Difunctionalization of Alkenes and Alkynes Via Intermolecular Radical and Nucleophilic Additions

Review Difunctionalization of Alkenes and Alkynes via Intermolecular Radical and Nucleophilic Additions

Hongjun Yao 1,†, Wenfei Hu 2,† and Wei Zhang 2,*

1 College of Biological Science and Technology, Beijing Forestry University, 35 Qinghua East Road, Beijing 100083, China; [email protected] 2 Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Boulevard, Boston, MA 02125, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-617-287-6147 † These authors contributed equally to this work.

Abstract: Popular and readily available alkenes and alkynes are good substrates for the preparation of functionalized molecules through radical and/or ionic addition reactions. Difunctionalization is a topic of current interest due to its high efﬁciency, substrate versatility, and operational simplicity. Presented in this article are radical addition followed by oxidation and nucleophilic addition reactions for difunctionalization of alkenes or alkynes. The difunctionalization could be accomplished through 1,2-addition (vicinal) and 1,n-addition (distal or remote) if H-atom or group-transfer is involved

in the reaction process. A wide range of moieties, such as alkyl (R), perﬂuoroalkyl (Rf), aryl (Ar), hydroxy (OH), alkoxy (OR), acetatic (O2CR), halogenic (X), amino (NR2), azido (N3), cyano (CN), as well as sulfur- and phosphorous-containing groups can be incorporated through the difunctionalization reactions. Radicals generated from peroxides or single electron transfer (SET) agents, under photoredox or electrochemical reactions are employed for the reactions.

Keywords: difunctionalization; radical; nucleophilic; alkene; alkyne; photoredox; single electron transfer; vicinal-difunctionalization; distal-difunctionalization; photoredox; electrochemical reaction Citation: Yao, H.; Hu, W.; Zhang, W. Difunctionalization of Alkenes and Alkynes via Intermolecular Radical and Nucleophilic Additions. 1. Introduction Molecules 2021, 26, 105. https:// Radical-based reactions such as homolytic bond cleavage, single electron transfer, doi.org/10.3390/molecules26010105 atom or group transfer, radical addition, and radical coupling processes are important

Academic Editor: Derek J. McPhee organic transformations. In addition to the success of radical polymerization for making Received: 7 December 2020 synthetic polymers, organic radical reactions have also become an increasing important Accepted: 24 December 2020 tools for preparation of small molecules through radical addition, cyclization, cascade bond Published: 28 December 2020 formation, H-atom and group-transfer, and radical-radical coupling reactions [1,2]. Active researches on direct C-H bond functionalization [3], remote (distal) functionalization [4], Publisher’s Note: MDPI stays neu- Smile-type ipso-group rearrangement [5], cascade reaction [6], photoredox catalysis [7], and tral with regard to jurisdictional clai- electrochemical reaction [8] have significantly fueled the chemistry of synthetic radicals. ms in published maps and institutio- Radical difunctionalization of unsaturated carbon-carbon bonds is a topic of cur- nal affiliations. rent interest due to its high synthetic efficiency, substrate versatility, and operational simplicity [9–17]. Presented in this article are one-pot radical addition, oxidation and nucleophilic addition reactions to incorporate two functional groups to alkenes or alkynes. The difunctionalization could be accomplished through direct 1,2-addition (Scheme1I-A), Copyright: © 2020 by the authors. Li- 1,2-functionalization involving Smiles-type ispo aryl group migration (Scheme1I-B) [ 4,5], or censee MDPI, Basel, Switzerland. 1,n-functionalization involving H-atom transfer (Scheme1I-C) [ 4–6]. The majority examples This article is an open access article distributed under the terms and con- in this paper are direct 1,2-additions. Only a few cases are related to 1,2-functionalization ditions of the Creative Commons At- through Smiles-type rearrangement and distal difunctionalizations through 1,5-H-atom tribution (CC BY) license (https:// transfer. A wide range of moieties, such as alkyl (R), perfluoroalkyl (Rf), aryl (Ar), hydroxy 2 creativecommons.org/licenses/by/ (OH), alkoxy (OR), acetatic (O2CRRCO2), halogenic (X), amino (NR ), azido (N3), cyano 4.0/). (CN), as well as sulfur- and phosphorous-containing groups can be incorporated through

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transfer. A wide range of moieties, such as alkyl (R), perfluoroalkyl (Rf), aryl (Ar), hydroxy (OH), alkoxy (OR), acetatic (O2CRRCO2), halogenic (X), amino (NR2), azido (N3), cyano Molecules 2021, 26, 105 2 of 31 (CN), as well as sulfur- and phosphorous-containing groups can be incorporated through difunctionalization reactions. Radical reactions initiated with peroxides (such as dicumyl peroxide (DCP), di-t-butyl peroxide (DTBP), and t-butyl hydroperoxide (TBHP)) [18], pro- difunctionalization reactions. Radical reactions initiated with peroxides (such as dicumyl moted by single electron transfer agents (such as hypervalent iodine reagents (HIRs), ceric peroxide (DCP), di-t-butyl peroxide (DTBP), and t-butyl hydroperoxide (TBHP)) [18], promotedammoniumby singlenitrate electron (CAN), transfer Mn(OAc) agents2, and (such Na as2S hypervalent2O5), under iodinephotoredox reagents catalysis (HIRs), (such as Ru(bpy)3Cl2 and Ir(ppy)3) [7], and by electrochemical reactions [8] are included. In the rad- ceric ammonium nitrate (CAN), Mn(OAc)2, and Na2S2O5), under photoredox catalysis (suchical-initiated as Ru(bpy) difunctionalization3Cl2 and Ir(ppy)3)[ 7reactions,], and by electrochemical the catalysts reactionsare critical [8] for are included.oxidative SET to Inconvert the radical-initiated the intermediate difunctionalization radicals to carbocatio reactions,ns thefor catalyststhe sequential are critical reaction for oxida- with nucleo- tivephiles. SET to convert the intermediate radicals to carbocations for the sequential reaction with nucleophiles.This paper covers difunctionalization reactions which are initiated with a radical ad- ditionThis and paper ended covers with difunctionalization a nucleophilic addition. reactions whichIt is organized are initiated based with on a radical the nature addi- of initial tion and ended with a nucleophilic addition. It is organized based on the nature of initial radicals including C-, N-, O-, P-, S-centered and perfluoroalkyl (Rf) radicals. Reactions in- radicals including C-, N-, O-, P-, S-centered and perﬂuoroalkyl (Rf) radicals. Reactions involvingvolving electrophilic electrophilic addition addition (Scheme (Scheme1II-A), 1II-A), radical-radical radical-radical coupling coupling such as atomsuch trans-as atom trans- ferfer radical radical addition addition (ATRA) (ATRA) [19 ][19] or metal-catalyzed or metal-catalyzed coupling coupling (Scheme (Scheme1II-B )[20 1II-B)], radical [20], radical cyclizationcyclization for for ring ring formation formation (Scheme (Scheme1II-C) [ 211II-C)], and [21], cascade and reactions cascade [6 ]reactions involving more[6] involving thanmore two than steps two of radicalsteps of additions radical are additions not included are not in this included paper. Those in this type paper. of reactions Those type of mightreactions be the might topics be of the our topics future of review our future articles. review articles.

I) Reactions covered in this paper Nu + - X Nu X ()n R (A) ()n R direct 1,2-difunctionalization . [O] X HO Ar R O + Ar addition X 1) ipso X OH (B) ()n R 2) [O] ()n Ar ()n R 1,2-difunctionalization via 1) HAT ipso rearrangement 2) [O] Nu Nu- X + X (C) ()n R ()n R distal difunctionalization

II) Reactions not covered in this paper E - - X E X () R (A) n ()n R radical & electrophilic additions . [R] X Y addition X . + Y X ()n R (B) () R ()n R or met-cat n ATRA or cyclization metal-catalysis

X X (C) Z R R ()n-1 ()n-1 Z radical addition & cycization SchemeScheme 1. 1.Radical-initiated Radical-initiated difunctionalization difunctionalization reactions. reactions. (I-A), I- directA, direct 1,2-difuctionalization. 1,2-difuctionalization. (I-B), I-B, 1,2-difuctionalization1,2-difuctionalization involving involvingipso ipso-reaction-reaction process. process. (I-C), I- distalC, distal difunctionalization. difunctionalization. (II-A ),II- 1,2-A, 1,2- difuctionalizationdifuctionalization involving involving electrophilic electrophilic addition. addition. (II-B ),II- atom-transferB, atom-transfer addition addition with orwith without or without metalmetal catalysis. catalysis. (II-C II-C),, reaction reaction involving involving cyclization. cyclization. 2. Carbon Radical-Initiated Reactions 2. Carbon Radical-Initiated Reactions Presented in this section are carbon radical-initiated reactions and C-, O-, and N- containingPresented moieties in arethis served section as are the carbon nucleophiles radical-initiated for the difunctionalizations. reactions and C-, The O-, initial and N-con- carbontaining radicals moieties could are served be generated as the nucleophiles by metal-containing for the SETdifunctionalizations. agents, using peroxides, The initial car- orbon under radicals photoredox could be conditions. generated Most by metal-cont alkenes usedaining for difunctionalization SET agents, using are peroxides, styrene or un- derivatives. Because addition of initial radicals to styrenes to form stabilized benzylic

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der photoredox conditions. Most alkenes used for difunctionalization are styrene deriva- Molecules 2021, 26, 105 3 of 31 tives.der photoredox Because addition conditions. of initial Most radicals alkenes to used styrenes for difunctionalization to form stabilized benzylicare styrene radicals deriva- is regioselectivetives. Because whichaddition could of initial be readily radicals oxidized to styrenes to benzylic to form cations stabilized for benzylicnucleophilic radicals addi- is tions.regioselective which could be readily oxidized to benzylic cations for nucleophilic addi- radicalstions.The is regioselectiveDu and Wang which labs could developed be readily a oxidizedhighly efficient to benzylic Re-catalyzed cations for nucleophilic oxyalkylation of alkenesadditions.The using Du andhypervalent Wang labs iodine developed reagents a (HIRs) highly as efficient a dual functionalizationRe-catalyzed oxyalkylation agent to pro- of The Du and Wang labs developed a highly efﬁcient Re-catalyzed oxyalkylation of videalkenes alkyl using radicals hypervalent and carboxylic iodine reagents anions (HIRs)for additions as a dual (Scheme functionalization 2) [22]. In agentthe reaction to pro- alkenesvide alkyl using radicals hypervalent and carboxylic iodine reagents anions (HIRs) for additions as a dual functionalization(Scheme 2) [22]. agent In the to reaction process,provide alkyl cationic radicals species and carboxylic2 generated anions through for additions a heterolytic (Scheme cl2eavage)[22]. In of the an reaction I-O bond from process, cationic speciesI 2 generated through a heterolytic cleavage of an I-O bond from HIRprocess, are cationicreduced species by Re2 generatedto afford throughradical iodine a heterolytic intermediates cleavage of 3. an Homolytic I-O bond from breaking of I theHIRHIR remaining areare reduced reduced I-O by bondby Re IReto gives affordto afford acyloxy radical radical radicals iodine iodine intermediates which intermediates undergo3. Homolytic decarboxylation 3. Homolytic breaking breakingto of generate of alkylthethe remainingremaining radicals. I-O I-OAddition bond bond gives givesof acyloxyalkyl acyloxy radicals radicals radicals whichto alkene which undergo followed undergo decarboxylation bydecarboxylation oxidation to generate with to RegenerateI give cationsalkylalkyl radicals.radicals. 4. Finally, Addition Addition nucleophilic of of alkyl alkyl radicals attack radicals toof alkene 4to by alkene followedcarboxylic followed by anions oxidation by oxidationgives with difunctionalized Re Iwithgive ReI give productscationscations4 .4 1. Finally,.Finally, nucleophilic nucleophilic attack attack of 4 ofby 4 carboxylic by carboxylic anions anions gives difunctionalized gives difunctionalized productsproducts1 .1.

Scheme 2. Re-catalyzed difunctionalization with HIRs. SchemeScheme 2. 2.Re-catalyzed Re-catalyzed difunctionalization difunctionalization with with HIRs. HIRs. The Li group reported Ag-mediated 1,2-alkylarylation of styrenes with α-carbonyl The Li group reported Ag-mediated 1,2-alkylarylation of styrenes with α-carbonyl alkyl Thebromides Li group and reported indoles (Scheme Ag-mediated 3) [23]. 1, 2-alkylarylationThe Fe-salt is used of asstyrenes Lewis withacid toα-carbonyl stabilize alkylalkyl bromidesbromides and and indoles indoles (Scheme (Scheme3)[ 23 3)]. [23]. The Fe-saltThe Fe-salt is used is as used Lewis as acidLewis to stabilizeacid to stabilize thethe radicals.Theradicals.The initial initial alkyl alkyl radicals radicals6 produced 6 produced from fromα-carbonyl α-carbonyl alkyl bromides alkyl bromides in the in the the radicals.The initial alkylI radicals 6 produced from α-carbonyl alkyl bromides in the presence ofof 2 2 equiv equiv of of Ag AgI salt salt add add to styrenesto styrenes to afford to afford radicals radicals6 which 6 which are oxidized are oxidized by by I AgpresenceIIII to cationscations of 2 and equivand then then of undergo Ag undergo salt the add Friedel–Craftsthe to Friedel–Crafts styrenes reaction to afford reaction with radicals indoles with toindoles6 which give products to are give oxidized 5products. by 5Ag. II to cations and then undergo the Friedel–Crafts reaction with indoles to give products 5.

Scheme 3.3.Ag-catalyzed Ag-catalyzed 1,2-alkylarylation 1,2-alkylarylation of styrenes. of styrenes. Scheme 3. Ag-catalyzed 1,2-alkylarylation of styrenes.

