CâH Functionalization of Azines - Chemical Reviews (ACS Publications)

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C−H Functionalization of Azines Kei Murakami,*,† Shuya Yamada,† Takeshi Kaneda,† and Kenichiro Itami*,†,‡ †

Institute of Transformative Bio-Molecules (WPI-ITbM) and Graduate School of Science, and ‡JST-ERATO, Itami Molecular Nanocarbon Project, Nagoya University, Chikusa, Nagoya 464-8602, Japan ABSTRACT: Azines, which are six-membered aromatic compounds containing one or more nitrogen atoms, serve as ubiquitous structural cores of aromatic species with important applications in biological and materials sciences. Among a variety of synthetic approaches toward azines, C−H functionalization represents the most rapid and atom-economical transformation, and it is advantageous for the late-stage functionalization of azine-containing functional molecules. Since azines have several C−H bonds with different reactivities, the development of new reactions that allow for the functionalization of azines in a regioselective fashion has comprised a central issue. This review describes recent advances in the C−H functionalization of azines categorized as follows: (1) SNAr reactions, (2) radical reactions, (3) deprotonation/functionalization, and (4) metal-catalyzed reactions.

CONTENTS 1. 2. 3. 4. 5.

Introduction SNAr Reactions of Azines Radical Reactions of Azines Deprotonative Metalation of Azines Metal-Catalyzed C−H Functionalization of Azines 5.1. Azines with Electron-Withdrawing Groups 5.2. Azines without Directing Groups 5.2.1. Reactions of Azines Catalyzed by Group 3 and 4 Metals 5.2.2. Reactions of Azines Catalyzed by a Group 6 Metal 5.2.3. Reactions of Azines Catalyzed by Group 8 Metals 5.2.4. Reactions of Azines Catalyzed by Group 9 Metals 5.2.5. Reactions of Azines Catalyzed by Group 10 Metals 5.2.6. Reactions of Azines Catalyzed by a Group 11 Metal 6. Summary Author Information Corresponding Authors ORCID Author Contributions Notes Biographies Acknowledgments References

inherently electron-deficient and Lewis basic. For example, it is well-known that pyridine displays extremely low reactivity in aromatic electrophilic substitution (SEAr) reactions such as halogenation or nitration. Classical examples reveal that SEAr reactions require temperatures greater than 300 °C (Figure 2). In addition, as a Lewis base, pyridine inactivates Lewis acids and consequently suppresses Friedel−Crafts reactions. On the other hand, the nucleophilic aromatic substitution (SNAr) of azines takes place relatively easily. Owing to the electronically biased structure of azines, they react with a variety of nucleophiles, and strong nucleophiles are usually required. This trend can be clearly understood from its resonance structure, in which the C2- or C4-positions are electrophilic (Figure 3). Despite the high utility of the azine moiety, azines are inherently less reactive than 5-membered heteroaromatics and difficult to functionalize under mild reaction conditions with high selectivity owing to azine’s coordinating nitrogen atom(s) and electron-deficient nature. A variety of synthetic approaches toward azines therefore have been widely studied since the dawn of organic chemistry. Classically, the azine ring has been constructed from the corresponding components. In 1894, Knoevenagel pioneered the synthesis of multisubstituted pyridines from β-keto esters, aldehydes, and hydroxylamines.1 Owing to the development of efficient routes toward highly substituted pyridines, substantial progress has been made in the synthesis of azines through ring-forming approaches, as summarized in recent reviews.2−4 Recent advancement of C− H functionalization enables one to conduct direct functionalization of azines.5−16 C−H functionalization allows the rapid and direct transformation of azine cores, and is particularly useful for the late-stage functionalization of azine-containing functional molecules. Since azines contain several C−H bonds with different reactivities, the development of new synthetic methods that allow for the functionalization of azines in a

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1. INTRODUCTION Azines are six-membered aromatic compounds containing one or more nitrogen atoms, and they serve as important structural cores of aromatic species with interesting and useful applications in biological and materials sciences (Figure 1). Azines are structurally related to benzene, but their properties are substantially different. Owing to the presence of the electronegative nitrogen atom within the ring, azines are © 2017 American Chemical Society

Special Issue: CH Activation Received: January 11, 2017 Published: April 26, 2017 9302

DOI: 10.1021/acs.chemrev.7b00021 Chem. Rev. 2017, 117, 9302−9332

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2. SNAr REACTIONS OF AZINES19−22 Pioneering work on pyridine functionalization was carried out in 1914 by Chichibabin and co-workers (Scheme 1).23 By Scheme 1. Early Report on C−H Functionalization of Azines

taking advantage of the electrophilic nature of the C2-position of pyridine, they synthesized 2-aminopyridine via the reaction of pyridine with sodium azide in N,N-dimethylaniline. In 1938, Evans and Allen found that pyridine could react with carbon nucleophiles (Scheme 2).24 The reaction of pyridine with Scheme 2. C2-Phenylation with Phenyllithium

phenyllithium occurs preferentially at the C2-position to give 2phenylpyridine. The reaction with quinoline or isoquinoline also proceeds with Grignard reagents (Scheme 3).25 Very

Figure 1. Examples of functional molecules with azine moieties.

Scheme 3. C2-Arylation of Quinoline and Isoquinoline

recently, Jeffrey and Sarpong applied the reaction for the direct alkylation of pyridyl alcohols (Scheme 4).26 A lithium alkoxide Scheme 4. Direct Alkylation of Pyridyl Alcohols Using Alkyllithium Figure 2. Classical examples of aromatic electrophilic substitution reactions.

