Remote C-H Functionalization via Selective Hydrogen Atom

Synthesis Review/ShortReview

TemplateforSYNTHESIS©ThiemeStuttgart·NewYork 2018-05-22 page1of17

RemoteC-HFunctionalizationviaSelectiveHydrogenAtomTransfer

Received:Accepted:Publishedonline:DOI:

Abstract The selective functionalization of remote C-H bonds viaintramolecular hydrogen atom transfer (HAT) is transformative for organicsynthesis.Thisradical-mediatedstrategyprovidesaccesstonovelreactivitythat is complementary to closed-shell pathways. As modern methods formild generation of radicals are continually developed, inherent selectivityparadigms of HAT mechanisms offer unparalleled opportunities fordevelopingnewstrategiesforC-Hfunctionalization.ThisReviewoutlinesthehistory, recent advances, andmechanistic underpinnings of intramolecularHATasaguidetoaddressingongoingchallengesinthisarena.1 Introduction2 Nitrogen-centeredradicals2.1 sp3N-radicalinitiation2.2 sp2N-radicalinitiation3 Oxygen-centeredradicals3.1 Carbonyldiradicalinitiation3.2 Alkoxyradicalinitiation3.3 Non-alkoxyradicalinitiation4 Carbon-centeredradicals4.1 sp2C-radicalinitiation4.2 sp3C-radicalinitiation5 Conclusion

Key words Hydrogen Atom Transfer, Remote C-H Functionalization,Radicals,Nitrogen-centeredradicals,Oxygen-centeredradicals

1Introduction

In modern organic synthesis, C-H functionalization is thechemical equivalent of adding the final brush strokes to apainting.Whileitconvenientlyallowsforblemishestobeswiftlycorrected without restarting from a blank canvas, it alsonecessitates great care not to disrupt the overall beauty of anear-finished piece. Similarly, since the C-H bond is the mostubiquitousmotifinorganicchemistry,itsmodificationwithinacomplexmoleculenecessitatesahighlevelofcareandprecision.Thus, themost important challenge of C-H functionalization isselectivity.1–4 In recent decades, metal-based C-H activation5–7and insertion8,9 mechanisms have been employed withincreasingfrequencytoaddressthechallengesofchemo-regio-andstereo-selectivity.

Incontrast,radical-mediatedC-Hfunctionalization,10whilediscoveredearlier,11–13hasplayedamuchlesssignificantroleinadvancingthefrontiersofselectiveC-Hfunctionalization.Thisissomewhat surprisinggiven that intramolecularhydrogenatomtransfer (HAT)14 of aC-H to a remote radical site15 is typicallyquite selective16–18 and exergonic.14 The latter feature suggeststhese processes may be promoted under milder reactionconditions than their metal-mediated counterparts. In ourestimation, however, the traditionally harsh conditionsemployed for radical generation have precluded an objectiveevaluationofthefullsyntheticpotentialofopen-shellpathways.For instance, radical initiation has historically been conductedwith strong acid, refluxing peroxides, or high energy UV light.Fortunately,modernmethodsnowallowmildaccesstoradicals(e.g. iodoniumreagents,19–21photoredoxcatalysts22–24), therebyenabling synthetic chemists tomore fully explore the inherentselectivity of C-H functionalizations mediated by the diversechemistry25–28ofsingle-electrontransfer(SET)pathways.

This Review is intended to be more instructive thanexhaustive. Therefore, its focus on intramolecular HAT willhighlight the key discoveries in these areas,with emphasis onthe development of new strategies to (i) generate uniqueradicals (ii) from tailored precursors and to (iii) trap theserelayedradicalsinnovelways.Ourobjectiveistoillustratetheinnovations and general lessons from pioneering – and morerecent–contributionsineachoftheseareas,inordertoinformthereaderofthechallengesandopportunitiesthatlieahead.

Thegeneralstrategyofremote,directedC-Hfunctionaliz-ation via HAT can be divided into four main components, asoutlined above and detailed further in Scheme 1. Specifically,themechanisticfeaturesthatarecommontoall intramolecularHATreactionsinclude:(1)generationofaradicalprecursor;(2)initiationoftheradical;(3)regioselectiveHAT;and(4)trappingoftherelayedradical.Abriefoverviewofthesalientaspectsofeachelementarystepisdescribedbelow.

LeahM.StatemanaKohkiM.Nakafukua

DavidA.Nagib*a

aDepartmentofChemistryandBiochemistry,TheOhioStateUniversity,Columbus,Ohio,43210,UnitedStates

[email protected]

R

XH

R

X

R

HXH

Rradical

initiationregioselective

HAT

remote, selectiveC-H functionalization

X

R

H

radicaltrap4

3

1

2Y

radicalprecursor

via hydrogen atom transfer (HAT)

ZXH



Scheme1Fundamentalmechanisticstepsofintramolecularhydrogenatomtransfer(HAT)

(1) Radical precursor. The first, and perhaps mostimportant,stepinpromotinganintramolecularHATisthetwo-electron construction of a precursor thatwill enable access tothekey,single-electronintermediate.ThemostcommonformofHAT-initiation is from N- O- or C-centered radicals,28 and thisReview is organized into three parts, each describing thereactivityofoneoftheseradicals.AsshowninScheme1,thereisarangeofrelatedmethodsforaccessingeachradicaltype.Forexample, N-centered radicals are typically accessed via SETreductionorhomolysisofaweakN-Xbond,whereXisahalideor N2 nucleofuge. Similarly, O-centered radicals are typicallyaccessed via homolysis of a weak O-X bond (or via photo-excitation of a carbonyl). Historically, theseweak heteroatom-halidebondshavebeenpre-formed,buttheyarenowtypicallygenerated in situ.19Finally,C-centered radicals (alkyl, aryl, andvinyl)canbeaccessedfromweakC-XorC-N2precursors.

(2) Radical initiation. The next, key step in any HATmechanism is the generation of the open-shell intermediate.Historically, this has been the most limiting aspect of HATchemistry, as typical strategies employ strong acid, hightemperatures, unstable peroxides, toxic organotin reagents, orhigh energy UV light. More recently, however, earth abundantmetals(e.g.Fe,Cu,Ni),hypervalentiodinereagents,andvisible-light-mediated photoredox catalysts enable mild access toradicals,harnessinginherentHATselectivitypathways.

(3) Regioselective HAT. Despite the rapid, exergonicnature of many intramolecular H-atom transfer events, H�abstraction frequently occurswith complete d regioselectivity.The1,5-HATpathwayismosttypicalthankstoapre-organized,six-membered, cyclic transition state, with nearly linear C-H-Xgeometry(153°forO�).16FortheC�mediatedprocess,thereisa

strongenthalpicpreferencefor1,5-HATover1,4-HAT(DDH:6.6kcal/mol).29Incontrast,1,5-HATover1,6-HATselectivitystemsfromalowerentropicbarrier(DDS:8.3eu,2.5kcal/mol)intheO�pathway.30Asaconsequence, therateof1,5-HATisat least10x faster (2.7 × 107 s-1) vs the 1,4 or 1,6 variants.31 Rareexceptions17tothisrulearecaseswhereC-5lacksanHatom,orwhenadjacentC-Hbondsaresignificantlyweaker(e.g.benzylic,tertiary, α-oxy), or when geometry precludes 1,5-HAT.Otherwise, selective 1,5-HAT of an initiating radical typicallyoffersaccesstoaδcarbonradical,exclusively.

(4)Radical trap.Last, but certainly not least, the overalltransformation – and the specific identity of the group that isincorporatedviaC-Hfunctionalization–reliesonthetrapthatisused. In this regard, radical-mediated processes offer a widearray of synthetic complementarity to other metal-mediatedapproaches.Forexample,unlikethestrongrelianceofthelatteronarylhalideororganometalliccouplingpartners,radicaltrapscanrangefromcagedradicals(X�,NO�,ON�)toweaklybondedmain groupmolecules (N-X, Si-X, Sn-H, Sn-allyl) tometal salts(CuX, CuSCN, CuN3) to π-systems (alkenes, arenes). Thisdiversityofmethodssuitable for terminatingHATmechanismsallowsforthewidestscopeofreactivitythatisavailableforC-Hfunctionalizationviaanysingleapproach.

Thefollowingisaselectedcollection,showcasingtherangeof intramolecular HAT-mediated reactions, classified by theidentityoftheradicalthatinitiatesH-atomtransfer(e.g.N,O,C).

2Nitrogen-centeredradicals

In the field of intramolecular HAT chemistry, N-centeredradicals enjoy a prominent role.18 Historically, these radicals

XH

R

ZXH

R

HX

R

HXH

Rradicalinitiation

regioselectiveHAT

X

R

H

radicaltrap

431 2Y

radicalprecursor

4

3

1

2

radical precursors

radical initiation regioselective HAT

radical trap

N•

NX

HNX, H

EWG

X = Cl, Br, I • EWG = Ts, NO2, CN, PO(OR)2 • Z = C, N, OZ

NX

Z

NRO

N3 N3

O• C•

NR2O

X, HO

OHO

MO

O *

X = Cl, Br, I • M = Pb, Ce

X

H2C

XHC

O

OH I, N2+

C

X = Br, I

Sn•

RO•

Fe, Cu

Ni, Pd

photocatalyst

(Ru, Ir, Rh, organic) 1,5-HATfavored T.S.

