Radical Cross-Coupling

Review pubs.acs.org/CR

Recent Advances in Radical C−H Activation/Radical Cross-Coupling Hong Yi,† Guoting Zhang,† Huamin Wang,† Zhiyuan Huang,† Jue Wang,† Atul K. Singh,† and Aiwen Lei*,†,‡ †

College of Chemistry and Molecular Sciences, The Institute for Advanced Studies (IAS), Wuhan University, Wuhan, Hubei 430072, China ‡ National Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330022, China ABSTRACT: Research and industrial interest in radical C−H activation/radical crosscoupling chemistry has continuously grown over the past few decades. These reactions offer fascinating and unconventional approaches toward connecting molecular fragments with high atom- and step-economy that are often complementary to traditional methods. Success in this area of research was made possible through the development of photocatalysis and first-row transition metal catalysis along with the use of peroxides as radical initiators. This Review provides a brief and concise overview of the current status and latest methodologies using radicals or radical cations as key intermediates produced via radical C−H activation. This Review includes radical addition, radical cascade cyclization, radical/radical cross-coupling, coupling of radicals with M−R groups, and coupling of radical cations with nucleophiles (Nu).

CONTENTS 1. Introduction 2. Radical Addition 2.1. Radical Addition to CC Double Bonds 2.1.1. Radical Alkylation 2.1.2. Radical Alkenylation 2.1.3. Radical Difunctionalizations of Alkenes 2.2. Radical Addition to Carbon−Carbon Triple Bonds 2.3. Radical Addition to NN Bonds 2.4. Radical Addition to Aromatic Arenes 3. Radical Cyclization 3.1. Radical Cascade Cyclization 3.1.1. Radical Cyclization with Acrylamides 3.1.2. Radical Cyclization with Isonitriles 3.1.3. Radical Cyclization with Alkyne Derivatives 3.1.4. Others 3.2. Radical Cyclization Using Carbonyl Compounds 3.2.1. Synthesis of Dihydrofuran Derivatives 3.2.2. Synthesis of Furan, Pyrrole, and Indolizine Derivatives 3.2.3. Synthesis of Other Rings 3.3. Radical Cyclization with Phenol Compounds 3.4. Intramolecular Radical Cyclization 4. Radical−Radical Cross-Coupling 4.1. Carbon Radical/Carbon Radical Cross-Coupling 4.1.1. C(sp3)−C(sp2) Bond Formation 4.1.2. C(sp3)−C(sp3) Bond Formation 4.1.3. C(sp3)−C(sp) Bond Formation 4.2. Carbon Radical/Nitrogen Radical Cross-Coupling

4.3. Carbon Radical/Oxygen Radical Cross-Coupling 4.4. Carbon Radical/Sulfur Radical Cross-Coupling 4.5. Carbon Radical/Phosphonyl Radical CrossCoupling 5. Coupling of Radicals and M−R Groups 5.1. Coupling of Radicals with Pd−R Groups 5.1.1. Nitrogen Heterocyclic Rings as Directing Groups 5.1.2. Ketone Oxime Ethers as the Directing Groups 5.1.3. Anilides as Directing Groups 5.1.4. Azoxy Groups as Directing Groups 5.1.5. Amides as Directing Groups 5.1.6. Other Directing Groups 5.2. Coupling of Radicals with Cu−R Groups 5.2.1. C−N Bond Formation 5.2.2. C−O Bond Formation 5.2.3. C−C Bond Formation 5.3. Coupling of Radicals with M(Ni, Mn, Ag, Fe)− R Groups 5.3.1. Radical/Ni−R 5.3.2. Radical/Mn−R 5.4. Cross-Coupling of Radicals and Fe−R Groups 5.5. Cross-Coupling of Radicals with I−R Groups 5.6. Coupling of Radicals with N−F Groups 6. Radical Coupling of Radical Cation/Nucleophiles 6.1. Radical Cation Formation via Photoredox Catalysis

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Special Issue: CH Activation

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Received: September 8, 2016 Published: June 22, 2017 © 2017 American Chemical Society

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DOI: 10.1021/acs.chemrev.6b00620 Chem. Rev. 2017, 117, 9016−9085

Chemical Reviews 6.2. Radical Cation Formation via Electrochemical Oxidation 6.3. Radical Cation Formation via Traditional Oxidation 7. Outlook and Challenges Author Information Corresponding Author ORCID Notes Biographies Acknowledgments Abbreviations References

Review

electron to generate a cation intermediate. One important branch of C−H bond functionalization is the generation of a carbocation intermediate by losing two electrons via radical C− H activation, which will then react with another nucleophile.11,12 C−H bond functionalization based on carbocation intermediates is another type of radical C−H bond activation, but is not extensively discussed in this Review. Radicals and radical cations are active intermediates and have a range of properties and reactivities,13 for example, nucleophilicity, electrophilicity, hydrogen abstraction reactions, and selfcoupling reactions; a variety of C−H activation reactions via radical processes have been developed recently. This Review aims to define the state-of-the-art of the rapidly expanding area of research on radical C−H bond activation. Specifically, recent advances in C−X bond formation utilizing C−H bond functionalization of C−H compounds have been highlighted, with an emphasis on their scope, limitations, and underlying mechanisms. This Review focuses on the key intermediates

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1. INTRODUCTION Direct C−H functionalization has been recognized as a reliable method to construct complex molecules due to its high step- and atom-economy as well as the readily available starting materials.1 In recent decades, intensive research efforts have led to the development of various reaction conditions for challenging C−H bond functionalizations, among which transition-metal-catalyzed transformations arguably constitute thus far the most valuable tool.2−4 Palladium catalysis dominates this research area for achieving various chemical bond formations between two nucleophiles. In terms of the mechanistic aspects of palladium catalysis in oxidative cross-couplings, a general catalytic cycle was determined in which reductive elimination is usually the key step for the final bond formations. Most palladium-catalyzed processes are not thought to be radical processes. While new reports of C−H bond functionalization using late transition metals continue to emerge, growing concerns regarding their toxicity and cost-effectiveness have prompted interest in the use of cheap, benign, and readily available first-row metals such as Fe and Cu.5,6 Along with the development of oxidative crosscouplings, more first-row transition metal catalysis has been discovered in which single-electron transfer (SET) processes usually dominate. Direct C−H bond functionalization via a radical pathway has emerged as a promising approach toward molecular construction with high atom- and step-economy. In transition-metal-catalyzed C−H functionalization reactions, C−M (Pd, Rh, Ru, etc.) species are believed to be formed, serving as the key intermediates in coupling reactions that have already been discussed by several reviews.7−9 By this model, direct C−H bond activation by transition metals has been a useful and powerful route in organic synthesis. Another type of C−H bond activation via the loss of one proton with one electron, simultaneously forming a radical, is involved in singleelectron transfer processes.10 The radical and radical cation can serve as key intermediates in C−H functionalization (Scheme 1). The radical can also go through further oxidation and loss of one

Scheme 2. Representative Reaction Types of Radical C−H Activation

(radicals or radical cations) produced via radical C−H activation. The main achievements in the field have been categorized according to the representative types of reactions (Scheme 2), including radical additions, radical cascade cyclizations, radical/ radical cross-coupling reactions, radical coupling of radicals with M−R groups, and radical coupling of radical cations with nucleophiles. This Review is concluded with a discussion of the likely directions of future research.

2. RADICAL ADDITION 2.1. Radical Addition to CC Double Bonds

The addition of radicals to unsaturated bonds is a well-known process in radical chemistry.13 However, radical addition to alkenes usually results in reductive addition or difunctionalization because there is a lack of elimination protocols. Recent achievements have also revealed that the carbon radical intermediate generated from radical addition can go through a SET oxidation/elimination step to recover the alkenyl functionality. In this part, we divide the radical addition to carbon−carbon double bonds into three parts (Scheme 3):

Scheme 1. C−H Activation via a Single-Electron Transfer Pathway

Scheme 3. Radical Addition to Alkenes

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radical alkylation (section 2.1.1), radical alkenylation (section 2.1.2), and radical difunctionalizations of alkenes (section 2.1.3). 2.1.1. Radical Alkylation. Aldehydes exist extensively in nature and serve as key intermediates in organic synthesis. Traditionally, acyl hydrazides, acyl hydrazines, thiol esters, and others have been used as radical precursors to generate the acyl radicals.14−16 However, a significant synthetic breakthrough would be the development of an easy method for the generation of acyl radicals directly from the corresponding aldehydes. Considering this, photocatalysis would be a good way to solve this problem. In 2007, Fagnoni and co-workers reported the photocatalytic activation of aldehyde 1, which provided an easy

Scheme 5. Acylation of Electrophilic Olefins Using Aromatic Aldehydes

Scheme 6. Direct Acylation of C60

Scheme 4. Acylation of Electrophilic Olefins through Activation of Aldehydesa

a

Fullerenes (such as C60) have a special double bond and show high reactivity with radicals.20 Orfanopoulos and co-workers successfully developed a straightforward method for the direct acylation of C60 (8) (Scheme 6).21 After a solution of C60 was irradiated with 100 equiv of benzaldehyde and 0.2 equiv of TBADT in a mixture of chlorobenzene/CH3CN (85:15), using a 300 W xenon lamp, alkyl aldehydes and allylic aldehydes were transformed into the desired products 9 smoothly. This method opens a new route to a wide variety of previously unexplored fullerene-based materials. The cleavage of the C(sp3)−H bond adjacent to oxygen can easily proceed in the presence of an oxidant. Tu and co-workers reported an iron-catalyzed cross-coupling reaction of alcohols 10 with alkenes 11, providing an efficient method for the synthesis of the substituted alcohols 12.22 Experimental results indicated that the pathway of this iron-catalyzed cross-coupling reaction was quite different from the “oxidation/hydroacylation/reduction” or “transfer hydrogenative coupling” processes. A possible homolysis of the C−H bond at the α position of alcohols

P: (nBu4N)4[W10O32] (photocatalyst).

method to access acyl radicals from aldehydes, and trapped them with equimolar amounts of electrophilic alkenes 2 to afford the unsymmetrical ketones 3 in moderate to good yields (Scheme 4).17 The utilization of low amounts of tetrabutylammonium decatungstate (TBADT) (2 mol %) as photocatalyst and equimolar amounts of the reagents makes this protocol not only an atom-economical route for the syntheses of ketones, but also represents a new “green” synthetic method. The mechanism of this reaction involves hydrogen abstraction from aldehyde 1 by excited TBADT (P*) to form acyl radical 4, which then adds to the alkene 2 to produce radical intermediate 5. The product was formed via the back-hydrogen-transfer of adduct radical 5. Recently, Maruoka and co-workers have achieved a diastereoselective radical hydroacylation of olefins with aliphatic aldehydes in combination with a hypervalent iodine(III) reagent and UV light irradiation.18 Fagnoni and co-workers demonstrated that the same system could be used for aromatic aldehyde activation. Moderate to good yields of several β-functionalized aryl alkyl ketones 7 were obtained by irradiation of aromatic aldehydes 6 and electrondeficient olefins in MeCN at 310 or 366 nm using TBADT as a photocatalyst (Scheme 5).19 Because of the mild reaction conditions, the method had a wide tolerance for aromatic aldehydes.

Scheme 7. Iron-Catalyzed Cross-Coupling of Alcohols with Alkenes

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catalyzed by iron is proposed in Scheme 7. The key step was the electron transfer between the alcohol and iron species via the key intermediate 13.

Toluene, a readily available alkylarene, has been used as a versatile building block, the C−H bonds of which can also be Scheme 11. Et3B-Mediated Radical Addition to Dimethyl Fumarate

Scheme 8. Photocatalyzed Activation of 1,3-Benzodioxoles

The next contributions to the C(sp3)−H activation of ethers came from Fagnoni and co-workers in 2011. A photocatalyzed activation of 1,3-benzodioxole derivatives (14) was achieved in the presence of tetrabutylammonium decatungstate (TBADT) (Scheme 8).23 This protocol presented a mild and general method for the synthesis of potentially bioactive 2-substituted-

activated via a radical process.27 In 2011, Miyata and co-workers demonstrated the direct generation of a benzyl radical via C−H bond activation of toluene derivatives, and the radical was successfully added to an electron-deficient olefin (Scheme 11).28 Mechanistic investigations revealed that the first step involves the generation of an ethoxy radical or an ethylperoxy radical via the oxidation of Et3B by molecular oxygen. The corresponding radical abstracts a hydrogen atom from toluene derivatives to produce benzyl radical 21, followed by addition to dimethyl fumarate 19, forming the α-carbonyl radical 22. The radical 22 is trapped by toluene derivatives to give product 20 and regenerates the benzyl radical. Later, Nishibayashi and co-workers demonstrated a visiblelight-mediated C(sp3)−H activation of amines with electrondeficient alkenes 23 using the transition metal polypyridyl complex 24 as the photocatalyst (Scheme 12).29 A variety of amines could be activated to the corresponding radical species and then added to electron-deficient alkenes. The dialkylarylamines and diisopropylmethylamines were applicable, giving the corresponding amines alkylated at the methyl group in high yields. A radical clock experiment supported the intermediacy of alkyl radicals in this transformation (Scheme 13). In 2014, MacMillan and co-workers demonstrated a direct βalkylation of saturated aldehydes with Michael acceptors, merging organocatalysis and photoredox catalysis (Scheme 14).30 This C−H bond activation method is entirely redoxneutral and atom-economical, and requires no preactivation of either coupling partner. Notably, aryl substituents at the αposition of acrylate olefins and various aliphatic aldehydes showed high reactivity with good yields and high efficiency. Importantly, β-amino aldehydes were competent substrates for the formation of stereogenic amines with good levels of reaction efficiency. Considering the low bond dissociation energy (BDE) of alkyl nitriles,31 the cleavage of the α-C−H bond of an alkyl nitrile to form a radical intermediate would occur prior to other sp3 C−H bonds. In 2015, Liu and co-workers reported a radical antiMarkovnikov addition of alkyl nitriles 25 to unactivated alkenes for the synthesis of substituted functionalized nitriles 26 via selective sp3 C−H bond functionalization (Scheme 15).32 The reaction could be easily scaled up to gram level, which suggests that it possesses prospects for use in industry. The initial KIE was

Scheme 9. Photocatalyzed C−H Activation of Alkanes and Coupling with CO and Electrophilic Alkenes

1,3-benzodioxoles 15. Moderate to good yields were given by this method with no interference by benzene ring substituents, such as OR, COOMe, Me, or CHO. In the same year, Ryu, Fagnoni, and co-workers used the same catalytic system to achieve the C− H activation of cycloalkanes (Scheme 9).24 The unsymmetrical Scheme 10. Metal-Free Radical Addition of Alcohols to Olefins

ketones 16 were synthesized by photopromoted C−H activation of alkanes and interaction with CO and electrophilic alkenes using this method. Recently, a metal-free cross-coupling of C(sp3 )−H groups adjacent to oxygen and olefins was demonstrated by Han (Scheme 10).25 In this transformation, a variety of N-allylbenzamides 17 and alcohols led to the corresponding products 18 in good yields using DTBP as the oxidant. Recently, Kamijo and co-workers have developed a photoinduced catalytic Michael-type radical addition of nonacidic C(sp3)−H bonds to 1,1-bis(phenylsulfonyl)ethylene utilizing 2-chloroanthraquinone (2-ClAQ) as the photocatalyst.26 9019


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Scheme 12. Visible-Light-Mediated C(sp3)−H Activation of Amines with Electron-Deficient Alkenes

process using CuI as the catalyst and dicumyl peroxide (DCP) as the oxidant. The acetonitrile radical reacted with an alkene to form carbon-centered radical 28, which then abstracted one H atom from acetonitrile to afford the final product and regenerate radical 27. 2.1.2. Radical Alkenylation. Alkenylation with simple olefins is a fundamental transformation in organic synthesis. The most well-known process is the palladium-catalyzed Heck reaction, which has now become a fundamental synthetic transformation.33 However, the transition-metal-catalyzed Heck reaction mainly deals with the alkenylation of aryl or vinyl electrophiles. Recently, several Heck-type reactions between alkyl halides and olefins have been developed.34 In contrast to traditional Heck reactions, mechanistically, these reactions were believed to involve radical processes. The C−H bonds such as alkanes could be converted into the corresponding radicals under oxidative conditions. The radical addition to

Scheme 13. Radical Clock Experiment

Scheme 14. Direct β-Alkylation of Saturated Aldehydes

Scheme 17. Copper-Catalyzed Radical Oxidative CrossCoupling between Alkenes and Aldehydes Scheme 15. Radical Addition of Alkyl Nitriles to Simple Alkenes

significant (KH/KD = 10.1), which suggested that the C(sp3)−H bond cleavage might be involved in the rate-determining step. The acetonitrile radical 27 was generated through an oxidation Scheme 16. Radical C−H Alkenylation

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preparation of (E)-alkyl-substituted alkenes 33 (Scheme 19).37 This protocol was compatible with a range of styrene derivatives and heterocyclic aromatics such as indenes, furans, and coumarins. In addition, other cycloalkanes such as cyclopentane,

olefins and further oxidation generated alkenyl functionalities (Scheme 16). Lei and co-workers reported a copper-catalyzed radical oxidative cross-coupling between alkenes and aldehydes (Scheme 17).35 This work provided a novel approach to the construction of α,β-unsaturated ketones 29 using the CuCl2/ TBHP system. Aromatic aldehydes and styrenes were found to be suitable for this transformation, while highly electron-deficient styrenes were ineffective. An oxidative radical alkenylation pathway is proposed by the authors for this reaction, which is shown in Scheme 17. Initially, TBHP is reduced by low-valent Cu(I) to generate a tert-butoxyl radical, which abstracts one hydrogen atom of an aldehyde to form acyl radical 30. The following radical addition to styrene furnishes benzyl radical 31. Finally, the further oxidation of benzyl radical 31 by a Cu(II) complex affords the alkenylation product 29.

Scheme 20. Isotopic Effect Experiment

cycloheptane, and cyclooctane also worked well, and all gave the desired products in good yields. The significant primary isotopic effect (KH/KD) observed was 5.67, which indicated that the

Scheme 18. Direct Alkenylation between Ethers and Olefins

Scheme 21. Radical Alkenylation of Thioethers and 1,1Disubstituted Olefins

The direct alkenylation of α-C−H groups of ethers with olefins would represent an ideal approach to the synthesis of allylic ethers. In 2014, Lei and co-workers reported a direct radical alkenylation between olefins and simple ether derivatives (Scheme 18).36 In this transformation, CuI was used as the catalyst precursor and DTBP was utilized as the oxidant under N2 protection. Many substituted olefins and various simple ethers were well tolerated in this transformation and gave corresponding alkenylation products 32 in good to excellent yields. Moreover, the open-chain ethers could also be tolerated under these reaction conditions. In the same year, a novel Cu-catalyzed direct alkenylation of simple unactivated alkanes with styrenes was also realized by Wei and co-workers, providing a mild and simple reaction for the

cleavage of the C(sp3)−H bond was involved in the rate-limiting step (Scheme 20). Later, a radical alkenylation of thioethers and 1,1-disubstituted olefins was achieved by Lei and co-workers via C(sp3)−H functionalization (Scheme 21).38 Both cyclothioethers and openchain thioethers could react to generate the corresponding products 34 in excellent yields. A radical-trapping experiment using TEMPO was performed to probe the possibility of a radical mechanism in this transformation. Oxindole is a key intermediate in organic synthesis. Liu and coworkers reported an I2-catalyzed intermolecular olefination of C(sp3)−H bonds between 3-substituted-2-oxindoles 35 and alkenes (Scheme 22).39 The reaction was conducted with a catalytic amount of iodine, and atmospheric oxygen was used as

Scheme 19. Direct Alkenylation of Simple Unactivated Alkanes with Styrenes

Scheme 22. I2-Catalyzed Intermolecular Olefination between 3-Substituted-2-oxindoles and Alkenes

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the oxidant. In addition, good yields were achieved in gram-scale reactions. The olefination products of 2-oxindoles 36 could be further converted into indole alkaloids bearing a fused cyclic amine and spirocyclic 2-oxindoles.

