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Jury :
le
Université Toulouse 3 Paul Sabatier (UT3 Paul Sabatier)
Diandian KEmercredi 28 septembre 2016
Cooperative Catalysis by 2-Indenediide Pincer Complexes
ED SDM : Chimie organométallique de coordination - CO 043
Laboratoire Hétérochimie Fondamentale et Appliquée
Mathieu SAUTHIER, Professeur de l'University of Lille 1, Lille (Rapporteur)Florian MONNIER, Professeur de l'Ecole Nationale Supérieure de Chimie de Montpellier,
Montpellier (Rapporteur)Canac YVES, Directeur de Recherche C.N.R.S. à Toulouse
Blanca MARTIN-VACA, Professeur de l'Université Paul Sabatier, C.N.R.S. à ToulouseDidier BOURISSOU, Directeur de Recherche C.N.R.S. à Toulouse
Didier BOURISSOUBlanca MARTIN-VACA
UniversitéToulouse3PaulSabatier(UT3PaulSabatier)
CooperativeCatalysisby2‐IndenediidePincerComplexes
DiandianKE
28/09/2016
EDSDM:Chimieorganométalliquedecoordination‐CO043
Directeur/trice(s)deThèse:
DidierBOURISSOU
BlancaMARTIN‐VACA
Jury:
MathieuSAUTHIER,Professeurdel'UniversityofLille1,Lille(Rapporteur)
FlorianMONNIER,Professeurdel'EcoleNationaleSupérieuredeChimiedeMontpellier,Montpellier(Rapporteur)
CanacYVES,DirecteurdeRechercheC.N.R.S.àToulouse
BlancaMARTIN‐VACA,Professeurdel'UniversitéPaulSabatier,C.N.R.S.àToulouse
DidierBOURISSOU,DirecteurdeRechercheC.N.R.S.àToulouse
I
AcknowledgementsBeinghere inFrance for thepursuitofmyPh.Ddegreewastrulyanunforgettableand
meaningfulexperienceforme,andIdidhaveafulfillingandenjoyabletimeinToulousefor
thepastthreeyears.Always,pleasantdayswentbysoquickly,asmyPhDstudyeventually
cametoitsepilogue.ThisPh.Ddissertationbeingsuccessfullycompletedwasalsoattributed
tomanypeopleoffthescenes,whoinfluencedandhelpedmealotwiththeirconsiderable
supports.
Iwouldliketotakethisopportunitytothankallthecommitteemembers:Prof.Mathieu
Sauthier,Prof.FlorianMonnier,andProf.CanacYves,fortheiracceptancetobethejuryto
assessmyPh.Dworkinsucharelativelytensetimeandoffertheirinsightfulcommentsand
suggestions.
Iwouldliketoexpressmysincereappreciationtomysupervisors:Dr.DidierBourissou
andProf.BlancaMartin‐Vaca,forofferingmethepreciousopportunitytojointhislovelyand
passionatefamilyandtosystematicallystudythefascinatingfieldregardingorganometallic
chemistry.Theirprofoundknowledgeon chemistry aswell as rigorous researchattitude
greatlyinfluenceme,andwillbenefitmethewholelife.Theywerealwayspatientandkind
toanswerallmyquestions,andgavemelotsofinvaluablesuggestionsonthePh.Dproject,
experimentallyandtheoretically.Andtheirsupportsandencouragementsgreatlyhelpedme
getthroughsomedifficulttimes.
Equally,IwouldbewholeheartedlygratefulforthetremendoushelpofDr.JulienMonot
overthepastthreeyears,notonlyinstructingnewexperimentalskillsandorganometallic
knowledgetomeinthelaboratorylife,butalsoassistingmetosolvealotofproblemsinreal
life.Youwerealwayssopatienttoexplainmetheoreticalknowledgeandalsoteachmenew
manipulations,andgavemepracticalideastomakethisprojectworksmoothly.
MyspecialthankalsogoestoDr.NoelAngelEspinosaJalapa,whohadworkedinthelab
togetherwithmeforthefirsttwoyears,andgavemealotofexperimentalinstructionsall
thetime.Iwillalwaysrememberthetreasuredmomentswesharedfastfoodatnightinthe
officeafteralongdayofworking,andsomedayshadarunningtogetherinthefields.
II
IamalsoveryappreciativetoProf.GhenwaBouhadirandProf.AbderrahmaneAmgoune,
whoalwayspointedoutthequestionsinmypresentationsdirectlyduringthegroupmeeting
andgavetheirprecioussuggestionandopinionsogenerously,whichgreatlyhelpedmeto
performbetterandbetterinthefuture.
Andofcourse,itwasagreatpleasuretoworkwithallmyfriendsintheLBPBandLHFA
group.Ididlearnalotfromallofyou:MarcDevillard,MaximilianJoost,FerielRekhroukh,
Gwenaëlle Gontard, Richard Declercq, Franck Kayser, Abdallah Zeineddine, Paul Brunel,
Charlie Blons, Maxime Boudjelel, Sytze Buwalda, Amos Rosenthal, Maxim Dekhtiarenko,
NebraMunizNoél,SamuelHo,YanliMao,QianLiao,YingyingGu,XuanLiu,NataliaDelRio
Garcia, Marta Rodriguez, Florian D’accriscio, Sébastien Dreyfuss, Alexia Ohleier, Laura
Bousquet, RaphaëlMirgalet, Noémi Deak, Antonio Reina, etc. Because of you all, I had a
wonderfultimeinthis lovelyandpassionatelab.Additionally, Iwould liketoexpressmy
gratitudetotheadministrativeandtechnicalstaffs:MaryseBeziat, IsabelleFavier,Olivier
ThillayeduBoullay,RomaricLenk,OlivierVolpato,ChristianPradel.
Mydeeply‐feltthanksalsogotoalltheChinesefriendsinFrance,particularly,ZhouyeChen,
YuChen,CongzhangGao,FaqiangLeng,WeikaiZong,RenjieWang,GuanghuaJin,YandiLan,
Chunxiang Chen, ChanglongWang, etc., with whom I really had a wonderful life in this
beautifulcountry.Iwillalwaysremembertheenjoyabletimeour“JourneytotheWest”team
traveledtogetheracrosstheEuropeancontinentwithcheersandlaughter.Andalso,Iam
indebtedtomybestfriendNannaninNetherlands.