C•H•

X•X•C•

H•X•

C•

H•

1,4-HAT 1,6-HAT

R3Sn

R3Sn H/D CuXCuSCNCuN3FePh•O-NR2

R2N X

X SiR3

EWG

CO O2Ph

( )n

− X•

( )n

or + H•

( )n

H

( )n

intramolecular:

D

hν

•X

•NO

ΔΔH: 6.6 kcal/molX = C

ΔΔS: 2.5 kcal/molX = O

entropic barrierenthalpic barrier



were the first used to initiate remote H-atom transfer.Additionally, they are the most tunable (via N-substitution),enabling finemodulationof theirpolarity,32which isknowntohighly influenceHATreactivity.And thanks to theirversatility,N-centered radicals arenowaccessiblevia thewidest rangeofmild,radical-initiationmethods.33,34

2.1sp3Nradicalinitiation

The earliest example of selective C-H functionalization viaHATwasreportedbyHofmanninthelate1800’s(Scheme2).35ThisN-centered radical reaction, nowknown as theHofmann-Löffler-Freytag(HLF)reaction,arisesfromphotolytichomolysisof a cationic N-haloamine.36,37 The resulting aminium radicalcation is sufficiently polarized32 to enable the abstraction of ahydrogenatomfromthedcarbon,producinganewC-centeredradical. Theselectivityof this1,5-HAT isgovernedbyachair-liketransitionstate.TheensuingdC-radical isthentrappedbyrecombinationwithacagedX� (orN-X) togenerateadhalide,which is then displaced via base-induced, intramolecularcyclization. This strategy for accessing pyrrolidines directlyfrom amines viad C-H amination has enabled the streamlinedsynthesisofseveralnaturalproductsandtheirderivatives.Forinstance, Löffler and Freytag employed this reaction in thesynthesis of nicotine from the corresponding N-halo amine,38and later, Corey and Hertler employed this approach in thesynthesis of a series of cyclo-aminated steroid derivatives.39BaldwinandDollextendedthismethodtotheuseofamidesinthe total synthesis of gelsemincine.40 Overall, theHLF reactionhas played a vital role in demonstrating HAT as a robust andselectiveradical-mediatedC-Hfunctionalizationmethod.

Scheme2dC-HAminationviaN-centeredradicalsbyN-Xhomolysis

Hofmann’sseminalreportinspiredcontinueddevelopmentof intramolecular HAT strategies for selective C-H function-alization, especially via N-centered radicals. In the originalreports of the HLF reaction, the use of strong acid and hightemperatureswererequiredtogeneratethepolarizedN-radical,therebyprohibiting theuseofacid-sensitive functionalgroups.Additionally, the need forN-X pre-formation limited the scopeand efficiency of this method. In 1985, nearly a century later,

Suárezandco-workers circumvented theneed topre-form theN-haloamine by generating N-I in situ (Scheme 3).41 Byemployingmolecular iodine and a hypervalent iodine oxidant,PhI(OAc)2,N-IisgeneratedfromtransientlyformedAcO-I,42andtheensuingweakN-Ibondishomolyzedbylighttogeneratetheanalogouselectrophilicnitrogen-centeredradical.Furthermore,theneedforstronglyacidicmediaiscircumventedbytheuseofelectron-deficient protecting groups (e.g. NO2, CN) to polarizetheN-radical.ThroughthismodifiedHLFreactionmechanism,aseries of pyrrolidines were generated, including steroidderivatives. Suárez and co-workers applied these milderreactionconditionstothesynthesisofbicycliclactamsviatrans-annularC-Hlactamization,43aswellastothedC-Haminationofcarbohydratesattheanomericcarbon.44,45

Scheme3dC-HAminationviainsituN-Iformationandhomolysis

In 2015, the groups of Herrera46 and Muñiz47 separatelyexploredfurthermodificationsof theHLFreaction(Scheme4).WhereastheSuárezHLFreactionefficientlyaminatesweakC-Hbonds (benzylic, tertiary, α-oxy), Herrera and co-workersinvestigated1,5-HATfromprimaryC-Hbonds.Thechallengeofthis transformation arises from the high BDE of primary C-Hbonds(>100kcalvs90kcal,benzylic).48Theirsolutioninvolvesadding PhI(OAc)2 oxidant to the reaction portion-wise toprevent over-oxidized side-products, in favor of desiredreactivity. Alternatively, divergent reactivity to access lactamswas accomplished using slow addition of I2, providing a widescopeof2-pyrrolidinonesinstead.

Scheme4ModernimprovementstoSuarez’sdC-Hamination

Inthesameyear,MartínezandMuñizreportedacatalyticvariantoftheSuárezreaction,using10mol%ofI2andatailored

Hofmann-Löffler-Freytag Reaction

NH2

R

HNH2

R

H

N

R

HN

R

NH2

R

Cl

Cl

1,5-HAT- HCl

H

Löffler & Freytag, 1909 Corey, 1958

homolysis

radical trap

Cl

hν or Δ;base

H

H H H

N

NMe

nicotine

Me2N

Me

N MeH

Baldwin, 1979Me

NAc

OO

NCS ortBuOCl

HN R

δ C-H amination

Me

H H

dihydroconessine gelsemincinecore

H

N

Suárez, 1985

R1 = NO2, CN, P(O)(OEt)2

C8H17

NR

Me

ON

(PhO)2(O)P

Me

OMeOMeMeO

Suárez, 2002

I2, hνPhI(OAc)2 - HI N

R1

R2

δ C-H amination

NH

R2

H

R1

O

R = NO2

Suárez, 1989

1,5-HAT

NH

R2

I

R1

N

R2

H

R1

I

Suárez Modification

transannularC-H amination

NH

R

I

TsI2, hνPhI(OAc)2 - HI N

Ts

δ C-H amination

NH

R

H

Ts

1,5-HAT

Herrera, 2015: primary C-H Muñiz, 2015: benzylic, tertiary C-H

NTs

MeNTs

MeNTs Me

Ph

NTs

I2, PhI(OAc)2 (slow addition) catalytic: 10% I2, PhI(mCBA)2

R R

R

R

R = H, aryl

O

slow I2slow PhI(OAc)2



hypervalentiodineoxidant.47Thisrepresentsthefirst,catalyticHLFreaction.ItsutilityisbestforweakerbenzylicandtertiaryC-H bonds. In 2017, the labs of Muñiz and Reiher reported adual-catalyticmethod ford C-Hamination inwhichanorganicphotoredoxcatalystallowsforcatalyticre-oxidationoftheI−tothe I2 co-catalyst. In this pathway, air serves as the terminaloxidanttoreformI2fromtheHIbyproduct.49

Although many HLF modifications are iodine-mediated,excessI2cangenerateundesiredoxidizedside-products,leadingto poor product formation in cases such as the amination ofsecondaryC-Hbonds.Ourgrouprecentlyintroducedasolutionto this challenge that circumvents the build-up of excess I2 bygenerating it in situvia slowoxidation ofNaI (Scheme5).50 Inthis approach, triiodide (I3−) is generated in equilibrium uponcombination of I2 and NaI, whereby I− scavenges I2 and limitsside-productsderivedfromI2oxidation.Thistriiodide-mediatedapproach is the first toenabledC-HaminationofamineswithsecondaryC-Hbonds, and serves to complementmethods thatarebettersuited forstrongerC-Hbonds.Notably, thisreactionis selective ford secondaryC-H functionalization–even in thepresenceofweaker tertiaryC-Hbonds–andprovidesabroadscope of substituted pyrrolidines from these ubiquitousprecursors. Interestingly, the use of NaCl or NaBr facilitatesinterception of two key intermediates in the proposedmechanism:theN-Clamine,aswellastheδ-Bramine.

Scheme5TriiodidestrategyfordC-Haminationofmethylenes

Azides have been implemented as an alternative to halo-amines as precursors to N-centered radicals, enabling similarreactivity (Scheme 6). Kim et al generated N-radicals bycombinationofalkylazidesandBu3Sn�,followedbylossofN2.51Theresultant,Sn-stabilizedN-radicaleffectivelyperformsa1,5-HATtoyieldtheδC-radical,which is thentrappedbyBu3Sn-Daffordingselectived-deuteration.Inlateryears,metal-catalyzedvariants were also developed for conversion of azides tonitrenoids. Zhang and co-workers first employed this strategyusing a Co(II)metalloporphyrin catalyst.52Mechanistic studiessuggest the reaction proceeds through H-atom abstraction.53Similarly, the Betley group reported a nitrene-mediated C-Hamination of both activated and unactivated C-H bonds d toazides, using high-spin Fe(II) catalysts.54 The mechanism wasproposedtooccureitherviaintramolecularHATfromtheimidoradical,orviaaclosed-shellC-Hinsertionpathway.