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The Bao group reported Fe-catalyzed decarboxylative alkyl etherification of vi- The Bao group reported Fe-catalyzed decarboxylative alkyl etheriﬁcation of viny- nylarenes with aliphatic acids and alcohols (Scheme 4) [24]. Primary, secondary and ter- larenesThe with Bao aliphatic group acidsreported and alcoholsFe-catalyzed (Scheme decarboxylative4)[24]. Primary, alkyl secondary etherification and tertiary of vi- tiary aliphatic acids could be used as alkylating reagents, and primary and secondary al- aliphaticnylarenes acids with could aliphatic be used acids as alkylatingand alcohols reagents, (Scheme and 4) primary [24]. Primary, and secondary secondary alcohols and ter- as cohols as nucleophiles. Alkyl radicals generated from theII reaction of FeIIX2 complex with nucleophiles.tiary aliphatic Alkyl acids radicalscould be generated used as alkylating from thereaction reagents, of and Fe Xprimary2 complex and with secondary peresters al- addperesters to styrenes add toto form styrenes benzylic to form radicals benzylic which are radicals oxidized which to carbocations are oxidized by Fe toIII carbocationsspecies by cohols as nucleophiles. Alkyl radicals generated from the reaction of FeIIX2 complex with III andperestersFe then species undergoadd and to styrenes nucleophilicthen undergo to form reaction benzylicnucleophilic to giveradicals products reaction which8 .toare give oxidized products to carbocations 8. by FeIII species and then undergo nucleophilic reaction to give products 8.

SchemeScheme 4.4. 4. Fe-catalyzedFe-catalyzed Fe-catalyzed alkylalkyl alkyl etheriﬁcationetherifica etherification withtionwith with aliphaticaliphatic alip acids.haticacids. acids.

The Nishikat group reported a Cu-catalyzed reaction for difunctionalizing styrenes TheThe Nishikat Nishikat group group reported reported a Cu-catalyzed a Cu-catalyzed reaction reaction for difunctionalizing for difunctionalizing styrenes styrenes usingusing αα-bromocarbonyl-bromocarbonyl compoundscompounds asas aa sourcesource forfor tertiarytertiary alkylalkyl radicalsradicals andand alcoholsalcohols asas using α-bromocarbonyl compounds as a source for tertiaryI alkyl radicals and alcohols as nucleophilesnucleophiles (Scheme(Scheme5 5))[ [25].25]. SingleSingle electronelectron transfertransfer (SET)(SET) of of Cu CuIinduces induces thethe formationformation I ofofnucleophiles radicalsradicals 10 fromfrom (Scheme αα-bromocarbonyl-bromocarbonyl 5) [25]. Single compounds. compounds. electron Thetransfer The additi addition (SET)on of ofradicalsof radicalsCu induces to styrenes to styrenes the fol- formation II followedlowedof radicals by by oxidation oxidation10 from with α with-bromocarbonyl Cu CuII toto benzylic benzylic compounds.cations cations and and trapping trapping The additi with on alcohol of radicals nucleophilesnucleophiles to styrenes fol- II givegivelowed productsproducts by oxidation9 9.. ItIt waswas foundwithfound Cu thatthatto LewisLewis benzylic acidsacids (LA),cations(LA), such such and as as Zn(OTf) trappingZn(OTf)22,, couldcouldwith acceleratealcoholaccelerate nucleophiles the the nucleophilicnucleophilicgive products additionaddition 9. It was ofof alcohols.alcohols. found that Lewis acids (LA), such as Zn(OTf)2, could accelerate the nucleophilic addition of alcohols.

SchemeScheme 5.5. Cu-catalyzedCu-catalyzed difunctionalizationdifunctionalization ofof styrenes.styrenes.

TheThe YangYang group group reported reported Fe-catalyzed Fe-catalyzed decarbonylative decarbonylative alkylazidation alkylazidation of styrenes of styrenes with aliphaticwithScheme aliphatic 5. aldehydes Cu-catalyzed aldehydes and trimethylsilyldifunctionand trimethylsilylalization azide azideof (Scheme styrenes. (Scheme6)[ 26 6)]. [26]. Using Using (t-BuO) (t-BuO)2 (DTBP)2 (DTBP) as anas oxidantan oxidant and and radical radical initiator, initiator, a series a series of aliphatic of aliphatic aldehydes aldehydes were were converted converted to primary, to pri- secondarymary,The secondary Yang and tertiary andgroup tertiary alkylreported alkyl radicals radicalsFe-catalyzed to react to react with decarbonylativewith styrenes styrenes followed followed alkylazidation by by nucleophilic nucleophilic of styrenes azidationazidationwith aliphatic withwith TMSNTMSN aldehydes33.. InIn thethe and presencepresence trimethylsilyl ofof thethe FeFe catalyst,catalyst,azide (Scheme tt-butoxy-butoxy 6) radicalradical [26]. formedformedUsing ( throughthrought-BuO)2 (DTBP) thetheas an homolytichomolytic oxidant cleavage cleavageand radical of of DTBP DTBP initiator, abstracts abstracts a series the the hydrogen of hydrogen aliphatic from from aldehydes aldehydes aldehydes followedwere followed converted by de- by to pri- decarbonylationcarbonylationmary, secondary to togive and give alkyl tertiary alkyl radicals radicals alkyl which radicals which then then toreact react react with with with styrenes styrenes styrenes to from followed to from benzylic benzylic by radi-nucleophilic azidation with TMSN3. In the presence of the Fe catalyst, t-butoxy radical formed through the homolytic cleavage of DTBP abstracts the hydrogen from aldehydes followed by de- carbonylation to give alkyl radicals which then react with styrenes to from benzylic radi-

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radicals.cals. Formation Formation of ofcations cations by by oxidization oxidization followed followed withwith the the reaction reaction of of TMSN TMSN3 give3 give prod- productsucts 11. 11The. The authors authors also also proposed proposed another another mechanismmechanism of of radical radical coupling coupling in the in the for- cals. Formation of cations by oxidization followed with the reaction of TMSN3 give prod- formation of products. uctsmation 11. ofThe products. authors also proposed another mechanism of radical coupling in the formation of products.

SchemeScheme 6.6. 6. Fe-catalyzedFe-catalyzed Fe-catalyzed alkylazidationalkylazidation alkylazidation ofof styrenes.styrenes. of styrenes.

The Zhu group reported a Cu-catalyzed methylalkoxy difunctionalization of alkenes TheThe Zhu Zhu group group reported reported a Cu-catalyzed a Cu-catalyzed methylalkoxy methylalkoxy difunctionalization difunctionalization of alkenes of alkenes usingusing dicumyldicumyl peroxide peroxide (DCP) (DCP) as as a methyl a methyl source source and alcoholsand alcohols as nucleophiles as nucleophiles (Scheme (Scheme7 )[27]. using dicumyl peroxide (DCP) as a methyl source and alcohols as nucleophiles (Scheme The7) [27].t-alkoxy The t-alkoxy radical generatedradical generated from the from cleavage the cleavage of DCP undergoesof DCP undergoesβ-scission β-scission to release to therelease7) [27]. methyl the The methyl radical. t-alkoxy radical. It isradical captured It is generatedcaptured by alkenes by from alkenes to the produce tocleavage produce benzyl of benzyl DCP radicals radicalsundergoes13 which 13 which β are-scission to II oxidizedarerelease oxidized the to carbeniums methylto carbeniums radical. by Cuby It Cu isandII capturedand then then react react by with alkenes with alcohols alcohols to produce to to furnish furnish benzyl the the methylated methylated radicals 13 which etheretherare oxidized productsproducts to12 12 .carbeniums. by CuII and then react with alcohols to furnish the methylated ether products 12.

SchemeScheme 7.7. Cu-catalyzedCu-catalyzed methylalkoxylmethylalkoxyl difunctionalizationdifunctionalization ofof styrenes.styrenes.

TheThe KlussmannKlussmann groupgroup reportedreported aa reactionreaction forfor difunctionalizationdifunctionalization ofof styrenesstyrenes withwith Scheme 7. Cu-catalyzed methylalkoxyl difunctionalization of styrenes. carboncarbon radicalsradicals derivedderived fromfrom thioxanthene/xanthenethioxanthene/xanthene and thiophenols followedfollowed byby nucle-nucle- ophilicophilic additionaddition ofof acetylacetyl nitrilenitrile oror alcoholsalcohols (Scheme(Scheme8 )[8) [28].28]. TheThe combinationcombination ofof benzoylbenzoyl peroxideperoxideThe (BPO)(BPO) Klussmann withwith HPF6 group is a keyreported factor factor ofa of reactionthis this reaction. reaction. for Thedifunctionalization The benzoyloxyl benzoyloxyl radical radical of gener-styrenes gen- with eratedatedcarbon from from radicals BPO BPO abstracts abstractsderived H-atom from H-atom fromthioxanthene/xanthene from thioxant thioxanthenehene to give to give anda new a thiophenols new radical radical which whichfollowed then thenadds by nucle- addstoophilic styrenes to styrenes addition to form to formof the acetyl thebenzylic benzylic nitrile cations or cations alcohols 1515 afterafter (Scheme oxidation oxidation 8) with with[28]. BPO BPOThe in incombination the presence ofof benzoyl HPF6.HPF6.peroxide AcetonitrileAcetonitrile (BPO) with oror alcoholsalcohols HPF6 reactreactis a key withwith factor thethe carbocationscarbocations of this reaction. in in thethe fashionfashion The benzoyloxyl ofof aa RitterRitter reactionreaction radical gener- totoated generategenerate from productsBPOproducts abstracts14a 14aor or H-atom14b 14b.. from thioxanthene to give a new radical which then adds to styrenes to form the benzylic cations 15 after oxidation with BPO in the presence of HPF6. Acetonitrile or alcohols react with the carbocations in the fashion of a Ritter reaction to generate products 14a or 14b.

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SchemeScheme 8.8. Nitro-Nitro- andand oxyalkylationoxyalkylation ofof styrenes.styrenes.

TheThe GreaneyGreaney groupgroup reportedreported photoredoxphotoredox catalyticcatalytic arylalkoxyarylalkoxy oror alkylaminoalkylamino difunc-difunc- tionalizationtionalization ofof styrenesstyrenes usingusing Zn(OAc)Zn(OAc)22 toto enhanceenhance thethe reactionreaction processprocess (Scheme(Scheme9 9))[ [29].29]. III III ArylAryl radicalsradicals generatedgenerated fromfrom thethe reduction reduction of of Ar Ar2IBF2IBF44 underunder thethe catalysiscatalysis ofofIr IrIII addadd toto IV styrenesstyrenes toto formform benzylic radicals radicals which which are are oxidized oxidized with with Ir IrIV to tocations. cations. Addition Addition of nu- of nucleophiles (alcohols, H O or nitriles) afford difunctionalized products 16. cleophiles (alcohols, H2O2 or nitriles) afford difunctionalized products 16.

SchemeScheme 9.9. Aryl/alkyloxyAryl/alkyloxy or alkylamino difunctionalization of styrenes. * excited catalyst.

TheThe GloriusGlorius lablab developeddeveloped aa methodmethod forfor alkyloxylationalkyloxylation ofof styrenesstyrenes throughthrough photophoto electronelectron transfer-initiated transfer-initiated reaction reaction of ofN-(acyloxy)phthalimides N-(acyloxy)phthalimides (Scheme (Scheme 10)[ 10)30]. [30]. Water Water and alcoholsand alcohols act as act nucleophiles as nucleophiles and hydrogen-bond and hydrogen donors-bond todonors afford to alcohol afford and alcohol ether and products ether + 17products. The reactions 17. The involve reactions SET ofinvolve light-emitting SET of diode light-emitting (LED) excited diode [Ir(ppy) (LED)2(dtbbpy)] excited + with[Ir(ppy) the2 hydrogen(dtbbpy)]+ bond with complexesthe hydrogen18 tobond give complexes radical anions 18 to 19give, which radical then anions undergo 19, which N-O bondthen undergo cleavage N-O followed bond by cleavage decarboxylation followed toby afford decarboxylation alkyl radicals. to afford Radical alkyl addition radicals. to 2+ 2+ oleﬁnRadical followed addition by to oxidation olefin followed with [Ir(ppy) by oxidation2(dtbbpy)] withafford [Ir(ppy) cations2(dtbbpy)] which2+ are afford trapped cations by nucleophileswhich are trapped to afford by alkyloxylatednucleophiles to products afford alkyloxylated17. products 17.

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Scheme 10. Visible-light-mediated alkyloxylation. * excited catalyst. SchemeScheme 10. 10.Visible-light-mediatedVisible-light-mediated alkyloxylation. alkyloxylation. ** excitedexcited catalyst. catalyst. The Li lab reported an alkylaryl reaction of styrenes with α-carbonyl alkyl bromides TheThe Li lab Li lab reported reported an an alkylary alkylaryll reaction reaction ofof styrenes styrenes with withα-carbonyl α-carbonyl alkyl alkyl bromides bromides and N,N-disubstituted anilines under photoredox catalysis of Ru(bpy)3Cl2 in the presence and N,N-disubstituted anilines under photoredox catalysis of Ru(bpy)3Cl2 in the presence and N,N-disubstituted anilines under photoredox catalysis of Ru(bpy)3Cl2 in the presence 2+ 32+ ofof aa Cu Cu salt salt (Scheme (Scheme 11)[ 11)31 ].[31]. The Th lighte light excited excited catalyst catalyst Ru(bpy) Ru(bpy)3 transferstransfers single electron single electron of a Cu salt (Scheme 11) [31]. The light excited catalyst Ru(bpy)32+ transfers single electron toto ethylethyl 2-bromo-2-methylpropanoates 2-bromo-2-methylpropanoates to form to form alkyl alkyl radicals radicals21 which 21 addwhich to styrenes,add to styrenes, to ethyl 2-bromo-2-methylpropanoates3+ 3+ to form alkyl radicals 21 which add to styrenes, oxidizedoxidized by by Ru(bpy) Ru(bpy)3 to3 cationicto cationic intermediates intermediates22, followed 22, followed by the Friedel–Crafts by the Friedel–Crafts reaction reac- 3+ oxidizedtotion give toby products give Ru(bpy) products203. to 20cationic. intermediates 22, followed by the Friedel–Crafts reaction to give products 20.

