654 | Chem. Soc. Rev., 2018, 47, 654--667 This journal is©The Royal Society of Chemistry 2018

Cite this: Chem. Soc. Rev., 2018,

47, 654

Distal radical migration strategy: an emergingsynthetic means

Weipeng Li,a Wentao Xu,a Jin Xie, *a Shouyun Yu *a and Chengjian Zhu *ab

The remote radical migration strategy has gained considerable momentum. During the past three years,

we have witnessed the rapid development of sustainable and practical C–C and C–H bond functionaliza-

tion by means of long-distance 1,n-radical migration (n = 4, 5, 6) events. Its advent brings our chemical

community a new platform to deal with the challenging migration transformations and thus complements

the existing ionic-type migration protocols. In this review, the recent achievements in distal radical

migration triggered C–C and C–H bond functionalization are summarized.

Key learning points(1) Long-distance radical migration strategy.(2) Selective C–C bond functionalization.(3) Selective C–H bond functionalization.(4) Radical rearrangement.

1 Introduction

The organic radical is one of the most notoriously reactiveintermediates and thus controllable radical chemistry has earnedgreat momentum in synthetic chemistry. A plethora of well-known radical reactions, such as the Hofmann–Loffler reaction,Barton deoxygenation reaction, Giese reaction and Minisci reac-tion etc., have been well exploited over the past century, providingpowerful strategies for the construction of structurally diversecompounds.1 Typically, electrolytic, photolytic, borane oxidativehomolytic, and organo-tin hydride systems can be employed togenerate different kinds of radical species. In the past decade, therenaissance of radical transformation occurred along with theblooming development of transition-metal catalysis and photo-redox catalysis.1,2 Radical reactions have been esteemed as anexcellent complement for transition-metal-catalyzed classicalionic-type chemical bond formation between electrophiles andnucleophiles (Scheme 1).

Functionality migration, namely a functional group movingfrom one position to a new position, is a well-known workhorserearrangement transformation in organic chemistry (Scheme 1).Historically, the ionic-type Favorskii, Beckmann, pinacol rearran-gements have been developed with a wide range of applications.Very recently, the radical-mediated distal functionality migrationhas gained increasing attention and a great number of exampleshave sprung up like mushrooms. Radical-mediated migration isable to reconstruct the molecular structures and synthesize valu-able compounds in an efficient way which are not easily availablethrough other methods. This kind of strategy offers new syntheticprotocols to organic synthesis. Although several mini-reviews havesummarized the major achievements in radical-mediated 1,n-Hatom transfer and in particular 1,2-aryl migration,3–5 it is stillhighly desirable to especially stress the breakthrough in long-distance radical migration and also its synthetic applications.6,7 Inthis review, the recent achievements in long-distance 1,n-radical

Scheme 1 Long-distance functionality migration.

a State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of

Advanced Organic Materials, School of Chemistry and Chemical Engineering,

Nanjing University, Nanjing 210023, P. R. China. E-mail: xie@nju.edu.cn,

yushouyun@nju.edu.cn, cjzhu@nju.edu.cnb State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic

Chemistry, Shanghai 200032, P. R. China

Received 24th September 2017

DOI: 10.1039/c7cs00507e

rsc.li/chem-soc-rev

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migration (n = 4, 5, 6) induced C–C and C–H bond functiona-lization are discussed.

2 The C–C scission by distal radicalmigration

C–C bond functionalization is an important strategy to modify theskeletons of simple substrates, which can be used to constructcomplex molecules in an efficient and economical way. However,the high activation energy barrier of the single C–C bond rendersit challenging to achieve selective C–C cleavage of non-strainedcompounds in the frontiers of organic chemistry. In the recentthree years, the radical-mediated functionality migration offersa new choice for remote C–C bond functionalization of non-strained substrates (Scheme 2). This new C–C functionalizationstrategy is distinguished by the mild reaction conditions, exclusiveselectivity and excellent functional group tolerance.

2.1 Recent radical aryl migration

Although the radical 1,2-arylation migration has been wellstudied, long-distance radical aryl migration is currently under-developed. In recent years, the remote aryl migration protocolwas actively pursued. For example, in 2014, Liang’s groupdisclosed a copper-catalyzed radical trifluoromethylation/1,4-aryl migration of homo-propargylic alcohols (Scheme 3), whichprovided tetrasubstituted CF3-containing alkenes in moderate

Scheme 2 Remote radical C–C migration/functionalization.

Weipeng Li

Weipeng Li was born in Henan,China, in 1989. He received hisBachelor degree from HenanNormal University in 2011, andhis PhD degree from NanjingUniversity in 2016, supervised byProf. Chengjian Zhu. Currently, heworks as postdoctoral fellow withProf. Chengjian Zhu at NanjingUniversity. His current researchinterests are focused on visible-light induced organic transforma-tion and gold catalysed oxidativecoupling.

Wentao Xu

Wentao Xu was born in HubeiProvince, China. He received hisBachelor degree from the HefeiUniversity of Technology in 2014and Master degree at the sameuniversity in 2017, under thesupervision of Professor HuajianXu. He is currently conducting hisPhD studies under the supervisionof Prof. Jin Xie and Prof. ChengjianZhu at Nanjing University. Hiscurrent research interest focuseson Au(I)/Au(III) chemistry.