Scheme6dC-HAminationviaazide-derivedN-radicalsandnitrenes

InadditiontoselectiveC-Haminations,N-centeredradicalshave also been employed to generate other functional groupsfrom inert, distal C-H bonds. For example, intercepting the δ-halointermediateoftheHLFmechanismhasbeendevelopedasan importantmethod for installing a versatile halide group atthe δ position via remote C-H functionalization (Scheme 7).Nikishin and co-workers reported the first d chlorination in1985usingstoichiometricCuCl2andsodiumpersulfate.55Morerecently, S. Yu and co-workers reported a modern variant toaccessd chlorination using photoredox catalysis from the pre-formed N-Cl amine.56 While the I2-mediated HLF reactiontypicallyresultsinrapidcyclizationoftheδiodide,earlyreportsbySuárezincludedtheobservationofasmallamountofδiodideremaining,aswellastraceδdi-iodidebyproduct.43Togoandco-workers demonstrated that these multi-iodination productscouldbeharnessedinthesynthesisofsaccharidesviaatripleC-Hiodinationofo-tosylamidesatthebenzylicposition, followedbyring-closureandhydrolysis.57

Scheme7dC-HHalogenationviahalideradicaltraps

Nagib, 2016: secondary C-H

R = alkyl

NaI, hνPhI(OAc)2 N

Ts

R

δ C-H amination

NH

R

H

Ts

NTs

F3C MeN

Me

MeMe

NTs

Me

TBSO

I2 + I I3

2° over 3° C-H selectivity

xs I

Ts

I2 scavenged as I3-

NH

R

Br

Ts

via NaBr

SN3

BnN

Kim, 1997N3

R1

H

R1 = H, Me

NH

R1

D1,5-HATN

R1

H

SnBu3

Co catalyst

OO

NR2S

HN

BnN

OO

N

N3

R

HFe

catalyst NBoc

Betley, 2013

Zhang, 2010

N

R1

H

M

N

R1

HM

O

N3

R1

H

- N2

H

δ C-H deuteration

Bu3SnDAIBN, Δ

H

C-H insertion HAT

HAT or C-H

insertionvia nitrene

RR = H, alkyl

then Boc2O

N

R2

HO NH

R2

F

tBuO

Cook, 2016NH

F

tBuO

Ph10% Fe(OTf)2

no benzylicfluorination

NH

R2

X

R1

δ C-H halogenation

NH

R2

Cu

R1

Cl

N

R2

HR1

Br

N

R2

HR1

Cl

NHR1

I

Ir cat, hv, via N-Cl

I2, PhI(OAc)2I

AcOBr, PhI(OAc)2Br

ClCuCl2, Na2S2O8

Nikishin, 1985

Corey, 2006

S. Yu, 2015

Suárez, 1989S

N

I I

Me

OO

SN Me

OO

OH2O

Togo, 1999

NH

R2

H

R1

1,5-HAT

X conditions

tBu

R2

NHR2

selective1,5-HAT

F



SelectiveC-HbrominationwasobtainedbyCoreyand co-workersusinginsitugenerationofatrifluoroacetamideN-Brviadirect amide combinationwith acetyl hypobromite (AcO-Br).58Underthesereactionconditions,HLFaminationdoesnotoccurontheδbromide.Recently,J.-Q.Yuandco-workersintroducedaCu-catalyzedapproachtothedbrominationusingMe3Si-N3andNBS to generate transient amidyl radicals and and intercepttheird-Cradicals.59Completingthehalogenseries,Cookandco-workers reported the first d C-H fluorination, enabled by Fe-catalyzed transposition of an N-F to a benzylic C-F withcompleteselectivity,derivedfrom1,5-HATofanamidylradical,eveninthepresenceofotherbenzylicC-Hbonds.60

In2008,Baranandco-workersdevelopedanHAT-basedC-H halogenation strategy to access 1,3-diols from N-bromocarbamates (Scheme 8).61 Following photo-initiated homolysisofN-Br, 1,6-HAToccurs alongwithBr� trapping, affording thealkyl bromide. Although the HLF reaction typically undergoes1,5-HAT, this carbamate tether promotes a seven-membered,cyclic transition state, affording the g halide. The caveat is H�abstractionmust be from a benzylic or tertiary C-Hbond. Theresultingalkylbromide is thendisplaced,generatingan imino-carbamate.This intermediate ishydrolyzed tounmask the1,3-diol,providingaccesstoasyntheticallyvaluablemotifinaone-pot synthesis from the N-bromo carbamate. Notably, thisstrategyenabledthetotalsynthesisofseveralnaturalproducts,including rengyol and isorengyol. In 2017, Roizen and co-workersreportedN-chlorosulfamatesfacilitatehighlyselectiveg halogenation of secondary C-H bonds.62 This photo-initiatedchlorinationremainsg-selectiveeveninthepresenceofweakerC-Hbonds that are tertiaryorα toheteroatoms. It is expectedthis robust g-selectivity – dictated by sulfamate geometry – isextendabletoothergC-Hfunctionalizations.

Scheme8gC-HHalogenationofalcoholsviaN-Xhomolysis

Recently,J.-Q.Yuandco-workersutilizedamidylradicalstosimultaneouslyfunctionalizebothganddC-Hbondsinasinglecascade reaction to generate iodolactams from alkyl amides(Scheme9).63ThistransformationbeginswithinsituconversionofanamidetoitscorrespondingN-IintermediatebytreatmentwithNIS.Following1,5-HAT, iodination, and lactam formation,themechanismthenproceedsviaanazidoradical-mediatedβ-scissionoftheC-Ntoformaterminalolefin.Subsequent5-exo-trig cyclizationand I� trappingyields thed-iodo-g-lactam.Thisselectivedual-functionalizationmethodconvertstworemoteC-Hbondsintovicinalfunctionalitiesinasinglestep.

Scheme9g,d-amino-iodinationofamidesviaamination/scissioncascade

The common feature in all of the previously describedmechanismsistheSETreductionorhomolysisofaweakN-Xtogenerate an N� intermediate. Even themodern Suárez variantemploys insituN-Xformation.Inallthesecases,theremustbeanX�orweakN-Xpresent;and thesearegreat traps for theδradical.Thus,whilethereareseveralmethodsofaccessingδC-Hfunctionalization with halides and heteroatoms, there is nopossibilityforaccessingC-Cformationviathismechanism.

Scheme10Photoredox-catalyzedgordC-Halkylationviaamidylradicals

In 2016, the labs of Knowles64 andRovis65 independentlyreported methods to construct distal C-C bonds via amidylradicals and circumvented the need for pre-installation, or insitu generation, of an N-X bond (Scheme 10). Thismechanismproceedsviaaneutralamidyl radical,which isgenerated fromoxidativeproton-coupledelectrontransfer(PCET)byanexcitediridium photocatalyst. As in the HLF reaction, the resultingamidylradicalundergoesa1,5-HATto formacarbon-centeredradical. However, instead of undergoing typical X� trapping(since there is no halogen), the C-radical is trapped via 1,4-addition into a Michael acceptor, producing a new C-C bond

Baran, 2008

O

R3

OH

R3

SN1;hydrolysis

O

N O

R3

N

O

BrR2 R2 R2

OHBr hν

R1 = CH2CF3H

R11,6-HAT

R1 H

1,3-diol

Roizen, 2017

OS

Et

O

NCl hν

H

R

1,6-HAT

O

γ selective C-H chlorination

OS

Et

O

NR

O

ClO

S

Et

O

NR

H

OH

OS

Et

O

NR

OH

J.-Q. Yu, 2015

N

Me

H1,5-HAT

Ar

homolysis

β-scission

selective γ & δ functionalization

N3

N

Ar

MeO

INH

H

ArO

Me

NIS, ΔMe3Si–N3 N

H

ArO

Me

I

ON

Ar

MeO

HN

ArO

I

δ C-Hamination

H

H

N

O

Ar

IN

O

IMe Ar

N

O

ArAcO

Me

I

N Ar

Et

O

I

Me

H

Me

NH

MeH

1,5-HAT

Knowles, 2016

Interrupted HLF via proton-coupled electron transfer (PCET)

radical trap

δ C-H alkylation

Rovis, 2016 (δ)Rovis, 2017 (γ)

Me

COR

electron transfer

EWG

N

MeH

Me

COR

NH

MeMe

RO

NH

RO

Me Me

EWG

NH

RO

Me Me

EWG

NHCOR

Me Me

EWG

H

[IrII] [IrIII]

proton transfer

BH

B

Me

Me

H

H

H H

MeR

O

CO2Bn

TBSO

MeMe

NH

O

ArO

Me

hνIrIII cat, base

- H•

NH(Bz)

NH(TFA)δ:

γ:



from a tertiary δ C-H bond. Reduction of the newly formed α-EWGC-radicalprovides a stabilizedanionand regenerates theIr(III) catalyst. Upon protonation of the anion, the remotefunctionalized product is isolated. This first, interrupted HLFreactionrepresentstheonlymethodforδC-HalkylationbyHATfromanN-radical.It’ssuccessstemsfromavoidingtheneedforhalogens(X2or insituN-X) togenerate theN-radical,andthusnon-halidebasedtrappingmechanismsmaynowbeaccessed.

In2017,Rovisandco-workersreportedarelatedmethod,whereinC-Halkylationoccursonthecarbonylsidechainoftheamide(ratherthantheN-substituent).66Sinceregioselectivityisagaindictatedbya1,5-HATmechanismfromanamidyradical,C–Halkylationisγselectiveinthiscase.

