Catalytic meta-selective C-H functionalization to construct quaternary carbon centres

Article abstract of DOI:10.1039/c5cc03951g

A catalytic meta-selective C-H functionalization of 2-phenylpyridines using a range of tertiary halides is described. The protocol is simple to perform and uses commercially available reagents to construct challenging quaternary carbon centres in a regioselective manner. Preliminary studies suggest the C-H functionalization proceeds through a radical process directed via a remote σ-activation.

Full text of DOI:10.1039/c5cc03951g

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Page 1 of 4
Pleaseꢀd Co hꢀ ne omt ꢀ Ca do jmu smt ꢀmarginsꢀ
View Article Online
DOI: 10.1039/C5CC03951G
JournalꢀNameꢀ
COMMUNICATIONꢀ
ꢀ
Catalyticꢀmeta-selectiveꢀC-Hꢀfunctionalizationꢀtoꢀconstructꢀ
quaternaryꢀcarbonꢀcentresꢀꢀ
Receivedꢀ00thꢀJanuaryꢀ20xx,ꢀ
Acceptedꢀ00thꢀJanuaryꢀ20xxꢀ
a
b
ꢀb
cꢀ
AndrewꢀJ.ꢀPaterson, ꢀSahraꢀStꢀJohn-Campbell, ꢀMaryꢀF.ꢀMahon ,ꢀNeilꢀJ.ꢀPress andꢀChristopherꢀG.ꢀ
ab
Frost* ꢀ
DOI:ꢀ10.1039/x0xx00000xꢀ
www.rsc.org/ꢀ
Aꢀ catalyticꢀ meta-selectiveꢀ C-Hꢀ functionalizationꢀ ofꢀ 2- theꢀ difficultꢀ oxidativeꢀ additionꢀ ofꢀ aꢀ metalꢀ complexꢀ intoꢀ aꢀ bulkyꢀ C–Xꢀ
1
0
phenylpyridinesꢀusingꢀaꢀrangeꢀofꢀtertiaryꢀhalidesꢀisꢀdescribed.ꢀ bond. ꢀWeꢀhypothesizedꢀthatꢀaꢀcatalyticꢀσ-activationꢀstrategyꢀwouldꢀ
Theꢀ protocolꢀ isꢀ simpleꢀ toꢀ performꢀ andꢀ usesꢀ commerciallyꢀ thereforeꢀbeꢀamenableꢀtoꢀestablishingꢀquaternaryꢀcarbonꢀcentresꢀbyꢀ
availableꢀreagentsꢀtoꢀconstructꢀchallengingꢀquaternaryꢀcarbonꢀ avoidingꢀaꢀgeneralꢀoxidativeꢀadditionꢀpathway.ꢀ
centresꢀinꢀaꢀregioselectiveꢀmanner.ꢀPreliminaryꢀstudiesꢀsuggestꢀ
(
a) Key catalytic strategies for meta-directed C-H functionalization
theꢀ C-Hꢀ functionalizationꢀ proceedsꢀ throughꢀ aꢀ radicalꢀ processꢀ
directedꢀviaꢀaꢀremoteꢀσ-activation.
R
R
Template
DG
Theꢀtransition-metalꢀcatalyzedꢀcleavageꢀandꢀfunctionalizationꢀofꢀinertꢀ
C-Hꢀbondsꢀisꢀevolvingꢀintoꢀaꢀfundamentalꢀmethodologyꢀforꢀtheꢀdesignꢀ
[M]
[Pd]
L
[Pd] N
C
1
ofꢀatomꢀeconomicalꢀapproachesꢀtoꢀusefulꢀorganicꢀmolecules. ꢀWhileꢀ
Transient mediator (L) installed
by ortho-directing group (DG)
Covalent template for
remote activation
Steric/electronic control
theꢀ directꢀ functionalizationꢀ atꢀ theꢀ orthoꢀ positionꢀ ofꢀ aromaticꢀ
compoundsꢀbyꢀchelationꢀassistedꢀC-Hꢀbondꢀcleavageꢀhasꢀbecomeꢀwellꢀ
establishedꢀinꢀrecentꢀyears,ꢀdevelopingꢀreactionsꢀwithꢀcomplementaryꢀ
regioselectivityꢀ continuesꢀ toꢀ challengeꢀ contemporaryꢀ catalyticꢀ
Previous work: Catalytic σ-activation
[Ru] DG
H
R
H
R
X
N
N
2
ꢀ
cat. [Ru]
Base
H
methodology. Inꢀthisꢀcontext,ꢀexamplesꢀofꢀmetaꢀselectiveꢀcatalyticꢀC-
Hꢀfunctionalizationꢀhaveꢀbeenꢀreportedꢀofferingꢀdiversityꢀinꢀmolecularꢀ
designꢀ throughꢀ alternativeꢀ reactionꢀ strategiesꢀ (Schemeꢀ 1a).ꢀ Theseꢀ
σ-activation for remote
C-H functionalization
H
R = SO Ar Frost et al, J. Am. Chem. Soc., 2011, 133, 19298
2
3
ꢀ
includeꢀ substrateꢀ controlledꢀ systems, transientꢀ mediatorsꢀ suchꢀ asꢀ aꢀ
R = sec-alkyl Ackermann et al, J. Am. Chem. Soc., 2013, 135, 5877
4
carboxylicꢀacid orꢀnorbornene ꢀandꢀcovalentꢀtemplateꢀstrategiesꢀforꢀ
ꢀ
5
(b) This work: Catalytic meta-directed construction of quaternary carbon centres
6
ꢀ
remoteꢀ activation. Weꢀ firstꢀ reportedꢀ aꢀ novelꢀ catalyticꢀ σ-activationꢀ
X
Features:
H
-Selective meta-functionalisation
-Operationally simple to perform
with commercial reagents
-Remote σ-activation overcomes
difficult oxidative addition
-Proposed to proceed through a
radical process
protocolꢀforꢀC-Hꢀfunctionalizationꢀthatꢀallowsꢀtheꢀmetaꢀsulfonationꢀofꢀ
7
H
R3
R2
R1
ꢀ
N
2
-phenylpyridinesꢀ viaꢀ cyclometalatedꢀ rutheniumꢀ intermediates.