SchemeScheme 11. 11.Alkyl Alkyl & aryl& aryl difunctionalization difunctionalization of styrenes. of styrenes. * excited catalyst. Scheme 11. Alkyl & aryl difunctionalization of styrenes. The Klussmann group reported an Ir-promoted photoredox reaction of styrenes with aldehydesThe Klussmann and N group-alkylindoles reported (Scheme an Ir-promote 12) [32].d photoredoxBoth aryl and reaction aliphatic of styrenes aldehydes with could aldehydesbe used and for Nthe-alkylindoles generation of(Scheme acyl radicals. 12) [32]. t-Butoxyl Both aryl radical and aliphatic generated aldehydes through thecould SET of be usedphoto-excited for the generation IrIII and oftBuOOBz acyl radicals. (TBPB) t-Butoxyl react with radical aldehydes generated to form through acyl radicalsthe SET ofwhich photo-excited IrIII and tBuOOBz (TBPB) react with aldehydes to form acyl radicals which

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The Klussmann group reported an Ir-promoted photoredox reaction of styrenes with Molecules 2021, 26, 105 aldehydes and N-alkylindoles (Scheme 12)[32]. Both aryl and aliphatic aldehydes could8 of 31

addbe used to styrenes for the generation to from of24 acyl which radicals. thent -Butoxyloxidized radical with generatedIrIV to carbocations. through the SETThe of Friedel– Craftsphoto-excited reaction Ir IIIofand carbocationstBuOOBz (TBPB)with N react-alkylindoles with aldehydes give final to form products acyl radicals 23. which IV addadd toto styrenes styrenes to to from from24 24which which then then oxidized oxidized with with Ir to Ir carbocations.IV to carbocations. The Friedel–Crafts The Friedel– reactionCrafts reaction of carbocations of carbocations with N -alkylindoleswith N-alkylindoles give ﬁnal give products final products23. 23.

Scheme 12. Acyl radical and N-alkylindole difunctionalization of styrenes. * excited catalyst. SchemeScheme 12.12. AcylAcyl radicalradical andand NN-alkylindole-alkylindole difunctionalizationdifunctionalization ofof styrenes.styrenes. ** excitedexcited catalyst.catalyst.

3.3.3. Nitrogen Nitrogen Radical-InitiatedRadical-Initiated ReactionsReactions Reactions Presented in this section are azido radical (N ·)-initiated3 difunctionalization reactions. PresentedPresented inin thisthis section section are are azido azido radical radical3 (N3 ·)-initiated(N ·)-initiated difunctionalization difunctionalization reac- reac- The azido radical can be generated from the Zhdankin’s reagent or TMSN [33]. tions.tions. TheThe azido radical radical ca can nbe be generated generated from from the Zhthedankin’s Zhdankin’s reagent reagent or 3TMSN or TMSN3 [33]. 3 [33]. TheThe Zhu group groupgroup developed developeddeveloped a a transition-metal-fa transition-metal-free transition-metal-free reactionree reaction reaction for for azidocyanation for azidocyanation azidocyanation of al- of of al- kenesalkeneskenes involvinginvolving involving 1,4- 1,4- 1,4- or or or1,5-cyano 1,5-cyano 1,5-cyano migration migration migration (Scheme (Scheme 13) [34]. 1313))[ [34].34An]. azido AnAn azido azidoradical radical radical generated gen- generated erated from the reaction of TMSN3 with PhI(OAc)2 adds to cyanohydrin alkenes. The fromfrom thethe reaction of of TMSN TMSN3 with3 with PhI(OAc) PhI(OAc)2 adds2 adds to cyanohydrin to cyanohydrin alkenes. alkenes. The resulted The resulted resulted radicals undergo 1,4-cyano group migration (n = 1) through a cyclization and radicals undergo 1,4-cyano group migration (n = 1) through a cyclization and ring-open- radicalsring-opening undergo process 1,4-cyano to give group more stablemigration hydroxyalkyl (n = 1) through radicals a25 cyclization. Oxidation and of ring-open- the inging processprocess toto givegive more more stable stable hydroxyalkyl hydroxyalkyl radicals radicals 25. Oxidation 25. Oxidation of the ofradicals the radicals with with radicals with PhI(OAc)2 (PIDA) followed by deprotonation affords the desired product. PhI(OAc)2 (PIDA) followed by deprotonation affords the desired product. The Zhu group PhI(OAc)The Zhu group2 (PIDA) applied followed this strategy by deprotonation for the reaction affo ofrdsγ -hydroxyalkenesthe desired product. in the The synthe- Zhu group applied this strategy for the reaction of γ-hydroxyalkenes in the synthesis of 1,2-difuction- appliedsis of 1,2-difuctionalized this strategy for the compounds reaction 26of γinvolving-hydroxyalkenes the 1,4-heteroaryl in the synthesis group migration of 1,2-difuctionalized compounds 26 involving the 1,4-heteroaryl group migration (Scheme 14) [35]. alized(Scheme compounds 14)[35]. 26 involving the 1,4-heteroaryl group migration (Scheme 14) [35].

Scheme 13. Azidocyanation of olefins involving cyano migration.

SchemeScheme 13. AzidocyanationAzidocyanation of of oleﬁns olefins involving involving cyano cyano migration. migration.

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Scheme 14. Azidoheteroarylation involving heteroaryl migration.

The Tang group reported an azidotrifluoromethoxylation of styrenes with SchemeScheme 14. 14.Azidoheteroarylation Azidoheteroarylation involving involving heteroaryl heteroaryl migration. migration. Zhdankin’s reagent and trifluoromethyl arylsulfonate (TFMS) (Scheme 15) [36]. The reac- tionsThe were Tang conducted group reported under an azidotrifluoromethoxylation photoredox conditions of styrenesusing Ru with and Zhdankin’s Ag as dual catalysts. reagentThe and trifluoromethylTang group arylsulfonatereported (TFMS)an azidotrifl (Schemeuoromethoxylation 15)[36]. The reactions wereof styrenes with [Ru(bpy)3]2+-Promoted formation of an azido radical from Zhdankin’s reagent adds to sty- conductedZhdankin’s under reagent photoredox and conditionstrifluoromethyl using Ru arylsulfonate and Ag as dual (TFMS) catalysts. (Scheme [Ru(bpy) ]15)2+- [36]. The reac- renes followed by oxidation to benzyl carbocations 28 and Ag-catalyzed3 trifluoromethox- Promotedtions were formation conducted of an azido under radical photoredox from Zhdankin’s condit reagentions addsusing to styrenesRu and followed Ag as dual catalysts. byylation oxidation give to desired benzyl carbocationsproducts 2728. Theand reaction Ag-catalyzed tolerates trifluoromethoxylation a wide range of give functional groups [Ru(bpy)3]2+-Promoted formation of an azido radical from Zhdankin’s reagent adds to sty- desiredand is productsapplicable27. Theto late-stage reaction tolerates azidotrifluoromethoxylation a wide range of functional of groups more and complicated is mole- renes followed by oxidation to benzyl carbocations 28 and Ag-catalyzed trifluoromethox- applicablecules. to late-stage azidotrifluoromethoxylation of more complicated molecules. ylation give desired products 27. The reaction tolerates a wide range of functional groups and is applicable to late-stage azidotrifluoromethoxylation of more complicated molecules.

SchemeScheme 15. 15.Ag/Ru-catalyzed Ag/Ru-catalyzed azidotriﬂuoromethoxylation azidotrifluoromethoxylation of styrenes. of * excited styrenes. catalyst.

Zhu and coworkers developed a photoredox reaction for 1,2-difuctionalization of Zhu and coworkers developed a photoredox reaction for 1,2-difuctionalization of 1,3- 1,3-dienesScheme 15. with Ag/Ru-catalyzedN-aminopyridinium azidotrifluoromethoxylation salts and TMSNCS (Scheme 16of)[ styrenes.37]. Under the photo- catalysisdienes with of fac-Ir(ppy) N-aminopyridinium3, amino radicals derived salts and from TMSNCS the N-aminopyridinium (Scheme 16) salts[37]. add Under to the photoca- 1,3-dienestalysis of to fac form-Ir(ppy) allylic3, radicals amino30 radicalswhich are derived oxidized from to cations the followedN-aminopyridinium by a reaction salts add to Zhu and coworkers developed a photoredox reaction for 1,2-difuctionalization of 1,3- with1,3-dienes TMSNCS to to form give difunctionalizedallylic radicals products 30 which29. are oxidized to cations followed by a reaction dienes with N-aminopyridinium salts and TMSNCS (Scheme 16) [37]. Under the photoca- with TMSNCS to give difunctionalized products 29. talysis of fac-Ir(ppy)3, amino radicals derived from the N-aminopyridinium salts add to 1,3-dienes to form allylic radicals 30 which are oxidized to cations followed by a reaction with TMSNCS to give difunctionalized products 29.

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SchemeScheme 16.16. DifunctionalizationDifunctionalization ofof 1,3-dienes.1,3-dienes. ** excitedexcited catalyst.catalyst.

4.4. OxygenOxygen Radical-InitiatedRadical-Initiated ReactionsReactions DifunctionalizationDifunctionalization reactionsreactions ofof unsaturatedunsaturated carboncarbon doubledouble bondsbonds initiatedinitiated withwith thethe additionaddition ofof oxygenoxygen radicalsradicals areare limitedlimited inin literature.literature. TheThe oxygenoxygen radicalsradicals describeddescribedin inthis this sectionsection areare alkoxy,alkoxy, acyl acyl and and phthalimidephthalimideN N-oxyl-oxyl (PINO) (PINO) radicals radicals which which are are generatedgenerated from from thethe homolytichomolytic cleavagecleavage ofof N-ON-O oror O-HO-H bonds.bonds. TheThe Zhu Zhu group group developed developedt-butyl t-butyl hydroperoxide hydroperoxide (TBHP)-induced (TBHP)-induced synthesis synthesis of α-hydroxy of α-hy- estersdroxy 31aestersor 31aα-hydroxy or α-hydroxy amines amines31b by 31b the by reaction the reaction of alkenes of alkenes with with carboxylic carboxylic acids acids or amines in the presence of H2O and using TBHP (70% in water) as an oxidant (Scheme 17) [38]. or amines in the presence of H2O and using TBHP (70% in water) as an oxidant (Scheme t-Butoxyl and t-butylperoxy radicals generated from TBHP induce the formation of car- 17) [38]. t-Butoxyl and t-butylperoxy radicals generated from TBHP induce the formation boxyl radicals which add to styrenes followed by oxidation to benzyl cations and trapped of carboxyl radicals which add to styrenes followed by oxidation to benzyl cations and with H2O to give products 31a. trapped with H2O to give products 31a.

SchemeScheme 17.17. nn-Bu-Bu44NI-catalyzed difuctionalizationdifuctionalization ofof alkenes.alkenes.

TheThe XiaXia group reported a a method method for for oxyazidation oxyazidation of of alkenes alkenes with with TMSN TMSN3 and3 and N- Nhydroxyphthalimide-hydroxyphthalimide (NHPI) (NHPI) for for making making 2-azido-2-(phenylethoxy)isoindolinone2-azido-2-(phenylethoxy)isoindolinone com-compounds 32 (Scheme 18)[39]. The oxygen-centered PINO radical generated from NHPI

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Molecules 2021, 26, 105 11 of 31 pounds 32 (Scheme 18) [39]. The oxygen-centered PINO radical generated from NHPI re- actspounds with 32 styrenes (Scheme followed 18) [39]. byThe oxid oxygen-centeredation to carbocations PINO radical with PhI(OAc) generated2 to from from NHPI cations re- reactsacts with with styrenes followed followed3− by by oxidation oxidation to carbocations to carbocations with PhI(OAc)with PhI(OAc)2 to from2 to cations from cations 33 which react with N− to give oxyazidation products 32. 3333which which react react with with N3 N3to− to give give oxyazidation oxyazidation products products32. 32.

Scheme 18. PINO radical-initiated difunctionalization of alkenes. SchemeScheme 18. 18.PINO PINO radical-initiated radical-initiated difunctionalization difunctionalization of alkenes. of alkenes. The Dagousset group reported an alkoxy radical-initiated difunctionalization reac- TheThe Dagousset Dagousset group group reported reported an alkoxy an alkoxy radical-initiated radical-initiated difunctionalization difunctionalization reaction reac- oftion alkenes of alkenes for the for synthesis the synthesis of functionalized of functionalized diethers 34a diethersor amino 34a ethers or amino34b under ethers batch 34b under tion of alkenes for the synthesis of functionalized diethers 34a or amino ethers 34b under orbatch ﬂow or reaction flow reaction conditions conditions (Scheme 19 (Scheme)[40]. A 19 radical/cationic) [40]. A radical/cationic addition mechanism addition was mechanism conﬁrmedwasbatch confirmed or flow by electron reaction by electron paramagnetic conditions paramagnetic resonance(Scheme resonance 19 (EPR)) [40]. studies. A (EPR) radical/cationic Alkoxy studies. radicals Alkoxy addition generated radicals mechanism gener- was confirmed by electron paramagnetic resonance (EPR) studies. Alkoxy radicals gener- fromated 4-cyano-substitutedfrom 4-cyano-substitutedN-alkoxypyridinium N-alkoxypyridinium salt under the salt catalysis under of thefac catalysis-Ir(ppy)3 add of fac to-Ir(ppy)3 + alkenesaddated tofrom followedalkenes 4-cyano-substituted byfollowed the SET by of Ir(ppy)the N SET-alkoxypyridinium3 toof formIr(ppy) corresponding3+ to form salt correspondingunder carbocations. the catalysis Nucleophilic carbocations. of fac-Ir(ppy) Nu-3 additioncleophilicadd to alkenes of alcoholsaddition followed or of acetonitrile alcohols by the or givesSET acetonitrile of difunctionalized Ir(ppy) gives3+ to formdifunctionalized products corresponding34. products carbocations. 34. Nu- cleophilic addition of alcohols or acetonitrile gives difunctionalized products 34.