AspecialthankalsogoestomymastersupervisorXiaolanCheninZhengzhouUniversity
ofChina,whoalwaysencouragedmeandgavemesupportsallthetime.
IwouldliketothankourgovernmentandChinaScholarshipCouncil(CSC)tofinancially
supportmeforthepast3years,whichgrantedmetopursuemyacademicdream.
Atlast,Iwouldliketoextendmydeepestgratitudetomyfamily,fortheirunconditional
loveandsupport.
III
Tomyfamily.
IV
V
TableofContentsListofAbbreviations............................................................................................................................................VII
ListofComplexesandProducts.......................................................................................................................IX
GeneralIntroduction...............................................................................................................................................1
Chapter1CooperativeCatalysis........................................................................................................................5
1.1Multi‐CenterCatalysis:DifferentModes............................................................................................................6
1.1.1Organo‐OrganoCooperativeCatalysis.......................................................................................................8
1.1.2Metal‐MetalCooperativeCatalysis..............................................................................................................9
1.1.3Metal‐OrganoCooperativeCatalysis.........................................................................................................11
1.2Metal‐LigandCooperation.....................................................................................................................................15
1.2.1RedoxNon‐InnocentLigands.......................................................................................................................17
1.2.2CooperativeNon‐InnocentLigands...........................................................................................................21
1.3Metal‐LigandCooperativeCatalyticProcesses.............................................................................................25
1.3.1Metal‐LigandCooperationuponHydrogenation.................................................................................25
1.3.2Metal‐LigandCooperationuponDehydrogenation............................................................................28
1.3.3Metal‐LigandCooperationbeyondHydrogenation/Dehydrogenation......................................35
1.3.4Metal‐LigandCooperationandCycloisomerizationofAlkynoicAcids:ContextofMyPhDResearchProject...........................................................................................................................................................40
1.4Summary.......................................................................................................................................................................41
1.5References....................................................................................................................................................................42
Chapter2CycloisomerizationviaPalladiumPincerComplexes......................................................45
2.1Introduction.................................................................................................................................................................45
2.2ResultsDiscussion....................................................................................................................................................55
2.2.1PreliminaryStudyandObservedLimitation.........................................................................................56
2.2.2ProbeintotheLimitationofCurrentSystem........................................................................................60
2.3DesignforStructuralModulation.......................................................................................................................62
2.4EvaluationoftheNewComplexesinCycloisomerizationofAlkynylamides...................................65
2.5InvestigationuponAmideScope........................................................................................................................67
2.6MechanisticStudy.....................................................................................................................................................74
VI
2.7Summary.......................................................................................................................................................................79
2.8ExperimentPart.........................................................................................................................................................80
2.8.1GeneralConsiderations..................................................................................................................................80
2.8.2SynthesisofLigand..........................................................................................................................................80
2.8.3SynthesisofComplexes..................................................................................................................................82
2.8.4SelectedCrystalData.......................................................................................................................................86
2.8.5SynthesisofN‐tosylAlkynylamidesSubstrates...................................................................................89
2.8.6CatalysisforLactams.......................................................................................................................................95
2.9References.................................................................................................................................................................102
Chapter3WhenPtOutperformsPdinCatalyticCycloisomerization..........................................105
3.1Introduction..............................................................................................................................................................105
3.2ResultsDiscussion.................................................................................................................................................110
3.2.1DesignandSynthesisofPtComplexes..................................................................................................110
3.2.2EvaluationoftheCatalyticActivityofthePtComplexes...............................................................113
3.2.3SubstrateScope:Medium‐SizeRingFormation................................................................................116
3.2.4SubstratesBearingInternalAlkynes.....................................................................................................121
3.2.5MechanisticStudy..........................................................................................................................................124
3.3AdditiveImpact.......................................................................................................................................................127
3.3.1Introduction.....................................................................................................................................................127
3.3.2EvaluationoftheAdditivesImpactontheEfficiencyofthePtPincerComplexIIIb.........130
3.3.3PyrogallolImpactuponInternalSubstrates.......................................................................................133
3.4Conclusion.................................................................................................................................................................135
3.5ExperimentPart......................................................................................................................................................136
3.5.1SynthesisofComplexesII‐IV.....................................................................................................................136
3.5.2SynthesisofAmideandAcidSubstrates..............................................................................................142
3.5.3CatalysisforLactamsandLactones.......................................................................................................147
3.5.4SelectedCrystalData....................................................................................................................................153
3.6References.................................................................................................................................................................157
GeneralConclusion.............................................................................................................................................159
INTRODUCTIONGENERALE...........................................................................................................................161
VII
ListofAbbreviations
AIM Atoms inmolecule
Ar Generalarylgroup
BA Brønstedacid
BQ Benzoquinone
Cat. Catalyst
CDCl3 Deuteratedchloroform
Conv. Conversion
Cp Cyclopentadienylgroup
Cy Cyclohexylgroup
DCM Dichloromethane
DFT Densityfunctionaltheory
DMSO Dimethylsulfoxide
EA Elementalanalysis
ee Enantiomericexcess
Equiv. Equivalent
ESI Electrosprayionization
Et Ethylgroup
GC‐MS Gaschromatography–massspectrometry
HOAc Aceticacid
HOMO Highestoccupiedmolecularorbital
HRMS Highresolutionmassspectrometry
Ind Indenyl
VIII
iPr Isopropylgroup
IR Infra‐red
LUMO Lowestunoccupiedmolecularorbital
M.P. Meltingpoint
Me Methyl group
Mes Mesitylgroup
MS Molecularsieve
NBO Naturalbondorbital
NHC N‐HeterocyclicCarbene
NMR Nuclearmagneticresonancespectroscopy
OA Oxidizationaddition
PA Phosphoricacid
Prep‐HPLC Pre‐High‐performanceliquidchromatographic
PS‐DIEA N,N‐(Diisopropyl)aminomethylpolystyrene
RE Reductiveelimination
RT RoomTemperature
tBuOK Potassiumtert‐butoxide
THF Tetrahydrofuran
TM Transitionmetal
TOF Turnoverfrequency
TON Turnovernumber
TS TransitionState
Ts‐ Tosyl(p‐toluenesulfonyl)group
XRD X‐raydiffraction
IX
ListofComplexesandProducts
PincerComplexes:
1stgeneration
Ia (Cl)
Ib (I)
Ib
2ndgeneration
II
III
3rdgeneration
IVa
[N(nBu)4]
PPh2Ph2P
S SPt
Cl
IVb
IIIa
IIIb
PiPr2iPr2P
S SPt
2
X
LactamandLactoneProducts:
1
N
O
Ts
2
3
4
5
6
7
8
9
10
11
12
XI
13
(Traceamount,Observedonly)
14
15
(Traceamount,Observedonly)
16
17
18
19
20
21
XII
1
O
O
2
3
4
5
6
7
8
9
10
1
GeneralIntroduction
AllalongthesecondhalfoftheXXthcentury,theperformancesoforganometalliccatalystshavebeen
improved thanks to the tuning of their stereo‐electronic properties via ligand modulation. One
representativeexampleconcernsthe(co‐)polymerizationofpolarolefins.Theearlytransitionmetal(TM)
metalloceneorCGC(ConstrainedGeometryComplexes)complexesdevelopedinthe1980’swerehighly
activeinethyleneandα‐olefin(co‐)polymerization,butshowedpoorefficiencywithpolarolefinsmainly
duetocompatibilityissues.1,2Inthemid‐1990s,amajorbreakthroughwasachievedbyBrookhartandco‐
workerswiththedevelopmentofPd(II)andNi(II)complexesbearingdiiminechelateligands,capableof
co‐polymerizingalargerangeofpolarmonomers.Furthertuningoftheancillaryligandsresultedten
yearslaterinthedescription,byDrent,Jordan,Nozakiandco‐workersofanewfamilyofchelateligands,
namelythephosphine‐sulfonates.2Usingtheseligands,successfulco‐polymerizationofpolarmonomers
leading selectively to linear polymers can now be achieved. In these systems, the stereo‐electronic
propertiesoftheligandsare“transferred”tothemetalcenter,whichresultsinimprovedcatalyticprocess.