Figure 3. Resonance structures of pyridine.

is generated by the deprotonation of alcoholic proton of the substrate with butyllithium. The generation of the alkoxide is critical for the C6-alkylation with high regioselectivity. The products can be good precursors for asymmetric hydrogenation reactions.27,28 Although it is beyond the scope of this review, Nactivated azines29−64 and two-step nucleophilic addition/ oxidations65−78 are widely utilized for the synthesis of substituted pyridines. Chichibabin-type C−H fluorinations of pyridines and diazines were reported by Fier and Hartwig in 2013.79 Commercially available and easy-to-handle silver fluoride is used as a fluorinating reagent. The wide scope of the reaction allows for the use of various bioactive molecules (Figure 4). On the basis of kinetic isotope effects (KIE) experiments, Fier and Hartwig postulated that the deprotonating aromatization step was the most energetically unfavorable (Figure 5). This reaction is advantageous because the previous methods80,81

regioselective fashion has comprised a central issue. This review describes recent advances in the C−H functionalization of azines categorized as follows: (1) SNAr reactions, (2) radical reactions, (3) deprotonation/functionalization, and (4) metalcatalyzed reactions. In order to focus on the functionalization of nitrogen-containing six-membered aromatic rings, we do not cover C−H functionalization of aromatic rings that are fused with azines (i.e., we cover C−H functionalization of quinoline at the C2−4 positions but not the C5−8 positions). The reactions of N-activated azines or azines with directing groups are not discussed here, because they were summarized recently.17,18 9303


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Figure 4. C−H fluorination of bioactive pyridine-containing molecules.

Figure 6. Late-stage C4-functionalization of bioactive molecules.

Scheme 5. Radical Alkylation of Pyridine

Inspired by Minisci’s work, Baran’s group developed the radical arylation of azines with arylboronic acids (Figure 7).93,94

Figure 5. KIE experiments and proposed mechanism.

require hazardous fluorine gas to directly fluorinate pyridine cores. Fier and Hartwig combined C−H fluorination with nucleophilic aromatic substitution to substitute fluoride with various nucleophiles for the late-stage functionalization of complex molecules.82 Very recently, McNally and co-workers reported a new approach for the two-step C4-functionalization of pyridine (Figure 6).83 Heterocyclic phosphonium salts, which can be prepared via reactions of azines with triphenylphosphine in the presence of trifluoromethanesulfonic anhydride,84,85 undergo SNAr reactions with various nucleophiles such as alkoxides, thiolates, azides, or organolithium reagents. The reaction of C4substituted azines proceeds at the C2-position. Figure 7. Silver-catalyzed radical arylation of azines.

3. RADICAL REACTIONS OF AZINES86−89 In 1971, Minisci et al. reported the radical alkylation of pyridine with alkylcarboxylic acids in the presence of a catalytic amount of silver(I) salts (Scheme 5).90 The alkyl radical is generated from the reaction of Ag(I) with a carboxylic acid. The regioselectivity of the reaction is similar to that of nucleophilic aromatic substitution reactions since most alkyl radicals are electron-rich in nature. The reaction preferentially proceeds at the electrophilic 2- and 4-positions. Minisci et al. discovered that aryl radicals can be utilized for the arylation of pyridines.91,92

The borono-Minisci reaction is applicable not only to pyridine but also to pyrimidine, pyridazine, pyrazine, quinoline, isoquinoline, and phthalazine. A proposed mechanism is shown in Figure 8. The reaction of Ag(I) with S2O82− affords reactive SO4•− as an aryl radical generator, which then reacts with arylboronic acid. The generated aryl radical then reacts with azines. Similarly, alkyl- or alkoxymethyltrifluoroborates were employed for the radical alkylation of azines.95 Iron has a similar catalytic activity as silver in the arylation of pyridines,96,97 quinolines,97 or pyrazines98 (Scheme 6). Metal9304


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Figure 8. Proposed mechanism of radical arylation.

Scheme 6. Iron-Catalyzed Arylation

Figure 10. Alkylation of azines with amino acids.

free reactions at higher temperatures are possible for the direct arylation of diazines with arylboronic acid.99 Silver-catalyzed systems are also effective for decarboxylative arylation (Figure 9)100,101 or alkylation of azines (Figure 10).102 The decarbon-

Scheme 7. Transition-Metal-Free Arylation of Pyridine

Scheme 8. Visible-Light, Heterogeneous Catalysis of Pyridine Arylation with Diazonium Salts

Figure 9. Decarboxylative radical arylation of pyridines.

ylative Minisci-type alkylation of azines was also reported.103 Similarly, the photoredox-catalyzed alkylation of azines with peroxides was reported by DiRocco et al.104 Arylhydrazine can be an efficient arylating reagent.105 Pyridine reacts with phenylhydrazine at room temperature within 24 h without the addition of catalysts (Scheme 7). Aryldiazonium reagents act as radical precursors to arylate 3hydroxypyridines106 or isoquinolines.107 The photoinduced arylation of pyridines under the catalytic influence of TiO2 (Scheme 8)108 or a ruthenium complex109 were also reported. Visible light combined with photoredox catalysts promote the generation of radicals at the α-position of ethers (Figure 11).110 α-Oxyalkyl radicals can react with azines through Minisci-type111 reactions. Notably, the addition of an Ir catalyst and irradiation with light were found to be critical. Under

Figure 11. Photoredox-catalyzed reaction of azines with ethers.

modified reaction conditions, the reaction proceeds without the addition of a photoredox catalyst with a wide substrate scope.112 In the presence of an oxidant, a similar reaction takes place in the absence of light or a catalyst.113 The alkylation of quinolines at the C2-position using alkanes or ethers with PhI(O2CCF3)2 as a radical initiator was reported 9305


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(Figure 12).114 Recently, hydroxyalkylation with alcohols was also reported (Scheme 9).115,116 A radical abstracts the α-

Figure 13. Proposed mechanism for alkylation of azines with alcohols.

Scheme 11. Photoredox-Catalyzed Minisci-type C−H Alkylation

Figure 12. C2-Alkylation of quinolines.

Scheme 9. Hydroxymethylation of 3,6-Dichloropyridazine scope of the reaction is wide enough to employ various quinoline derivatives, pyridines, 1,10-phenanthroline derivatives, pyrimidines, and pyrazines. The reaction tolerates functional groups such as ester, amine, halogen, or hydroxy groups. Thanks to the high functional group compatibility, natural products were smoothly alkylated. Chen, Zhao, and their co-workers reported the photocatalytic reaction of pyridine (Scheme 12).119 Interestingly, they proposed that pyridine was activated with TiO2 photocatalyst, which then reacted with 1,1-diphenylethylene.

hydrogen from an alcohol to generate the corresponding nucleophilic radical, which reacts with azines. Jin and MacMillan disclosed the bioinspired alkylation of azines with alcohols.117 The reaction is amenable to a wide variety of substrates and alcohols (Scheme 10). The reaction initiates from the addition of α-oxy radicals to azines (Figure 13). The liberation of the proton affords α-amino radicals, which are dehydrated to give pyridylmethyl radicals. A single-electron transfer from the catalyst affords the corresponding products. Chen and co-workers reported Minisci-type, photoredoxcatalyzed C−H alkylation of azines (Scheme 11).118 The