Jin Xie

Prof. Jin Xie was born inChongqing, China, in 1985. Hereceived his Bachelor degree fromNortheast Forestry University in2008, and a PhD degree in 2013from Nanjing University workingunder the direction of Prof.Chengjian Zhu. From 2014–2017, he was a postdoctoralresearch associate in the groupof Prof. A. S. K. Hashmi atHeidelberg University. In 2017,he came back to Nanjing Univer-sity, as an associate professor, to

start his independent career. His current research interests lie intransition-metal catalysis, biomimetic radical transformations andhomogeneous gold catalysis.

Shouyun Yu

Prof. Shouyun Yu obtained hisbachelor degree in Chemistryfrom Nanjing University in 2001.After completing doctoral studiesunder the supervision of Prof.Dawei Ma in 2006 at theShanghai Institute of OrganicChemistry (SIOC) in Shanghai,China, he worked as an assistantresearch professor in the sameinstitute for one more year. Thenhe moved to Jeffrey W. Bode’sgroup at the University ofPennsylvania as a postdoctoral

research fellow in late 2007. In September, 2010, he was appointedas an associate professor of School of Chemistry and ChemicalEngineering at Nanjing University. He is currently a full professor inthe same university. His current research focuses on photochemistry,radical chemistry and asymmetric synthesis and their applications inthe synthesis of biologically important molecules.

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to good yields.8 Togni’s reagent serves as a CF3 radical sourcevia a SET process with CuI. The addition of the CF3 radical tothe triple bond of substrate 1 forms vinyl radical 3, followedby 1,4-aryl migration to deliver radical intermediate 5. Then,oxidation of radical 5 with CuII gives the desired product 2. It isof high regio- and stereo-selectivity via 5-exo ipso addition ofintermediate 4, resulting in the CF3 group and migrated-aryl intrans-selectivity exclusively.

In the same year, Pohmakotr and co-workers developedan enantioselective intramolecular radical cyclization/ipso-1,4-aryl migration reaction, which afforded chiral 3,3-difluoro-2-propanoylbicyclo-[3.3.0]octane products as single isomers.9 Theauthors initially synthesized starting material 6 as a mixtureof diastereomers (1 : 1) from a chiral material with the aim ofgetting tricyclic radical addition product 7. Surprisingly, inthe treatment of 6 with Bu3SnH (1.75 equiv., 0.02 M) in thepresence of a catalytic amount of AIBN, 1,4-aryl migrationcompound 8 was obtained instead of the expected tricyclicproduct 7 (Scheme 4a). A further study indicated that with alow concentration of Bu3SnH, radical cyclization/ipso-1,4-arylmigration product 9 could be exclusively obtained in 78% yield asa single isomer (Scheme 4b). A suggested mechanism is shownin Scheme 4b. First, addition of the tributylstannyl radical toterminal alkyne followed by 5-exo-trig cyclization produces

bicyclic radical intermediate 10. This reactive species undergoesstereospecific ipso-addition and gives intermediate 11. Then astereoselective 1,4-aryl migration process occurs followed byelimination of the phenylsulfanyl group, leading to 12 whichdelivers product 9 as a single isomer after work-up with silica gel.With an excess tributylstannyl radical, intermediate 12 could beconverted to 8 via a cascade defluorination process.

The radical Smiles rearrangement6 has been known fordecades, and exhibits widespread applications in organicchemistry.10 Despite the great advances, the domino Smilesrearrangement remains rather elusive. In 2015, the Nevadogroup developed a multistep radical Smiles rearrangementreaction with the well-designed ortho-vinyl- or ortho-styryl-substituted N-(arylsulfonyl)arylamides as substrates (Scheme 5).11

In this domino radical transformation, the addition of the phos-phonyl or azidyl radical to activated alkenes triggers the classicalSmiles rearrangement, producing 5- and 7-membered ring carbo-cyclic products in high stereoselectivity.

As their follow-up work, the Nevado group documentedanother elegant example of the multi-step radical cascade reactionof N-(arylsulfonyl)acrylamides.12 This reaction proceeded via aradical addition/ipso-cyclization/aryl migration/intramolecularcyclization pathway, which is used for constructing four chemicalbonds in a one-pot fashion. Two different scaffolds 18 and 24

Scheme 3 Copper-catalyzed trifluoromethylation/aryl migration ofinternal alkynes.

Scheme 4 An asymmetric intramolecular radical cyclization/ipso-1,4-aryl migration cascade.

Scheme 5 Tandem radical Smiles rearrangement of N-(arylsulfonyl)-acrylamides.

Chengjian Zhu

Prof. Chengjian Zhu was born inHenan, China, in 1966. Heobtained his PhD from theShanghai Institute of OrganicChemistry (CAS) in 1996 underthe supervision of Professor Qian.Then he worked as a postdoctoralfellow successively in Universite deBourgogne, the University ofOklahoma, and then the Univer-sity of Houston from 1997 to2000. He joined Nanjing Univer-sity as an associate professor in2000. Since 2003, he has been a

professor at Nanjing University. His present research interests lie inorganometallic chemistry and asymmetric catalysis.