Buttuningthestereo‐electronicpropertiesoftheTMisnottheonlypossibleroleforligands.Indeed,
inthelast20years,catalystsinwhichtheligandplaysanactiveroleinsubstrateactivation(exhibitinga
so‐callednon‐innocent character) haveemergedafter thepioneeringworkofNoyoriandShvo.3,4 In
thesecomplexes,themetalcenterandoneofitsligandsactinconcerttopromotechemicalprocesses
taking inspiration from cooperative catalysis found in biological systems. Such metal / ligand
cooperation enables to activate / formchemical bondsundermild conditions.Most interestingly,
mechanisticallythisprocessdoesnotinvolveoxidationstatevariationatthemetal,andrepresents
analternativetothetypicaloxidativeaddition/reductiveeliminationpathways.5,6Transformation
otherwiseunattainablehavebeensuccessfullyachievedthankstothesecooperativesystems.
2
Thismanuscriptfitsintheframeworkofmetal‐ligandcooperationwithorganometalliccatalysts
bearingnon‐innocentligands.Moreparticularly,itconcernscatalyticapplicationsofPdandPtpincer
complexesbearingabis(thiophosphinoyl)indenediideligandonthecycloisomerizationreactionof
alkynoic acids and alkynyl amides. Themanuscriptwill bemainly divided into three chapters as
follows:
The1st chapter compilesanon‐exhaustivebibliographical surveyof the fielduponcooperative
catalysis.First,threekindsofdual‐componentcatalyticsystems,namelymetal‐metal,organo‐organo
andmetal‐organosystemswillbeintroducedandillustratedwithselectedexamples.Metal‐ligand
cooperation in catalysis will then be discussed on several representative systems, from the
pioneeringworkofNoyoriusingamido‐Rutheniumcomplexesforhydrogenation,totherecentwork
of Milstein’s pincer complexes based on dearomatized pyridine. The chapter will end with the
catalytic applications of such metal / ligand cooperative systems in several important
transformations,i.e.H‐Hactivation,hydrogenation/dehydrogenation,H2transfer,aswellastheX‐H
bond(Si‐H,N‐H,etc.)activations.
The2ndchapterwillfocusonthedesignandsynthesisofnovelPdindenediidepincercomplexes
by structuralmodulation of the ligand, and their applications in catalytic cycloisomerization via
metal‐ligand cooperation.7 Initially, a range of N‐alkynylamides, which are derived from the
corresponding alkynoic acids and supposed to be more challenging substrates, were readily
prepared.Preliminaryresultsdisclosedthattheindenediidepincersystemiscapabletoachievethe
cycloisomerization of N‐tosyl alkynylamides to form the related lactam products. Nevertheless,
incomplete conversion regarding the formation of 6‐membered ring lactams even under harsh
conditionsindicatedthelimitationofthecurrentcatalyticsystem.Inaddition,31PNMRmonitoring
ofthereactionprocessrevealedthatthecomplexesarenotstablewiththefreeligandobserved.A
structuralmodulationwasthusenvisionedbyreplacingthePhsubstituentsatphosphorusforiPr,in
attempttoincreasetherobustnessofthePdpincercomplexesandenhancetherebytheircatalytic
performance.
3
Accordingly,twonewPdcomplexesweresuccessfullypreparedandfully characterized(NMR,IR,
XRD).Asexpected,thenewcomplexesdemonstratedabetterperformancethantheirPh‐substituted
counterparts. Subsequently, theN‐tosyl alkynylamide scopewas extensively studied, from linear
non‐substitutedC5‐C7,tosubstituted,benzo‐fused,andfinallytointernalalkyneones. Eventually,a
majorityofexolactamproducts,togetherwiththeunusualinternalendolactamcanbepreparedin
excellentyields(mostoften90%).Noteworthily, the7‐memberringmethylenecaprolactamwas
obtained for the first time via cycloisomerization. However, incomplete conversion for such 7‐
memberedringandnoreactionofinternalC6amidepromptedustofurtherimprovethecatalytic
system.
