, benzylnitrile, isocyanide, tosyl cyanide (TsCN), 2,2′-azobis(isobutyronitrile) (AIBN), N-cyanosuccinimide, and N-cyanoN-phenyl-p-toluenesulfonamide (NCTS) groups as well as combined cyano-group sources such as NH3(aq)/DMF, NH4I/ DMF, and NH4HCO3/DMSO. Some previous excellent reviews have partially focused on cyanation reactions.7 In 2011, Beller reviewed the palladiumcatalyzed cyanation of aryl halides.7a In 2012, the syntheses of aromatic nitriles were reviewed by Chang using nonmetallic cyano-group sources.7b Yan also reviewed the formation of C− CN bonds via transition-metal-catalyzed coupling reactions7c In 2014, Wang reviewed copper-mediated cyanation reactions.7d However, the topic of this current review is catalytic methodologies in direct C−H bond cyanation reactions as classified by the cyano-group sources. This review includes all methods reported in the literature until the beginning of 2016.

2. ORGANIC CYANO-GROUP SOURCES 2.1. N-Cyano-N-phenyl-p-toluenesulfonamide (NCTS). In 2011, Beller and co-workers used N-cyano-N-phenyl-ptoluenesulfonamide (NCTS) as an environmentally benign electrophilic cyanating reagent for [{Rh(OH) (cod)} 2]catalyzed cyanation of aryl- and alkenylboronic acids.8a They also described the electrophilic cyanation of aromatic Grignard reagents using NCTS.8b The NCTS can be easily synthesized from readily available phenylurea with p-toluenesulfonyl chloride via a dehydrative tosylation reaction.9

Figure 1. Representative biologically active benzonitriles.

intermediates for the preparation of various compounds via various transformations, including hydrolysis, hydration, reduction, cycloaddition, and nucleophilic addition.3 In addition, benzonitriles and α-aminonitriles are practical synthetic and natural scaffolds.4 Therefore, efficient and selective synthesis of benzonitriles or α-aminonitriles is very important to both organic and medicinal chemists. Great progress has been made in cyanation reactions in the past century. Classic synthetic methods include the Rosenmund− von Braun reaction5 and Sandmeyer reaction6 using aryl halides and aryldiazonium salts as starting materials, respectively. A useful alternative for the preparation of such compounds is © 2016 American Chemical Society

Received: June 9, 2016 Revised: July 30, 2016 Published: August 1, 2016 5989

DOI: 10.1021/acscatal.6b01632 ACS Catal. 2016, 6, 5989−6005

Review

ACS Catalysis Due to the superiority of NCTS, Wang and co-workers described direct cyanation of indoles and pyrroles catalyzed by a Lewis acid (BF3·OEt2) (Scheme 1).10 They believed that a

Scheme 3. Rh(III)-Catalyzed C7 Cyanation of Indolines and Indoles

Scheme 1. BF3·OEt2-Catalyzed Cyanation of Indoles and Pyrroles

carbamoylindolines readily reacted with NCTS in the presence of catalytic amounts of rhodium(III) species to afford the corresponding C7-cyanated indolines in moderate to good yields. Interestingly, this protocol could be applied in the synthesis of C2-cyanated indoles using pyrimidyl as a directing group in excellent yields. The authors proposed that the electrophilic cyanation mechanism (Figure 2) may start with

catalytic amount of Lewis acid might activate the NCTS to facilitate this C−H bond cyanation process. The efficiency of BF3·OEt2 was much better than that of other Lewis acids such as FeCl3, AlCl3, In(OTf)3, and AgOTf. Under optimized reaction conditions, various indole and pyrrole substrates smoothly underwent this C−H bond functionalization to afford the corresponding 3-cyanoindoles and 2-cyanopyrroles regioselectively in good to excellent yields. Complementarily, Anbarasan and co-workers recently reported the selective synthesis of 2-cyanoindoles via a rhodium-catalyzed directing group (such as 2-pyridyl, 2pyrimidyl, and 2-quinolyl) assisting in the C2-cyanation progress using a less toxic and easily accessible electrophilic cyanating reagent (NCTS) (Scheme 2).11 A wide range of Scheme 2. Rh-Catalyzed C2 Cyanation of Indoles and Pyrroles

Figure 2. Possible mechanism of Rh-catalyzed C7 cyanation of indolines.

the generation of the reactive cationic Rh(III) species A followed by C−H metalation to form cyclometalated complex B followed by NCTS coordination to yield intermediate C. Subsequent insertion of the CN group provides intermediate D, which undergoes rearrangement to provide the desired cyanated product and Rh(III) species E that undergoes ligand exchange leading to the active rhodium species A. In 2013, on the basis of reports of Rh-catalyzed C−H functionalization,13 Fu developed a practical method to prepare aromatic nitriles via a Rh-catalyzed directed C−H cyanation reaction using NCTS as the cyano source (Scheme 4).14 OMethyl oxime and some other N-based directing groups such as pyrazole, dihydroimidazole, dihydrooxazole, and pyridine were all useful in this transformation. In addition, the reaction could be used to synthesize various cyanated aromatic heterocycles, including furan, thiophene, pyrrole, and indole derivatives. The reaction tolerates a wide substrate scope, including free

substituted substrates proceeded efficiently to give the desired 2-cyanoindoles in moderate to excellent yields. Fortunately, this methodology offered a facile access to C2-selective cyanation of pyrrole derivatives. Recently, Kim demonstrated that the directing groups assisted in the selective C−H cyanation of indolines and indoles (Scheme 3).12 The results showed that N-carbonyl or 5990


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In addition, this methodology could be used for the formal synthesis of menisporphine (Scheme 6)an isoquinoline alkaloid possessing cytotoxic activity.

Scheme 4. Rh-Catalyzed Cyanation of Arenes with NCTS

Scheme 6. Application of Rh-Catalyzed Cyanation in Synthesis of Menisporphine

phenols, ArI, epoxide, and protected boronic acids. The proposed mechanism involves three steps. The first step involves Rh-catalyzed C−H activation to form the rhodacycle intermediate. This compound then undergoes the coordination of NCTS to Rh(III) followed by insertion into the CN moiety. The last step involves the formation of product and the elimination of a tosylaniline-coordinated Rh(III) complex, which occurs in the next catalytic cycle (Figure 3).