Scheme 25. Proposed Mechanism

Scheme 23. Radical Oxidative Coupling of Enones and Toluene Derivatives

In the same year, Huang and co-workers reported a coppercatalyzed regioselective synthesis of α-substituted enones via radical oxidative coupling of enones 37 and toluene derivatives (Scheme 23).40 Under these reaction conditions, a variety of toluenes were applied to prepare the α-substituted enones 38, which are important structural units in many biologically active compounds. The KIE experiment indicated that the oxidation of benzylic C(sp3)−H bonds might be involved in the rate-limiting step of this oxidative coupling. Decarboxylative cross-coupling reactions have emerged as a powerful synthetic technique in recent years, which permits the use of readily available and cost-competitive carboxylic acids as green replacements for conventional organometallic reagents.41 The acrylic acids can also serve as the alkenyl skeletons via

Scheme 26. Decarboxylative Coupling between Cinnamic Acids and N,N-Substituted Amides

derivatives 44 were produced via the radical sp3 C−H activation of amides with acrylic acids. While using CuF2·H2O as catalyst (10 mol %) and TBHP (4 equiv) as oxidant, N-(3-oxo-3phenylpropyl)acetamides were obtained via the oxyalkylation of N,N-substituted amides with alkenes. In 2014, Wen and coworkers reported a nickel- and manganese-mediated selective

Scheme 24. Copper-Catalyzed Radical Decarboxylative Olefination Reaction

Scheme 27. Decarboxylative Coupling between Cinnamic Acids and Cyclic Ethers

decarboxylative cross-coupling between cyclic ethers and α,βunsaturated carboxylic acids (Scheme 27).44 Oxyalkylation was achieved when nickel acetate was used as a catalyst, while manganese acetate promoted the alkenylation reaction.

decarboxylative processes. In 2012, Liu and co-workers realized a radical decarboxylative olefination reaction between aryl- or heteroaryl-substituted acrylic acids 39 and alcohols, ethers, and hydrocarbons (Scheme 24).42 The reaction proceeded using copper as catalyst (2 mol %) and TBHP as oxidant. This process representes a novel pathway for the stereospecific synthesis of substituted (E)-alkenes via a radical addition−elimination mechanism. The proposed mechanism by the authors was depicted in Scheme 25. First, a tert-butoxy radical was formed via the homolysis of TBHP. The tert-butoxy radical interacted with alcohols to generate the α-carbon-centered radical 40. The addition of radical 40 at the α-position of the double bond in cupric cinnamate intermediate 41 then gave the radical 42. The crucial radical 42 would go through an elimination of carbon dioxide and Cu(I) species to obtain the product. A similar system could also be used for decarboxylative alkenylation between cinnamic acids and N,N-substituted amides 43 (Scheme 26).43 This process was catalyzed with 20 mol % CuO and DTBP as the oxidant. The N-cinnamylacetamide

Scheme 28. Visible-Light-Mediated Radical Alkenylation of Tetrahydrofuran

A visible-light-mediated radical alkenylation via oxidative decarboxylative coupling of cinnamic acid derivatives with tetrahydrofuran was also achieved by Wang and co-workers (Scheme 28).45 In this reaction, the combination of 2 mol % Ru(bpy)3Cl2 and benzoyl peroxide (BPO) was found to be the best photocatalyst/oxidant at room temperature. The (E)-(29022


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arylvinyl)tetrahydrofuran 45 was obtained with high selectivity.

radical, 49, which subsequently released a phenylsulfonyl radical

The six-membered cyclic ethers tetrahydropyran, 1,4-dioxane,

to afford alkenylated product 50 (Scheme 30).

Scheme 29. Radical Decarboxylative Alkylation of Cinnamic Acids with Simple Alkanes

Scheme 31. Copper-Catalyzed Oxidative Alkenylation of Nitrostyrenes

β-Nitrostyrenes are another type of flexible intermediate used in many classes of reactions, and they undergo free-radical addition to generate (E)-β-alkylstyrenes.49,50 Recently, Yuan, Xiang, and co-workers have reported a copper-catalyzed oxidative alkenylation coupling between (E)-nitrostyrenes 51

and diethyl ether were also afforded as desired products in this transformation. A radical decarboxylative alkylation of cinnamic acids with simple alkanes under transition metal-free conditions was developed by Sun and co-workers (Scheme 29).46 In this case, peroxides such as DTBP and DTBP/TBHP acted as efficient oxidants. Moreover, alkanes and various substituents on the aryl ring of cinnamic acids were tolerated well in this reaction system. When TBHP was added to the reaction mixture, the aryl ketones were formed in high selectivity. The trans-1,2-bis(phenylsulfonyl)ethylene has proven to be a good radical acceptor and has been used in several radical addition reactions.47 A photoinduced radical alkenylation of C(sp3)−H bonds using trans-1,2-bis(phenylsulfonyl)ethylene was achieved.48 Photoexcited Ph2CO was used as a hydrogenabstracting agent, and t-BuOAc was used as a solvent. The transformation was believed to occur via the following pathway: first, the cleavage of C(sp3)−H bond was initiated by photoexcited Ph2CO, a highly reactive oxyl radical species, to generate carbon radical intermediate 46 and ketyl radical 47. The addition of an electron-rich carbon radical to 1,2bis(phenylsulfonyl)ethylene 48 then generated another carbon


with benzylic hydrocarbons, alcohols, ethers, and alkanes (Scheme 31).51 This represents a new method for the sp3 C− H activation and stereospecific synthesis of (E)-β-alkylstyrene derivatives. This reaction was conducted with a low loading of a copper catalyst (1 mol %), and DTBP was utilized as the oxidant. The possible reaction pathway proposed by the authors is depicted in Scheme 32. First, the copper promotes the decomposition of DTBP to form a tert-butoxyl radical, which could abstract a hydrogen from a C−H bond of the methyl group of toluene to generate benzyl radical 52. The addition of the benzyl radical to β-nitrostyrene 51 then generates a radical intermediate 53, followed by the elimination of the NO2 free radical to achieve the product. A new dimethylzinc-initiated radical coupling reaction between β-bromostyrenes 54 and ethers or tertiary amines, to introduce the styryl group, was developed by Madsen et al. (Scheme 33).52 This reaction was proposed to proceed by a radical addition−elimination mechanism in the presence of Me2Zn/O2 with 10 mol % MnCl2. The coupling could be achieved with a range of cyclic and acyclic ethers/amines as well

Scheme 30. Photoinduced Radical Alkenylation of C(sp3)−H Bonds with 1,2-Bis(phenylsulfonyl)ethylene

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Scheme 33. Dimethylzinc-Initiated Radical Coupling of βBromostyrenes

Scheme 35. Iron-Catalyzed Carbonylation-Peroxidation of Alkenes

as various substituted β-bromostyrenes to yield (E)-styrene derivatives. 2.1.3. Radical Difunctionalizations of Alkenes. 2.1.3.1. Direct Alkene Difunctionalizations. Direct alkene difunctionalization has attracted considerable attention because it provides the most attractive strategy for the assembly of functionalized organic compounds.53 MacMillan and co-workers achieved the difunctionalization of styrenes via radical C−H activation (Scheme 34).54 The C(sp3)−H bonds of aldehydes could be activated through a radical process using imidazolidinone 55 as the SOMO catalyst and ceric ammonium nitrate (CAN) as the stoichiometric oxidant to successfully synthesize γnitrate-α-alkyl aldehyde products 56. Later, a practical protocol involving iron-catalyzed carbonylation-peroxidation of alkenes via radical activation of aldehydes was achieved by Li and co-workers (Scheme 35).55 A variety of βperoxy ketones 57 were selectively and efficiently constructed by the three-component reactions of alkenes, aldehydes, and hydroperoxides with FeCl2 as the catalyst. The reaction was also allowed the synthesis of α-carbonyl epoxide 58 through the epoxidation of β-peroxy ketone 57 in an alkaline environment or by simply adding a base to the three-component reaction mixture. A tentatively proposed reaction mechanism of this transformation by the authors is shown in Scheme 35. The alkyloxy and alkyperoxy radicals were generated with the assistance of an iron catalyst. The crucial acyl radical was obtained by hydrogen abstraction from the aldehyde. The final product was formed via radical addition and radical coupling of an acyl radical with an alkene. The above radical activation strategy could also be used in the synthesis of γ-peroxyketone products. Klussmann and coworkers demonstrated a multicomponent alkylation-peroxidation interaction between styrene derivatives and ketones mediated by strong Brønsted acids (Scheme 36).56 The γperoxyketone products 59 are synthetically efficient intermediates that can be further transformed into 1,4-diketones, alkyl ketones, and homoaldol products. In 2015, a similar trans-

Scheme 36. Multicomponent Alkylation-Peroxidation between Styrenes and Ketones

Scheme 37. Coupling of Alcohols with Alkenes and Hydroperoxides

formation was reported by Loh and co-workers. The difunctionalization product 60 was obtained via the coupling of sp3 α-carbon atoms of alcohols with alkenes and hydroperoxides promoted by copper or cobalt catalysis (Scheme 37).57 Wang and co-workers demonstrated a visible-light-promoted synthesis of α,β-epoxy ketones 61 from styrenes and benzaldehydes (Scheme 38).58 0.02 equiv of Ru(bpy)3Cl2 was

Scheme 34. Difunctionalization of Styrenes with Aldehydes

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Scheme 38. Visible-Light-Promoted α,β-Epoxy Ketone Synthesis

used as the photocatalyst under visible light irradiation, and tBuOOH was utilized as the oxidant. Neither the electronic nature of nor the substitution patterns on the aryl rings of either

to react with the ethers. The use of a pure O2 atmosphere led to higher yields and was more effective for this transformation. The same reaction was achieved by Wang and co-workers using diatomite-supported Mn3O4 nanoparticles (SMONP-1) as heterogeneous catalyst (Scheme 41).62 Internal alkenes performed well in this reaction and afforded the desired products with good yields. A possible pathway is proposed by the authors, which is shown in Scheme 41. Initially, the tetrahydrofuran radical was formed via the reaction of tetrahydrofuran with O2 catalyzed by SMONP-1. This tetrahydrofuran free-radical 66 reacted with styrene to form carbon-centered radical 67, which was ultimately trapped by dioxygen to give peroxide 68. Homolytic cleavage of the O−O bond generated 69, which abstracted a hydrogen atom from THF to afford alcohol intermediate 70. Finally, alcohol intermediate 70 was further oxidized to produce ketone product 71. Later, Wang, Xing, and co-workers reported a direct oxidative coupling of ketones with terminal vinylarenes by copper/ manganese cocatalysis (Scheme 42).63 Various 1,4-dicarbonyls 72 were achieved with excellent regioselectivity via the free radical addition of ketones to vinylarenes. Under open-air conditions, the reaction still achieved the desired coupling product successfully. However, acetyl acetone and α-methylstyrene were not compatible with this reaction. The oxidative radical oxyalkylation between vinylarenes and aliphatic alcohols mediated by MnCl2 was also achieved (Scheme 43).64 Oxyalkylated products of vinylarenes (73) were achieved under these mild conditions, and a wide range of vinylarenes were applied. Aliphatic primary or secondary alcohols could easily react with both electron-poor and electron-rich vinylarenes. Wan and co-workers reported a Co-catalyzed radical-polar crossover coupling of 1,3-dioxolanes with electron-deficient alkenes and vinylarenes via a radical addition and a Kornblum− DeLaMare rearrangement (Scheme 44).65 Co(salen) was used as the catalyst, and TBHP was used as the oxidant. This reaction exhibited high functional group tolerance and wide substrate scope. The possible reaction pathway proposed by the authors is shown in Scheme 45. The C(sp3)−H activation of the 1,3dioxolane was achieved by the tBuO• or tBuOO• radical and then formed the nucleophilic radical 74. The addition of the nucleophilic radical to the electron-deficient alkene would afford the electrophilic radical 75, which then added to the vinylarene to generate a stabilized benzyl radical 76. The peroxide intermediate 77 would be afforded after the radical crosscoupling between the benzyl radical and the tBuOO• radical, which then underwent a Kornblum−DeLaMare rearrangement to form the desired product 78. Using a similar cobalt catalytic system, an efficient synthesis of various highly functionalized β-ester-γ-amino ketones 79 from available α-diazo esters, amines, and olefins was realized (Scheme 46).66 Co(acac)2 was utilized as the catalyst, and the TBHP was used as the oxidant under inert atmospheres. Several sp3 C−H bonds of tertiary amines could be activated and well tolerated in this system. The β-ester-γ-amino ketones 79 were generated through interception of the cobalt-based carbene radical with an α-aminoalkyl radical and the Kornblum−DeLaMare reaction.

Scheme 39. Three-Component Reaction of Olefins, Alkyl Nitriles, and Alcohols

reactant seemed to have a significant influence on the reaction efficiency. The synthetic application of this process was illustrated by a gram-scale preparation of α,β-epoxy ketones. The multicomponent carboetherification reactions have been a general route to allow the introduction of more synthetically versatile functional handles.59 In 2015, Zhu and co-workers reported a three-component copper-catalyzed reaction of an olefin, a nonactivated alkyl nitrile, and an alcohol (Scheme 39).60 A variety of α-substituted styrenes underwent smooth transformation with unactivated alkyl nitriles and alcohols to afford γScheme 40. Copper-Catalyzed Oxidative Cross-Coupling of Cinylarenes with Cyclic Ethers

alkoxy alkyl nitriles 62 with the formation of a quaternary carbon center. 2.1.3.2. Radical Oxyalkylation. 2.1.3.2.1. Radical Oxyalkylation of Vinylarenes. Oxyalkylation of vinylarenes provides another type of difunctionalization reaction of carbon−carbon double bonds. In 2009, Zhang and co-workers reported a coppercatalyzed oxidative cross-coupling of vinylarenes with cyclic ethers to generate oxyalkylation products (Scheme 40).61 Both electron-poor and electron-rich vinylarenes (63−65) were found 9025


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Scheme 41. Mn3O4-Promoted Oxidative Cross-Coupling of Cinylarenes with Cyclic Ethers

to α-aryl-β-oxyalkylated carbonyl ketones 80 was reported by Xu, Ji, and co-workers (Scheme 47).69 In this reaction, 2 equiv of TBPB was used as the oxidant under open-air conditions. The radical capture experiment performed with TEMPO suggested a single-electron pathway for this transformation. A plausible mechanism proposed by the authors is illustrated in Scheme 48. The 1,4-dioxane radical 81 was generated via the radical activation of a C(sp 3 )−H group of 1,4-dioxane. The intermolecular radical addition then was followed by migration of the electron-deficient aryl group to afford the radical intermediate 82. The product 83 could be obtained through further oxidation of the radical intermediate 82. The direct alkylation of simple carbonyl compounds (ketones, esters, and amides) with α,α-diaryl allylic alcohols could also be realized by this oxidative system. The 1,5-diketones 84 were synthesized by using simple ketones (Scheme 49). Ester and amide substrates could also provide γ-acyloxy ketones and γamido ketones under these reaction conditions.70 The oxidative cross-coupling radical alkylation reaction of α,αdiaryl allylic alcohols with simple alkanes was also achieved by Han and co-workers (Scheme 50).71 This reaction was achieved under metal-free conditions and only used DTBP as the oxidant under the open air. It tolerated a wide range of unsymmetrical or symmetrical α,α-diaryl allylic alcohols. The intermediate cyclohexane radical generated by the tert-butoxy radical is crucial in the radical process. This method provides a new strategy for selective functionalization of simple alkanes. Zhu and co-workers reported a copper-catalyzed alkylation of allylic alcohols by alkyl nitriles (Scheme 51).72 In this reaction system, Cu(OTf)2 was utilized as the catalyst and (tBuO)2 was

Scheme 42. Oxidative Radical Oxyalkylation of Ketones with Vinylarenes

Scheme 43. Oxidative Radical Oxyalkylation between Alcohols and Vinylarenes

Scheme 44. Cocatalyzed Radical-Polar Crossover Coupling of 1,3-Dioxolanes with Electron-Deficient Alkenes and Vinylarenes

2.1.3.2.2. Radical Oxyalkylation of α,α-Diaryl Allylic Alcohols. The radical addition of α,α-diaryl allylic alcohols can form a variety of α-aryl-β-oxyalkylated carbonyl ketones through a neophyl-type rearrangement. These studies have been reported by several research groups.67,68 In 2014, a direct C(sp3)−H bond functionalization of simple ethers with α,α-diaryl allylic alcohols

Scheme 45. Proposed Mechanism of Radical-Polar Cross-Coupling

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Scheme 46. Tandem Reaction for the Construction of β-Ester-γ-amino Ketones

Scheme 47. Direct C(sp3)−H Coupling of Simple Ethers with α,α-Diaryl Allylic Alcohols

Scheme 49. Direct Oxyalkylation of Simple Carbonyl Compounds with α,α-Diaryl Allylic Alcohols

Scheme 50. Radical Oxyalkylation of α,α-Diaryl Allylic Alcohols with Simple Alkanes

used as the oxidant under N2 atmosphere. The protocol provided an efficient route to functionalized ketones 85 containing a quaternary center. In this system, the electron-poor aryl groups preferentially underwent 1,2-migration over electron-rich aryl groups. At almost the same time, an alkylation reaction of acetonitrile and alkanes with allylic alcohols by 1,2-aryl migration under metal-free conditions was demonstrated by Ji.73 Recently, Tu and co-workers have reported a nickel-catalyzed oxidative C(sp3)−H functionalization of α,α-diaryl allylic alcohols with amides involving 1,2-aryl migration (Scheme 52).74 This method to prepare α-amino ketones 86 containing an all-carbon quaternary center had satisfactory yields. The acetamidomethyl radical was involved in the reaction, which was evidenced by a trapping experiment with TEMPO (Scheme 53). 2.1.3.2.3. Others. In 2007, MacMillan and co-workers used SOMO catalysis to accomplish the enantioselective organocatalytic α-enolation of aldehydes with an enolsilane (Scheme 54).75 In this case, 2 equiv of ceric ammonium nitrate (CAN) was

used as oxidant, and amine 87 was utilized as a catalyst. To achieve high levels of enantioselectivity, water and 2,6-di-tertbutylpyridine (DTBP) were necessary for the reaction. Enamides are powerful building blocks in organic synthesis, and they can also be widely used in radical coupling reactions.76 Xu and co-workers reported the MnO2-catalyzed oxidative


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Scheme 51. Radical Oxyalkylation of α,α-Diaryl Allylic Alcohols with Alkyl Nitriles

Scheme 54. Oxyalkylation of Aldehydes with an Enolsilane

Scheme 52. Nickel-Catalyzed Radical Oxyalkylation of α,αDiaryl Allylic Alcohols with Amides

Scheme 55. MnO2-Catalyzed Oxidative Alkylation of Enamides

alkylation of enamides 88 with C(sp3)−H bonds adjacent to oxygen atoms (Scheme 55).77 This reaction provided a simple and practical protocol for the synthesis of β-oxo ketones 89. 2.2. Radical Addition to Carbon−Carbon Triple Bonds

Alkyne functionalization, the addition of functional groups across a triple bond, represents a class of reactions with significant synthetic potential. In 2009, Liu and co-workers demonstrated an efficient radical coupling of alcohols and alkynes to prepare allylic alcohols 90 via direct C(sp2)−C(sp3) bond formation (Scheme 56).78 Apart from aliphatic alcohols, tetrahydrofuran (THF) and 1,4-dioxane were also suitable for this transformation. The homolytic cleavage of the TBHP initiated the radical process and formed the alkoxyl and hydroxyl radical. During the hydrogen abstraction from the alcohol, the formed αhydroxyalkyl radical 91 added to an alkyne to generate the alkenyl radical 92. The alkenyl radical 92 further abstracted hydrogen from alcohol to form the hydroxyalkyl radical and product (Scheme 57). Later, Lu and co-workers developed a dirhodium caprolactamate [Rh2(cap)4] (93)-catalyzed alkoxyalkylation of terminal alkynes in the presence of tert-butyl hydroperoxide (TBHP) under mild conditions (Scheme 58). This method provides an effective route to 2-vinyl ether 94 through the radical addition pathway between alkynes and ether derivatives.79 A similar sp3 C−H activation of tetrahydrofuran and vinylations of alkynes via visible light photocatalysis were accomplished by Wang (Scheme 59).80 In the presence of Eosin Y (0.05 equiv) as photocatalyst and t-BuOOH (4.0 equiv) as oxidant under visible light (45 W house bulb), this reaction has established a straightforward and versatile protocol that employs abundantly available alkynes as vinyl-function donors under mild reaction conditions. Substituted alkynes, very useful building blocks in organic synthesis, are prepared traditionally by the transition-metalcatalyzed Sonogashira reaction starting from terminal alkynes, and alkyl or aryl halides.81 However, a high loading of the transition metal catalyst is needed in these transformations. Meanwhile, radical alkynylation can provide an alternative

Scheme 56. Radical Coupling of Alcohols and Alkynes


method for the synthesis of substituted alkynes.82,83 In 2013, Liang and co-workers developed a novel sodium-fluoride-

Scheme 53. Trapping Experiment with TEMPO

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tetrahydrofuran with the aid of the fluoride anion to regenerate the tetrahydrofuran radical. Another radical alkynylation of C(sp3)−H bonds adjacent to a nitrogen atom was recently realized by Inoue and co-workers (Scheme 62).85 The enantioselective C(sp3)−H alkynylation could be achieved using p-tolyl tert-butyldimethylsilylethynyl sulfoximine 97 and benzophenone under photoirradiation conditions. A wide scope of secondary C−H bonds adjacent to nitrogen-based functional groups was tolerated under the reaction conditions. No additional step was needed to remove

Scheme 58. Rh-Catalyzed Alkoxyalkylation of Terminal Alkynes

Scheme 59. Visible-Light-Mediated Vinylations of Alkynes

Scheme 63. Oxidative C(sp3)−H/C(sp)−H Cross-Coupling of Unactivated Alkanes with Terminal Alkynes

Scheme 60. Radical C−H Alkynylation of Alkynyl Bromides

promoted radical alkynylation of alkynyl bromide for the synthesis of 2-alkynyltetrahydrofuran 95 (Scheme 60).84 The direct functionalization of the C(sp3)−H bond adjacent to an Scheme 61. Proposed Mechanism of C−H Alkynylation of Alkynyl Bromides

of the chiral auxiliary from the product due to the cleavage of the sulfoximine moiety during the process. There is no doubt that direct C−H/C−H coupling is the best synthetic methodology to construct C−C bonds. Lei and coworkers have uncovered a Cu/Ni/Ag multimetallic catalytic system to achieve the direct and selective oxidative C(sp3)−H/ C(sp)−H cross-coupling of unactivated alkanes with terminal alkynes (Scheme 63).86 In this work, the di-tert-butyl peroxide (DTBP) was used as oxidant and 1,4-bis(diphenylphosphino)butane (dppb) as a ligand in chlorobenzene. Many substituted cycloalkanes were well tolerated and gave the corresponding products with good yields, while linear alkanes, for example, npentane, n-hexane, and n-heptane, afforded mixtures of regioisomers. A kinetic isotope effect (KIE) experiment demonstrated that the cleavage of the C(sp3)−H bonds was the rate-limiting step. In the first step, copper and silver work synergistically for the C(sp)−H activation of the terminal alkyne, which leads to the formation of an alkynyl Cu(II) complex 98. The alkynyl Cu(II) complex is then transmetaled with Ni(II) species to generate an alkynyl Ni(II) complex 99. At the same time, an alkyl radical can be generated through hydrogen abstraction by the in situ-generated tert-butoxyl radical 100. This radical then reacts with the Ni(II) alkynyl complex to form the product 101 through either radical homolytic substitution or reductive elimination, and the released Ni(I) species can be oxidized to a Ni(II) species by DTBP to complete the nickel catalytic cycle.

oxygen atom with various alkynyl bromides has been achieved under transition-metal-free reaction conditions. Sodium fluoride was found to promote remarkably efficient functionalization. On the basis of experimental observations, the authors proposed the following reaction mechanism for the synthesis of 2-alkynyltetrahydrofuran derivatives (Scheme 61). Initially, the tetrahydrofuran radical was generated with the aid of small amounts of peroxide in tetrahydrofuran. A direct radical addition to the alkynyl bromide then formed bromovinyl radical 96, which underwent elimination of a bromine radical to afford the product. The bromine radical then captured the hydrogen atom of Scheme 62. Enantioselective C(sp3)−H Alkynylation of pTolyl tert-Butyldimethylsilylethynyl Sulfoximine 97

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Scheme 64. Visible-Light-Mediated Direct sp3 C−H Amination of Benzocyclic Amines

2.3. Radical Addition to NN Bonds

abstraction from alkanes by phthalimide N-oxyl radical (PINO), which was generated from the oxidation of NHPI.