The3rdchapterisdevotedtothecontinuousmodulationofthepincercomplexes,andtheircatalytic
application uponmore challenging substrates.8A straightforward strategy is to switch themetal
center from palladium to platinum, as the latter claims itswell‐known efficiency to activate C‐C
multiplebonds,inparticulartriplebonds.Additionally,itwasworthwhiletoexplorethescarcely‐
reportedcyclizationofalkynoicacidsandrelatedamidescatalyzedbyplatinumcomplexes.Tothis
end,fourPtpincercomplexesweresuccessfullysynthesizedfollowingthesamesyntheticstrategyas
forPdcomplexes,andthen fullycharacterized(NMR, IR,XRD). Initially,a rapidevaluationof the
catalyticperformancesamong these complexeson the cycloisomerizationof5‐hexynoicacidwas
carriedout.ThedimericPtcomplexbearingiPrgroupwasshowntobethebestcatalysttoachieve
completeconversioninmuchshortertimewithasharpdecreaseofthecatalystloadingcomparedto
therelatedPddimer,whichshowsthesignificantimprovementovertheprevioussystem.Then,a
range of model substrates aiming for the formation of 5‐/6‐membered lactones/lactams were
employedinthepresenceoftwopotentdimericcomplexes(PdvsPt),fordirectcomparisonoftheir
catalyticactivity.Forsmall5‐memeberedringformation,bothcomplexesexhibitedsimilarresults,
while Pt dimer obviously outperformed its Pd analogue upon 6‐membered ring formation, by
completingthereactionwithinaconsiderablyshortenedtime,nottomentionreducingthecatalytic
loadingtodreadfullylow.Inthelightoftheseresults,weholdmuchpromiseforusingdimericPt
complex upon more challenging substrates, aiming to form medium size rings, including for
substratesbearinginternalalkynes.
Subsequently,awidearrayofsubstrateswaspreparedandsubmittedtocyclizationinthepresence
ofthePtdimer.Theinitialtestswereperformedwiththelinearacidandamidefor7‐memberedring
formation.Completeconversionof6‐heptynoicacidcanbeobtained this timewith thePtdimer.
Notably,thisefficientpreparationofε‐alkylidenelactonescanbescaleduptomulti‐gramscale.These
productsareinterestingmonomersforringopeningpolymerization(ROP)andmaybeusedforthe
4
preparationoffunctionalizedbiodegradablepolymers.Also,thePtcomplexgaveexcellentresultin
the cycloisomerization ofN‐tosyl alkynylamide into 7‐membered lactam. Both results showed a
significant improvement of the Pt complex over its Pd analogue. The substrate scope was then
extendedtoformationofother7‐memberedrings,whichindicatedthegeneralityofsuchPtcomplex
system.Inaddition,severalsubstratesbearinginternalalkynes,thatareparticularlychallengingfor
cycloisomerizationintermsofactivityaswellasexo/endoselectivity,wereinvestigated.Notably,
the internal C5 amideswere converted exclusively via a 6‐endo cyclization to give alkylidene δ‐
lactams,whileforinternalC6amide,Ptcomplexcantriggerthereaction,butonlylowconversionis
observed.
Thankstoabetterunderstandingofthemechanism,H‐bondingadditiveswereintroducedinthe
catalytic system for further improvements.9 Several catecholswere used,which showed inmost
cases shortened reaction times, and higher the exo/endo selectivities for internal substrates.
Noteworthily,theinternalC6amidecanbecompletelycyclizedinthepresenceofadditives.
Insummary,theoriginally‐developedcooperativenon‐innocentmetal‐ligandindenediidepincer
complexes demonstrated their powerful activity towards the cycloisomerization of a series of
alkynoic acids and N‐tosyl alkynylamides. This work further demonstrates the importance of
structuralmodulationinordertoimprovethecatalyticactivityandthekeyrolethatthemechanistic
investigationmayhaveinthisimprovements.
(1) Nakamura, A.; Ito, S.; Nozaki, K. Chem Rev 2009, 109, 5215. (2) Piche, L.; Daigle, J. C.; Rehse, G.; Claverie, J. P. Chem Eur J 2012, 18, 3277. (3) Shvo, Y.; Czarkie, D.; Rahamim, Y.; Chodosh, D. F. J Am Chem Soc 1986, 108, 7400. (4) Noyori, R.; Ohkuma, T. Angew Chem Int Ed 2001, 40, 40. (5) Grutzmacher, H. Angew Chem Int Ed 2008, 47, 1814. (6) Askevold, B.; Roesky, H. W.; Schneider, S. ChemCatChem 2012, 4, 307. (7) Espinosa‐Jalapa, N. Á.; Ke, D.; Nebra, N.; Le Goanvic, L.; Mallet‐Ladeira, S.; Monot, J.; Martin‐Vaca, B.; Bourissou, D. Acs Catal 2014, 4, 3605. (8) Ke, D.; Espinosa, N. Á.; Mallet‐Ladeira, S.; Monot, J.; Martin‐Vaca, B.; Bourissou, D. Adv Synth Catal 2016, 358, 2324. (9) Monot, J.; Brunel, P.; Kefalidis, C. E.; Espinosa‐Jalapa, N. Á.; Maron, L.; Martin‐Vaca, B.; Bourissou, D. Chem Sci 2016, 7, 2179.
5
Chapter1CooperativeCatalysisCatalysishasbeenknownasaphenomenonfromveryprimevaltimes,althoughdevelopmentsof
itstheoryandcharacteristicscamerelativelyafterward.Nowadays,itplaysafundamentalroleinthe
manufactureofavastmajorityofchemicals,andattractsagreatdealofattentionacademicallyand
industrially. The demand for novel and improved catalytic systems has continuously stimulated
chemists.Commoncatalyticprocessesnormally involve the interactionofasinglecatalystwitha
substrate (or the substrates), thereby generating an activated species to react with a second
substrate (eventually activated also). Although thismono‐center catalysis strategyhas beenwell
documented inavastnumberofreactionsovermanydecades,multi‐centercatalysisconcepthas
latelyemergedasanewstrategytosurpassitspredecessorswithprospectstoachievedifficultor
otherwise unattainable reactions. The multi‐center catalysis concept is inspired from biological
systemsinwhichmulti‐centercatalysisisverycommon.1Arepresentativeexampleisillustratedin
Figure1.1,thatdepictsthecombinationofthreedifferentactivesites(Brönstedacid,Brönstedbase
andametallicLewisacid)asencounteredinclassIIaldolases.
Figure1.1Schematicrepresentationofmulti‐centercatalysisbyclass‐IIaldolases(formation/cleavageof
carbohydrates).