Concurrently, Fu and Anbarasan reported the rhodium(III)catalyzed cyanation of substituted vinylamides and alkenes with NCTS for the synthesis of alkenyl nitriles, respectively (Scheme 7 and 8).16 Fu found that a variety of synthetically important Scheme 7. Rh(III)-Catalyzed Cyanation of Vinylic C−H Bonds

Scheme 8. Synthesis of a Chlorpheniramine-Based Antagonist Figure 3. Possible mechanism of Rh-catalyzed cyanation with NCTS.

In 2013, Anbarasan developed a Rh-catalyzed cyanation of directing-group-assisted C−H bonds using NCTS as a cyanating reagent for the synthesis of various aryl nitriles containing different functional groups in good to excellent yield (Scheme 5).15 It is noteworthy that pyridine, isoquinoline, benzoquinoline, pyrazine, and pyrimidine derivatives were readily employed as chelating groups in the cyanation reactions.

functional groups (e.g., aryl-Cl, heterocycles) are tolerated in his process. Furthermore, both acrylamides and ketoximes can be employed as directing groups in this new C−H cyanation transformation (Scheme 7).16a On the basis of Anbarasan’s protocol, the formal synthesis of a chlorpheniramine-based antagonist was demonstrated (Scheme 8).16b Great attention has been paid to organophosphorus structural motifs in both synthetic and natural products.17 Great progress has been made in the C−H functionalization of organophosphorus compounds. Recently, Gu reported the ortho C−H cyanation of arylphosphonate and related compounds using NCTS as a practical cyanating reagent (Scheme 9).18 Inspired by the above Rh-catalyzed C−H cyanation reaction, Yi reported the Rh-catalyzed direct C−H cyanation of a diverse range of N-methoxybenzamides using NCTS as the cyanating reagent (Scheme 10).19 The reaction shows many remarkable features such as mild reaction conditions, good regioselectivity,

Scheme 5. Rh-Catalyzed Cyanation of Arenes

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ACS Catalysis Scheme 9. Rh-Catalyzed Ortho Cyanation of Arylphosphates with NCTS

Scheme 12. Cobalt-Catalyzed Cyanation of Arenes

Scheme 10. Rh(III)-Catalyzed Cyanation of NMethoxybenzamides

Recently, Buchwald and Yang reported a copper-catalyzed ortho C−H cyanation of vinylarenes (Scheme 13).23 The Scheme 13. Cu-Catalyzed Cyanation of Vinylarenes

moderate to good yields, wide substrate scope, and good functional group tolerance. Ruthenium(II) complexes are powerful catalysts for chelation-assisted C−H functionalization reactions. In 2014, Ackermann described direct cyanation of various aromatic amides using the versatile ruthenium(II) catalyst [RuCl2(pcymene)]2 (Scheme 11).20 Arenes and heteroarenes (such as thiophenes, furans, benzothiophenes, benzofurans, and indoles) could be used as effective substrates in this catalytic system.

transformation involves a cascade copper-catalyzed borylation and ortho C−H cyanation reactions. The CC bond was used as the reaction site and the directing group in this process. Various versatile building blocks can be obtained effectively via this method. These can be easily transformed into other useful complex molecules. The methodology shows unique site selectivity and involves a tandem copper-promoted electrophilic cyanative dearomatization and subsequent base-catalyzed hydrogen transposition. More recently, Yang demonstrated another copper-catalyzed cascade process of substituted 1-allyl-2-vinylnaphthalenes, which includes the borylation/ortho-cyanation/Cope rearrangement sequence (Scheme 14).24 It should be noted that regioand stereospecific 1,3-allyl group transfer is a key feature of this

Scheme 11. Ru(II)-Catalyzed Cyanation of Benzamides

Scheme 14. Copper-Catalyzed Cyanation of 1-Allyl-2vinylnaphthalenes

Co-catalyzed C−H functionalization reactions are particularly attractive due to their being a heavier congener of Rh as well as their similarity in various homogeneous catalytic reactions. Recently, Ackermann21 and Glorius22 simultaneously and independently reported the cyanation of arenes and heteroarenes with NCTS under a [Cp*Co(CO)I2]/AgSbF6/ acetate catalytic system (Scheme 12). In both cases, the combination of silver and acetate as additives were critical for the catalysis. This could presumably promote the formation of active cationic Co(III) acetate species. 5992


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ACS Catalysis work. On the basis of the experiments, a plausible mechanism was proposed, as shown in Figure 4.

Scheme 16. Rh(III)-Catalyzed Cyanation and Subsequent Denitrosation of N-Nitroso Arylamines

chemicals due to its strong C−CN bond energy (133 kcal mol−1). It is well-known that the reactivity of organic functional groups is often dramatically altered via coordination with transition metals. Recently, transition-metal-promoted acetonitrile C−CN bond cleavage has been reported.27 Cheng27d and Li27e reported the cyanation of aryl halides using acetonitrile as the cyanide source catalyzed by a palladium/zinc species and a copper catalyst, respectively. Obviously, if acetonitrilethe most widely used, cheap, and commercially available organonitrilecan be used as a nitrile source to realize the direct C−H bond cyanation of arenes, then this strategy could be an important tool to avoid using various toxic metal cyanides and structurally complex electrophilic organic CN sources. In fact, direct cyanation of C−H bonds using acetonitrile as the cyanide source has recently emerged as an alternative and intriguing method. In 2013, Zhu demonstrated a copper-catalyzed regioselective C2 cyanation of indoles using acetonitrile as the cyanide source (Scheme 17).28 The installation of a removable pyrimidyl or

Figure 4. Possible mechanism of Cu-catalyzed cyanation of 1-allyl-2vinylnaphthalenes.

