Room-Temperature meta-Functionalization: Pd(II)-Catalyzed Synthesis of 1,3,5-Trialkenyl Arene and meta-Hydroxylated Olefin

Article abstract of DOI:10.1021/acscatal.6b00675

Development of meta-C-H functionalization reactions at room temperature continues to be a tough challenge. Use of a phosphonate linkage allowed a Pd (II)-catalyzed meta-C-H functionalization at room temperature while incorporating a cyanophenol-based dire

Full text of DOI:10.1021/acscatal.6b00675

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Letter
Room-Temperature meta-Functionalization: Pd(II)-Catalyzed
Synthesis of 1,3,5-trialkenyl Arene and meta-Hydroxylated Olefin
Milan Bera, Santosh Kumar Sahoo, and Debabrata Maiti
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b00675 • Publication Date (Web): 27 Apr 2016
Downloaded from http://pubs.acs.org on April 27, 2016
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ACS Catalysis
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Room-Temperatureꢀmeta-Functionalization:ꢀPd(II)-CatalyzedꢀSyn-
thesisꢀofꢀ1,3,5-trialkenylꢀAreneꢀandꢀmeta-HydroxylatedꢀOlefinꢀꢀ
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MilanꢀBera,*ꢀSantoshꢀK.ꢀSahoo,ꢀandꢀDebabrataꢀMaiti*ꢀ
DepartmentꢀofꢀChemistry,ꢀIndianꢀInstituteꢀofꢀTechnologyꢀBombay,ꢀPowai,ꢀMumbai-400076,ꢀIndiaꢀ
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SupportingꢀInformationꢀPlaceholderꢀ
ABSTRACT:ꢀDevelopmentꢀofꢀmeta-C–Hꢀfunctionalizationꢀreactionsꢀatꢀroomꢀtemperatureꢀcontinuesꢀtoꢀbeꢀaꢀtoughꢀchallenge.ꢀUseꢀ
ofꢀ phosphonateꢀ linkageꢀ allowedꢀ aꢀ Pdꢀ (II)-catalyzedꢀ meta-C–Hꢀ functionalizationꢀ atꢀ roomꢀ temperatureꢀ whileꢀ incorporatingꢀ aꢀ
cyanophenolꢀ basedꢀ directingꢀ moiety.ꢀ Successfulꢀ implementationꢀ ofꢀ sequentialꢀ di-meta-olefinationꢀ ledꢀ toꢀ theꢀ synthesisꢀ ofꢀ tri-
alkenylꢀareneꢀhavingꢀapplicationsꢀinꢀorganicꢀelectronicsꢀandꢀoptoelectronics.ꢀUnderꢀrobustꢀconditions,ꢀC–Oꢀbondꢀformationꢀhasꢀ
beenꢀdiscoveredꢀforꢀtheꢀmeta-hydroxylationꢀandꢀmeta-acetoxylation.ꢀ
Keywords:ꢀ Meta-olefination,ꢀ hydroxylation,ꢀ acetoxylation,ꢀ room-temperature,ꢀ 1,3,5-trialkenylꢀ arene,ꢀ meta-hydroxyꢀ olefin,ꢀ
Palladium.ꢀ
ꢀ
ꢀꢀꢀꢀOrganophosphonatesꢀ haveꢀ playedꢀ importantꢀ roleꢀ inꢀ bio-
selectivityꢀ wasꢀ achievedꢀ forꢀ theꢀ meta-olefinationꢀ reaction.ꢀ