O
H
H
O
OPO3
2-
Zn2+
O
O
R H
OH
O
His94
His155
His92
Brönsted acid
Brönsted base Lewis acid
6
1.1Multi‐CenterCatalysis:DifferentModes
We can roughly pigeonhole homogenous catalysts into transition metal catalysis and organic
catalysis.Bothofthemareextensivelyusedinaplethoraofsynthetictransformations.Thenewly
emergingtrendofmulti‐centercatalysisaimsatcombiningtheadvantagesofbothtransitionmetal
and organo catalysis under one‐pot reaction conditions. It is becoming ubiquitous and popular
nowadays.2‐5Inregardtotherolesofsuchmulti‐centercatalystsduringthereactionprocess,four
distinctmodesinmulti‐catalyticscenarioscanbecategorized,thetwolast‐onesbeingcloselyrelated
toeachother(Figure1.2).Theywillbesuccinctlyrepresentedbeforefocusingonthecooperative
onesandinparticularonmetal‐ligandcooperation.
Figure1.2Classificationofmulti‐catalyticsystems.
The firstmode, termed “double activation catalysis” (mode I), entails the participation of two
catalysts(denotedascat1andcat2),workinginchorusuponactivationofonesubstrate.Thesecond
mode,termed“cascadecatalysis”(modeII),consistsinasequentialprocessinwhichcat1activates
asubstratetoproduceafirstintermediatethatissubsequentlyactivatedbythesecondcatalystto
reactwithasecondnon‐activatedsubstrate.
Incontrast,thecooperativeorsynergisticmodemakesuseofthetwocatalyststosimultaneously
activate the two substrates in anorchestratedway, topromote a single chemical transformation
(modesIIIandIII’).Herewecandistinguishbetweentheuseoftwoindividualcatalysts(two‐center
cooperativecatalysisIII)andthebifunctionalcatalysis,whereonlyonecatalystisexploited,butthe
twosubstratesareneverthelessactivatedbytwodiscretefunctionalsitesofthesamecatalyst(mode
III’).
7
Notably, the cooperative catalysis is nowadays emerging as a high‐value strategy for bond
activationandformingprocess.6Threecombinations,namelymetal‐metal,organo‐organoandmetal‐
organo,canbeenvisioned.Thebroadrangeofcooperativecatalyticsystemsreportedintheliterature
overthelastfewdecadeshavesubstantiatedthatanidealcombinationcansignificantlyimprovethe
existingchemicaltransformations,intermsofreactivityandselectivity;andmoreremarkably,can
promotesurprising,new,otherwiseunachievabletransformations.
Abroaddiversityofactivesites(metalandorgano‐based)canbeinvolvedincooperativecatalysis.
Selected examples of basic transitionmetal catalysts (e.g., PdCl2(PPh3)2, PtCl2, Pd(OAc)2, …) and
organo‐catalysts (Brønsted acids,7,8 amines,9,10 cinchona,11,12 N‐heterocyclic carbenes (NHCs)13,14),
aredepictedinFigure1.3.Themodularityofthecatalyticsystemsrepresentsagreatopportunityfor
thefuturedevelopmentofcooperativecatalysis.Mechanisticinvestigationsarealsohighlyvaluable
inordertopreciselyunderstandthefactorscontrollingtheactivityandselectivityof thesemulti‐
centercatalysts,andultimatelyenablerationaldesignandoptimization.
Figure1.3Selectedtransitionalmetalandorganocatalysts.
Thefollowingsectionwillproviderepresentativeexamplesoftwo‐centercooperativecatalysis,in
termsofthethreedifferentcombinationspreviouslymentioned,namelymetal‐metal,organo‐organo
andmetal‐organo systems. Then, the bifunctional systems involvingmetal / ligand cooperation,
whicharethefocusofthiswork,willbediscussed.
8
1.1.1Organo‐OrganoCooperativeCatalysis
Asmentionedabove,theBrønstedacids,amines,cinchonaalkaloids,andNHCsareamongthemost
successfully utilized organocatalysts to accomplish a broad scope of synthetic transformations.
Undoubtedly,judiciouscombinationsoforgano‐organocatalystscanleadtoremarkablecooperative
performance.
AniceillustrationistheunprecedentedexampleofcooperativecatalysisbyusingNHCandchiral
phosphoric acid for the highly enantioselective [3+2] annulation reaction of α,β‐alkynals and α‐
ketoestersreportedbyScheidtandco‐workers.15Thisprocessfurnishesγ‐crotonolactonesinhigh
yieldsandlevelsofenantioselectivity(Scheme1.1).
Scheme1.1NHC/Brønstedacidcatalyzed[3+2]annulationreaction.
Mechanistically,NHCandBrønstedacidrespectivelyactivatethealkynylaldehydeandα‐ketoester
(Figure1.4).Subsequently,C‐Cbondformationfollowedbyatautomerizationgivesanacylazolium
intermediate, which thenundergoesO‐acylation tooffer the lactoneproductandregenerates the
catalysts.
Figure1.4TSoftheC‐Cformingstepshowingtheactivationofthealkynylaldehydeandoftheα‐ketoester
bytheNHCandtheBrønstedacid,respectively.
9
1.1.2Metal‐MetalCooperativeCatalysis
Comparatively,thecooperativedual‐catalyticsystemscombiningtwotransition‐metalcomplexes
havebeenlessexplored, inpartduetothedifficulty inensuringredoxcompatibilitybetweenthe
catalystsandavoidingcatalystdeactivation.16Additionally,themechanisticcomplexityofthesedual‐
catalysis systemshasmade itknotty tobe fullyunderstoodandconsequentlyhinders its further
development.
C‐CCouplingreactionsareamongthetransformationsforwhichmetal‐metalcooperationhasbeen
welldemonstrated.Thecouplingreactionbetweenarylhalidesorvinylhalideswithterminalalkynes
catalyzedbyaPd(II)/Cu(I)systemiswell‐knownastheSonogashiracoupling.17Itisahighlyuseful
andpracticalmethodforstraightforwardconstructionofsp2‐spC‐Cbonds.Generally,cuprousiodide
ischosenasthebestcoppercatalyst,whilethechoiceofpalladiumcounterpartismoreadjustable
with a range of Pd(II) precursors (e.g. (PPh3)2PdCl2, (PPh3)4Pd, (dppe)2PdCl2, Pd(OAc)2/PPh3,
Pd2(dba)3/AsPh3),inthepresenceofsecondaryortertiaryalkylamines.(Scheme1.2).
Scheme1.2Pd/Cucatalyzedalkynylationreaction.