Recently, much progress has been made in transition-metalcatalyzed ortho C−H functionalization of aromatic azo compounds using azo as a directing group, including halogenation, acylation, alkoxylation, and amidation. Ortho cyanation of symmetrical azobenzenes was demonstrated by Zhu and co-workers via Rh-catalyzed C−H cyanation using NCTS as a cyanide source (Scheme 15).25 Various substrates Scheme 15. Rh-Catalyzed C−H Cyanation of Aromatic Azo Compounds

Scheme 17. C2 Cyanation of Indoles with CH3CN

with electron-donating or electron-withdrawing groups at the ortho, meta, or para position underwent this transformation smoothly to provide only the corresponding monocyanated product in moderate to good yields. On the basis of H/D exchange experimental studies, the proposed mechanism is similar to that of Kim’s, as mentioned above (Figure 2).12 Recently, the application of nitroso as a favorable directing group to carry out inert C−H functionalization has aroused much attention. Sun and co-workers described a Rh-catalyzed ortho C(sp2)−H bond cyanation of N-alkyl-N-nitrosoarylamines directed by the nitroso group using NCTS as the CN source to form 2-(alkylamino)benzonitriles effectively (Scheme 16).26 Importantly, this cyanation reaction strategy involves a denitrosation process. Various active functional groups on the aryl ring and the amino group of the N-nitrosoarylamines were compatible in this catalytic system. 2.2. Acetonitrile. Acetonitrile is mainly used as the solvent in most reactions and is inert to transition metals and other

pyridinyl group on the indole nitrogen atom as the directing group is crucial for this selective C2 cyanation. This reaction provides a novel and alternative method for the synthesis of various indole-2-carbonitrile derivatives. In addition, 2-(1Hpyrrol-3-yl)pyrimidine also can work in this cyanation reaction. A possible mechanism is described in Figure 5. In 2013, Shen reported novel Cu-catalyzed direct C−H bond cyanation of arenes via cleavage of the relatively inert acetonitrile C−CN bond (Scheme 18).29 The addition of stoichiometric amounts of the Lewis acid (Me3Si)2 is critical to promote C−CN bond cleavage and enhance the reaction rate. A variety of 2-arylpyridines were compatible in this system and provided the monocyanated products. Fortunately, when Npyridyl or N-pyrimidyl indoles were subjected to the standard 5993


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ACS Catalysis Scheme 19. Cu-Catalyzed Cyanation of Arenes

sequential iodination/cyanation process under the Cu/Si/ TEMPO system to give the corresponding aromatic nitriles in good to excellent yields. TEMPO was used as a cheap oxidant to promote the reaction. TEMPO-CH2CN is the active intermediate for promoting the formation of the cyanation product. At the same time, this group also discovered that 3cyanoindoles could be obtained in moderate to good yields through tandem iodination/cyanation of indoles with acetonitrile under a Cu/Si/TEMPO system (Scheme 20).31

Figure 5. Proposed mechanism of Cu-catalyzed cyanation with CH3CN.

Scheme 18. Cu-Catalyzed Cyanation of Arenes

Scheme 20. Cu-Catalyzed Cyanation of Indoles

reaction conditions, 2-cyanoindoles were obtained exclusively in good yields with high regioselectivity. In addition, several other long-chain primary, secondary, and tertiary nitriles can also be used as the cyano source under standard conditions. The possible mechanism involves CuII-mediated acetonitirile C−CN cleavage with the assistance of disilane (Me3Si)2 via an SN2-type cleavage pathway to provide the copper cyanide species CuIICN (Figure 6). The CuIICN coordinates to 2-

2.3. tert-Butyl Isocyanide. Isocyanides are uniquely versatile intermediates in organic synthesis due to their structural and reactive properties, which have been widely used as powerful C1 building block to construct various desirable molecules.32 Independently, Xu33 and Zhu34 almost simultaneously reported the Pd-catalyzed regioselective cyanation of heteroarenes using tert-butyl isocyanide as the CN source. Three equivalents of Cu(TFA)2 was added to the reaction system as an oxidant to promote the formation of the cyanation product. Xu found that aromatic rings such as indoles and pyrroles could be efficiently cyanated with high regioselectivity via the newly established C−H bond activation protocol (Scheme 21).33 In addition, the indoles cyanated at the C2 or C3 position can be controlled according to the nature of the N substitution. Zhu reported the Pd-catalyzed cyanation of substituted 2alkyl(aryl)indoles and 2-arylpyridine (Scheme 22).34 Mechanistic studies indicate that the catalytic process may involve the formation of a key electrophilic imidoyl palladium(II)

Figure 6. Possible mechanism of Cu-catalyzed cyanation of arenes with CH3CN.

Scheme 21. Cyanation of Indoles with Isocyanide

phenylpyridine followed by C−H activation in the presence of another molecule of CuII as an oxidant to give the aryl CuIII intermediate and a CuI salt. Reductive elimination of aryl CuIII intermediate produces the corresponding cyanated product and the CuI salt. Finally, the CuI species is oxidized by oxygen to regenerate the CuII species entering the next catalytic cycle. Recently, the Shen group also developed the Cu-catalyzed cyanation of simple arenes using acetonitrile as the cyano source (Scheme 19).30 The transformation involves a 5994


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of electron-rich heterocycles such as pyrroles, thiophenes, and indoles under mild conditions (Scheme 24).36 Commercially

Scheme 22. Cyanation of Arenes with Isocyanide

Scheme 24. PIFA-Mediated Cyanation of Heterocycles

intermediate and the following C−N bond cleavage to yield the cyanation product and tert-butyl carbon cation fragment. In 2014, Xu reported a novel Rh-catalyzed regioselective C− H bond cyanation of (hetero)arylpyrimidines with tert-butyl isocyanide (Scheme 23).35 Furthermore, the vinyl C−H bond

available trimethylsilyl cyanide (TMSCN) was used as a stable and effective cyanide source in this transformation. The N substituent of pyrroles is crucial to avoid the formation of undesired bipyrroles. Further investigation has indicated that this transformation involves an active hypervalent iodine(III) species having cyano ligands that were generated in situ from PIFA and TMSCN. This novel cyanation protocol features several advantages: (i) direct and selective cyanation of unfunctionalized heterocycles can be carried out under mild conditions, (ii) the stable organo cyanide source can be used, and (iii) the aryl bromide is maintained, which can be further transformed into other useful cyanation products. The plausible mechanism might involve a cation radical from heterocycles induced by PIFA-BF3·Et2O (Figure 8).

Scheme 23. Rh-Catalyzed Cyanation of Arenes with Isocyanide

cyanation of cycloalkenes has been achieved with high regioselectivity. The transformation may involve the formation of rhodacycle A in the first step via electrophilic rhodation directed by a pyrimidyl group. Subsequent insertion of the isocyanide forms intermediate B followed by the β-tert-butyl elimination to produce the cyanation product and expulsion of isobutene. Finally, the Rh(III) catalyst is regenerated from Rh(I) species via reoxidation by Cu(II), which could be derived from Cu(I) (Figure 7). 2.4. TMSCN. In 2005, Kita and co-workers developed a hypervalent iodine(III) reagent (phenyliodine bis(trifluoroacetate) (PIFA)) to mediate the oxidative cyanation

Figure 8. Possible mechanism of PIFA-mediated cyanation.