Furthermore,ꢀ meta-selectiveꢀ C–Oꢀ bondꢀ formationꢀ reactionsꢀ
canꢀbeꢀpromotedꢀbyꢀusingꢀthisꢀscaffold.ꢀDirectꢀhydroxylationꢀ
hasꢀ beenꢀ achievedꢀ underꢀ mildꢀ oxidizingꢀ conditionꢀ usingꢀ
PhI(TFA)
hydrolysis.ꢀꢀ
1
organicꢀchemistryꢀandꢀpharmaceuticals. ꢀTheseꢀareꢀpowerfulꢀ
synthonsꢀ forꢀ aꢀ numberꢀ ofꢀ usefulꢀ syntheticꢀ transformationsꢀ
includingꢀtheꢀpreparationꢀofꢀalkenylꢀderivativesꢀviaꢀHorner-
Wadsworth-Emmonsꢀ reactions. ꢀ Recently,ꢀ directedꢀ C–Hꢀ
functionalizationsꢀofꢀphosphonatesꢀhaveꢀalsoꢀbeenꢀstudied. ꢀꢀ
2
2
ꢀasꢀtheꢀhydroxylatingꢀagentꢀfollowedꢀbyꢀitsꢀin-situꢀ
3
ꢀ
ꢀꢀꢀꢀAlthoughꢀ transitionꢀ metalꢀ catalyzedꢀ ortho-C–Hꢀ
Pd(OAc)2 (10 mol%)
Ac-Phe-OH (20 mol%)
Ag CO (2 equiv)
O
4
functionalizationꢀreactionsꢀareꢀwellꢀexplored, ꢀrelatedꢀmeta-
C–Hꢀ activationꢀ posesꢀ aꢀ significantꢀ challenge. ꢀ Regardlessꢀ ofꢀ
P
OEt
DG
DG =
O
R
5
2
3
O
P
OEt HFIP (1.5 mL)
DG
R
CN
theꢀfunctionalization,ꢀaꢀsuccessfulꢀmeta-C–Hꢀbondꢀactivationꢀ
reliesꢀ onꢀ theꢀ perfectꢀ designꢀ ofꢀ theꢀ directingꢀ groupꢀ (DG)ꢀ
linkage,ꢀ coordinatingꢀ siteꢀ andꢀ theꢀ choiceꢀ ofꢀ metals.ꢀ
Overcomingꢀ theseꢀ significantꢀ difficulties,ꢀ DGꢀ assistedꢀ
oxidativeꢀmeta-selectiveꢀfunctionalizationꢀofꢀareneꢀhasꢀbeenꢀ
RT, 36h
0.4 mmol
R
2
R1
H
R1
R
2
0.2 mmol
isolated
O
O
P
R = CO Et; 2a, 84%
P
OEt
2
OEt
DG
2
R = CO Me; 2b, 82%
6
DG
pioneeredꢀbyꢀYu. ꢀInꢀthisꢀcontext,ꢀweꢀhaveꢀdemonstratedꢀtheꢀ
R = CO Bn; 2c, 68%
2
R1 = Me; 2f, 78%
R1 = Ph; 2g, 75%
R = COMe; 2d, 80%
potentialꢀ ofꢀ commerciallyꢀ available,ꢀ simpleꢀ 2-cyanophenolꢀ
2
R = P(O)(OEt) ; 2e, 65%
SO
2
R1
moietyꢀ asꢀ theꢀ directingꢀ scaffoldꢀ forꢀ meta-C–Hꢀ
functionalizationꢀreactions. ꢀ
R
7
O
P
O
O
P
P
OEt
OEt
DG
R4
R3
R1
OEt
DG
DG
h, 82%
DG
2
2i, 71%
2j, 79%
MeOC
2
EtO C
OH
O2S
2
CO Et
3-hydroxy olefin
1,3,5-trialkenyl arene
R2
O
O
P
P
O
OEt
DG
OEt
DG
DG
meta-C−H olefination at room temparature
Excellent meta-selectivity
P
OEt
DG
R2
R2 = Me; 2m, 74%c
R2 = OMe; 2n, 75%c
2k, 56%b
b
This Work
Commercially available directing group
Easily removable phosphonate linker
Wide synthetic applicability
O
2l, 61%
FG
2
CO Et
2
= CMe ; 2o, 15%b,c
meta-selective C-C &
C-O bond formation
R
3
NO
2
OAc
O
P
O
O
O
O
P
OR2
OEt
F
O1 Et
P
meta
P
P
P
ortho
ref. 3
OEt
OEt
DG
OEt
DG
OEt
OR
FG
This Work
OR
F DG
Cl
Br
FG
R1 = H, OEt
R2 = DG
ꢀ
2p, 76%
CO Et
2q, 74%
