untitled European Journal of Chemistry 7 (2) (2016) 248‐270 European Journal of Chemistry ISSN 2153‐2249 (Print) / ISSN 2153‐2257 (Online)  2016 Atlanta Publishing House LLC ‐ All rights reserved ‐ Printed in the USA http://dx.doi.org/10.5155/eurjchem.7.2.248‐270.1412 European Journal of Chemistry Journal webpage: www.eurjchem.com Recent advance in direct sp3 carbon‐hydrogen bond functionalizations Xiao‐Hua Cai *, Jun Jin and Bing Xie National School of Medicine, Guizhou Minzhu University, Guiyang 550025, China * Corresponding author at: National School of Medicine, Guizhou Minzhu University, Guiyang 550025, China. Tel.: +86.851.83610313. Fax: +86.851.83610313. E‐mail address: caixh1111@163.com (X.‐H. Cai). REVIEW INFORMATION ABSTRACT DOI: 10.5155/eurjchem.7.2.248‐270.1412 Received: 20 February 2016 Accepted: 19 March 2016 Published online: 30 June 2016 Printed: 30 June 2016 Direct and selective carbon‐hydrogen bond functionalization has attracted enormous attention because it provides more efficient strategies for preparing valuable functional molecules from easily available substrates. Significant and exciting developments in functionalization of un‐activation Csp3‐H bonds have continuously been made over the past few decades. This review mainly summarizes recent advances on direct Csp3‐H bond functionalization for the formation of C‐C and C‐heteroatom bond under transition‐metal‐ catalysed and metal‐free conditions. KEYWORDS Metal‐free C‐H bond activation C‐C bond formation Transition‐metal‐catalyzed C‐heteroatom bond formation Csp3‐H bond functionalization Cite this: Eur. J. Chem. 2016, 7(2), 248‐270 1. Introduction In the past several decades, the direct C‐H functiona‐ lizations have attained continuous interest because it provides efficient and straightforward approaches for the construction of complex chemical molecules in atom‐economical manners [1‐13]. For example, the activation of Csp2‐H bond has gradually become more convenient and efficient strategies for the synthesis of numerous available aromatic compounds. However, functionalizations of inert Csp3‐H bond are a tremendous challenge owing to their high bond‐dissociation energy and low polarity. The inactive Csp3‐H bonds are very difficult to functionalize and the transformation Csp3‐H bonds to available functional molecules has become the center of attention in theoretical and experimental researches and exhibits significant role in the field of modern synthesis [14‐ 24]. Compared with traditional organohalide electrophiles or organometallic reagents, the Csp3‐H bond activation reactions demonstrated wide availability, sustainability and high atom‐ economy. Great progress has been achieved in the development of inert Csp3‐H bond functionalization reactions through oxidative coupling and radical reactions in recent decades. Below this review will primarily provide a perspective on Csp3‐H bond functionalization from C‐C and C‐ heteroatom bond forming reactions under transition‐metal‐ catalyzed and metal‐free conditions. 2. Transition‐metal‐catalyzed Csp3‐H functionalization Transition metal catalyzed Csp3‐H functionalization has become a significant and useful synthetic approach for preparation of various practical organic molecules. Increased attention has been focused on development of Csp3‐H functionalization because these reactions can be performed reasonably mild conditions with remarkably high selectivity and atom‐ and step‐efficiency. 2.1. Formation of C‐C bond via Csp3‐H functionalizations The direct functionalization of Csp3‐H bonds is an emerging strategy for the construction of C‐C bond in view of C‐C bonds are the most basic constituent part in organic molecules. Many efforts have focused on the formation Csp3‐ Csp1, Csp3‐Csp2 and Csp3‐Csp3 bonds through functionalization of Csp3‐H bond employing transition‐metal as catalysts in the past twenty years. 2.1.1. Reaction between Csp1 and Csp3‐H bond In 2013, Vachhani et al. [25] reported a simple and efficient gold‐catalyzed functionalization of Csp3‐H for the preparation of cyclopentapyridinones and spirocyclopenta pyridinones (Scheme 1). Cai et al. / European Journal of Chemistry 7 (2) (2016) 248‐270 249 Scheme 1 Scheme 2 Scheme 3 The approach was the Ugi‐4CR of regioselective tandem cyclization of N‐propynylbutynamide giving the corresponding cyclopentapyridinones with moderate to good yields. In 2014, Wang et al. [26] described a copper‐catalyzed oxidative cyanation of α‐C‐H tertiary amines employing “CN” source from trimethylsilyl azide (Scheme 2). The reaction smoothly proceeded and afforded the C1‐cyanation of tetrahydroiso‐ quinolines with 58‐93% yields under environmentally friendly