2.2sp2Nradicalinitiation

Animinyl(sp2)N-centeredradicalexhibitscomplementaryreactivitytoaminyl(sp3)N-radicals.ExtensivekineticstudiesbyNewcomb and co-workers67 have shown that iminyl radicalsundergo faster addition to olefins and slower reduction by anintermolecularH-atomrelative toneutral aminyl radicals.Thisdistinct kinetic profile of the N(sp2)-centered radical allowsaccess to different synthetic avenues. While pioneering workfromForrester68,Zard69,Narasaka70,andWeinreb71haveshownthe syntheticutilityof iminyl radicalsby their addition intoπ-systems,therearefewreportsonN(sp2)radical-basedHAT.Theharshconditionstypicallyemployedtogenerateiminylradicals(strongoxidants,elevatedtemperatures)have likely limitedanextensiveexplorationofthisreactivity.

Scheme11gC-HFunctionalizationviaiminylN(sp2)radicals

An initial report by Forrester et al in 1979 demonstratediminyl radicals are capable of performing 1,5-HAT to form aradicalδtoN–andγtoanimine(Scheme11).72Theseradicalsweregeneratedbydecompositionofoximesbearingapendant

acid.73 Upon Cu-catalyzed, persulfate-mediated 1e− oxidation,andsubsequentlossofCO2andCO,theiminylradicalengagesinseveralreactivepathways,includingHAT.Theresultingbenzylicradical is oxidized under these conditions and trapped by theimine via intramolecular cyclization. Various tetralonederivativesweresynthesizedvia thisnew iminyl-radicalbasedapproach,includingpyridylanalogs.74,75

In 2011, Chiba and co-workers reported a Cu-catalyzedbenzylic oxygenation via iminyl radicals.76 The radicalprecursors were generated by in situ Grignard addition intonitriles to formaryl imines.Next,directCu-catalyzedoxidationunderO2atmospherefacilitated1,5-HAToftheiminylradicaltoformabenzylicradical,whichissubsequentlytrappedbyO2toprovidea1,4-keto-imine,whichuponhydrolysisaffordsthedi-ketoproduct.

In 2017, Shu and Nevado reported a mild, photoredoxcatalyzedmethodtoaccessandharnessiminylradicals(Scheme11).77Employingacyloximesasradicalprecursors,itwasfoundthat Ir photocatalysts could reduce theweak N-O bond of theoximetogeneratean iminylradical.UponHAT, theδC-radicalcould either result in C–N or C–C formation, depending onreactionconditions.Intheformercase,anoxidationeventturnsover the photocatalyst and allows for C–H amination via ring-closureinthepresenceofDBU.Ontheotherhand,C–HarylationisobservedinaCH3CN/H2Omixturewhentheradicalfirstaddsintoanarenebeforeoxidationbythecatalyst.

H. Fu and colleagues78 have similarly employed an oximefor photoinduced iminyl radical formation.79 However, bydesigningamoreeasilyreduced(2,4-dinitrophenyl)nucleofuge,itwasfoundthatametalcatalystisnotneeded.Instead,tertiaryamines are able to form an excited state complex with thedinitrophenyl group to promote photo-induced fragmentation.Intheirsystem,theresultantiminylradicalundergoes1,5-HATtogenerateanα-aminoradical.Oxidationofthisspeciesaffordstransientformationofaniminium,whichisthentrappedbythependant imine. An additional oxidation under the reactionconditionsprovidestheheterocyclicproduct.

Typically,N(sp2)radicalprecursorsaregeneratedbyeithercondensationofhydroxylamineontoaketone,oracylationofanoxime.However,Nevado’slabrecentlyemployedasyntheticallydistinctroutetogenerateaniminylradical(Scheme12)80–viaSuzuki’s method of C� addition into vinyl azides.81 Upondecarboxylativeradicalformationandadditionintovinylazide,the intermediary α-azido radical rapidly expels N2 to form animinylradicalthatpromotesHATandsubsequentγ-arylation.

Scheme12C-HArylationviavinylazide-derivedN(sp2)radicals

N

O

MeMe

Forrester, 1979

Ph

NOR

R = CH2CO2H

Me

Ph

NH

Forrester, 1981

Chiba, 2011

Ar

OPh O

hν • heteroarene trap

Cu cat • O2 trap

Nevado, 2017

C-H arylation

OMe

Me

NPh

C-H amination

Ph

NH

N

Ph

γ C-H amination

Ir catalyst

H. Fu, 2017N

PhN

via 1,5-HAT, [O],then iminium trap

1,5-HAT

N

PhNN

ONO2

NO2

Ph

R

NO

Ph

R

O

CF3

Cu catNa2S2O8

- CO- CO2

- e-Cu-catalyzedamination

no catalyst [O]

- H•

hν

hν

Ph

N3

Nevado, 2017

Me

CO2H

Me

- H•- CO2

– N2

N3

PhMe

N

PhMe

HNH

PhMe

OMe

H

Ag catK2S2O8

1,5-HAT



In 2012, Chiba’s lab reported the first use of an amidinylradicalinHAT(Scheme13).82Theseamidineradicalprecursorsare readily derived from amines, and can be oxidized directlyusing a Cu catalyst and O2 as the oxidant. Upon HAT fromtertiaryorbenzylicC-Hbonds,theresultingradical(δtotheN,orβtotheamidine)canbetrappedindivergentwaystoaccesseither β-oxygenation or β-amination. In the former case, O2serves as the trap, and an ensuing Cu-mediated fragmentationand cyclization affords oxazolines via β-oxygenation. Shortlyafter, Chiba and co-workers reported N-Ph amidines areconvertedtoimidazolinesviaanalternateβ-aminationpathwaythat employs PhI(OAc)2 as the oxidant instead of O2.83 ThispowerfulmethodofconvertinganaminetoavicinaldiamineviaβC-HaminationwasfurtherextendedbyChiba’sgroupin2014through thedevelopmentof a redox-neutral variant.84Theuseofamidoximes,ortheoximevariantofanamidine,asaradicalprecursorallowsforanoxidant-freeapproach. Inthiscase, theCuservesasaradicalinitiatorbyreducingtheweakN-Ooftheoxime,andtheoxidizedCulaterservesasatrapoftherelayedradical,wherein oxidation allows for redox turnover of the Cucatalystalongwithformationoftheimidazoline.

Scheme13βC-HFunctionalizationofaminesviaamidineradicals

Recently,ourgroupreportedacomplementarystrategytoconvert alcohols to β-amino alcohols by C-H amination via insitu generated imidate radicals (Scheme 14).85 To achieve thegoalofsimplifiedaccesstoanN(sp2)radical fromanabundantfunctional group (e.g. an alcohol), we envisioned imidates asradical precursors. They are easily prepared in situ via nitrilecondensationwithalcohols,86andtheirclosed-shellreactivityiswellunderstood(e.g.theOvermanrearrangement).87However,imidate radicals were previously only employed in π-additioncyclizations.88 Fortunately, under our triiodide-mediated δ C-Haminationconditions(i.e.NaI,PhI(OAc)2), itwasobservedthattheβC-Haminationofarangeofalcoholswaspossibleviathisimidate-basedstrategy.Inthemechanism,theimidateformsanN–Ibond insitu,which ishomolyticallycleavedbyvisible lighttogenerateanN(sp2)radical.Ensuing1,5-HATtranslocatestheradicaltotheβcarbon,whichissubsequentlytrappedbyI•anddisplaced intramolecularly to afford an oxazoline product.Notably, benzylic, allylic, secondary and even primary C-Hbondsareaminatedinthisapproach.Theidentityoftheimidate

enables the amination of these bonds of varying strength. Forexample, trichloroacetimidate promotes benzylic and allylicamination, quantitatively, while benzimidates enable C-Haminationofstronger,primaryandsecondaryC-Hbonds.Asanillustration of its synthetic utility, the oxazoline intermediatecanbehydrolyzed to a freeβ-aminoalcohol, or substitutedbynucleophilicadditiontoaccessafamilyofβamines.

Scheme14βC-HAminationofalcoholsviaimidateradicals

3Oxygen-centeredradicals

Another common initiator of intramolecular HAT is theoxygen-centeredradical.Themoreelectronegativeoxygenatom(χ=3.4,Ovs3.0,Nor2.5,C)providesagreaterdrivingforceforHATduetothefollowingtwo,relatedfactors:(1)anopen-shellis highly disfavored for this atom, whose electronegativity issecondonlytofluorine,therebypromotingHAT;and(2)theO-HthatformsuponHATisratherstrong(BDE=110kcal,O-HvsN-H,C-H,<100kcal).Thanks to these favorabledriving forces,theremoteradicalsgeneratedviaHATfromO-centeredradicalshave become the most synthetically versatile, allowing forhalogen, heteroatom, and even alkyl trapping of theintermediate carbon radical. The challenge for thismechanismultimately lies in thegenerationofradicalsonsuchanelectro-negative atom. The three most common pathways (carbonylphoto-excitation, and alkoxy or non-alkoxy radical initiation)aredescribedbelow.