The double bond of azodicarboxylate esters can serve as a good radical acceptor in radical addition reactions. In 2012, Nishibayashi and co-workers reported a direct C(sp3)−H amination of benzocyclic amines using the Ir catalyst 102

Scheme 66. Radical Dehydrogenative Cross-Coupling of Azoles with Alcohols or Ethers

Scheme 65. Radical Amination of C(sp3)−H Bonds with Dialkyl Azodicarboxylate

2.4. Radical Addition to Aromatic Arenes

Heterocyclic compounds are important units in biologically active natural products, unnatural pharmaceuticals, and organic functional materials.89 Radical additions to heteroaromatic bases are sometimes referred to as “Minisci reactions” in the literature.90 Minisci reactions represent powerful methods for C−H functionalization of heteroaromatic arenes. In 2009, a metal-free radical dehydrogenative cross-coupling of azoles with alcohols and ethers was achieved by Wang and co-workers (Scheme 66).91 Aliphatic alcohols such as ethanol, n-propanol, and 2-propanol tolerated the conditions well and gave high yields of the desired products. Meanwhile, tetrahydrofuran and 1,4dioxane reacted with fused azoles, such as benzothiazole and benzoxazole, also achieving the desired products. Later, Zhu and co-workers developed a gold-catalyzed C−C bond formation based on direct oxidative C(sp3)−H/C(sp2)−H coupling reactions involving N-heterocycles 106 and alcohols (Scheme 67).92 This method provides a facile method for direct acylation of the N-heterocycles. In addition, the ESI−MS and radical inhibition experiments reveal that the reaction proceeds through the activation of α C−H bond of alcohols through a radical mechanism. The free carbon radical 107 was geneeated via a hydrogen atom abstraction process. Subsequently, the radical reacts with the gold-activated lepidine to form the radical

(Scheme 64).87 The N,N-acetals 103 were afforded through the addition of α-aminoalkyl radicals to azodicarboxylate esters. Various derivatives of amines were tolerated under the reaction conditions. Furthermore, the products of N,N-acetals could be further transformed into various benzocyclic amines via substitution reactions. A radical amination of C(sp3)−H bonds was also developed by Inoue and co-workers employing N-hydroxyphthalimide (NHPI) as catalyst and dialkyl azodicarboxylate 104 as the trapping agent (Scheme 65).88 This C−H amination proceeds in a highly chemoselective manner with a wide applicability to functionalize benzylic, propargylic, and aliphatic C−H bonds. Furthermore, the obtained hydrazine compounds 105 could be further transformed into the corresponding carbamates or amines. This radical-based reaction was initiated by hydrogen 9030


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Scheme 67. Gold-Catalyzed Coupling between NHeterocycles and Alcohols

Scheme 70. Direct α-Arylation of Cyclic Ethers with ElectronDeficient Heteroarenes

diverse C1-acyl-substituted heterocycles could be synthesized with good efficiency.95 Scheme 71. Coupling of Ethers/Alkanes and ElectronDeficient Heteroarenes

Scheme 68. Direct Coupling of Heterocycles with Aldehydes

Under photoinduced conditions, Macmillan and co-workers reported a direct C−H functionalization/α-arylation of cyclic and acyclic ethers with electron-deficient heteroarenes (Scheme 70).96 This selective and efficient C−H functionalization/ heteroarylation reaction used [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 as photocatalyst and Na2S2O8 as oxidant. This method shows a broad scope with regard to both the dialkyl ether and the 108, which is rearomatized to generate alcohol intermediate 109. Finally, the alcohol intermediate is further turned into the acylation product 110. In contrast to the acylation of electron-rich aromatic compounds (the Friedel−Crafts reaction), the acylation of electron-deficient heterocycles is less well developed. The Minisci reaction can be used as one of the most straightforward strategies to achieve the addition of acyl radicals to electron-

Scheme 72. Visible-Light-Mediated C−H Arylation of Ethers

heteroarene substrates, providing a mild route to α-oxyalkylated arenes 111. The coupling of ethers/alkanes and electron-deficient heteroarenes was also reported by Singh and co-workers under metal-free conditions (Scheme 71). In the presence of K2S2O8 (3.0 equiv) and acetone/H2O (v/v = 2/1) at 120 °C for 6 h, various α-oxyalkyl- and alkyl-containing heteroarenes were generated in moderate to excellent yields. Moreover, the reaction did not require any external acid, making it an excellent alternative for this type of reaction.97 Recently, Shah and coworkers developed a visible-light-mediated C−H arylation of ethers and electron-deficient arenes without photocatalyst (Scheme 72).98 This reaction was performed in the presence of K2S2O8 (2 equiv) and H2O (2−5 mL) under the irradiation of a 27 W CFL, generating the corresponding α-arylated products efficiently. The oxidative cross-coupling of heteroarenes with simple unfunctionalized alkanes was initially reported by Antonchick and co-workers in 2013 (Scheme 73).99 This reaction performed

Scheme 69. TBHP/TFA-Promoted Direct Coupling of Heterocycles with Aldehydes

deficient heterocyclic aromatic bases.93 In 2013, Antonchick and co-workers developed a direct coupling of heterocycles with aldehydes at ambient temperature (Scheme 68). This reaction was performed in the presence of (bis(trifluoroacetoxy)iodo)benzene (PhI(OCOCF3)2) and TMSN3. Various heterocycles and aldehydes were well-tolerated in this system. Moreover, this one-step cross-coupling reaction was utilized in the synthesis of a collection of natural products.94 A similar reaction was subsequently realized by Li, Liu, and co-workers in the presence of TBHP/TFA (Scheme 69). A broad range of structurally 9031


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This method exhibited excellent chemoselectivity, affording exclusive benzylated products 114 in the presence of DTBP and

Scheme 73. Oxidative Cross-Coupling of Heteroarenes with Unfunctionalized Alkanes

Scheme 76. Oxidative C(sp3)−H Functionalization of Simple Alkanes with Chromones

Scheme 74. BPO-Initiated Cross-Coupling of NIminopyridine Ylides with Simple Alkanes

a catalytic amount of Y(OTf)3. The benzoylated products were generated when the conditions were changed to TBHP with a catalytic amount of MnO2. This reaction can be used in a broad range of structurally diverse C1-benzyl and -benzoyl isoquinolines.101 The chromanone skeleton is an important type of heterocycle found in a number of bioactive natural products and pharmaceutical molecules. Between them, 2-alkyl chromanone Scheme 77. Selective Functionalization of Simple Alkanes with 2-Alkylchromanones well using PIFA (2 equiv) and NaN3 (2 equiv) in dichloromethane at ambient temperature. In addition, this method allowed the preferential transformation of stronger C(sp3)−H bonds in the presence of weaker C(sp3)−H bonds. All of the desired products were smoothly formed at ambient temperature. Scheme 75. Oxidative Cross-Coupling of Isoquinolines with Methyl Arenes

represents an extremely important type of bioactive compound.102 Antonchick and co-workers achieved a selective oxidative C(sp3)−H functionalization of simple alkanes with chromones 115 mediated by hypervalent iodine (Scheme 76).103 This C(sp3)−C(sp2) cross-dehydrogenative coupling methodology under metal-free conditions is also the first report of a direct oxidative functionalization of the C-2 position of (thio)chromones to access bioactive compounds. Using the same strategy for C(sp3)−H activation, Han and coworkers described a metal-free oxidative C(sp3)−H bond functionalization and a subsequent conjugate addition reaction using di-tert-butyl peroxide (DTBP) as the oxidant via a radical addition process (Scheme 77).104 This process could tolerate a wide range of simple alkanes to react with different substituted chromones for the direct preparation of 2-alkylchromanones in moderate to good yields. This method is not only a simple and

Liu, Wang, and co-workers developed a BPO-initiated crossdehydrogenative coupling reaction of N-iminopyridine ylides 112 with simple alkanes and alcohols with high regioselectivity through a radical process (Scheme 74). A new and mild method for synthesizing the alkylated pyridine derivatives 113 was provided in this work. In addition, this direct C−H bond alkylation transformation provided moderate to excellent yields without the need for an additional reduction to remove the activated group.100 The direct use of readily available methyl arenes as coupling partners to avoid unproductive steps is an attractive possibility. Liu and co-workers developed an oxidative cross-dehydrogenative coupling of isoquinolines with methyl arenes (Scheme 75). 9032


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Scheme 78. Copper-Catalyzed Regioselective Cross-Coupling of Coumarin with Toluenes

atom-economical route for the syntheses of 2-alkylchromanones 116, but also represents a new strategy for selective functionalization of simple alkanes. A copper-catalyzed coupling of the alkenyl C(sp2)−H bond of coumarin 117 and the benzylic C(sp3)−H bond to achieve regioselective 3-benzylation 118 was reported by Duan (Scheme 78).105 In this transformation, 5 mol % of Cu(OAc)2 was utilized as the catalyst and 2 equiv of tert-butylperoxy benzoate (TBPB) was used as the oxidant, providing a convenient method for the preparation of diverse 3-benzylcoumarins. Moreover, other unactivated C(sp3)−H bonds such as alcohols or ethers were also tolerated in the reaction with moderate yields. The process

Scheme 80. Anodic Cross-Coupling Reaction between Phenols and Arenes

Scheme 79. Regioselective Coupling of Coumarin and Flavone Derivatives A novel and significantly improved anodic cross-coupling reaction between phenol and arene was developed by Waldvogel and co-workers. This reaction proceeded through a metal-free Scheme 81. Proposed Mechanism of Anodic Cross-Coupling Reaction

was initiated by the homolysis of TBPB or single-electron transfer of the CuI complex to TBPB to generate the tert-butoxyl radical. The generated tert-butoxyl radical then subsequently underwent a hydrogen atom abstraction from toluene to afford the benzyl radical 119. The benzyl radical 119 selectively added to the double bond of the coumarin 117 to give the more stable radical intermediate 120, followed by single-electron oxidation of the radical by Cu(II) to the corresponding benzylic carbocation 121. Finally, the benzylic carbocation delivered the product by the loss of a proton. Ge and co-workers also developed two regioselective coupling reactions of coumarin and flavone derivatives with different ethers via radical C(sp3)−H activation (Scheme 79).106 These processes gave two new types of ether-substituted derivatives with the ether substituent at the α-position of coumarins 122 in the presence of FeCl3, TBHP, and DBU, and the β-position of flavones 123 in the presence of CuO, TBHP, and DABCO, respectively, in good yields and high regioselectivities.

electrochemical method using boron-doped diamond (BDD) anodes in HFIP media (Scheme 80).107 Advantageously, various nonsymmetrical biaryls 124 were obtained via highly selective transformations without any additional leaving functionality required. Moreover, this approach allowed the synthetic use of highly reactive intermediates that usually cause complete substrate degradation. It also represents a powerful and practical method for direct arylation by C−H bond functionalization in contemporary organic synthesis. The phenoxyl radicals are generated via the electron and proton transfer under electrochemical conditions (Scheme 81). The products are formed through an addition and oxidation process between phenoxyl radicals and arenes. 9033


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Scheme 82. Radical Cyclization of N-Arylacrylamide Derivative 126

3. RADICAL CYCLIZATION

reported an oxidative coupling of N-arylacrylamides and alcohols to synthesize hydroxyl-containing oxindoles under metal-free conditions (Scheme 83).110 A large KIE effect was obtained in the competition experiment involving a 1:1 mixture of methanol and [D4]-methanol, demonstrating that the cleavage of the C−H bonds of alcohols might be the rate-limiting step. The oxidative tandem coupling of N-arylacrylamides with acyl radicals generated from aldehydes was accomplished under metal-free conditions by several groups (Scheme 84). In Li’s work, anhydrous TBHP was used as the oxidant. Both aryl and aliphatic aldehydes were compatible with this transformation. A free radical process was confirmed by control experiments in the presence of radical inhibitors. Kinetic isotope experiments suggested that cleavage of the carbonyl C−H bond was the rate-determining step.111 Recently, Zhang and co-workers also developed a metal-free cascade oxidative decarbonylative alkylarylation of acrylamides with aliphatic aldehydes.112 In Guo’s report, 10 mol % TBAI was utilized as the catalyst, and K2S2O8 was used as the oxidant under a nitrogen atmosphere.113

3.1. Radical Cascade Cyclization

3.1.1. Radical Cyclization with Acrylamides. Oxindole is one of the most important heterocycles in bioactive natural products and the pharmaceutical industry due to its remarkable biological and medicinal activity.108 Using N-arylacrylamide derivatives 126 as substrates, several transition-metal-catalyzed or metal-free oxidative difunctionalization/annulation apScheme 83. Oxidative Coupling of N-Arylacrylamides and C(sp3)−H Bonds

Scheme 85. Cu-Catalyzed Benzylarylation of Acrylamides with Benzyl Hydrocarbons proaches of alkenes have recently been developed to achieve the synthesis of functionalized oxindoles 127. By employing different radical precursors, many functional groups can be installed into oxindole frameworks. In these reactions (Scheme 82), the general pathway includes (i) generation of a carboncentered radical from the hydrocarbons; (ii) selective radical addition to the C−C double bond in N-arylacrylamides; (iii) intramolecular radical cyclization; and (iv) rearomatization. In 2013, Li and co-workers developed a Fe-catalyzed oxidative 1,2-alkylarylation of activated alkenes with an aryl C(sp2)−H bond and a C(sp3)−H bond adjacent to a heteroatom to synthesize oxindoles (Scheme 83). Compounds with a C(sp3)− H bond adjacent to an oxygen, sulfur, and nitrogen atom were tested in this transformation.109 Similarly, Duan and co-workers

Guin and co-workers further improved this transformation to avoid the use of metal and peroxide. In the reaction, the optimized conditions only utilized ethyl acetate as the solvent in the presence of O2 (1 atm). The scope of this transformation was evaluated with different aliphatic aldehydes, and linear aldehydes were found to be less efficient than branched aldehydes because Scheme 86. Radical Spirocyclization of 1,3-Dicarbonyl Compounds with Hydroxymethylacrylamide 129

Scheme 84. Oxidative Tandem Coupling of NArylacrylamides with Acyl Radicals

the corresponding linear alkyl radical formed after decarbonylation of the primary acyl radical was energetically less favorable.114 In 2013, Duan and co-workers reported a Cu-catalyzed benzylarylation of acrylamides with benzyl hydrocarbons to generate oxindoles 128 (Scheme 85).115 A benzyl radical could be formed by using TBPB as the oxidant and Cu2O as the catalyst. The rate-limiting step was the cleavage of the benzyl C− H bond, which was demonstrated by a KIE experiment. In the same year, Duan and co-workers reported a metal-free radical spirocyclization of 1,3-dicarbonyl compounds with 9034


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Scheme 87. Radical Cascade Cyanomethylation of NArylacrylamides with Alkyl Nitriles

Scheme 89. Cyclization of Dichloromethane with NArylacrylamides

Scheme 90. Copper-Catalyzed Alkylarylation of NArylacrylamides with Alkanes

hydroxymethylacrylamide 129 (Scheme 86).116 This procedure achieved intramolecular dehydration and C−H functionalization, forming the C−C bonds and C−O bonds. Various substituents on the acrylamides underwent the process to provide the corresponding spirooxindoles 130 with the use of potassium persulfate as a radical initiator in mixed solvents. It was noteworthy that higher yields were observed when 10 mol % AgNO3 was added to the reaction. A radical cascade cyanomethylation of N-arylacrylamides with acetonitrile was achieved by utilizing CuCl as the catalyst and DTBP as the radical initiator (Scheme 87a). The transformation could be dramatically suppressed by radical scavengers such as TEMPO and BHT. Reactions proceeded smoothly with Nmethyl and N-benzyl N-phenylacrylamides, but not with the N− H and N-acetyl N-phenylacrylamides.117 Later, Zhu and coworkers also demonstrated a similar transformation under ironcatalyzed conditions (Scheme 87b).118 Sheng also developed an azo-compound-mediated radical cyanoalkylation of activated alkenes using CuI as catalyst, which allowed for the general preparation of various oxindoles (131 and 132) bearing various nitrile moieties, especially rarely reported examples bearing αcyano quaternary carbon centers (Scheme 88).119 The C(sp3)−H bond activation/cyclization of dichloromethane with N-arylacrylamides was demonstrated by Liu and co-workers (Scheme 89).120 This reaction provides an efficient method for the synthesis of the dichloromethylated oxindoles 133 via the radical cyclization/addition of N-arylacrylamides. The C−H bond cleavage is preferred over the C−Cl bond cleavage as the enthalpy of formation of the dichloromethyl radical is lower than that of the chloromethyl radical. Liu and co-workers demonstrated a copper-mediated alkylarylation of N-arylacrylamides with alkanes to construct oxindoles 134 (Scheme 90).121 In this reaction, Cu2O was used as the catalyst, and DCP (dicumylperoxide) was utilized as the oxidant. The C−H bonds of the simple alkanes affected the

Scheme 91. Copper-Catalyzed Oxidative Cyclization of Acrylamides with Nonactivated Ketones

Scheme 92. Metal-Free Radical Addition/Cyclization Reaction

Scheme 88. Copper-Catalyzed Coupling of N-Arylacrylamides with Alkyl Nitriles

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reaction, and the reactivity was found to increase in the order primary < secondary < tertiary. A copper-catalyzed oxidative cyclization of acrylamide derivatives with various nonactivated ketones for the generation

Scheme 95. Visible-Light-Facilitated Cyclization of 1,6Dienes with Alkyl Chlorides

Scheme 93. Oxidative Radical Cyclization of Benzene-Linked 1,n-Enynes

oxidized by TBPB to form the cation intermediate 140. Finally, loss of a proton from 140 afforded the product 141. A visible-light-facilitated 5-exo-trig cyclization of 1,6-dienes 142 with alkyl chlorides was developed by the same group (Scheme 95). Aryldiazonium tetrafluoroborate 143 was utilized as the radical initiator, and Ru(bpy)3Cl2 was used as the photoredox catalyst.125 This photocatalyst/visible-light system also contributed to this reaction due to its ability to facilitate the generation of the aryl radical. The aryl radical served as the key intermediate for the C−H activation. Duan and co-workers reported a Cu-catalyzed tandem oxidative cyclization of cinnamamides 144 with benzyl hydrocarbons via direct cross-dehydrogenative coupling to form various dihydroquinolinones 145 (Scheme 96a). Sterically hindered ortho-substituted cinnamamides were also tolerated in this transformation, while unprotected N-arylcinnamamides did not react at all. Ethers, alcohols, and alkanes could also be successfully employed instead of benzyl hydrocarbons in the reaction. Only one stereoisomer was formed in all cases of this kind of transformation. 126 A metal-free radical tandem cyclization of N-arylcinnamamides and aldehydes was reported by Lu and co-workers for the synthesis of 3-acyl-4-aryldihydroquinolin-2(1H)-ones 146 (Scheme 96b). In the reaction, 1.0 equiv of TBAB was utilized as the initiator and K2S2O8 was used as the oxidant under mild conditions at 80 °C.127 A metal-free cascade alkylation of alkanes with N-phenyl-N(phenylsulfonyl)-methacrylamides 147 was developed by Zhu via a cyclization intermediate (Scheme 97).128 In the proposed mechanism, an alkyl radical could be formed from H atom abstraction by peroxide. The addition of an alkyl radical to the

of 3,3-disubstituted oxindoles 135 was achieved by Eycken with the assistance of microwave radiation (Scheme 91).122 Xia and co-workers reported a metal-free alkyl radical addition/ cyclization reaction of acrylamide for the synthesis of isoquinolinonediones 136 (Scheme 92).123 CH3SO3H was utilized as the catalyst in combination with TBHP as the oxidant. Meanwhile, ketones, alcohols, and ethers were well tolerated as the precursors of radicals in this reaction system. Li and co-workers reported a metal-free oxidative radical [2+2+1] carbocyclization of benzene-linked 1,n-enynes with two C(sp3)−H bonds adjacent to the same heteroatom (Scheme 93).124 Both aryl and alkyl groups at the alkyne terminus were tolerated. The reaction could also be conducted successfully on a gram scale. The mechanism for this transformation proposed by the authors is shown in Scheme 94. Initially, hydrogen atom abstraction from a C(sp3)−H group adjacent to the oxygen atom by TBPB generated the alkyl radical. Subsequently, the addition of an alkyl radical across a C−C double bond in the 1,n-enynes produced the radical intermediate 137, followed by cyclization with a C−C triple bond to afford the vinyl radical intermediate 138. The intermediate 138 then underwent a 1,5-H shift and a radical cyclization with the C−C double bond to selectively yield the radical intermediate 139. The intermediate 139 was then Scheme 94. Proposed Mechanism of Cyclization