conditions. Song and coworkers [27] developed a convenient and efficient strategy for the formation of 3‐alkynyl poly‐ substituted furans from easily available starting substrates through gold‐catalyzed oxidative Csp3‐H/Csp‐H cross‐coupling of between 1,3‐dicarbonyl compounds and terminal alkynes (Scheme 3 and 4). The reaction involved a cascade process including cyclization and in situ oxidative alkynylation and tolerated a variety of terminal alkynes as substrates giving the corresponding poly‐substituted furans with moderate yields under mild reaction condition. A proposed mechanism for cross‐coupling reaction was exhibited in Scheme 5. In 2015, Hashmi and coworkers [28] developed a highly efficient radical Csp3‐H alkynylation of tertiary aliphatic amines catalyzed by [Au2(m‐dppm)2]2+ employing sunlight as a green and sustainable energy source under mild reaction conditions (Scheme 6 and 7). The Csp3‐H alkynylation reaction exhibited higher region selectivities and tolerated to additional functional groups. Mechanistic studies proposed the Csp3‐Csp bond formation was a radical coupling between an α‐ aminoalkyl and an alkynyl. 250 Cai et al. / European Journal of Chemistry 7 (2) (2016) 248‐270 Scheme 4 Scheme 5 Scheme 6 2.1.2. Reaction between Csp2 and Csp3‐H bond In 2011, Sundararaju et al. [29] developed a highly regioselective C(3)‐alkylation reaction promoted by ruthenium(II) complexes via functionalization of Csp3‐H bond of saturated cyclic amines (Scheme 8). The catalytic reaction involved activation of Csp3‐H bond through initial dehydroge‐ nation of cyclic amines and hydrogen auto transfer processes and provided the resulting products with moderate to good yields. In 2012, Piou et al. [30] reported an efficient palladium(0)‐catalyzed domino carbopalladation for one‐pot synthesis of spirooxindoles through functionalization of Csp3‐ H bond with reaction of aldehyde (Scheme 9). This reaction provided a novel and useful approach for the elaboration of domino reactions using Csp3‐Csp3 bond forming reactions as an elementary step. Li and coworakers [31] described a CuCl2‐catalyzed base‐ switched methylenation and formylation employing tetramethylethylenediamine (TMEDA) as a carbon source and atmospheric oxygen as an oxidant under mild conditions (Scheme 10 and 11). The electronic properties of the N‐ protecting groups and substituents including substituted pattern played important roles in the reactivity of methylenation and formylation reactions. The reaction smoothly proceeded and gave the corresponding product bis‐ indolylmethanes, diphenylmethanes and 3‐formylindoles with good yields and high regioselectivities. Cai et al. / European Journal of Chemistry 7 (2) (2016) 248‐270 251 Scheme 7 Scheme 8 Scheme 9 Scheme 10 252 Cai et al. / European Journal of Chemistry 7 (2) (2016) 248‐270 Scheme 11 Scheme 12 Scheme 13 In 2014, Liu and coworkers [32] described a highly efficient strategy for the preparation of alkyl‐substituted oxindoles with up to 93% yields via Cu‐catalyzed oxidative alkylarylation of acrylamides with simple alkanes (Scheme 12). The reaction was a free‐radical cascade process through selective activation of unactivated Csp3‐H functionalization/C‐ C bond formation. Gharpure and coworkers [33] developed a simple and efficient synthesis of isochromene derivatives via an intramolecular, benzylic Csp3‐Csp2 bond forming Heck reaction on vinylogous carbonates (or β‐alkoxyacrylates) (Scheme 13). The competitive Heck reaction between a normal olefin and a vinylogous carbonate moiety resulted in corres‐ ponding dihydronaphthalene products through coupling with olefin exclusively. The protocol was widely used in the synthesis of a core of natural products cis‐dihydrokalafungin and monocerolide. Shi and coworkers [34] developed palladium‐catalyzed activation of an inert Csp3‐H bond for the preparation of 3,3‐ disubstituted 3,4‐dihydroquinolinone derivatives 3,4‐dihydro quinolinones from simple ortho‐halogenated acetilide derivatives under mild conditions (Scheme 14). A plausible mechanism proposed that the reaction involved infrequent key intermediate seven‐membered palladacycle in the catalytic cycle (Scheme 15). Another group described [35] a direct and novel Pd(OAc)2‐promoted arylation of methylene Csp3‐H bonds in aliphatic amides with PIP directing group (Scheme 16 and 17). The protocol showed good structural versatility and high functional group tolerance in both aryl halides and aliphatic amides and providing the corresponding β‐arylated carboxylic acid derivatives with up to 78% yields. Maes and coworkers [36] developed a novel method for α‐ alkylation of piperidines with dioxolane protected alkenones using a