Althoughthewholepictureofthemechanismisnotthatexplicitatpresent,especiallyregarding
theexactformofthecatalyticallyactivespecies,aswellasthepreciseroleofthecuprousiodide,itis
presumedthatthereactionfollowsnormaloxidativeaddition–reductiveeliminationstepscommon
toPd‐catalyzedcrosscouplingreactions.Whilethearylorvinylhalideisactivatedbythepalladium
catalyst,thecuprousacetylideisconcomitantlyformedinthepresenceofamine.Latertheacetylide
group is transferred from Cu to Pd and the coupling product is finally obtained by reductive
eliminationatPd.TheCuandPdfragmentsactinconcertinthekeytransmetallationstep(Scheme
1.3).18
10
Scheme1.3ProposedmechanismintheSonogashirareaction.
11
1.1.3Metal‐OrganoCooperativeCatalysis
Transitionmetalcatalysishasbeenlongestablishedasoneofthemostusefulandpowerfultools
fororganicsynthesis,becausetransitionmetalsoftendisplayuniquereactivityandselectivity.19Over
thepastdecades, organocatalysishas grownexplosively tobecomeanotherextremely important
researchareaincurrentorganicchemistry,inparticularconcerningenantioselectiveprocesses.20‐27
Thecombinationofthesetwokindsofcatalystscanpotentiallyprovideafurtherpowerfultoolfor
carryingout(asymmetric)transformations.28,29
1.1.3.1CombinationofTransitionMetalCatalystwithanAmine
Amines,ontheirown,haveconsistentlyattractedintensiveattentionforalongtimeaseffective
organocatalysts. Amine catalysis, including secondary amine catalysis and more recent primary
aminecatalysis,playsanimportantroleintheactivationofcarbonylcompounds.30.Generally,amines
catalyze organic reactions according to two modes of action: enamine activation31 and iminium
activation(Scheme1.4).32
Scheme1.4Activationmannersinaminescatalysis.
ThefirstexampleofcombinedamineandtransitionmetalcatalysiswasreportedbyCόrdovaand
co‐workersin2006,viathemergingofenamineandpalladiumcatalysisforthedirectintermolecular
α‐allylic alkylation of unactivated aldehydes and ketones with allyl acetate (Scheme 1.5).33 This
unprecedented combination of palladium and enamine catalysis furnished α‐allylic alkylated
aldehydesandcyclicketoneschemo‐andregioselectivelyinhighyields.
Scheme1.5Directα‐allylationofunactivatedaldehydesandketones
viacooperativeenamineandpalladiumcatalysis.
12
It is presumed that two powerful catalytic cycles, including the electrophilic activation of allyl
acetatebypalladiumcatalyst,andthenucleophilicactivationoftheketonebypyrrolidine,takeplace
inparallel toforminsituthetransientPd(0)complexIandpyrrolidineenamineII(Scheme1.6).
Subsequently,themetal‐andorgano‐catalyticcyclesconvergeasthetwoactivatedintermediates
reactwitheachothertogivetheα‐allyliminiumionIII.Finally,thenetproductα‐allylcarbonylIVis
releasedbyhydrolysis,withregenerationofboththeamineandpalladiumcatalysts.
Scheme1.6Proposedmechanismforamineandpalladiumcatalyzedα‐allylicalkylation.
1.1.3.2CombinationofTransitionMetalCatalystwithaBrønstedAcid
ApplicationofBrønstedacidsincatalysishasexperiencedanimpressivedevelopmentinthelast
twodecades,inparticularthankstotheintroductionofchiralphosphoricacids,initiallydiscovered
byTeradaandAkiyamain2004.34,35.Chiralphosphoricacidscanpromoteorganocatalyticreactions
viaprotonationtogenerate(chiral)ionpairs.36,37Arangeofrecentpublicationshashighlightedtwo
maingroupsofphosphoricacids,whichcanbederivedrespectively fromabinolora spirocyclic
framework(Figure1.5).
13
Figure1.5ExamplesofcommonlyusedchiralBrønstedPhosphoricacids.
Overthelastdecade,anumberofmechanisticstudieshavebeenperformedonchiralBrønstedacid
catalyzedstereoselectivereactions.Itisbelievedthatthebulkysubstituentstypicallypresentatthe
3,3’positionsofthebinolframeworkcontributepredominantlytothestereoselectivity.38,39
ThestrategybyemployingchiralBrønstedacidsinconjugationwithtransitionmetalshasattracted
agreatdealofinterestforpromotingenantioselectivetransformations.
Asanexample,Raineyandco‐workersdescribedanenantioselectiveallylicC‐Hactivationforthe
synthesisofopticallyactivespirocyclicrings,viaemployingconcomitantlythephosphoricacidand
apalladium(II) catalyst (Scheme1.7).40Suchspirocyclic skeletons, featuringaquaternarycarbon
center, can be found in several biologically relevant molecules, and are notoriously difficult to
synthesize.41‐43
Scheme1.7ChiralBrønstedacidsandPalladium‐catalyzedallylicactivation.
ControlexperimentsrevealedthatbothPd(OAc)2andthechiralphosphoricacidarecrucialtothis
reaction,asnoconsumptionofthestartingmaterialsisobservedintheabsenceofeitherofthem.A
plausiblemechanismwasproposedbytheauthors(Scheme1.8).Pd(OAc)2andthephosphoricacid
additive(S)‐1bfirstundergoanexchangereactiontogenerateanactivePd(II)‐OP(=O)(OAr)2species.
Then, the substrate is coordinated to the active Pd(II) catalyst, resulting in the formation of
intermediateII.Subsequently,followingaC‐Hactivationreactionwhilethephosphoricanionforms
14
ahydrogenbondwiththehydroxylgroup,acrucialπ‐allylpalladiumintermediateIIIisgenerated.
Finally,thecombinedPd(II)andphosphatecooperativelycatalyzethesemipinacolringexpansion,
resultingintheformationofthefinalproduct.
Scheme1.8ProposedmechanismforBrønstedacidsandpalladiumcatalyzedreaction.
Takingintoaccountthismechanism,andinparticularthekeyintermediateIII,itappearsthatthis
system is at the frontier between two‐center cooperative catalysis and bifunctional catalysis, in
which themetal (Pd) and the ligand (phosphoric acid) act in concert to form the final product.
Organometalliccatalystsinwhichtheligandcooperateswiththemetaltotheactivation/formation
ofchemicalbondsarecalledmetal/ligandCooperativesystems.Theyareactuallythefocusofthis
workandarepresentedinmoredetailinthenextsection.