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Scheme 96. Tandem Oxidative Cyclization of Cinnamamides with Benzyl Hydrocarbons

Scheme 97. Cascade Cyclization of Alkanes with N-Phenyl-N-(phenylsulfonyl)-methacrylamides 147

substitution involving a C-radical addition to 2-isocyanobiphenyls has become a crucial approach to preparing phenanthridine compounds. Studer and co-workers have disclosed a method for the direct synthesis of 6-aroylated phenanthridines 152 starting with readily prepared 2-isocyanobiphenyls 153 and commercially available aromatic aldehydes (Scheme 98).130 The pathway of this transformation proposed by the authors is presented in Scheme 99. The tert-butoxyl radical generated from the dissociation of tBuOOH can abstract the H atom from the aldehyde to yield the acyl radical, which adds to the isonitrile to give the imidoyl radical 154. Subsequently, this radical would cyclize to the arene to form the cyclohexadienyl radical 155, which is further aromatized to yield the product. Besides aldehydes, this C−H functionalization/annulation strategy can also be applied in other C−H bond of hydrocarbons, such as formamides. Yu and co-workers demonstrated a direct aromatization and carboxamidation of formamides with isonitriles promoted by TBHP. The high temperature was still crucial for the transformation (Scheme 100).131 Similarly, Pan and co-workers reported a metal-free oxidative radical reaction

alkene then afforded radical intermediate 148. The 5-ipsocyclization on the aromatic ring generated intermediate 149, and Scheme 98. Radical Cyclization of 2-Isocyanobiphenyls with Aromatic Aldehydes

a rapid desulfonylation afforded the key amidyl radical 150. After hydrogen abstraction, amidyl radical 150 was transformed into the desired product 151. 3.1.2. Radical Cyclization with Isonitriles. Phenanthridines are biologically important compounds that occur in nature and have been successfully used as drugs or drug candidates in medicinal chemistry.129 Cascade radical hemolytic aromatic 9037


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Scheme 103. Oxidative Cyclization of N-Arylpropiolamides 156 with Aldehydes

Scheme 100. Oxidative Radical Reaction between Amide Derivatives and 2-Isocyanobiphenyls

Scheme 101. Radical Cyclization of 2-Isocyanobiaryls with 1,4-Dioxane

bonds. A kinetic isotope experiment (KIE) demonstrated that cleavage of the C(sp3)−H bond would be the rate-determining step. 3.1.3. Radical Cyclization with Alkyne Derivatives. Li and co-workers demonstrated a metal-free oxidative ipsocarboacylation of N-arylpropiolamides 156 with aldehydes for the synthesis of 3-acylspiro[4,5]trienones 157 with TBHP as the oxidant (Scheme 103). Various N-arylacrylamide derivatives tolerated the reaction conditions well. The proposed mechanism indicated that a single-electron transfer (SET) process was involved in the reaction process.136 A proposed mechanism is depicted in Scheme 104, wherein the acyl radical generated in the presence of peroxide adds to the N-arylpropiolamides 156 to yield vinyl radical intermediate 158. Subsequently, the selective ipso-carbocyclization of 158 formed intermediate 159, which underwent addition of •OH to afford intermediate 160. Finally, oxidation of intermediate 160 by TBHP gave the desired 3acylspiro[4,5]trienone 157. This reaction manifold has also been used to access a wide variety of 3-substituted spiro-[4,5]trienones (Scheme 105). For example, a difunctionalized trifluoromethylation of N-arylpropiolamides has been performed by copper catalysis through a CF3 radical intermediate generated from NaSO2CF3.137 Using peroxide DTBP as the oxidant, the alkyl radical could be generated from simple alkanes and was trapped by Narylpropiolamides to form 3-alkyl spiro-[4,5]trienones when Cu(OAc)2 was used as the catalyst.138 When ethers were used instead of simple alkanes, 3-etherified azaspiro[4.5]trienones could be accessed directly from the corresponding ethers.139 A tandem oxidative acylation/cyclization between alkynoates with aldehydes for the synthesis of 3-acyl-4-arylcoumarins 161 was reported by Wu and co-workers (Scheme 106).140 In contrast to the reaction conditions in the previous work, K2S2O8

Scheme 102. Cyclization of Isocyanides with Simple Alkanes and Alcohols

between amide derivatives and 2-isocyanobiphenyls using TBPB as the oxidant under a nitrogen atmosphere.132 Ji133 and Cheng134 also developed an insertion reaction of 2isocyanobiaryls with 1,4-dioxane to synthesize 6-alkyl phenanthridine derivatives under metal-free conditions (Scheme 101). In the work of Ji, TBPB was used as the oxidant and radical initiator, while BPO was used in the report of Cheng. The cyclization of isocyanides with simple alkanes and alcohols was also realized by Liu using copper catalysis (Scheme 102).135 This method provided an efficient method to synthesize 6-alkyl-substituted phenanthridine and derivatives via selective functionalization of unactivated C(sp3)−H and C(sp2)−H 9038


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Scheme 105. Synthesis of 3-Substituted Spiro-[4,5]trienones via Radical Cyclization

Scheme 106. Oxidative Acylation/Cyclization between Alkynoates with Aldehydes

of alkynoates for the synthesis of trisubstituted olefins under copper catalysis142 or metal-free conditions.143 A TBAI-catalyzed addition/cyclization of toluene derivatives with diaryl(arylethynyl)phosphine oxides 163 was developed by Gao to synthesize benzo[b]phosphole oxides 164 via C−H functionalization (Scheme 108).144 This was a one-step reaction without the use of a transition metal catalyst, with DTBP as the oxidant and pyridine as the additive. Kinetic isotope effect experiments indicated that C−H bond cleavage on the methyl group of toluene was not involved in the rate-limiting step. The cascade cyclization of 1,6-enynes 165 with aldehydes for the synthesis of fluorene derivatives 166 was developed by Liang and co-workers under metal-free conditions (Scheme 109).145 The reaction proceeded smoothly with various aromatic and

was utilized instead of TBHP, and the 3-acyl-4-arylcoumarins were obtained as the main products. Under the optimized conditions, a variety of aldehydes gave the corresponding products in good yields. The intramolecular and intermolecular kinetic isotope effects indicated that the C−H cleavage was not the rate-limiting step in the acylation/cyclization reaction process. Pan and co-workers reported an oxidative difunctionalization of alkynoates through alkylation and migration decarboxylative arylation by using DTBP as the oxidant (Scheme 107). Sevenand five-membered cycloalkanes react smoothly to give the desired products 162, while no transformation was observed with larger cycloalkanes as substrates in the reaction.141 Ethers were also suitable for this cascade radical oxidative difunctionalization 9039


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Scheme 107. Radical Coupling of Alkynoates and Simple Alkanes

Scheme 109. Cascade-Cyclization of 1,6-Enynes 165 with Aldehydes

An iron-catalyzed radical cyclization of alkenes with aldehydes was reported by Li and co-workers under similar conditions, providing a simple and convenient method for the synthesis of various multifunctional 3,4-dihydropyran derivatives 172 (Scheme 113).150 The iron catalyst played an important role in tuning the diastereoselectivity. Mechanistic studies demonstrated that the iron catalyst was necessary for the cyclization and might participate in the convergent radical reaction. 3.2. Radical Cyclization Using Carbonyl Compounds

3.2.1. Synthesis of Dihydrofuran Derivatives. Radical cyclization with carbonyl compounds is currently an important transformation in organic synthesis. A number of chemists have developed novel and efficient methods for this transformation. Maiti and co-workers reported a copper-catalyzed annulation of aromatic olefins with aryl ketones to synthesize the 2,3dihydrofuran derivatives 173 (Scheme 114).151 The C−H activation of carbonyl compounds via a single-electron transfer (SET) process is involved in this transformation. The α-H position of aryl carbonyl compounds hosts the radical center, which then interacts with olefins. The cyclic radical is then transformed into the corresponding 2,3-dihydrofuran through SET and deprotonation processes. 2,3-Dihydrofuran derivatives could also be generated through the interaction of styrenes and 1,3-dicarbonyl compounds under different conditions.152,153 In recent years, different systems have been developed to realize this transformation. Guo and coworkers reported a transition-metal-free radical addition/ cyclization process of this transformation (Scheme 115).154 The β-keto esters could also react with olefins to achieve this cyclization. A one-step direct oxidative coupling/annulation of alkenes with 2-pyridinyl-β-esters or β-keto esters was reported by Lei (Scheme 116). I2 and TBPB were utilized as the catalyst and the oxidant, respectively, in the reaction.155 Electron-rich pmethoxystyrene and halide substituents on the styrenes were tolerated well in the reaction. However, electron-deficient substituents did not undergo the reaction. Li and co-workers demonstrated a new approach to dihydrofurans and dicarbonyl enamides from 1,3-dicarbonyl compounds and α-aryl enamides (Scheme 117). It was found that the addition of dicarbonyl compounds, Mn(OAc)3·2H2O, and MeCN in a batch-wise fashion gave the coupling product 174 in high yield.156

heteroaromatic aldehydes, but was limited to aliphatic aldehydes. A radical substitution mechanism was supported by intramolecular and intermolecular kinetic isotope effect (KIE) experiments and radical suppression tests. A large KIE for the reaction implied that the cleavage of the carbonyl C−H bond was the rate-determining step. During the proposed mechanism (Scheme 110), the acyl radical was generated from the aldehydes via a hydrogen abstraction process. The addition of the acyl radical to the C−C triple bond formed the radical 167. The aromatization process, followed by the intramolecular addition of radical 168 to the arene, generated the intermediate radical 169. The radical 169 was further oxidized to obtain the desired product. 3.1.4. Others. Zhu and co-workers reported a coppercatalyzed oxyalkylation of alkenes 170 with alkylnitriles for the synthesis of 3,3-disubstituted phthalides and isochromanones 171 (Scheme 111).146 Cu(OTf)2 was used as the catalyst and DTBP as the oxidant with the addition of base K3PO4 and water to promote the reaction. The electronic effects of the aromatic rings of the alkenes had no significant influence on this reaction. Recently, Zhu and co-workers have achieved a copper-catalyzed cyanoalkylative cycloetherification of alkenes with alkylnitriles as alkyl donors using a catalytic amount of copper(II) tetrafluoroborate hydrate [Cu(BF4)2·6H2O].147 In 2015, Guo148 and Li149 demonstrated the iron-catalyzed radical cyclization of olefinic dicarbonyl compounds with benzyl hydrocarbons or benzylaldehydes, which provided effective methods for the synthesis of substituted dihydrofurans (Scheme 112). FeCl2 was employed as the catalyst in conjunction with peroxide in these radical cascade transformations.

Scheme 108. TBAI-Catalyzed Cyclization of Toluene Derivatives with Diaryl(arylethynyl)phosphine Oxides

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Scheme 111. Copper-Catalyzed Cyclization of Alkenes 170 with Alkylnitriles

Scheme 112. Radical Cyclization of Olefinic Carbonyl Compounds with Benzyl Hydrocarbons or Benzylaldehydes

Scheme 114. Copper-Catalyzed Annulation of Aromatic Olefins with Aryl Ketones

Scheme 113. Iron-Catalyzed Radical Cyclization of Alkenes with Aldehydes

To further the development and understanding of the mechanism of radical cyclization for the synthesis of dihydrofur9041


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Scheme 119. Oxidative Coupling of α-Carbonyl Radicals with 2,3-Dichloro-5,6-dicyanobenzoquinone

Scheme 115. K2S2O8-Catalyzed Oxidative Coupling/ Annulation

Scheme 116. I2-Catalyzed Oxidative Coupling/Annulation

Scheme 117. Oxidative Cyclization between 1,3-Dicarbonyl Compounds and α-Aryl Enamides

to generate furan derivatives had been developed by Deng and co-workers (Scheme 119).158 This group reported an oxidative coupling of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) with β-diketones, simple ketones, and β-keto thioamides for the synthesis of 2,3-dicyanofurans and thiophenes. In this process, the DDQ-mediated radical transformation was crucial and

Scheme 118. Copper-Catalyzed Cyclization of 1,3-Diketone and Alkenes

Scheme 120. Silver-Catalyzed Oxidative Cyclization

initiated the radical steps. The radical 177 was generated through a single-electron transfer (SET) from 1,3-dicarbonyl compound to DDQ. The DDQ-substrate adduct 179 was then formed via cross-coupling between 177 and 178. The cyclization and subsequent deprotonation of 179 formed the intermediate 180, which would be converted into dihydrofuran 181 with the release of dichloromaleic anhydride. The product was generated via the further oxidation of dihydrofuran 181. Wang and co-workers reported a silver-catalyzed crosscoupling of two C(sp3)−H groups for the synthesis of tetrasubstituted furans, thiophenes, and pyrroles from benzylketone derivatives (Scheme 120).159 10 mol % AgF was utilized as the catalyst in the solvent xylene with the acid TsOH to achieve the optimal conditions. In the reported methodology, deoxybenzoins with both electron-withdrawing and -donating groups on the aromatic ring substituent were found to react smoothly and provided tetrasubstituted furans in excellent yields.

ans, Lei and co-workers have recently reported a mechanistic study on the CuI/CuII redox process using X-ray absorption and EPR spectroscopy (Scheme 118).157 The reduction of CuII to CuI by a 1,3-diketone has been observed, and the oxidative properties of the formed CuI were also investigated. The acetylacetone radical, which was generated through the oxidation of acetylacetone and a CuII species, could coordinate with copper to generate the radical, which attacks the alkene to give another carbon radical (175). The adduct 175 undergoes keto−enol tautomerism to the intermediate 176, which then undergoes the intramolecular combination of the acetylacetate radical with the CuII to form the C−O bond, giving the desired dihydrofuran product. 3.2.2. Synthesis of Furan, Pyrrole, and Indolizine Derivatives. The novel radical addition/elimination reaction 9042


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combination (Scheme 123). Notably, this reaction proceeded smoothly on a gram scale.162 The group of You achieved the gold-catalyzed oxidative C(sp3)−H/C(sp)−H cross-coupling of 1,3-dicarbonyl compounds with terminal alkynes (Scheme 124). The proposed mechanism suggested that the domino reaction was initiated by the reaction of the terminal alkyne 184 and gold(III) precatalyst to form the gold(III) acetylide 186. The reaction of 186 with 183 then generated the 2-alkynyl-1,3-dicarbonyl 187 and the gold(I) species. After the intramolecular nucleophilic attack by the oxygen at the alkyne, the species 187 afforded the gold(I) complex 188. Furthermore, the transmetalation from 188 to 186 led to the formation of gold(III) intermediate 189. Through the elimination of 189, the corresponding product 185 was generated.163 A copper-catalyzed C(sp3)−H functionalization of ketones with vinyl azides for the formation of substituted pyrroles was demonstrated by Adimurthy (Scheme 125). This method provides an efficient way to prepare 2,3,5-trisubstituted-1Hpyrroles 190. For the variously substituted pyrroles, both electron-donating and electron-withdrawing groups were tolerated in the reaction and gave the desired products in moderate to good yields.164 Jia and co-workers demonstrated a Cu/I2-catalyzed cross-coupling/cyclization between 2-(pyridin2-yl)acetate derivatives 191 and alkenes to construct indolizine 192 (Scheme 126). The reaction proceeded using Cu(OAc)2· H2O/I2 as the catalyst with Bu4NCl as additive. In the transformation, aromatic olefins were found to be more effective than aliphatic olefins.165 3.2.3. Synthesis of Other Rings. Other rings could also be afforded via the radical cyclization of carbonyl compounds and alkenes. MacMillan and co-workers reported an asymmetric SOMO-catalyzed (4+2) cross-coupling between conjugated olefins and aldehydes with SbF6− as the counterion (Scheme 127). This protocol offered a direct synthesis of six-membered carbocycles 193 with high stereoselectivity and regioselectivity.166 A copper-catalyzed radical oxidative cyclopropanation between acetophenones and electron-deficient olefins was developed by Antonchick to stereoselectively construct fused cyclopropane 195 (Scheme 128). In this report, CuI was used as the catalyst with bipy as the ligand, and DTBP was employed as the oxidant under Ar protection.167 A plausible mechanism was proposed in which the copper(I) species is initially oxidized to a [CuII]-OtBu species by DTBP. The oxidation of acetophenone by the copper(II) species forms an acetophenone radical, which then reacts with the maleimide 194 to generate the key radical intermediate 196. Later, addition of 196 to the copper(II) species generates the intermediate 197. Enolization of the keto group causes the ligand exchange and forms the cyclic intermediate 198 and tert-butanol. Finally, reductive elimination of copper(I) from 198 gave the final product 195.

The coupling of ketones and alkynes for the synthesis of furan derivatives could also be achieved, and many researchers have Scheme 121. I2-Catalyzed Oxidative Cross-Coupling/ Cyclization

recently focused on this topic. Work by Lei et al. has disclosed an I2-catalyzed oxidative cross-coupling/cyclization for the synthesis of furans and indolizines. Between the interaction of Scheme 122. Cu(I)-Catalyzed Cyclization of ElectronDeficient Alkynes and Acetophenones

ketones with alkyne derivatives, iodine addition at the α-position of 1,3-dicarbonyl derivatives initiated the transformation. Subsequently, through equilibrium under heating, the addition compounds formed radicals with the loss of an iodine radical. In the next step, radical addition to the alkyne generated an olefinic carbon radical 182, which underwent subsequent intramolecular radical addition to a C−O double bond. Finally, the product was formed through oxidation under the reaction conditions to terminate the process (Scheme 121).160 The same year, Scheme 123. Copper(I)-Mediated Annulation of Ketones with Alkynoates

3.3. Radical Cyclization with Phenol Compounds

Antonchick and co-workers introduced a Cu(I)-catalyzed addition of electron-deficient alkynes and acetophenones for the construction of multisubstituted furans (Scheme 122). CuBr· Me2S was employed as the catalyst, and DTBP was used as the oxidant. The KIE results indicated that the rate-limiting step was the abstraction of at least one H from the acetophenones, and radical scavengers were found to completely inhibit the reaction.161 Recently, He and co-workers developed a copper(I)-mediated annulation of ketones with alkynoates, in which CuI/BPO was found to be the optimal catalyst/oxidant

Phenols are some of the most readily available and versatile synthetic organic building blocks. Radical cyclization using phenol as a synthetic building block is a useful and practical method for the construction of aryl cyclo compounds. In 2013, the Lei group presented an iron-catalyzed oxidative radical crosscoupling/cyclization between a phenol and an olefin toward the synthesis of dihydrobenzofuran 199 at room temperature in a highly selective manner (Scheme 129). The mechanism indicated that the FeCl3 played a key role in this oxidative 9043


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Scheme 124. Gold-Catalyzed Oxidative C(sp3)−H/C(sp)−H Cross-Coupling of 1,3-Dicarbonyl Compounds with Terminal Alkynes

strategy could be applicable to achieve various oxidative transformations under mild conditions.169 Vincent and co-workers reported the direct oxidative [3+2] coupling between phenol and indole nuclei, leading to the regioselective formation of the benzofuro[3,2-b]indolines 201 (Scheme 132).170 The double bond adjacent to the nitrogen atom reacted with the phenol to afford the product. In this transformation, FeCl3 played a key role in activating the phenol derivatives. Recently, a metal-free oxidative transformation of 2-naphthols with terminal alkynes for the synthesis of 2-arylnaphtho[2,1b]furans 202 has been achieved by Yin (Scheme 133).171 In this reaction, BF3·Et2O was utilized as the catalyst and DDQ was used as the oxidant in a mixed solvent of toluene and CHCl3. For terminal alkynes, electron-donating groups such as methyl and tbutyl provided excellent yields of the corresponding products regardless of their positions on the phenyl ring.