CO Et
2r, 84%
CO Et
2
Schemeꢀ1.ꢀOverviewꢀofꢀtheꢀpresentꢀworkꢀꢀ
2
2
R3
O
R4
O
Br
ꢀꢀꢀꢀꢀDespiteꢀtheseꢀrecentꢀdevelopments,ꢀmeta-C–Hꢀactivationꢀ
methodsꢀstillꢀrequireꢀelevatedꢀtemperature.ꢀFurther,ꢀtheꢀlackꢀ
ofꢀ selectivityꢀ forꢀ mono-meta-ꢀ vs.ꢀ bis-meta-functionalizationꢀ
encouragedꢀusꢀtoꢀponderꢀforꢀaꢀmildꢀreactionꢀconditionꢀthatꢀ
wouldꢀ allowꢀ aꢀ completeꢀ mono-selectiveꢀ meta-
O
P
P
OEt
DG
OEt
P
OEt
DG
DG
F
R3 = Br; 2s, 81%
R3 = Me; 2t, 77%
R4 = Br; 2u, 82%
R4 = Me; 2v, 80%
2
w, 75%
2
CO Et
2
CO Et
2
CO Et
8
ꢀ
functionalizationꢀofꢀarenes. ꢀꢀ
b
o
c
meta-selectivity>20:1;ꢀ reactionꢀ performedꢀ atꢀ 80sꢀ C,ꢀ reactionꢀ
performedꢀuptoꢀ48ꢀh.ꢀAc-Phe-OH,ꢀN-acetylꢀphenylalanine.ꢀ
ꢀ
ꢀꢀꢀꢀWeꢀ reportꢀ hereinꢀ theꢀ firstꢀ exampleꢀ ofꢀ Pd(II)-catalyzedꢀ
meta-C–Hꢀolefinationꢀofꢀareneꢀatꢀroomꢀtemperatureꢀ(Schemeꢀ
).ꢀ ꢀ Usingꢀ aꢀ benzylicꢀ phosphonateꢀ ester,ꢀ completeꢀ mono-
Schemeꢀ2.ꢀMeta-selectiveꢀmono-olefinationꢀꢀ
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ACS Paragon Plus Environment

ACS Catalysis
Page 2 of 5
ꢀ
ꢀꢀꢀꢀWhileꢀ changingꢀ PhI(TFA)
2
ꢀ withꢀ PhI(OAc)
2
,ꢀ theꢀ meta-
Schemeꢀ 3.ꢀ Meta-selectiveꢀ homoꢀ andꢀ heteroꢀ di-
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acetoxylatedꢀ productꢀ wasꢀ generated.ꢀ Removalꢀ ofꢀ
phosphonateꢀ linkerꢀ canꢀ generateꢀ di-ꢀ orꢀ tri-alkenylꢀ arene,ꢀ aꢀ
distinctꢀ π−conjugatedꢀ organicꢀ materials,ꢀ whichꢀ haveꢀ beenꢀ
spurredꢀ onꢀ byꢀ anꢀ interestꢀ inꢀ theirꢀ applicationsꢀ inꢀ organicꢀ
olefinationꢀꢀ
ꢀꢀꢀꢀꢀAsꢀ expected,ꢀ ortho-ꢀ andꢀ meta-ꢀ substitutedꢀ (bromoꢀ andꢀ
methyl)ꢀestersꢀalsoꢀunderwentꢀalkenylationꢀatꢀmetaꢀpositionꢀ
(2s-2v).ꢀFinally,ꢀ3-bromo-4-fluoroꢀsubstitutedꢀestersꢀaffordedꢀ
theꢀdesiredꢀproductsꢀinꢀgoodꢀyieldsꢀ(2w). ꢀꢀꢀ
ꢀꢀꢀꢀWeꢀsubsequentlyꢀexploredꢀhomoꢀdi-olefinationꢀandꢀheteroꢀ
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electronicsꢀandꢀoptoelectronics. ꢀꢀ
ꢀ
ꢀꢀꢀꢀPresentꢀ studiesꢀ towardsꢀ developingꢀ aꢀ mildꢀ meta-C–Hꢀ
functionalizationꢀbeganꢀbyꢀinvestigatingꢀolefinationꢀreaction.ꢀ
Theꢀ meta-functionalizationꢀ ofꢀ benzylicphosphonatesꢀ isꢀ
expectedꢀtoꢀbeꢀchallengingꢀdueꢀtoꢀtheꢀpresenceꢀofꢀbothꢀortho-
directingꢀ [P(O)(OEt)]ꢀ andꢀ meta-directingꢀ cyanophenolꢀ
motifsꢀ inꢀ theꢀ presentꢀ scaffoldꢀ (Schemeꢀ 1).ꢀ Reactionꢀ
conditionsꢀ wereꢀ optimizedꢀ withꢀ 2-cyanophenylꢀ ethylben-