ruthenium catalytic system (Scheme 18 and 19). The process was effectively proved on the α‐alkylation of various piperidines with a pyridin‐2‐yl directing group and provided the corresponding monoalkylated and bisalkylated products with moderate to good yields from readily accessible subst‐ rates. Mao and coworkers [37] developed a copper‐catalyzed oxidative coupling reaction of N,N‐substituted amides with olefins or cinnamic acids for the synthesis of N‐(3‐oxo‐3‐ phenylpropyl)‐acetamide and N‐cinnamylacetamide deriva‐ tives through oxyalkylation of vinylarenes and decarboxylative alkenylation of Csp3‐H (Scheme 20). The simple and practical protocol could provide the resulting products as potential precursors for the preparation of β‐amino carbonyls and cinnamyl amines through further hydrolysis. Cai et al. / European Journal of Chemistry 7 (2) (2016) 248‐270 253 Scheme 14 N R3 O R2 R4 R1 Pd(OAC)2 Pd[0] X R2N R3 O R1 oxidative addition Pd ON R3 R1 Ln R2 R4 R5 Pd O O H R3 O R2 R4 LR1 Pd R3 O R2 R4 LnR1 reductive addition PivOH PivO Scheme 15 Scheme 16 Scheme 17 254 Cai et al. / European Journal of Chemistry 7 (2) (2016) 248‐270 Scheme 18 Scheme 19 Scheme 20 Scheme 21 Li and coworker [38] developed a selective synthesis of β‐ amino ketones and α,β‐unsaturated amides via oxidative coupling of unactivated terminal alkenes with amides employing peroxides as oxidant (Scheme 21). This reaction proceeded through an oxidative radical pathway involved selective functionalization of the amide Csp3‐H bonds of versus Csp2‐H functionalization of the carbonyl with a broad substrate scope and excellent chemselectivities. Chen and coworkers [39] achieved an economical and efficient copper‐ catalyzed arylcarbocyclization reaction of alkynes for the formation of C‐C bond via activation of inert Csp3‐H bond (Scheme 22). This method was promoted diaryliodonium salts and providing the resulting products carbocycles with moderate to good yields. In 2015, Cheng and Loh [40] developed a copper‐ and cobalt catalyzed direct three‐component oxidative coupling of olefins and alcohols through α‐C‐H activation of alcohols empolying hydroperoxides as radical initiator (Scheme 23 and 24). Cai et al. / European Journal of Chemistry 7 (2) (2016) 248‐270 255 Scheme 22 Scheme 23 Scheme 24 R1 N R2 O Fe(acac)2 (5 mol%), + CH3CN air, 12 h, 120 oC R1 N O R2 CN R1 = H, Me, Cl, NO2, Ph, I, MeO F, CF3, CF3O, Br, CO2Et R2 = Me, Bn, Ph, MeOCH2 MeOAc, etc. 61-81% yield t-BuOO t-Bu (3 equiv) Scheme 25 256 Cai et al. / European Journal of Chemistry 7 (2) (2016) 248‐270 Scheme 26 N H O Ph R O N H O O R Ph . TBPA +. O2 path a povarov reaction Aromatization N H O Ph R O e N H O O R Ph path b . N H O O R Ph Aromatization Scheme 27 Scheme 28 Alkylation‐peroxidation of various aliphatic, silylated, and aryl 1,3‐enynes gave β‐peroxy alcohols and β‐hydroxyketones with extreme functional group tolerance, and the corres‐ ponding products β‐peroxy alcohols further transformed to propargylic 1,3‐diols and β‐hydroxyynones. Later, Pan et al. [41] described an efficient strategy for the synthesis of oxindoles through radical cyanomethylation/arylation of arylacrylamides using Fe(acac)2 as catalyst and acetonitrile as the radical precursor (Scheme 25). This reaction mainly involved dual C‐H bond functionalization of Csp3‐H of acetonitrile and C sp2‐H of the phenyl group. The process showed excellent functional groups compatibility and transformed to the corresponding products in higher yields. Jia and coworker [42] achieved a novel synthesis of quinoline‐fused lactones and lactams from readily accessible starting materials via Csp3‐H bond oxidation of N‐aryl glycine esters and amides under catalytic radical cation salt‐induced conditions (Scheme 26). This reaction involved intramolecular annulation catalytic Csp3‐H oxidation two new C‐C bond and two new hetercyclolic ring. The approach exhibited some advatanges including mild reaction conditions, high level compatibility with a variety of functional groups and high efficiency in the construction of polycyclic products. Plausible mechanism of radical‐cation‐prompted intramolecular annula‐ tion was showed in Scheme 27. Muramatsu and Nakano [43] developed a practical Csp3‐H bond functionalization employing safe and green oxidants and 5.0 mol % of AZADOL as catalyst under wild condition (Scheme 28). The catalytic reaction smoothly proceeded with a broad range of substrates and nucleophiles tolerance and transformed to the corresponding products with up to 99% yields. Yu and coworkers [44] reported Pd(II)‐catalyzed cross‐ coupling of Csp3‐H bonds carboxylic acid derivatives with arylsilanes in moderate to good yields (Scheme 29). The potential