Scheme 125. Copper-Catalyzed Cyclization of Ketones with Vinyl Azides

Scheme 126. Cu/I2-Catalyzed Cyclization between 2(Pyridin-2-yl)acetates 191 and Alkenes

Scheme 127. (4+2) Cross-Coupling between Olefins and Aldehydes

3.4. Intramolecular Radical Cyclization

Intramolecular radical cyclization is an important class of cyclization reaction, and one that achieves high atom utilization.172 Kundig and co-workers developed a method for synthesizing 3,3-disubstituted oxindoles 203 via intramolecular radical cyclization (Scheme 134).173 Using tBuONa as a base and in the presence of CuCl2, direct coupling of aryl C(sp2)−H and C(sp3)−H groups was realized. First, a radical adjacent to the aryl group of 204 was generated from the reaction mediated by CuCl2 with the oxidant and base. The key radical 204 then provided the resonance-stabilized aryl radical 205, which was oxidized to form the species 206. The elimination of one proton of 206 and interaction with base produced the product. Moreover, by using di-tert-butyl peroxide (DTBP) to promote the reaction without a metal catalyst, Roy realized a metal-free intramolecular dehydrogenative coupling (IDC) of C(sp2)−H and C(sp3)−H

coupling as the Lewis acid, and Fe coordinates to the oxygen atom to form radical intermediate 200. The radical reacted with alkenes to obtain the desired cycloproducts (Scheme 130).168 Later, Yoon and co-workers developed a robust photocatalytic method for the oxidative [3+2] cycloaddition of phenols and electron-rich styrenes (Scheme 131). The ruthenium complex Ru(bpz)3(PF6)2 was utilized as the photoredox catalyst, and the ammonium persulfate was used as the terminal oxidant. This 9044


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Scheme 128. Copper-Catalyzed Oxidative Cyclopropanation between Acetophenones and Electron-Deficient Olefins

Scheme 129. Iron-Catalyzed Oxidative Radical Cyclization between Phenols and Olefins

Scheme 132. Oxidative [3+2] Coupling between Phenols and Indoles


Scheme 133. Oxidative Cyclization of 2-Naphthols with Terminal Alkynes

reaction, CuO, Cu2O, FeCl3, Fe2O3, TiO2, ZnO, and Ag2O and their nanoparticles could be utilized as catalysts under solventfree and aerobic conditions. A metal-free oxidative coupling/annulation of 2-aryloxybenzaldehyde 207 for the synthesis of xanthone 208 was achieved by radical aldehyde activation by Li and co-workers (Scheme 135).176 This transformation was promoted by tetrabutylammonium bromide (TBAB) in an aqueous medium. Furthermore, the TBAB-TBHP system was found to act as the acyl radicalgenerating system in this transformation.

groups to obtain oxindoles. A variety of different β-N-arylamido nitriles and esters provided the corresponding oxindoles in moderate to very good yields.174 Recently, Ha further demonstrated a synthesis of substituted anilides and pyridinylamides catalyzed by a range of metal salts and oxides.175 In this

Scheme 131. Visible-Light-Mediated Oxidative [3+2] Cycloaddition of Phenols and Alkenes

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Scheme 134. Copper-Mediated Intramolecular Radical Cyclization

Scheme 137. Intramolecular Cyclization of 2-(NArylamino)aldehydes 209

subsequent single-electron transfer (SET) process. The carbamoyl radical abstracted one hydrogen of substrate 212 resulting in α-amino alkyl radical 215, which then added to the carbonyl group to form the radical intermediate 216. The DMF could form the radical again through the abstraction of the hydrogen by intermediate 216. 3-Hydroxyindoline intermediate 217 was formed as the primary product. After dehydration of species 217, the indole product 213 was synthesized, which tolerated a wide scope of derivatives. Du and co-workers demonstrated a CoCl2/TBHP-catalyzed intramolecular oxidative cyclization of N-(2-formylphenyl) amides 218 (Scheme 139).181 This method achieved C−O bond formation between the aldehyde carbon and amide oxygen. A variety of N-(2-formylphenyl)benzamide substrates were tested in the reaction to afford the cyclization products 219. Cyclopentane lactones could also be synthesized through intramolecular cyclization. Recently, Burton and co-workers developed a manganese(III)-acetate-mediated oxidative radical cyclization of pentenyl malonate 220 for the synthesis of [3.3.0]bicyclic γ-lactones 221 (Scheme 140).182 With protecting groups such as alkynes and silyl groups, the lactones were formed efficiently under the reaction conditions and with high levels of stereocontrol. The C-centered radical 222 is accessible by exposure of a suitably substituted pentenyl malonate to manganese(III) acetate, and the resulting C-centered radical 222 undergoes 5-exo-trig radical cyclization to give adduct radical 223. The adduct radical would then undergo further singleelectron oxidation followed by hydrolysis to afford the product [3.3.0]-bicyclic γ-lactone potentially via the corresponding carbenium ion 224. The cyclization of α-TMS and α-cyano/aryl-capped alkynyl aryl ketones 225 was demonstrated by Shia. The reaction proceeded smoothly in the presence of catalyst tert-butyl hydroperoxide (TBHP) and the cocatalyst tetrabutylammonium iodide (TBAI) with the solvent benzene under a nitrogen atmosphere (Scheme 141). The tricyclic products 226 were

Scheme 135. Oxidative Annulation of 2Aryloxybenzaldehydes

Furthermore, a large scope of xanthones could be synthesized from aldehydes under similar conditions. A cross-dehydrogenative coupling reaction via homolytic aromatic substitution (HAS) was reported by Studer using FeCp2 as the catalyst (Scheme 136). In this case, commercially available tBuOOH was utilized as the oxidant.177 Zhao and co-workers reported a metalfree intramolecular cross-dehydrogenative coupling (CDC) reaction of 2-(N-arylamino)aldehydes 209 (Scheme 137). Various 2-(N-arylamino)aldehydes with different substituent groups achieved the desired products in good yields. The acyl radical 211 served as a key intermediate for the cyclized product 210.178 Recently, Patel and co-workers demonstrated a metalfree intramolecular carbonylation of arenes via oxidative functionalization of methyl C−H bonds.179 A metal-free intramolecular dehydrogenative coupling of tertiary amines and ketones was reported by Yan in the synthesis of indole derivatives (Scheme 138).180 This transformation was promoted by the KOtBu/DMF system under an argon atmosphere. For the reaction mechanism, the crucial initiator is presumably the carbamoyl radical 214 generated from DMF. The carbamoyl radical 214 was generated by deprotonation and a Scheme 136. Iron-Catalyzed Oxidative Cyclization

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Scheme 138. Metal-Free Intramolecular Dehydrogenative Coupling

Scheme 139. Intramolecular Oxidative Cyclization of N-(2Formylphenyl)amides 218

Scheme 141. Radical Cyclization of 225

Scheme 140. Oxidative Radical Cyclization of Pentenyl Malonate

4. RADICAL−RADICAL CROSS-COUPLING Radical−radical cross-coupling reactions have emerged as powerful tools for the construction of new chemical bonds. However, this field is still in its infancy as compared to classical bond-formation strategies. Despite the fact that the activation energy of radical−radical coupling reactions is nearly zero, the selectivity of the cross-coupling of two different reactive radicals remains a challenging task, which suffers from inescapable homocoupling reactions of either of the two radicals.184 To achieve the radical/radical cross-coupling in high selectivity, a persistent radical and a transient radical should be engaged according to the persistent radical effect.185 4.1. Carbon Radical/Carbon Radical Cross-Coupling

prepared in excellent yields under standard conditions. The initial α-keto radical intermediate 227 formed via C(sp3)−H activation might undergo the first intramolecular 5-exo-dig cyclization to generate the vinyl radical intermediate 228. The vinyl radical intermediate 228 underwent 6-endo-trig addition to form the radical intermediate 229, followed by the aromatic homolytic substitution to form the product.183

C−C bonds are found in countless compounds, and are the pivotal components of the skeletons of organic compounds. Being a fundamental transformation, the development of C−C bond formation reactions via efficient and direct strategies has received ever-increasing attention. With the development of green chemistry for atom- and step-economical transformations in modern chemistry, several novel synthetic methodologies have 9047


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Later, Inoue and co-workers developed a photochemical metal-free 4-pyridination of C(sp3)−H bonds for the formation of 4-alkylpyridine derivatives 237 with high chemoselectivity (Scheme 144).187 Using benzophenone as photosensitizer in combination with 4-cyanopyridine 236 as the pyridination reagent, a variety of alkylaromatics, even alkenes and alkanes, were viable in the transformation in aqueous acetonitrile. The key step of the reaction was the H atom abstraction by photochemically generated oxyl radical 238, producing the alkyl radical and the α-hydroxy radical. The proton-coupled electron transfer between electron-donating α-hydroxy radical and electron-withdrawing 4-cyanopyridine generated the stable arene radical anion. It was speculated that the desired product could be obtained through the direct coupling of the alkyl radical and arene radical anion via a similar pathway found in MacMillan’s work. Recently, Wang and co-workers have reported the α-C−H electron-deficient arylation of N-acylprotected tetrahydroisoquinolines with different aromatic and heteroaromatic nitriles under oxidant-free conditions.188 In the same year, MacMillan and co-workers developed a direct β-arylation of saturated aldehydes and ketones via a selective radical−radical cross-coupling process (Scheme 145).189 In this transformation, the amine catalyst 239 and Ir(ppy)3 were utilized to mediate the reaction with the addition of DABCO and DMPU. This process enabled the transient generation of 5π-electron β-enaminyl radicals from ketones and aldehydes to couple with a cyano-substituted aryl radical anion. An oxidative quenching mechanism was proposed by the authors (Scheme 146), in which the excited state of tris(2phenylpyridinato-C2,N)iridium(III) can be oxidized by 1,4dicyanobenzene to generate a relatively stable radical anion 240. Meanwhile, the amine catalyst could condense with an aldehyde substrate to form the electron-rich enamine 241, which could donate an electron to the oxidized photocatalyst IrIV(ppy)3 to generate a radical cation and thereby complete the photoredox catalytic cycle. As a key mechanistic consideration, it was believed that the formation of β-enaminyl radical cation 242 would sufficiently weaken the β-C−H bonds of carbonyls so as to allow deprotonation and formation of the β-enamine radical 243 via the critical 5π-electron activation mode. The intermolecular coupling of radical anion 240 and β-enamine radical 243 then

Scheme 142. Photoredox-Catalyzed C−H Arylation of Amines

been demonstrated, especially the radical−radical cross-coupling method. 4.1.1. C(sp3)−C(sp2) Bond Formation. In 2011, MacMillan and co-workers developed a photoredox-catalyzed C−H arylation of amines for the synthesis of the corresponding benzylic amines 230 via a radical−radical cross-coupling process (Scheme 142).186 In this transformation, Ir(ppy)3 was utilized as the photocatalyst and NaOAc was used as the base under a 26 W fluorescent light source. Moreover, the synthesis of several heterobenzylic amines could also be achieved in this transformation. A single-electron transfer pathway was proposed in the process, and CN− was found to be a suitable leaving group for the ultimate aromatization step. The detailed mechanism is described in Scheme 143. The photocatalyst Ir(ppy)3 could be excited by irradiation with visible light to generate its excited state [*Ir(ppy)3], which is a powerful reductant. The single-electron transfer from [*Ir(ppy)3] to 1,4DCB could then afford the corresponding arene radical anion 231. The generated strong oxidant IrIV(ppy)3 would be capable of oxidizing the amine to form the amine radical cation 232 and IrIII(ppy)3. The C−H bond next to the nitrogen atom of 232 was weakened by about 40 kcal/mol, and could furnish α-amino radical 233 after deprotonation by NaOAc. A radical−radical coupling reaction then took place between intermediates 231 and 233 to afford anion intermediate 234, which underwent elimination of CN− to finally generate the coupled product 235. Scheme 143. Proposed Mechanism

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Scheme 144. Photochemical Metal-Free 4-Pyridination of C(sp3)−H Bonds

Scheme 145. Direct β-Arylation of Saturated Aldehydes


Scheme 147. Direct Arylation of Benzylic Ethers

Similarly, with a parallel dual-catalytic system, the crosscoupling of α-benzyl ether radical with a stable electron-deficient arene radical anion was further studied for the direct arylation of

formed a new carbon−carbon bond. Hydrolysis of the resulting enamine 244 would then complete the organocatalytic cycle and eventually delivered the β-aryl aldehyde product 245. 9049


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Scheme 148. Arylation of Allylic C−H Bonds

benzylic ethers (Scheme 147).190 Through the combination of Ir(ppy)3 and methyl 2-mercaptoacetate 246 as organocatalyst, benzyl radicals could be generated via a hydrogen-atom transfer process from various benzyl ethers. Furthermore, diverse benzyl ethers including cyclic analogues were compatible with this transformation and showed good functional group tolerance. The arylation of allylic C−H bonds was also developed using this powerful dual-catalysis paradigm in 2015, which is a longstanding and significant challenge in synthetic chemistry (Scheme 148).191 The triisopropylsilanethiol 247 was used as the cocatalyst instead of methyl 2-mercaptoacetate. A diverse range of electron-deficient arenes were found to be viable to couple with various unfunctional cyclic and acyclic alkenes in this transformation. This protocol could also be employed to

Apart from the above visible-light-induced cross-couplings, Lei and co-workers also reported a nickel-catalyzed C(sp3)−H functionalization for C−C bond formation via selective radical− radical cross-coupling (Scheme 150).193 In the presence of Ni(acac)2 acting as the catalyst, a range of arylborates, such as arylboronic acids, arylboronic acid esters, and 2,4,6-triarylboroxines, were all found to be viable coupling partners with cyclohexane in this transformation. As for the mechanistic study, the cyclohexyl radical was successfully captured by 1,1diphenylethene, and KIE experiments suggested that the C−H cleavage of cyclohexane might be involved in the rate-limiting step. A mechanism involving nickel-catalyzed radical cross-coupling was supported by DFT calculations and further proved by radical-trapping experiments (Scheme 151). The cyclohexyl radical was produced via radical substitution, which then coordinated to the catalyst to furnish a relatively stable nickel(III) complex 252. he phenyl radical 253, which was generated from the oxidation of phenylboronic acid 251, then could react with 252 to yield the desired product 254 via the radical cross-coupling. Recently, the Hashimi group has developed a visible-lightpromoted radical−radical cross-coupling reaction for the monofluoroalkenylation of dimethylamino derivatives with gem-difluoroalkenes 255 (Scheme 152). 194 Ir[dF(CF 3 )ppy]2(dtbbpy)PF6 was employed as the photocatalyst under blue LED irradiation. In this transformation, acyclic, cyclic N-Ar, and aliphatic tertiary amines were well tolerated. A radical− radical coupling between an α-aminoalkyl radical and a monofluoroalkenyl radical is proposed in Scheme 152. Initially, the excited-state photocatalyst formed under visible light irradiation underwent single-electron transfer (SET) by accepting one electron from the tertiary amine to generate radical cation 256, which upon deprotonation produced α-aminoalkyl radical 257. Subsequent SET reduction of gem-difluoroalkene 255 gave radical anion 258, generating fluoride and fluoroalkenyl radical 259 via C−F bond fragmentation. Selective crosscoupling of the less reactive radical 257 with the more reactive monofluoroalkenyl radical 259 then would afford the desired product 260 according to the “persistent-radical effect”. Alternatively, chemoselective radical C−C heterocoupling of αaminoalkyl radical 257 with radical anion 258 and subsequent elimination of fluoride could also efficiently realize the product 260. 4.1.2. C(sp3)−C(sp3) Bond Formation. Because of the significance of C−C bond formation, methods for the construction of C(sp3)−C(sp3) bonds have emerged, in addition to C(sp3)−C(sp2) bond formation. In 2013, MacMillan and coworkers reported a,β-functionalization of cyclic ketones with aryl ketones under dual-catalytic conditions with the combination of photoredox catalysis and organocatalyst 261 (Scheme 153).195 The proposed mechanism for the β-ketone coupling involves two cycles, the photoredox catalytic cycle and the organocatalytic cycle. Irradiation of tris(2-phenylpyridinato-C2,N)iridium(III) [Ir(ppy)3] with visible light produced a long-lived photoexcited state, *Ir(ppy)3. Electron transfer (ET) between an aryl ketone

Scheme 149. Photoredox-Catalyzed α-Heteroarylation with 2-Halobenzothiazoles 249

synthesize β-aryl ketones. Because the allylic C−H bonds of alkenes are relatively weak, the olefins could undergo hydrogen atom abstraction using the organocatalyst to generate transient allylic radicals, which then coupled with produced arene radical anions through a radical−radical cross-coupling pathway. A photoredox-catalyzed α-heteroarylation of tertiary amines 248 with 2-halobenzothiazoles 249 for the construction of benzylic amine pharmacophore 250 was also achieved via the same strategy (Scheme 149).192 Ir(ppy)2(dtbbpy)PF6 was utilized as the photocatalyst. The α-arylation was compatible with both acyclic and cyclic dialkylanilines. This reaction was Scheme 150. Nickel-Catalyzed Cross-Coupling of Cyclohexane with Arylborates

scaled up to gram scale and provided the possibility of efficient preparation of the heterocycles found in medicinal agents. A reductive quenching cycle was suggested by a Stern−Volmer study, supporting the homolytic aromatic substitution mechanism. 9050


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Scheme 153. Direct β-Functionalization of Cyclic Ketones with Aryl Ketones

Scheme 152. Visible-Light-Promoted Cross-Coupling for the Monofluoroalkenylation of Dimethylamino Derivatives

262 and the excited-state species would then provide the oxidized IrIV(ppy)3 and radical anion 263. The condensation of amine catalyst 261 with cyclohexanone 264 generates an electron-rich enamine 265. Through the SET process, the desired enaminyl radical cation 266 was formed and increased the acidity of the allylic C−H bond, which would facilitate deprotonation at the β-position. The transiently formed 5πelectron species 267 should then readily couple with ketyl radical 263 to form the γ-hydroxyketone enamine 268. Finally, enamine hydrolysis would release the product γ-hydroxyketone 269 and regenerate the amine to complete the organocatalytic cycle. A direct β-coupling of cyclic ketones 270 with imines 271 via selective radical−radical cross-coupling was achieved by a synergistic combination of photoredox catalysis and organocatalysis (Scheme 154). It is worth mentioning that DABCO was utilized both as a base and as an electron transfer agent, in combination with Ir(ppy)2(dtbbpy)PF6 as the photocatalyst. The reaction was compatible with both diaryl and aryl alkyl ketimines.196 Transient β-enaminyl radicals, derived from ketones via single-electron oxidation of the enamine intermediate, could selectively couple with the persistent in situgenerated α-amino radicals. Similarly, a coupling was accomplished between benzylic ethers 272 and imines using methyl thioglycolate 273 as a hydrogen-atom-transfer (HAT) catalyst

Scheme 154. Direct β-Coupling of Cyclic Ketones 270 with Imines 271

combined with Ir(ppy)2(dtbbpy)PF6 as the photoredox catalyst (Scheme 155).197 Ooi and co-workers reported a redox-neutral α-coupling between N-sulfonyl aldimines 274 and N-arylaminomethanes 275 with high enantioselectivity (Scheme 156).198 The reaction 9051


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Scheme 155. Radical Cross-Coupling of Benzylic Ethers 272 with Imines

Scheme 156. Radical Coupling between N-Sulfonyl Aldimines 274 and N-Arylaminomethanes 275

thane would then produce the desired products. A similar visiblelight-induced radical−radical coupling protocol for the construction of unsymmetric 1,2-diamines was developed by Rueping’s group through the cross-coupling of aldimines with N,N-dimethylaniline (Scheme 157).199 In this report, the Ir(ppy) 2 (dtbbpy)PF 6 was used as the photocatalyst in conjunction with Li2CO3 as the base. Particularly, carbonyl compounds could also be utilized as potential acceptors to produce ketyl radicals. In general, the benzaldehydes could be successfully converted to the desired products, while both cyclic and aryl ketones were inactive in this transformation. With the employment of a chiral iridium complex 280, Meggers and co-workers described a visible-light-induced asymmetric cross-coupling between trifluoromethyl ketones

proceeded smoothly with the combination of P-spiro chiral arylaminophosphonium barfate 276 and an iridium photosensitizer under visible light irradiation. A variety of aromatic Nsulfonyl imines, fused heteroaromatic, and aromatic imines were tolerated, whereas aliphatic imines remained inactive in this

Scheme 159. Visible-Light-Promoted Radical Cross-Coupling of Amines with Ketones

Scheme 157. Radical Cross-Coupling of Aldimine with N,NDimethylaniline 277 and tertiary amines 278 for the construction of 1,2-amino alcohols 279 with high enantioselectivity (Scheme 158).200 The chiral iridium complex 280 was used as both a Lewis acid and a photoredox catalyst. Notably, this mild method fulfilled the requirements of both perfect atom economy and sustainable chemistry. Besides trifluoromethyl ketones, other general carbonyl substrates were also applied to a visible-light-promoted cross-coupling with amines for the construction of 1,2-amino alcohols 281 by Xiao and co-workers (Scheme 159).201 This reaction of secondary and tertiary amines with diaryl ketones and aldehydes was successfully conducted with fac-Ir(ppy)3 as the

transformation. The N-sulfonyl imines could accept an electron from the reduced photocatalyst to form an anion radical. The enantioselective cross-coupling of a radical ion with an aminomethyl radical generated from N,N-diphenylaminome-

Scheme 158. Asymmetric Cross-Coupling between Trifluoromethyl Ketones 277 and Tertiary Amines 278

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Scheme 160. Construction of Multi-Substituted Nitrogen Heterocycles 283 via a Biradical Intermediate

Scheme 161. Visible-Light-Induced Redox-Neutral α-Allylation of Amines

photocatalyst. In addition, a range of α-silylamines were also employed as sources of α-amino radicals. In addition to intermolecular cross-coupling, a visible-lightpromoted intramolecular radical−radical coupling has likewise been accomplished. In 2016, Zhu and co-workers described this novel coupling for the construction of multisubstituted nitrogen heterocycles 283 via biradical intermediate 284 (Scheme 160). Notably, high yields were obtained when employing substrates bearing a strong electron-deficient group on the benzene ring. In the proposed mechanism, photoinduced single-electron oxidation formed a thiyl radical, which abstracted H from 3(benzyl(phenyl)amino)-1-phenylpropan-1-one (282), providing the α-amino radical. Meanwhile, electron transfer to the carbonyl group of the reactant by the reduced photocatalyst furnished biradical intermediate 284, which preferred to undergo intramolecular coupling in its less hindered structure, forming a cis-conformation in the main diastereomer.202 In addition to visible-light-mediated cross-coupling via the combination of photoredox catalysis and organocatalysis, another method employing transition metal catalysis instead of organocatalysis was also accomplished. Lu, Xiao, and co-workers depicted a visible-light-induced redox-neutral α-allylation of amines through radical cross-coupling by combining Pd(PPh3)4 with [Ir(ppy)2(dtbbpy)]PF6 as a dual-catalytic system at room temperature (Scheme 161). Notably, substrates with a vinyloxy functional group were viable in this transformation, and 8oxoprotoberberine derivatives could also be synthesized by this protocol.203 A reductive quenching mechanism is proposed by the authors, which is shown in Scheme 162. Single-electron oxidation of amine substrates 285 by a visible-light-excited IrIII* species generated the radical cation 286, and further deprotonation of the radical cation gave the α-amino alkyl radical 287. On the other hand, the interaction of palladium and allyl phosphate 288 would form the allylpalladium species 289, which can be reduced by IrII to afford the allyl radical 290 and regeneration of the Pd(0) catalyst. Finally, the radical cross-coupling of 287 and 290 produced the desired allylation product 291. Although another reaction pathway involving the addition of α-amino radical 287 to a p-allylpalladium species might be possible and cannot be totally ruled out, the fact that no enantioselectivity was observed


when chiral ligands were used in the reaction argues in favor of radical cross-coupling. 4.1.3. C(sp3)−C(sp) Bond Formation. The C(sp3)−C(sp) bond formation could also be achieved via a radical/radical crosscoupling strategy. In 2015, Hashmi and co-workers demonstrated a gold-catalyzed α-C(sp3)−H alkynylation of tertiary aliphatic amines with 1-iodoalkynes 292 as radical alkynylating reagents (Scheme 163).204 [Au2(μ-dppm)2]2+ 293 was utilized as a photosensitizer with sunlight at room temperature. According to mechanistic experiments, a radical pathway via a SET process was suggested by the addition of radical inhibitors, as depicted in Scheme 163. It was proposed that the product 296 was produced from the cross-coupling of the α-aminoalkyl radical 294 and the alkynyl radical 295 instead of the previously reported radical addition/elimination pathways. In addition, a gram-scale reaction was also successfully performed. 9053


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Scheme 163. Gold-Catalyzed α-C(sp3)−H Alkynylation of Tertiary Amines with 1-Iodoalkynes

Scheme 164. Nickel-Catalyzed Oxidative C(sp3)−H/N−H Cross-Coupling


reaction was the hydrogen abstraction of THF and that the nickel made no difference. DFT calculations indicated that both the nitrogen and the carbon radicals are reactive, although the nitrogen radical is more stable than the carbon radical. The interaction between the nitrogen radical and Ni(acac)2 was calculated to be exothermic and a slightly favorable process. The small energy change suggested that the coordination of the nitrogen radical to nickel might be a rapid equilibrium. Thus, the generated complex 300 could be considered as a nitrogen radical pool, which could prolong the lifetime of the nitrogen radical and make it a somewhat persistent radical, allowing it to couple with the α-alkoxyl carbon-centered radical. Later, a copper-catalyzed C−H/N−H radical/radical crosscoupling was also reported by Lei for the synthesis of allylic amine 301 (Scheme 166).206 Cu(OTf)2 was utilized as the catalyst and DTBP was used as the oxidant in solvent DCE. NMethoxybenzamide derivatives bearing electron-rich substituents on the aryl rings provided the corresponding products in better yields than those with electron-deficient groups. The EPR results indicated that with N-methoxybenzamide the coordination environment of copper changed during the oxidation process (Scheme 166). The cation [Cu(OTf) (PhCONHOMe)2]+ (302) was evidenced by ESI−MS analysis, which underwent hydrogen abstraction to form the nitrogen-centered radical Cu(II) species 303. The selective cross-coupling of 303 and the carbon-centered radical 304 afforded complex 305.

