Para-Selective, Iridium-Catalyzed C-H Borylations of Sulfated Phenols, Benzyl Alcohols, and Anilines Directed by Ion-Pair Electrostatic Interactions

Article abstract of DOI:10.1021/jacs.9b08464

Para C-H borylations (CHB) of tetraalkylammonium sulfates and sulfamates have been achieved using bipyridine-ligated Ir boryl catalysts. Selectivities can be modulated by both the length of the alkyl groups in the tetraalkylammonium cations and the substituents on the bipyridine ligands. Ion pairing, where the alkyl groups of the cation shield the meta C-H bonds in the counteranions, is proposed to account for para selectivity. The 4,4′-dimethoxy-2,2′-bipyridine ligand gave superior selectivities.

Full text of DOI:10.1021/jacs.9b08464

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Communication
Para-Selective, Iridium-Catalyzed C–H Borylations of Sulfated Phenols,
Benzyl Alcohols, and Anilines Directed by Ion-Pair Electrostatic Interactions
Jose R. Montero Bastidas, Thomas J Oleskey, Susanne L. Miller, Milton R. Smith, and Robert E. Maleczka
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b08464 • Publication Date (Web): 16 Sep 2019
Downloaded from pubs.acs.org on September 16, 2019
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Journal of the American Chemical Society
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Para-Selective, Iridium-Catalyzed C–H Borylations of Sulfated Phe-
nols, Benzyl Alcohols, and Anilines Directed by Ion-Pair Electrostatic
Interactions
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JoseꢀR.ꢀMonteroꢀBastidas,ꢀThomasꢀJ.ꢀOleskey, ꢀSusanneꢀL.ꢀMiller,ꢀMiltonꢀR.ꢀSmith,ꢀIII,*ꢀandꢀRobertꢀE.ꢀ
,
Maleczka,ꢀJr.*ꢀ
DepartmentꢀofꢀChemistry,ꢀMichiganꢀStateꢀUniversity,ꢀ578ꢀSouthꢀShawꢀLane,ꢀEastꢀLansing,ꢀMichiganꢀ48824,ꢀUnitedꢀStatesꢀ
SupportingꢀInformationꢀPlaceholder
ABSTRACT:ꢀParaꢀC–Hꢀborylationꢀ(CHB)ꢀofꢀtetraalkylammoniumꢀ
sulfatesꢀandꢀsulfamatesꢀhaveꢀbeenꢀachievedꢀusingꢀbipyridine-
ligatedꢀIrꢀborylꢀcatalysts.ꢀSelectivitiesꢀcanꢀbeꢀmodulatedꢀbothꢀ
byꢀtheꢀlengthꢀofꢀtheꢀalkylꢀgroupsꢀinꢀtheꢀtetraalkylammoniumꢀ
cationsꢀ andꢀ theꢀ substituentsꢀ onꢀ theꢀ bipyridineꢀ ligands.ꢀ Ion-
pairing,ꢀwhereꢀtheꢀalkylꢀgroupsꢀofꢀtheꢀcationꢀshieldꢀtheꢀmetaꢀ
C–Hꢀbondsꢀinꢀtheꢀcounter-anions,ꢀisꢀproposedꢀtoꢀaccountꢀforꢀ
paraꢀ selectivity.ꢀ Theꢀ 4,4´-dimethoxy-2,2´-bipyridineꢀ ligandꢀ
gaveꢀsuperiorꢀselectivities.ꢀ
theseꢀ limitations,ꢀ moreꢀ selectiveꢀ Irꢀ catalystsꢀ haveꢀ beenꢀ de-
signed.ꢀ Theꢀ firstꢀ examplesꢀ wereꢀ ortho-selective,ꢀ relyingꢀ onꢀ
13,14
stronglyꢀ coordinatingꢀ functionalꢀ groupsꢀ inꢀ theꢀ substrate,
whileꢀlaterꢀreportsꢀexploitedꢀweakerꢀinteractionsꢀforꢀorthoꢀse-
ꢀ
15,16
lectivity.