Scheme 12. Photocatalytic Activation of Pyridine

Scheme 10. Alkylation of Azines with Alcohols Acyl radicals, generated under Fenton-type reaction conditions,120 can react with pyridine (Scheme 13).121 This acetylation of azines is applicable to the synthesis of alkaloids.122 Recently, Paul and Guin applied the auto-oxidation of aldehydes to generate acyl radicals that react with pyridine (Scheme 14).123 Redox-neutral radical arylation is accomplished by the combination of azines with aryl iodides in the presence of KOtBu (Figure 14).124 Following the seminal report by Itami and co-workers, many groups reported the radical arylation of arenes initiated by KOtBu.125−131 Other radical initiators such as AIBN are applicable for the functionalization of pyridines with pyridyl halides.132 The photoredox-catalyzed generation of aryl radicals from diphenyliodonium salts can be applied for the arylation of pyridine (Scheme 15).133 As compared to the heat-induced 9306


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Scheme 13. Alkylation and Acylation of Pyridine under Fenton-type Conditions

Scheme 16. Radical Phenylation of Azines with Diphenyliodonium Salts

significant interest not only from synthetic chemists but also from the pharmaceutical community. Radical approaches are promising options for the installation of fluoroalkyl groups on arenes. Classically, photo- or thermogenerated trifluoromethyl radicals from CF3Br or CF3I have been utilized in the trifluoromethylation of azines.135,136 Recently, a variety of fluoroalkyl radical precursors have been developed. Ritter developed new fluoroalkylating reagents from CF3I and tetramethylguanidine.137 A variety of photoredox-induced fluoroalkylation reactions of azines were reported.138−141 Liu and co-workers found that the difluoroacetamidation of azines could be accomplished using a photoredox catalyst.142 Baran and co-workers developed fluoroalkylsulfonates as radical precursors.143−147 The reactions of heteroarenes with sodium trifluoromethylsulfinate (CF3SO2Na)148 give the corresponding trifluoromethylated products (Scheme 17).143 Baran’s group

Scheme 14. Acylation of Pyridine Initiated by AutoOxidation with O2

Scheme 17. Trifluoromethylation of Pyridines with Sodium Trifluoromethylsulfinate

also developed a new reagent for difluoromethylation (Scheme 18).144 Treatment of CF2HSO2Cl with zinc metal affords Scheme 18. Difluoromethylation of Pyridines

Figure 14. KOtBu-promoted radical arylation of azines.

generation of phenyl radicals (Scheme 16),134 the photoredox approach requires a lower reaction temperature. The installation of fluoroalkyl groups can alter various molecular properties, such as metabolic stability or lipophilicity. New methods to install fluoroalkyl groups thus garner

Zn(SO2CF2H)2 (DFMS), which acts as an efficient difluoromethylating reagent. Notably, the reagent was extended to various alkylating reagents (R−SO2)2Zn [R = CF3, CF2H, CF3CH2, CH2F, CH(CH3)2, CH3(CH2CH2O)3].145 The efficient iodination of quinoline can be accomplished under oxidative conditions (Scheme 19).149 Iodine reacts with tBuOOH to give tBuOI or HOI in situ, which should act as an iodinating reagent. The reaction likely proceeds through a radical pathway, because the addition of TEMPO or BHT completely suppresses the reaction. Similarly, Lupton, Maiti, and their co-workers reported the regioselective iodination of quinolines, quinolones, pyridones, pyridines, and uracil.150

Scheme 15. Photoredox-Catalyzed Arylation of Pyridine with Iodobenzene

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the corresponding organolithium species. It is notable that C− H acidity was calculated and the relationship with regioselectivity was nicely summarized.196−200 For example, Quéguiner and co-workers reported C3-lithiation of 2-methoxypyridine in the presence of a catalytic amount of secondary amine (Scheme 21).173 An active lithium amide is generated in the system,

Scheme 19. C3-Iodination of Quinoline

Scheme 21. Lithiation of 2-Methoxypyridine with a Catalytic Amount of Lithium Amide

Nitrogen-centered radicals can react with azines to give the corresponding aminated products.151,152 Ritter and co-workers reported that N-fluorobenzenesulfonimide acts as an imidating reagent that reacts with pyridine at the 3- and 5-positions153 (Scheme 20). Ritter and colleagues then found para-selective

which would enhance the deprotonation reaction. As the example shows, lithiation takes place at the ortho-position of a directing substituent (i.e., the methoxy group in Scheme 21). An interesting reaction was reported by Caubère and coworkers, in which the addition of N,N′-dimethyl-2-ethanol could change the regioselectivity of lithiation of the 6-position of 2-alkoxypyridine or 2-chloropyridine (Scheme 22).200,201

Scheme 20. Palladium-Catalyzed Imidation of Azines

Scheme 22. C6-Lithiation of 2-Methoxypyridine

C−H amination with Selectfluor.154 Similarly, the groups of Baran (Figure 15),155 Sanford,156 Lee,157 and Itami158−160 reported the imidation of pyridine or pyrimidine using imidyl radicals.

4. DEPROTONATIVE METALATION OF AZINES161−171 It is well-known that strong bases such as lithium amide172−188 or organolithium189−195 abstract protons from azines to give

The resulting lithiated azine intermediates are utilized for further transformations in drug and natural product syntheses.202−209 However, functional groups are not tolerated under these reaction conditions due to the high nucleophilicity of the organolithium reagent. Therefore, it is difficult to lithiate azines during the late stages of synthesis. Mongin and co-workers showed the deprotonation of chloropyridines with lithium magnesates (Scheme 23).210 Scheme 23. Deprotonative Magnesiation of Chloropyridine with Lithium Magnesates

Magnesiation occurs at o-chloro group and no pyridine formation is observed. In 2006, Knochel and co-workers developed TMPMgCl·LiCl as an efficient deprotonation reagent.211−216 The treatment of isoquinoline in THF at 25 °C for 2 h with TMPMgCl·LiCl affords the corresponding arylmagnesium reagents in high yields (Scheme 24). Usually, the deprotonation occurs at the most acidic proton. Pyridines

Figure 15. Radical imidation of azines. 9308


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presence of BF3, whereas the C8-position is metalated in the presence of ZnCl2.