zylphosphonateꢀ (1a)ꢀ andꢀ ethylꢀ acrylateꢀ asꢀ theꢀ modelꢀ
2
di-olefinationꢀatꢀtheꢀmetaꢀpositionꢀbyꢀusingꢀPd(OAc) ꢀ(10ꢀ%),ꢀ
o
N-acetylꢀglyceneꢀ(Ac-Gly-OH,ꢀ20%)ꢀinꢀHFIPꢀsolventꢀatꢀ80ꢀ C.ꢀ
Aꢀ rangeꢀ ofꢀ acrylates,ꢀ MVKꢀ andꢀ cyclicꢀ olefinsꢀ producedꢀ di-
alkenylatedꢀ productsꢀ inꢀ highꢀ yieldꢀ (3a-3d,ꢀ Schemeꢀ 3).ꢀ
Furthermore,ꢀ heteroꢀ diolefinatedꢀ productsꢀ (3e-3h)ꢀ wereꢀ
obtainedꢀviaꢀincorporationꢀofꢀanotherꢀolefinꢀintoꢀtheꢀmono-
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10
olefinatedꢀproductꢀ2a. ꢀꢀ
10
substrates.ꢀ Afterꢀ extensiveꢀ experimentation, ꢀ theꢀ desiredꢀ
ꢀꢀꢀꢀꢀTheꢀ versatilityꢀ ofꢀ thisꢀ templateꢀ basedꢀ approachꢀ wasꢀ
extendedꢀ toꢀ carbon-heteroatomꢀ bondꢀ formationꢀ byꢀ
performingꢀ meta-hydroxylationꢀ andꢀ acetoxylation.ꢀ Initialꢀ
attemptsꢀ ofꢀ hydroxylationꢀ wasꢀ unsuccessfulꢀ underꢀ strongꢀ
olefinatedꢀ productꢀ (2a)ꢀ wasꢀ obtainedꢀ inꢀ 84%ꢀ isolatedꢀ yieldꢀ
withꢀ excellentꢀ meta-selectivity(≥20:1)ꢀ inꢀ presenceꢀ ofꢀ
Pd(OAc) ꢀ (10%),ꢀ N-acetylꢀ phenylalanineꢀ (Ac-Phe-OH,ꢀ 20%)ꢀ
2
1
0
inꢀHFIPꢀsolventꢀatꢀroomꢀtemperature.ꢀ
oxidizingꢀ conditions. ꢀ Thereafter,ꢀ theꢀ meta-hydroxylatedꢀ
compoundꢀ (4a)ꢀ wasꢀ obtainedꢀ inꢀ 70%ꢀ isolatedꢀ yieldꢀ withꢀ
excellentꢀ meta-selectivityꢀ (>20:1)ꢀ byꢀ usingꢀ mildꢀ oxidizingꢀ
conditionꢀ suchꢀ asꢀ PhI(TFA)2ꢀ (4ꢀ equiv.)ꢀ asꢀ theꢀ hydroxylatingꢀ
ꢀꢀꢀꢀꢀSubsequently,ꢀ weꢀ examinedꢀ scopeꢀ ofꢀ theꢀ protocolꢀ withꢀ
variousolefinsꢀ asꢀ wellꢀ asꢀ benzylicphosphonates.ꢀ Mostꢀ
importantly,ꢀ thisꢀ protocolꢀ allowsꢀ mono-olefinationꢀ withoutꢀ
formationꢀ ofꢀ anyꢀ di-olefinatedꢀ product.ꢀ Differentꢀ acrylatesꢀ
andꢀ methylꢀ vinylꢀ ketoneꢀ (MVK)ꢀ producedꢀ desiredꢀ mono-
olefinatedꢀproductsꢀinꢀgoodꢀyieldsꢀ(2a-2d,ꢀSchemeꢀ2).ꢀOlefinsꢀ
withꢀ phosphonateꢀ andꢀ sulfoneꢀ moietyꢀ resultedꢀ meta-
selectiveꢀ productsꢀ asꢀ wellꢀ (2e-2h,ꢀ Schemeꢀ 2).ꢀ Interestingly,ꢀ
di-substitutedꢀ olefinꢀ andꢀ cyclicꢀ tri-substitutedꢀ olefinꢀ wereꢀ
successfullyꢀemployedꢀ(2iꢀandꢀ2j).ꢀ
1
2
13
agent, ꢀ followedꢀ byꢀ itsꢀ in-situꢀ hydrolysis. ꢀ Theꢀ optimizedꢀ
reactionꢀconditionꢀinvolvedꢀN-tert-butyloxycarbonyl-alanineꢀ
2
(Boc-Ala-OH,ꢀ20%)ꢀasꢀtheꢀligandꢀforꢀPd(OAc) ꢀ(10ꢀmol%)ꢀinꢀ
1
0
HFIP. ꢀ Withꢀ theꢀ optimizedꢀ condition,ꢀ theꢀ scopeꢀ ofꢀ theꢀ
reactionꢀ wasꢀ exploredꢀ withꢀ benzylphosphonatesꢀ (4a-4g,ꢀ