ꢀ
Forꢀtwoꢀcompetingꢀpathways,ꢀaꢀdifferenceꢀinꢀbarrierꢀheightsꢀ
-1
ofꢀ2.5ꢀkcal·mol ꢀisꢀsufficientꢀforꢀ99%ꢀofꢀtheꢀreactantsꢀtoꢀfollowꢀ
theꢀfavoredꢀpathwayꢀinꢀaꢀchemicalꢀreaction.ꢀThisꢀisꢀlowerꢀthanꢀ
theꢀbarrierꢀforꢀconvertingꢀtheꢀanti-conformerꢀofꢀbutaneꢀtoꢀtheꢀ
1
gaucheꢀform. ꢀInꢀtransition-metalꢀmediatedꢀreactions,ꢀaꢀclassicꢀ
modeꢀforꢀselectivelyꢀfunctionalizingꢀbondsꢀinꢀaꢀsubstrateꢀreliesꢀ
onꢀtheꢀcoordinationꢀofꢀanꢀatomꢀinꢀaꢀreactantꢀfunctionalꢀgroupꢀ
toꢀtheꢀmetalꢀcenterꢀofꢀaꢀcompoundꢀorꢀcatalyticꢀintermediate.ꢀ
Theꢀmagnitudesꢀofꢀtheꢀligand-metalꢀinteractionsꢀareꢀatꢀleastꢀanꢀ
orderꢀ ofꢀ magnitudeꢀ greaterꢀ thanꢀ theꢀ differenceꢀ inꢀ barrierꢀ
heightsꢀnecessaryꢀforꢀ99:1ꢀselectivity.ꢀConsequently,ꢀdesignꢀofꢀ
catalystsꢀwhereꢀselectivityꢀisꢀconferredꢀbyꢀweaklyꢀcoordinatingꢀ
2
groups, ꢀasꢀwellꢀasꢀcatalystsꢀthatꢀleverageꢀevenꢀweakerꢀinter-
actionsꢀ (e.g.ꢀ hydrogen-bonding,ꢀ ion-pairing,ꢀ dipole-dipole,ꢀ
3,4
etc.)ꢀforꢀselectiveꢀtransformations, ꢀisꢀattractingꢀsignificantꢀat-
tention.ꢀ
C–Hꢀfunctionalizationsꢀofferꢀbothꢀatomꢀandꢀstepꢀeconomicalꢀ
meansꢀofꢀconvertingꢀubiquitousꢀC–Hꢀbondsꢀtoꢀaꢀrangeꢀofꢀfunc-
5,6
tionalꢀgroups. ꢀC–Hꢀborylationsꢀ(CHBs)ꢀconvertꢀC–Hꢀbondsꢀtoꢀ
C–Bꢀbondsꢀandꢀareꢀmediatedꢀbyꢀbothꢀmetalꢀandꢀmetal-freeꢀcat-
7–9
alysts. ꢀCHBꢀreactionsꢀareꢀvaluableꢀdueꢀtoꢀ(i)ꢀfacileꢀsubstitu-
tionꢀofꢀtheꢀboronꢀmoietyꢀbyꢀnumerousꢀfunctionalꢀgroups,ꢀandꢀ
(
ii)ꢀ functionalꢀ groupꢀ toleranceꢀ ofꢀ CHBꢀ catalysts,ꢀ particularlyꢀ
thoseꢀcontainingꢀIr.ꢀꢀ
2
TheꢀfirstꢀIrꢀCHBꢀcatalystsꢀenabledꢀC(sp )–Hꢀfunctionalizationsꢀ
withꢀ highꢀ selectivityꢀ forꢀ theꢀ mostꢀ stericallyꢀ accessibleꢀ C–Hꢀ
Figureꢀ1.ꢀParaꢀC-Hꢀborylations.ꢀ
10–12
bonds.
ꢀInꢀsubstratesꢀwhereꢀmultipleꢀC–Hꢀbondsꢀareꢀsteri-
Byꢀ comparison,ꢀ metaꢀ andꢀ paraꢀ CHBsꢀ poseꢀ differentꢀ chal-
lengesꢀbecauseꢀtheirꢀC–Hꢀbondsꢀareꢀfurtherꢀfromꢀtheꢀfunctionalꢀ
group.ꢀOneꢀmeta-selectiveꢀCHBꢀhasꢀbeenꢀascribedꢀtoꢀaꢀclassicalꢀ
callyꢀaccessible,ꢀearlyꢀgenerationꢀcatalystsꢀoftenꢀgiveꢀisomerꢀ
mixtures,ꢀasꢀwellꢀasꢀmultiplyꢀborylatedꢀproducts.ꢀToꢀovercomeꢀ
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chelate-directedꢀmechanism, ꢀwhileꢀothersꢀrelyꢀonꢀIrꢀligandsꢀ
bearingꢀgroupsꢀthatꢀengageꢀinꢀnon-covalentꢀinteractionsꢀwithꢀ
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substrateꢀfunctionalꢀgroupsꢀtoꢀeffectꢀmetaꢀCHB.