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could be obtained by changing the substrates and radicalsources (Scheme 6). When N-[(2-ethynyl)arylsulfonyl]acryl-amide 17 is employed, the chemoselective radical addition tothe carbon–carbon double bond could generate radical inter-mediate 19. Then a radical Smiles rearrangement takes place,generating amidyl radical intermediate 21 followed by intra-molecular [3+2] cyclization, which finally delivers CF3-, SCF3-,Ph2(O)P-, and N3-containing indolo[2,1-a]isoquinolin-6(5H)-ones 18in good yields catalysed by Cu2O (R = CF3) or AgNO3 (R = Ph3PO) orunder other conditions (R = SCF3, N3) (Scheme 6a). Alternatively,with 1,3-dicarbonyl compounds as radical precursors, the authorsexplored Ag(I)-catalyzed radical addition to N-(aryl)(arylsulfonyl)-acrylamide 22. In this process, the reactive radical intermediate25 was proposed as an important intermediate for 1,4-aryl migra-tion (Scheme 6b).

In addition, aryl alkynoates can also undergo the radical1,4-aryl migration. In 2016, Wu and co-workers reported a catalyst-free tandem sulfonyl radical addition and subsequent 1,4-arylmigration of aryl alkynoates for the synthesis of 3-sulfonylcoumarin derivatives (Scheme 7).13 The sulfonyl radical 30

can be generated by the treatment of easily readily availablearyldiazonium salt 27 and commercially available sulfur dioxidesurrogate DABCO�(SO2)2 28 via a single electron transfer (SET)process. As shown in Scheme 7, the radical addition of 30 to arylpropiolates 26 results in the formation of reactive vinyl radical31, which subsequently undergoes ipso-cyclization to providespirocyclic intermediate 32 that can be oxidized to cation 33 byDABCO radical cation 34. The resulting intermediate 33 under-goes 1,4-aryl migration and aromatization to ultimately furnishproduct 29.

In the same year, Wang and co-workers reported a benzylradical initiated intramolecular 1,4-aryl migration of aryl alkynoatesusing TBHP as an oxidant (Scheme 8).14 This method is able toprovide trisubstituted alkenes with toluene derivatives via acascade C(sp3)–H bond functionalization/1,4-aryl migration/decarboxylation process.

Medium-ring skeletons are commonly found in a variety ofnatural products, but they rarely appear in man-made drugsand functional materials. Arguably, the synthesis of mediumrings is a challenging yet attractive subject of research inorganic synthesis. In 2016, Liu and co-workers established aradical induced ring expansion strategy to construct a library ofbenzannulated 8–11 and 14-membered cyclic ketones using readilyavailable materials and reagents (Scheme 9).15 The reactions wereinitiated by radical azidation, trifluoromethylation, phosphonyla-tion, sulfonylation, or perfluoroalkylation of unactivated alkenesfollowed by 1,4 or 1,5-aryl migration and ring expansion. More than37 benzannulated medium-sized molecules with potential bioactivitywere obtained in moderate to good yields. It was found that thereaction proceeded in a highly stereoselective manner. The medium-ring benzannulated products with a chiral carbon centre could beobtained from enantiomerically pure substrates with completelychiral transfer (Scheme 9). It is worth mentioning that thebenzannulated ketones could be conveniently transferred toother complex medium-bridged scaffolds.

Lately, the same group reported another example of intra-molecular remote 1,4(5)-(hetero)aryl migration of tertiary alcoholstriggered by radical azidation, trifluoromethylation, or phosphonyla-tion (Scheme 10).16 In some cases, heteroarylation substitutedsubstrates, such as pyridine rings, selectively underwent1,4/1,5-migration to afford heteroaryl migrated products.

Heteroaromatic rings are prevalent structural segments dis-tributed in natural products, medicines, and agrochemicals.

Scheme 6 Tandem radical Smiles rearrangement to construct C–N andC–C bonds.

Scheme 7 Synthesis of 3-sulfonyl coumarins triggered by sulfonyl radicaladdition. Scheme 8 1,4-Aryl migration of aryl alkynoates initiated by benzyl radicals.

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The direct incorporation of heteroaryl groups is a convenientstrategy to synthesize heteroaryl-containing compounds. Althoughremote radical aryl migration reactions are reported by severalgroups, selective heteroaryl migration is still highly challenging.Zhu and co-workers realized radical-mediated heteroaryl ipso-migration of substituted tertiary alcohols 46 with Langlois’reagent (CF3SO2Na) 47 as a CF3 radical source, providingfluoroalkyl functionalized heteroarenes 48 in good to excellentyields (Scheme 11).17 Most of the heteroaryl groups, includingbenzothiazole, benzoxazole, thiazole, imidazole and pyridine,migrated smoothly to afford the corresponding heteroarylmigration products. Notably, the electron-withdrawing hetero-arene is a preferential migration functionality compared withelectron-rich heteroarene (48e and 48f). This is completelyopposite to the classical ionic-type migration rule. One limita-tion of the reaction was that the internal alkene failed. Control

experiments also revealed that five- and six-membered cyclictransition states favoured the remote migration process andfour- and seven-membered transition states disfavoured it.