utility of quinoline‐based ligands was essential for the key to catalytic coupling reaction. The direct oxidative Csp3‐H functionalization through radical pathway formed C‐heteroatom (C, O, S) bonds has attracted extensive attentions in recent years. Yuan and coworkers [45] demonstrated Cu‐promoted the addition of a benzyl or alkyl radical to β‐nitrostyrenes with up to 88% yields employing di‐tert‐butyl peroxide (DTBP) as the oxidant. The reaction exhibited highly tolerant to additional functional groups, various substituted β‐nitrostyrenes could be successfully to proceed and converted to the corresponding (E)‐β‐alkylstyrene derivatives via the radical addition and denitro‐elimination mechanism. A proposed mechanism was shown in Scheme 30. Firstly, DTBP decomposes to produce the tert‐butoxyl radical in the presence of copper. Next, tert‐ butoxyl radical acts on C‐H bond of methyl in toluene and resulting in the benzyl radical. Cai et al. / European Journal of Chemistry 7 (2) (2016) 248‐270 257 Scheme 29 Scheme 30 N O O N H O TAH N O O N H O TAH Ar Pd(OAc)2 (10.0 mol%) AgOAc (1.5 equiv) HFIP, 100 oC, 5 h 68-90% yield + ArI Ar N O O N H O TAH PhthHN N O N N N hexyl Pd OAc PhthHN N O N N N hexyl Pd OAc PhthHN N O N N N hexyl Pd OAc Ar I PhthHN N O N N N hexyl Pd OAc (II) (II) (VI) (II) product Arylated Pd(II) C-H Palladation ArI oxidative addition reductive elimination Scheme 31 Then addition of the benzyl radical to the β‐position of the C‐C double bond in β‐nitrostyrenes gemerated an intermediate radical. Finally, the intermediate radical converted to the product through elimination of the NO2 free radical. Ding and co‐worker [46] achieved palladium‐catalyzed Csp3‐H arylation of amino acid derivatives with various aryl iodides using click‐triazoles as conveniently approachable and easily removable directing group. The protocol provided a practical strategy for the synthesis of both natural and synthetic amino acids with moderate to good yields and exhibited high level functional group tolerance and wide applications. Proposed reaction mechanism was exhibited in Scheme 31. 258 Cai et al. / European Journal of Chemistry 7 (2) (2016) 248‐270 Scheme 32 Scheme 33 Scheme 34 Scheme 35 Shi and coworkers [47] described a highly efficient for alkenylation of unactivated Csp3‐H bonds with vinyl iodides employing catalytic system including Ni(acac)2 as the catalyst and BINOL as the ligand (Scheme 32). The reaction smoothly accomplished with a wide variety of functional groups tolerance and transformed the resulting products functionalized carboxamides bearing α‐quaternary carbon centers. Kang and coworkers [48] developed an efficient cascade reaction for the synthesis of benzofuran derivatives from 1‐ sulfonyl‐1,2,3‐triazoles with up to 88% yields through rhodium‐catalyzed Csp3‐H insertion and copper‐catalyzed aerobic oxidation (Scheme 33). The cascade reaction provided more convenient approach for one‐pot synthesis of benzo‐ furan starting from terminal alkyne via copper‐catalyzed alkyne‐azide cycloaddition and dehydrogenation cascade reaction. 2.1.3. Reaction between Csp3 and Csp3‐H bond In 2011, Mitsudera and Li [49] achieved a novel protocol for the synthesis of trifluoromethylated products through oxidative Csp3‐H activation of various tetrahydroisoquinoline derivatives at the α‐position of nitrogen employing DDQ and Ruppert‐Prakash reagent (Scheme 34). The approach could successfully generate the corresponding trifluoromethylated products using various amines as substrates in 15‐90% yields under mild conditions. Lei and coworkers [50] reported a simple and useful method for the synthesis arylvinylketones and arylvinylpyridines from arylketones and 1‐aryl‐1‐ pyridinemethanes through a direct copper‐catalysed oxidative Csp3‐H methylenation to terminal olefins using DMF as one carbon source (Scheme 35 and 36). The reaction showed high level of functional group tolerace and giving the corresponding products with potential biological activities and pharma‐ ceutical applications. Cai et al. / European Journal of Chemistry 7 (2) (2016) 248‐270 259 Scheme 36 Scheme 37 Scheme 38 Li et al. [51] developed a convenient and effective protocol for the preparation of C1‐difluoro‐ methylated tetrahydroiso quinoline derivatives through C‐H functionalization of tertiary amines employing visible‐light photoredox catalysis (Scheme 37). This method used stable, easily obtained α,α‐difluorinated gem‐diol as the CF3 source and resulting in the corresponding products with moderate to high yields at ambient tempera‐ ture. A possible mechanism for direct Csp3‐H difluro‐ methylation was shown in Scheme 38. Four‐membered heterocycles like β‐lactams were