N
cat. [Ru]
Base
Interestingly,ꢀ theꢀ catalyticꢀ σ-activationꢀ strategyꢀ provedꢀ effectiveꢀ forꢀ
8
meta-alkylationsꢀwithꢀsecondaryꢀalkylꢀhalides ꢀwhilstꢀacylꢀhalidesꢀandꢀ
R
R
H
R3
R2
R1
primaryꢀ alkylꢀ halidesꢀ affordꢀ onlyꢀ theꢀ ortho-functionalizedꢀ productsꢀ
Schemeꢀ1ꢀCatalyticꢀmeta-directedꢀC-Hꢀfunctionalizationꢀ
consistentꢀ withꢀ aꢀ mechanismꢀ involvingꢀ oxidativeꢀ additionꢀ ofꢀ theꢀ
9
organohalide. ꢀ
Inꢀ preliminaryꢀ experiments,ꢀ 2-phenylpyridineꢀ 1aꢀ wasꢀ treatedꢀ underꢀ
conditionsꢀ analogousꢀ toꢀ thoseꢀ developedꢀ inꢀ ourꢀ meta-sulfonationꢀ
Hereꢀweꢀreportꢀaꢀnewꢀcatalyticꢀmeta-selectiveꢀC-Hꢀfunctionalizationꢀofꢀ
2
-phenylpyridinesꢀ toꢀ constructꢀ quaternaryꢀ carbonꢀ centresꢀ (Schemeꢀ
2 2
reaction:ꢀ [RuCl (p-cymene)]2ꢀ (5ꢀ mol%)ꢀ K CO3ꢀ (2ꢀ equiv),ꢀ t-BuBrꢀ 2aꢀ (3ꢀ
1
b).ꢀ Theꢀ transition-metalꢀ catalyzedꢀ couplingꢀ ofꢀ tertiaryꢀ alkylꢀ halidesꢀ
7
equiv)ꢀusingꢀMeCNꢀasꢀtheꢀsolvent. ꢀUnfortunatelyꢀnoꢀcoupledꢀproductsꢀ
wereꢀ formedꢀ underꢀ theseꢀ conditionsꢀ howeverꢀ theꢀ desiredꢀ meta-
substitutedꢀ productꢀ wasꢀ observedꢀ inꢀ 12%ꢀ conversionꢀ whenꢀ theꢀ
reactionꢀsolventꢀwasꢀchangedꢀtoꢀ1,4-Dioxaneꢀ(Tableꢀ1:ꢀEntriesꢀ1-2).ꢀByꢀ
andꢀaromaticꢀC-Hꢀbondsꢀisꢀanꢀespeciallyꢀchallengingꢀreactionꢀdueꢀtoꢀ
2 3
simplyꢀ changingꢀ theꢀ baseꢀ fromꢀ K CO ꢀ toꢀ variousꢀ acetateꢀ salts,ꢀ aꢀ
significantꢀ increaseꢀ inꢀ conversionꢀ wasꢀ observedꢀ withꢀ KOAcꢀ provingꢀ
theꢀmostꢀeffectiveꢀ(Entryꢀ6).ꢀInꢀtheꢀabsenceꢀofꢀrutheniumꢀcomplex,ꢀnoꢀ
productꢀwasꢀobservedꢀ(Entryꢀ11).ꢀThisꢀcatalyticꢀsystemꢀwasꢀfoundꢀtoꢀ
performꢀ wellꢀ inꢀ aꢀ rangeꢀ ofꢀ solventsꢀ asꢀ wellꢀ asꢀ underꢀ solventꢀ freeꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
J.ꢀName.,ꢀ2013,ꢀ00,ꢀ1-3ꢀ|ꢀ1ꢀꢀ
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Page 2 of 4
COMMUNICATIONꢀ
JournalꢀNameꢀ
conditionsꢀandꢀwasꢀcompletedꢀinꢀasꢀlittleꢀasꢀ4ꢀhoursꢀ(Entryꢀ14).ꢀWhenꢀ InꢀadditionꢀtoꢀtheꢀalkylꢀhalideꢀreagentsꢀoutlinedꢀinꢀSchVeiemweAsrtꢀi2clꢀeaOnndliꢀn3e,ꢀ
DOI: 10.1039/C5CC03951G
t-BuClꢀ 2bꢀ wasꢀ usedꢀ asꢀ theꢀ couplingꢀ reagent,ꢀ aꢀ significantꢀ dropꢀ inꢀ tertiaryꢀα-bromoꢀesterꢀ2cꢀwasꢀeffectivelyꢀcoupled,ꢀgeneratingꢀmeta-
conversionꢀwasꢀobserved,ꢀhoweverꢀbyꢀusingꢀaꢀcombinationꢀofꢀK
andꢀKOAc,ꢀtheꢀreactionꢀperformedꢀcompetitivelyꢀ(Entryꢀ17).ꢀꢀ
2
CO
3
ꢀ
substitutedꢀ productsꢀ 8a,ꢀ 8cꢀ andꢀ 8d,ꢀ compoundsꢀ withꢀ aꢀ usefulꢀ
functionalꢀhandle,ꢀinꢀreasonableꢀisolatedꢀyieldsꢀ(Schemeꢀ4).ꢀThisꢀresultꢀ
providedꢀ keyꢀ insightꢀ intoꢀ theꢀ reactionꢀ mechanismꢀ andꢀ stronglyꢀ
ꢀ
Tableꢀ1ꢀOptimizationꢀofꢀcatalyticꢀmetaꢀtertiaryꢀalkylationꢀꢀ
E
suggestedꢀ aꢀ radicalꢀ typeꢀ pathway,ꢀ ratherꢀ anꢀ S Arꢀ typeꢀ mechanismꢀ
7
previouslyꢀproposedꢀinꢀourꢀmeta-sulfonationꢀreaction. ꢀꢀ
X
X = Br 2a
X = Cl 2b
H
H
Br
N
N
N
[
RuCl2(p-cymene)]2 (5 mol %)
H
H
R3
R2
H
R1
Base (2 equiv)
H
H
N
N
Solvent, 120 oC, 15h.