ꢀꢀ
Figureꢀ1ꢀdepictsꢀapproachesꢀforꢀpara-selectiveꢀCHB.ꢀTheꢀfirstꢀ
CHBsꢀwithꢀhighꢀparaꢀselectivityꢀinvolvedꢀelectrophilicꢀadditionsꢀ
21
ofꢀboreniumꢀcationsꢀtoꢀarenesꢀbearingꢀortho,para-directors. ꢀ
Stericallyꢀ directedꢀ CHBsꢀ relyꢀ onꢀ hinderedꢀ phosphineꢀ ligandsꢀ
22
andꢀsubstratesꢀwithꢀlargeꢀsubstituents. ꢀMoreꢀrecently,ꢀparaꢀ
borylationsꢀofꢀestersꢀhaveꢀbeenꢀachievedꢀthroughꢀnon-cova-
lentꢀinteractionsꢀwithꢀKꢀionsꢀorꢀcoordinationꢀofꢀtheꢀesterꢀoxy-
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genꢀtoꢀhinderedꢀLewisꢀacids.
ꢀ
Figureꢀ2.ꢀLowestꢀenergyꢀconformationꢀgeometryꢀofꢀ1a’.ꢀ
OurꢀinspirationꢀwasꢀbasedꢀonꢀtheꢀPhipps’ꢀgroupꢀion-pairꢀdi-
19
Therefore,ꢀweꢀtestedꢀcommerciallyꢀavailableꢀsubstitutedꢀbi-
pyridineꢀandꢀphenanthrolineꢀligandsꢀ(Tableꢀ1)ꢀinꢀCHBꢀreactionsꢀ
runꢀatꢀ80ꢀ°C.ꢀTheꢀreactivityꢀofꢀtheꢀligandsꢀisꢀinꢀaccordanceꢀwithꢀ
rectedꢀCHBsꢀwithꢀoneꢀkeyꢀdifference. ꢀInsteadꢀofꢀusingꢀoppo-
sitelyꢀchargedꢀgroupsꢀonꢀtheꢀligandꢀandꢀsubstrate,ꢀcombina-
tionsꢀwhereꢀgroupsꢀonꢀtheꢀligandꢀandꢀsubstrateꢀhadꢀtheꢀsameꢀ
chargeꢀwereꢀsurveyedꢀwithꢀtheꢀexpectationꢀthatꢀparaꢀboryla-
tionꢀ wouldꢀ beꢀ favoredꢀ becauseꢀ electrostaticꢀ repulsionsꢀ be-
tweenꢀtheꢀligandꢀandꢀsubstrateꢀwouldꢀbeꢀminimized.ꢀHowever,ꢀ
aꢀ controlꢀ experimentꢀ whereꢀ tetrabutylammoniumꢀ 2-chloro-
phenylꢀsulfateꢀ(1a´)ꢀwasꢀsubjectedꢀtoꢀstandardꢀborylationꢀcon-
26
previouslyꢀnotedꢀelectronicꢀeffects, ꢀwithꢀelectronꢀrichꢀligandsꢀ
affordingꢀaꢀmoreꢀactiveꢀsystemꢀrelativeꢀtoꢀelectronꢀpoorꢀlig-
ands.ꢀ Theꢀ borylationꢀ inꢀ THFꢀ withꢀ 4,4´-dimethoxy-2,2´-bipyri-
dineꢀ(L5)ꢀasꢀtheꢀligandꢀwentꢀtoꢀ100%ꢀconversionꢀandꢀaffordedꢀ
theꢀbestꢀparaꢀselectivityꢀ(13:1).ꢀThisꢀobservationꢀisꢀnotableꢀinꢀ
thatꢀL5ꢀisꢀaꢀnon-traditionalꢀCHBꢀligand.ꢀSwitchingꢀtheꢀsolventꢀtoꢀ
dioxaneꢀslightlyꢀincreasedꢀtheꢀparaꢀselectivity,ꢀwhereasꢀotherꢀ
apolarꢀsolventsꢀworsenedꢀregioselectivityꢀ(seeꢀSIꢀforꢀdetails).ꢀ
Runningꢀtheꢀreactionsꢀatꢀlowerꢀtemperatureꢀ(60ꢀ°Cꢀ(entryꢀ10)ꢀ
andꢀ 40ꢀ °Cꢀ (entryꢀ 11))ꢀ furtherꢀ improvedꢀ theꢀ paraꢀ selectivityꢀ