important structural motifs owing to their rich biological activities as well as their high propensity of ring‐opening in organic reactions. In 2014, Cramer and coworkers [52] reported a stereoselective strategy for the synthesis of wide valuable β‐lactams via functionalization of Csp3‐H from readily accessible chloroacetamide substrates employing aldol phosphoramidite ligand in combination with adamantyl carboxylic acid as cocatalyst (Scheme 39). The reaction provided an economical and efficient process for functiona‐ lization of four‐membered heterocycles with excellent yields and enantio selectivities. In 2015, Curto and Kozlowski [53] described a novel selective coupling of a carbon nucleophile with methyl, ethyl, propyl, and butyl arenes without directing group using a simple system consisting of Pd(OAc)2 and pivalic acid (Scheme 40). 260 Cai et al. / European Journal of Chemistry 7 (2) (2016) 248‐270 Scheme 39 Scheme 40 Scheme 41 Scheme 42 These double C‐H activation showed desirable selectivity for at the terminal methyl sites of alkyl arenes substitite for arene Csp2 ‐H activation more commonly observed. Mechanistic studies indicated the resultant azlactone products obtained through a radical process for oxidation with Pd(OAc)2 and consistent with a Pd‐catalyzed C‐H activation. The process provided alkylarene derivatives which can readily transform to α‐amino acid with moderate to good yield under wild conditions. 2.2. Formations C‐Heteroatom bond via Csp3‐H functionalizations Over the past decades, the construct of C‐heteroatom bond (C‐O, C‐N, C‐S, etc.) via the direct functionalizations C‐H bond has attracted extensive attention. In particular, remarkable success has been achieved with respect to the functiona‐ lization of unactive Csp3‐H bonds. 2.2.1. C‐N bond formations The C‐N bond was one of the most substantial part in the construction of many natural products and complicated organic molecules. In 2014, Zhou et al. [54] reported an oxidative Csp3‐H/N‐H cross‐coupling reaction of N‐alkoxy‐ amides with aliphatic hydrocarbons employing Ni(acac)2 as catalyst and di‐tert‐butyl peroxide as oxidant (Scheme 41). Experiments and DFT calculations disclosed that the reaction involved transition‐metal‐assisted radical/radical cross‐ coupling with the transient sp3 carbon radical to form Csp3‐N bonds. A plausible mechanism based on these assumptions and experimental results was exhibited in Scheme 42. Wang et al. [55] achieved an efficient protocol for the preparation of quinolin‐8‐ylmethanamine derivatives via the amidation reactions of cationic 8‐methylquinolines with azides using rhodium(III) complex as catalyst (Scheme 43). Cai et al. / European Journal of Chemistry 7 (2) (2016) 248‐270 261 Scheme 43 Scheme 44 Scheme 45 The reaction smoothly proceeded and gave the corresponding products with various 8‐methylquinolines external oxidants or basesin higher yields. Huang and coworkers [56] developed an convenient strategy for the preparation of 6‐alkyl phenanthridines through a cascade alkylarylation reaction of 2‐isocyanobiphenyls with simple alkanes (Scheme 44). The synthetic process was mainly based on dual Csp3‐H/Csp2‐H functionalizations via both copper‐ catalyzed and DTBP promoted pathways, and demonstrated some advantages including higher yields, high level compatibility of functional groups and mild reaction conditions. Ge and coworkers [57] reported a nickel‐mediated functionalization of unactivated Csp3‐H bond for the highly selective preparation of 2,2‐disubstituted propionamides through intramolecular dehydrogenative cyclization of aliphatic amides (Scheme 45). The aliphatic amides with the assistance of a bidentate directing group could transform to the cyclization of aliphatic amides with high functional‐group tolerance. 262 Cai et al. / European Journal of Chemistry 7 (2) (2016) 248‐270 Scheme 46 NH2 NH2 R COOH+ FeCl3 (10 mol%) DMF, air N N R R = C6H5, 90%; R = 4-MeOC6H4, 80%; R = 4-HOC6H4, 79% R = 4-NH2C6H4, 75%; R = 4-NO2C6H4, 90% ; R = 4-BrC6H4, 83% R = 3-ClC6H4, 83%; R = Naphthyl, 78%; R = Thienyl, 81% Scheme 47 Scheme 48 Scheme 49 Scheme 50 Moreover, Csp3‐H bond functionalization of β‐methyl groups was favored over the aromatic Csp2‐H bonds this reaction. Chen et al. [58] reported a green protocol for the construction of N‐heterocycles from carboxylic acid derivatives and o‐substituted anilines through aerobic oxidative functionalization of Csp3‐H bonds using iron as a catalyst and molecular oxygen or air as oxidant (Scheme 46‐ 48). These processes mainly involved three steps including aerobic oxidation of Csp3‐H bond, decarboxylation and subsequent oxidation cyclization. A plausible reaction mechanism