[RuCl2(p-cymene)]2 (5 mol %)
1
a
meta-3a
ortho-not observed
R
R
KOAc (2 equiv)
Dioxane, 120 oC, 15h.
R3
R2
ꢀ
R1
Entryꢀ
t-Bu-Xꢀ
Baseꢀ
Solventꢀ
ꢀꢀꢀConversionꢀꢀꢀꢀ
a
(
%) ꢀ
1
2
3
4
5
6
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
2aꢀ
2aꢀ
2aꢀ
2aꢀ
2aꢀ
2aꢀ
2aꢀ
2aꢀ
2aꢀ
2aꢀ
2aꢀ
2aꢀ
2aꢀ
2aꢀ
2bꢀ
2bꢀ
2bꢀ
K
K
2
2
CO
CO
3
3
ꢀ
ꢀ
MeCNꢀ
0ꢀ
1,4-Dioxaneꢀ
neatꢀ
12ꢀ
69ꢀ
68ꢀ
61ꢀ
74ꢀ
60ꢀ
31ꢀ
64ꢀ
13ꢀ
0ꢀ
N
N
N
KOAcꢀ
KOAcꢀ
KOAcꢀ
KOAcꢀ
Me
MeO
F
2-Me-THFꢀ
2-Butanoneꢀ
1,4-Dioxaneꢀ
1,4-Dioxaneꢀ
1,4-Dioxaneꢀ
1,4-Dioxaneꢀ
1,4-Dioxaneꢀ
1,4-Dioxaneꢀ
1,4-Dioxaneꢀ
1,4-Dioxaneꢀ
1,4-Dioxaneꢀ
1,4-Dioxaneꢀ
1,4-Dioxaneꢀ
1,4-Dioxaneꢀ
3b 48%
3c 80%
3d 61%
bꢀ
7
2 3
K CO ꢀ
8
ꢀ
ꢀ
NaOAcꢀ
CsOAcꢀ
9
N
N
N
1
0ꢀ
4
Bu NOAcꢀ
EtO2C
R
Cl
cꢀ
1
1
KOAcꢀ
KOAcꢀ
KOAcꢀ
KOAcꢀ
KOAcꢀ
dꢀ
1
2
25ꢀ
50ꢀ
72ꢀ
20ꢀ
27ꢀ
63ꢀ
e
1
3 ꢀꢀ
3g R = CF3 0%
3h R = NO2 0%
3
e 62%
3f 33%
f
1
4 ꢀ
1
1
1
5ꢀ
6ꢀ
K
2
CO
KOAcꢀ(0.5ꢀequiv)ꢀ
CO3ꢀ(1.5ꢀequiv)ꢀ
3
ꢀ
ꢀ
N
7
N
K
2
MeO
bꢀ
1
8
2bꢀ
K
2
CO
3
ꢀ
1,4-Dioxaneꢀ
62ꢀ
aꢀ
1
Conversionꢀ ofꢀ 1aꢀ toꢀ 3aꢀ byꢀ Hꢀ NMR.ꢀ Withꢀ 30ꢀ mol%ꢀ MesCOOHꢀ Withoutꢀ
bꢀ
cꢀ
dꢀ
e
f
[
2 2 2
RuCl (p-cymene)] .ꢀ Reactionꢀinꢀair.ꢀ ꢀ[RuCl (p-cymene)]2ꢀ (1ꢀmol%).ꢀ ꢀReactionꢀ
4
a 61%a
4c 57%a
timeꢀ4ꢀh.ꢀ
ꢀ
Schemeꢀ 2ꢀ Catalyticꢀ metaꢀ functionalizationꢀ usingꢀ tertiaryꢀ alkylꢀ bromides.ꢀ
1
Numbersꢀquotedꢀareꢀdirectꢀconversionsꢀtoꢀproductꢀbyꢀ HꢀNMR.ꢀ ꢀUsingꢀKOAcꢀ
0.5ꢀequiv)ꢀandꢀK CO ꢀ(1.5ꢀequiv).ꢀꢀ
a
Withꢀoptimizedꢀcatalyticꢀsystemsꢀinꢀhand,ꢀweꢀthenꢀinvestigatedꢀhowꢀ
reactionꢀ conversionsꢀ wereꢀ affectedꢀ whenꢀ substituentsꢀ atꢀ theꢀ 4-
positionꢀ ofꢀ theꢀ arylꢀ ringꢀ wereꢀ variedꢀ (Schemeꢀ 2).ꢀ Itꢀ wasꢀ foundꢀ thatꢀ
electronꢀ donatingꢀ substituentsꢀ favouredꢀ theꢀ reactionꢀ whereasꢀ
stronglyꢀelectronꢀwithdrawingꢀgroupsꢀshutꢀtheꢀreactionꢀdownꢀentirely.ꢀ
Theꢀreactionꢀwasꢀtolerantꢀofꢀhalogenꢀandꢀesterꢀsubstituentsꢀwhichꢀisꢀ
usefulꢀforꢀfurtherꢀsyntheticꢀtransformations.ꢀTheꢀreactionsꢀledꢀtoꢀtheꢀ
soleꢀ formationꢀ ofꢀ theꢀ monoꢀ substitutedꢀ metaꢀ productsꢀ withꢀ noꢀ
decompositionꢀ orꢀ by-productsꢀ observedꢀ althoughꢀ quantitativeꢀ
separationꢀ byꢀ conventionalꢀ methodsꢀ wasꢀ notꢀ alwaysꢀ possibleꢀ (seeꢀ
supportingꢀ informationꢀ forꢀ fullꢀ analysis).ꢀ Intriguingly,ꢀ 1-
bromoadamantaneꢀwasꢀfoundꢀtoꢀbeꢀanꢀeffectiveꢀcouplingꢀpartnerꢀandꢀ
productꢀ 4cꢀ wasꢀ characterisedꢀ byꢀ X-rayꢀ analysisꢀ confirmingꢀ theꢀ
(
2
3
1
1
regioselectiveꢀ metaꢀ substitutionꢀ (Figureꢀ 1). ꢀ Ourꢀ procedureꢀ alsoꢀ