15
1.2Metal‐LigandCooperation
Metal‐ligandcooperationisnowbecominganextremelyimportantconceptincatalysis.Different
from“classical”transitionmetalcatalysiswheretheligandonlytunesthestereoelectronicproperties
ofthemetalcenter,metal‐ligandcooperativecatalysisemploysboththemetalandtheligand,which
participateconcertedlyinbondactivation/formationprocesses.Thesecooperativeligandsarethe
so‐callednon‐innocentligands.
Theterm“innocent”wasfirstintroducedinchemistrybyJørgensenin1966.44Aninnocentligand
allowsunambiguousdeterminationoftheoxidationstateofthecentralmetalatom.Incontrast,a
non‐innocent ligandusuallypossessesadelocalizedπ‐system,whichmakesneithertheoxidation
stateofthecentralmetalatomnorthechargesonthedonoratomsoftheligandeasytobeprecisely
defined.Anelegantexampleofcomplexbearinganon‐innocentligandistheneutralnickelcomplex
withglyoxalbis(2‐mercaptoanil)Ni(gma)2characterizedbythepresenceofanextensivesystemof
conjugatedπbonds(Figure1.6).45 Thiscomplexcanbeconsideredasa16‐electronNi(II)complex
withdiiminodithiolate(1a)ordi(imino‐thiosemiquinonate)(1b),asa14‐electronNi(IV)complex
(1c)or,alternatively,asan18‐electronNi(0)complex(1d).Itiswidelyacceptedthattheformula
withdelocalizedbonds(1e)representsthebestdescriptionofthetrueelectronicstructureofthe
metalcomplexNi(gma)2.
Non-innocent ligands
SNi
N N
S SNi
N N
S
SNi
N N
S SNi
N N
S
II II
IV 0
SNi
N N
S1e
(best described)
1a 1b
1c 1dNi(gma)2
Figure1.6RepresentativeNicomplexbearinganon‐innocentN2S2ligand.
Itisnotuntilearly1990sthatsuchnon‐innocentconceptgainedwideacceptanceandattracted
considerableattention.Theconceptof“non‐innocent”ligandswasextendedlatertoligandsthatare
16
directly involvedon theactivationof thesubstrates.So, twomain typesof reactivity,namely the
redoxorcooperativemanner,inwhichthenon‐innocentligandisinvolved,canbecategorized.Redox
non‐innocentligandsnormallyparticipateinthecatalyticcycleonlybyaccepting/donatingelectrons;
whereascooperativenon‐innocentligandsdirectlyparticipateintheformation/breakingofcovalent
bondsforthesubstrates.
Redoxnon‐innocentligandscanbeeasilyoxidizedorreducedbyoneormultiple(mosttypically
two)electrons,whichcaneitherdirectlytunethepropertyofthewholecomplexespeciallythemetal
center, or function as electron reservoirs avoiding uncommon oxidation state of themetal. The
cooperative non‐innocent ligands also avoid variation of the oxidation state of the metal by
participating in the activation/formation of covalent bonds so that the process do not require
oxidative addition/reductive elimination to take place. Thanks to these properties, catalytic
applicationshavebeendevelopedforbothtypesofnon‐innocentligands,andsomerepresentative
examplesaredescribedhereafter.
17
1.2.1RedoxNon‐InnocentLigands
Itisknownthatthereactivityandcatalyticbehaviorofacomplexcanbestronglyaffectedbytuning
the electronic properties of the ligand. Such modulations are typically attained by introducing
electron‐withdrawing or donating groups at the ligand, which may require laborious synthesis.
However, through straightforward oxidation or reduction of a redox non‐innocent ligands, the
propertyofthewholecomplex,especiallytheLewisacidityofthemetal,canbeeasilytunedwithout
large changes in the steric environment of the complex. In 2008, Rauchfuss and co‐workers
introducedthisconceptintheoxidationofdihydrogenbyanIr(III)complex(Scheme1.9).46,47
Scheme1.9LigandoxidationleadingtoincreasedLewisacidityofthemetal.
UponOxidation of complex I by the silver tetrafluoroborate, the resultant cationic complex II,
containingaone‐electronligand‐radical,makesthemetalastrongerLewisacidthanthatofformer
non‐oxidizedformI,whilemaintainingitsoxidationdegree.Thissimplemethodallowsreactionwith
H2 to afford the adduct III. Later on, doubledeprotonationby thenon‐coordinatingbase2,6‐ (t‐
Bu)2C5H3N(2,6‐di‐tBu‐pyridine;TBP)efficientlyleadstotheoxidationofH2.
Comparatively,themostprevalentapplicationoftheredoxnon‐innocentligandsincatalysisisto
employ them as electron‐reservoirs. In “classical” homogeneous catalysis,many transformations
involvetwoelectrontransfersbetweenthemetalandthesubstrateviareductiveelimination(RE)or
oxidationaddition(OA).Suchtransformationsarecommonfor2ndand3rdrowtransitionmetals,in
particularthenobleones,suchasPd,Pt,Rh,etc.,butratherdifficultforcheaperandearthabundant
1st row transition metals (Fe, Co, etc.). In this context, if the redox non‐innocent ligands can
temporarilystoreextraelectronsorviceversa, thecomplexasawhole iscapable tomediate the
18
multipleelectron transformations, concomitantlymaintaining themost common/stableoxidation
stateofthemetal.Thatistosay,theredoxnon‐innocentligandscanendow1strowtransitionmetals
withnewreactivityandbehaveasnoblemetals.Itisforeseenthatsuchcombinationsofredoxnon‐
innocentligandsandtransitionmetalswillleadtocatalyticimprovementsinexistingprocesses.
Althoughthedevelopmentofredoxnon‐innocentsystemsisstillinitsinfancy,ahandfulofsuch
ligands,includingquinones,dithiolensandα‐dimines,48havebeenwidelyrecognizedandthoroughly
investigated.Lately,theuseofligandssuchasbis(imino)pyridines,diphenylamines,andevenFischer
carbeneshavereceivedincreasingattentionsforredoxchemistry.49Particularly,bis(imino)pyridines
haveshowntoundergoligand‐basedredoxevents,whichmaintaintheformaloxidationstateofthe
coordinatedmetal.49‐51Chirikandco‐workersmadesignificantprogressbytakingadvantageofsuch
electron‐reservoirsproperties(Scheme1.10).52,53Inanillustrativeexample,adianionictridentate
NNN‐ligand,whichisactuallythe2e‐reducedformoftheredox‐active2,6‐diiminepyridineligand,
hasbeenefficientlyappliedtointramolecular[2+2]cycloadditions.50,54
N
Fe NNL L
iPr
iPr iPr
iPr
AReducedligand
FeII
N
Fe NNArAr
BReducedligand
FeII
X
X
N
Fe NNArAr
COxidizedligand
FeII
X
X
X= CH2,NAlk,C(CO2Et)2
Scheme1.10Redoxnon‐innocent2,6‐diiminepyridineligandasanelectron‐reservoir.