Recently, much attention has been paid to the direct oxidative cyanation of C−H bonds adjacent to nitrogen atoms because α-cyanoamines are versatile intermediates. These have been widely used in organic synthesis. In 2009, Ofial and Han reported the selective synthesis of α-cyanonitriles catalyzed by nontoxic iron salts using TMSCN as a cyano-group source under mild and acid-free conditions (Scheme 25).37 A series of Scheme 25. FeCl2-Catalyzed Cyanation with TMSCN

tertiary anilines including 1,2,3,4-tetrahydroisoquinolines and N-phenyl-substituted cyclic amines were investigated as substrates to efficiently provide the desired products. In 2011, Zhu and co-workers demonstrated a gold-catalyzed sp3 C−H bond activation of tertiary amines using TMSCN as a cyano source and tert-butyl hydroperoxide as an oxidant under acid-free conditions (Scheme 26).38 The reaction proceeds smoothly with high efficiency to yield the corresponding αcyanated amines in good to excellent yields. Substituted N,N-

Figure 7. Proposed mechanism for Rh-catalyzed cyanation of arenes with isocyanides. 5995


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ACS Catalysis Scheme 26. Gold Complex Catalyzed Oxidative α-Cyanation

This was produced by a LED photoreactor in the presence of a catalytic amount of tetraphenylporphyrin (TPP).42 The αaminonitriles were isolated in good to excellent yields when TMSCN was used as the imine trapping reagent. At room temperature, secondary α-aminonitriles were formed from primary amines via oxidative coupling and a cyanide addition sequence (Scheme 30). Primary α-aminonitriles were obtained Scheme 30. Oxidative Cyanation with TMSCN at Room Temperature

dialkylanilines and some other heterocycles such as piperidine, pyrrolidine, and tetrahydroisoquinoline derivatives can all be applied efficiently to provide the corresponding α-cyanoamines. In 2013, Zhu also reported the same cyanation reaction catalyzed by a stable oxorhenium(V) complex (Re-Bu) (Scheme 27).39 The protocol offers another facile route for the synthesis of α-aminonitriles. Scheme 27. Re-Bu Complex Catalyzed Cyanation

in high yields from the corresponding primary amines if a substoichiometric amount of TBAF was added at −50 °C through the oxidative Strecker reaction (Scheme 31). Scheme 31. Cyanation of Primary Amines with TMSCN at −50 °C

In 2011, Prabhu and co-workers reported the synthesis of αaminonitriles through oxidative cross-dehyrogenative coupling under aerobic conditions catalyzed by a catalytic amount of MO2(acac)2 (Scheme 28).40 This environmentally benign reaction was performed under solvent-free conditions and with molecular oxygen as the terminal oxidant. Scheme 28. Mo-Catalyzed Oxidative α-Cyanation 2.5. Benzyl Cyanide. In 2012, Wang showed the Pdcatalyzed cyanation of aryl halides using benzyl cyanide as a cyanide anion surrogate. 43 Based on this work, they subsequently reported the copper-catalyzed cyanation of arenes (Scheme 32).44a In addition to pyridine and pyrimidine, other directing groups such as pyrazole and 3-methylpyrazole have also reacted smoothly to give the corresponding cyanated products in moderate yields. The cascade cyanation strategy involves the copper-catalyzed aerobic C−H oxidation to form the cyanide anion through a retro-cyanohydrination process.

Recently, Xiong developed a direct oxidative cyanation reaction to give α-aminonitriles using a combination of PIFA with TMSCN in the absence of metal catalysts (Scheme 29).41 Scheme 29. Hypervalent Iodine Promoted Cyanations with TMSCN

Scheme 32. Cyanation of 2-Arylpyridine with Benzyl Cyanide

Generally, various substituted N,N-dimethylanilines can be efficiently converted into products, while cyclic amines show poor results. Interesting, Na2SO4 was found to be an efficient additive to promote the reaction. The reaction was speculated to be carried out via active hypervalent iodine(III)−CN intermediates generated in situ from bis(trifluoracetoxy)iodobenzene (PIFA) and TMSCN. Recently, Seeberger and co-workers described the oxidation of primary and secondary amines to imines by singlet oxygen. 5996


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derivatives can yield nitriles induced under photochemical conditions using tosyl cyanide (TsCN) as a radical acceptor. The reaction selectively occurs at the most electron rich C−H bond. The transformation involves several well-ordered radical reactions (Figure 10). The first step involves the generation of

Subsequently, the substrate undergoes a copper-catalyzed aerobic oxidative C−H cyanation via a single electron transfer (SET) mechanism (Figure 9).

Figure 9. Possible mechanism for the Cu-catalyzed cyanation between arene and benzyl cyanide.

Figure 10. Proposed mechanism for transformation of sp3 C−H bonds to sp3 C−CN bonds.

With the same cyanide source, they also reported the coppercatalyzed direct cyanation of indoles to provide the corresponding 3-cyanoindoles effectively under mild reaction conditions. The method features good functional group tolerance and high regioselectivity (Scheme 33).44b This transformation might involve tandem C−H iodination and copper-catalyzed aerobic cyanation.

an electrophilic oxyl radical A via a photochemical action. Subsequently, hydrogen is abstracted from the electron-rich substrate to give carbon radicals B and C. Then radical B reacts with the electron-deficient radical acceptor TsCN to give the desired product with expulsion of sulfinyl radical D. Finally, the sulfinyl radical D reacts with ketyl radical B to regenerate Ph2CO and close the cycle. In 2009, Liang and co-workers described a PhI(OAc)2mediated selective cyanation of tetrahydroisoquinoline using malononitrile as the cyano-source (Scheme 35).46 The reaction