for iron‐catalyzed aerobic oxidative functiona‐ lization of Csp3‐H bonds was described in Scheme 49. Yu and coworker [59] developed a novel and efficient intermolecular Csp3‐H amination reaction using a Pd0/PdII catalytic cycle and an electron‐deficient triarylphosphine ligand (Scheme 50). Cai et al. / European Journal of Chemistry 7 (2) (2016) 248‐270 263 Scheme 51 Scheme 52 Scheme 53 Scheme 54 The catalytic reaction cycle underwent oxidative addition of R2N‐OBz to a Pd0/PAr3 catalyst and then Pd‐NR2 intermediate was produced by cleavage of a Csp3‐H bond. The reaction smoothly proceeded and generated synthetic precursors for novel β‐amino acids in 52‐78% yields without external oxidants. The electron‐deficient triaryl‐phosphine was significant for the realization of Csp3‐H amination reaction. 2.2.2. C‐O bond formations In 2014, Zhao et al. [60] developed a useful strategy for the synthesis of α‐acyloxy ethers through iron‐catalyzed cross‐ dehydrogenative coupling esterification of unactive Csp3‐H bonds with carboxylic acids employing di‐tert‐butyl peroxide (DTBP) as the oxidant (Scheme 51). The protocol tolerated various cyclic ether substrates to react with aromatic acids, and resulting in the corresponding products α‐acyloxy ethers with up to 98% yields. A proposed mechanism from an intermolecular competing kinetic isotope effect (KIE) experi‐ ment was exhibited in Scheme 52. Luo et al. [61] achieved a simple method for the direct construction of alkoxyamine derivatives from easily available 1,3‐dicarbonyl with 2,2,6,6‐tetramethylpiperidine‐1‐oxyl (TEMPO) and its derivatives through copper‐catalyzed oxidative activation of Csp3‐H bond compounds (Scheme 53). This protocol provided a practical green and useful approach for the one‐pot synthesis of alkoxyamines with 75‐95% yields which was properly applied to the preparation of quaternary α‐hydroxy acid derivatives. 2.2.3. C‐S bond formations In 2014, Chen et al. [62] developed a copper‐catalyzed trifluoromethylthiolation of benzylic Csp3‐H bonds through indirected oxidative C‐H activation employing t‐BuOOBz(3‐ CF3) as the oxidant and AgSCF3/KCl as the active trifluoro‐ methylthio source (Scheme 54). The process gave a simple and efficient method for the synthesis of various benzyl trifluoromethyl sulfides with 24‐92 yields. 264 Cai et al. / European Journal of Chemistry 7 (2) (2016) 248‐270 Scheme 55 N R2 R1 R3 N R2 R1 O R3 N ClCl O MsOH (4.0 equiv) CH2Cl2, 30 oC, 2-24 h (2.0 equiv) N O R3 1 23 4 5 6 R3 = 4F, 75 %; R3 = 4Cl, 71% h; R3 = 4Br, 65% R3 = 4CH3O, 84%; R3 = 4CF3, 51%; R3 = 5F, 48% R3 = 5CH3, 56%; R3 = 5CF3, 76%; R3 = 3F, 72%N R3 1 23 4 5 6 N Bn R N O Ph R R = Me, 50% R = Bn, 40% N N O R3 = H, 56% R3 = 4-Cl, 42% R3 R3 R3 = 4-F, 52% N N O N O 30% 25% Scheme 56 Scheme 57 In 2015, Zhang and coworkers [63] developed an efficient process for nickel‐catalyzed β‐thioetherification of unactivated Csp3‐H bond of propionamides with the assistance of 8‐ aminoquinoline produced the β‐thio carboxylic acid derivatives in 35‐75% yields (Scheme 55). The thioetheri‐ fication reaction exhibited high regioselectivity and functional‐ group compatibility, resulting in the successful construction of C‐S bonds via the direct coupling of disulfide with unactivated Csp3‐H bonds. 3. Metal‐free Csp3‐H functionalizations Although transitional metal‐catalyzed Csp3‐H bond func‐ tionalization have made considerable advances in the past several decades, More and more interests have been attracted in the development of environmental friendly and efficient non‐metallic oxidative system for functionalization Csp3‐H bond. 3.1. C‐C bond formations In 2012, Chen et al. [64] achieved a direct and practical pyridine‐N‐oxide‐mediated ring‐closing reaction via Csp3‐H functionalization of inertial aryl alkynes under metal‐free condition (Scheme 56). In this reaction, the Brösted acid MsOH could efficiently promoted the intramolecularly cyclization reaction producing the resulting products with 25‐84% yields. Zhang et al. [65] developed an original and practical strategy for the formation of 2,3‐dichloro‐5,6‐dicyanobenzoquinone (DDQ)‐mediated Csp3‐Csp3 bonds via intramolecular oxidative cross‐coupling reaction under mild conditions (Scheme 57). The economical approach mediated by (DDQ) provided the various tetrahydroquinoline derivatives with 48‐95% yields. A proposed mechanism for intramolecular oxidative coupling reaction under metal‐free conditions was exhibited in Scheme 58. Cai et al. / European Journal of Chemistry 7 (2) (2016) 248‐270 265 Scheme 58 Scheme 59 Scheme 60 Scheme 61 In 2014, Cao et al. [66] developed a pratical approach for the formation of 6‐alkyl phenanthridines via the 2‐ isocyanobiaryl insertion with 1,4‐dioxane mediated by tert‐ butyl peroxybenzoate (Scheme 59). The process formed two new C‐C bonds through a sequential functionalization of Csp3‐ H/ Csp2‐H bond giving the corresponding products in up to 86% yield under metal‐free conditions. Liu and coworkers [67] reported an efficient Ph3CClO4‐promoted Csp3‐H func‐ tionalization for the construction of various α‐substituted N‐ benzyl and N‐allyl carbamates under ambient temperature and metal‐free condition (Scheme 60). The approach showed excellent functional‐group tolerance with respect to both N‐ carbamates and nucleophile partners offering the resulting products with moderate to excellent yields. Xiao and coworkers [68] developed an efficient and innovative strategy for the synthesis of biologically significant azaarene 2‐substituted chromanones via tandem Csp3‐H functionalization/ decarboxylation of 4‐oxo‐4H‐chromene‐3‐ carboxylic acid with 2‐alkylazaarenes (Scheme 61). The reaction tolerated a variety of electronically and sterically diverse azaarenes and transformed to coupled products with moderate to good yields. A proposed mechanism was exhibited in Scheme 62. Yuan and coworkers [69] developed a novel methylenation reaction for synthesis of methylene‐bridged bis‐1,3‐dicarbonyl compounds through oxidative Csp3‐H activation and C‐N cleavage of N‐methyl amines under transition‐metal‐free (Scheme 63). The process exhibited outstanding advantages including employing cheap oxidant and methylene source, convenient operational, wild reaction conditions and avoiding the use of transition metal catalyst. Long and coworkers [70] developed a economical and green intramolecular oxidative Csp3‐H/Csp3‐H coupling reaction for the construction of 2‐ arylquinolin‐4(1H)‐ones under metal‐free condition (Scheme 64). The oxidative Mannich reaction directly produced a variety of 2‐arylquinolin‐4(1H)‐ones with up to 98% yield from simple readily available N‐arylmethyl‐2‐aminophenyl ketone using TEMPO as the oxidant and KOtBu as the base. Han and coworker [71] described a radical alkylation reaction of α,α‐diaryl allylic alcohols with simple alkanes through oxidative Csp3‐H bond functionalization of alkanes and alkylation using di‐tert‐butyl peroxide as the oxidant (Scheme 65). The reaction smoothly proceeded with a wide range of simple alkane substrates and α,α‐diaryl allylic alcohols and generated the resulting products α‐aryl‐β‐ alkylated carbonyl ketones in up to 93% yield. 266 Cai et al. / European Journal of Chemistry 7 (2) (2016) 248‐270 O O O O H N O O O O HN H O O O O H N H O O O O H N O OH N CO2 O O N Scheme 62 Scheme 63 R3 O N H R1 R2 R3 O N H R1 R2 TEMPO (2 equiv) DMSO (0.05 M) 80 oC Up to 98% yield KOtBu Scheme 64 Scheme 65 Scheme 66 The reaction still involved the formation of new C(Ar)‐Csp3 and Csp3‐Csp3 bond in one step through functionalization of Csp3‐H bond and cascade process of 1,2‐aryl migration. A proposed catalytic cycle for the rearrangement is showed in Scheme 66. Initially, tert‐butoxy radical intermediate (i) was generated by homolysis of DTBP. Secondly, the reaction of intermediate (i) and cyclohexane produced a cyclohexane radical intermediate (ii) which reacted with allylic alcohol to afford radical (iii). Next, migration of the aryl group through spiro[2,5]octadienyl radical (iv) formed radical intermediate (v). Finally, the intermediate E reacted with tert‐butoxy radical intermediate A resulting in the goal product and t‐BuOH. 3.2. C‐Heteroatom bond formations In 2013, Gao et al. [72] developed an efficient strategy for the synthesis of 2,5‐disubstituted oxazoles via Csp3‐H func‐ tionalization promoted by I2 from easily available methyl ketones and benzylamines under metal free and peroxide‐free conditions (Scheme 67). Cai et al. / European Journal of Chemistry 7 (2) (2016) 248‐270 267 Scheme 67 Scheme 68 120 oC, 3 h Ar Ar Ar or or + H2N NH HCl R I2 (20 mol%) TBHP (3.0 equiv) DMSO, H N Ar O O O R R = H, CH3, NO2, MeO 82-92% yield Scheme 69 O R1 N R2 H R1 N R2 O O I2 (20 mol%) DMSO, 120 oC 12-24 h R1 = H, Me, I, Br, Ph R2 = H, alkyl, aryl 52-97% yield O N Bn H O N Bn H I O N Bn H O N O O I H Bn N O O Bn DMSO S MeMe + HI .. I2 HI 2HI I2 DMSO S MeMe + H2O Scheme 70 The reaction involved dual functionalization of α‐Csp3‐H of carbonyl and α‐Csp3‐H of nitrogen atom and produced the corresponding oxazole derivatives with up to 94% yield. A plausible mechanism for I2‐promoted dual Csp3‐H functionalization of acetophenone and benzylamine was proposed in Scheme 68. Chaskar and coworkers [73] developed a simple synthetic protocol for iodine‐catalyzed synthesis α‐ketoimide from diverse substrates via sp3, sp2 and sp C‐H functionalization subsequent oxidative cross coupling with benzamidines hydrochloride under metal‐free conditions (Scheme 69). This process showed eminent advantages, such as, good functional group tolerance, inexpensive catalyst, operational simplicity and good to excellent yields of the products. Rajeshkumar et al. [74] described a highly applicant molecular iodine‐catalyzed Csp3‐H oxidation and intramolecular C‐N bond formation of 2’‐ aminoacetophenones for the synthesis of isatins under metal and peroxide free reaction conditions. The reaction provided corresponding products isatins in excellent yields with tolerance to a range of substrates. The proposed mechanism was exhibited in Scheme 70. 