3.1Carbonyldiradicalinitiation

IntheearliestexampleofHATmediatedbyanO-centeredradical,Norrish reported thephoto-initiatedgenerationof1,4-diradicals from alkyl or aryl ketones bearing γ C-H bonds(Scheme 15).89 Upon photo-excitation of the ketone, themorereactiveO-radicalundergoes1,5-HATtogeneratea1,4-diradicalintermediate – with both C-radicals remaining. Depending onthenatureof thephoto-excited state, thediradical specieswilltheneitherrecombinetoyieldcyclobutanol(viatripletstate,T1)or fragment via β-scission to form an enol and alkene (viasingletstate,S1).90

Chiba, 2012NH

N

R1H

R3

R2

β C-H oxygenation

N

OR1

R3

R2

NH

N

R1O

R3

R2

O

O2 as oxidant & trap

N

N

R1H

R3

R2

NH

N

R1

R3

R2

1,5-HAT

R = H

R = Ph

β C-H amination

N

NR1

R3

R2

Chiba, 2013

N

N

PhH

PhMe

OAc

Chiba, 2014 Cu catalystredox-neutral

Cu catPhI(OAc)2

N

NPh

MePh

R

RPh

R

HCu

catalystΔ

oxidant

N

OPhPh

Ph N

NPh

Ph

imidazoline viaβ amination

oxazoline viaβ oxygenationBnBn

Ph

Cucat

Nagib, 2017

NH

OR

1,5-HAT

RHO

RO

NHR1

RO

NR1 R1H

- HI NO

R

R1

NH2

RHO

RNu

HN

β amines

Nu = I, Br, Cl,

H, N3, SR

in situ N-I; hν

I

β C-H amination

NaIPhI(OAc)2

hν

R = H, alkyl, aryl

R1

O

Me

HMe

H

H

H

Me

HOHN

>20:1 drCCl3

O

HN

HO

Ph

O

>20:1 dr

Me

Me

- RCO2H

+ R1CN

+ Nu



Scheme15NorrishphotochemicalstrategyforC-Hfunctionalization

Taking advantage of thismode of carbonyl reactivity in alandmarkdiscovery,Breslowandco-workersachievedselectiveabstraction of the C14 hydrogen atomwithin a steroid via thediradical of a benzophenone carbonyl, which was tethered tothe C3 alcohol via esterification.91 In this case, a subsequent,oxidative HAT adjacent to the resulting C-radical furnishes aremote olefin. More recently, in the synthesis of ouabagenin,Baran and co-workers utilized the C-C bond-forming, Norrishreaction to construct the key C19 oxidation en route to thenaturalproductfromanacyclic,β-methylketoneprecursor.92

3.2Alkoxyradicalinitiation

Since alcohols are one of themost common and versatilefunctional groups in synthesis, the formation of O-centeredradicalsfromalcoholshasenabledthedevelopmentofafamilyof important C-H functionalizationmethods. The first exampleofHAT from an alcohol-derived alkoxy radicalwas discoveredby Sir Derek Barton in 1960, and was eventually recognizedwith aNobelPrize in1969 (Scheme16).93–95Barton’s solutionfor generating the reactive O-radical was to first synthesize aprecursor containing a weak N-O bond. This nitrite can beconveniently prepared via combination of an alcohol withnitrosyl chloride in dry pyridine. Photolytic homolysis formsboth�NOandanalkoxyradical.Upon1,5-HAT,theδC-radicalofthealcoholrecombineswiththe�NOtoformaδ-nitrosoalcohol,which tautomerizes to form the δ-aminated oxime product.Bartonandco-workersdemonstratedthesyntheticutilityofthisnew C-H functionalization reaction within a variety of steroidcores,includingaldosterone.96Therehavebeenmanyimportantapplications of this method for the remote C-H amination ofhydrocarboncores,suchasCoreyandco-workers’synthesisofhistrionicotoxin.97 As an added example of the broad utility ofthisstrategyfortheincorporationoffunctionalityatremoteC-Hbonds,theδ-aminationofMe10-carboranewasaccomplishedbyHawthorneandco-workers.98

Scheme16TheBartonReaction:dC-HaminationviaO-centeredradicals

Within a year of Barton’s discovery of an O-centeredradicalsyntheticroutevianitritehomolysis,thelabsofSmith99andWalling100 developed alternate pathways to access alkoxyradical-mediatedHATviahomolysisofO-Xbonds(Scheme17).InanalogytotheN-ClprecursoroftheHLFreaction,theO-Clofhypochloriteprecursorsarereadilyhomolyzedbyphotolysistogivealkoxyradicals.UponHAT,theδC-radicalrecombineswiththe�Cltoformaδ-chloroalcohol,whichisreadilycyclizedwithbasetoformtetrahydrofurans.101

Scheme17dC-HHalogenationviametal-mediatedO-Xcleavage

Inthefollowingdecades,atourdeforceofapplicationsofthis approach was developed by Čeković and co-workers.16Amongthem,theuseofhydroperoxidesenablestheisolationofthese relativelymore stable, radical precursors. Iron-mediatedcleavage of the peroxide O-O bond affords the δ C-radicalintermediate, which can be trapped by cupric salts in rapid,radical-combination mechanisms reminiscent of thosepioneered by Kochi.102,103 For example, the use of Cu(OAc)2facilitates the subsequent, single-electron transfer (SET)oxidation and elimination to form the δ-unsaturatedalcohol.104,105 Alternatively, when other copper salts (CuX2,whereX=SCN,N3,Cl,Br,I)areemployed,substitutionoftheδCwiththeXligandofCuX2isachieved,offeringaccesstoarangeof δ-functionalized alcohols.106Amodernvariant of this familyof Čeković reactions includes the catalytic version reportedby

Norrish Type II, 1934

1,5-HAT

Baran, 2013

R1

R

OH R1

R

OH R1

R

OR1H

hν

R1

ROHcyclization

β-scission

R

OR1H

R

O

Me

Me

H HH

O

O

O

OH

ouabagenin intermediatevia Norrish cyclization

T1

S1

Me RMe

O

O

OHH

Breslow, 1973

unsaturation via 1,16-HAT

The Barton Reaction

O

R

HOH

R

H

O

R

HOH

R

OH

R

N

NO

1,5-HAT

Barton, 1960 Corey, 1975

homolysis

radical trap

NO

hν

aldosterone

Hawthorne, 1998

NOCl

pyridine

histrionicotoxin Me10 carborane

δ C-H aminationR

O

NOHHO

MeHO

O

NHO

O

OAcBu

HON OH

OH

NOH

H H

H

Smith; Walling, 1961

X = Cl, Br, OH

hν + X•

δ C-H halogenation

O

R

HX

Čeković, 1974

OH

R

XO

R

H

1,5-HAT

Čeković, 1982 Ball, 2010

Taniguchi, 2014

OH

R

OH

RSET oxidationvia Cu(OAc)2

CuX2OH

R

X

X = SCN, N3,Cl, Br, I

X = OH

OH

R

Cl

10% L•CuCl+ NH4Cl

OH

O [Fe]10% Fe(Pc)

O2, NaBH4

OHOHO-O homolysis;

1,5-HAT;

O2, NaBH4

[Fe]



Ballandco-workersin2010.107Inthisprotocol,theconversionofhydroperoxidestoδ-chloroalcoholsisachievedviatheuseofa sub-stoichiometric amountof aCu catalyst for the first time,also in the presence of a terminal chloride source, NH4Cl, inexcess. The use of a tridentate amine ligand appears vital forpromoting catalytic peroxide reduction, likely due to themorereducingnatureofthisATRPcatalyst.

Taniguchiandco-workershaverecentlydisclosedanotherinteresting peroxide-based HAT, which is promoted by a sub-stoichiometric ironphthalocyanine catalyst.108 In their cascademechanism, alkenes are converted to hydroperoxides bycombination of Fe(Pc), O2 and NaBH4. The ensuing O-Oreduction is mediated by the Fe catalyst, whose turnover isagainmediatedbyO2andNaBH4,resultinginformationofa1,4-diolfromtheparentalkene.

Scheme18dC-HOxygenationofalcoholsviainsituO-Xformation

In 1962, on the heels of Barton, Smith, and Walling’sdiscoveries of HAT reactionsmediated by O-centered radicals,Kalvodaandco-workersreportedthefirstexampleofthedirectgeneration of an alkoxy radical from an alcohol.109 The key tothissolution is insitu formationofanO-Xbondbythereagentcombination of Pb(OAc)4 and I2. A hypoiodite, AcO-I, is likelyformed, which can combine with the alcohol to generate theweak O-I bond of the alcohol hypoiodite.42 Upon homolysis,HAT,andhalideradicaltrap,theδ-iodoalcoholisformedinsitu,whichreadilycyclizestoformtheδ-oxygenatedtetrahydrofuranproduct.Kalvodaandco-workersemployedthisapproachtothesynthesisof thepregnanesteroids. In1998,Ryudemonstratedtheδ-carbonradicalcouldbe interceptedbyCOtoprovide thecarbonylated radical, which is oxidatively combined with thealcohol to provide a cyclic ester.110 This approach offers avaluable synthetic approach to access lactones directly fromalcoholsviaδC-Hoxygenation.111