Schemeꢀ4;ꢀmeta-selectivityꢀ>20:1).ꢀ
ꢀ
ꢀꢀꢀꢀStyreneꢀderivativesꢀsuchꢀasꢀ4-acetoxyꢀandꢀ3-nitroꢀstyreneꢀ
wereꢀeffectiveꢀwithꢀthisꢀprotocolꢀ(2kꢀandꢀ2l).ꢀDifferentꢀpara-
substitutedꢀ benzylicꢀ phosphonateꢀ estersꢀ promotedꢀ
olefinationꢀ inꢀ syntheticallyꢀ usefulꢀ yieldsꢀ (2m-2q).ꢀ However,ꢀ
para-tertbutylꢀ phosphonateꢀ esterꢀ gaveꢀ onlyꢀ 15%ꢀ olefinatedꢀ
productꢀ2o.ꢀSimilarly,ꢀ2,5-difluoroꢀareneꢀcanꢀbeꢀincorporatedꢀ
underꢀtheꢀoptimizedꢀreactionꢀconditionꢀ(2r).ꢀꢀ
R1
Pd(OAc)2 (10 mol%)
Ac-Gly-OH (20 mol%) R2
Ag2CO3 (2 equiv)
O
P
O
OEt
DG
DG =
P
OEt
DG
R
O
HFIP (1.5 mL)
CN
8
0 oC, 24h
R2
isolated
R
R2
R
1 0.4 mmol
R1
ꢀ
0
.2 mmol
Boc-Ala-OH,ꢀN-tert-butyloxycarbonyl-alanine.ꢀ
R3
O
COMe
P
OEt
O
Schemeꢀ4.ꢀMeta-selectiveꢀhydroxylationꢀ
DG
P
OEt
DG
R3 = CO2Et, 3adi, 85%; 3amono, 5%
R3 = COMe, 3bdi, 78%; 3bmono, 8%
ꢀꢀꢀꢀꢀInterestingly,ꢀ changingꢀ theꢀ acylatingꢀ agentꢀ fromꢀ
PhI(TFA) ꢀ toꢀ PhI(OAc) ꢀ ledꢀ toꢀ theꢀ formationꢀ ofꢀ meta-
2 2
acetoxylatedꢀcompoundꢀasꢀtheꢀsoleꢀproduct.ꢀThisꢀisꢀlikelyꢀdueꢀ
toꢀ theꢀ reducedꢀ electrophilicityꢀ ofꢀ theꢀ acetateꢀ comparedꢀ toꢀ
trifluoroacetate.ꢀ Forꢀ meta-acetoxylation,ꢀ N-acetyl-glyceneꢀ
MeOC
R3
3cdi, 69% ;3cmono, 11%
CO2Me
R4
O
O
P
10
OEt
DG
(Ac-Gly-OH)ꢀwasꢀfoundꢀtoꢀbeꢀtheꢀligandꢀofꢀchoice. ꢀSeveralꢀ
P
OEt
DG
substratesꢀ withꢀ differentꢀ substitutionꢀ patternsꢀ underwentꢀ
meta-acetoxylationꢀ successfullyꢀ toꢀ giveꢀ acetoxylatedꢀ
compoundsꢀ inꢀ moderateꢀ toꢀ goodꢀ yieldsꢀ andꢀ oftenꢀ withꢀ
excellentꢀ metaꢀ selectivityꢀ (Schemeꢀ 5,ꢀ 5a-5f;ꢀ meta-selectivityꢀ
R4 = COMe; 3e, 82%
R4 = CO2Me; 3f, 81%
MeO2C
3ddi, 72%; 3dmono, 8%
CO Et
2
R5
O
P
OEt
DG
>
20:1).ꢀ
R5 = COMe; 3g, 84%
R5 = SO2Me; 3h, 78%
CO2Me
ꢀ
Ac-Gly-OH,ꢀN-acetylꢀglyceneꢀ
2
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Page 3 of 5
ACS Catalysis
ꢀ
ꢀꢀꢀꢀWeꢀ thenꢀ performedꢀ intermolecularꢀ competitionꢀ
1
2
3
4
5
6
7
8
9
experimentꢀbetweenꢀdifferentlyꢀpara-substitutedꢀ(chloroꢀandꢀ
methoxy)ꢀbenzylphosphonateꢀesters,ꢀaꢀ(1.3:1)ꢀyieldꢀratioꢀwasꢀ
obtainedꢀ forꢀ bothꢀ electron-deficientꢀ andꢀ richꢀ counterparts.ꢀ
Thisꢀ phenomenonꢀ indicatesꢀ aꢀ simpleꢀ electrophilicꢀ
substitutionꢀ typeꢀ mechanismꢀ unlikelyꢀ toꢀ beꢀ involved.ꢀ Inꢀ
additionꢀ intermolecularꢀ competitionꢀ betweenꢀ [D
simpleꢀ undeuteratedꢀ benzylphosphonateꢀ estersꢀ 1aꢀ gaveꢀ theꢀ