Scheme 24. Deprotonative Magnesiation of Isoquinoline with TMPMgCl·LiCl

Scheme 27. Regioswitching Metalation of Cinnoline

and pyrazines with trifluoroacetamide moieties are smoothly deprotonated at the o-trifluoroacetamide moiety with TMPMgCl·LiCl.217 Air-stable ArZnOPiv reagents can be prepared from azines with TMPMgCl·LiCl.218,219 (TMP)2Mg· 2LiCl was developed to deprotonate less reactive arenes.220−222 By taking advantage of the coordinating ability of azines, the deprotonation step is facilitated by the addition of Lewis acids such as ZnCl2.223−225 Notably, the use of TMP magnesium base in the presence of zinc chloride is superior to TMP2Zn· 2MgCl2·2LiCl (vide infra) (Scheme 25). The addition of zinc

Arylzinc reagents exhibit better functional group compatibility than organomagnesium reagents toward esters, nitriles, and ketones. A pioneering work on the C−H zincation of azines with zincate was carried out in 1999 by Kondo and coworkers (Scheme 28).233−235 In 2007, Wunderlich and Knochel Scheme 28. TMP−Zincate for Directed ortho-Metalation

Scheme 25. Acceleration of Metalation via Stepwise Activation with Zinc Salts

reported a new zinc amide base, TMP2Zn·2MgCl2·2LiCl, which can deprotonate a variety of azines with high functional group compatibility. For example, the 4-position of 2-chloro-3ethoxycarbonylpyridine is selectively deprotonated to give the corresponding arylzinc reagent (Scheme 29).236 The resulting Scheme 29. Zincation of Pyridine with TMP2Zn·2MgCl2· 2LiCl

chloride might activate the substrate through coordination, which would allow for the facile deprotonation with TMPMgCl·LiCl and transmetalation with zinc. Inspired by previous works on BF3-accelerated metalation,226−228 Knochel and co-workers employed BF3 as a regioswitching reagent for metalation. In contrast to the ortho deprotonation of 2phenylpyridine with TMPMgCl·LiCl, the proton in the 2position of pyridine is abstracted in the presence of BF3 (Scheme 26).229−231 Interestingly, the regioselectivity of the deprotonation of cinnoline is switched upon addition of BF3 or ZnCl2 (Scheme 27).232 The C3-position is deprotonated in the Scheme 26. BF3-Accelerated Magnesiation of Azines

pyridylzinc intermediate reacts with acyl chlorides to give the pyridyl ketone in good yields. TMP2Zn·2MgCl2·2LiCl were proved to be scalable.237 Although this reagent is efficient, there is room for improvement in terms of reaction yield and selectivity for electron-deficient substrates. In 2009, TMPZnCl· LiCl was reported as a chemoselective base for diazines (Figure 16) as well as other sensitive arenes.238−244 Notably, air-stable solid zinc pivalates can be used for sensitive arenes instead of TMPZnCl·LiCl.245 Do and Daugulis revealed a unique type of Glaser−Hay reaction of arenes (Figure 17).246 They employed hindered magnesium or zinc amide as a base to deprotonate azines. The resulting arylmagnesium or arylzinc then dimerize to give the products. 9309


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Scheme 31. Comparison of Batch and Flow Conditions

Figure 16. Deprotonation of diazine with TMPZnCl·LiCl. aObtained by palladium-catalyzed cross-coupling using Pd(dba)2 (3 mol %) and (o-furyl)3P (6 mol %) with ethyl 4-iodobenzoate. b4-Fluorobenzoyl chloride was reacted after transmetalation was performed with 1.1 equiv of CuCN·2LiCl. cAllyl bromide was reacted after transmetalation was performed with 5 mol % of CuCN·2LiCl.

which can be quenched with iodine to give the product.253 The procedure can be applied with a range of substrates (Figure 18). Lithium, magnesium, or zinc amides, as well as other metal amides such as Cu,257−261 Co,262 Fe,263 Mn,264−266 Zr,267 La,268 Al,269 or Cd270−272 can be employed as bases to abstract protons from azines.

Figure 17. Glaser−Hay reaction of arenes.

Mongin and co-workers reported the deprotonation of pyrazine, pyridazine, pyrimidine, and quinoxaline. An in situ mixture of zinc salts with LiTMP is the key for the reaction.247 Recently, ketone-tolerated C−H abstraction of pyridyl ketones with LiTMP was accomplished in the presence of zinc salts (Scheme 30).248 Pyridyl ketones are first treated with 1 equiv of ZnCl2·TMEDA and then deprotonated with LiTMP, where zinc salts would trap the resulting lithium pyridine intermediate in situ.

Figure 18. Selected examples of azine functionalization.

Not only organometallic base but also organic base can deprotonate azines (Figure 19).273 Kondo and co-workers reported that the bulky organic base tBu-P4 abstracted the acidic proton of azine rings, which were then reacted with ketones.

Scheme 30. C−H Abstraction of Pyridyl Ketone

5. METAL-CATALYZED C−H FUNCTIONALIZATION OF AZINES274−282 5.1. Azines with Electron-Withdrawing Groups

A pioneering work on C−H functionalization of perfluorinated arenes was carried out by Fagnou and co-workers in 2006.283 2,3,5,6-Tetrafluoropyridine was reacted with p-bromotoluene under palladium catalysis to give the corresponding C−H arylation product in a high yield (Scheme 32). The reaction is significant because it does not require pre-deprotonation of the azine ring, so that arylated azines can be formed through a direct transformation. Mechanistically, the carbonate on the palladium abstracts a proton from the fluoropyridine via a concerted metalation−deprotonation (CMD) pathway (Scheme 33). Fagnou and co-workers reported room-temper-

Flow chemistry249−252 enables the magnesiation of azines with TMPMgCl·LiCl (Scheme 31).253−256 Under batch conditions, TMPMgCl·LiCl can abstract the proton in the 2position within 2 h at −40 °C. Unproductive decomposition through oligomerization is observed under higher reaction temperatures. However, continuous flow metalation can be used for rapid deprotonation within 30 s to give the corresponding pyridylmagnesium prior to decomposition, 9310


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Scheme 34. Room-Temperature Direct Arylation of Multifluorinated Pyridines

35).285 Do and Daugulis reported the direct arylation of (multi)fluorinated arenes under copper catalysis (Scheme 36).286 Scheme 35. Direct Arylation of Multifluorinated Pyridines on Water

Figure 19. Selected examples of azine functionalization.