whileꢀstillꢀallowingꢀforꢀfullꢀconversion.ꢀTheꢀreactionꢀatꢀroomꢀ
temperatureꢀ (entryꢀ 12)ꢀ affordedꢀ 21:1ꢀ paraꢀ selectivity,ꢀ butꢀ
startingꢀmaterialꢀremainedꢀevenꢀafterꢀ50ꢀh.ꢀ
ditionsꢀwithꢀaꢀneutralꢀbipyridineꢀligandꢀ(sealedꢀtubeꢀwithꢀB
2 2
pin ꢀ
asꢀtheꢀboronꢀsource,ꢀ1.5ꢀmolꢀ%ꢀ[Ir(cod)OMe] ꢀasꢀtheꢀprecata-
2
lystꢀandꢀ3ꢀmolꢀ%ꢀdtbpyꢀasꢀtheꢀligand,ꢀinꢀTHFꢀatꢀ80ꢀ°C)ꢀshowedꢀ
promisingꢀresultsꢀwithꢀ6:1ꢀparaꢀtoꢀmetaꢀregioselectivityꢀ(Tableꢀ
1,ꢀentryꢀ1).ꢀWeꢀhypothesizedꢀthatꢀsubstrateꢀion-pairingꢀinter-
actions,ꢀwhereꢀtheꢀn-butylꢀgroupsꢀofꢀtheꢀcationꢀshieldꢀtheꢀmetaꢀ
C–Hꢀbondsꢀofꢀtheꢀcounter-anions,ꢀaccountedꢀforꢀtheꢀparaꢀse-
lectivity.ꢀꢀ
Withꢀ theꢀ experimentsꢀ inꢀ Tableꢀ 1ꢀ establishingꢀ 4,4´-di-
methoxy-2,2´-bipyridineꢀandꢀdioxaneꢀasꢀourꢀligandꢀandꢀsolventꢀ
ofꢀ choice,ꢀ weꢀ nextꢀ investigatedꢀ theꢀ effectꢀ ofꢀ theꢀ
tetraalkylammoniumꢀsaltꢀonꢀparaꢀselectivity.ꢀDFTꢀgeometryꢀop-
timizationꢀofꢀ1a’ꢀ(Figureꢀ2),ꢀusingꢀB3LYPꢀfunctionalꢀandꢀ6-31G*ꢀ
basisꢀsetꢀforꢀallꢀtheꢀatomsꢀsuggestedꢀtoꢀusꢀthatꢀaꢀslightlyꢀshorterꢀ
alkylꢀchainꢀwouldꢀstillꢀblockꢀtheꢀmetaꢀpositionꢀbutꢀleaveꢀtheꢀ
paraꢀ positionꢀ moreꢀ exposed,ꢀ thusꢀ potentiallyꢀ leadingꢀ toꢀ im-
provedꢀ paraꢀ selectivity.ꢀ Asꢀ shownꢀ inꢀ Schemeꢀ 1,ꢀ theꢀ CHBꢀ ofꢀ
tetrapropylammoniumꢀ 2-chlorophenylꢀ sulfateꢀ (1a)ꢀ validatedꢀ
thisꢀhypothesis,ꢀasꢀrunningꢀtheꢀreactionꢀwithꢀligandꢀL5ꢀinꢀdiox-
aneꢀatꢀ40ꢀ°Cꢀpushedꢀtheꢀparaꢀselectivityꢀtoꢀ22:1.ꢀWeꢀalsoꢀexam-
inedꢀ tetraethylammoniumꢀ 2-chlorophenylꢀ sulfateꢀ (1a”)ꢀ asꢀ aꢀ
substrate.ꢀInꢀtermsꢀofꢀchainꢀshortening,ꢀclearlyꢀdiminishingꢀre-
turnsꢀhadꢀsetꢀinꢀasꢀtheꢀparaꢀselectivityꢀdecreasedꢀtoꢀ6:1.ꢀ
InꢀNakao’sꢀstudy,ꢀligandꢀgeometryꢀplayedꢀaꢀkeyꢀroleꢀinꢀen-
24
hancementꢀ ofꢀ theꢀ paraꢀ selectivity. ꢀ Similarly,ꢀ weꢀ haveꢀ ob-
servedꢀ thatꢀ ligandꢀ choiceꢀ canꢀ impactꢀ CHBꢀ regiochemistryꢀ
whereꢀ thereꢀ isꢀ littleꢀ stericꢀ differentiationꢀ betweenꢀ differentꢀ
25ꢀ
areneꢀC–Hꢀbonds.
Tableꢀ1.ꢀLigandꢀEffectꢀonꢀParaꢀCHBꢀofꢀ1a’ꢀ
Basedꢀonꢀourꢀresults,ꢀweꢀchoseꢀtoꢀtestꢀaꢀseriesꢀofꢀphenolꢀde-
aꢀ
aꢀ
+
entryꢀ
ligandꢀ(Rꢀ=)ꢀ
solventꢀ
THFꢀ
TꢀºCꢀ conv.