SchemeScheme 19. 19.Dialkoxylation Dialkoxylation and and aminoalkoxylation aminoalkoxylation of alkenes. of alkenes. * excited * excited catalyst. catalyst. Scheme 19. Dialkoxylation and aminoalkoxylation of alkenes. * excited catalyst. 5.5. PhosphorousPhosphorous Radical-Initiated Radical-Initiated Reactions Reactions 5. PhosphorousPhosphorous radical-initiatedRadical-Initiated difunctionalization Reactions reactions are highlighted in this sec- Phosphorous radical-initiated difunctionalization· reactions are highlighted· in this tion. So far we only found reactions of phosphinoyl [R2(O)P ] and phosphonyl [(RO)2(O)P ] Phosphorous radical-initiated difunctionalization reactions are · highlighted in this radicalssection. generated So far we from only corresponding found reactions phosphine of oxides phosphinoyl and phosphonates [R2(O)P []41 and]. phosphonyl section. So· far we only found reactions of phosphinoyl [R2(O)P·] and phosphonyl [(RO)The2(O)P Zou] andradicals Zhang generated groups reported from correspondin Cu-catalyzed difunctionalizationg phosphine oxides of alkenes and phosphonates with [(RO)2(O)P·] radicals generated from corresponding phosphine oxides and phosphonates diphenylphosphine[41]. oxide (HPOPh2) and trimethylsilylcyanide (TMSCN) (Scheme 20)[42]. The[41]. phosphinoyl The Zou and radicals Zhang generated groups from reported the oxidation Cu-catalyzed of HPOPh difunctionalization2 with Mn(OAc)3 react of alkenes II – withwith alkenes Thediphenylphosphine Zou which and are Zhang oxidized oxide groups with (HPOPh Cu reportedand then2) and Cu-catalyzed cyanylated trimethylsilylcyanide with difunctionalization CN to give (TMSCN) products 35of .(Scheme alkenes 20)with [42]. diphenylphosphine The phosphinoyl oxide radicals (HPOPh generated2) and trimethylsilylcyanide from the oxidation (TMSCN)of HPOPh (Scheme2 with Mn(OAc)20) [42]. 3The react phosphinoyl with alkenes radicalswhich are ge oxidizednerated withfrom Cu theII and oxidation then cyanylated of HPOPh with2 withCN– toMn(OAc) give products3 react with 35. alkenes which are oxidized with CuII and then cyanylated with CN– to give products 35.

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Scheme 20. Phosphinoylation and cyanylation of alkenes.

Wang and coworkers reported Ce-catalyzed phosphinoylation and nitration reac- SchemeScheme 20. 20.Phosphinoylation Phosphinoylation and and cyanylation cyanylation of alkenes. of alkenes. tions of alkenes (Scheme 21) [43]. CAN (NH4)2Ce(NO3)6was used as P-radical initiator and alsoWangWang nitrate and and coworkers donor coworkers reportedto afford reported Ce-catalyzed β -nitrooxyphosphonatesCe-catalyzed phosphinoylation phosphinoylation and nitration 36 and. The reactions nitration phosphinoyl reac- radicals gener- of alkenes (Scheme 21)[43]. CAN (NH4)2Ce(NO3)6was used as P-radical initiator and also tions of alkenes (Scheme 21) [43]. CAN (NH4)2Ce(NO3)6was used as P-radical initiator and nitrateated donorform to phosphine afford β-nitrooxyphosphonates oxides or phosphonates36. The phosphinoyl through radicals a generated SET with CeIV add to alkenes to formalso phosphinenitrate donor oxides to orafford phosphonates β-nitrooxyphosphonates through a SET with 36 Ce. TheIV add phosphinoyl to alkenesto radicals form gener- form benzylic cations after the second SET with CAN.IV Reaction of benzylic cations with benzylicated form cations phosphine after the oxides second or SET phosphonates with CAN. Reaction through of benzylica SET with cations Ce with add nitrate to alkenes to givenitrateform products benzylic give36 .cationsproducts after 36the. second SET with CAN. Reaction of benzylic cations with nitrate give products 36.

Scheme 21. P-radical initiated difunctionalizations of styrenes.

Fang and coworkers reported TBHP and FeCl3-promoted difunctionalization of al- Scheme 21. P-radical initiated difunctionalizations of styrenes. Schemekenes with 21. phosphine P-radical oxides initiated or phosphonates difunctionalizations and anilines of for styrenes. the synthesis of products

37 (SchemeFang and 22) coworkers [44]. In the reported reaction TBHP with and diph FeClenylphosphine3-promoted difunctionalization oxide, phosphinoyl of radicals alkenesadd toFang withalkenes phosphine and to form coworkers oxides carbocations or phosphonates reported after oxidation and TBHP anilines with and for FeCl the FeCl synthesis3. Trapping3-promoted of products of carbocations difunctionalization of al- 37 (Scheme 22)[44]. In the reaction with diphenylphosphine oxide, phosphinoyl radicals kenesby amines with afford phosphine corresponding oxides α,β-phosphinoamination or phosphonates products and anilines 37. for the synthesis of products add to alkenes to form carbocations after oxidation with FeCl3. Trapping of carbocations by37 amines (Scheme afford 22) corresponding [44]. In αthe,β-phosphinoamination reaction with diph productsenylphosphine37. oxide, phosphinoyl radicals Using a similar strategy of heteroaryl group migration described in Scheme 14, the Zhu add to alkenes to form carbocations after oxidation with FeCl3. Trapping of carbocations group accomplished phosphinoyl or phosphonyl radical-initiated difunctionalization of γby-hydroxyalkenes amines afford (Scheme corresponding 23)[45]. In the presence α,β of-phosphinoamination TBHP, the P-radicals generated products from 37. phosphine oxides or phosphonates add to alkenes followed by 1,4-heteroaryl migration of 39 to form radicals 40, oxidation of the radicals to cations to give products 38 after proton transfer. In addition to heteroaryl, other groups such as cyano and imino, could also be used as R2 for the migration.

Scheme 22. Phosphinoamination of styrenes.

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Scheme 20. Phosphinoylation and cyanylation of alkenes.

Wang and coworkers reported Ce-catalyzed phosphinoylation and nitration reactions of alkenes (Scheme 21) [43]. CAN (NH4)2Ce(NO3)6was used as P-radical initiator and also nitrate donor to afford β-nitrooxyphosphonates 36. The phosphinoyl radicals generated form phosphine oxides or phosphonates through a SET with CeIV add to alkenes to form benzylic cations after the second SET with CAN. Reaction of benzylic cations with nitrate give products 36.

Scheme 21. P-radical initiated difunctionalizations of styrenes.

Fang and coworkers reported TBHP and FeCl3-promoted difunctionalization of alkenes with phosphine oxides or phosphonates and anilines for the synthesis of products 37 (Scheme 22) [44]. In the reaction with diphenylphosphine oxide, phosphinoyl radicals Molecules 2021, 26, 105 13 of 31 add to alkenes to form carbocations after oxidation with FeCl3. Trapping of carbocations by amines afford corresponding α,β-phosphinoamination products 37.

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Using a similar strategy of heteroaryl group migration described in Scheme 14, the Zhu group accomplished phosphinoyl or phosphonyl radical-initiated difunctionalization of γ-hydroxyalkenes (Scheme 23) [45]. In the presence of TBHP, the P-radicals generated from phosphine oxides or phosphonates add to alkenes followed by 1,4-heteroaryl migration of 39 to form radicals 40, oxidation of the radicals to cations to give products 38 SchemeafterScheme proton 22. 22.Phosphinoamination Phosphinoamination transfer. In addition of styrenes. of styrenes.to heteroaryl, other groups such as cyano and imino, could also be used as R2 for the migration.

SchemeScheme 23. 23.Radical-mediated Radical-mediated phosphinoyl-functionalization phosphinoyl-functionalization of alkenes. of alkenes.

6.6. SulfurSulfur Radical-Initiated Radical-Initiated Reactions Reactions · · Sulfur-centered radicals, such as sulfenyl (RS ), sulfonyl [RS(O)2S ], and thiocyanate Sulfur-centered radicals, such as sulfenyl (RS·), sulfonyl [RS(O)2S·], and thiocyanate (SCN) radicals, have been used for difunctionalization reactions [41]. The sulfur radicals (SCN) radicals, have been used for difunctionalization reactions [41]. The sulfur radicals could be generated from corresponding reagents through homolytic N-S bond cleavage, singlecould electronbe generated oxidation from of corresponding KSCN, and electrochemical reagents through and photoredox homolytic catalytic N-S bond reactions. cleavage, singleThe electron Wu group oxidation reported of a methodKSCN, for and the elec synthesistrochemical of β-halo and vinylsulfones photoredox through catalytic Cu- reac- catalyzedtions. reaction of alkynes with aryldiazonium tetraﬂuoroborates and DABCO·(SO2)2 (SchemeThe 24 WuA) [group46]. Arylsulfonyl reported a radicals method42 forgenerated the synthesis from the of reactionβ-halo vinylsulfones of aryldiazonium through cationsCu-catalyzed with DABCO reaction·(SO 2)of2 attackalkynes alkynes with to formaryldiazonium stable alkenyl tetrafluoroborates radicals which are and oxidizedDABCO·(SO to alkenyl2)2 (Scheme cations 24A) with [46]. CuCl Ar followedylsulfonyl by radicals nucleophilic 42 generated addition from with the halides reaction to of givearyldiazoniumβ-halo vinylsulfones cations with41. The DABCO·(SO research group2)2 attack also extendedalkynes to the form scope stable of the alkenyl reaction radicals of arylwhich alkenes are oxidized under photoredox to alkenyl conditions cations with and usingCuCl alkylfollowed nitriles by as nucleophilic nucleophiles addition to afford with aminosulfonylationhalides to give β-halo products vinylsulfones43 (Scheme 41. 24TheB) [research47]. group also extended the scope of the reaction of aryl alkenes under photoredox conditions and using alkyl nitriles as nucleophiles to afford aminosulfonylation products 43 (Scheme 24B) [47].

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Scheme 24. Halosulfonylation of aryl alkynes. (A) reaction of alkenes. (B) reaction of alkynes. Scheme 24. Halosulfonylation of aryl alkynes. (A) reaction of alkenes. (B) reaction of alkynes. Scheme 24. Halosulfonylation of aryl alkynes. (A) reaction of alkenes. (B) reaction of alkynes. MajeeMajee and and coworkers coworkers reported reported a method a method for dithiocyanation for dithiocyanation of alkynes of alkynes and alkenes and alkenes 2 2 8 withwith KSCN MajeeKSCN and andand Na coworkersNa2S2OS8Ototo give reportedgive products products a method44 and 44 45and for, respectively 45dithiocyanation, respectively (Scheme (Scheme of 25 alkynes)[48]. 25) In and the[48]. alkenes In the reactionreactionwith KSCN of of alkynes, alkynes, and Na the 2theS thiocyanate2O 8thiocyanate to give radical products radical generated 44 generated and from 45, therespectively from oxidation the oxidation of(Scheme KSCN adds of25) KSCN [48]. to In adds the alkynes,toreaction alkynes, followed of alkynes,followed by oxidization the by thiocyanateoxidization and reaction andradical reaction with generated KSCN with to give fromKSCN dithiocyanation the to oxidation give dithiocyanation alkenes of KSCN adds al- 44kenesto. Otheralkynes, 44 than. Other followed nucleophilic than nucleophilicby oxidization addition of addition thiocyanate and reaction of thiocyanate anion, with coupling KSCN anion, of to thiocyanate couplinggive dithiocyanation radicalof thiocyanate al- isradicalkenes also a44 possibleis. alsoOther a pathway. possiblethan nucleophilic pathway. addition of thiocyanate anion, coupling of thiocyanate radical is also a possible pathway.

SchemeScheme 25. 25.Dithiocyanation Dithiocyanation of alkynesof alkynes and alkenes.and alkenes. Scheme 25. Dithiocyanation of alkynes and alkenes. The Han group developed an electrochemical oxysulfuration reaction of styrenes by The Han group developed an electrochemical oxysulfuration reaction of styrenes by addition of sufenylradicals and alkoxy nucleophiles (Scheme 26)[49]. The arylsufenyl radicalsadditionThe generated ofHan sufenylradicals group from developed thiophenol and alkoxy throughan electrochemical nucleophiles the SET oxidation oxysulfuration(Scheme at the 26) anode [49]. reaction add The to arylsufenyl alkenes of styrenes rad- by andicalsaddition then generated oxidize of sufenylradicals tofrom carbocations thiophenol and at alkoxy thethrough anode. nucleophiles the Trapping SET oxidation (Scheme of the carbocations 26)at the [49]. anode The by alcoholsarylsufenyl add to alkenes rad- affordsandicals then generated the oxidize oxysulfuration from to carbocations thiophenol products 46 throughat. the anode. the SET Trapping oxidation of theat thecarbocations anode add by to alcohols alkenes affordsand then the oxidize oxysulfu to rationcarbocations products at 46the. anode. Trapping of the carbocations by alcohols affords the oxysulfuration products 46.