productꢀdistributionꢀvaluesꢀofꢀ4.5ꢀ[P /P ],ꢀsuchꢀaꢀhighꢀvalueꢀ
ofꢀ [P /P ]ꢀ likelyꢀ establishesꢀ C–Hꢀ activationꢀ asꢀ theꢀ rateꢀ de-
7
]ꢀ andꢀ
H
D
H
D
terminingꢀstepꢀ(Schemeꢀ6).ꢀꢀ
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ꢀSchemeꢀ5.ꢀMeta-selectiveꢀacetoxylationꢀ
ꢀꢀꢀꢀInꢀ considerationꢀ ofꢀ theꢀ uniqueꢀ catalyticꢀ activityꢀ ofꢀ theꢀ
Pd(II)-MPAAꢀ metal-ligandꢀ system,ꢀ weꢀ studiedꢀ someꢀ
preliminaryꢀ mechanisticꢀ experimentsꢀ ofꢀ meta-selectiveꢀ C–Cꢀ
andꢀ C–Oꢀ bondꢀ formationꢀ reactions.ꢀ Inꢀ bothꢀ theseꢀ cases,ꢀ
nitrileꢀ groupꢀ ofꢀ theꢀ substrateꢀ linearlyꢀ coordinatedꢀ withꢀ theꢀ
ligatedꢀpalladiumꢀspecies.ꢀTheꢀpalladium-nitrileꢀcoordinationꢀ
ꢀ
wasꢀsupportedꢀbyꢀdownfieldꢀshiftꢀofꢀorthoꢀandꢀparaꢀprotonꢀofꢀ
1
2
-cyanoꢀ phenolꢀ coreꢀ inꢀ Hꢀ spectraꢀ (Figureꢀ 1).ꢀ Weꢀ haveꢀ per-
formedꢀ ESI-MSꢀ studiesꢀ ofꢀ stoichiometricꢀ combinationꢀ ofꢀ
Pd(OAc) ,ꢀAc-Phe-OH,ꢀandꢀsubstrate.ꢀInterestingly,ꢀaꢀmetal-
2
+
II
substrateꢀ adductꢀ [(Ac-Phe-OH)-H )Pd (1a)]ꢀ wasꢀ appearedꢀ
withdesiredꢀisotopicꢀpatternꢀ(Figureꢀ2).ꢀ
Schemeꢀ6.ꢀIntermolecularꢀcompetitionꢀexperimentsꢀꢀ
ꢀ
ꢀꢀꢀꢀOlefinationꢀ likelyꢀ followedꢀ aꢀ pathꢀ (depictedꢀ asꢀ Aꢀ inꢀ
Schemeꢀ 7)ꢀ involvingꢀ C–Hꢀ activation,ꢀ olefinꢀ binding,ꢀ 1,2-
migratoryꢀ insertion,ꢀ andꢀ β-hydrideꢀ eliminationꢀ toꢀ generateꢀ
theꢀ productꢀ 2a.ꢀ Theꢀ C–Oꢀ bondꢀ formationꢀ reactionꢀ mightꢀ
II
IV
proceedꢀ viaꢀ aꢀ Pd /Pd ꢀ cycleꢀ (pathꢀ B).ꢀ Theꢀ palladacycleꢀ
IV
2
intermediateꢀ isꢀ oxidizedꢀ byꢀ PhI(OCOR) ꢀ toꢀ affordꢀ aꢀ Pd ꢀ
intermediate,ꢀ whichꢀ undergoesꢀ aꢀ reductiveꢀ eliminationꢀ
processꢀtoꢀfurnishꢀtheꢀacetoxylatedꢀproductꢀ5aꢀandꢀliberatesꢀ
II
theꢀPd ꢀcatalyst.ꢀꢀSubsequentꢀhydrolysisꢀofꢀtrifluoroacetoxy,ꢀ
3
OCOCF ,ꢀgroupꢀprovidesꢀcompoundꢀ4a.ꢀ
1
Figureꢀ1. HꢀNMRꢀstudyꢀofꢀPd(OAc)
2
,ꢀAc-Phe-OH,ꢀandꢀ1aꢀ
ꢀ
ꢀꢀꢀꢀTheꢀC–Hꢀpalladationꢀstepꢀlikelyꢀinvolvesꢀtheꢀformationꢀofꢀ
aꢀ11-memberedꢀpalladacycle.ꢀESI-MSꢀstudiesꢀofꢀstoichiometricꢀ
combinationꢀ ofꢀ Pd(OAc) ,ꢀ Ac-Phe-OH,ꢀ andꢀ 4-methylꢀ
substitutedꢀ phosphonicꢀ esterꢀ 1b,ꢀ suggestedaꢀ ligandꢀ freeꢀ
2
II
+
intermediateꢀ [Pd (1b-H )]ꢀ (Figureꢀ 2).ꢀ Effortsꢀ toꢀ isolateꢀ thisꢀ
speciesꢀremainedꢀunsuccessfulꢀtillꢀdate.ꢀ
Schemeꢀ7.ꢀPlausibleꢀpathwayꢀforꢀmeta-functionalizationꢀꢀ
ꢀꢀꢀꢀꢀFurthermore,ꢀtheꢀ-P(O)(OR) ꢀtetherꢀlinkageꢀcanꢀbeꢀeasilyꢀ
cleavedꢀbyꢀmodifiedꢀHorner-Wadsworth-Emmonsꢀreaction.