In 1969, Trahanovsky and co-workers demonstrated thatceric ammonium nitrate (CAN) could also be employed as analternativetothePb-basedpathway.112Theintermediateradicalmay be trapped by the single-electron, Ce oxidant via eitherinner or outer sphere SET oxidation. Notably, in 1984, Suárezand co-workersmade perhaps themost significant advance inthis area by employing hypervalent iodine, PhI(OAc)2, togeneratethealkoxyradical,inlieuofaPborCeoxidant.113Thislead-freealternativeoffersacomplementarypathwaytoaccess

the weak O-I bond of the alcohol hypoiodite, and the ensuingetherification cascade pathway. Suárez and co-workersdemonstrated the broadutility of thismild, photolyticmethodin the synthesis of a range of δ-oxygenated steroid andcarbohydrateanalogs.44,114

Scheme19dC-HAlkylationviaO-SPhorO-NPhthcleavage

InadditiontohomolysisofO-XandO-Obonds,O-centeredradicalsmaybeaccessedviascissionofweakO-SorO-Nbonds.Forexample, in1997,ČekovićreportedthattheO-SPhbondofbenzenesulfenates is cleaved by photolytic generation of athiophilic tin radical (Scheme 19).115–117 In this alternateapproachto the typicalhomolysispathway, thealkoxyradicalsthat are formed no longer have a radical counterpart and areavailable to interact with a range of traps following 1,5-HAT.Notably,theseδ-carbonradicalscombinerapidlywithelectron-deficientolefins (kadd=3x105M-1s-1), even in thepresenceofSn-H, which provides the terminal H-atom for this alkylationcascade. This strategy for multi-component δ C-H alkylation,pioneeredbyČekovićandco-workers,hasbeentheonlyknownapproach for HAT-mediated δ C-C bond formation, until therecentPCET-basedmethodforN-centeredradicals.64,65

As a bench-stable, isolable alternative to sulfenates, Kimandco-workersintroducedN-alkoxy-phthalimides,whoseweakO-NbondcanalsobecleavedbySnradicals.118Inthiscase,Sn�combines with the imide carbonyl to form a captodativelystabilized C-radical, whose β-scission forms an alkoxy radical.When Sn-D is employed, δ-deuteration is observed, indicatingthe presence of an alkoxy-radical-mediated HAT mechanism.Sammis and co-workers employed theseN-alkoxy-phthalimideprecursors to enable intramolecular trapping of electronicallyneutral alkenes.119,120 Recently, a Sn-free alternative has beendeveloped via the use of photoredox catalysis. In this case, aphoto-excited Ir catalyst serves as a SET reductant capable ofreducingtheN-Obondgeneratingaspectatorphthalimideanionalong with the alkoxy radical. In 2016, Chen and co-workerswereabletotraptheδradicalwithallylsulfonestoenableδC-H

Kalvoda, 1962

MeAcO

AcOH

Ryu, 1998

δ C-H oxygenation

O

R

Suárez, 2000

via Pb(OAc)4, I2

O RX

O

O

OnPr

+ CO (80 atm)via Pb(OAc)4

OO

Me

OMeOMeMeO

via PhI(OAc)2, I2

Kalvoda, 1962 Trahanovsky, 1969 Suárez, 1984

MX OH

R

HOH

R

H X

H H

H

Pb(OAc)4, I2(NH4)2Ce(NO3)6PhI(OAc)2, I2

Me

pregnanes carbonylation carbohydrates

X = NPhth, SPh

radical initiation

Bu3SnH

or hν + H•δ C-H alkylation

O

R

HX OH

R

O

R

H

1,5-HAT

Kim, 1998Čeković, 1997

N

O

OR

O

via Sn• orIr photocatalyst

OH

X = SPh

CO2EtMe

Me

via Bu3SnH+ acrylate trap

EWG

OHD

OPh

X = NPhthvia Bu3SnD

Sammis, 2009

O

X = NPhthalkylationvia Bu3SnH

Chen, 2016

Me

X = NPhth

CO2Ar

allylationvia Ir cat, hν

Meggers, 2016

O

X = NPhth

COAr

asymmetric alkylationvia *L•Rh & Ir cats, hν

H

CO2Ar

HO HO HO Me *

Me

SO2PhO

Ar

Me

intramolecularalkene trap

EWG

H

H

92% ee



allylation.121 In the same year, Meggers and co-workersdemonstratedthattheIrphotoredoxcatalyzedSETreductionoftheN-Ocouldbecoupledwithasecondcatalyticcycle,whereina chiral Rh complex could exhibit stereocontrol over the δradicaladditionintoenones.122Indeed,thisalkylationisthefirstand only method for enabling asymmetric termination of aradicalresultingfromanintramolecularHAT.

3.3Non-alkoxyradicalinitiation

Alongsidealkoxyradicals, theO-centeredradicals thataresubstituted with adjacent heteroatoms (e.g. N-O�), are alsosyntheticallyuseful,sincethey(1)aretypicallyeasiertoaccessvia oxidation, and (2) afford distinct classes of products. Forexample, Chiba and co-workers have shown that both oximesandhydrazones,whichareeach readilyaccessibleby carbonylcondensation,areprone to facileoxidationwhenheated in thepresenceofTEMPO(Scheme20).123Theheteroatom-substitutedO�isstabilizedbyresonance,whichfacilitatesitsgenerationbymildoxidants,especiallycomparedtoalcohols,whicharenotaseasilyoxidized.Furthermore,theα-Ninfluencesthereactivityofthe O� mediated HAT, as well as the ensuing cyclization togeneratetheisoxazolineproduct.Withfurtherarylsubstitution,Chibaandco-workersfoundthatisoxazolesarealsoaccessible.In a mechanistically similar vein, Pierce and co-workers havedemonstrated that thiohydroxamic acids can be oxidized byDDQtoformanN-O�thateffectsHATandsubsequentoxidativecyclizationtoaccessoxathiazoles.124

Scheme20dC-HOxygenationviainsituoxime-derivedradicals

Ina complementarypathway toSETreductionof theN-Oin N-alkoxy-phthalimides, Kanai and co-workers have shownthatoxidativeconditionscanleavetheN-OintactandformanO-centeredradicalinstead(Scheme21).Whenthishydroxylamineradical is reversibly appended onto an alcohol, it can facilitate1,6-HAT due to conformational constraints of the directingactivatorgroup.In2016,theKanailabshowedthatCocatalystsunder aerobic conditions can initiate radical generation andterminate the ensuing radical to afford γ-ketones onhydroxylamine-radical-appended alcohols.125 In the same year,theKanailabalsoshowedthattheseradicalprecursorscaffoldscanbecombinedwith in situ generatedNOx species to formγ-nitratedalcohols.126

Scheme21dC-HOxygenationviainsituhydroxylamineradicals

A final class of O-centered radicals employed in HAT isgeneratedfromcarboxylates(Scheme22).Althoughit iseasiertoaccessO�fromacarboxylate(1.4Vvs>2Vforalcohol)127viaSEToxidationusingAg,Pb,orI,theoverridingchallengeofthisapproach is that decarboxylation is quite facile (c.f. Kolbe,Hunsdiecker reacions). In 1983, Nikishin and co-workersdiscoveredamethodofbypassingthismajorbyproduct-formingpathwaybyusingaCuCl/Na2S2O8oxidant.128TheensuingHAT,Cl�trap,andchloridediscplacementaffordsγ-lactonesviaγC-Hoxygenationofacids.Interestingly,aNaCl/Na2S2O8combinationisalsoeffective inpromotingthis transformation, thustheroleof the copper remains unclear.Most recently, DuBois and co-workershaveshownthatphenylbutyricacidderivativesbearinga benzylic γ C-H bond are also mediated by a Cu-catalyzedprocess.129 However, mechanistic experiments indicate that incontrast to non-benzyl carboxylates, intermolecular HAT of abenzylC-Hbysulfateradicalsismorelikelyinthiscase.

Scheme22dC-HLactonizationviainsitucarboxylateO-Hoxidation

4Carbon-centeredradicals

HATmediated by C-centered radicals aremore rare thantheir heteroatom counterparts. Unlike the N� and O� initiatedmechanisms,inwhichC-HisexchangedforastrongerN-HorO-Hbond,18 theC� pathway suffers from the challenge that boththe HAT precursor and product similarly contain a C-H bond.Therefore, a necessary driving force is required in thesetransformations, such as the exchange of an C(sp2)-centeredradicalforalowerenergyC(sp3)radicalviaHATofanalkylC-HtoformastrongerarylC-Hbond.Althoughbondstrengthisnotthe only determinant of HAT-based chemical reactivity (sinceHATreactionsareoftenirreversible,exothermicprocesseswithearly transition states),14 BDE of reactants often serve as ausefulguideforpredictingHATreactivity.