p:m
rivedꢀsulfatesꢀwithꢀn-Pr
4
N ꢀasꢀtheꢀcounterionꢀtoꢀdetermineꢀsub-
strateꢀscope.ꢀAsꢀillustratedꢀinꢀSchemeꢀ2,ꢀborylationsꢀofꢀaꢀseriesꢀ
ofꢀ2-substitutedꢀphenolꢀderivedꢀsulfatesꢀproducedꢀtheꢀparaꢀre-
gioisomerꢀasꢀtheꢀmajorꢀisomer,ꢀoftenꢀwithꢀ>20:1ꢀselectivity.ꢀ
Mostꢀisolatedꢀyieldsꢀwereꢀinꢀtheꢀ70–80%ꢀrange.ꢀNotablyꢀuponꢀ
1
2
3
4
5
6
7
8
9
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
t-Buꢀ(L1)ꢀ
CNꢀ(L2)ꢀ
80ꢀ
80ꢀ
80ꢀ
80ꢀ
80ꢀ
80ꢀ
80ꢀ
80ꢀ
80ꢀ
60ꢀ
40ꢀ
rtꢀ
100ꢀ
6:1ꢀ
NDꢀ
THFꢀ
0ꢀ
Hꢀ(L3)ꢀ
THFꢀ
89ꢀ
7:1ꢀ
Meꢀ(L4)ꢀ
OMeꢀ(L5)ꢀ
tmphenꢀ(L6)ꢀ
phenꢀ(L7)ꢀ
NMe2ꢀ(L8)ꢀ
OMeꢀ(L5)ꢀ
OMeꢀ(L5)ꢀ
OMeꢀ(L5)ꢀ
OMeꢀ(L5)ꢀ
1
THFꢀ
96ꢀ
10:1ꢀ
13:1ꢀ
6:1ꢀ
THFꢀ
100ꢀ
100ꢀ
45ꢀ
100ꢀ
100ꢀ
100ꢀ
100ꢀ
83ꢀ
Schemeꢀ1.ꢀEffectꢀofꢀalkylꢀchainꢀlengthꢀonꢀregioselectivityꢀ
THFꢀ
THFꢀ
9:1ꢀ
dioxaneꢀ
dioxaneꢀ
dioxaneꢀ
dioxaneꢀ
dioxaneꢀ
12:1ꢀ
14:1ꢀ
16:1ꢀ
17:1ꢀ
21:1ꢀ
1
1
0ꢀ
ꢀ
1
bꢀ
12
a
b
Determinedꢀbyꢀ HꢀNMRꢀanalysis.ꢀ Reactionꢀcarriedꢀoutꢀfor
0ꢀhꢀ
5
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aꢀ
aꢀ
Schemeꢀ2.ꢀBorylationꢀofꢀphenolꢀderivedꢀsulfates
Schemeꢀ3.ꢀBorylationꢀofꢀanilineꢀderivedꢀsulfamates
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a
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19
Para/metaꢀratiosꢀwereꢀmeasuredꢀbyꢀ H-NMRꢀ(orꢀ F-NMRꢀfor
4c’)ꢀonꢀcrudeꢀreactionꢀmixturesꢀofꢀtheꢀborylatedꢀsulfates.ꢀYields
referꢀtoꢀisolatedꢀmaterialꢀwithꢀtheꢀpara/metaꢀratioꢀofꢀtheꢀisolatedꢀ
materialꢀgivenꢀinꢀparentheses.ꢀSeeꢀtheꢀSIꢀforꢀexperimentalꢀdetails,
b
includingꢀpreparationsꢀofꢀtheꢀstartingꢀsulfamates.ꢀ Runꢀwithꢀthe
+
c
4
n-Pr N ꢀcounterion.ꢀ Productꢀisolatedꢀasꢀtheꢀacetamide.ꢀ
borylatedꢀtheꢀsulfateꢀofꢀphenolꢀandꢀobservedꢀtheꢀpara,ꢀmeta,ꢀ
andꢀ3,5-dimetaꢀborylatedꢀproductsꢀinꢀaꢀratioꢀofꢀ4.4:1.1.8,ꢀorꢀaꢀ
para/metaꢀratioꢀofꢀ1.6:1.ꢀThisꢀresultꢀisꢀconsistentꢀwithꢀtheꢀas-
sumptionꢀthatꢀtheꢀion-pairingꢀcanꢀonlyꢀblockꢀoneꢀmetaꢀsiteꢀandꢀ
thusꢀtheꢀreactionsꢀneedꢀaꢀ2-substituentꢀtoꢀstericallyꢀblockꢀtheꢀ
secondꢀmetaꢀCHꢀbond.ꢀ
Turningꢀ toꢀ anilinesꢀ (Schemeꢀ 3),ꢀ weꢀ subjectedꢀ tetraprop-
ylammoniumꢀ2-chlorophenylsulfamateꢀ(3a)ꢀtoꢀourꢀnowꢀstand-
ardꢀconditions.ꢀTheꢀparaꢀselectivityꢀ(40:1)ꢀwasꢀevenꢀbetterꢀthanꢀ
thatꢀobservedꢀforꢀ1a.ꢀQuestioningꢀifꢀtheꢀchainꢀlengthꢀofꢀtheꢀ
tetraalkylammoniumꢀsaltꢀwouldꢀalsoꢀimpactꢀtheꢀparaꢀselectiv-
ityꢀforꢀanilineꢀderivatives,ꢀweꢀpreparedꢀandꢀreactedꢀtheꢀtet-