2
2
ꢀ
Meta-functionalizedꢀ productsꢀ wereꢀ reactedꢀ withꢀ
benzaldehydeꢀinꢀtheꢀpresenceꢀofꢀpotassiumꢀtert-butoxideꢀtoꢀ
affordꢀ correspondingꢀ alkenesꢀ inꢀ goodꢀ yieldsꢀ (Schemeꢀ 8).ꢀ Inꢀ
addition,ꢀesterꢀmoietyꢀofꢀmetaꢀdi-olefinatedꢀcompoundsꢀcanꢀ
Figureꢀ2.ꢀESI-MSꢀstudyꢀwithꢀ1aꢀandꢀ1b.ꢀ
3
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beꢀ removedꢀ toꢀ produceꢀ 1,3,5-trialkenylatedꢀ arenesꢀ inꢀ goodꢀ
yieldsꢀ(Schemeꢀ9,ꢀ6dꢀandꢀ6e).ꢀ
*ꢀE-mailꢀforꢀD.M.:ꢀdmaiti@chem.iitb.ac.inꢀ
*ꢀE-mailꢀforꢀM.B.:ꢀmiluom@gmail.comꢀꢀ
Notesꢀ
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Theꢀauthorsꢀdeclareꢀnoꢀcompetingꢀfinancialꢀinterests.ꢀ
ACKNOWLEDGMENTꢀ
ThisꢀactivityꢀisꢀsupportedꢀbyꢀSERB,ꢀIndiaꢀ(EMR/2015/000164).ꢀ
FinancialꢀsupportsꢀwereꢀreceivedꢀfromꢀDSTꢀunderꢀFastꢀTrackꢀ
Schemeꢀ(M.ꢀB.),ꢀandꢀIIT-Bꢀ(S.S.).ꢀꢀ
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Schemeꢀ8.ꢀRemovalꢀofꢀphosphonatesꢀlinkerꢀ
(
(
2)ꢀSelectedꢀexamplesꢀofꢀHorner-Wadsworth-Emmonsꢀreaction,ꢀsee:ꢀ
a)ꢀWadsworth,ꢀW.ꢀS.;ꢀEmmons,ꢀW.ꢀD.ꢀJ.ꢀAm.ꢀChem.ꢀSoc.ꢀ1961,ꢀ83,ꢀ
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2
009,ꢀ131,ꢀ1753-1765.ꢀ
(
3)ꢀ Orthoꢀ C-Hꢀ activationꢀ ofꢀ phosphonateꢀ esters,ꢀ see:(a)ꢀ Meng,ꢀ X.;ꢀ
Kim,ꢀ S.ꢀ Org.ꢀ Lett.ꢀ 2013,ꢀ 15,ꢀ 1910-1913;ꢀ (b)ꢀ Meng,ꢀ X.;ꢀ Kim,ꢀ S.ꢀ J.ꢀ Org.ꢀ
Chem.ꢀ2013,ꢀ78,ꢀ11247-11254;ꢀ(c)ꢀChan,ꢀL.ꢀY.;ꢀKim,ꢀS.;ꢀRyu,ꢀT.;ꢀLee,ꢀP.ꢀ
H.ꢀChem.ꢀCommun.ꢀ2013,ꢀ49,ꢀ4682-4684;ꢀ(d)ꢀZhao,ꢀD.;ꢀNimphius,ꢀC.;ꢀ
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Cheong,ꢀL.;ꢀKim,ꢀS.ꢀOrg.ꢀLet.ꢀ2013,ꢀ15,ꢀ2186-2189;ꢀ(f)ꢀChary,ꢀB.ꢀC.;ꢀKim,ꢀ
S.ꢀOrg.ꢀBiomol.ꢀChem.ꢀ2013,ꢀ11,ꢀ6879-6882;ꢀ(g)ꢀJeon,ꢀW.ꢀH.;ꢀSon,ꢀJ.-Y.;ꢀ
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(4)ꢀ Selectedꢀ reviews/examplesꢀ ofꢀ orthoꢀ C-Hꢀ activation,ꢀ see:ꢀ (a)ꢀ
Alberico,ꢀD.;ꢀScott,ꢀM.ꢀE.;ꢀLautens,ꢀM.ꢀChem.ꢀRev.ꢀ2007,ꢀ107,ꢀ174-238;ꢀ