Scheme 32. Direct Arylation of Multifluorinated Arenes, Including Fluorinated Pyridines

Scheme 33. Mechanism for Direct Arylation of Multifluorinated Arenes

Scheme 36. Copper-Catalyzed Direct Arylation of Fluorinated Pyridines

ature C−H arylation. Although the underlying reason is not clear, biphasic conditions (ethyl acetate/H2O = 2.5:1) improved the efficiency of the direct arylation of polyfluorinated arenes (Scheme 34).284 In 2012, Zhang and co-workers reported the direct arylation of polyfluoroarenes on water; notably, a reaction temperature of 70 °C was required (Scheme

In the presence of a bulky alkylphosphine ligand, 1 equiv of pyridine with an electron-withdrawing group (EWG) such as nitro, cyano, fluoro, or chloro can be arylated with aryl bromide (Figure 20).287 The reaction takes place at the C3-position (EWG on C4) or C4-position (EWG on C3). Palladation takes place at the protons adjacent to the EWGs because the EWG increases the acidity of the hydrogen atom. The coordination of the lone pair of nitrogen to a Lewis acid disfavors palladation at the C2-position. Several examples of the olefination of perfluoropyridines have been reported.288−290 Treatment of tetrafluoropyridine with alkenes in the presence of a palladium catalyst and silver carbonate as an oxidant affords the corresponding C−H alkenylation products (Scheme 37). Oxidative arylation reactions of tetrafluoropyridine with heteroarenes (Scheme 38)291 or with arylboronic acids 9311


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co-workers.293 The reaction utilized oxygen as an oxidant (Scheme 40). Scheme 40. Copper-Catalyzed Alkynylation with Terminal Alkynes

An interesting approach to copper-catalyzed oxidative arylation was reported by Do and Daugulis (Figure 21).294

Figure 20. Palladium-catalyzed arylation of pyridine with electronwithdrawing groups.

Scheme 37. Palladium-Catalyzed Olefination of Perfluoropyridines

Figure 21. Copper-catalyzed arene cross-dimerization.

They mix two heteroarenes in the presence of a catalytic amount of copper salt with iodine. In the reaction system, more reactive heteroarene (red) reacts with iodine to give the corresponding iodoarene, which then reacts with the other heteroarene (blue) to give the product. Nakao, Hiyama, and their co-workers reported the alkenylation of fluoropyridines with alkynes under nickel catalysis (Scheme 41).295 Mechanistically, the oxidative

Scheme 38. Palladium-Catalyzed Arylation with Heteroarenes

Scheme 41. Nickel-Catalyzed Alkenylation of Fluoropyridines

(Scheme 39)292 were reported. Silver carbonate was effective for these reactions. Copper-catalyzed alkynylation of polyfluoroarenes or polychloroarenes was reported by Hong and Scheme 39. Palladium-Catalyzed Arylation with Arylboronic Acids

addition of the C−H bond of fluoropyridine affords the arylnickel intermediate, which reacts with alkyne to give the alkenylnickel species. Finally, reductive elimination proceeds to provide the product. 5.2. Azines without Directing Groups

In this section, we present metal-catalyzed C−H functionalization reactions with a focus on the employed metal. The metalcatalyzed C−H functionalization of unactivated azines without 9312


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Table 1. Summary of Regioselectivity of Metal-Catalyzed Reactions of Azines

directing groups through nonradical pathways is described here. The regioselectivity of the metal-catalyzed reactions is summarized in Table 1. Most metals have inherent reactivities toward specific positions of the azine core. Notably, the regioselectivity of reactions catalyzed by group 10 metals can be controlled by the catalyst or reaction conditions. 5.2.1. Reactions of Azines Catalyzed by Group 3 and 4 Metals. A variety of studies using group 3 and 4 metals on the ortho-metalation of pyridine have been reported since the 1980s (Sc,296,297 Y,298−304 lanthanides,305,306 Ti,307−309 Zr,310−321). Jordan and co-workers carried out pioneering work on the cationic zirconium metallocene catalyzed reaction of propene and 2-methylpyridine (Scheme 42).322−325 In 2011, Guan and

Scheme 44. Scandium-Catalyzed Reaction of Pyridine with Allenes

corresponding chiral half-sandwich rare-earth dialkyl complexes (Scheme 45). Among the viable catalysts, ligands with triisopropylsiloxy moieties [R = OSi(iPr3)3] show the highest enantioselectivity (Scheme 46).329

Scheme 42. Zirconium-Catalyzed Reaction of Propene with 2-Methylpyridine

Scheme 45. Preparation of Chiral Scandium Complexes

Hou revealed that rare-earth metals could catalyze the reaction of pyridine with olefins via the o-C−H activation of pyridines (Scheme 43).326 The scope of the reaction includes a variety of Scheme 43. Rare-Earth-Catalyzed Reaction of Pyridine with Olefins

Scheme 46. Enantioselective C−H Bond Addition of Pyridines to Alkenes

substituted pyridines as well as olefins. Mechanistic studies based on DFT calculations revealed that the coordination of pyridine is more favorable than that of olefins, which suppresses the undesirable olefin polymerization pathway.327 Modified scandium complexes are suitable catalysts for the reaction of pyridine with allenes, which furnish the corresponding alkenylpyridines (Scheme 44).328 The alkylation was then extended to the asymmetric version. The complexation of rareearth metals with chiral cyclopentadiene ligands affords the

Group 3 metal triamido complexes can catalyze the reaction of pyridines with imines (Scheme 47).330 This reaction is initiated by the coordination of pyridine to the catalyst (Figure 22). Abstraction of the o-hydrogen atom of the pyridine ring with an amidometal moiety affords the corresponding pyridylmetal intermediate. The resulting pyridylmetal then reacts with the imine to give the product. Through a similar mechanism, yttrium catalyzes the synthesis of 2,2′-bipyridines via a nucleophilic pyridylmetal intermediate.331 Urabe and co-workers reported the interesting example of C4-alkylation with a yttrium reagent (Scheme 48).332 The 9313


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Scheme 47. Group 3 Metal Triamido Complex Catalyzed Reaction of Pyridines with Imines

Figure 23. Scope of chromium-catalyzed C4-selective alkylation of pyridines. Figure 22. Proposed mechanism for group 3 metal triamido complex catalyzed reaction of pyridines with imines.