effectivelyꢀcoupledꢀaꢀrangeꢀofꢀtertiaryꢀalkylꢀchlorides,ꢀreagentsꢀwhichꢀ
areꢀ readilyꢀ availableꢀ andꢀ generallyꢀ consideredꢀ toꢀ beꢀ lessꢀ reactiveꢀ
Figureꢀ 1ꢀ Theꢀ asymmetricꢀ unitꢀ inꢀ theꢀ crystalꢀ structureꢀ ofꢀ 4c.ꢀ Ellipsoidsꢀ areꢀ
illustratedꢀatꢀ30%ꢀprobability.ꢀ
(
Schemeꢀ3).ꢀInꢀtheseꢀexamples,ꢀitꢀwasꢀfoundꢀthatꢀtheꢀincorporationꢀofꢀ
longerꢀalkylꢀchainꢀlengthsꢀmaintainedꢀhighꢀconversionsꢀandꢀenabledꢀ
betterꢀ separationꢀ ofꢀ theꢀ productsꢀ byꢀ normalꢀ phaseꢀ flashꢀ
chromatography.ꢀ
2
ꢀ|ꢀJ.ꢀName.,ꢀ2012,ꢀ00,ꢀ1-3ꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
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Pleaseꢀd Co hꢀ ne omt ꢀ Ca do jmu smt ꢀmarginsꢀ
JournalꢀNameꢀ
ꢀCOMMUNICATIONꢀ
benzoquinolineꢀ1jꢀwasꢀhoweverꢀeffectivelyꢀalkylatedꢀgeVnieewraAtrtiincgleꢀO10nlꢀinaesꢀ
DOI: 10.1039/C5CC03951G
Cl
theꢀonlyꢀisolatedꢀproduct.ꢀ
R
2
3
H
H
H
R
1
R
N
N
Br
[
2 2
RuCl (p-cymene)] (5 mol %)
2
c
H
H
R
R
EtO
2
C
KOAc (0.5 equiv)
CO (1.5 equiv)
N
K
2
3
R
2
N
R
1
3
[RuCl
2
(p-cymene)] (5 mol %)
2
R
Dioxane, 120 oC, 15h.
R
R
KOAc (2 equiv)
Dioxane, 120 oC, 15h.
2
EtO C
8
8
8
a R = H 46%
c R = OMe 57%
d R = F 47%
N
N
N
MeO
F
MeO
trace elimination
EtO
-
HBr
EtO
Br
C
N
3
c 71%
3d 87%(61%)
a
5c 75%(54%)a
2
2
C
R
EtO
2
C
2
CO Et
N
N
N
MeO
MeO
9a R = H 9%
9
9
c R = OMe 12%
d R = F 13%
n-hept
n-hept
Schemeꢀ 4ꢀ Catalyticꢀ metaꢀ functionalizationꢀ withꢀ α-bromoꢀ esterꢀ 2c.ꢀ Numbersꢀ
quotedꢀareꢀisolatedꢀyields.ꢀ
a 60%(43%)a
6c 70%(47%)
a
7c 36%(16%)a
6
Schemeꢀ 3ꢀ Catalyticꢀ metaꢀ functionalizationꢀ usingꢀ alkylꢀ chlorideꢀ reagents.ꢀ
1
a
Numbersꢀ quotedꢀ areꢀ directꢀ conversionsꢀ toꢀ productꢀ byꢀ Hꢀ NMR.ꢀ ꢀ Numbersꢀ inꢀ
bracketsꢀindicateꢀisolatedꢀyields.ꢀ
Br
2
c
EtO2C
N
No reaction
N
Heterolyticꢀ cleavageꢀ ofꢀ theꢀ C-Xꢀ bondꢀ ofꢀ 2cꢀ inꢀ anꢀ S 1-typeꢀ mannerꢀ
[RuCl2(p-cymene)]2 (5 mol %)
wouldꢀresultꢀinꢀaꢀstronglyꢀdisfavouredꢀcarbocationꢀresidingꢀalphaꢀtoꢀanꢀ
electronꢀwithdrawingꢀester.ꢀItꢀisꢀthereforeꢀunlikelyꢀthatꢀreactionꢀwithꢀ
theꢀaromaticꢀsubstrateꢀwouldꢀoccurꢀinꢀthisꢀfashion.Theꢀpossibilityꢀofꢀ
KOAc, Dioxane, 120 oC, 15h.
H
H
1i
Br
2c
N
S 2ꢀtypeꢀreactivityꢀcanꢀalsoꢀbeꢀeffectivelyꢀruledꢀoutꢀgivenꢀtheꢀstericꢀ
EtO2C
N
effectsꢀ ofꢀ theꢀ tertiaryꢀ alkylꢀ halidesꢀ used.ꢀ Theꢀ generationꢀ ofꢀ tertiaryꢀ
alkylꢀ radicalsꢀ hasꢀ howeverꢀ beenꢀ widelyꢀ reportedꢀ withꢀ aꢀ rangeꢀ ofꢀ
transitionꢀmetalꢀcatalystsꢀandꢀshownꢀtoꢀbeꢀeffectiveꢀinꢀtheꢀsubstitutionꢀ
N
KOAc, Dioxane, 120 oC, 15h.