The azide moiety is one useful building block, which couldbe readily converted to various N-containing functional groups.In 2017, Liu’s group reported an interesting copper-catalysedtrifluoromethylation/1,4-aryl migration of homopropargylazides to access trifluoromethylated nitriles (Scheme 12).18

Herein the CF3 radical can be generated via a single electrontransfer process between Cu(I) and Togni’s reagent. Theaddition of the CF3 radical to the triple bond of substrate 49triggers a consecutive cascade process to generate radical 53which undergoes single electron oxidation and extrusion ofN2 to produce nitrile compound 50. Importantly, the productsare obtained in a highly selective manner, which keeps CF3 andmigrated aryl groups always in the trans-position.

Indeed, the reaction mode of radical aryl migration isnot limited to radical addition to alkenes and alkynes. If theScheme 10 1,4(5)-(Hetero)aryl migration of tertiary alcohols.

Scheme 11 Chemoselective radical heteroaryl migration.Scheme 9 Radical induced ring expansion to access medium-ringskeletons.

Scheme 12 Copper-catalyzed 1,5-aryl migration of homopropargyl azides.

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carbon- or heteroatom-centred radical can be generated at asuitable position, the radical migration is also feasible. In 2015,one impressive radical Smiles rearrangement was disclosed fromStephenson’s group.19 The remote aryl group directly migrated tothe difluoroalkyl radical which was generated in situ by means ofphotoredox catalysis (Scheme 13). This protocol enabled concisesynthesis of a diverse range of difluoroethanoxyl-containing aryl/heteroaryl products. A series of bioactive heterocyclic substrateswere compatible, and furnished the desired products in moderateto good yields (43–89%). Interestingly, both NBu3 and formic acidserved as the electron and H donor. As illustrated in Scheme 13,the mechanism starts from the photoinduced SET and thegenerated radical 57 undergoes intramolecular ipso addition/extrusion of SO2 to form alkyloxyl radical 59, which wouldundergo H-atom abstraction from the NBu3 radical cation, finallyleading to the desired product 60. Notably, the authors declaredthat a radical chain pathway might also be involved.

Different from the preceding carbon-centred radical initiatedaryl migration, the distal aryl migration can also be triggered byelectrophilic nitrogen radicals. For example, in 2015, Shi’s groupreported an elegant Ag(I)-catalyzed 1,4-aryl migration from thecarbon to nitrogen centre followed by C–O bond formation,affording g-hydroxy amines or tetrahydroquinoline derivativesin satisfying yields (Scheme 14).20 During optimization of thereaction conditions, the authors found that oxidants, solventsand protecting groups on nitrogen atoms were requisite for thistransformation. Among the oxidants tested, PhI(OTFA)2 was thesuperior one. DCE was determined to be the best solvent, andfurther investigation demonstrated that the addition of PhCl as aco-solvent could dramatically promote the reaction efficiency.This reaction was sensitive to protecting groups on nitrogenatoms; only the sulfonamides worked well and the othersubstrates, such as Boc, Ac, CO2Me, Ts or Ms-protected amides,resulted in no reaction or low conversion. The migratory apti-tude of different aryl groups was also tested with unsymmetricalsubstrates; the results indicated that compared to electron-deficient phenyl groups, electron-rich aryl rings preferred tomigrate (see Scheme 14, 62e and 62f). This point is similar tothe ionic-type migration sequence.

The authors further performed several control experimentsto gain insight into the mechanistic pathway. With 1.0 or 0.5equiv. TEMPO as a radical scavenger, migration was completelysuppressed. By the treatment of the modified substrate 64 witha classical radical system of triethylborane/O2, the expectedmigration occurred smoothly with good yield (Scheme 15a).These experiments indicated that a radical pathway should beinvolved. A possible mechanism was proposed in Scheme 15b.The N-centred radical 68 could be generated in the presence ofa catalytic amount of Ag(I)/ligand and PhI(OTFA)2 as well asa suitable base. Then, intramolecular ipso-addition occurs togenerate radical 69 which subsequently undergoes C–C bondcleavage to give benzylic radical 70. Finally, SET oxidation ofradical 70 to its cation species 71 followed by nucleophilicattack provides product 62a.

Another example of long-distance aryl migration to nitrogenatoms enabled by redox-neutral photoredox catalysis wasreported by Nevado’s group in 2017 (Scheme 16).21 This reac-tion is initiated by the deprotonation of 72 with K2HPO4 togenerate more reductive anion 77. The SET oxidation of 77 withphotoexcited Ir(III) leads to a reactive amidyl radical 78. TheN atom ipso-attack of aryl followed by C–C bond cleavageproduces radical 80 which is trapped by sulfonyl acrylates 73

Scheme 13 Smiles rearrangement induced by the difluoroalkyl radical.Scheme 14 Silver-catalyzed radical aryl migration from carbon to nitrogenatoms.

Scheme 15 Possible mechanism of aryl migration at nitrogen atoms.

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or alkenes 74 to finally give carbon-to-nitrogen aryl migrationproducts 75 or 76.