4.2. Carbon Radical/Nitrogen Radical Cross-Coupling

With more efforts focusing on radical−radical cross-coupling, research has not been limited to C−C bond formation; several methodologies have been developed to construct C−N bonds. Lei and co-workers developed a nickel-catalyzed oxidative C(sp3)−H/N−H cross-coupling reaction between aliphatic hydrocarbons and N-alkoxyamides 297 (Scheme 164).205 Ni(acac)2 was used as the catalyst combined with DTBP as the oxidant. A variety of ethers, benzylic hydrocarbons, and even simple alkanes could also be tolerated in this transformation. It was believed that the reaction proceeded through a transition-metal-assisted oxidative radical/radical cross-coupling process of generated nitrogen radical 298 and α-alkoxyl carboncentered radical 299. Although both of these species belong to the class of transient radicals due to their high reactivity, the nickel catalyst performs a crucial role in stabilizing the nitrogen radical (Scheme 165). An intermolecular competition experiment between THF and THF-d8 was performed, whereby the reaction exhibited nearly the same isotopic effects both with and without the nickel catalyst, revealing that the critical step of this 9054


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radical/radical cross-coupling happened between the nitrogencentered radical and the acyl radical in this transformation. Apart from the several cross-coupling protocols mentioned above, an essential visible-light-induced methodology utilizing photoredox catalysis has also been paid much attention. In 2016,

Scheme 166. Copper-Catalyzed C−H/N−H Radical/Radical Cross-Coupling

Scheme 169. Photoinduced Benzylic C−H Azidation

Chen and co-workers reported a visible-light-induced azidation and halogenation of tertiary aliphatic C−H bonds (Scheme 168). In this case, Ru(bpy)3Cl2 was used as the photosensitizer at room temperature. TEMPO was found to almost entirely suppress the reaction, and the azidation reactions were consistent with the radical-chain mechanisms proposed. The iodanyl radical and the azido radical might be generated after the homolytic cleavage of the I−N3 bond in 307.208 Greaney and co-workers reported an azidation of benzylic C−H groups by a copper photoredox catalyst and the Zhdankin reagent (Scheme 169).209 A Scheme 170. Visible-Light-Mediated Amination of Phenols Using Cyclic Anilines 308

Scheme 167. AIBN-Catalyzed Amidation of Aldehydes with N-Chloroamines

Finally, 305 released Cu(OTf)2 and produced the corresponding product to complete the catalytic cycle. Without using a transition metal catalyst, Singh and coworkers reported an AIBN-catalyzed amidation of aldehydes with N-chloroamines 306 as another alternative (Scheme 167).207 AIBN was utilized as the radical initiator, and TBHP was used as the oxidant under metal-free and base-free conditions. A variety of primary and secondary N-chloroamines were tolerated in this reaction. The process was totally suppressed in radical trapping experiments, suggesting the involvement of radical intermediates. It was proposed that a

photoinduced C(sp3)−H azidation was also presented by Kamijo and co-workers for the construction of aliphatic azides. The reaction was conducted in the presence of 4-benzoylpyridine with irradiation by 365 nm LEDs, and using tosyl azide as the azide source.210 Recently, Xia and co-workers have realized a visible-lightmediated amination of phenols in the absence of photocatalyst, using cyclic anilines 308 with single regioselectivity through a radical cross-dehydrogenative coupling process (Scheme 170).211 K2S2O8 was utilized as the oxidant at room temperature. A gram-scale reaction was successfully conducted with TMSprotected sesamol, while Ac- and Bz-protected sesamols failed to generate any products. The C−N product 309 was generated via the selective coupling of the phenoxonium radical 310 and the transient N-radical 311. Another approach to a radical crossdehydrogenative coupling for the amination of phenols was reported by Patureau and Jin, utilizing sodium periodate as oxidant at 40 °C.212

Scheme 168. Visible-Light-Induced Azidation and Halogenation of Tertiary Aliphatic C−H Bonds

4.3. Carbon Radical/Oxygen Radical Cross-Coupling

The direct oxidative cross-coupling of hydrocarbons with oxycompounds has emerged as a promising method for the construction of C−O bonds. The nitroxide radical is one of the most well-known persistent radicals, due to its relatively long lifetime. Therefore, it is possible to achieve the selective coupling of several radicals with the nitroxide radical for the construction of C−O bonds. In 2008, Chang and co-workers described a 9055


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developed a similar C−O bond formation by using an n-Bu4NI/tBuOOH system.214

Scheme 171. Copper-Catalyzed Oxygenation of Benzyl and Allylic C−H Bonds

Scheme 174. Visible-Light-Induced α-Oxyamination

Similarly, the 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO), as a persistent radical, has also been employed in this radical cross-coupling methodology. In 2008, Studer and coworkers reported an NHC-catalyzed oxidation of aldehydes with TEMPO as the oxidant (Scheme 173).215

copper-catalyzed oxygenation of compounds containing benzyl and allylic C−H bonds (312) with N-hydroxyphthalimide (313) Scheme 172. Proposed Mechanism

Scheme 175. Cu-Mediated α-Aminoxylation of 1,3Dicarbonyl Compounds

Later, Tan and co-workers reported a visible light-induced αoxyamination reactions between TEMPO and 1,3-dicarbonyl compounds using Rose Bengal as the photocatalyst (Scheme 174).216 Notably, this metal-free reaction also proceeded smoothly in water. A strongly electron-deficient aromatic βketoester gave a faster reaction than electron-rich substrates. No reaction was observed with alkyl ketones. The mechanism was

(Scheme 171). N-Oxy radical (PINO), generated in situ from the NHPI precursor, was not only employed as a reactive catalytic species for C−H activation, but also as a stoichiometric reactant for the C−O bond formation.213 A relatively high KIE value (KH/KD = 10.8) was determined in this reaction, indicating that a quantum tunneling effect might be involved, and that the rate-limiting step is possibly the hydrogen abstraction from available hydrocarbons. In the proposed mechanism (Scheme 172), the CuCl played the role of catalytic activator of PhI(OAc)2, resulting in the formation of an acetoxychlorocopper species, which then transformed NHPI (313) to the PINO radical 314. The alkyl radical 315 was then formed by hydrogen abstraction from the hydrocarbons by PINO. This might be the rate-determining step in the transformation. Later, the recombination of 315 and 314 provided the desired PINO adducts 316. Du and co-workers

Scheme 176. Photocatalyzed Oxygenation of Cycloalkane

further studied through control experiments and DFT calculations. In 2014, Deng and co-workers also reported a Cumediated α-aminoxylation of 1,3-dicarbonyl compounds with TEMPO and its derivatives as oxygen sources (Scheme 175).217 Molecular dioxygen (O2) is another example of a stable radical that can easily trap in situ-generated transient radicals, for example, benzylic radicals, for selective C−H aerobic oxygenation reactions.218−224 As a representative example, Fukuzumi and co-workers reported a metal-free photocatalyzed oxygenation of cycloalkane 317 to achieve cyclohexanone, cyclohexanol, and hydrogen peroxide in 2011 (Scheme 176).225 The combination of Acr+-Mes 318 and HCl was utilized as the catalyst under visible-light irradiation. This suggested a chain radical pathway with cleavage of the C−H bond of the cyclohexane followed by the addition of O2 to generate the cyclohexyl peroxyl radical.

Scheme 173. NHC-Catalyzed Oxidation of Aldehydes with TEMPO

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demonstrated a visible-light-triggered thiolation of α-C(sp3)−H groups of ethers using disulfides. Acridine red was employed as the photocatalyst and TBHP was utilized as the oxidant under air (Scheme 179).229 The addition of TEMPO totally inhibited the process, and a radical intermediate captured by TEMPO was also detected. KIE experiments showed that the C−H cleavage was the rate-limiting step. In the presence of molecular sieves, Li and co-workers described an efficient oxidative thiolation at the C(sp3)−H bond adjacent to the N atom with disulfides (Scheme 180).230 TBHP was used as the oxidant under metal-free conditions. Notably, the N−CH2 group reacted preferentially over the N−Me group in this reaction. This protocol could also be applied for the synthesis of benzothiazoles. Besides disulfides, diselenides, as analogous substrates with similar chemical reactivity, were applied to a metal-free C(sp3)− H functionalization of methyl arenes for the synthesis of selenide ethers and thioesters by Lee and co-workers (Scheme 181a).231 DTBP was employed as the oxidant under solvent-free conditions. Both diaryl and dialkyl diselenides and disulfides were found to be viable coupling partners. The thioesters could also be generated from methyl arenes and disulfides (Scheme 181b). The authors also demonstrated a metal-free crosscoupling between aldehydes and disulfides. Steric hindrance and electronic nature had little influence on the efficiency of the reaction; however, alkyl aldehydes were not tolerated in this transformation.232 Similarly, using TBP as oxidant, a metal-free oxidative coupling between aldehydes and disulfides or diselenides was achieved by Sun and co-workers (Scheme 182a).233 A number of alkyl disulfides were well tolerated, whereas electron-rich groups on the benzene ring of aldehydes were observed to decrease the yields. A series of aliphatic and heterocyclic aromatic aldehydes were also found to be suitable for this transformation. Later, Wu and co-workers demonstrated a metal-free α-arylchalcogenation of acetone using diaryl dichalcogenides with a 2:1 mixture of TBHP and DTBP as the oxidant (Scheme 182b).234 A range of diaryl disulfides were viable in this transformation, but only trace yields were obtained in the presence of nitro and amino substituents. Unfortunately, this transformation was exclusively limited to acetone. Wang and co-workers reported a silver/copper-cocatalyzed sulfenylation and selenylation of electron-rich arenes with aryl disulfides 323 and diselenides 324 (Scheme 183).235 In this reaction, AgSbF6 combined with Cu(OAc)2·H2O was used as the oxidant in solvent DCE, making the reaction conditions mild and allowing excellent functional group tolerance and high

Scheme 177. Thiolation of Ethers with Disulfides

4.4. Carbon Radical/Sulfur Radical Cross-Coupling

Organosulfur compounds are widely found in nature. Transitionmetal-catalyzed C−S bond formation has received wide attention and has been applied in pharmaceutical synthesis.226 Disulfide bonds are weak and can undergo rapid cleavage under mild conditions. In other words, the dimerization of two sulfur radicals and the homolytic cleavage of disulfides can be in equilibrium. Therefore, disulfides can act as stored intermediates for sulfur radicals in selective radical cross-coupling processes. In 2013, Xiang and co-workers demonstrated the thiolation of ethers with disulfides 319 via oxidation of C(sp3)−H bonds (Scheme 177). DTBP was used as the oxidant in the solvent dioxane in the absence of a metal catalyst.227 In the proposed mechanism, the tert-butoxyl radical was formed after the decomposition of DTBP. This abstracted a hydrogen atom from the ether to produce the carbon radical intermediate 321, which then reacted with 319 to provide the desired product and radical 322. The selective cross-coupling of radicals 321 and 322 furnished the product 320. Similarly, Sun and co-workers exploited a metal-free methodology for the construction of C−S bonds via direct oxidative functionalization of the C(sp3)−H bonds in alkanes (Scheme 178).228 Utilizing TBP as the oxidant in an argon atmosphere, the reaction proceeded smoothly. Notably, air and O2 inhibited the reaction to a great extent. In addition, C−Se bonds could also be formed in this reaction system. Recently, Wang and co-workers Scheme 178. Direct Oxidative Thiolation of Alkanes

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Scheme 179. Visible-Light-Triggered Thiolation of α-C(sp3)−H Bonds of Ethers

Scheme 180. Oxidative Thiolation at C(sp3)−H Bonds Adjacent to a N Atom with Disulfides

Scheme 184. Oxidative Radical Cross-Coupling for Asymmetric Diaryl Thioethers

Scheme 181. Metal-Free C(sp3)−H Functionalization of Methyl Arenes for the Synthesis of Selenide Ethers and Thioesters

Scheme 182. Oxidative Coupling between Aldehydes and Disulfides or Diselenides

electronic nature of the thiols had no significant influence on the yields, and halide substituents were also tolerated. Moreover, substrates bearing a mercapto group on the heteroaromatic ring were also compatible. The involvement of radical intermediates in this transformation was confirmed through radical-inhibition experiments. In addition, DFT calculations and kinetic experiments were also conducted to study the process further, indicating that the formation of an aryl radical cation (and not the C−H bond cleavage) was the rate-limiting step. In the proposed mechanism (Scheme 185), 4-chlorobenzenethiol was oxidized by DDQ via a HAT process to afford the thiyl radical 325, which was then stabilized by the formation of persistent radical [DDQ-326]•. On the other hand, 1,3,5-trimethoxybenzene was converted into aryl radical cation 327 through a SET process. Radical cross-coupling between 327 and 326 then afforded cation intermediate 328, followed by deprotonation of the intermediate to yield the C−S product 329.

Scheme 183. Sulfenylation and Selenylation of Electron-Rich Arenes

4.5. Carbon Radical/Phosphonyl Radical Cross-Coupling

In 2015, Lei and co-workers reported a Cu-catalyzed selective radical/radical C(sp3)−H/P−H cross-coupling for the construction of C−P bonds (Scheme 186).237 This furnished a direct method for the synthesis of β-ketophosphonates via the oxidative coupling between aryl ketone o-acetyloximes 330 and phosphine oxides 331. CuCl was employed as the catalyst, and PCy3 was added as the ligand in dioxane. The ketone o-acetyloximes acted not only as reaction substrates but also as internal oxidants. According to EPR, iminium radicals, derived from the reduction of ketone o-acetyloximes, could be converted to α-sp3-carbon radical species via isomerization of 332. The oxidation of phosphine oxides by CuII could produce phosphorus radicals. The radical cross-coupling between carbon radical 332 and phosphorus radicals 333 is the key step in the C−P bond construction.

regioselectivity. Recently, Lei and co-workers developed a similar oxidative radical cross-coupling for the synthesis of asymmetric diaryl thioethers mediated by DDQ (Scheme 184).236 In this report, DDQ was used as the oxidant under N2 protection. The 9058


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Scheme 186. Cu-Catalyzed Selective Radical/Radical C(sp3)−H/P−H Cross-Coupling

Scheme 187. Direct ortho-Acylation of Arenes Using Pyridyl as the Directing Group

5. COUPLING OF RADICALS AND M−R GROUPS

directing group. In 2010, using pyridyl as a directing group, Li and co-workers achieved a palladium-catalyzed direct orthoacylation of arenes with both aromatic and aliphatic aldehydes by using tert-butyl hydroperoxide (TBHP) as oxidant under solvent-free conditions (Scheme 187).239 It is worth mentioning that the natural product citronellal was tolerated under the oxidative conditions and produced the desired ketone product in good yield without racemization. Mechanistic studies indicated that a Pd(II)/Pd(0) catalytic cycle involving the direct reaction of the palladium complex with aldehydes and β-hydride elimination can be ruled out, while the interaction of the acyl

5.1. Coupling of Radicals with Pd−R Groups

Recent advances have been made in Pd-catalyzed regioselective direct C−H functionalizations involving a carbon-centered radical.238 A wide range of compounds containing directing groups such as pyridyl, imino, alkoxycarbonyl, carbonyl, oxazolino, amido, and cyano groups undergo ortho functionalization via ortho-C−H bond cleavage under palladium catalysis. 5.1.1. Nitrogen Heterocyclic Rings as Directing Groups. It is well-known that an aryl palladium species can be accessed through C(sp2)−H bond activation assisted by a pyridyl 9059


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Scheme 188. Direct ortho-Acylation of Arenes Using Azole as the Directing Group

of corresponding acylated products could be isolated from both aromatic and aliphatic aldehydes without the use of additives (Scheme 188b).241 Patel and co-workers also developed the ortho-acylation of other 2-aryl heterocyclic compounds, such as

radical 335 with organopalladium(II) complex 334 is the key step in this transformation. Similar to 2-arylpyridine, assisted by the benzoxazole directing group, the palladium-catalyzed ortho-acylation of 2-arylbenzoxazoles was achieved by Wu and Yang in 2013. In the presence of TBHP as the oxidant, aldehydes can be applied as easily

Scheme 190. Direct ortho-Aroylation of 2-Phenoxypyridines 336

Scheme 189. Palladium-Catalyzed Acylation of 2-Aryl-1,2,3triazoles and 6-Anilinopurines

3,5-diarylisoxazoles (Scheme 188c)242 and 2,3-diarylquinoxalines with the Pd/TBHP system (Scheme 188d).243 Assisted by 1,2,3-triazolyl directing groups, the palladiumcatalyzed acylation of 2-aryl-1,2,3-triazoles with aldehydes was achieved by Kuang and co-workers in 2014 (Scheme 189). A wide variety of products were isolated in good to excellent yields.244 A year later, Swamy and co-workers developed a palladium-catalyzed ortho-acylation of 6-anilinopurines with aldehydes or α-oxocarboxylic acids as acylating sources. The purinyl group served as the directing group in this transformation. The protocol was also successfully applied to 6anilinopurine nucleosides.245 Similarly, the direct ortho-aroylation of 2-phenoxypyridines 336 with aldehydes was developed by Chu, Wu, and co-workers using palladium acetate as catalyst and tert-butyl hydroperoxide (TBHP) as oxidant (Scheme 190).246 Moreover, on the basis of intra- and intermolecular kinetic isotope effects, radical trapping, and control experiments, an intermediate Pd III or Pd IV

accessible acyl sources to furnish acylated 2-arylbenzoxazoles in moderate to good yields. Furthermore, other heterocycles, such as 2-phenylbenzothiazole and benzo[h]quinolone, could also be applied as substrates to afford the corresponding products in excellent yields, while no conversion was observed by using benzimidazole as the directing group (Scheme 188a).240 The same year, Patel and co-workers achieved another procedure for ortho-aroylation of 2-arylbenzoxazoles. Good to excellent yields 9060


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Scheme 191. Direct Acylation of Indoles

coordination compound was proposed to be involved in the transformation. Indoles are a class of compounds known to have a range of pharmacological effects. The introduction of heterocyclic aromatic directing groups on the nitrogen atoms of the indoles can realize regioselective C2-acylation processes via C−H bond activation. Liu and co-workers developed an efficient protocol for the Pd-catalyzed C2-acylation of pyridine-protected indoles,


Scheme 192. Direct ortho-C−H Acylation of Aromatic Oxime Ethers 337

which allows for the use of aromatic, aliphatic, and conjugated aldehydes as acyl sources, utilizing TBHP as oxidant and PivOH as an additive (Scheme 191a).247 With N-pyrimidine-protected indoles as substrates and aldehydes as the coupling partners, 2aroylindoles were produced in moderate to good yields in the group of Sekar (Scheme 191b).248 Conversely, without the directing group, Kianmehr reported that the Pd-catalyzed oxidative acylation of indoles with aldehydes occurs at the 3position of indoles (Scheme 191c).249 3-Benzoylbenzofurans and 3-benzoylbenzothiophenes were also produced in good yields by a cross-dehydrogenative coupling reaction with TBHP as the oxidant in chlorobenzene at 120 °C (Scheme 191d).250 5.1.2. Ketone Oxime Ethers as the Directing Groups. In 2010, Yu and co-workers applied an analogous strategy in the direct ortho-C−H acylation of aromatic oxime ethers 337, providing a versatile route to 1,2-diacylbenzenes after depro-