Scheme 48. C4-Alkylation of Pyridine with Yttrium Reagent

combination of styrene derivatives with a mixture of yttrium chloride, butyllithium, and DIBAL-H provides a benzylmetal species, which reacted with pyridine at the C4-position. 5.2.2. Reactions of Azines Catalyzed by a Group 6 Metal. The chromium-catalyzed C4-selective alkylation of pyridines was disclosed in 2016 (Figure 23).333 The treatment of pyridine with styrene in the presence of a chromium catalyst and cyclohexylmagnesium reagent affords C4-alkylated pyridines. Branched products are exclusively obtained and linear products are not observed. The reaction mechanism is unclear at present. 5.2.3. Reactions of Azines Catalyzed by Group 8 Metals. Iron catalyzes the C2-arylation of pyridine with arylboronic acid (Figure 24).334 Although the mechanism is unclear at present, Hu, Yu, and their co-workers claim that the reaction does not proceed through a radical pathway, because the reaction is not affected by the addition of radical scavengers. It is well-known that metal cluster complexes and group 8 metals can abstract the o-hydrogen atoms of pyridines.335−340 In 1992, Moore and co-workers reported the acylation of pyridines at the C2-position under ruthenium cluster catalysis (Scheme 49).341−343 Suzuki and co-workers reported the catalytic dehydrogenative dimerization of pyridine (Figure 25).344,345 A variety of substituents in the 4-position, such as methyl, methoxy, dimethylamino, and ethoxycarbonyl groups, are tolerated.

Figure 24. Iron-catalyzed reaction of pyridine with arylboronic acid.

Scheme 49. Ruthenium-Catalyzed Acylation of Pyridines

The use of the ruthenium cluster is required to activate the C2-position of pyridines. Murakami and Hori reported the ruthenium-catalyzed alkenylation of pyridines (Figure 26).346,347 The reaction of trimethylsilylacetylene with ruthenium affords the corresponding ruthenium vinylidene complex, which attacks pyridine. 5.2.4. Reactions of Azines Catalyzed by Group 9 Metals. In 2014, Chirik and co-workers reported the cobaltcatalyzed borylation of pyridines at the 2- or 4-position (Figure 9314


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shown in Scheme 50. The metal hydride complex reacts with alkenes to form the corresponding alkylmetal intermediates. Scheme 50. Working Hypothesis for C4-Selective Alkylation

The alkylmetal then attacks the C4-position of pyridine to afford the dihydropyridine intermediate. Finally, the metal hydride is regenerated by the rearomatization step, which gives the final product. The reaction displays higher branched selectivity when styrene derivatives are used as alkylating reagents (Figure 28). The reactions with aliphatic alkenes afford the corresponding linear products. The reaction is reliable enough to perform on a large scale (Scheme 51).

Figure 25. Ruthenium-catalyzed dehydrogenative dimerization of pyridine.

Figure 26. Ruthenium-catalyzed alkenylation of pyridine.

27).348 The reaction favorably takes place at the C4-position when C2-substituted pyridines are employed as substrates. On the other hand, C2-borylation occurs with 2,4-disubstituted pyridines. Kanai, Matsunaga, and their co-workers reported a catalytic nucleophilic addition/rearomatization for the C4-selective alkylation of pyridines.349,350 Their working hypothesis is

Figure 28. Selected scope of cobalt-catalyzed C4-alkylation.

Scheme 51. Large-Scale Synthesis of C-4 Alkylated Pyridines

Figure 27. Cobalt-catalyzed borylation of pyridines. 9315


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Bergman, Ellman, and their co-workers carried out pioneering works on the C−H alkylation of quinazoline in the presence of a rhodium catalyst.351 Unfortunately, the reaction is limited to alkylation and arylation does not take place under the reaction conditions.352 In order to extend their chemistry, they studied the reaction mechanism and isolated two intermediates (Scheme 52).353 Inspired by the study of the Carmona354 and Scheme 52. C−H Activation of Quinazoline by a Rhodium Catalyst

Figure 29. C−H borylation as a key step in the total synthesis of complanadine A.

355

groups, in which C2−H bonds of pyridine or Esteruelas quinoline were activated with iridium or osmium, Bergman, Ellman, and their co-workers worked on the C2−H functionalization of pyridines and quinolines. As a result, they found that pyridine could be alkylated with alkenes in the presence of a catalytic amount of [RhCl(coe)2]2 and PCy3 (Scheme 53).356 The reaction is applicable to intramolecular ring-closing reactions.357 Finally, they developed rhodiumcatalyzed C2-arylation of pyridines with aryl bromides (Scheme 54).358

Scheme 56. Iridium-Catalyzed C−H Borylation of 2,6Disubstituted Pyridine

Scheme 57. Iridium-Catalyzed Reaction of Pyridines with Aldehydes Promoted by Triethylsilane

Scheme 53. Rhodium-Catalyzed C2-Alkylation of Pyridines

Scheme 54. Rhodium-Catalyzed C2-Arylation of Pyridines silyliridium species. Oxidative addition of the C3−H of pyridine to silyliridium affords pyridyliridium, which should act as a nucleophile and attack the aldehyde; subsequent reductive elimination furnishes the product. Cheng and Hartwig disclosed the iridium-catalyzed C−H silylation of arenes.372 The scope of the reaction is wide enough to cover a variety of arenes, including azines. The reaction takes place at the β-position of the azine nitrogen (Figure 31). 5.2.5. Reactions of Azines Catalyzed by Group 10 Metals. Nakao, Hiyama, and their co-worker reported a nickel/ Lewis acid-cocatalyzed reaction of pyridine with alkynes (Figure 32).373 In the presence of diphenylzinc as a Lewis acid, alkenylpyridines are obtained. The proposed mechanism is shown in Figure 33. Pyridine is activated by a Lewis acid, which oxidatively adds to nickel(0). Hydronickelation takes place with the alkyne to give the corresponding alkenylnickel, which finally furnishes the product through reductive elimination. A similar catalytic system can be applied to alkenylate triazolopyridines at the C7-position.374 The regioselectivity can be altered to induce C4-selectivity when bulky Lewis acids are utilized as cocatalysts (Scheme 58).375 Owing to the bulkiness of methylaluminum bis(2,6-ditert-butyl-4-methylphenoxide (MAD), oxidative addition to nickel occurs at the C4-position of pyridine, which affords the corresponding product (Figure 34). Ong and co-workers also reported the C4-alkylation, in which the product can be