There are very few examples about the long-distance radicalaryl migration between two heteroatoms. In 2016, Jana andco-workers reported a silver(I)-catalyzed 1,4-aryl migration of2-aryloxybenzoic acids which incorporated a radical aryl migra-tion between oxygen or sulfur and oxygen atoms.22 The carboxylradical 86 can be generated through SET oxidation of carboxylacid 83 with Ag(II) generated in situ. The 1,4-ipso attack byoxygen atom takes place with concomitant C–X (X = O or S)bond cleavage, leading to radical intermediate 88. The radical88 could undergo a H-atom shift (X = O) or homo-coupling(X = S) to give product 84 or 85 (Scheme 17).

Very recently, Li and Cao reported a similar aryl migrationbetween two oxygen atoms promoted by photoredox catalysiswithout external oxidant under mild conditions (Scheme 18).23

In this transformation, electron-rich aryls are more likely toundergo aryl migration than electron-deficient aryl groups.

2.2 Radical migration of other carbon-based groups

In addition, the distal migration of other carbon-based functionali-ties, such as –CN, –CHO, –alkynyl groups was recently developed.

In 2016, the group of Zhu reported a metal-free remote nitrilemigration triggered by azidyl radical addition to give unacti-vated olefins (Scheme 19).24 First, the azido radical is generatedfrom commercial available TMSN3 in the presence of PhI(OAc)2

as an oxidant. Then addition of the azido radical to alkene 91leads to the formation of alkyl radical 93, which would undergointramolecular addition at carbon atoms of nitrile groups,affording cyclic transition state 94. The resulting unstable cyclicintermediate 94 undergoes immediate C–C homolysis at roomtemperature to afford the CN migration intermediate 95.Finally, oxidation of 95 by PhI(OAc)2 affords 1-azido-2-nitrileproduct 92. In this reaction, the 1,4- or 1,5-CN migration via athermodynamically stable 5- or 6-membered cyclic transition stateis more favourable than 1,3 or 1,6 migration.

Lately, Liu’s group extended this strategy and achievedcyanofunctionalization of terminal alkenes via distal cyanomigration with diverse radical species (Scheme 20).25 The TMS-protection of hydroxyl was an essential factor for high yields.

After this disclosure, Liu and co-workers further applied the distalradical migration strategy to achieve 1,2-formylfunctionalizationof alkenes through radical formyl migration (Scheme 21).26 WithTogni’s reagent as a CF3 radical source in the presence of20 mol% CuI, radical 1,4- and 1,5-formyl migration proceeded

Scheme 16 Visible-light-mediated aryl migration from carbon to nitrogenatoms.

Scheme 17 1,5-Aryl migration from oxygen or sulfur to carboxylate oxygen.

Scheme 18 Photoredox catalysed aryl migration between oxygen atoms.

Scheme 19 Azidocyanation of unactivated alkenes triggered by distalradical nitrile migration.

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smoothly to afford 1-CF3-2-CHO products in moderate to goodyields. Other radical species, such as the perfluoroalkyl radical,difluoromethyl radical and sulfonyl radical, were also able totrigger this migration under photoredox catalysis. It is notedthat 1,4 and 1,5-carbonyl migration of cyclic a-hydroxyketones isalso available, producing various medium-ring structures withCF3 or N3 groups catalysed by CuI. The possible mechanism isdepicted in Scheme 21d taking Togni’s reagent as an example.The generated CF3 radical adds to substrate 99 followed by intra-molecular cyclization, yielding a cyclic transition state 101,which undergoes homolysis followed by SET to give trifluoro-methylated product 100a.

Alkynes are versatile synthetic blocks in organic chemistry.Recently, Zhu and co-workers first disclosed a novel radicalalkynyl migration reaction which could accomplish alkynylation

of unactivated olefins promoted by visible light photoredoxcatalysis under mild reaction conditions (Scheme 22).27 WithUmemoto’s reagent and a catalytic amount of fac-Ir(ppy)3 as aphotocatalyst, a highly reactive CF3 radical and a strong oxidantIr(IV) are generated under blue LED irradiation. The CF3 radicalreacts with the terminal alkene of 103, giving alkyl radical 105,which subsequently undergoes cyclization/homolysis to affordalkyne migration intermediate 107. Oxidation of 107 by a strongoxidant Ir(IV)-species affords the desired product 104. Thecontrol experiments showed that 5 and 6-membered cyclictransition states were much more favourable for the alkynylmigration. Various g or d-alkynylation alkyl ketones were con-structed in good yields. Unpleasingly, 1,1-disubstituted alkenesand internal alkenes cannot undergo this transformation dueto the relatively lower reactivity.

Lately, the group of Studer reported a similar radical alkynylmigration of tertiary propargylic alcohols.28 Different fromZhu’s work, Studer and co-workers used cheap perfluoroalkyliodides as perfluoroalkyl radical sources in the absence oftransition metal via electron catalysis (Scheme 23).

3 The C–H scission by distal radicalmigration

In the past decade, C(sp3)–H bond functionalization has emergedas a powerful platform to construct new carbon–carbon or

Scheme 20 Distal radical nitrile migration of TMS-protected tertiaryalcohols.

Scheme 21 Radical formyl migration of tertiary alcohols.

Scheme 22 Distal alkynyl migration for radical trifluoromethylativealkynylation of unactivated olefins.