H
1a
EtO2C
1
2
ofꢀaromatics,ꢀheteroaromaticsꢀandꢀolefins. ꢀ
N
Ru
Br
Cl
A (10 mol %)
Inꢀ contrastꢀ toꢀ theꢀ reactionsꢀ withꢀ simpleꢀ alkyl-halidesꢀ outlinedꢀ inꢀ
Schemesꢀ 2ꢀ andꢀ 3ꢀ whichꢀ ledꢀ toꢀ theꢀ soleꢀ formationꢀ ofꢀ oneꢀ product,ꢀ
reactionꢀwithꢀ2cꢀgeneratedꢀadditionalꢀby-products.ꢀCompoundsꢀ9a,ꢀ9cꢀ
andꢀ 9dꢀ wereꢀ isolatedꢀ alongꢀ withꢀ spectroscopicꢀ evidenceꢀ ofꢀ traceꢀ
higherꢀ oligomersꢀ whichꢀ isꢀ consistentꢀ withꢀ aꢀ radicalꢀ conjugateꢀ
polymerisationꢀ pathway.ꢀ Weꢀ hypothesiseꢀ thatꢀ aꢀ tertiaryꢀ carbon-
centeredꢀ radicalꢀ speciesꢀ canꢀ addꢀ ontoꢀ eliminationꢀ productsꢀ formedꢀ
underꢀ theꢀ reactionꢀ conditions,ꢀ whichꢀ canꢀ inꢀ turnꢀ propagateꢀ ontoꢀ aꢀ
cyclometalatedꢀ (σ-activated)ꢀ substrateꢀ moleculeꢀ toꢀ affordꢀ theꢀ
observedꢀby-products.ꢀFurthermore,ꢀtheꢀadditionꢀofꢀradicalꢀscavengerꢀ
TEMPOꢀprovedꢀdetrimentalꢀtoꢀtheꢀreactionꢀwithꢀnoꢀdesiredꢀproductꢀ
observedꢀwhenꢀstoichiometricꢀquantitiesꢀwereꢀusedꢀ(SeeꢀSupportingꢀ
Information).ꢀ
8a 43%
2c
H
H
EtO2C
N
N
[RuCl2(p-cymene)]2 (5 mol %)
N
KOAc, Dioxane, 120 oC, 15h.
1j
1
0 35%
Br
2
c
EtO2C
H
N
EtO C
N
2
Furtherꢀmechanisticꢀworkꢀwasꢀconductedꢀtoꢀprovideꢀadditionalꢀinsightꢀ
intoꢀ theꢀ interestingꢀ metaꢀ selectivityꢀ displayedꢀ byꢀ thisꢀ reactionꢀ
[
RuCl2(p-cymene)]2 (5 mol %)
H
KOAc, Dioxane, 120 oC, 15h.
1
k
11 22%
(
Schemeꢀ 5).ꢀ Itꢀ hasꢀ previouslyꢀ beenꢀ proposedꢀ thatꢀ initialꢀ rutheniumꢀ
insertionꢀ intoꢀ anꢀ orthoꢀ C-Hꢀ bondꢀ toꢀ generateꢀ aꢀ cyclometalatedꢀ
7
,8
Schemeꢀ5ꢀMechanisticꢀInvestigation.ꢀNumbersꢀquotedꢀareꢀisolatedꢀyields.ꢀ
complexꢀisꢀkeyꢀtoꢀthisꢀtypeꢀofꢀreactivity. ꢀInꢀsupportꢀofꢀthis,ꢀreactionꢀ
ofꢀtheꢀortho,ꢀorthoꢀdimethylꢀsubstrateꢀ1iꢀresultedꢀinꢀnoꢀconversionꢀtoꢀ
theꢀdesiredꢀmetaꢀsubstitutedꢀproduct.ꢀTheꢀimportanceꢀofꢀrutheniumꢀ
σ-activationꢀ isꢀ alsoꢀ highlightedꢀ withꢀ theꢀ successfulꢀ meta-selectiveꢀ
reactionꢀ usingꢀ pre-formedꢀ complexꢀ A.ꢀ Conformationallyꢀ lockedꢀ
Togetherꢀtheseꢀresultsꢀsuggestꢀthatꢀsubstitutionꢀoccursꢀpreferentiallyꢀ
atꢀaꢀpositionꢀparaꢀtoꢀtheꢀC-Ruꢀbondꢀformedꢀfollowingꢀcyclometalation.ꢀ
Interestingly,ꢀanalogousꢀreactivityꢀhasꢀalsoꢀrecentlyꢀbeenꢀreportedꢀinꢀaꢀ
1
4ꢀ
stoichiometricꢀprocessꢀonꢀiridiumꢀcomplexes. Inꢀlightꢀofꢀthisꢀworkꢀweꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
J.ꢀName.,ꢀ2013,ꢀ00,ꢀ1-3ꢀ|ꢀ3ꢀ
Pleaseꢀdoꢀnotꢀadjustꢀmarginsꢀ

Pleaseꢀd Co hꢀ ne omt ꢀ Ca do jmu smt ꢀmarginsꢀ
Page 4 of 4
COMMUNICATIONꢀ
JournalꢀNameꢀ