Scheme 33. Cyanation of Indoles with Benzyl Cyanide

Scheme 35. PhI(OAc)2-Mediated Oxidative Cyanation with Malononitrile

2.6. Other Organic Cyano-Group Sources. In 2011, Inoue and co-workers reported the transformation of C(sp3)− H bonds to C(sp3)−CN bonds via a photochemically induced radical process (Scheme 34).45 Various substrates such as cyclic alkanes, benzylic compounds, other O- or N-containing heterocycles such as cyclic ethers or amines, and even alcohol

selectively occurs at the benzylic sp3 C−H bonds that are adjacent to a nitrogen atom. This oxidative cross-coupling reaction provided an attractive route to α-amino nitrile. Although the detailed mechanism is still unclear, the possible pathway might involve a cross-dehydrogenative coupling (CDC) and C−CN bond cleavage of malononitrile. In 2011, König also demonstrated the same reaction catalyzed by eosin Y via a visible light induced oxidative coupling under metal-free conditions (Scheme 36).47 Inspired by Beller’s work on the cyanation reaction of boronic acids and Grignard reagents using N-cyanophthalimide as cyanating reagent,48 Chang developed a cobalt-catalyzed C− H cyanation reaction of arenes using N-cyanosuccinimide as a new electrophilic cyanating reagent (Scheme 37).49 In addition to pyridine, pyrazole, pyrimidine, and benzo[h]quinoline were all effective directing groups. The reaction proceeds efficiently over a wide scope of substrates including various heterocycles

Scheme 34. Photochemically Induced Radical Cyanation with TsCN

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ACS Catalysis Scheme 36. Eosin Y Catalyzed Visible Light Mediated Cyanation

Scheme 37. Co-Catalyzed Cyanation with NCyanosuccinimide Figure 11. Possible mechanism for cyanation of indoles with DMF.

cyanation product. However, the mechanism of this transformation remains unclear. Scheme 40. Cu-Catalyzed Cyanation with Nitromethane

In 2013, Okamoto and Ohe reported the copper-catalyzed C−H cyanation of terminal alkynes using cyanogen iodide (ICN) as the cyano source (Scheme 41).53 Importantly, 2,2,6,6-

such as thiophenes, furans, pyrroles, indoles, and 6-arylpurines with excellent functional group tolerance. Recently, Han reported a novel method for copper-mediated direct cyanation of 2-arylpyridine with 2,2′-azobis(isobutyronitrile) (AIBN) as the cyano-group source (Scheme 38).50 The mechanistic study indicated that the current strategy involves a CN free-radical mechanism instead of the commonly reported CN anion protocols.

Scheme 41. Cyanation of Terminal Alkynes with ICN

Scheme 38. Copper-Mediated Cyanation with AIBN

tetramethylpiperidine (TEMP) as a sterically congested base that efficiently promotes the reaction. Control experiments showed that the transformation involves the formation of alkynyl iodides intermediate and the subsequent cyanation of iodides catalyzed by CuOTf. In 1986, Whitten reported the synthesis of 2-cyanoimidazoles via N-cyanoimidazole ylides utilizing the cyanogen chloride (CNCl) (Scheme 42).54a However, cyanogen chloride is an extremely toxic gas that is not readily available. Subsequently, they investigated an alternative reagent (CNBr) for the synthesis of 2-cyanoimidazoles in 1988 (Scheme 43).54b With this activated cyanating reagent, 1-cyano-4-dimethylaminopyridinium bromide (CAP) generated from 4-dimethylaminopyridine and cyanogen bromide, N-substituted imidazoles

DMF is widely used as the solvent, while Jiao and co-workers reported the cyanation of indoles and benzofurans catalyzed by Pd(OAc)2 using DMF as both the solvent and cyano source (Scheme 39).51 The authors offered a plausible mechanism for Scheme 39. Pd-Catalyzed Cyanation with DMF

the reaction in Figure 11 involving electrophilic aromatic palladation, electrophilic reaction, reductive elimination, and oxidation processes. In 2006, the Yu group described the Cu-catalyzed cyanation of 2-arylpyridine using O2 as an oxidant and nitromethane (MeNO2) as the cyano-group source and solvent (Scheme 40).52 They found that TMSCN as the CN source has the same

Scheme 42. Cyanation of Imidazole with CNCl

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ACS Catalysis Scheme 43. Cyanation of Imidazoles with CNBr

Scheme 45. Ru-Catalyzed Oxidative Cyanation with NaCN

essential to this process, and no cyanation product was observed under acetic acid free conditions. This indicates that the real cyanation reagent is HCN instead of CN in this system. In 2008, they also developed the same oxidative cyanation reaction using H2O 2 as the oxidant.56b The probable mechanistic pathway is shown in Figure 13. At first, the

were smoothly converted into the corresponding 2-cyanoimidazoles. More recently, Wang reported that 3,5-di(trifluoromethyl)phenyl(cyano)iodoniumtriflate (DFCT) could be readily applied to the cyanation of arenes including various heteroaromatic compounds (Scheme 44).55 Electron-donating Scheme 44. Fe-Catalyzed Direct Cyanation of Arenes with DFCT

Figure 13. Proposed mechanism for Ru-catalyzed oxidative cyanation with NaCN.

tertiary amine undergoes α-C−H activation via the ruthenium catalyst to produce an iminium ion and a ruthenium hydride intermediate that reacts with O2 to generate ruthenium hydroperoxide. The nucleophilic attack of HCN was generated in situ from NaCN and AcOH to afford the α-aminonitrile, H2O, and Ru species. Subsequently, the oxoruthenium species was formed when the Ru species reacted with H2O2, which further reacts with amines to form α-aminonitriles. Inspired by Murahashi’s report, Sain described the same oxidative cyanation reaction of various tertiary amines with NaCN in the presence of catalytic amounts of V2O5 and molecular oxygen as the terminal oxidant under mild conditions (Scheme 46).57

substituents facilitate the transformation of benzene derivatives. The cyanation of heteroaromatic compounds such as pyrroles, benzofurans, benzothiophenes, and indoles have better reactivity, although the regioselectivity can be controlled by the steric effects of the substituent. On the basis of previous work and experimental studies, a possible mechanism was proposed involving a single-electron-transfer (SET) sequence (Figure 12).

Scheme 46. V2O5-Catalyzed Cyanation with NaCN

3. METALLIC CYANO-GROUP SOURCES 3.1. NaCN. In 2003, Murahashi first reported the aerobic Ru-catalyzed oxidative cyanation of tertiary amines using NaCN as a cyano source to give the corresponding α-aminonitriles effectively (Scheme 45).56a The addition of acetic acid is

In 2010, Daugulis described the copper-catalyzed cyanation of heterocycles (Scheme 47).58 Several aromatic heterocycles including benzoxazole, benzothiazole, benzimidazole, pyridine, caffeine, and various triazoles, as well as azulene, can undergo effective cyanation in reasonable yields with NaCN as a cyanogroup source and iodine as the oxidant. This promotes the sequential iodination/cyanation reactions with high regioselectivity.