rabutylammoniumꢀsaltꢀ(3a’).ꢀInꢀcontrastꢀtoꢀtheꢀphenolꢀsulfates,ꢀ
employingꢀthisꢀcounterionꢀmetꢀwithꢀ43:1ꢀparaꢀselectivityꢀandꢀaꢀ
higherꢀisolatedꢀyield.ꢀOwingꢀtoꢀthisꢀresultꢀandꢀthatꢀtheꢀtetrabu-
a
1
Para/metaꢀratiosꢀwereꢀmeasuredꢀbyꢀ H-NMRꢀonꢀcrudeꢀreactionꢀ
mixturesꢀofꢀtheꢀborylatedꢀsulfates.ꢀYieldsꢀreferꢀtoꢀisolatedꢀmaterial
withꢀtheꢀpara/metaꢀratioꢀofꢀtheꢀisolatedꢀmaterialꢀgivenꢀinꢀparen-
thesesꢀ(2oꢀandꢀ2pꢀwereꢀnotꢀisolated).ꢀSeeꢀtheꢀSIꢀforꢀexperimental
details,ꢀincludingꢀpreparationsꢀofꢀtheꢀstartingꢀsulfates.ꢀ
tylammoniumꢀsaltsꢀareꢀsomewhatꢀeasierꢀtoꢀprepareꢀandꢀiso-
+
late,ꢀweꢀchoseꢀn-Bu
4
N ꢀasꢀtheꢀcounterionꢀforꢀCHB’sꢀofꢀaꢀseriesꢀ
ofꢀ anilineꢀ sulfamates.ꢀ Theꢀ paraꢀ selectivitiesꢀ forꢀ 3b’,ꢀ andꢀ 3d’ꢀ
wereꢀexcellent,ꢀwhileꢀagainꢀselectivityꢀforꢀaꢀ3-fluoroꢀsubstrateꢀ
isolationꢀtheꢀparaꢀtoꢀmetaꢀisomerꢀwasꢀenhanced,ꢀinꢀsomeꢀcasesꢀ
toꢀ>50:1.ꢀꢀ
(
3c’)ꢀsuffered,ꢀgivingꢀonlyꢀaꢀ2.4:1ꢀpara/metaꢀratio.ꢀIsolationꢀofꢀ
2
7
theꢀhydrolyzedꢀanilineꢀfollowingꢀborylationꢀofꢀ3cʹꢀprovedꢀdiffi-
cult.ꢀTherefore,ꢀtheꢀreactionꢀwasꢀquenchedꢀwithꢀacetylꢀchlo-
ride,ꢀfacilitatingꢀtheꢀisolationꢀofꢀ4cʹ.ꢀꢀ
Givenꢀ thatꢀ CHBꢀ orthoꢀ toꢀ smallꢀ substituentsꢀ isꢀ common, ꢀ
borylationꢀatꢀtheꢀC-3ꢀandꢀC-5ꢀmetaꢀCHꢀbondsꢀofꢀ2-fluoro-ꢀ(1e)ꢀ
andꢀ2-cyanophenolꢀsulfateꢀ(1i)ꢀareꢀpossible.ꢀIndeed,ꢀanalysisꢀofꢀ
theꢀcrudeꢀreactionꢀmixtureꢀindicatedꢀthatꢀ1iꢀgaveꢀaꢀmixtureꢀofꢀ
theꢀparaꢀtoꢀ5-Bpinꢀtoꢀ3,5-diBpinꢀproductsꢀinꢀaꢀratioꢀofꢀapproxi-
matelyꢀ7.5:1:0.4.ꢀForꢀsubstratesꢀ1eꢀandꢀ1lꢀ,theꢀobservedꢀminorꢀ
isomerꢀwasꢀthatꢀwithꢀtheꢀBpinꢀorthoꢀtoꢀtheꢀfluoroꢀgroupꢀandꢀnoꢀ
diborylationꢀwasꢀobserved.ꢀGivenꢀthisꢀpreference,ꢀitꢀwasꢀper-
hapsꢀ somewhatꢀ surprisingꢀ thatꢀ 3-fluorophenolꢀ sulfateꢀ (1d)ꢀ
producedꢀaꢀrelativelyꢀlargeꢀamountꢀofꢀtheꢀmetaꢀregioisomer.ꢀ
Finally,ꢀweꢀsurveyedꢀthreeꢀbenzylꢀalcoholꢀderivedꢀsulfatesꢀ
(
Schemeꢀ 4).ꢀ Generally,ꢀ theseꢀ substratesꢀ reactedꢀ withꢀ some-
whatꢀdiminishedꢀparaꢀselectivityꢀrelativeꢀtoꢀtheirꢀphenolꢀandꢀ
anilineꢀcounterparts.ꢀProductsꢀ6bꢀandꢀ6dꢀwereꢀgeneratedꢀinꢀ
lowerꢀyieldsꢀowingꢀinꢀpartꢀtoꢀlowerꢀconversionsꢀandꢀforꢀ6d,ꢀlossꢀ
ofꢀmetaꢀisomerꢀuponꢀisolation.ꢀAgain,ꢀborylationꢀofꢀaꢀsubstrateꢀ
withꢀ fluorineꢀ inꢀ theꢀ 2-positionꢀ (5g)ꢀ affordedꢀ aꢀ significantꢀ
amountꢀofꢀproductꢀwithꢀtheꢀBpinꢀorthoꢀtoꢀtheꢀfluorine.ꢀApply-
ꢀ