Iridium-catalyzed C−H borylation preferentially occurs at the C3-position of pyridines, rather than the C4-position (Scheme 55).359−366 Notably, the pyridine borylation methodScheme 55. Iridium-Catalyzed C−H Borylation of Pyridine

ology was utilized in the total synthesis of complanadine A by Fischer and Sarpong (Figure 29).367 When 2,6-disubstitued pyridines were employed as a substrate, C4-positions were borylated under iridium catalysis (Scheme 56).368−370 Similar to the reactivity of boryliridium, silyliridium activates the C3-position of pyridines. Li and Shi reported an iridiumcatalyzed reaction of pyridines with aldehydes (Scheme 57).371 The reaction mechanism is proposed in Figure 30. Iridium reacts with triethylsilane to generate the corresponding 9316


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Figure 32. Nickel/Lewis acid-cocatalyzed reaction of pyridine with alkynes.

Figure 33. Proposed mechanism for nickel/Lewis acid-cocatalyzed reaction of pyridine with alkynes.

Figure 30. Proposed mechanism for iridium-catalyzed reaction of pyridines with aldehydes.

Scheme 58. Nickel-Catalyzed C4-Alkylation of Pyridines

Figure 31. Iridium-catalyzed C−H silylation of pyridine.

switched by the ligand (Figure 35).376,377 Alkenylation was also reported by Ong and co-workers (Scheme 59).378 A unique arylation of azines was reported by Tobisu, Chatani, and their co-worker.379,380 Treatment of pyridine with diarylzinc reagents in the presence of catalytic amounts of nickel and a phosphine ligand affords C2-arylated pyridines (Scheme 60). The key intermediate of the reaction is 2aryldihydropyridine, which aromatizes to give the product (Figure 36). Their approach is also applicable for the C4arylation of acridine (Scheme 61).381

Figure 34. Proposed mechanism for regioselective alkylation of pyridines.

Cross-dehydrogenative coupling (CDC) between pyridine and heteroarenes at the C2-position of pyridine was 9317


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Figure 36. Proposed mechanism for nickel-catalyzed C2-arylation of pyridine with diarylzinc reagent.

Scheme 61. Nickel-Catalyzed C4-Arylation of Acridine

Scheme 62. Palladium-Catalyzed CDC between Pyridine and Heteroarenes

Figure 35. Nickel-catalyzed C4-alkylation of pyridines.

Scheme 59. Nickel-Catalyzed C4-Alkenylation of Pyridines

palladium can catalyze the alkenylation of pyridine at the C2position (Scheme 64).384 Scheme 63. CDC between Quinoline and Chloroarene

Scheme 60. Nickel-Catalyzed C2-Arylation of Pyridine with Diarylzinc Reagent Weix and co-workers disclosed that 2,2′-bipyridine or 2,2′:6′,2″-terpyridines could be synthesized by the oxidative coupling of 4-substituted pyridines (Scheme 65).385 The reaction is catalyzed by Pd/C with MnO2 as an oxidant. This Scheme 64. C2-Alkenylation of Pyridine accomplished by You and co-workers (Scheme 62).382 The reaction shows high functional group compatibility, as carbonyl, nitro, chloro, cyano, and hydroxy groups are tolerated under the reaction conditions. The C2-selective CDC reaction also proceeds between chloroarene and quinoline under palladium catalysis (Scheme 63).383 Under similar reaction conditions, 9318


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is a useful method since the reagents are readily available and the reaction is scalable. Scheme 65. Palladium-Catalyzed Synthesis of 2,2′Bipyridines or 2,2′:6′,2″-Terpyridines

Palladium is a unique transition metal that can be used for the selective functionalization of the C3- and C2-position of azines in a regiodivergent fashion. Itami and co-workers utilized organic halides as regioswitching oxidants for the CDC reaction (Figure 37).386 The CDC between pyridine and benzoxazole proceeds with C3 selectivity when MesBr is utilized as an oxidant, whereas the C2-selective reaction takes place when BnBr is used.

Figure 39. C3-Alkenylation of pyridine.

Scheme 66. KIE in C3-Alkenylation of Pyridines

Scheme 67. C3-Alkenylation of Pyridine Using Amino Acids as Ligands Figure 37. Palladium-catalyzed regiodivergent CDC reaction.

A pioneering C3-functionalization was accomplished by Yu and co-workers, who postulated that the low reactivity of the pyridyl ring was attributed to the strong coordination of the pyridine N atom to the catalyst. Therefore, his group envisioned that the addition of a bidentate nitrogen-based ligand could enhance the ligand exchange to form an active intermediate, in which the pyridine ring coordinates to the Pd center using π-electrons (Figure 38).387 Accordingly, they

acetate with 1,10-phenanthroline was critical. Notably, the reaction proceeds with a variety of aryl halides and azines with high C3-selectivity (Figure 40). KIE experiments were carried out in order to elucidate the reaction mechanism (Scheme 68). A significant isotope effect indicated that electrophilic palladation may not be operative. The proposed mechanism is shown in Figure 41, in which the C3-selectivity is explained as a trans-effect (Figure 38). The pyridine arylation of Yu and co-workers can be applied for the reaction with aryl tosylates (Scheme 69)390 or triflates (Scheme 70).391 In 2016, Yu and co-workers reported the oxidative arylation of pyridine to afford various 3,3′-bipyridines and 3-arylpyridines (Figure 42).392 The reaction mechanism is similar to that proposed in Figure 36. C3-Arylation of quinolines with chloroarenes was accomplished by Huang and co-workers (Scheme 71).393 A variety of functional groups, such as nitro, methoxy, and methoxycarbonyl groups, are tolerated. The scope of azines is limited to quinolines and pyridine (Scheme 72).