Figure 12. Proposed mechanism of Fe-catalyzed direct cyanation of arenes with DFCT. 5999


Review

ACS Catalysis Scheme 47. Cu-Catalyzed Cyanation of Heterocycles

Scheme 50. Pd-Catalyzed Cyanation of 2-Arylpyridines

In 2014, Jain reported a visible photoredox-catalyzed oxidative cyanation of a tertiary amine with a chemically functionalized nanocrystalline TiO2 grafted ruthenium(II) polyazine complex.59a Recently, they developed another novel efficient route for oxidative cyanation of tertiary amines combining NaCN and hydrogen peroxide in acetic acid using PEGylated magnetic nanoparticles as the catalyst (Scheme 48).59b This environmentally friendly nanocatalyst can be easily recovered and recycled several times without significant activity loss. Scheme 48. PEG@Fe3O4-Catalyzed Cyanation

Secondary and tertiary amines could be cyanated via C−H activation catalyzed by a magnetic graphitic carbon nitride (Fe@g-C3N4). This was generated by adorning a graphitic carbon nitride (g-C3N4) support with iron oxide via a noncovalent interaction (Scheme 49).60 This magnetic catalyst is recyclable.

Figure 14. Possible mechanism for Pd-catalyzed cyanation with CuCN.

Scheme 51. Pd-Catalyzed Cyanation of Indoles

Scheme 49. Fe@g-C3N4-Catalyzed α-Cyanation

substituted indoles to give the corresponding 3-cyanated derivatives in good yields with high regioselectivity. In 2011, Chen described an efficient iron-mediated C−H cyanation of electron-rich arenes (such as methoxybenzene and indole) as well as 2-arylpyridine using PhI(OAc)2 as the oxidant (Scheme 52).63 Cyanation of 1,3-dimethoxybenzene and 1,2,4trimethoxybenzene predominately occurred at the 4- and 5positions, respectively. Electron-donating groups on the indoles promote cyanation. However, the free indole failed to yield the cyanated product under standard conditions. Liu also reported the straight Cu-catalyzed regioselective cyanation of 2-arylpyridines and pyrazoles using CuCN as the cyano source in moderate to good yields (Schemes 53 and 54).64 The addition of KI clearly accelerates the reaction. The addition of 10 equiv of AcOH is critical when pyrazole was used

3.2. CuCN. In 2009, Cheng reported the Pd-catalyzed ortho cyanation of 2-arylpyridine with CuCN as the cyano source (Scheme 50).61 The possible reaction mechanism is depicted in Figure 14. First, the substrate-directed C−H activation of 2arylpyridine gives a cyclopalladated intermediate. Second, the transformation of CN− from CuCN to palladium affords the Pd(II) species. Finally, the elimination of carbo-palladium yields the product and a Pd(0) species that is oxidized to Pd(II) by Cu(II) and/or air. On the basis of Cheng’s work,61 Reddy described the Pd(II)catalyzed cyanation of indoles via C−H bond activation employing CuCN as the cyano-group source (Scheme 51).62 The reaction tolerated various free indoles with both electronwithdrawing and electron-donating substituents as well as N6000


Review

ACS Catalysis Scheme 52. Iron-Mediated Cyanation of Arenes

Scheme 56. Cyanation of Indoles with K4[Fe(CN)6]

optimized conditionseven free indole worked well. A possible mechanism for this cyanation reaction is proposed in Figure 15. First, CN is transmetalated from K4[Fe(CN)6] to

Scheme 53. Cu-Catalyzed Cyanation of 2-Arylpyridines

Scheme 54. Cu-Catalyzed Cyanation of Pyrazoles Figure 15. Proposed cyanation mechanism of indoles with K4[Fe(CN)6].

palladium to deliver the Pd(II) species, which undergoes electrophilic palladation at the C3 position of the indole to give the Pd(II) complex. Subsequent reductive elimination provides the desired product along with a Pd(0) species, which was oxidized to Pd(II) by Cu(II) and/or air. In 2012, Khorshidi described the 3-cyanation of indoles catalyzed by Ru(III)-exchanged NaY zeolite (RuY) using K4[Fe(CN)6] as the cyanation agent (Scheme 57).67

as the substrate because it can efficiently inhibit byproducts such as the intermolecular coupling product and the amination product. 3.3. K4[Fe(CN)6]. In 2009, encouraged by Yu’s work,52 Cheng reported Pd-catalyzed cyanation of 2-arylpyridine and 1arylpyrazole using K3Fe(CN)6 as a safe and nontoxic cyanide source. This provided the corresponding aromatic nitriles in moderate to good yields (Scheme 55).65 The catalytic system tolerates various functional groups such as methoxy, chloro, fluoro, cyano, trifluoromethyl, and carbomethoxy groups.

Scheme 57. Ru-Catalyzed 3-Cyanation of Indoles

3.4. KCN. In 1994, Sono first reported cyanation of caffeine via electrochemical oxidation using KCN as an electrolyte (Scheme 58).68 The 8-cyanocaffeine was obtained in 13.6%

Scheme 55. Pd-Catalyzed Cyanation with K3Fe(CN)6

Scheme 58. Electrochemical Oxidation Cyanation

yield with this method. Several other caffeine functionalization steps were carried out with similar electrochemical oxidation to afford the 8-fluorocaffeine, 8-methoxycaffeine, and 8-chlorocaffeine, respectively. In 2005, Katritzky reported that the nitric acid and trifluoroacetic anhydride promoted direct cyanation of pyridine using KCN as the cyanide source. This provided the corresponding 2-cyanopyridines regioselectively in moderate to good yields (Scheme 59).69 This protocol avoids the preparation of N-oxides or isolation of any other intermediate.

In 2010, Wang found that Pd-catalyzed 3-cyanation of indoles could be smoothly performed with K4[Fe(CN)6] as the cyanating reagent (Scheme 56).66 The homocoupling of the indole at the C2 and C3 positions was found to be the only byproduct when indole without a substituent at the C2 position was used as the substrate. The 2-substituted indoles were smoothly converted to the desired cyanation products under 6001


Review

ACS Catalysis Scheme 59. Cyanation of Pyridine

Figure 16. Possible pathway for the formation of “CN”.

