Synthesis Review/ShortReview
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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
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
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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
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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
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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
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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:
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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
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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
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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]
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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
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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
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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
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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)
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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
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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).
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