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Scheme 26. Electrochemical difunctionalization of styrenes. SchemeScheme 26. 26.Electrochemical Electrochemical difunctionalization difunctionalization of styrenes. of styrenes. Guo and coworker reported electrochemical sulfonylheteroarylation reaction of al- kenesGuoGuo involving and and coworker coworker heteroaryl reported reported electrochemical group electrochemical migration sulfonylheteroarylation (Ssulfonylheteroarylationcheme 27) [50]. reaction The of alkenesarylsulfonylreaction of al- radicals involving heteroaryl group migration (Scheme 27)[50]. The arylsulfonyl radicals gener- kenesgenerated involving from heteroaryl sulfinic acid group at themigration anode (Saddcheme to benzothiazole 27) [50]. The arylsulfonyl ring for heteroaryl radicals migra- ated from sulﬁnic acid at the anode add to benzothiazole ring for heteroaryl migration followedgeneratedtion followed by from single-electron by sulfinic single-electron acid oxidation at the at anodeoxidation the anode add at toto affordthebenzothiazole anode cations to and afford ring then for cations products heteroaryl and47 thenmigra- products aftertion47 after deprotonation.followed deprotonation. by single-electron This ipso This-aryl ipso group oxidation-aryl migration group at the process migration anode is to similar afford process to cations those is presentedsimilar and then to in productsthose presented Schemes47in afterSchemes deprotonation.14 and 14 23 and. 23. This ipso-aryl group migration process is similar to those presented in Schemes 14 and 23.

Scheme 27. Electrochemical sulfonylheteroarylation of alkenes. SchemeScheme 27. 27.Electrochemical Electrochemical sulfonylheteroarylation sulfonylheteroarylation of alkenes. of alkenes. An electrochemical oxidative alkoxysulfonylation of alkenes with sulfonyl hydra- zinesAn Anand electrochemical electrochemicalalcohols have oxidative been oxidative reported alkoxysulfonylation alkoxysulfonylation by the Lei of group alkenes (Scheme with of sulfonyl alkenes 28) [51]. hydrazines with The sulfonylreactions hydra- andwere alcohols carried have out beenat room reported temperature by the Lei and group only (Scheme molecular 28)[ nitrogen51]. The reactions and hydrogen were are re- carriedzines outand at alcohols room temperature have been and onlyreported molecular by nitrogenthe Lei and group hydrogen (Scheme are released 28) [51]. as The reactions leased as byproducts. Sulfonyl radicals generated from sulfonyl hydrazines through oxi- byproducts.were carried Sulfonyl out at radicals room generatedtemperature from and sulfonyl only hydrazines molecular through nitrogen oxidation and athydrogen are re- anodedationleased react atas anode withbyproducts. alkenes react andwith Sulfonyl then alkenes undergo radicals and second then ge oxidationundergonerated atsecond from anode sulfonyl tooxidation form benzyl hydrazines at anode cation to throughform oxi- benzyl cation intermediates. Nucleophilic attack of cations with alkoxyl anions give intermediates.dation at anode Nucleophilic react with attack alkenes of cations and with then alkoxyl undergo anions give second alkoxysulfonylation oxidation at anode to form productsalkoxysulfonylation48. The alkoxyl products anions are 48 generated. The alkoxyl from anions alcohols are on generated the cathode. from alcohols on the cathode.benzyl cation intermediates. Nucleophilic attack of cations with alkoxyl anions give alkoxysulfonylation products 48. The alkoxyl anions are generated from alcohols on the cathode.

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O 2 Ar2 Ar Ni (+) C (-), 12 mA 2 O 1 1 2 R O Ar Ar S NHNH2 ++R OH S 1 1 O R 2 MeCN, Bu4NF4,rt,3h R Ar2 O Ar Ni (+)undividedC (-), 12 cell mA 2 O 1 1R1 =alkyl,Ph 2 R O Ar Ar S NHNH2 ++R OH 48, 42-97%S 2 1 1 RO= alkyl, cycloalkylR MeCN, Bu4NF4,rt,3h R O 1 undivided cell R =alkyl,Ph 48, 42-97% R2 = alkyl, cycloalkyl O O O anode [O] -N 1 1 2 1 Ar S NHNH2 Ar S N N Ar S -3H+,-3e O O OO 1 anode [O] -N2 R 1 1 Ar1 S Ar S NHNH2 + Ar S N N -3H ,-3e 2 O O O Ar R1 2 2 2 Ar Ar 2 2 O 1 2 Ar O ArO 1 R O Ar R OH Ar1 anode [O] Ar S S S R1 2 -H+ 1 + -e 1 Ar O R 2 R Ar2 O 2 48 O 1 2 Ar O O O 1 R O Ar R OH Ar1 anode [O] Ar S S 1 + S -e R 2 O -H+ R1 + 2 - R1 Cathode48 R OH + 3H +4eO 2H2 +RO O

Scheme 28. Electrochemical2 + oxidative alkoxysulfonylation2 - of alkenes. Cathode R OH + 3H +4e 2H2 +RO SchemeSchemeThe 28. 28. LeiElectrochemical Electrochemical group also oxidative reported oxidative alkoxysulfonylation sulfenylalkoxysulfonylation radical-initiated of alkenes. of alkenes. oxysulfenylation and aminosulfenylation of alkenes using thiophenols/thiols as thiolating agents and alcohols/amines TheThe Lei Lei group group also also reported reported sulfenyl sulfenyl radical-initiated radical-initiated oxysulfenylation oxysulfenylation and aminosulfeny- and amino- lationas nucleophilesof alkenes using (Scheme thiophenols/thiols 29) [52]. Under as thiolating electrochemical agents and alcohols/aminesreaction conditions, as nu- thiophe- sulfenylation of alkenes using thiophenols/thiols as thiolating agents and alcohols/amines cleophilesnols/thiols (Scheme are converte 29)[52].d Under to sulfenyl electrochemical radicals reactionfor addition conditions, to alkenes thiophenols/thiols followed by anode areasoxidation nucleophiles converted of toresulting sulfenyl (Scheme radicalsradicals 29) [52]. for to additionUndercations el toandectrochemical alkenes nucleophilic followed reaction byaddition anode conditions, oxidationwith alcohols thiophe- or ofnols/thiolsamines resulting to give radicalsare converteoxysulfenylation to cationsd to and sulfenyl nucleophilic products radicals 49 addition and for aminosulfenylationaddition with alcohols to alkenes or amines productsfollowed to give 50 by, respec- anode oxysulfenylationoxidationtively. of resulting products radicals49 and aminosulfenylation to cations and productsnucleophilic50, respectively. addition with alcohols or amines to give oxysulfenylation products 49 and aminosulfenylation products 50, respectively.

SchemeScheme 29. 29.Electrochemical Electrochemical oxysulfenylation oxysulfenylation and aminosulfenylation and aminosulfenylation of alkenes. of alkenes.

SchemeHanHan 29. and and Electrochemical coworkers coworkers reported reportedoxysulfenylation a photoredox-catalyzed a photoredox-catalyzed and aminosulfenylation chlorosulfonylation chlorosulfonylation of alkenes. reaction ofreaction of alkynes using sulfonyl chlorides as both sulfonyl radical and chlorine sources (Scheme 30)[53]. alkynes using sulfonyl chlorides as both sulfonyl radical and chlorine sources (Scheme 30) A variety of (E)-selective β-chlorovinyl sulfones 51 were prepared from terminal and [53]. HanA variety and coworkers of (E)-selective reported β-chlorovinyl a photoredox-catalyzed sulfones 51 were chlorosulfonylation prepared from terminal reaction and of internalalkynes alkynes. using sulfonyl chlorides as both sulfonyl radical and chlorine sources (Scheme 30) internalThe Niealkynes. and Niu group reported the preparation of β-ketosulfones 52 via graphitic [53]. A variety of (E)-selective β-chlorovinyl sulfones 51 were prepared from terminal and carbon nitride (p-g-C3N4)-photocatalyzed hydrosulfonylation of alkynes in aerobic aque- ousinternal medium alkynes. (Scheme 31)[54]. The heterogeneous semiconductor is recyclable at least 6 times without signiﬁcant reducing activity. Arylsulfonyl radicals generated from the 1 complex of DABCO·(SO2)2and Ar -N2BF4 add to arylalkynes to form arylalkenyl radicals and then arylalkenyl cations after SET oxidation. Hydrolysis of the cations give β-keto sulfones 52.

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MoleculesMolecules 20212021, 26, 26, ,105 105 17 of 31 17 of 31

Scheme 30. Chlorosulfonylation of arylalkynes. * excited catalyst.

The Nie and Niu group reported the preparation of β-ketosulfones 52 via graphitic carbonScheme 30.nitride Chlorosulfonylation (p-g-C3N4)-photocatalyzed of arylalkynes. * excited hydrosulfonylation catalyst. of alkynes in aerobic aqueous medium (Scheme 31) [54]. The heterogeneous semiconductor is recyclable at least 6 timesThe without Nie and significant Niu group reducing reported activity. the preparation Arylsulfonyl of β-ketosulfones radicals generated 52 via graphitic from the com- carbon nitride (p-g-C3N4)-photocatalyzed1 hydrosulfonylation of alkynes in aerobic aque- plex of DABCO·(SO2)2and Ar -N2BF4 add to arylalkynes to form arylalkenyl radicals and thenous medium arylalkenyl (Scheme cations 31) after[54]. TheSET heterogeneouoxidation. Hydrolysiss semiconductor of the iscations recyclable give atβ-keto least sulfones6 times without significant reducing activity. Arylsulfonyl radicals generated from the com- 52. plex of DABCO·(SO2)2and Ar1-N2BF4 add to arylalkynes to form arylalkenyl radicals and

then arylalkenyl cations after SET oxidation. Hydrolysis of the cations give β-keto sulfones SchemeScheme52. 30. 30.Chlorosulfonylation Chlorosulfonylation of arylalkynes. of arylalkynes. * excited * excited catalyst. catalyst.

The Nie and Niu group reported the preparation of β-ketosulfones 52 via graphitic carbon nitride (p-g-C3N4)-photocatalyzed hydrosulfonylation of alkynes in aerobic aqueous medium (Scheme 31) [54]. The heterogeneous semiconductor is recyclable at least 6 times without significant reducing activity. Arylsulfonyl radicals generated from the complex of DABCO·(SO2)2and Ar1-N2BF4 add to arylalkynes to form arylalkenyl radicals and then arylalkenyl cations after SET oxidation. Hydrolysis of the cations give β-keto sulfones 52.

Scheme 31. Light-promoted hydrosulfonylation of arylalkynes. SchemeScheme 31. 31.Light-promoted Light-promoted hydrosulfonylation hydrosulfonylation of arylalkynes. of arylalkynes. The Zhu group reported photoredox heteroarylsulfonylation and oximinosulfonyla- TheThe Zhu Zhu group group reported reported photoredox photoredox heteroarylsulfonylation heteroarylsulfonylation and oximinosulfonyla- and oximinosulfonyla- tiontion of of unactivated unactivated alkenes alkenes via sulfonyl via radical sulfonyl addition radical followed addition by heteroaryl followed or oximino by heteroaryl or tion of unactivated alkenes via sulfonyl radical addition followed by heteroaryl or groupoximino migration group and migration oxidation of and hydroxyl oxidation to ketone of to affordhydroxyl products to 53ketone(Scheme to 32 )[afford55]. products 53 oximino group migration and oxidation of hydroxyl to ketone to afford products 53 The(Scheme reaction 32) process [55]. isThe similar reaction to that process presented is in si Schememilar to14 .that presented in Scheme 14. (Scheme 32) [55]. The reaction process is similar to that presented in Scheme 14.

Scheme 31. Light-promoted hydrosulfonylation of arylalkynes.

The Zhu group reported photoredox heteroarylsulfonylation and oximinosulfonyla-

tion of unactivated alkenes via sulfonyl radical addition followed by heteroaryl or SchemeScheme 32. 32.Heteroarylsulfonylation Heteroarylsulfonylation and and oximinosulfonylation oximinosulfonylation of alkenes. of alkenes. Schemeoximino 32. group Heteroarylsulfonylation migration and oxidation and oxim of inosulfonylationhydroxyl to ketone of alkenes. to afford products 53 (Scheme 32) [55]. The reaction process is similar to that presented in Scheme 14.

Scheme 32. Heteroarylsulfonylation and oximinosulfonylation of alkenes.