4.2. Combination of NH4I and DMF. In 2012, the Chang group reported another combined CN sourceammonium iodide and DMF (Scheme 62).72 Using this new combined CN

In 2011, Lambert and Allen reported the tropylium ion mediated α-cyanation of amines with KCN. The substrate scope is very broad and shows intriguing regioselective preferences (Scheme 60).70 Cycloheptatriene is the only

Scheme 62. Cyanation of Arenes with NH4I and DMF

Scheme 60. Tropylium Ion Mediated α-Cyanation

source, Chang described cyanation of electron-rich arenes under Cu-mediated oxidative conditions. Furthermore, the procedure could also be applied to other substrates including boronic acids, boronates, and borate salts. In this reaction, NH4I was found to play a dual role. It supplies both iodide and N to the cyano unit. Mechanistic studies indicated that the reaction involves cascade iodination and cyanation process. 4.3. Combination of NH4HCO3 and DMSO. In 2011, Cheng and Chen also reported the palladium-catalyzed cyanation of indole using a new safely combined cyano source (NH4HCO3/DMSO) (Scheme 63).73 This method provides a

byproduct in this transformation and is a volatile hydrocarbon. When this protocol was employed, α-cyanate(−) sparteine was obtained in high yield (90%).

4. COMBINED CYANO SOURCES 4.1. Combination of NH3 and DMF. To pursue greener and safer CN sources, Chang developed a Pd-catalyzed C−H bond cyanation process using a combined CN source (DMF/ NH3(aq)) (Scheme 61) in 2010.71 Isotopic incorporation

Scheme 63. Cyanation of Indoles with NH4HCO3 and DMSO

Scheme 61. Cyanation with NH3 and DMF

new and efficient route to 3-position cyanated indoles with excellent regioselectivity. The 13C-DMSO labeling experiment showed that the carbon atom in the CN group came from DMSO. Other results indicated that the Cu(OAc)2 is critical to the in situ formation of CN− from NH4HCO3 and DMSO. The possible mechanism involves C−H activation, ligand exchange, and reductive elimination (Figure 17). On the basis of the previous C−H bond cyanation of a combined cyano source, Kantam recently reported the Pd(II)/

experiments indicated that the C and N atoms of the CN group originate from DMF and ammonia, respectively. This cyanation process has excellent regioselectivity and affords only the monocyanated product at the less hindered C−H position. Although a detailed mechanism is still unclear, the authors proposed a possible pathway to form the cyano unit CN (Figure 16). 6002


Review

ACS Catalysis

Scheme 65. Synthesis of Aryl Nitriles from Methyl Arenes

broad-spectrum antipicornavirus activity. The reasonable mechanism of this transformation might involve a radical pathway (Figure 18). Scheme 66. Synthesis of a Tetrazole Analogue Related to Disoxaril Figure 17. Possible mechanism of cyanation of indoles with NH4HCO3 and DMSO.

(Mg-La) mixed oxide catalyzed cyanation of arenes using a combination of NH4HCO3 and DMSO (Scheme 64).74 The Scheme 64. Cyanation of Arenes with NH4HCO3 and DMSO

Figure 18. Possible mechanism for the direct transformation of methyl arenes to aryl nitriles.

addition of Cu(NO3)2·3H2O (2 equiv) as an oxidant is very important to obtaining high yields. The catalyst used here can be readily recovered with simple centrifugation. It can be recycled three times without significant loss of activity and selectivity. Interestingly, the tandem Suzuki cyanation reaction of 2-bromopyridine was performed smoothly using the present catalytic system. This gave the desired cyanated product in moderate yield.

In 2014, Feng and Song also reported the synthesis of benzonitriles by a copper-catalyzed reaction of phenylacetic acids with urea as the nitrogen source (Scheme 67).76 The transformation involves a sequence of decarboxylation, dioxygen activation, C−H bond functionalization, and nitrile formation. Molecular oxygen was found to play an important

5. MISCELLANEOUS CYANATIONS Furthermore, there are some other cases for the synthesis of aryl nitriles based on direct C−H bond functionalization. One of the strategies was described in copper-catalyzed transformation of substituted methyl arenes to aryl nitriles by Jiao and co-workers in 2009 (Scheme 65).75 The method was useful for the preparation of functionalized aryl nitriles from the corresponding electron-rich toluenes. This transformation involves the cleavage of three C−H bonds with NaN3 as the nitrogen source and phenyliodonium diacetate (PIDA) as oxidant. The protocol offered a key step for the synthesis of a tetrazole analogue related to Disoxaril (Scheme 66), which has