Chiba, 2013

TEMPO

1,5-HAT

-TEMPO-H

ΔTEMPO

δ C-H oxygenationPh

NXH

MeMe

X = OR, NR2

Ph

NO

MeMe Ph

N O MeMe

Ph

NOH

MeMe Ph

NOH

O

Me

NR2

MePh

NOH

Me

Me

Chiba, 2013

Ph

N O

Ph

PhPh

N

S

OPh

Ph

N

S

OH

Ph

Pierce, 2015

Ph

NOH

PhPh

DDQTEMPO

H H

γ C-Hoxidation

Kanai, 2016

via Co catalyst+ O2 (1 atm)

+ ROH

N OH

O

OMeF3C

N OH

O

OF3C R

1,6-HAT

O R

OH

=

OO

Kanai, 2016

via NaNO2, H+

+ O2 (1 atm)

O R

OH OONO

O R

OH ONO2

O R

OH O

1,5-HATR

- CO2

major pathwaywith most oxidants (e.g. Ag, Pb, I2)

Du Bois,2016

O

OO

+ CuCl

OH

R

O

Nikishin, 1983 NaClor CuCl2

Na2S2O8

OH

R

HO

δ C-H oxygenation

O ROOH

R

ClO



4.1sp2Cradicalinitiation

The translocation of C� sites by intramolecular HATbetweenC-HbondswasfirstreportedbyCurranetalin1988.130This pioneering work made use of the energy differencebetween C(sp2) and C(sp3) radicals to promote HAT from analkylC-H toavinyl radical (Scheme23). In theirearly reports,Curran et al demonstrated that vinyl bromides are capable ofserving as both radical precursor and intramolecular trap, toafford substituted cyclopentanes. In this mechanism, Bu3Sn-Halso plays a dual role in chain propagation, via vinyl radicalinitiation as well as alkyl radical termination.131 A recentsynthesisbyVellucciandBeaudryoftheaspidospermaalkaloid,goniomitine, via a vinyl-bromide initiated HAT cascade.132 AnexcellentreviewbyDénès,Beaufils,andRenauddescribesmajordevelopments in the synthesis of five-membered rings by thisapproachoftranslocationandcyclizationofvinylradicals.133

Scheme23dAlkylationviavinylbromide-derivedC(sp2)radicals

An important application of this mechanism is theincorporationofarylradicalprecursorsasprotectinggroupsonalcohols,aseitherbenzylorsilylethers.Anexampleofthelatterincludesuseofo-iodo-phenylsilyletherasaradicalprecursor,which enables selective 1,5-HAT from an α-oxy C-H (Scheme24).134,135 This stabilized radical was trapped by electrophilicolefins in an intramolecular fashion. Inspired by this radicaltranslocation reaction, Gevorgyan and co-workers recentlydevelopedamethod to introduceanolefin functionalityviaPdcatalysis.136 In thismechanism, radical initiation andpost-HATelimination are both mediated by Pd in a mechanism thatcombinesmetal-catalysisandintramolecularHAT.

Scheme24α-EtherC-HfunctionalizationviaHATfromarylradicals

Likealcohols,aminesarealsoreadilyconvertedtoradicalprecursors that can facilitate intramolecular HAT. The

collaboratinglabsofSnieckusandCurrandemonstratedthato-iodo-benzamides are suitable radical precursors that providestreamlinedaccesstoα-aminoradicalsviaHAT(Scheme25).137Upon tin-mediated abstraction of C(sp2)-I to form an arylradical,HATenablesdistalfunctionalizationsviabothintra-andinter-moleculartrappingoftheα-aminoradical.Applicationsofthisα-aminoC-Hfunctionalizationincludecyclization,allylation,anddeuteration.137–140Themechanismof formationof thearylradicalbyBu3Sn-Hhasbeenstudiedextensively.141

Scheme25C-HFunctionalizationofα-amidesviaHATfromarylradicals

Itoandco-workersdemonstratedamines(vsamides)alsoundergo HAT via an o-iodo-benzyl precursor (Scheme 26).142EmployingSmI2asaradicalinitiator,α-aminoC-Habstractionisfollowed by ketone trapping to afford α C-H alkylated amines.The postulated, penultimate intermediate is an α-amino Smspecies that readily combineswith carbonyls.143 Undheim andco-workers extended this radical translocation of aminesubstratestointermolecularα-aminoC-Halkylationwithalkenetraps,suchasacrylate.144,145Usinga2-Brindoleasaprecursor,Gribble et al employed a C2-indole radical to effect HAT.Ensuing α-amido radical addition back into the indole trapforms indolines.146 As a Sn-free alternative, Murphy and co-workers developed a strategy that employs dialkylphosphineoxide as a radical initiator for iodide abstraction of o-anilides.FollowingHAT, theα-acyl radical combineswith theanilide toformindoloneheterocyclesviaC-Harylation.147

Curran, 1988

R

1,5-HAT

H

Bu3SnHAIBNBr

R R

H

Rcyclization

R

H

R = OTBS, CO2Me, Ph

RMeO2C

MeO2C

H

H

Gevorgyan, 2016

Curran, 1988

SiO

EtEt

Pd

Me2SiO

H

R

IMe2Si

O R

H

Me2SiO R

Zradical

trap

OSi

Me Me

EtO2C

1,5-HAT

Bu3SnHAIBN

desaturation

SiO

EtEt

Sn (Ar-Br)intramolecular

alkene trap

I

H

(Z)

I

O NMe

Curran, 1990

O NMe

H

N

cyclization;

NO

OMeO

intermolecular acrylate trap

MeO( )3

intermolecular tin deuteride trap

N

intermolecularallyl tin trap

Curran, 1993

OMe

Me

OAc

N

OMe

Me

OAc

D

( )3

E E

1,5-HAT

Bu3SnHAIBN

H H

E

α-amide alkylations

Curran, 1990



Scheme26C-HAlkylationofα-aminesandα-amidesviaarylradicals

Modern adaptations of these aryl radical-mediated HATreactions employ metal catalysts to serve the dual roles ofradical initiationandtermination. In2010,Nakamurareportedan iron-catalyzed α-amino arylation reaction, in which arylGrignards are cross-coupledwith theα-amino radical (Scheme27).148 Similarly, Ni and Ir-catalyzed variants of this class ofreactions have been developed by the labs of Kalyani149 andXu,150 respectively. In these mechanistically, related reactions,pendant arenes serve as radical traps. AMg-mediated versionwasalsorecentlyreportedbytheZenggroup.151Here,either1e–reduction, or fluoride abstraction, generates the aryl radicalspecies,whicheffects1,5-HATtoyieldaMg-stabilizedα-amidoradicalthatistrappedbychlorosilanestoconstructC-Sibonds,expanding the radical translocation method beyond theintroductionofC-X,C-O,C-C,andC-Nbonds.

Scheme27Metal-catalyzedαC-Hfunctionalizationviaarylradicals

While aryl halides are most common, other substitutedarenescanalsobeemployedasradicalprecursors.Forexample,

aryl diazoniums, ArN2+, are synthetically useful aryl radicalprecursors152 that facilitate efficient C-C formation, such as intheMeerwein arylation of olefins.153 In 1954, Hey and Turpindemonstrated that o-N2-benzamides are de-methylated upondiazonium decomposition.154 Building on this pioneeringdiscovery,Weinrebandcoworkersdevelopedageneralmethodfor α-functionalization of benzamides (Scheme 28).155 Thismethod involvesCu-catalyzeddecomposition of thediazoniumto an aryl radical, followed by 1,5-HAT of the α-amino C-H.Rapid oxidation of this electron-rich radical leads to transientiminiumcationformationthat is trappedbyalcohols.Recently,thelabsofZhangandQihavedevelopedmetal-freeversionsofthis transformation,usingascorbicacidas theradical initiator,or organic photocatalysts.156,157 Additionally, the hemiaminalproductswere treatedwithaLewisacidandeitherallyl-SiMe3or Me3Si-CN to afford a net C-H α-allylation or α-cyanation.Alternatively, Maulide and co-workers employed a hydrazinethatservestworoles:reductanttogeneratethearylradical,andnucleophileforadditionintothetransientiminiumformeduponα-aminoradicaloxidation.158Theresultantcyclicaminalsopento formstablehydrazones,whichcanbetreatedwithasecond(alkyne)nucleophiletoprovidering-openedadditionproducts.

Scheme28α-AminoC-HfunctionalizationviaArN2-derivedradicals

In2012,Baranandco-workersemployedanaryl triazeneas a radical precursor, since it serves as an aryl diazonium-equivalent upon loss of an amine (Scheme 29).159 In thepresence of an acid or metal salt, the in situ generateddiazonium is rapidly reduced and extrudesN2 to form an arylradical. After a rare, 1,7-HAT (likely dictated by the sulfonategeometry), subsequent oxidation and elimination is facilitatedbyTEMPOtoformremotealkenes.Thisremotedesaturationisaccessible forbothalcoholsandaminesbyuseof the triazene-based precursor/protecting groups. In a related method,Ragains and co-workers employed an Ir photocatalyst topromote the same triazene sulfonate-mediated 1,7-HAT.160However, the terminationentailsacatalyst-turnoveroxidation,which affords a tertiary cation that is hydrolyzedwith H2O toyieldanetγC-Hhydroxylation.