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7.7. FluorocarbonFluorocarbon Radical-InitiatedRadical-Initiated ReactionsReactions FluorineFluorine atomatom andand fluorinatedfluorinated alkylalkyl groupsgroups couldcould bebe usedused toto improveimprove molecules’molecules’ sta-sta- bility,bility, bioavailability, bioavailability, and and other other physical, physical, chemical chemical and and biological biological properties properties [56 ].[56]. The The devel- de- velopment of new synthetic methods to introducing flouring-containing groups, such as opment of new synthetic methods to introducing flouring-containing groups, such as CF2R, CF2R, CF3 and multi-carbon perflourinated alkyls (Rf), is a topic of current interest in both CF3 and multi-carbon perflourinated alkyls (Rf), is a topic of current interest in both organic andorganic medicinal and medicinal chemistry chemistry [57]. Radical-initiated [57]. Radical-initiated difunctionalization difunctionalization is a good approachis a good forap- theproach synthesis for the of synthesis fluorinated of compoundsfluorinated [comp58]. Mostounds fluorocarbon [58]. Most fluorocarbon radicals presented radicals in thispre- sectionsented arein this generated section byare metal-catalyzed generated by me photo-redoxtal-catalyzed or photo-redox electrochemical or electrochemical reactions from thereactions substrates from including the substrates Umemoto’s including [59], Togni’s Umemoto’s [60], and [59], Langlois’ Togni’s (CF [60],3SO 2andNa) Langlois’ reagents. Perfluoroalkanesulfonyl(CF3SO2Na) reagents. chloridePerfluoroalkanesulfonyl (CF3SO2Cl), α-bromo-2,2-difluoroacetates, chloride (CF3SO2Cl), bromodifluo-α-bromo-2,2- romethylphosphonates,difluoroacetates, bromodifluoromethylphospho and perfluoroalkyl-containingnates, hypervalentand perfluoroalkyl-containing iodines are also good hy- sourcespervalent for iodines fluorocarbon are also radicals. good sources for fluorocarbon radicals. TheThe KoikeKoike andand AkitaAkita groupgroup developeddeveloped aa photoredoxphotoredox catalyzedcatalyzed oxytrifluoromethyla-oxytrifluoromethyla- tiontion reaction reaction of of alkenes alkenes using usin Umemoto’sg Umemoto’s reagent reagent as theas the CF3 CFsource3 source (Scheme (Scheme 33)[ 6133)]. [61]. In this In catalyticthis catalytic system, system, the sunlightthe sunlight is an is efficientan efficient light light source. source. The The reaction reaction process process includes includes thethe generationgeneration ofof aa CFCF33 radicalradical fromfrom Umemoto’sUmemoto’s reagentreagent byby photophoto catalyticcatalytic SET,SET,addition addition ofof CFCF33 radicalradical toto alkenesalkenes toto formform intermediateintermediate carboncarbon radicals,radicals, oxidationoxidation totocarbocation carbocation intermediatesintermediates byby catalyticcatalytic SET,SET, and and alcohol alcohol nucleophilic nucleophilic addition addition give give products products54 54. .

SchemeScheme 33.33. PhotoredoxPhotoredox catalyzedcatalyzed oxytriﬂuoromethylationoxytrifluoromethylationof of alkenes. alkenes. ** excitedexcited catalyst.catalyst.

TheThe KoikeKoike and and Akita Akita group group also also reported reported photoredox photoredox reaction reaction of alkenes of alkenes using Umem- using oto’sUmemoto’s reagent reagent as CF3 sourceas CF3 source and Ru(bpy) and Ru(bpy)3(PF6)23(PFas a6) catalyst2 as a catalyst for the for synthesis the synthesis of aminotri- of ami- ﬂuoromethylationnotrifluoromethylation products products55 (Scheme 55 (Scheme 34A) [34A)62]. The[62]. Magnier The Magnier and Masson and Masson group group used theused similar the similar reaction reaction conditions conditions in the in synthesis the synthesis of β-triﬂuoromethylated of β-trifluoromethylated azides azides56a and 56a aminesand amines56b (Scheme 56b (Scheme 34B) [34B)63]. [63].

Scheme 34. Difunctionalization using Umemoto’s reagent. (A) reaction with R2CN/H2O. (B) reac- Scheme 34. Difunctionalization using Umemoto’s reagent. (A) reaction with R2CN/H2O. (B) reaction tion with TMSN3/R4NH2. with TMSN3/R4NH2.

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TheThe SheShe andand LiLi groupgroup reportedreported acyloxytriﬂuoromethylationacyloxytrifluoromethylation ofof alkenesalkenes withwith thethe UmemotoUmemoto IIII reagentreagent usingusing Ru(bpy) Ru(bpy)33(PF(PF66))22 as a photoredox catalystcatalyst (Scheme(Scheme 3535))[ [64].64]. N,NN,N-- DimethylformamideDimethylformamide (DMF)(DMF) waswas employedemployed asas aa solventsolvent andand alsoalso anan acetylationacetylation reagent.reagent. CFCF33 radical generated from from the the Umemoto’s Umemoto’s reagent reagent through through catalytic catalytic SET SET adds adds to toarylal- ary- lalkeneskenes to to give give stable stable benzyl benzyl radicals radicals which which ar aree oxidized oxidized to benzyl carbocationscarbocations followedfollowed byby nucleophilicnucleophilic additionaddition ofof DMFDMF toto givegive imineimine intermediatesintermediates andand thenthen hydrolyzedhydrolyzed toto givegive desireddesired productsproducts57 57..

SchemeScheme 35.35. AcyloxytriﬂuoromethylationAcyloxytrifluoromethylation ofof styrenes.styrenes. ** excitedexcited catalyst.catalyst.

TheThe KoikeKoike andand AkitaAkita groupgroup reportedreported trifluoromethylation-initiatedtrifluoromethylation-initiated reactionreaction forfor thethe synthesissynthesis of αα-trifluoromethylated-trifluoromethylated ketones ketones 5858 (Scheme(Scheme 36) 36 [65].)[65 CF].3 CF radical3 radical generated generated from III fromthe Togni’s the Togni’s reagent reagent II through II through photocatalytic photocatalytic reductive reductive SET SETof fac of-[IrfacIII-[Ir(ppy)(ppy)3] adds3] addsto al- tokenes alkenes followed followed by oxidative by oxidative SET SETgave gave β-CFβ3-CF-substituted3-substituted carbocationic carbocationic intermediates. intermediates. Nu- Nucleophiliccleophilic attack attack of ofDMSO DMSO to to carbocations carbocations affords affords alkoxysulfonium alkoxysulfonium intermediates whichwhich thenthen reactreact withwitho o-iodobenzoate-iodobenzoate for for Korblum Korblum oxidation oxidation to to give give final final products products58 58. .

SchemeScheme 36.36. PhotocatalyticPhotocatalytic keto-triﬂuoromethylationketo-trifluoromethylation ofof styrenes.styrenes. ** excitedexcited catalyst.catalyst.

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MoleculesMolecules2021 2021, ,26 26,, 105 105 20 ofof 3131 The Magnier and Masson group reported a photoredox-catalyzed carbotrifluoro- methylation of enecarbamates using Togni’s reagent II as the CF3 source and various O-, N-, and C-containing compounds as nucleophiles (Scheme 37) [66]. The CF3 radical gen- eratedTheThe from MagnierMagnier Togni’s and and Massonreagent Masson group by group reductive reported reported aphotoredox photoredox-catalyzed a photoredox-catalyz SET adds carbotriﬂuoromethy- toed enecarbamates carbotrifluoro- to form methylation of enecarbamates using Togni’s reagent II as the CF3 source and various O-, lationα-amido of enecarbamates radicals which using are Togni’squickly reagent oxidized II as to the acyliminium CF3 source andcations various by O-,a SET N-, process. andN-, and C-containing C-containing compounds compounds as nucleophiles as nucleophiles (Scheme (Scheme 37)[ 37)66 ].[66]. The The CF CF3 radical3 radical gener- gen- Nucleophilic trapping by alcohol, NaN3, or KCN affords the corresponding trifluorometh- atederated from from Togni’s Togni’s reagent reagent by by reductive reductive photoredox photoredox SET SET adds adds to to enecarbamates enecarbamates to to formform αylatedα-amido-amido adducts radicalsradicals 59a whichwhich–c. areare quicklyquickly oxidizedoxidized toto acyliminiumacyliminium cationscations byby aa SETSET process.process. NucleophilicNucleophilictrapping trapping byby alcohol,alcohol, NaN NaN33,, oror KCNKCN affords affords the the corresponding corresponding triﬂuoromethy- trifluorometh- latedylated adducts adducts59a 59a–c–.c.

Scheme 37. Difunctionalization of enecarbamates. * excited catalyst. SchemeScheme 37.37. DifunctionalizationDifunctionalization ofof enecarbamates.enecarbamates. ** excitedexcited catalyst.catalyst. The Lei group reported an electrochemical reaction for oxytrifluoromethylation and TheThe LeiLei groupgroup reportedreported anan electrochemicalelectrochemical reactionreaction forfor oxytrifluoromethylationoxytrifluoromethylation andand aminotrifluoromethylation of alkenes using sodium trifluoromethanesulfinate aminotrifluoromethylationaminotrifluoromethylation of alkenesof alkenes using sodiumusing trifluoromethanesulfinatesodium trifluoromethanesulfinate (CF3SO2Na) 3 2 3 3 2 as(CF the3SOSO source2Na)Na) as ofas the CF the3 sourceradical source of (Scheme ofCF CF3 radical 38 radical)[67 (Scheme]. CF(Scheme3SO 38)2Na [67]. 38) is oxidized CF[67].3SO CF2Na atSO theis oxidizedNa anode is viaoxidized at SET the at the toanode afford viavia CF SET SET3 radical to to afford afford which CF CF3 addsradical3 radical to which styrenes which adds to adds to generate styrenes to styrenes benzylic to generate to radicals generate benzylic followed benzylic radicals by radicals oxidationfollowed by toby oxidation carbocations. oxidation to tocarbocations.Subsequent carbocations. Subsequent nucleophilic Subsequent nucleophilic attack nucleophilic on the attack carbocations attackon the carbocationson produces the carbocations desiredproduces products desired desired60 products .products 60 .60 .

C(+)/Pt(-)C(+)/Pt(-) = 15 mA = 15 mA Nu Nu n-BuN4BF4,Y(OTf)3 NuH n-BuN4BF4,Y(OTf)3 CF3 Ar + CF3SO2Na + CF3 Ar + CF3SO2Na + NuHCH CN, rt, 3 h Ar 2 CH CN, rt, 3 h Ar Nu = OR, NR1R2 undivided2 cell 60, 39-89% Nu = OR, NR1R2 undivided cell 60, 39-89%

anodic [O] Ar anodic [O] CF3 CF3SO2Na CF CF3 Ar anodic-e [O] 3 Ar Ar -e anodic [O] CF3 CF3SO2Na CF CF3 Ar -e 3 Ar -e NuH -H+ NuH -H+ + Nu Cathode NuH + H +e H2 +Nu + CFNu3 Cathode NuH + H +e H2 +Nu Ar 60 CF Ar 3 60 Scheme 38. Trifluoromethylative Difunctionalization of Alkenes Using CF3SO 2 Na.

SchemeScheme 38. 38.Trifluoromethylative Trifluoromethylative Difunctionalization Difunctionalization of Alkenes of Alkenes Using CFUsing3SO2 Na.CF3SO2Na. Han and coworkers reported a photoredox catalytic reaction for 1,2-chlorotrifluoro- methylationHanHan and and of coworkers coworkersalkenes using reported reported CF3SO a a photoredox2Cl photoredox as a source catalytic ca fortalytic CF reaction3 reactionradical for and for 1,2-chlorotrifl- chloride1,2-chlorotrifluoro- ion uoromethylation(Scheme 39A) [68]. of The alkenes CF3 radical usingCF generated3SO2Cl asfrom a source CF3SO for2Cl CF through3 radical reductive and chloride SET of ion Ru methylation of alkenes using CF3SO2Cl as a source for CF3 radical and chloride ion (catalystScheme add39A )[to68 alkenes,]. The CF followed3 radical by generated oxidative from SET CFto 3carbocationsSO2Cl through and reductive nucleophilic SET ofaddi- Ru catalyst(Schemetion of chloride add 39A) to alkenes, [68].to give The followed chlorotrifluoromethylated CF3 radical by oxidative generated SET to from products carbocations CF3SO 61.2 andClThe through nucleophilicHan group reductive extended addition SET of Ru ofcatalystthe chloride scope add of to the giveto reactionalkenes, chlorotrifluoromethylated for followed alkynes toby ma oxidativeke vicinal products SET chlorotrifluoromethylated 61to. carbocations The Han group and extended nucleophilic alkenes the 62 addi- scopetionusing of ofIr-based chloride the reaction photoredox to forgive alkynes chlorotrifluoromethylated catalyst to make (Scheme vicinal 39B) chlorotrifluoromethylated [69]. The products resultant 61 .trifluoromethyl The alkenes Han 62groupusing sub- extended Ir-basedthestituted scope vinyl photoredox of thechlorides reaction catalyst can for be (Scheme usedalkynes for 39 SuzukitoB) [ma69].ke coupling The vicinal resultant to chlorotrifluoromethylated make trifluoromethyl 1,1-bis-arylalkenes. substituted alkenes 62 vinylusing chlorides Ir-based can photoredox be used for catalyst Suzuki coupling (Scheme to 39B) make [69]. 1,1-bis-arylalkenes. The resultant trifluoromethyl substituted vinyl chlorides can be used for Suzuki coupling to make 1,1-bis-arylalkenes.