Scheme 67. Synthesis of Benzonitriles from Aromatic Acetic Acids and Urea

6003


Review

ACS Catalysis

Georg Thieme: Stuttgart, Germany, 2001. (b) Larock, R. C. In Comprehensive organic transformations: a guide to functional group preparations; Wiley-VCH: Weinheim, Germany, 1989; pp 819−995. (2) Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D. Pharmaceutical substances: syntheses, patents, applications, 4th ed.; Georg Thieme Verlag, Stuttgart, 2001; pp 302, 533, 542, 1077. (3) (a) Fatiadi, A. J. In Preparation and synthetic applications of cyano compounds; Patai, S., Rappoport, Z., Eds.; Wiley-VCH: New York, 1983. (b) Rappoport, Z. In Chemistry of the cyano group; Wiley: London, 1970; pp 121−312. (4) (a) Crabtree, R. H. J. Organomet. Chem. 2004, 689, 4083−4091. (b) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. Rev. 2002, 102, 1731− 1770. (c) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633−639. (d) Dyker, G. Angew. Chem., Int. Ed. 1999, 38, 1698−1712. (5) (a) Rosenmund, K. W.; Struck, E. Ber. Dtsch. Chem. Ges. B 1919, 52, 1749−1756. (b) Lindley, J. Tetrahedron 1984, 40, 1433−1456. (6) (a) Sandmeyer, T. Ber. Dtsch. Chem. Ges. 1884, 17, 1633−1635. (b) Galli, C. Chem. Rev. 1988, 88, 765−792. (7) (a) Anbarasan, P.; Schareina, T.; Beller, M. Chem. Soc. Rev. 2011, 40, 5049−5067. (b) Kim, J.; Kim, H. J.; Chang, S. Angew. Chem., Int. Ed. 2012, 51, 11948−11959. (c) Yan, G.; Yu, J.; Zhang, L. Youji Huaxue 2012, 32, 294−303. (d) Wen, Q.; Jin, J.; Zhang, L.; Luo, Y.; Lu, P.; Wang, Y. Tetrahedron Lett. 2014, 55, 1271−1280. (8) (a) Anbarasan, P.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed. 2011, 50, 519−522. (b) Anbarasan, P.; Neumann, H.; Beller, M. Chem. - Eur. J. 2011, 17, 4217−4222. (9) (a) Kurzer, F. J. Chem. Soc. 1949, 1034. (b) Kurzer, F. J. Chem. Soc. 1949, 3029. (10) Yang, Y.; Zhang, Y.; Wang, J. Org. Lett. 2011, 13, 5608−5611. (11) Chaitanya, M.; Anbarasan, P. J. Org. Chem. 2015, 80, 3695− 3700. (12) Mishra, N. K.; Jeong, T.; Sharma, S.; Shin, Y.; Han, S.; Park, J.; Oh, J. S.; Kwak, J. H.; Jung, Y. H.; Kim, I. S. Adv. Synth. Catal. 2015, 357, 1293−1298. (13) Reviews: (a) Satoh, T.; Miura, M. Chem. - Eur. J. 2010, 16, 11212−11222. (b) Colby, D. A.; Tsai, A. S.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2012, 45, 814−825. (c) Patureau, F. W.; WencelDelord, J.; Glorius, F. Aldrichim. Acta 2012, 45, 31−41. (d) Song, G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651−3678. (14) Gong, T.-J.; Xiao, B.; Cheng, W.-M.; Su, W.; Xu, J.; Liu, Z.-J.; Liu, L.; Fu, Y. J. Am. Chem. Soc. 2013, 135, 10630−10633. (15) Chaitanya, M.; Yadagiri, D.; Anbarasan, P. Org. Lett. 2013, 15, 4960−4963. (16) (a) Su, W.; Gong, T.-J.; Xiao, B.; Fu, Y. Chem. Commun. 2015, 51, 11848−11851. (b) Chaitanya, M.; Anbarasan, P. Org. Lett. 2015, 17, 3766−3769. (17) (a) Wydysh, E. A.; Medghalchi, S. M.; Vadlamudi, A.; Townsend, A. J. Med. Chem. 2009, 52, 3317−3319. (b) Sivendran, S.; Jones, V.; Sun, D. Q.; Wang, Y.; Grzegorzewicz, A. E.; Scherman, M. S.; Napper, A. D.; McCammon, J. A.; Lee, R. E.; Diamond, S. L.; McNeil, M. Bioorg. Med. Chem. 2010, 18, 896−908. (c) Gu, L.; Jin, C. Org. Biomol. Chem. 2012, 10, 7098−7102. (d) Han, W.; Mayer, P.; Ofial, A. R. Adv. Synth. Catal. 2010, 352, 1667−1676. (e) Mucha, A.; Kafarski, P.; Berlicki, Ł. J. Med. Chem. 2011, 54, 5955−5980. (18) Gu, L.-J.; Jin, C.; Wang, R.; Ding, H.-Y. ChemCatChem 2014, 6, 1225−1228. (19) Zhang, S.; Zhou, J.; Shi, J.; Wang, M.; Xu, H. E.; Yi, W. Chin. J. Catal. 2015, 36, 1175−1182. (20) Liu, W.; Ackermann, L. Chem. Commun. 2014, 50, 1878−1881. (21) Li, J.; Ackermann, L. Angew. Chem., Int. Ed. 2015, 54, 3635− 3638. (22) Yu, D.-G.; Gensch, T.; de Azambuja, F.; Vásquez-Céspedes, S.; Glorius, F. J. Am. Chem. Soc. 2014, 136, 17722−17725. (23) (a) Yang, Y.; Buchwald, S. L. Angew. Chem., Int. Ed. 2014, 53, 8677−8681. (b) Yang, Y.; Liu, P. ACS Catal. 2015, 5, 2944−2951. (24) Yang, Y. Angew. Chem., Int. Ed. 2016, 55, 345−349. (25) Han, J.; Pan, C.; Jia, X.; Zhu, C. Org. Biomol. Chem. 2014, 12, 8603−8606.

role in this catalytic system, which is the ideal terminal oxidant for oxygenation. Various substituted phenylacetic acids, even naphthylacetic acid, and heteroaromatic acetic acids are suitable substrates under the standard conditions. On the basis of control experiments and previous reports, the proposed mechanism involves decarboxylation of aryl acetic acid, and the following oxidation into aldehyde by copper(II)/O2, reaction with the ammonia surrogate to form imine, and oxidative condensation to give benzonitrile (Figure 19).

Figure 19. Possible mechanism for the synthesis of benzonitriles from aromatic acetic acids.

6. SUMMARY AND OUTLOOK In this review, we have summarized achievements in C−H bond direct cyanation, including both sp2 C−H cyanation of arenes and alkenes and sp3 C−H cyanation of amines to provide α-aminonitriles. In addition to palladium- and coppercatalyzed cyanations, several other transition-metal-mediated (Rh, Ru, Au, Fe, Co, Re, V, and Mo) cyanations were described. Furthermore, the C−H bond cyanation reactions can even be carried out via photochemical45,47 or electrochemical68 oxidation. Although the facile introduction of cyano groups into arenes or amines has been achieved using metallic CN sources (such as CuCN, NaCN, KCN, and K4[Fe(CN)6]), several drawbacks (including their toxicity and passivation of the catalyst via coordination of the transition metal with an excess amount of cyanide anions) limits their further application. Therefore, it is extremely urgent to develop more efficient and selective cyanation methods by studying less toxic organic cyano-group sources or combined cyano-group sources from easily available compounds. In addition, further research efforts will likely broaden the substrate scope.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail for Q.D.: [email protected]. *E-mail for Y.P.: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the National Natural Science Foundation of China (21262016), and the Natural Science Foundation of Jiangxi Province of China (20133ACB20008) is gratefully acknowledged. We thank LetPub (www.letpub.com) for linguistic assistance during the preparation of this paper.

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REFERENCES

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