268 Cai et al. / European Journal of Chemistry 7 (2) (2016) 248‐270 Scheme 71 Scheme 72 Scheme 73 Zhang et al. [75] described a practical and direct amination of allylic and benzylic Csp3‐H with anilines mediated by n‐ Bu4NI/TBHP for the formation of N‐substituted anilines under metal‐free conditions (Scheme 71 and 72). The novel approach provided a straightforward efficient pathway for the synthesis various N‐substituted anilines for easily available substrates. Du and coworkers [76] developed a direct amination of various alkyl ethers with different amines for constructing hemiaminal ether skeletons promoted by n‐Bu4NI/t‐BuOOH (Scheme 73 and 74). The organocatalytic amination of alkyl ethers involved intermolecular oxidative Csp3‐N bond formation employing t‐BuOOH as oxidant and n‐Bu4NI as catalyst under metal‐free and wild reaction conditions. Du and coworkers [77] described an intramolecular Csp3‐ O bond formation through intramolecularly functionalizing Csp3‐H bonds adjacent to the nitrogen in N,N‐diaryl tertiary amines mediated by PhI(OAc)2/NaN3 (Scheme 75). The protocol provided a convenient path for the direct synthesis of a series of 1,2‐dihydro‐(4H)‐3,1‐benzoxazin‐4‐one and 1,2‐ dihydro‐(4H)‐3,1‐benzoxazine derivatives in up to 92% yield under mild reaction conditions. Cai et al. / European Journal of Chemistry 7 (2) (2016) 248‐270 269 Scheme 74 Scheme 75 Although considerable advances in the field of Csp3‐H functionalization under metal‐free conditions have been achieved in recent years, the development of more efficient and versatile strategies for functionalization Csp3‐H bond is a more challenging task and represents an significant trends in synthetic chemistry. In particular, more efforts should be paid in the exploring novel catalytic oxidative systems and further studies on reaction mechanism. 4. Conclusions Functionalization Csp3‐H bond represents one of the most powerful approaches for the direct and selective transformation of ubiquitous C‐H bonds into various functional groups in the field of organic synthesis. Most of Csp3‐H bond functionalizations are mainly based on the applications of transition metal compounds and radical systems as initiators. Great efforts have been made in the development of direct Csp3‐H bond functionalizations through oxidative coupling and radical reactions in recent decades. Although Csp3‐H bond functionalization has steadily acquired a great deal of inspiring acheivements in recent years, new challenges and opportunities arise along with these researches. For example, the most common strategies for the transformations need to be expanded less substrate‐ dependent and utilization of a directing group. Most proposed reaction mechanisms are only preliminary speculations without further experimental and theoretical evidences. The highly region‐selective and enantioselective Csp3‐H functiona‐ lization may still remain significant challenges for impeding widespread application of the reactions. An increasing demand for green, metal‐free and highly region‐ or enantio‐selective Csp3‐H functionalization will represent current directions in the field. We believe the ideal Csp3‐H functionalization is only just beginning to be realized and will undoubtedly continue to acquire more satifactory achievements in the near future. Acknowledgements Financial support was provided by the National Natural Science Foundation of China (21562016), the Natural Science Foundation of the Guizhou Science and Technology Depart‐ ment (JZ [2014]2010) and the Science and Technology Planing Project of Guiyang city [(2012204)23]. References [1]. Borovik, A. S. Chem. Soc. Rev. 2011, 40, 1870‐1874. [2]. Gutekunst, W. R.; Baran, P. S. Chem. Soc. Rev. 2011, 40, 1976‐1991. [3]. Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068‐5083. [4]. Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem. Int. Ed. 2012, 51, 8960‐9009. [5]. Wencel‐Delord, J.; Glorius, F. Angew. Chem. Int. 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