Scheme 23 Radical alkynyl migration with perfluoroalkyl iodides as per-fluoroalkyl radical sources.

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carbon–heteroatom bonds.29 The transition metal, such as Cu,Pd, Rh, Ru, Ir, catalyzed C–H bond functionalization has beenrecognized as one of the most attractive approaches to achieveC(sp3)–H bond transformation. However, these methodsusually suffer from one of the following drawbacks: (1) viablefor the C–H bond adjacent to N, O, S atoms; (2) the requirementof directing groups; (3) challenges in controlling the selectivity.Inarguably, the radical migration strategy offers a new chanceto deal with selective and mild C–H bond functionalization(Scheme 24). In this section, hydrogen-atom transfer (HAT)triggered C(sp3)–H bond functionalization will be discussed.

3.1 HAT triggered by carbon centred radicals

Enantioselective functionalization of the C(sp3)–H bond is a directand efficient manner to construct chiral sp3 carbon–carbon andcarbon–heteroatom bonds. In 2014, Liu’s group developed a copperand chiral phosphoric acid co-catalyzed enantioselective a-C(sp3)–Hfunctionalization of amides enabled by radical trifluoromethylationof unactivated alkenes concomitant with 1,5-hydrogen transferwithout the need for an external oxidant (Scheme 25).30 It startsfrom the CF3 radical addition to 113, giving rise to alkyl radical 115;the resulting alkyl radical immediately abstracts the hydrogen atomadjacent to the nitrogen atom to form a more stable a-aminoalkylradical 116. This intermediate is easily oxidized to generate iminecompound 117. Interestingly, the utilization of chiral phosphoricacid could elegantly control its stereoselectivity. A diverse rangeof chiral CF3-containing N,O-aminal derivatives were obtainedin excellent enantioselectivity and good yields. A similarracemic phosphine catalyzed strategy was also reported fromthe same group.31

In 2015, Liu and co-workers accomplished a series of remotea-C–H functionalization of carbonyl compounds via radicalH-atom transfer (Scheme 26).32 The CF3 radical addition toalkene followed by a 1,5-H shift and SET oxidation providedcation intermediate 122. This reactive intermediate could betrapped by different nucleophiles.

In 2016, Gevorgyan and co-workers reported a visible-light-mediated 1,5-H transfer reaction of hybrid aryl-Pd(I)-radicalspecies generated via a SET process between aryl iodide andPd(0) (Scheme 27).33 With the irradiation of blue LEDs, anunprecedented single electron oxidation addition of aryl iodideto Pd(0) occurs, furnishing the hybrid aryl-Pd(I)-radical species126. This aryl radical complex specifically abstracts a-hydrogenadjacent to the oxygen atom, and produces alkyl Pd-radicalintermediate 127, which finally affords silyl enols ether 128 viaa SET oxidation or b-H elimination pathway.

As we discussed above, almost all the 1,5-H shift exampleswere focused on the functionalization of relatively weak C–Hbonds. Very recently, Gagosz and co-workers developed a coppercatalyzed 1,5-hydrogen shift of homoallylic alcohols with thebenzyl group as a traceless hydrogen donor (Scheme 28).34 WithCF3- or N3-containing hypervalent iodine reagents as radicalsources in the presence of a catalytic amount of copper salts,g-trifluoromethyl or azido substituted alcohols can be obtainedin moderate to good yields.

In 2016, the group of Zhu successfully developed a coppercatalyzed remote C–H amidation of aldehydes via 1,5-H transferfrom C–H aldehyde groups.35 Both alkenes and aldehydes

Scheme 24 C–H functionalization induced by a radical 1,n-H shift.

Scheme 25 Enantioselective C(sp3)–H bond functionalization via1,5-HAT.

Scheme 26 HAT-triggered remote a-C(sp3)–H bond functionalization ofcarbonyl compounds.

Scheme 27 Pd-Catalyzed HAT for the synthesis of silyl enols.

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could be functionalized. As their follow-up work, they recentlydocumented a Pd-catalyzed difluoroalkylation and remote C–Harylation of alkenyl aldehydes through a tandem radical addi-tion/1,5 or 1,6-HAT/Suzuki coupling process with readily avail-able fluoroalkyl bromides and arylboronic acids (Scheme 29).36

Importantly, radical intermediate 138 was justified as one keyintermediate for the addition of Pd(I) to undergo the traditionaltransmetalation with ArB(OH)2 to deliver the final product 137.

3.2 HAT triggered by nitrogen-centered radicals

Nitrogen-centred radicals serve as versatile synthetic intermedi-ates and play an important role in many chemical transforma-tions. Nitrogen-centred radicals have long been recognized ashighly reactive intermediates that are capable of triggering distalC–H bond transfer. One of the most well-known and usefultransformations is the Hofmann–Loffler reaction. Despite thegreat advances, the harsh reaction conditions seriously limit itssynthetic applications. In 2015, the Muniz group reporteda modified version. The sunlight initiated, iodine catalyzedHofmann–Loffler reaction provided an efficient and straight-forward access to a general class of saturated nitrogenatedheterocycles under practical conditions (Scheme 30).37 Choosingthe suitable oxidant was crucial. After systematic optimization ofreaction conditions, the authors found that with one equivalentof PhI(mCBA)2 (mCBA = 3-chlorobenzoate) as an oxidant and2.5 mol% iodine as a catalyst made the reaction very clean.A possible mechanism was proposed by the authors. First, in thepresence of iodine and PhI(mCBA)2, the reactive intermediate141 can be formed. Then photolysis of the N–I bond results in

electrophilic N-centred radical 142 which undergoes a 1,5-H shiftto give benzylic radical 143. A chain propagation between 141and 143 can produce iodinated intermediate 144 and regenerateN-radical 142. Finally, the cyclization of 144 affords pyrrolidinederivatives. Almost at the same time, Herrera and co-workersreported a similar Hofmann–Loffler reaction to construct pyrro-lidines or 2-pyrrolidinones with excess oxidant and I2.38