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Molecules 2021, 26, 105 21 of 31 Molecules 2021, 26, 105 21 of 31

Scheme 39. Chlorotrifluoromethylation of alkenes and alkynes. (A) Ru(phen)3Cl2-catalyzed reac-

tion. (B) Ir(ppy)3-catalyzed reaction. * excited catalyst. SchemeScheme 39. 39.Chlorotrifluoromethylation Chlorotrifluoromethylation of alkenes of and alkenes alkynes. and (A) Ru(phen)alkynes.3Cl (A2-catalyzed) Ru(phen) reaction.3Cl2-catalyzed reac- (B) Ir(ppy)3-catalyzed reaction. * excited catalyst. tion. The(B) Ir(ppy)3-catalyzed Zhu group applied reaction. photoredox * excited catalyst.catalysi s reaction for difluoroalkylarylation of styrenesThe Zhu using group α-carbonyl applied photoredox difluoroalkyl catalysis bromides reactionfor for difluoroalkylarylation CF2R radicals and ofindoles as nucle- The Zhuα group applied photoredox catalysis reaction for difluoroalkylarylation of styrenesophiles using in the-carbonyl synthesis difluoroalkyl of difluorolated bromides indole for CF 2derivativesR radicals and 63 indoles (Scheme as nucle- 40) [70]. The CF2 R ophilesradicalsstyrenes in thegenerated using synthesis α-carbonyl from of difluorolated α-carbonyl difluoroalkyl indole difluoroalkyl derivatives bromides63 bromides(Schemefor CF2 R40 )[radicals through70]. The and CFreductive2 Rindoles SET as nucle- with radicals generated from α-carbonyl difluoroalkyl bromides through reductive SET with Ir-photocatalystophiles in the synthesis add to alkenes of difluorolated followed indole by oxidative derivatives SET to63 cations(Scheme and 40) then [70]. react The CFwith2 R Ir-photocatalystradicals generated add to alkenesfrom α followed-carbonyl by oxidativedifluoroalkyl SET to cationsbromides and thenthrough react withreductive SET with indolesindoles to to give give difluoroalkylated difluoroalkylated products products63 after base-mediated 63 after base-mediated deprotonation. deprotonation. Ir-photocatalyst add to alkenes followed by oxidative SET to cations and then react with indoles to give difluoroalkylated products 63 after base-mediated deprotonation.

SchemeScheme 40. 40.Photoredox Photoredox diﬂuoroalkylative difluoroalkylative difunctionalization difunctionalization of alkenes. of alkenes.

Yang and coworkers reported a photocatalyzed reaction for aminodifluoromethylphos- SchemeYang 40. Photoredoxand coworkers difluoroalkylative reported dia functionalizationphotocatalyzed of alkenes.reaction for aminodifluoro- phonation of alkenes using bromodifluoromethylphosphonates as the source of CF2 radical (Schememethylphosphonation 41)[71]. The NaI was of usedalkenes as additive using tobromod stabilizeifluoromethylphosphonates the carbocation intermediates as the source Yang and coworkers reported a photocatalyzed reaction for aminodifluoro- andof CF increase2 radical the product(Scheme yields. 41) [71]. The difluorocarbon The NaI was radicals used as produced additive through to stabilize the SET the carbocation processintermediatesmethylphosphonation of bromodifluoromethylphosphonates and increase of alkenes the produc using add bromodt toyields. alkenesifluoromethylphosphonates The followed difluorocarbon by SET oxidation radicals to as theproduced source cations for nucleophilic addition with amines to give the products 64 after deprotonation. throughof CF2 radical the SET (Scheme process 41) of [71]. bromodifluorom The NaI wasethylphosphonates used as additive to addstabilize to alkenes the carbocation followed byintermediates SET oxidation and to increasecations for the nucleophilic product yields. addition The with difluorocarbon amines to give radicals the products produced 64 afterthrough deprotonation. the SET process of bromodifluoromethylphosphonates add to alkenes followed by SET oxidation to cations for nucleophilic addition with amines to give the products 64 after deprotonation.

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MoleculesMolecules 20212021, 26, 26, ,105 105 22 of 31 22 of 31

Scheme 41. Photocatalyzed aminodifluoromethylation of alkenes. * excited catalyst. SchemeScheme 41. 41.Photocatalyzed Photocatalyzed aminodifluoromethylation aminodifluoromethylation of alkenes. of alkenes. * excited * excited catalyst. catalyst. The Koike and Akita group reported a photocatalytic oxydifluoromethylation of al- kenesTheThe Koike Koikeusing and and Akitashelf-stable Akita group group reported reportedand a photocatalyticeasy-to-handlea photocatalytic oxydifluoromethylation oxydifluoromN-tosyl-S-difluoromethyl-ethylation of of al-S- alkenes using shelf-stable and easy-to-handle N-tosyl-S-difluoromethyl-S-phenylsulfoximine kenesphenylsulfoximine using shelf-stableas a CF2H source and for theeasy-to-handle synthesis of β-CFN2-tosyl-H-substitutedS-difluoromethyl- products 65S- as a CF2H source for the synthesis of β-CF2H-substituted products 65 including alco- includingphenylsulfoximine alcohols, ethers,as a CF and2H source an ester for (Scheme the synthesis 42) [72]. of The β-CF CF2H-substituted2H radical generated products from 65 hols, ethers, and an ester (Scheme 42)[72]. The CF2H radical generated from N-tosyl-S- difluoromethyl-includingN-tosyl-S-difluoromethyl- alcohols,S-phenylsulfoximine ethers, Sand-phenylsulfoximine an ester by SET (Scheme process by42) reacts SET[72]. with proce The alkenes CFss 2reactsH radical to afford with generated carbo-alkenes tofrom af- cationicNford-tosyl- carbocationic intermediatesS-difluoromethyl- intermediates after oxidativeS-phenylsulfoximine after SET oxidative with Ir(IV) by SETand SET thenwith proce solvolysisIr(IV)ss reactsand withthen with ROHsolvolysis alkenes to towith af- produceROHford carbocationic to oxydifluoromethylatedproduce oxydifluoromethylated intermediates products after65 oxidative. products SET 65. with Ir(IV) and then solvolysis with ROH to produce oxydifluoromethylated products 65.

SchemeScheme 42. 42.Photocatalytic Photocatalytic oxydifluoromethylation. oxydifluoromethylation. * excited * excited catalyst. catalyst. Scheme 42. Photocatalytic oxydifluoromethylation. * excited catalyst. TheThe Qing Qing group group developed developed a photoredox-catalyzed a photoredox-catalyzed bromodifluoromethylation bromodifluoromethylation reac- reac- tion of alkenes using difluoromethyltriphenylphosphonium bromide for generating CF2H tion ofThe alkenes Qing groupusing difluoromethyltriphedeveloped a photoredox-catnylphosphoniumalyzed bromodifluoromethylation bromide for generating CF reac-2H radical and also brominated anion as a nucleophile (Scheme 43A) [73]. The bromonated tionradical of alkenesand also using brominated difluoromethyltriphe anion as a nucleophilenylphosphonium (Scheme bromide 43A) [73]. for Thegenerating bromonated CF2H products 66 can be converted to CF2H-containing alkenes via an elimination process. Theradicalproducts research and 66 also groupcan bebrominated also converted reported anion to a CF oxydifluoromethylation 2asH-containing a nucleophile alkenes (Scheme reaction via an43A) ofelimination styrenes[73]. The using process.bromonated The difluoromethyltriphenylphosphoniumresearchproducts group66 can also be converted reported ato oxydifluoromet CF bromide2H-containing as ahylation radical alkenes source reaction via and an alcohols/waterofelimination styrenes usingprocess. as difluo- The nucleophilesromethyltriphenylphosphoniumresearch group for the also synthesis reported of CF a 2oxydifluorometH-containing bromide as alcoholsa rahylationdical and source reaction ethers and67 (Schemeof alcohols/water styrenes 43B) using [74]. as difluo- nucle- ophilesromethyltriphenylphosphonium for the synthesis of CF2H-containing bromide as aalcohols radical andsource ethers and 67alcohols/water (Scheme 43B) as [74] nucle-. ophiles for the synthesis of CF2H-containing alcohols and ethers 67 (Scheme 43B) [74].

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Scheme 43. Bromodifluoromethylation and oxydifluoromethylation of alkenes. (A) reaction with SchemeSchemeBr- as nucleophile. 43.43. BromodifluoromethylationBromodifluoromethylation (B) reaction withand andR3OH oxydifluoromethylation oxydifluoromethylation as nucleophile. * excited of of alkenes. alkenes. catalyst. (A (A) reaction) reaction with with Br - - 3 asBr nucleophile. as nucleophile. (B) ( reactionB) reaction with with R3OH R OH as nucleophile.as nucleophile. * excited * excited catalyst. catalyst. The Magnier and Masson group employed S-perfluoroalkyl sulfilimino iminium ions The Magnier Magnier and and Masson Masson group group employed employed S-perfluoroalkyl S-perfluoroalkyl sulfilimino sulfilimino iminium iminium ions 69 as a source of Rf radicals for oxyperfluoroalkylation of alkenes under photoredox ca- ions69 as69 a assource a source of R off radicals Rf radicals for oxyperfluoroalkylation for oxyperfluoroalkylation of alkenes of alkenes under under photoredox photoredox catalysis conditions (Scheme 44) [75]. These stable perfluoroalkyl reagents containing CF3, catalysistalysis conditions conditions (Scheme (Scheme 44) 44 )[[75].75]. These These stable stable perfluoroalkyl perfluoroalkyl reagents reagents containing CFCF33,, C4F9, CF2Br, or CFCl2 can be readily prepared at gram scale from corresponding sulfox- CC44F9,, CF 2Br,Br, or CFClCFCl22 cancan bebe readily readily prepared prepared at at gram gram scale scale from from corresponding corresponding sulfoxides. sulfox- Theides.ides. spin-trapping/electron The The spin-trapping/electron spin-trapping/electron paramagnetic paramagnetic paramagnetic resonance resonance resonance experiments experiments experiments confirmed confirmed that confirmed key that radi- key that key calradicalradical intermediates intermediates intermediates involved involved involved in the in radical/cationic the in theradical/cationic radical/cationic process. process. Rf radicalsprocess. Rf radicals generated Rf radicals generated from generated69 fromby from reductive6969 byby reductive reductive SET add SET SET to alkenesadd add to alkenesto to formalkenes to stabilized form to form stabilized benzylic stabilized benzylic radicals benzylic andradicals then radicals and corresponding then and corre- then corre- carbocationsspondingsponding carbocations carbocations after oxidative after after oxidative SET. oxidative Final SET. trapping SET. Final Final withtrapping methanoltrapping with methanol provideswith methanol provides corresponding provides corre- corre- productsspondingsponding68 products .products 68 .68 .

SchemeScheme 44. 44.Oxyperﬂuoroalkylation Oxyperfluoroalkylation with with sulﬁlimino sulfilimino iminium iminium ions. * excitedions. * catalyst.excited catalyst.

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The Zhu group developed a visible light-promoted difluoroalkylarylation reaction of The Zhu group developed a visible light-promoted difluoroalkylarylation reaction ofallylic allylic alcohols alcohols for for the the synthesis synthesis of of difluoro difluoro 1,5-dicarbonyl 1,5-dicarbonyl compounds 70 70through through radical radicaladdition addition and 1,2-aryl and 1,2-aryl migration migration process process (Scheme (Scheme 45) 45 [76].)[76 ].The The initial initial fluorocarbon fluorocarbon radicals radicalsgenerated generated from ethyl from ethyl2-bromo-2,2-difluoroacetate 2-bromo-2,2-difluoroacetate or or CF CF3II under SETSET add add to to allylic allylic alco- alcoholshols followed followed by by ipsoipso 1,2-aryl1,2-aryl migration migration viaviaspiro[2.5]octadienyl spiro[2.5]octadienyl radicals radicals71 to 71 give to give hy- hydroxycarbondroxycarbon radicals. radicals. Oxidative Oxidative SETSET ofof thethe radicals radicals to to corresponding corresponding carbocations carbocations fol- followedlowed by by deprotonation deprotonation give give products 70 70.. TheThe Zhu Zhu group group extended extended the the scope scope of theof the reac- reactiontion for for1,4-aryl 1,4-aryl and and other other group group migrations migrations using using β-hydroxyβ-hydroxy alkenes alkenes as as starting starting materials 72a 72b materialsfor the synthesis for the synthesis of 72a and of 72band [77]. [77].

SchemeScheme 45. 45.Difunctionalization Difunctionalization involving involving a 1,2- a or1,2- 1,4-group or 1,4-group migration. migration. (A) 1,2-migration (A) 1,2-migration reaction. reaction. ((BB)) 1,4-migration 1,4-migration reaction. reaction. * excited * excited catalyst. catalyst.

TheThe Ma Ma and and Li Li group group reported reported a photoredox-catalyzeda photoredox-catalyzed 1,6-oxyfluoroalkylation 1,6-oxyfluoroalkylation of of al- alkeneskenes using using DMSODMSO as as an an oxidant oxidant and and also also a solvent a solvent (Scheme (Scheme 46)[78 46)]. The [78]. perfluoroalkyl The perfluoroalkyl (Rf) radicals are produced from RfBr through the photoredox of the Ir-catalyst in the (Rf) radicals are produced from RfBr through the photoredox of the Ir-catalyst in the assis- assistance of the Ag salt. The benzylic radicals generated from the addition of Rf radicals tance of the Ag salt. The benzylic radicals generated from the addition of Rf radicals to to alkenes undergo 1,5-hydrogen atom transfer (1,5-HAT) and then the Kornblum reaction withalkenes DMSO undergo to afford 1,5-hydrogen 1,6-oxyfluoroalkylated atom transfer ketones (1,5-HAT)73. and then the Kornblum reaction with DMSO to afford 1,6-oxyfluoroalkylated ketones 73.

Molecules 2021, 26, 105 25 of 31 MoleculesMolecules 20212021,, 2626,, 105105 2525 ofof 3131

SchemeScheme 46.46. 1,6-Oxyﬂuoroalkylation1,6-Oxyfluoroalkylation1,6-Oxyfluoroalkylation ofofof alkenes.alkenes.alkenes. ** excitedexcited catalyst.catalyst.