Scheme 194. Oxidative Acylation of Methyl Ketone Oxime Derivatives 342

tection of the oxime group (Scheme 192).251 Good functional group tolerance was exhibited in this direct acylation reaction. 9061


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Scheme 197. Palladium-Catalyzed ortho-Acylation of NBenzyltriflamides 346

Aromatic, aliphatic, and heteroaromatic aldehydes could all be coupled with aromatic oxime ethers to afford corresponding ketones with remarkable regioselectivity. A plausible mechanism is shown in Scheme 193. First, the oxime-directed ortho-selective cyclometalation on the arene ring gave palladacycle complex 338. Subsequent interaction between the palladacycle with the acyl radicals 339, generated in situ by hydrogen atom abstraction of the aldehydes, would afford the desired product ketone 340 via the reductive elimination of either reactive Pd(IV) or dimeric Pd(III) intermediate 341. More recently, a Pd(OAc)2 and NHPI cocatalyzed aerobic oxidative acylation of methyl ketone oxime derivatives 342 with aldehydes has been reported by Jiao (Scheme 194).252 Molecular oxygen, a more environmentally friendly oxidant, was used as the

added to the reaction. In 2014, the same group also reported a three-step, one-pot reaction sequence involving the acylation of Scheme 198. ortho-Acylation of Azoxybenzene

Scheme 195. ortho-Acylation of Anilides

anilines, palladium-catalyzed acylation of anilides, and hydrolytic cleavage for the synthesis of aminobenzophenone derivatives 345 (Scheme 196).257 The palladium-catalyzed ortho-acylation of N-benzyltriflamides 346 with aldehydes was reported by Kim and co-workers (Scheme 197).258 In the presence of palladium acetate, acetic acid, and TBHP, triflamide-protected benzylamines were effectively coupled with aryl and alkyl aldehydes and provided the desired ortho-acyl-N-benzyltriflamides in good yields with high regioselectivity.

terminal oxidant in the reaction. This reaction exhibited good tolerance for a broad range of functional groups and a variety of aldehydes. Moreover, the acylation reaction proceeded smoothly for the pyridine-containing substrates, such as benzo[h]quinoline, 1-phenylpyrazole, 2-phenylpyridine, and 2-phenoxypyridine. However, it was not efficient for azobenzene and acetanilide, affording the corresponding products in relatively low yields. An intermolecular KIE experiment indicated that the C−H activation process is irreversible in this transformation. 5.1.3. Anilides as Directing Groups. Using a palladiumcatalyzed direct C−H activation strategy, the ortho-acylation of anilides was separately reported by the groups of Yu,253 Kwong,254 and Wang255 in 2011. In Yu’s work, aliphatic, aromatic, and heteroaromatic aldehydes could be applied as effective acylation reagents to generate 2-aminobenzophenone derivatives 343 with good regioselectivity and functional group tolerance (Scheme 195). This reaction was considered to proceed through the reactive Pd(IV) or dimeric Pd(III) key intermediates 344. A primary KIE value (kH/kD) of 3.6 was measured, which indicated that the C−H activation of the anilide is involved in the rate-determining step of the reaction. In 2013, Novak and co-workers further improved the acylation of anilides with aromatic aldehydes under mild aqueous conditions by palladium catalysis.256 To ensure better solubility of the organic reactants in water, 0.5 mol % sodium dodecyl sulfate (SDS) was

Scheme 199. Direct Acylation of Aromatic Azo Compounds

5.1.4. Azoxy Groups as Directing Groups. As a directing group, azoxy groups can assist the palladium-catalyzed radical ortho-acylation of C(sp2)−H bonds. In 2014, Sun and coworkers developed a regioselective ortho-acylation of azoxybenzene with aldehydes in the presence of Pd(TFA)2 and peroxide (TBHP) (Scheme 198). A range of desired products were formed in good to excellent yields with good functional group tolerance.259 In addition, the ortho-acylated azoxybenzenes could be easily transformed into the corresponding indazoles backbone under reductive conditions. A similar procedure was later developed by Cui, Wu, and co-workers using Pd(OAc)2 as the

Scheme 196. One-Pot Reaction Sequence Involving the Acylation of Anilines

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Scheme 200. Pd-Catalyzed C−H Activation/Annulation for Hydroxyl Isoindolones 348

A new method for the Pd(II)-catalyzed C−H acylation of 2phosphorylbiphenyl 352 with α-oxocarboxylic acids, aldehydes, alcohols, and toluene was developed by Yang and co-workers (Scheme 203).265 In contrast to previous examples, the R2(O)P group not only acted as the directing group but also as a ligand. Various substituted 2′-phosphorylbiphenyl-2-acyl compounds could be achieved in good yields with good functional group tolerance using different acylation reagents.

Scheme 201. Direct C−H Acylation/Rearrangement of Aryl Amides with Aldehydes

5.2. Coupling of Radicals with Cu−R Groups

5.2.1. C−N Bond Formation. Cundari, Warren, and coworkers reported a β-diketiminato copper(I) complex [(Cl2NN)Cu2(μ-benzene)], which enables the amination of C(sp3)−H bonds of Indane, ethylbenzene, and even cyclohexane with unactivated primary and secondary alkyl amines, employing DTBP as the oxidant. Initially, the Cu(I) complex could be oxidized by DTBP and then reacts with the amine to afford Cu(II) species 353. This Cu complex abstracts one H atom from a hydrocarbon substrate to afford copper(I)−amine adduct [(Cl2NN)Cu-(NH2Ad)] (354) and an organic radical (355). Radical coupling between carbon radical 355 and Cu(II) species 353 then occurs to afford the C−N product 356 (Scheme 204).266 Later, the authors expanded this C−H amination protocol to aromatic amine substrates. A variety of hydrocarbon substrates, such as cyclohexane, toluene, and ethylbenzene, gave the corresponding C−H amination product 357 with anilines when employing the copper(I) catalyst [(Cl 2 NN)Cu]2(benzene) in conjunction with the oxidant tBuOOtBu (Scheme 205).267 Decreasing the concentration of the copper catalyst and using aniline substrates with electron-withdrawing functional groups efficiently enhanced the formation of C−H amination products with a concomitant reduction of the diazene. With simple (sulfon)amides and imides, Hartwig and coworkers also reported a copper-catalyzed intermolecular amidation and imidation of unactivated alkanes, affording the corresponding N-alkyl products 358 (Scheme 206).268 In the presence of CuI and DTBP with (MeO)2Phen as the ligand, the amidation of alkanes preferentially forms the products at secondary sites over tertiary sites in moderate to good yields. Furthermore, on the basis of the kinetic isotope effect and radical-trapping experiments, a plausible mechanism was proposed wherein [(phen)Cu(phth)] 359 and [(phen)Cu(phth)2] 360 are potential intermediates and the turnoverlimiting step (TLS) is the C−H cleavage of cyclohexane by a tertbutoxy radical in the catalytic reaction (Scheme 207). Similarly, Huang and co-workers demonstrated a coppercatalyzed amination of inactive aliphatic alkanes and benzylic

catalyst at 80 °C. As compared to Sun’s procedure, aliphatic aldehydes gave lower yields and heteroaryl aldehydes could not be applied, which showed the importance of reaction temperature.260 Wang and co-workers also reported the acylation of azobenzenes to the desired acylated azobenzenes with aldehydes in good yields (Scheme 199).261 5.1.5. Amides as Directing Groups. In 2013, Zhao, Huang, and co-workers achieved an interesting Pd-catalyzed C−H activation/annulation reaction for the efficient synthesis of hydroxyl isoindolones 348 (Scheme 200).262 The reaction could be completed in a few minutes with N-substituted benzamides 347 and aldehydes as the substrates. Surprisingly, biaryl imino/ keto carboxylic acids 349 could be prepared from the same substrates by simple addition of the Lewis acid BF3·Et2O, which promoted aryl-amide-directed C−H acylation followed by ringclosing and ring-opening to afford the corresponding products (Scheme 201).263 5.1.6. Other Directing Groups. Apart from the general directing groups mentioned above, other groups have also been employed to assist the direct and novel synthesis of the corresponding products. Wang and Zhao reported a palladiumcatalyzed intermolecular [4+1] annulation for the synthesis of 1,2-benzoisoxazoles 351 from the coupling of N-phenoxyacetamides 350 with aldehydes in 2014 (Scheme 202).264 Following a C−H activation−acylation reaction sequence, the desired products were isolated in moderate to good yields. On the basis of DFT calculations, the authors proposed a Pd(II)− Pd(IV) catalytic cycle involving a concerted metalation− deprotonation process, which was the rate-determining step of the transformation.

Scheme 202. Palladium-Catalyzed Intermolecular [4+1] Annulation

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Scheme 203. Pd(II)-Catalyzed C−H Acylation of 2-Phosphorylbiphenyl 352

Scheme 204. Copper-Catalyzed Amination of C(sp3)−H Bonds

Scheme 208. Copper-Catalyzed Amination of Aliphatic Alkanes and Benzylic Hydrocarbons

for the traditional preactivated coupling partners. A plausible mechanism for the reaction involving a Cu(I)/Cu(II) redox process was proposed. The Cu(II) catalyst can react with sulfoximine leading to a Cu−N intermediate 362, which then interacts with the generated acyl radical to give the desired product. Recently, Kanai and co-workers have demonstrated a coppermediated intermolecular C(sp3)−H bond functionalization between isocyanates 363 and unactivated alkanes, which could provide the tertiary carbamates 364 directly, catalyzed by readily available first-row transition metal complexes with (tBuO)2 as the oxidant (Scheme 210).271 A mechanism involving a Cu(I)−Cu(II)−Cu(III) redox catalytic cycle is proposed by the authors, which is shown in Scheme 211. The Cu(II)−amide species 365 could be generated from the reaction of a tert-butoxy radical with an isocyanate and sequential oxidation of the Cu(I) species. The combination of this Cu(II)−amide complex with the in situ-generated alkyl radical 366 affords Cu(III) species 367, which can give the tertiary carbamate product after reductive elimination. The reaction had a broad substrate scope for cyclic and linear unactivated alkanes with site selectivity in the order tertiary > secondary > primary. The kinetic isotopic effects showed that the C−H bond cleavage might be the rate-determining step. 5.2.2. C−O Bond Formation. Besides C−N bond formation, diverse copper-catalyzed protocols for C−O bond formation have also attracted much attention. Li and co-workers reported a copper-catalyzed oxidative coupling of alkanes and carboxylic acids for the selective synthesis of allylic esters 368 (Scheme 212).272 This method achieves multiple dehydrogenation and esterification reactions, representing a new method for unactivated C(sp3)−H oxidative esterification of acids with common alkanes. Moreover, it was proposed that the reaction underwent the Kharasch−Sosnovsky mechanism273 (Scheme 213). In this Cu and DTBP system, a carbon-centered radical can be generated, which then reacts with the carboxylic acid copper complex to produce the desired products. Around the same time, Chaudhuri and co-workers also reported a copper-catalyzed oxidative cross-dehydrogenative coupling for the construction of α-acyloxy ethers 369 from cyclic ethers and carboxylic acids (Scheme 214).274 In this work, Cu(OAc)2 was used as a catalyst with tert-butyl hydroperoxide (TBHP) as the oxidant under atmospheric conditions. Apart

Scheme 205. C−H Amination of Aromatic Amine Substrates

Scheme 206. Amidation and Imidation of Unactivated Alkanes


hydrocarbons through the interaction of C(sp3)-centered radicals and Cu(II) species (Scheme 208).269 Notably, a low loading of tBuOK can promote the reaction without any ligands. By using CuBr as catalyst in conjunction with TBHP as oxidant, a novel dual C−H/N−H functionalization protocol for the formation of N-acylsulfoximines 361 from aldehydes was accomplished by Bolm and co-workers (Scheme 209).270 This new methodology provides an alternative method to rapidly access a diverse series of N-acylsulfoximines, avoiding the need 9064


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Scheme 209. Oxidative C−H/N−H Coupling for N-Acylsulfoximines 361

Scheme 210. Copper-Mediated Coupling between Isocyanates 363 and Unactivated Alkanes


Scheme 212. Copper-Catalyzed Oxidative Coupling of Alkanes and Carboxylic Acids for Allylic Esters 368

substrates to form the corresponding ester products. Besides salicylanilides and N,N′-dialkyl salicylamides, phenols with other directing groups, such as cyano, azo, and pyridyl, also tolerated the esterification reaction conditions. A mechanism involving a radical process is proposed in Scheme 216. The copper formed the coordination complex 370 with the directing group and then reacted with the acyl radical to obtain copper(III) intermediate 371. Subsequently, reductive elimination of this copper species afforded the product 372. 5.2.3. C−C Bond Formation. Using a similar direct functionalization strategy, Zhang, Wen, and co-workers developed a copper-catalyzed regioselective oxidative cross-

from 1,4-dioxane, THF and 1,3-dioxane also reacted smoothly, while no products were observed for diethyl ether or morpholine. A directing-group-assisted copper-catalyzed oxidative esterification of phenols with aldehydes was developed by Xuan and co-workers (Scheme 215).275 In the presence of Cu(OAc)2 and TBHP, not only substituted benzaldehydes with electrondonating and weakly electron-withdrawing groups, but also several heteroaryl and aliphatic aldehydes were applied as 9065


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benzyl radical to form the desired benzylation product 375 (Scheme 218). Ye and co-workers reported a catalytic amino-carbonylation of terminal alkynes with formamides, affording propionamides 376 in the presence of a CuH2BIP complex as catalyst (Scheme 219).277 It was found that a pincer ligand with two imidazolyl groups greatly promoted the reactivity. Control experiments indicated that the nature of the tridentate chelating ligand and N−H groups of the imidazoyl moieties plays a key role in the reaction. This reaction is highly sensitive to the electronic effects of the terminal alkyne and the steric effect of formamides, which failed to give the desired products with bulky groups. The high KIE value (KIE = 3.9) indicated that the cleavage of the formyl C−H bond is involved in the rate-determining step.

Scheme 214. Copper-Catalyzed Oxidative Coupling of Cyclic Ethers and Carboxylic Acids

Scheme 215. Copper-Catalyzed Oxidative Esterification of Phenols with Aldehydes

5.3. Coupling of Radicals with M(Ni, Mn, Ag, Fe)−R Groups

5.3.1. Radical/Ni−R. You and co-workers developed a coordinating activation strategy to illustrate a nickel-catalyzed radical oxidative coupling of α-C(sp3)−H bonds of amines with (hetero)arylmethyl free radicals (Scheme 220).278 The coordination activation of the substrates might also enable the αC(sp3)−H bonds of amines to directly trap a radical species, and further stabilizes the resulting radical intermediate of a SET process rather than the formation of an imine intermediate. The protocol tolerated a broad range of α-amino acids and (hetero)arylmethanes as well as arylmethylenes and arylmethines, to afford a large library of both α-tertiary and α-quaternary β-aromatic α-amino acids. The proposed mechanism of the reaction by the authors is depicted in Scheme 220. First, a tertbutoxy radical was generated from DTBP with the aid of a Ni(II) species. Subsequently, the 2-picolinamido α-amino-acid ester coordinated with the generated Ni(III) complex to yield the intermediate 377. The benzylic radical, formed through the interaction of arylmethane and tert-butoxy radical, attacked the α-carbon of 377 to give a radical cation intermediate 378, which then underwent an intramolecular SET with the high-valent Ni3+ to give the intermediate 379. Finally, the release of the low-valent Ni2+ species from 379 delivered the targeted product 380 and completed the catalytic cycle. Recently, photochemical nickel-catalyzed C−H arylation reactions have been achieved by the Doyle279 and Molander280 groups independently, both combining a photocatalyst with a nickel catalyst (Scheme 221). In Doyle’s work, aryl chlorides serve as both coupling partners and the chlorine radical source, while the bromine radical is thought to activate weak C(sp3)−H bonds to generate reactive alkyl radicals in Molander’s work. 5.3.2. Radical/Mn−R. A manganese-catalyzed oxidative fluorination via benzylic C−H activation was achieved by Groves (Scheme 222).281 In this transformation, a manganese porphyrin


coupling of N-pyrimidylindoles 373 with alkylarenes (Scheme 217).276 Notably, benzaldehyde proved to be an effective additive with the utilization of DTBP as a mild oxidant. A tentative mechanism revealed that the coordination-directed C−H cupration of N-(2-pyrimidyl)-indoles with Cu(II) species affords the metallacycle intermediate 374, which then interacts with a 9066


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Scheme 217. Oxidative Cross-Coupling of N-Pyrimidylindoles 373 with Alkylarenes

224. Initially, the iron catalyst reacted with the carboxylic acid and the oxidant DTBP, forming diiron(III) intermediate 384, which was further oxidized to give Fe(IV) intermediate 385. The intermediate 385 then reacted with a cyclic ether to generate intermediate 386, which subsequently undergoes a crosscoupling process to give the final product 387 and Fe(III) intermediate 384.


5.5. Cross-Coupling of Radicals with I−R Groups

Similar to metal catalysts, iodine was found to be an effective redox catalyst due to its abundant chemical valence states. Therefore, the reaction of radicals with hypervalent iodide would provide a complementary strategy for radical oxidative crosscoupling. Yu and co-workers developed an effective alkynylation of saturated heterocycloalkanes containing oxygen or nitrogen atoms with ethynylbenziodoxolones under metal-free conditions through direct α-C(sp3)−H bond activation (Scheme 225).283 In the presence of TBHP, both five- and six-membered heterocycles afforded the corresponding products in moderate to good yields with some regioselectivity. Recently, a similar concept was used by Feng, Xu, and co-workers in their elegant alkynylation of unactivated C(sp3)−H bonds with ethynylbenziodoxolones under metal-free conditions.284 In 2015, Zhu and co-workers developed a direct C−H alkynylation of an aldehyde with a hypervalent iodine alkynylation reagent 388 to provide ynones under metal-free conditions (Scheme 226).285 Various heteroaromatic, aliphatic, and α,β-unsaturated aldehydes were tested to establish the generality of this reaction. In the presence of peroxides, acyl radicals can be formed from aromatic and aliphatic aldehydes, which were trapped by TEMPO in radical inhibition experiments. At almost the same time, a direct alkynylation of C−H bonds of aldehydes with ethynylbenziodoxolones to afford ynones under metal-free conditions was described by Yu, Chen, and co-workers.286 Meanwhile, in addition to silyl-substituted EBX reagents, aryl- and alkyl-substituted EBX reagents were also applied in this transformation. This procedure was proposed to proceed through a radical pathway (Scheme 227). Initially, in the presence of TBHP or DTBP, the benzoyl radical was generated from aldehydes, which then formed a new radical intermediate (389) via the interaction between the benzoyl radical and hypervalent-iodide species 388. The final product 390 was afforded by the elimination of 389 with the formation of a benziodoxolonyl radical.

Scheme 219. Catalytic Amino-carbonylation of Terminal Alkynes with Formamides

381 was utilized as catalyst, and TREAT·HF and AgF were employed as fluorine sources, along with PhIO in acetonitrile. This protocol could be used to synthesize the benzylic fluorides via easily handled nucleophilic fluoride reagents without directing groups. On the basis of DFT calculations, the transition state for the fluorine transfer step and a linear Mn−F−C geometry resulted in relatively low enantioselectivities on a related manganese porphyrin system (Scheme 223). The key step leading to C−F bond formation is the interaction of a benzyl radical 383 and a [MnIV(salen)F2] complex 382.