Figure 38. Generation of reactive precursor via a trans-effect for the C3-functionalization of pyridines.

utilized 1,10-phenanthroline as a ligand to install olefins in the C3-position of pyridine (Figure 39). KIE experiments showed that the C−H bond cleavage was the rate-limiting step of the reaction (Scheme 66). Wu, Zeng, and their co-workers reported that amino-acid ligands were effective for the C3-alkenylation of pyridines (Scheme 67).388 C3-Arylation of pyridine with aryl halides was reported in 2011 by Yu and co-workers.389 The combination of palladium 9319


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Scheme 69. C3-Arylation of Pyridines with Aryl Tosylates

Scheme 70. C3-Arylation of Pyridines with Aryl Triflates

Figure 40. C3-Arylation of pyridine with aryl halides.

Scheme 68. KIE in C3-Arylation of Azines with Aryl Halides

Figure 42. Palladium-catalyzed arylation of pyridine with (hetero)arenes.

Scheme 71. C3-Arylation of Quinoline with Chlorobenzenes

Scheme 72. C3-Arylation of Pyridine with 1,2,3,4Tetrachlorobenzene

Scheme 73. Imidazo[1,2-a]pyridine Synthesis Catalyzed by Copper

Figure 41. Proposed mechanism for C3-arylation of pyridines with aryl halides.

5.2.6. Reactions of Azines Catalyzed by a Group 11 Metal. The copper-catalyzed synthesis of imidazopyridines was reported by Jiang and co-workers (Scheme 73).394 On the basis of the KIE experiments (KIE value = 1.0), C−H cleavage was determined not to be the rate-determining step (Scheme 74). 9320


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*K.I. e-mail: [email protected].

Similar copper-catalyzed395−397 or noncatalyzed398,399 annulation reactions of azines were also reported.

ORCID

Scheme 74. KIE in the Copper-Catalyzed Synthesis of Imidazopyridines

Kei Murakami: 0000-0001-5405-3069 Kenichiro Itami: 0000-0001-5227-7894 Author Contributions

The manuscript was written through contributions of all authors. All authors have approved the final version of the manuscript. Notes

The authors declare no competing financial interest. Biographies Kei Murakami received his Ph.D. degree from Kyoto University in 2012. After his JSPS postdoctoral fellowship, he started his academic career at the Hakubi Center for Advanced Research/Department of Chemistry, Graduate School of Science, Kyoto University. He moved to the Graduate School of Science of Nagoya University as an assistant professor in 2014 and became an associate professor in 2016. His research focuses on the development of new metal-catalyzed reactions for making novel functional/bioactive molecules.

Following several reports on the C−H/N−H-type dehydrogenative coupling of azine N-oxides with amines,400−402 the Cucatalyzed reaction of quinolines with azoles was reported (Scheme 75).403 Scheme 75. Copper-Catalyzed Reaction of Quinoline with Azoles

Shuya Yamada was born in Tokyo, Japan, in 1992. He received his B.S. (2015) and M.S. (2017) degrees in chemistry from Nagoya University. Currently, he is a graduate student in the group of Kenichiro Itami at Nagoya University, and is working with Kei Murakami as his cosupervisor focusing on the development of new efficient reactions for C−H functionalization of pyridine. Takeshi Kaneda received his B.S. degree in bioengineering from Tokyo Institute of Technology in 2002 and his M.S. degree from there in 2004. In 2004, he joined Daiichi Pharmaceutical as a process chemist. He moved to Daiichi Sankyo in 2007, which was established through the merger of Daiichi Pharmaceutical and Sankyo. His current research focuses on the design and implementation of practical synthetic methodologies for the synthesis of active pharmaceutical ingredients.

6. SUMMARY In this review, we summarized recent advances in the direct C− H functionalization of azines. Classical SNAr, radical, or deprotonation reactions are powerful methods to install various functional groups on azine rings. These methods allow for the functionalization of unreactive, simple azines as well as complex bioactive molecules. The reaction site of these reactions is predictable because the reactivity depends on the inherent electronic nature of the azine ring. However, in other words, these approaches could not change the regioselectivity at will. Compared with these reactions, the regioselectivity of the metal-catalyzed reaction is not strongly influenced by the substituents, and therefore, it is possible to change the regioselectivity by tuning the catalyst or reaction conditions. As summarized in Table 1, several reports on regioswitching reactions using group 10 metal catalysts have been already accomplished. However, the coordinative nature of the nitrogen in the azine ring and electron-deficient nature lowers the reactivity of the azine rings toward catalytic transformation. The scope of these emerging catalytic C−H functionalization methods is therefore limited and there is plenty of room for improvement for practical use. The development of novel C−H functionalization reactions of azines under mild conditions with a broad scope, high functional group compatibility, and perfect regioselectivity is needed to accelerate the production of azinebased functional molecules via C−H functionalization.

Kenichiro Itami was born in 1971 and raised in Tokyo. He studied chemistry at Kyoto University and completed his Ph.D. in 1998 with Prof. Yoshihiko Ito. He became an assistant professor at Kyoto University and then moved to Nagoya University as an associate professor in 2005 and was promoted to full professor in 2008. He has also held the post of director of the Institute of Transformative BioMolecules (ITbM) since 2012 and research director of the JSTERATO Itami Molecular Nanocarbon Project since 2013. His research focuses on the development of innovative functional molecules with significant structures and properties and the development of rapid molecular-assembly methods using unique catalysts.

ACKNOWLEDGMENTS This work was supported by JST ERATO Grant Numbers JPMJER1302, Japan (K.I.) and JSPS KAKENHI Grant Number JP26888007 (K.M.). ITbM is supported by the World Premier International Research Center Initiative (WPI), Japan. REFERENCES (1) Knoevenagel, E. 1,5-Diketone. Justus Liebigs Ann. Chem. 1894, 281, 25−126. (2) Allais, C.; Grassot, J.-M.; Rodriguez, J.; Constantieux, T. MetalFree Multicomponent Syntheses of Pyridines. Chem. Rev. 2014, 114, 10829−10868. (3) Hill, M. D. Recent Strategies for the Synthesis of Pyridine Derivatives. Chem. - Eur. J. 2010, 16, 12052−12062.

AUTHOR INFORMATION Corresponding Authors

*K.M. e-mail: [email protected]. 9321


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