TheThe ZhuZhuZhu groupgroupgroup developeddevelopeddeveloped aaa methodmethodmethod to toto generate generategenerate CF CFCF333 radical radicalradical from fromfrom CF CFCF33SO3SOSO22Na2NaNa andandand PhI(OPhI(O22CCFCCF33)))222 forforfor difunctionalization difunctionalization of of unactivated unactivated alkenes alkenes involvinginvolving distaldistaldistal heteroarylheteroarylheteroaryl groupgroup migrationmigration toto formform productsproducts 7474 (Scheme(Scheme(Scheme 4747A)47A)A) [[79].[79].79]. TheThe Umemoto’sUmemoto’s reagent reagent is is em-em- ployedployed asas CFCFCF333 radicalradical sourcesource forfor trifluoromethylativetrifluoromethylatitrifluoromethylativeve alkynylationalkynylation ofofof unactivatedunactivatedunactivated alkenesalkenesalkenes toto form form products products 757575 throughthroughthrough photocatalyzedphotocatalyzed photocatalyzed reactionreaction reaction involvinginvolving involving thethe the alkynylalkynyl alkynyl migrationmigration migration re-re- reactionactionaction (Scheme(Scheme (Scheme 47B)47B) 47B) [80].[80]. [80 The].The The WangWang Wang groupgroup group reporepo reportedrtedrted anan an electrochemicalelectrochemical electrochemical reactionreaction reaction forfor for fluoro-fluoro- fluo- roalkylarylationalkylarylationalkylarylation ofof of unactivatedunactivated unactivated alkenesalkenes alkenes toto to formform form productsproducts 7676 usingusing RRfffSOSO22NaNa as as fluorocarbonfluorocarbonfluorocarbon radicalradical sourcesource (Scheme(Scheme(Scheme 47 47C)47C)C) [[81][81]81]... AllAll thesethese threethree reactionsreactionsreactions involveinvolveinvolve distaldistaldistal groupgroupgroup migration migrationmigration andand theirtheir mechanismsmechanisms areare similarsimilarsimilar tototo thatthatthat presentedpresentedpresented in inin Scheme SchemeScheme 14 14.14..

SchemeScheme 47.47. FluorocarbonFluorocarbon radicalradical reactionsreactions involving involving distal distal group group migration. migration. (( AA)) heteroarylheteroaryl groupgroup migrationmigration reaction.reaction. ((BB)) alkynylalkynyl groupgroupgroup migrationmigrationmigration reaction. reaction.reaction. (((CC))) electrochemicalelectrochemicalelectrochemical reaction reactionreaction conditions. conditionsconditions

TheThe StuderStuder groupgroup reportedreportedreported aaa methodmethodmethod forforfor perfluoroalkyltriflationpeperfluoroalkyltriflationrfluoroalkyltriflation ofofof alkynesalkynesalkynes usingusingusing phenyl(perfluoroalkyl)iodoniumphenyl(perfluoroalkyl)iodoniumphenyl(perfluoroalkyl)iodonium triflates triflatestriflates 787878 ininin thethe the presencepresence presence ofof of CuClCuCl CuCl toto to affordafford afford selectiveselective selective E-E- E-difunctionalizeddifunctionalizeddifunctionalized alkenealkene alkene productsproducts products 777777 (Scheme(Scheme(Scheme 48)48)48)[ [82].[82].82]. R Rff radicalsradicals generated generated from from 787878 throughthrough reductivereductive SETSET withwithwith CuClCuClCuCl addaddadd tototo alkynesalkynesalkynes tototo fromfromfrom vinyl vinylvinyl radicals radicalsradicals and andand then thenthen vinylic vinylicvinylic cationscations afterafter oxidation.oxidation. TrappingTrapping ofofof cations cationscations with withwith triflate triflatetriflate anion anionanion affords affordsaffords the thethe products productsproducts77 7777...

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MoleculesMolecules 20212021, 26, 26, 105, 105 26 of 31 26 of 31

Scheme 48. Perfluoroalkyltriflation of alkynes. SchemeScheme 48. 48.Perfluoroalkyltriflation Perfluoroalkyltriflation of alkynes. of alkynes. Han and coworkers reported photoredox catalytic ketofluoromethylation of alkynes Han and coworkers reported photoredox catalytic ketofluoromethylation of alkynes (SchemeHan 49) and [83]. coworkers The CF 3reported radical generatedphotoredox from catalytic Umemoto’s ketofluoromethylation reagent through of reductive alkynes (SchemeSET add 49 to)[ 83alkynes]. The CF to3 produceradical generated vinyl radicals from Umemoto’s which are reagent oxidized through to vinyl reductive cations by SET SET(Scheme add to 49) alkynes [83]. toThe produce CF3 radical vinyl radicals generated which from are oxidized Umemoto’s to vinyl reagent cations through by SET reductive and then trapped by H2O to give products 79 after deprotonation− with BF4− and enol-keto andSET then add trapped to alkynes by H2 toO toproduce give products vinyl79 radicalsafter deprotonation which are withoxidized BF4 andto vinyl enol-keto cations by SET tautomerization.tautomerization.and then trapped by H2O to give products 79 after deprotonation with BF4− and enol-keto tautomerization.

SchemeScheme 49. 49.Ketotrifluoromethylation Ketotrifluoromethylation of alkynes. of alkynes. * excited * catalyst.excited catalyst. Scheme 49. Ketotrifluoromethylation of alkynes. * excited catalyst. TheThe Zhu Zhu and and Li groupLi group reported reported photoredox-catalyzed photoredox-catalyzed remote ketofluoroalkylation remote ketofluoroalkylation and hydroxytrifluoromethylation of alkynes using RfX or Umemoto’s reagent as fluo- and hydroxytrifluoromethylation of alkynes using RfX or Umemoto’s reagent as fluoroal- roalkylThe source Zhu and and DMSO Li group or H 2reportedO as oxygen photoredox source for-catalyzed the synthesis remote of ε-oxygenated ketofluoroalkylation fluoroalkylatedkyland source hydroxytrifluoromethylation and (Z )-alkenesDMSO or80 Hand2O81 as(Scheme oxygen of alkynes 50 source)[84 using]. In for the R the reactionfX or synthesis Umemoto’s with the of Umemoto’s ε-oxygenated reagent as fluoroal- fluoro- reagent,alkylatedkyl source the ( Z CFand)-alkenes3 radicalDMSO generated80 or and H2O 81 asthrough (Scheme oxygen SET 50)source adds [84]. tofor In alkynes the reactionsynthesis to form with vinylof ε -oxygenatedthe radicals Umemoto’s fluoro- rea- whichgent,alkylated thenthe CF undergo(Z3)-alkenes radical 1,5-HAT generated 80 and followed 81 through(Scheme by oxidative SET 50) [84].adds SET toIn to form the alkynes reaction cationic to intermediatesform with vinyl the Umemoto’s radicals82 which rea- withthen a undergo (Z)-alkenyl 1,5-HAT group. Nucleophilic followed by attack oxidative of 82 by SET DMSO to form followed cationic by the intermediates Kornblum 82 with oxidationgent, the producesCF3 radical trifluoromethyl generated through (Z)-alkenyl SET ketones adds80 to. Alternatively,alkynes to form using vinyl H O radicals in- which a (Z)-alkenyl group. Nucleophilic attack of 82 by DMSO followed by the2 Kornblum oxi- steadthen ofundergo DMSO as1,5-HAT a nucleophile, followed trifluoromethylated by oxidative SET (Z)-alkenols to form81 cationicare produced intermediates from 82 with thedationa (Z reaction.)-alkenyl produces group. trifluorom Nucleophilicethyl (Z)-alkenyl attack of 82 ketones by DMSO 80. Alternatively, followed by theusing Kornblum H2O instead oxi- ofdation DMSO produces as a nucleophile, trifluorom trifluoromethylatedethyl (Z)-alkenyl ketones (Z)-alkenols 80. Alternatively, 81 are produced using Hfrom2O instead the reaction.of DMSO as a nucleophile, trifluoromethylated (Z)-alkenols 81 are produced from the reaction.

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Molecules 2021, 26, 105 27 of 31 Molecules 2021, 26, 105 R2 R 27 of 31 f fac-Ir(ppy)3,Ag2CO3 R1Z R2 (A) 1 + RfX R Z DMSO, rt, blue LED, 12 h O 80a, 40-83% 2 R Rf 2 fac-Ir(ppy)3,Ag2CO3 1 2 (A) R R Z CF3 R 1 + RfX Ru(bpy)3Cl2, NaHCO3 R Z DMSO, rt, blue LED, 12 h 1 2 R Z O R R1Z DMSO, rt, blue LED, 8 h 80a, 40-83% + O 2 R CF80b,3 30-80% Ru(bpy)3Cl2, NaHCO3 R1Z R2 (B) 1 R Z S DMSO, rt, blue LED, 8 h CF3 - +CF OTf fac-Ir(ppy) ,K CO 1 O 2 3 3 2 3 80b,R Z30-80% R 1 acetone/H O,rt,blueLED,2h (B) R = Me, Et, Ph; Z= O,S 2 OH 2 S CF81,3 50-78% R =alkyl,aryl - OTf 1 2 CF3 fac-Ir(ppy)3,K2CO3 R Z R

R1 = Me, Et, Ph; Z= O,S acetone/H2O,rt,blueLED,2h 2 81, 50-78%ROH R2 =alkyl,aryl CF3 R1Z CF3 R2 R1Z S CF3 OTf - 2+ Ru3+ I CF *Ru R1Z 3 1,5-HAT 2 CF3 R1Z R S CF3 - 3+ I OTf *Ru2+ Ru 1 2 CF3 R Z R Ru2+ 1,5-HAT R2 CF CF(3Z)- 3 CF3 1 2 1 2 2+ R Z R R Z R HRu2O R1Z R2 CF (Z)- 3 CF3 1 OH2 82 R Z 81 R H2O R1Z R2 DMSO 81 OH 82 CF3 DMSO CF3 1 2 1 2 R Z R base, - Me2S R Z R CF3 CF3 R1Z R2 1 2 O Kornnlumbase, - Me2 oxidationS R Z 80 R O S O Kornnlum oxidation 80 O S

Scheme 50. Photoredox-catalyzed remote oxyfluoroalkylation. (A) Rf-involved reaction. (B) CF3- Scheme 50. Photoredox-catalyzed remote oxyfluoroalkylation. (A) Rf-involved reaction. (B) CF3- Schemeinvolved 50. reaction.Photoredox-catalyzed * excited catalyst. remote oxyﬂuoroalkylation. (A)Rf-involved reaction. (B) CF3- involved reaction. * excited catalyst. involved reaction. * excited catalyst.

8.8. OtherOther Radical-Initiated Radical-InitiatedRadical-Initiated ReactionsReactions Reactions OtherOther thanthan than aboveabove above mentionedmentioned mentioned difunctionalizationdifunctionalization difunctionalization reactionsreactions reactions initiatedinitiated initiated withwith C-,C-, with N-,N-, O-,O-,C-, N-, O-, P-,P-, andand ﬂuorocarbon-radicals, fluorocarbon-radicals,fluorocarbon-radicals, wewe we foundfound found aa singlesing a single exampleexamplele example ofof iodoiodo of radical-initiated radical-initiatediodo radical-initiated difunc-difunc- difunc- tionalizationtionalizationtionalization reportedreported reported byby by thethe the ZhuZhu Zhu groupgroup group (Scheme(Sch (Scheme 51 eme51))[ 85[85]. 51)]. TheThe[85]. reactionreaction The reaction ofof TBHP TBHP of with withTBHP I 2I2 with I2 generatesgeneratest t -BuOIt-BuOI-BuOI andand and HOI.HOI. HOI. RadicalRadical Radical iodinationiodination iodination of of styrenesstyrenes of styrenes followed followed followed by by oxidation oxidation by oxidation to to cations cations to cations andand nucleophilicnucleophilic attackingattacking attacking byby by TBHPTBHP TBHP givegive give iodoalkylperoxylatediodoalkylperoxylated iodoalkylperoxylated products products products83 83. . 83.

Scheme 51. Iodoalkylperoxylation of alkenes. Scheme9. Conclusions 51. 51.Iodoalkylperoxylation Iodoalkylperoxylation of alkenes. of alkenes. 9. ConclusionsThis article summarizes the radical and nucleophilic difunctionalization reactions of 9. Conclusions alkenesThis and article alkynes summarizes involving the a radical cascade and process nucleophilic of radical difunctionalization generation, radical reactions addition, of alkenesoxidationThis and toarticle alkynes cation, summarizes involvingand trapping a cascadethe by radical a nucl processeophile. and of nucleophilic radical This one-pot generation, difunctionalization reaction radical process addition, demon- reactions oxi- of dationalkenesstrates to the and cation, step alkynes and pot trapping involving economies by a nucleophile.a as cascade well as operationalprocess This one-pot of simplicity.radical reaction generation, process A wide demonstrates range radical C-, O-, addition, oxidation to cation, and trapping by a nucleophile. This one-pot reaction process demonstrates the step and pot economies as well as operational simplicity. A wide range C-, O-,

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the step and pot economies as well as operational simplicity. A wide range C-, O-, N-, S-, P-centered and ﬂuorocarbon radicals are used in combination with C-, N-, O-centered and halogenic nucleophiles for difunctionalizations to show substrate versatility. Currently active research techniques such as photoredox catalysis and electrochemical reactions have been applied to the difunctionalization reactions. It is worth noting that in addition to radical and nucleophilic difunctionalization reactions presented in this paper, there are other radical-initiated difunctionalization reactions such as radical chain reactions, radical-radical coupling with or without metal catalysis. In some reaction processes, the radical difunctionalizations could have more than one pathways. The complex reaction processes have attracted the attention of synthetic chemists to conduct mechanism studies which could lead to the discovery of new reactions. We have no doubt that radical addition- initiated difunctionalization reactions for making molecules with potential biological, medical and functional material utilities will become important tools in organic synthesis.

Author Contributions: H.Y. literature search, review and original manuscript writing. W.H. revision of text and chem-drawing. W.Z. revision and supervision. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Data Availability Statement: Data sharing not applicable. Conﬂicts of Interest: The authors declare no conﬂict of interests.

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