NotꢀsurprisingꢀwasꢀthatꢀtheꢀCHBꢀofꢀ3-substitutedꢀphenolꢀsul-
+
ingꢀtheꢀCHBꢀconditionsꢀtoꢀtheꢀn-Bu
4
N ꢀcounterion,ꢀ5a–5cꢀre-
fatesꢀ(1n-p)ꢀgaveꢀtheꢀmetaꢀisomerꢀasꢀtheꢀmajorꢀproduct,ꢀshow-
ingꢀthatꢀsuchꢀion-pairꢀinteractionsꢀareꢀlimitedꢀinꢀtheirꢀabilityꢀtoꢀ
overcomeꢀ stericꢀ crowdingꢀ ofꢀ theꢀ paraꢀ CHꢀ position.ꢀ Last,ꢀ weꢀ
vealedꢀthatꢀtheꢀcounterionꢀhasꢀaꢀsimilarꢀinfluenceꢀonꢀtheꢀregi-
oselectivityꢀasꢀobservedꢀforꢀtheꢀphenols.ꢀꢀ
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 7
Notes
Schemeꢀ 4.ꢀ Borylationꢀ ofꢀ benzylꢀ alcoholꢀ derivedꢀ sul-
fates ꢀ
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9
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6
ConflictꢀofꢀInterest:ꢀS.L.M.,ꢀM.R.S.,ꢀandꢀR.E.M.ꢀownꢀaꢀpercent-
ageꢀofꢀBoroPharm,ꢀInc.ꢀ
a
ACKNOWLEDGMENT
WeꢀthankꢀDrs.ꢀDanielꢀHolmesꢀandꢀLiꢀXieꢀofꢀtheꢀMax.ꢀT.ꢀRogersꢀNMRꢀ
FacilityꢀandꢀtheꢀMSUꢀRTSFꢀMassꢀSpectrometryꢀCoreꢀforꢀtheirꢀassis-
tanceꢀ inꢀ compoundꢀ characterization.ꢀ Weꢀ thankꢀ theꢀ NIHꢀ
(GM63188)ꢀforꢀfinancialꢀsupportꢀandꢀBoroPharm,ꢀInc.ꢀforꢀaꢀgiftꢀofꢀ
B
2
pin
2
.ꢀ
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b
(
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1
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+
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4
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4
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28
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ASSOCIATED CONTENT
Supportingꢀ Information.ꢀ Experimentalꢀ procedures,ꢀ includingꢀ
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(
15)ꢀRoosen,ꢀP.ꢀC.;ꢀKallepalli,ꢀV.ꢀA.;ꢀChattopadhyay,ꢀB.;ꢀSingleton,ꢀD.ꢀ
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AUTHOR INFORMATION
Corresponding Author
*
*
ꢀEmail:ꢀsmithmil@msu.eduꢀ
ꢀEmail:ꢀmaleczka@chemistry.msu.eduꢀ
7
871.ꢀ
ACS Paragon Plus Environment

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Journal of the American Chemical Society
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(28)ꢀDuringꢀpreparationꢀofꢀourꢀmanuscriptꢀweꢀbecameꢀawareꢀthatꢀ
theꢀPhippsꢀgroupꢀhadꢀdevelopedꢀaꢀsimilarꢀapproachꢀtoꢀpara-selectiveꢀ
borylation.ꢀWeꢀareꢀgratefulꢀtoꢀthemꢀforꢀagreeingꢀtoꢀpublishꢀtheirꢀre-
sultsꢀinꢀaꢀback-to-backꢀfashionꢀwithꢀourꢀown.ꢀ
HꢀBorylationꢀDirectedꢀbyꢀaꢀSecondaryꢀInteractionꢀbetweenꢀLigandꢀandꢀ