nowꢀproposeꢀtheꢀfollowingꢀmechanismꢀ(Schemeꢀ6).ꢀInitialꢀorthoꢀC-Hꢀ 2ꢀ (a)ꢀF.ꢀJulia-Hernandez,ꢀM.ꢀSimonettiꢀandꢀI.ꢀLarrosa,ꢀVAienwgeAwrtic.ꢀleChOenmlin.e,ꢀ
DOI: 10.1039/C5CC03951G
Int.ꢀEd.,ꢀ2013,ꢀ52,ꢀ11458;ꢀ(b)ꢀJ.ꢀYang,ꢀOrg.ꢀBiomol.ꢀChem.,ꢀ2015,ꢀ13,ꢀ
insertionꢀgeneratesꢀaꢀcyclometalatedꢀcomplex,ꢀaꢀprocessꢀshownꢀtoꢀbeꢀ
1
reversibleꢀ andꢀ aidedꢀ byꢀ carboxylateꢀ ligands. Substitutionꢀ atꢀ theꢀ
5ꢀ
1930.ꢀꢀ
positionꢀparaꢀtoꢀtheꢀnewlyꢀinstalledꢀC-Ruꢀbondꢀthenꢀmostꢀlikelyꢀoccursꢀ 3ꢀ (a)ꢀ H.ꢀ A.ꢀ Duong,ꢀ R.ꢀ E.ꢀ Gilligan,ꢀ M.ꢀ L.ꢀ Cooke,ꢀ R.ꢀ J.ꢀ Phippsꢀ andꢀ M.ꢀ J.ꢀ
viaꢀ aꢀ radicalꢀ processꢀ wherebyꢀ single-electronꢀ transferꢀ (SET)ꢀ fromꢀ aꢀ
ruthenium(II)ꢀ speciesꢀ canꢀ generateꢀ aꢀ tertiaryꢀ alkylꢀ radicalꢀ andꢀ theꢀ
correspondingꢀ ruthenium(III)Xꢀ species.ꢀ Theꢀ carbon-centeredꢀ radicalꢀ
thenꢀaddsꢀtoꢀtheꢀaromaticꢀringꢀtoꢀgenerateꢀaꢀcyclohexadienylꢀradicalꢀ
intermediate.ꢀ Rearomatisationꢀ couldꢀ occurꢀ viaꢀ single-electronꢀ
Gaunt,ꢀAngew.ꢀChem.,ꢀInt.ꢀEd.,ꢀ2011,ꢀ50,ꢀ463;ꢀ(b)ꢀR.ꢀJ.ꢀPhippsꢀandꢀM.ꢀ
J.ꢀGaunt,ꢀScience,ꢀ2009,ꢀ323,ꢀ1593.ꢀForꢀanꢀexcellentꢀreviewꢀofꢀofꢀnon-
chelate-assistedꢀC-Hꢀactivation,ꢀsee:ꢀ(c)ꢀN.ꢀKuhl,ꢀM.ꢀN.ꢀHopkinson,ꢀJ.ꢀ
Wencel-Delordꢀ andꢀ F.ꢀ Glorius,ꢀ Angew.ꢀ Chem.,ꢀ Int.ꢀ Ed.,ꢀ 2012,ꢀ 51,ꢀ
10236.ꢀ
oxidationꢀ andꢀ deprotonationꢀ toꢀ regenerateꢀ aꢀ ruthenium(II)ꢀ complexꢀ 4ꢀ (a)ꢀJ.ꢀLuo,ꢀS.ꢀPreciadoꢀandꢀI.ꢀLarrosa,ꢀJ.ꢀAm.ꢀChem.ꢀSoc.,ꢀ2014,ꢀ136,ꢀ
ꢀ
andꢀfurnishꢀtheꢀmetaꢀalkylatedꢀproductꢀafterꢀproto-demetalation.ꢀ
4109;ꢀ(b)ꢀS.ꢀMochida,ꢀK.ꢀHirano,ꢀT.ꢀSatohꢀandꢀM.ꢀMiura,ꢀOrg.ꢀLett.,ꢀ
2010,ꢀ12,ꢀ5776;ꢀ(c)ꢀJ.ꢀCornella,ꢀM.ꢀRighiꢀandꢀI.ꢀLarrosa,ꢀAngew.ꢀChem.,ꢀ
Int.ꢀEd.,ꢀ2011,ꢀ50,ꢀ9429.ꢀ
ꢀ
5
ꢀ
(a)ꢀX.ꢀ-C.ꢀWang,ꢀW.ꢀꢀGong,ꢀL.ꢀ-Z.ꢀFang,ꢀR.ꢀ-Y.ꢀZhu,ꢀS.ꢀLi,ꢀK.ꢀM.ꢀEngleꢀandꢀ
J.-Q.ꢀYu,ꢀNature,ꢀ2015,ꢀ519,ꢀ334;ꢀ(b)ꢀZ.ꢀDong,ꢀJ.ꢀWangꢀandꢀG.ꢀDong,ꢀJ.ꢀ
Am.ꢀChem.ꢀSoc.,ꢀ2015,ꢀ137,ꢀDOI:ꢀ10.1021/jacs.5b02809.ꢀꢀ
H
meta-directed
tertiary alkylation
N
X
N
R3
R2
R1
R3
R2
6ꢀ Forꢀselectedꢀexamples,ꢀsee:ꢀ(a)ꢀD.ꢀLeow,ꢀG.ꢀLi,ꢀT.-S.ꢀMeiꢀandꢀJ.-Q.ꢀYu,ꢀ
Nature,ꢀ2012,ꢀ486,ꢀ518;ꢀ(b)ꢀH.-X.ꢀDai,ꢀG.ꢀLi,ꢀX.-G.ꢀZhang,ꢀA.ꢀF.ꢀStepanꢀ
andꢀ J.-Q.ꢀ Yu,ꢀ J.ꢀ Am.ꢀ Chem.ꢀ Soc.,ꢀ 2013,ꢀ 135,ꢀ 7567;ꢀ (c)ꢀ L.ꢀ Wan,ꢀ N.ꢀ
Dastbaravardeh,ꢀ G.ꢀ Liꢀ andꢀ J.-Q.ꢀ Yu,ꢀ J.ꢀ Am.ꢀ Chem.ꢀ Soc.,ꢀ 2013,ꢀ 135,ꢀ
R1
H
Ru(II)
chelation-assisted
cyclometalation
cat. [Ru]
Base
— HX
demetalation
1
8056;ꢀ(d)ꢀG.ꢀYang,ꢀP.ꢀLindovska,ꢀD.ꢀZhu,ꢀJ.ꢀKim,ꢀP.ꢀWang,ꢀR.-Y.ꢀTang,ꢀ
Ru(III)X
[
LnRu]
N
M.ꢀMovassaghiꢀandꢀJ.-Q.ꢀYu,ꢀJ.ꢀAm.ꢀChem.ꢀSoc.,ꢀ2014,ꢀ136,ꢀ10807;ꢀ(e)ꢀ
R.-Y.ꢀTang,ꢀG.ꢀLiꢀandꢀJ.-Q.ꢀYu,ꢀNature,ꢀ2014,ꢀ507,ꢀ215.ꢀ