(b)ꢀSeregin,ꢀI.ꢀV.;ꢀGevorgyan,ꢀV.ꢀChem.ꢀSoc.ꢀRev.ꢀ2007,ꢀ36,ꢀ1173-1193;ꢀ
ꢀ
Schemeꢀ9.ꢀSynthesisꢀofꢀ1,3,5-trialkenylꢀareneꢀ
ꢀ
ꢀꢀꢀꢀTheꢀ utilityꢀ ofꢀ meta-C–Hꢀ functionalizationꢀ wasꢀ
demonstratedꢀ byꢀ attemptingꢀ furtherꢀ extensionꢀ ofꢀ theꢀ
hydroxylatedꢀ productꢀ (Schemeꢀ 10).ꢀ Triflateꢀ 7ꢀ wasꢀ easilyꢀ
preparedꢀ fromꢀ compoundꢀ 6cꢀ andꢀ thenꢀ transformedꢀ toꢀ
syntheticallyꢀusefulꢀmoleculesꢀviaꢀarylationꢀ7a,ꢀaminationꢀ7bꢀ
andꢀalkynylationꢀ7c.ꢀ
(
c)ꢀ Mkhalid,ꢀ I.ꢀ A.ꢀ I.;ꢀ Barnard,ꢀ J.ꢀ H.;ꢀ Marder,ꢀ T.ꢀ B.;ꢀ Murphy,ꢀ J.ꢀ M.;ꢀ
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ꢀ
Schemeꢀ10.ꢀFurtherꢀfunctionalizationꢀofꢀ6cꢀ
ꢀ
(
ꢀꢀꢀꢀInꢀsummary,ꢀweꢀhaveꢀdevelopedꢀfirstꢀtemplateꢀassistedꢀPdꢀ
II)-catalyzedꢀ directꢀ meta-olefinationꢀ atꢀ room-temperature.ꢀꢀ
Theꢀ meta-functionalizationcanꢀ beꢀ furtherꢀ extendedꢀ toꢀ
carbon-oxygenꢀ bondꢀ formationꢀ suchꢀ asꢀ meta-hydroxylationꢀ
andꢀ meta-acetoxylationꢀ reactionsꢀ byꢀ varyingꢀ theꢀ
(
p)ꢀZhang,ꢀF.;ꢀSpring,ꢀD.ꢀR.ꢀChem.ꢀSoc.ꢀRev.ꢀ2014,ꢀ43,ꢀ6906-6919;ꢀ(q)ꢀ
Schranck,ꢀJ.;ꢀTlili,ꢀA.;ꢀBeller,ꢀM.ꢀAngew.ꢀChem.ꢀInt.ꢀEd.ꢀ2014,ꢀ53,ꢀ9426-
9428;ꢀ(r)ꢀDeb,ꢀA.;ꢀBag,ꢀS.;ꢀKancherla,ꢀR.;ꢀMaiti,ꢀD.ꢀJ.ꢀꢀAm.ꢀChem.ꢀSoc.ꢀ
2014,ꢀ136,ꢀ13602-13605.ꢀ
2
acetoxylatingꢀagentꢀPhI(OCOR) .ꢀꢀDifferentꢀdi-ꢀandꢀtri-meta-
substitutedꢀalkenesꢀwereꢀsynthesizedꢀbyꢀremovingꢀtheꢀtetherꢀ
(
5)ꢀOtherꢀapproachesꢀforꢀmeta-functionalizations,ꢀsee:ꢀ(a)ꢀCho,ꢀJ.-Y.;ꢀ
Tse,ꢀM.ꢀK.;ꢀHolmes,ꢀD.;ꢀMaleczka,ꢀR.ꢀE.;ꢀSmith,ꢀM.ꢀR.ꢀScienceꢀ2002,ꢀ
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phosphonates.ꢀ
ꢀ
ASSOCIATEDꢀCONTENTꢀ
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R = H, Ac
meta-selective C-C &
R2
Room-temperature olefination
C-O bond formation
Easily removable phosphonate linker
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