Very recently, Nagib and co-workers described a triiodide-mediated Hofmann–Loffler reaction of unactivated C–H bondfor the formation of a broad range of functionalized pyrro-lidines (Scheme 31).39 The formation of an I3

� intermediatefrom NaI and PIDA was supposed to be one key element thatcould decrease the concentration of I2 in the reaction system andthus facilitate the formation of a N–I bond, which would initiatean exclusively selective 1,5-hydrogen atom transfer processthrough visible light induced homolysis of the N–I bond.

Although the above Hofmann–Loffler reaction proceeds wellunder mild conditions, stoichiometric amounts of hypervalentiodine reagents were required. In 2015, Yu’s group reportedthe first photoredox catalyzed Hofmann–Loffler reaction ofN-chlorosulfonamides without external oxidant.40 A variety of5-membered ring pyrrolidines and d-chlorinated sulfonamidewere prepared in good to excellent yields. In Yu’s work, amidylradical 151 can be generated by oxidative quenching of photo-excited *Ir(III) with N-chlorosulfonamides 149. The electrophilic

Scheme 28 Radical 1,5-HAT with the benzyl group as a traceless redox-active hydrogen donor.

Scheme 29 Pd-Catalyzed HAT for C–H arylation of aldehydes.

Scheme 30 I2-Catalyzed, sunlight-mediated oxidative Hofmann–Lofflerreaction.

Scheme 31 In situ generated I3� initiated oxidative Hofmann–Loffler

reaction.

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N-centred radical 151 goes through 1,5-H transfer to formradical 152. Subsequently, SET oxidation of 152 with Ir(IV) couldafford carbocation 153 and regenerates the photocatalytic cycle.Finally, trapping of cation 153 by chloride anions gives chlorina-tion product 154, which could be easily converted to pyrrolidinederivatives under base conditions (Scheme 32).

Based on their previous work on the I2-catalyzed Hofmann–Loffler reaction and photoredox catalysis, Muniz and co-workersrecently reported a dual visible-light-induced intramolecularamination of remote C(sp3)–H bonds by combination of light-activated homolysis of the N–I bond and photoredox catalysis(Scheme 33).41 This can avoid the use of stoichiometric amountsof hypervalent iodine reagents.

Despite the great achievements in the Hofmann–Lofflerreaction, the prevalent methods usually require N–X amidesas starting materials (either prepared or generated in situ).These methods are generally not amenable to the direct con-struction of intermolecular carbon–carbon (C–C) bonds.The direct generation of amidyl radicals from N–H bonds is along-standing challenge. In 2016, the Knowles group42 and theRovis group43 simultaneously made a major breakthrough inthis area by means of photoredox direct generation of nitrogen-centred radicals from N–H amides (Scheme 34). These reactionsfeature the formation of C–C bonds via 1,5-hydrogen atom transferand subsequent coupling with electron deficient alkenes. Bothalkyl and aryl enones were suitable coupling partners. In Knowles’swork, the strategy could also be expanded to intermolecularH-abstraction. In Rovis’s work, they also explored the possibilityof cascade C–H alkylation of substrates with more than one

tertiary C–H bond, and found that substrates with two adjacenttertiary C–H bonds could undergo 1,5-HAT first and thenfollowed by 1,6-HAT, providing access to incorporating twodistinct alkyls at different C–H bonds in one substrate. For boththese two reactions, the nitrogen atom bearing an electron-withdrawing group was crucial for the success.

Similar to amidyl radicals, the iminyl radicals are alsoreactive enough to undergo 1,5-H transfer to achieve remoteC–H bond functionalization. In the recent five years, oximederivatives have been recognized as suitable precursors to produceiminyl radicals by means of photocatalysis.44 In 2017, the group ofNevado reported a visible light-mediated redox-neutral remoteinert C(sp3)–H bond functionalization followed by intramolecularradical cyclization via an iminyl radical triggered HAT process(Scheme 35).45 This protocol proceeded smoothly to producemultisubstituted 3,4-dihydronaphthalen-1(2H)-ones 163 in moderateto excellent yields in aqueous media. By changing reactionconditions, C–N bonds could also be constructed in some cases togive dihydro-2H-pyrrole scaffold 167. The iminyl radical 164 is firstgenerated from oxime 162 by photoinduced N–O bond cleavage.Subsequently, 1,5-HAT takes place from the iminyl radicalcenter to generate alkyl radical 166. The resulting alkyl radicalimmediately undergoes intramolecular cyclization/single elec-tron oxidation followed by hydrolysis to give ketone 163. In the

Scheme 32 Redox-neutral, visible-light-induced Hofmann–Loffler reaction.