5.6. Coupling of Radicals with N−F Groups

5.4. Cross-Coupling of Radicals and Fe−R Groups

Catalytic C−H fluorination reactions have been developed to introduce fluorine atoms directly without prior functionalization. Inoue and co-workers reported a direct conversion of benzylic C−H bonds to C(sp3)−F bonds.287 In this transformation, a system composed of N,N-dihydroxypyromellitimide (391) and Selectfluor (392) was used to promote the process (Scheme 228). The NDHPI generated the N-oxyl radical through hydrogen abstraction from the benzylic C−H bonds. The Selectfluor then trapped the resulting carbon radical to generate

Han and co-workers reported an iron-catalyzed oxidative esterification between carboxylic acids and unactivated C(sp3)−H bonds from symmetric and asymmetric ethers, which might proceed through a radical oxidative coupling mechanism involving a diiron(III) intermediate (Scheme 224).282 Various carboxylic acids and several ethers were well tolerated in this catalytic system with moderate to excellent yields and high regioselectivities. A plausible mechanism is depicted in Scheme 9067


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Scheme 220. Radical Oxidative Coupling of α-C(sp3)−H Bonds of Amines

Scheme 221. Photochemical Nickel-Catalyzed C−H Arylation


Scheme 222. Manganese-Catalyzed Oxidative Fluorination via Benzylic C−H Activation

using 1,2,4,5-tetracyanobenzene (TCB) as the photocatalyst (Scheme 229b).289 Unactivated C−H bonds, such as C(sp3)−H bonds, are still a significant challenge for fluorination due to the current sophistication in fluorination reagents and processes. However, this strategy would provide a means to block site-selective metabolic degradation of drugs as well as novel methods of smallmolecule synthesis. Recently, traditional transient-metal-catalyzed and visible-light-photocatalyzed methods for C(sp3)−H fluorination have been reported by chemists. A radical-based mechanism has been investigated.290 Copper(I) was oxidized to

the C(sp3)−F bond. A variety of aromatic and aliphatic compounds served as efficient tools for the synthesis of fluorinated molecules. Later, the direct fluorination of benzylic C−H bonds with N-fluorobenzenesulfonimide was demonstrated by Britton (Scheme 229a).288 This process was mediated by either a decatungstate photocatalyst or by AIBN-initiation. Lectka and co-workers reported the photocatalyzed oxidation of benzylic compounds for the construction of benzylic fluorides 9068


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Scheme 224. Iron-Catalyzed Oxidative Esterification between Carboxylic Acids and Unactivated C(sp3)−H Bonds

Scheme 226. Direct C−H Alkynylation of Aldehydes

A photocatalytic system has also been used for C−F bond formation. Chen and co-workers reported a visible-lightpromoted metal-free C(sp 3 )−H fluorination (Scheme 232a).292 In this case, photoexcited acetophenone was used as the photocatalyst through irradiation by a household compact fluorescent lamp (CFL). The same process was demonstrated by Britton (Scheme 232b) utilizing the tetrabutylammonium salt of decatungstate (TBADT)/N-fluorobenzenesulfonimide (NFASI) with the addition of NaHCO3 to promote the process of fluorination.293 Recently, Sorensen and co-workers also used a visible-light photocatalyst for C(sp3)−H bond fluorination (Scheme 232c) using UO2(NO3)2·6H2O as catalyst with the combination of fluorine atom source NFSI.294 The general mechanism of C(sp3)−H fluorination under visible-light-catalyzed conditions has been studied and reported in Scheme 233. An alkyl radical could be obtained by the activated photocatalyst via a radical C(sp3)−H bond activation. The alkyl radical would then form the desired C−F bond by the interaction with fluorine atom sources (F-NRn) such as NFSI or Selectfluor. The radical of RnN returns the photoreduced HAT catalyst to the initial state to undergo further reaction. Tang and co-workers also demonstrated a silver-catalyzed benzylic C−H fluorination reaction for the synthesis of difluoromethylated arenes (Scheme 234).295 Commercially available Selectfluor was chosen as the fluorine source for various methylated arenes. This procedure proceeds via the activation/fluorination of benzylic C−H bonds using AgNO3 as catalyst and Na2S2O8 as oxidant in aqueous solution. The intermolecular KIE showed that the rate-limiting step might be the C−H bond cleavage. The proposed mechanism indicated that the procedure may involve a single-electron transfer (SET) or a radical-chain process in the transformation. The benzylic radical 396 was generated from oxidization of the benzylic C−H bond by the silver(II) species. The radical coupling of Selectfluor and the benzylic radical 396 then formed monofluorinated intermediate 397. This intermediate could generate a further benzylic radical (398) with the silver(II) species, and then produce difluoromethylated products 399 with Selectfluor.

copper(II) with a loss in fluoride from Selectfluor as a result of the inner-sphere SET reaction between copper and Selectfluor. The generated radical dication species 393 then abstracted a hydrogen atom from the alkanes to yield alkyl radicals 394. The product 395 was formed via the reaction between radical 394 and Selectfluor (392) (Scheme 230). In 2014, the Chen and coworkers demonstrated vanadium-catalyzed C(sp3)−H fluorination reactions with Selectfluor (Scheme 231).291 This provided a method to introduce a fluorine atom to the tertiary position of Lmenthone and 1,4-cineole selectively. Ten mol % V2O3 was utilized as the catalyst with 1.5 equiv of Selectfluor in acetonitrile. A KIE experiment (KH/KD = 4) indicated that C−H abstraction to form an alkyl radical was the rate-limiting step in the radical process. Scheme 225. Alkynylation of Cycloalkanes

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Scheme 228. Direct Conversion of Benzylic C−H Bonds to C(sp3)−F Bonds

Scheme 229. Direct Fluorination of Benzylic C−H Bonds

6. RADICAL COUPLING OF RADICAL CATION/NUCLEOPHILES

which are much more electrophilic than the neutral substrate.296,297 Subsequent nucleophilic attack and further oxidation of this radical ion species lead to C−H functionalization of these substrates under oxidative conditions (Scheme 235). Such electron-transfer-induced coupling reactions have

Radical ions are important intermediates in synthetic chemistry. The electron transfer from unsaturated substrates by a photocatalyst, electricity, or an oxidant produces radical cations, 9070


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Scheme 230. Copper-Catalyzed C(sp3)−H Fluorination

Scheme 234. Sliver-Catalyzed Benzylic C−H Fluorination

Scheme 231. Vanadium-Catalyzed C(sp3)−H Fluorination

attracted increasing attention because they provide powerful tools for environmentally benign synthesis. In this regard, we summarize the representative work on aromatic C−H functionalization via arene radical cations. 6.1. Radical Cation Formation via Photoredox Catalysis

Various compounds become redox-active upon photoexcitation and can promote a broad scope of one-electron oxidation or reduction processes. In 2011, Fukuzumi and co-workers disclosed that the highly oxidizing 3-cyano-1-methylquinolinium ion (QuCN+) can act as an efficient photosensitizer to achieve the single-electron oxidation of benzene to generate a radical cation. Through this intermediate, aryl C−H functionalization of benzene and other arenes was achieved with oxygen,298 and fluoride299 nucleophiles using O2 as the oxidant. Phenol is one of the most important chemicals in industry and can be formed via the direct oxygenation of benzene with water. Fukuzumi and coworkers have reported an efficient photocatalytic method for the selective oxygenation of benzene to phenol with dioxygen (O2) and water (H2O) (Scheme 236). The mechanism of the oxygenation process is shown in Scheme 237. The single-electron transfer of benzene to the singlet excited state of QuCN+ provided the benzene radical cation, which reversibly forms a π-dimer radical cation complex 400 with benzene. Nanosecond laser flash photolysis measurements showed that water acts as a nucleophile to trap the benzene radical cation to yield OH-adduct radical 401. Further hydrogen abstraction of OH-adduct radical 401 by hydroperoxyl radical HO2• (generated from the reduction of O2 by QuCN•) and protonation of superoxide afforded phenol and hydrogen peroxide. When alcohols were used as nucleophiles, photocatalytic alkoxylation of benzene with O2 using the 3-cyano-1methylquinolinium ion to yield the corresponding alkoxybenzenes followed a similar mechanism except for the reaction of the benzene radical cation with ROH instead of H2O. The photocatalytic oxygenation of benzene to phenol under visible-light conditions was further improved by using 2,3dichloro-5,6-dicyano-p-benzoquinone (DDQ) as the photosensitizer (Scheme 238).300 Visible-light-excited DDQ spontaneously provides a long-lived triplet excited state, which has a very strong oxidizing ability and is capable of oxidizing unreactive

Scheme 232. Photoinduced C(sp3)−H Bond Fluorination

Scheme 233. Proposed Mechanism of C(sp3)−H Fluorination under Visible Light

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Scheme 235. Reaction Model of Radical Cation/Nucleophile Coupling

Scheme 236. Single-Electron Oxidation of Benzene by QuCN+

Scheme 237. Proposed Mechanism of the Oxygenation of Benzene


Scheme 240. Photocatalytic C−H Bromination of Anisole Derivatives

Scheme 238. Photocatalytic Oxygenation of Benzene Using DDQ as the Photosensitizer

for arenes without overoxidation of the phenol product might be due to the back electron transfer (BET) process for the phenol cation radical, which is likely to be much faster than the reaction with H2O. A selective photocatalytic C−H bromination of anisole and derivatives with hydrogen bromide to construct the monobrominated product 406 was also developed by using the 9mesityl-10-methylacridinium ion (Acr+-Mes) under visible-light irradiation.301 As a photocatalyst, Mes-Acr-Me+ has attracted increasing attention in photocatalytic organic transformations due to its long-lived triplet state and strong oxidizing ability. In work by Fukuzumi and co-workers, photocatalytic C−H bromination could be achieved by using O2 as the oxidant (Scheme 240). The transformation followed a mechanism

substrates such as benzene. Using a xenon lamp (500 W) with a color glass filter (λ = 390−600 nm), irradiation of DDQ in oxygen-saturated acetonitrile containing benzene and H2O produced phenol and DDQH2 with 99% conversion. In accordance with the proposed mechanism (Scheme 239), followed by the photoinduced electron transfer between benzene and the triplet excited state of DDQ, water would add to the benzene cation radical 402 to produce the OH-adduct radical 403. On the other hand, DDQ•− 404 reacted with the OHadduct radical 403 to form phenol and DDQH2 (405). DDQH2 then was oxidized by reaction with TBN and O2, via NO2, to regenerate DDQ. The selectivity of the C−H functionalization 9072


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the yields of amination products 407 and diminished the formation of byproducts. When 3,6-di-tert-butyl-substituted acridinium Mes-(t-Bu)2Acr-Ph+ was used as the photocatalyst, the yields of desired products were further improved. The mechanism is presumably similar to that presented by Fukuzumi for the addition of halide nucleophiles to arene cation radicals. TEMPO could assist the hydrogen atom abstraction from the cyclohexadienyl radical. Later, a similar selective C(sp2)−H amination of arenes (alkyl-substituted benzenes, biphenyl, and anisole derivatives) was accompanied by hydrogen evolution by using heterocyclic azoles as nitrogen sources.303 Recently, a photocatalytic cross-coupling strategy for aromatic C−H functionalization, via a combination of photocatalysis and cobalt catalysis, was utilized for benzene amination and hydroxylation by Wu and co-workers (Scheme 242).304 In the absence of an oxidant, the amination and hydroxylation of benzene with ammonia and water were successfully accomplished in excellent yields and selectivities under unusually mild conditions. QuH+ClO4− (408) or QuCN+ClO4− (409) were selected as photocatalysts with Co(dmgBF2)2(CH3CN)2 (410) as the hydrogen-evolution catalyst, making this reaction a potentially facile and rapid way to access hydroxylated analogues of a broad range of substrates. At nearly the same time, König and co-workers reported a one-step direct procedure for C−H sulfonamidation using sulfonamides and pyrroles for the synthesis of N-(2-pyrrole)-sulfonamides 411 (Scheme 243).305 The acridinium dye was utilized as the photocatalyst and oxygen as the terminal oxidant for the oxidative C−N bond formation mediated by visible light. This photocatalytic reaction provided an efficient method to produce N-(2-pyrrole)-sulfonamides, and a wide range of substrates were tolerated well under the reaction conditions. Alkenes can also be transformed into their corresponding radical cations using the recently developed photocatalysis strategy,306 which can be used in cyclizations or alkene hydrofunctionalization reactions. In 2016, Lei and co-workers developed an unprecedented dehydrogenative Wacker-like oxygenation of olefins under oxidant-free conditions in the combination of photosensitizer 412 and cobaloxime 413 (Scheme 244).307 Mechanistic experiments suggested that the oxygen atom of the carbonyl group originated from water, and the rate-determining step in the transformation might involve the O−H bond cleavage of the activated water molecule. Recently, a new model of radical alkenylation under oxidant-free conditions was further developed by Lei and co-workers using the alkene radical cation as the key intermediate. Merging photocatalysis and cobalt catalysis, a direct C−H/X−H cross-coupling to C−O and C−N bond formation with H2 evolution has been accomplished to afford enol ether derivatives and N-vinylazoles (Scheme 245).308

Scheme 241. Site-Selective Amination of Arenes via Photoredox Catalysis

Scheme 242. Aromatic C−H Functionalization via the Combination of Photocatalysis and Cobalt Catalysis

Scheme 243. C−H Sulfonamidation of Pyrroles

6.2. Radical Cation Formation via Electrochemical Oxidation

For the preparation of radical ions, electrochemistry provides the most straightforward method. Furthermore, the experimental setups are quite simple and offer high levels of control over the redox potential. Recently, synthetic chemists have shown much interest in electrochemistry and developed a number of methodologies.309 Yoshida and co-workers recently reported an efficient metal-free method to achieve C−H/C−H crosscoupling of aromatic compounds (Scheme 246).310 This reaction provided a metal- and chemical-oxidant-free cross-dehydrogenative coupling. Notably, electron-rich benzenes gave the corresponding cross-coupling products with good yields, and

analogous to that of the previous oxygenation reactions, which proceeded through the addition of Br− anion to the radical cation generated from the PET of electron-rich arenes to the excited photocatalyst. H2O2 was formed as the byproduct, which could react with the arene and HBr to form another molecular product. In 2015, Nicewicz and co-workers developed a para-selective aryl C−H amination of electron-rich arenes via radical cation intermediates by using an acridinium ion photocatalyst (Scheme 241).302 It was found that the addition of TEMPO (2,2,6,6tetramethylpiperidine-1-oxyl) as a cocatalyst greatly improved 9073


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Scheme 244. Dehydrogenative Wacker-like Oxygenation of Olefins under Oxidant-Free Conditions

compounds was also achieved (Scheme 250).313 This provided a straightforward metal-free method to prepare N-substituted imidazoles. With these optimized conditions, a variety of Nmesylimidazole derivatives with aromatic and benzylic compounds were obtained in good yields. The Yoshida group also demonstrated an electrooxidative coupling method of aromatic compounds and primary alkylamines for the construction of Nalkylanilines and their derivatives (Scheme 251).314 In this transformation, the heterocyclization of functional primary alkylamines was the key process to achieve the desired products. Products bearing a variety of functional groups, such as hydroxyl and amino groups, were tolerated well.

Scheme 245. Direct C−H/X−H Cross-Coupling Leading to C−O and C−N Bond Formation

Scheme 246. C−H/C−H Cross-Coupling of Aromatic Compounds via Electrochemical Oxidation

6.3. Radical Cation Formation via Traditional Oxidation

Traditional oxidants can oxidize aromatic arenes to their corresponding radical cations, and this strategy has been used in several coupling reactions.315 A novel iron-catalyzed oxidative C−H/C−H cross-coupling between electron-rich arenes and alkenes has been developed by Lei and co-workers (Scheme 252).316 In this case, FeCl3 was utilized as the catalyst combined with DDQ as the oxidant. According to radical trapping and EPR (electron paramagnetic resonance) experiments, the proposed mechanism indicated that the DDQ was crucial in this transformation, which first oxidizes to form the aryl radical cation species. When R is an H atom, the triarylethane product 416 was formed through cross-coupling between the arene and the alkene. Moreover, when R is an aryl, the triaryl-ethylene product 417 was obtained. Waldvogel and co-workers reported research on the mechanism of the MoCl5-mediated dehydrogenative coupling of arenes (Scheme 253).317 In this report, a variety of approaches were employed for the study of the mechanism. It was observed that MoCl5 acted as a single-electron oxidant without TiCl4, but a two-electron oxidant with the addition of TiCl4. The anisole 418 could lose one electron to generate the arene radical cation 419, which added to the arene to form cationic intermediate 420. The radical cationic intermediate could be further oxidized to furnish the product 421.

iodine-containing compounds were obtained in good yields. From DFT calculations, the high regioselectivity of the crosscoupling might result from the HOMO coefficients and the spin density of the radical cation. Later, a new method for the C−H amination of aromatic compounds was also developed (Scheme 247).311 This amination of aromatic compounds by electrochemical oxidation was performed in the presence of pyridine via a subsequent chemical reaction of the resulting N-arylpyridinium ions with an alkylamine. In this transformation (Scheme 248), the key intermediate N-arylpyridinium ion was produced from the attack by pyridine followed by one-electron oxidation and elimination of a proton. The ions 414 could then react with piperidine through addition of piperidine to the 2-position of Narylpyridinium ions to afford intermediate 415, which could be further transformed into the aromatic primary amine products. The strategy could also be used to prepare benzoxazoles and benzothiazoles through intramolecular C−H amination and the treatment of the pyrimidinium ions with piperidine (Scheme 249).312 A method for C−N coupling of imidazoles through electrooxidative C−H functionalization of aromatic and benzylic

7. OUTLOOK AND CHALLENGES Radical C−H functionalization reactions have been widely explored during the past several years. This Review provides an updated summary of this rapidly developing area. New synthetic methodologies and novel reaction conditions that do not compromise product selectivity, energy efficiency, or environmental safety have become major targets in current chemical

Scheme 247. C−H Amination of Aromatic Compounds

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Scheme 249. Intramolecular C−H Amination

Scheme 250. Electrooxidative C−H Functionalization of Aromatic Compounds

Scheme 251. Electrooxidative Coupling of Aromatic Compounds and Primary Alkylamines

research. There are still many unknown synthetic methods, and a number of mechanisms are still being elucidated. Thus, many opportunities and challenges still remain.

Achieving selective radical C−H activation and transformation is still a considerable problem for inert hydrocarbon compounds. To control the reactivity and chemoselectivity of radical species, 9075


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Scheme 252. Iron-Catalyzed Oxidative C−H/C−H Coupling between Electron-Rich Arenes and Alkenes

research focuses on oxidative cross-coupling reactions and addition reactions of unsaturated bonds. Zhiyuan Huang obtained her B.S. degree (2014) from Wuhan University. She joined Prof. Aiwen Lei’s group during her second year of undergraduate studies and started her Ph.D. studies in September 2014 in the same group. She is currently a third-year Ph.D. student whose research focuses on oxidative cross-coupling reactions and singlesite catalysts for C−H functionalization reactions. Jue Wang was born in 1996. He joined Prof. Lei’s group in his the second year of his undergraduate studies in 2016 and is currently a junior student. His research is focused on visible light-mediated photocatalysis and C−H bond activation.

Scheme 253. MoCl5-Mediated Dehydrogenative Coupling of Arenes

Atul K. Singh was born in Mirzapur, Uttar Pradesh, India. He performed his Ph.D. research (2010−2014) under the supervision of Prof. L. D. S. Yadav at the Department of Chemistry, University of Allahabad, India, and received his Ph.D. in Organic Chemistry in 2014. Currently, he is working as a postdoctoral fellow in the research group of Prof. Aiwen Lei at Wuhan University, China. His postdoctoral research work is mainly focused on organic synthesis, especially photochemical reactions. Aiwen Lei obtained his Ph.D. (2000) under the supervision of Prof. Xiyan Lu at the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences (CAS). He then moved to Pennsylvania State University, and worked with Prof. Xumu Zhang as a postdoctoral fellow. He joined Stanford University in 2003, working with Prof. James P. Collman as a research associate. He then became a full professor (2005) at the College of Chemistry and Molecular Sciences, Wuhan University, China. His research focuses on novel approaches and understanding bond formation reactions.

it is essential to find more mild conditions and proper methods to achieve these transformations. For practical applications, these aspects are still crucial, including the synthesis of pharmaceuticals, natural products, agrochemicals, polymers, and commodity chemicals. Furthermore, in this developing field, no conclusive and convincing mechanistic pathways have been presented. Turnover numbers (TONs) and turnover frequencies (TOFs) are still problems to be solved in catalytic systems. Despite these challenges, radical C−H activation/radical cross-coupling is still important in organic synthesis and will undoubtedly witness improvement in the future.

ACKNOWLEDGMENTS This work was supported by the 973 Program (2011CB808600, 2012CB725302, and 2013CB834804), the National Natural Science Foundation of China (21390400, 21272180, 21302148, 2109343, and 21402217), the Research Fund for the Doctoral Program of Higher Education of China (20120141130002), the Ministry of Science and Technology of China (2012YQ120060), and the Program for Changjiang Scholars and Innovative Research Team in University (IRT1030). The Program of Introducing Talents of Discipline to Universities of China (111 Program) is also acknowledged.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. ORCID

ABBREVIATIONS AIBN azodiisobutyronitrile BDE bond dissociation energy BPO benzoyl peroxide PIFA [bis(trifluoroacetoxy)iodo]benzene 2-ClAQ 2-chloroanthraquinone QuCN+ 3-cyano-1-methylquinolinium ion CAN ceric ammonium nitrate CFL compact fluorescent light DTBP di-tert-butyl peroxide DDQ 2,3-dichloro-5,6-dicyanobenzoquinone DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone DABCO 1,4-diazabicyclo[2.2.2]octane; triethylenediamine DFT density functional theory (MeO)2Phen 4,7-dimethoxyphenantronline 1,4-DCB 1,4-dicyanobenzene ESI-MS electrospray ionization mass spectrometry ET electron transfer

Aiwen Lei: 0000-0001-8417-3061 Notes

The authors declare no competing financial interest. Biographies Hong Yi obtained his B.S. degree (2012) from Wuhan University. He joined Prof. Aiwen Lei’s group during his second year of undergraduate studies and started his Ph.D. studies in September 2012 in the same group. He is currently a fifth-year Ph.D. student whose research focuses on oxidative cross-coupling reactions and mechanistic studies. Guoting Zhang obtained his B.S. degree (2013) from Fuzhou University. He joined Prof. Aiwen Lei’s group and started his Ph.D. study in September 2013. He is currently a fourth-year Ph.D. student whose research focuses on visible-light-mediated cross-coupling reactions. Huamin Wang obtained his B.S. degree (2014) from Wuhan University. He joined Prof. Aiwen Lei’s group during his second year of undergraduate studies and started his Ph.D. studies in September 2014 in the same group. He is currently a third-year Ph.D. student whose 9076


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electron paramagnetic resonance 1,1,1,3,3,3-hexafluoro propan-2-ol kinetic isotope effect 4-methylbenzenesulfonic acid N-hydroxyphthalimide phthalimide N-oxyl radical phthalimide single-electron transfer singly occupied molecular orbital tetrabutylammonium decatungstate 2,2,6,6-tetramethylpiperidine-1-oxyl tert-butyl hydroperoxide tert-butylperoxy benzoate tetrabutyl ammonium bromide tetrabutyl ammonium iodide triethylamine trihydrofluoride 1,2,4,5-tetracyanobenzene

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