Substrate.ꢀNat.ꢀChem.ꢀ2015,ꢀ7,ꢀ712–717.ꢀ
(
controlꢀinꢀTransition-MetalꢀCatalysis:ꢀAꢀMeta-SelectiveꢀC-HꢀBorylationꢀ
ofꢀ Aromaticꢀ Quaternaryꢀ Ammoniumꢀ Salts.ꢀ J.ꢀ Am.ꢀ Chem.ꢀ Soc.ꢀ 2016,ꢀ
138,ꢀ12759–12762.ꢀ
19)ꢀDavis,ꢀH.ꢀJ.;ꢀMihai,ꢀM.ꢀT.;ꢀPhipps,ꢀR.ꢀJ.ꢀIonꢀPair-DirectedꢀRegio-
(
20)ꢀYang,ꢀL.;ꢀUemura,ꢀN.;ꢀNakao,ꢀY.ꢀMeta-SelectiveꢀC–HꢀBorylationꢀ
ofꢀBenzamidesꢀandꢀPyridinesꢀbyꢀanꢀIridium–LewisꢀAcidꢀBifunctionalꢀ
Catalyst.ꢀJ.ꢀAm.ꢀChem.ꢀSoc.ꢀ2019,ꢀ141,ꢀ7972–7979.ꢀ
(
PinacolꢀBoronatesꢀbyꢀDirectꢀAreneꢀBorylationꢀwithꢀBoreniumꢀCations.ꢀ
Angew.ꢀChem.ꢀInt.ꢀEd.ꢀ2011,ꢀ50,ꢀ2102–2106.ꢀ
(22)ꢀSaito,ꢀY.;ꢀSegawa,ꢀY.;ꢀItami,ꢀK.ꢀPara-C–HꢀBorylationꢀofꢀBenzeneꢀ
DerivativesꢀbyꢀaꢀBulkyꢀIridiumꢀCatalyst.ꢀJ.ꢀAm.ꢀChem.ꢀSoc.ꢀ2015,ꢀ137,ꢀ
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21)ꢀꢀ DelꢀGrosso,ꢀA.;ꢀSingleton,ꢀP.ꢀJ.;ꢀMuryn,ꢀC.ꢀA.;ꢀIngleson,ꢀM.ꢀJ.ꢀ
5
193–5198.ꢀ
23)ꢀHoque,ꢀM.ꢀE.;ꢀBisht,ꢀR.;ꢀHaldar,ꢀC.;ꢀChattopadhyay,ꢀB.ꢀNoncova-
(
lentꢀInteractionsꢀinꢀIr-CatalyzedꢀC-HꢀActivation:ꢀL-ShapedꢀLigandꢀforꢀ
Para-SelectiveꢀBorylationꢀofꢀAromaticꢀEsters.ꢀJ.ꢀAm.ꢀChem.ꢀSoc.ꢀ2017,ꢀ
139,ꢀ7745–7748.ꢀ
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SYNOPSISꢀTOCꢀ(WordꢀStyleꢀ“SN_Synopsis_TOC”).ꢀIfꢀyouꢀareꢀsubmittingꢀyourꢀpaperꢀtoꢀaꢀjournalꢀthatꢀrequiresꢀaꢀsynopsisꢀgraphicꢀ
and/orꢀsynopsisꢀparagraph,ꢀseeꢀtheꢀInstructionsꢀforꢀAuthorsꢀonꢀtheꢀjournal’sꢀhomepageꢀforꢀaꢀdescriptionꢀofꢀwhatꢀneedsꢀtoꢀbeꢀ
providedꢀandꢀforꢀtheꢀsizeꢀrequirementsꢀofꢀtheꢀartwork.ꢀ
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AuthorsꢀareꢀrequiredꢀtoꢀsubmitꢀaꢀgraphicꢀentryꢀforꢀtheꢀTableꢀofꢀContentsꢀ(TOC)ꢀthat,ꢀinꢀconjunctionꢀwithꢀtheꢀmanuscriptꢀtitle,ꢀ
shouldꢀgiveꢀtheꢀreaderꢀaꢀrepresentativeꢀideaꢀofꢀoneꢀofꢀtheꢀfollowing:ꢀAꢀkeyꢀstructure,ꢀreaction,ꢀequation,ꢀconcept,ꢀorꢀtheorem,ꢀ
etc.,ꢀthatꢀisꢀdiscussedꢀinꢀtheꢀmanuscript.ꢀConsultꢀtheꢀjournal’sꢀInstructionsꢀforꢀAuthorsꢀforꢀTOCꢀgraphicꢀspecifications.
O
O
1
.5 equiv B2pin2
S
O
O
S
O
O
1
.5 mol % [Ir(cod)OMe]2
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NPr3
R
R
MeO
OMe
N+
n-Pr
4
3
mol %
N
N
Bpin
dioxane (0.22 M)
0 °C, 16 h
4
ꢀ
6
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Figure 2. Lowest energy conformation geometry of 1a
162x103mm (200 x 200 DPI)
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