Ito, 1992

α-amino alkylation

Undheim, 1994

NMe

N

O

Bu3SnH (Ar-I)intermolecular

acrylate trap

Bu3SnH (Ar-Br)intramolecular

indole trap

Gribble, 2001

HP(O)R2 (Ar-I)intramolecular

aryl trap

Murphy, 2003

NMe

O

1,5-HAT

N

OCO2Me

H

Et Et

HON I

H

N HSmI2

O

EtEt N

Nakamura, 2010

1,5-HAT

N I

N N N Fe

N Ph

H L-Fe-Ph

cat. Fe(acac)3PhMgBr

H

Ir catalyst (Ar-I)intramolecular

arene trap

Zeng, 2016

O

NH

SiR3

R

Kalyani, 2013

Mg mediated (Ar-F)intermolecular

silane trap

Ni catalyst (Ar-Br)intramolecular

arene trap

N

O

iPr

MeMe

N

MeMe

Me

O

Xu, 2016

Ph

α C-H arylation

1st nucleophile

N

O

N2

H

N

O

H

1,5-HATthen [O]

N

O

N

O

HNNR2

OR

( )nNH

O

NHR2N

( )n

Rring opening;

2nd nucleophile

Maulide, 2016 (hydrazine)

or N2+ in situ

from NH2

ROH

α C-H oxygenationNHR2HN

BF3LiR

( )n ( )n

( )n

Weinreb, 1996 (Cu)Zhang, 2016 (organic)



Scheme29RemoteC-HfunctionalizationviaArN2-derivedradicals

H.Fuandco-workers incorporated these triazeneswithinamidestopromote1,6-HAT(dictatedbyformationofatertiaryradical).ThisremoteC(sp3)radicalistrappedbyapendantarylgrouptoformheterocycles.161Thefurtherdevelopmentofnewpathways based on such orthogonal radical precursors mayenable access to iterative HAT-based C-H functionalizationswithdifferenttrapsandselectivities.

4.2sp3Cradicalinitiation

The challenge associated with HAT initiated by C(sp3)-centeredradicalsisthelackofenergeticdifferencebetweentheinitial C� and the resultant C� after HAT. A solution to thisproblemwasdevelopedbyCrichetal,whereingenerationofamorestableα-oxyradicalisthedrivingforce(Scheme30).162Inapioneeringexampleofsp3C�initiatedHAT,epimerizationofα-mannosidetoβ-mannosidewasaccomplished–overcomingananomericstereo-preference,achallengeinitsownright.

Scheme30Anomericradicalsderivedfromalkylbromides

In this radical-mediated epimerization, Sn� initiatedreduction of an alkyl bromide affords a primary, sp3 C� thatundergoes1,5-HATtogenerateamorestable,secondary,α-oxyradical –with added anomeric stabilization. A terminal, chain-propagatingSn-Hreductionfromthelessstericallyencumberedbottomfaceaffordsa2:1ratioofα:βmannoside–favoringtheisomer not stabilized by the anomeric effect. The Ueno-Storkmethod was employed to rapidly install the sp3 C-Br, radical

precursor via bromoetherification.163,164 After epimerization,thistracelessketalishydrolyzedviaacidicwork-up.

Scheme31dC-HAlkylationviaatom-transferofanC(sp3)-I

Another strategy for promoting HAT via an sp3 C� is toemploy an α-EWG halide, whose C-X bond strength is weakerthanthetranslocated,secondaryC-X.In1997,Masnykreportedtheuseofanα-sulfonyliodideasaradicalprecursortoeffectanHAT-induced cyclization to form cyclopentanes from acyclicalkanesviaδC-Hfunctionalization(Scheme31).165Inthiscase,radical initiation via thermal peroxide initiation or photolyticSn-SncleavageprecedesI�abstractionfromaradicalprecursorthatiseasilypreparedbyα-iodinationoftheacidicalkylsulfone.Upon1,5-HAT,asecondarysp3C�abstractsaniodideviaradicalrecombination,orchainpropagation,toaffordanatom-transferadduct. The resulting δ-iodo sulfone undergoes base-mediatedintramolecular cyclization to generate cyclopentanes – an all-carbonversionoftheHLFreaction.

Althoughthesesp3C�inducedHATmechanismsarerarest,andmostchallenging,thereremainsgreatopportunitytodesignnew strategies that favor C� to C� translocation. For example,mechanistic studies by Wood et al have demonstrated thatcaptodativestabilizationcanoverrideakineticisotopeeffectindictating the fate of 1,5-HAT.166 In particular, it was observedthat radical translocation favors formation of more stable,amino acid α-radicals over simply α-amino ones that lack theadditionalpush-pulleffectsofcaptodativestabilization.167

Mostrecently,Gevorgyanandco-workersintroducedaPd-photocatalyzed remote desaturation of aliphatic alcohols(Scheme32).168Employingα-silyl-methyl-halidesasprecursors(developedbyNishiyamaetalforradicaladditiontoolefins),169they demonstrated a hybrid Pd-radical mechanism facilitatesSETreduction,regioselectiveHAT,andPd-catalyzedβ-hydrogeneliminationtoaffordselective,remotedesaturationofaliphaticalcohols.

Scheme32Pd-Catalyzed,remotedesaturationviaC(sp3)-I

via 1,7-HAT

Me

NHTsO

HN Me

OHNMe

MeO

HN

Bn

O

H2N

H. Fu, 2016

N

NHTs

Baran, 2012

OO

X

X = O, N

S

Me

NNNEt2 R

H

R1n

OO

XS

Me

Hn

R1

R

Me

via 1,6-HAT

R1 R

γ-unsaturation

TfOHTEMPO

C-H arylation

TsO OH

Ph Ph

C-H oxygenation

Ragains, 2015

via 1,7-HAT

Crich, 1996

β-mannoside

O

OMe

OO

OMe

Me OMe

HOO

Me OMeH H

OOOBzO

PhOMe

OO

OMe

Me OMe

Br

α-mannoside

Bu3SnHAIBN

1,5-HATOO

Me OMe

H

OMe

H+

radical epimerizationOMe

H

HBr2

Me

OMeOH OH

Masnyk, 1997

I

SO2Ph

Me

SO2Ph

Me

I

SO2Ph

Me1,5-HAT

(BzO)2, Δ or (Bu3Sn)2, hν cyclization

remotedesaturation

Gevorgyan, 2017

I SiO

Me

Me

Me

H SiO

R R MeR’

HO Me

Me

SiO

R RR’

H Me

HATPd cat, hν - H + TBAF



5Conclusions

SelectiveC-HfunctionalizationviaintramolecularHATisastrategy that benefits from amechanistically distinct pathwaywith complementary reactivity parameters tometal-basedC-Hactivation routes. As newmethods formild radical-generationcontinuallygivewaytonewreactiondevelopment,thereisalsoa sustained expansion of our understanding of the inherentchemo-regio-andstereo-selectivityrulesforHATmechanisms.While thismodeofC-H functionalization isperhaps theoldest,itscurrentrevivalofinterestwithnewtoolsandmethodsoffersampleopportunity for further,major contributions to the fieldof organic synthesis. For example, thanks to developments inthepastyearalone,δC-C formationhasbeenachieved for thefirsttime(forN�initiation),asymmetricδC-Cformationisnowpossible with chiral catalysis (via O� initiation), and anilinesofferorthogonalHATinitiationasdiazoniumsurrogates(byC�initiation).Inpursuitofsolvingongoingchallenges,newradicalprecursors will likely need to be designed, allowing for morecreativemethodsoftrappingtheserelayedradicals.Needlesstosay, with continued development of disruptive new methods,the futureofC-H functionalizationbyradical translocationwillcontinuetobeexciting.

FundingInformation

We thank the National Institutes of Health (R35 GM119812), NationalScienceFoundation(CAREER1654656),andAmericanChemicalSocietyPetroleumResearchFund for financial support.L.M.S. isgrateful foranNSFGraduateResearchFellowship.

Acknowledgment

WethankSeanRaffertyandEthanWappesforeditingthismanuscript.

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Biosketches

Lefttoright:Leah,Kohki,David

LeahStateman(OrlandPark,IL)earnedaB.Sc.withhonorsatIllinoisStateUniversityin2015,whereshestudiedthesynthesisofcarbaporphyrinoidswithProf.TimothyLash.AtOSU,shehaspioneeredourteam’sdevelopmentofcatalytic,remoteC-Hfunctionalizationsviahydrogenatomtransfer.Leahisa2016NationalScienceFoundationGraduateResearchFellow.KohkiNakafuku(Loveland,OH)earnedaB.Sc.withhonorsatDukeUniversityin2014,wherehestudiedthekineticsandmechanismofgold-catalyzedalleneracemizationwithProf.RossWidenhoefer.AtOSU,hehaspioneeredthedevelopmentofanHAT-basedradicalrelaychaperonestrategywithapplicationstowardsdirectedC-Hamination.DavidNagib(Philadelphia,PA)earnedaB.Sc.withhonorsatBostonCollegein2006,wherehestudiedpeptide-catalyzeddesymmetrizationwithProf.ScottMiller.AtPrincetonUniversity,heearnedaPhDin2011withProf.DavidMacMillan,wherehedevelopednewtrifluoromethylationsviaphotoredoxcatalysis.AsanNIHPostdoctoralScholarattheUniversityofCalifornia,Berkeley,hestudiedC-HactivationviaoxidativegoldmechanismswithProf.F.DeanToste.Since2014,DavidhasbeenanAssistantProfessorintheDepartmentofChemistryandBiochemistryatTheOhioStateUniversity,wherehisteam’sresearchonradical-mediatedC-HfunctionalizationhasbeenrecognizedbytheAmericanChemicalSociety(PRF,2015),NationalInstitutesofHealth(MIRA,2016),NationalScienceFoundation(CAREER,2017),andThiemeChemistryJournalAward(2017).

Documents

Remote C-H Functionalization via Selective Hydrogen Atom