Scheme 33 Redox-neutral, TPT and I2 co-catalyzed Hofmann–Lofflerreaction.

Scheme 34 Photoredox HAT for C–C coupling via N-centred radical.

Scheme 35 Photoredox HAT for remote C(sp3)–H bond functionaliza-tion of oximes.

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absence of water, an intramolecular C(sp3)–H amination processoccurs to furnish product 167.

Almost at the same time, the same group described a novelstrategy for selective functionalization of the C(sp3)–H bond toaccess diverse dihydronaphthalen-1(2H)-ones via 1,5-H transfer toiminyl radicals (Scheme 36).46 Mechanically, iminyl radical 171 isgenerated from 168 and 169 by radical addition to vinyl azidesand subsequent release of N2 in the presence of AgI and K2S2O8.The resulting radical 171 then participates in a series of transfor-mation involving a 1,5-H shift to give the final product 170.

The b-amino alcohol is one class of privileged substrates inpharmaceuticals, agrochemicals and natural products. Recently,Nagib’s group described a 1,5-hydrogen transfer induced intra-molecular C–H amination of alcohols to get b-amino alcoholproducts (Scheme 37).47 The substrate 173 serves as a tracelessdirector to generate iminyl radical 175 under a combined eventof NaI and PhI(OAc)2. Intermediate 175 undergoes 1,5-H shift/intramolecular cyclization/hydrolysis, accomplishing introduc-tion of ammonia at the b carbon of alcohols.

3.3 HAT triggered by oxygen-centered radicals

Owing to the high BDE of the O–H bond, alkoxyl radicalsreadily activate inert C–H bonds by a selective intramolecular1,n-hydrogen atom transfer (1,n-HAT). However, it is still diffi-cult to produce alkoxyl radicals under mild conditions.

In 2014, Taniguchi and co-workers reported an iron-catalyzedaerobic hydration of simple alkenes that involves hydration of theolefin, intramolecular 1,5-hydrogen shift/alkyl radical oxygenation(Scheme 38).48 A wide range of 1,4-diols were obtained in moderateyields using cheap and green reagents at room temperature. Inthis reaction, the structural nature of alkenes has a significantinfluence on the yields. Notably, it was found that additionalMe2S as an electron donor ligand was essential to suppress thecompeting byproduct monoalcohol.

Based on the radical HAT process, in 2016, the group of Chenreported the first selective C(sp3)–H allylation and alkenylationreactions enabled by photoredox conditions (Scheme 39a).49 Theoxidant and reductant were not needed. It represents an elegantredox-neutral photocatalyzed alkoxyl radical application inorganic synthesis. Later, the Meggers group also reported aphotoredox-mediated asymmetric C(sp3)–H activation through1,5-hydrogen transfer (Scheme 39b).50 In both works, photoredoxgeneration of alkoxyl radical 193 and subsequent 1,5-HAT occurto deliver alkyl radical 194 (Scheme 39c).

4 Conclusion

In conclusion, we have witnessed a rapid development ofsustainable long-distance radical migration induced C–C and

Scheme 36 Remote C(sp3)–H functionalization via 1,5-HAT to constructfused ketones.

Scheme 37 HAT for the synthesis of b-amino alcohols.

Scheme 38 Fe-Catalyzed dihydroxylation via a HAT process.

Scheme 39 C(sp3)–H bond functionalization via H-atom transfer fromalkoxyl radicals.

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C–H bond functionalization. Its advent brings our chemicalcommunity a new platform to deal with the challenging radicaltransformation and elusive rearrangement reactions. To date,this strategy has drawn great enthusiasm of organic chemists,and strongly indicates a promising application in the construc-tion of targeted molecules beyond the transition-metal-catalyzedC–C coupling technology. With the recent three years’ efforts,the remote radical migration strategy has become a powerfulmethod for the synthesis of intricate scaffolds.

Some challenges need to be addressed in the near future:(1) The exploitation of asymmetric HAT transformation for

enantioselective remote C–H and C–C bond functionalization.(2) The development of novel substrate types.(3) The application of this strategy for late-stage function-

alization of complex molecules.

Abbreviations

AIBN AzodiisobutyronitrileBDE Bond dissociation energydtbbpy 4,40-Di-tert-butyl-2,20-bipyridineDME 1,2-Ethanediol dimethyl etherDABCO 1,4-Diazabicyclo[2.2.2]octaneDCM DichloromethaneDCE 1,2-DichloroethaneEA Ethyl acetateHAT Hydrogen atom transferHFIP 1,1,1,3,3,3-Hexafluoropropan-2-olHE Hantzsch esterPIDA PhI(OAc)2

1,10-phen 1,10-PhenanthrolineSET Single electron transferTBHP tert-Butyl hydroperoxideTEMPO 2,2,6,6-Tetramethylpiperidine-1-oxylmCBA 3-Chlorobenzoate

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We gratefully acknowledge the National Natural Science Foun-dation of China (21732003, 21702098, 21672099, 21472084 and21372114).

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