[
LnRu]
N
R3
R2
R1
7ꢀꢀ (a)ꢀO.ꢀSaidi,ꢀJ.ꢀMarafie,ꢀA.ꢀE.ꢀW.ꢀLedger,ꢀP.ꢀM.ꢀLiu,ꢀM.ꢀF.ꢀMahon,ꢀG.ꢀ
Kociok-Köhn,ꢀ M.ꢀ K.ꢀ Whittleseyꢀ andꢀ C.ꢀ G.ꢀ Frost,ꢀ J.ꢀ Am.ꢀ Chem.ꢀ Soc.,ꢀ
radical addition
H
R3
R2
R1
H
2
011,ꢀ133,ꢀ19298;ꢀ(b)ꢀW.ꢀR.ꢀReynolds,ꢀP.ꢀM.ꢀLiu,ꢀG.ꢀKociok-Köhnꢀandꢀ
Schemeꢀ6ꢀProposedꢀCatalyticꢀCycle.ꢀ
C.ꢀG.ꢀFrost,ꢀSynlett,ꢀ2013,ꢀ24,ꢀ2687.ꢀ
8
9
ꢀ
N.ꢀHofmannꢀandꢀL.ꢀAckermann,ꢀJ.ꢀAm.ꢀChem.ꢀSoc.,ꢀ2013,ꢀ135,ꢀ5877.ꢀ
Inꢀsummary,ꢀweꢀhaveꢀdevelopedꢀaꢀnovelꢀmetaꢀselectiveꢀcatalyticꢀC-Hꢀ
functionalisationꢀofꢀ2-phenylpyridineꢀsubstratesꢀforꢀtheꢀinstallationꢀofꢀ
quaternaryꢀcarbonꢀcentres.ꢀTheꢀprocedureꢀisꢀoperationallyꢀsimpleꢀandꢀ
wasꢀ foundꢀ toꢀ coupleꢀ aꢀ usefulꢀ rangeꢀ ofꢀ tertiaryꢀ alkylꢀ bromidesꢀ andꢀ
moreꢀchallengingꢀtertiaryꢀalkylꢀchlorides.ꢀMechanisticꢀstudiesꢀindicateꢀ
thatꢀsiteꢀselectiveꢀradicalꢀadditionꢀoccursꢀatꢀtheꢀpositionꢀparaꢀtoꢀtheꢀC-
Ruꢀbondꢀformedꢀfollowingꢀcyclometalationꢀtoꢀaffordꢀproductsꢀwithꢀnetꢀ
metaꢀsubstitution.ꢀMoreꢀdetailedꢀmechanisticꢀstudiesꢀareꢀunderwayꢀtoꢀ
determineꢀtheꢀpreciseꢀnatureꢀofꢀtheꢀorganometallicꢀspeciesꢀandꢀredoxꢀ
processesꢀinvolved.ꢀ
ꢀꢀ (a)ꢀ P.ꢀ M.ꢀ Liuꢀ andꢀ C.ꢀ G.ꢀ Frost,ꢀ Org.ꢀ Lett.,ꢀ 2013,ꢀ 15,ꢀ 5862;ꢀ (b)ꢀ L.ꢀ
Ackermann,ꢀN.ꢀHofmannꢀandꢀR.ꢀVicente,ꢀOrg.ꢀLett.ꢀ2011,ꢀ13,ꢀ1875.ꢀ
0ꢀ Forꢀ selectedꢀ reviews,ꢀ see:ꢀ (a)ꢀ J.ꢀ Christoffersꢀ andꢀ A.ꢀ Mann,ꢀ Angew.ꢀ
Chem.ꢀ Int.ꢀ Ed.,ꢀ 2001,ꢀ 40,ꢀ 4591;ꢀ (b)ꢀ P.ꢀ G.ꢀ Cozzi,ꢀ R.ꢀ Hilgrafꢀ andꢀ N.ꢀ
Zimmermann,ꢀ Eur.ꢀ J.ꢀ Org.ꢀ Chem.ꢀ 2007,ꢀ 5969;ꢀ (c)ꢀ O.ꢀ Riantꢀ andꢀ J.ꢀ
Hannedouche,ꢀ Org.ꢀ Biomol.ꢀ Chem.ꢀ 2007,ꢀ 5,ꢀ 873;ꢀ (d)ꢀ Y.ꢀ Tuꢀ andꢀ B.ꢀ
Wang,ꢀ Acc.ꢀ Chem.ꢀ Res.ꢀ 2011,ꢀ 44,ꢀ 1207;ꢀ (e)ꢀ A.ꢀ Y.ꢀ Hongꢀ andꢀ B.ꢀ M.ꢀ
Stoltz,ꢀEur.ꢀJ.ꢀOrg.ꢀChem.,ꢀ2013,ꢀ2745;ꢀ(f)ꢀT.ꢀNishikataꢀandꢀS.ꢀIshikawa,ꢀ
Synlett,ꢀ2015,ꢀ26,ꢀ716.ꢀ
1
1
1ꢀ ꢀCrystallographicꢀdataꢀhaveꢀbeenꢀdepositedꢀwithꢀCambridgeꢀ
CrystallographicꢀDataꢀCentre;ꢀCCDC-1064109.ꢀꢀCopiesꢀofꢀtheseꢀdataꢀ
canꢀbeꢀobtainedꢀfreeꢀofꢀchargeꢀviaꢀ
WeꢀareꢀgratefulꢀtoꢀtheꢀUniversityꢀofꢀBath,ꢀEPSRCꢀDTCꢀinꢀSustainableꢀ
ChemicalꢀTechnologiesꢀandꢀNovartisꢀforꢀfunding.ꢀWeꢀacknowledgeꢀtheꢀ
valuableꢀ assistanceꢀ ofꢀ Dr.ꢀ Annekeꢀ Lubbenꢀ (Massꢀ Spectrometry,ꢀ
Universityꢀ ofꢀ Bath),ꢀ Dr.ꢀ Johnꢀ Loweꢀ andꢀ Drꢀ Catherineꢀ Lyallꢀ (NMRꢀ
Spectroscopy,ꢀUniversityꢀofꢀBath).ꢀ
http://www.ccdc.cam.ac.uk/conts/retrieving.htmlꢀꢀ(orꢀfromꢀtheꢀ
CambridgeꢀCrystallographicꢀDataꢀCentre,ꢀ12,ꢀUnionꢀRoad,ꢀ
Cambridge,ꢀCB2ꢀ1EZ,ꢀUK;ꢀFax:ꢀ+44ꢀ1223ꢀ336033;ꢀemail:ꢀ
deposit@ccdc.cam.ac.uk).
ꢀ
1
1
2ꢀ Forꢀselectedꢀexamples,ꢀsee:ꢀ(a)ꢀC.ꢀLiu,ꢀD.ꢀLiu,ꢀW.ꢀZhang,ꢀL.ꢀZhou,ꢀandꢀ
A.ꢀLei,ꢀOrg.ꢀLett.,ꢀ2013,ꢀ15,ꢀ6166;ꢀ(b)ꢀX.ꢀWu,ꢀJ.ꢀW.ꢀT.ꢀSee,ꢀK.ꢀXu,ꢀH.ꢀ
Hirao,ꢀJ.ꢀRoger,ꢀJ.-C.ꢀHierso,ꢀandꢀJ.ꢀS.ꢀZhou,ꢀAngew.ꢀChemieꢀInt.ꢀEd.,ꢀ
Notesꢀandꢀreferencesꢀ
ꢀ
1
ꢀ
Forꢀselectedꢀreviews,ꢀsee:ꢀ(a)ꢀJ.ꢀYamaguchi,ꢀA.ꢀD.ꢀYamaguchiꢀandꢀK.ꢀ
Itami,ꢀAngew.ꢀChem.,ꢀInt.ꢀEd.,ꢀ2012,ꢀ51,ꢀ8960;ꢀ(b)ꢀL.ꢀMcMurray,ꢀF.ꢀ
O’HaraꢀandꢀM.ꢀJ.ꢀGaunt,ꢀ Chem.ꢀSoc.ꢀRev.,ꢀ2011,ꢀ40,ꢀ1885;ꢀ(c)ꢀC.-L.ꢀ
Sun,ꢀB.-J.ꢀLiꢀandꢀZ.-J.ꢀShi,ꢀChem.ꢀRev.,ꢀ2011,ꢀ111,ꢀ1293;ꢀ(d)ꢀJ.Wencel-
Delord,ꢀ T.ꢀ Droge,ꢀ F.ꢀ Liuꢀ andꢀ F.ꢀ Glorius,ꢀ Chem.ꢀ Soc.ꢀ Rev.,ꢀ 2011,ꢀ 40,ꢀ
2
014,ꢀ 53,ꢀ 13573;ꢀ (c)ꢀ T.ꢀ Nishikata,ꢀ Y.ꢀ Noda,ꢀ R.ꢀ Fujimoto,ꢀ andꢀ T.ꢀ
Sakashita,ꢀJ.ꢀAm.ꢀChem.ꢀSoc.,ꢀ2013,ꢀ135,ꢀ16372.ꢀ
3ꢀ Thisꢀ pathwayꢀ isꢀ alsoꢀ favouredꢀ onꢀ stericꢀ groundsꢀ whenꢀ substrateꢀ
bearingꢀaꢀmethylꢀgroupꢀatꢀtheꢀ2-positionꢀofꢀtheꢀaromaticꢀringꢀwasꢀ
usedꢀ(seeꢀsupportingꢀinformation).ꢀꢀ
4
740;ꢀ(e)ꢀC.ꢀS.ꢀYeungꢀandꢀV.ꢀM.ꢀDong,ꢀChem.ꢀRev.,ꢀ2011,ꢀ111,ꢀ1215;ꢀ
f)ꢀTopicsꢀinꢀCurrentꢀChemistry:ꢀC–HꢀActivation,ꢀed.ꢀJ.ꢀ-Q.ꢀYuꢀandꢀZ.ꢀ
Shi,ꢀ1stꢀedn,ꢀ2010,Springer,ꢀBerlinꢀHeidelberg.ꢀ
1
1
4ꢀ ꢀJ.ꢀJ.ꢀDeveryꢀIII,ꢀJ.ꢀJ.ꢀDouglas,ꢀJ.ꢀD.ꢀNguyen,ꢀK.ꢀP.ꢀCole,ꢀR.ꢀA.ꢀFlowersꢀII,ꢀ
andꢀC.ꢀR.ꢀJ.ꢀStephenson,ꢀChem.ꢀSci.,ꢀ2015,ꢀ6,ꢀ537.ꢀ
(
5ꢀ (a)ꢀE.ꢀFerrerꢀFlegeau,ꢀC.ꢀBruneau,ꢀP.ꢀH.ꢀDixneufꢀandꢀA.ꢀJutand,ꢀJ.ꢀAm.ꢀ
Chem.ꢀSoc.,ꢀ2011,ꢀ133,ꢀ10161.ꢀ(b)ꢀ ꢀL .ꢀ Ackermann,ꢀ Chem.ꢀ Rev.,ꢀ 2011,ꢀ
1
11,ꢀ1315.ꢀꢀ
4
ꢀ|ꢀJ.ꢀName.,ꢀ2012,ꢀ00,ꢀ1-3ꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
Pleaseꢀdoꢀnotꢀadjustꢀmarginsꢀ