Theformedbis‐dinitrogenFe(II)complexAbearingsuchaligandcanreactwithadienesubstrate
to form theπ‐complexB. Subsequently, a two‐electronoxidative addition process takes place to
furnish intermediateC,with formationof anewC‐Cbondon thesubstrate.Remarkably, the two
electronsrequiredforthistransformationoriginatefromthebis(imino)pyridineligand,ratherthan
19
from iron, whichmaintains the energetically favorable Fe(II) oxidation state, instead of the less
favorable Fe(IV). The resultant intermediate C then undergoes a formal two‐electron reductive
elimination process, with formation of another new C‐C bond, to release the net product and
regenerate the complex A. Therefore, the electron‐storage capacity of the ligand makes iron to
maintainitsstableFe(II)oxidationstate,insteadoftheunstablehigh‐energyFe(0).Recently,such
kind of bis(imino)pyridine Fe(II) complexes have been intensively investigated and applied in a
varietyoftransformations,likeenynecyclization,55intermolecular[2+2]cycloadditionofalkenesto
butadienes,56andtheolefinpolymerization.57,58
Asmentionedabove,theapproachofemployingthe1strowtransitionmetalsinconjugationwith
redoxnon‐innocentligandsincatalysishasincreasinglydevelopedinrecentyears.Nevertheless,a
handfulofexamplesusing2ndand3rdrowtransitionmetalswithredoxnon‐innocentligandshave
alsobeengraduallyreported.
VanderVlugtetal.havereportedrecentlythesynthesisofanewredoxnon‐innocenttridentate
NNHOHligandLH2,whichcanreactwithPd(II)tofurnishaparamagneticiminobenzosemiquinonato
complexII, bearingthe ligand‐centeredradicalNNOISQ(L•),assupportedbyspectroscopic,X‐ray,
andcomputationaldata(Scheme1.11).59Aftersingle‐electronprocesses,complexIIcanbeeither
reducedtoadiamagneticamidophenolatecomplexI [CoCp2][PdCl(NNOAP)],oroxidizedtoaneutral
iminobenzoquinonecomplexIII[CoCp2][PdCl(NNOIBQ)].Notably,complexIwasshowncapable to
activatealiphaticazidesforintramolecularC‐Hbondaminationtogeneratepyrrolidines.
Scheme1.11PdIIcomplexesfeaturingaredoxnon‐innocentNNOligandsandassociated1e‐transfer
processes.
Experimentalinvestigations,includingisotopiclabelingandtrappingexperiments,altogetherwith
the computational study (DFT) support the ligand‐centered redox behavior of the complex, and
indicate a process that proceeds via intramolecular single‐electron transfer from the redox non‐
20
innocentligandtothesubstrateuponthermalactivationoftheazide(Scheme1.12).Asaresult,an
unusual‘nitrene‐radical,ligand‐radical’Pd(II)intermediateBisgenerated,withanopen‐shellsinglet
groundstate.BundergoesthenH‐abstractionandcyclizationprocessestoleadtothefinalproduct.
Theredoxnon‐innocentNNO ligand issuggested toendowsingle‐electronreactivityuponPd(II),
allowingradical‐typepathwayswithametalthatnormallyundergoestwo‐electronprocesses.
Scheme1.12Proposedmechanismforradicaltypesp3C‐HaminationwithI.
21
1.2.2CooperativeNon‐InnocentLigands
Cooperativenon‐innocentligands,whichfunctionasa“co‐actor”withmetalstodirectlyparticipate
intheformationandcleavageofchemicalbonds,areobviouslyofprimeimportanceincatalysis.A
wide rangeof catalytic systems involvingcooperativenon‐innocent ligandshavebeendeveloped
duringthelastdecade,butinthissectiononlytworepresentativeexampleswillbediscussedinorder
to illustrate the approach. Then, some of themost characteristic catalytic applications involving
metal‐ligandcooperationwillbediscussedinthenextsection.
Thefirsttypeofcooperativeligandistheamidoligands.Theyhavebeenrecognizedascooperative
ligandsforlongtime,andtransitionmetalamidocomplexeshavedemonstratedtobereactive60‐62
and play an important role in both stoichiometric and catalytic reactions, in particular, the
hydrogenationofunsaturatedsubstratesRR’C=X(X=O,NR).63
In2006,Bergmanandco‐workersreportedachiralzirconiumbis‐(amido)complexes,which is
formed in situ by combination of diphosphinic amides and Zr(NMe2)4 (Scheme 1.13).64 Such
complexesarecompetentcatalystsforintramolecularasymmetricalkenehydroamination,leading
topiperidinesandpyrrolidinesinhighyieldsandupto80%ee.Here,theamidoligandsplaytherole
ofbasesandaretypicallyliberatedfromthecoordinationsphereofthemetalasanamine.However,
thereactivityoftheamidogroup,capableofactivatingC‐HandN‐Hbonds,nicelyillustratesthehigh
potentialofthiskindofligand.
Scheme1.13Zirconiumamidocomplexcatalyzedintramolecularhydroamination.
In 2001,Noyoriwas awarded theNobel Prize for his spectacular achievements in asymmetric
catalysis.65Inparticular,hisgrouphasmadetremendouscontributionsonmetal‐ligandcooperative
transformations. Their feature chiral RuII amido complexes, display very high activity and
enantioselectivity (turnover frequency (TOF)>200 000 h‐1; turnover numbers (TON)>2 × 106;
ee>98%). The representative catalytic mechanism of hydrogenation of ketones by such amido
complexes is shownbelow (Scheme1.14). Initially, theH2molecule is coordinated to the vacant
coordinationsiteof thecoordinativelyunsaturatedRucenterviaaσbond,andsubsequently the
22
heterolyticcleavagetakesplaceacrosstheRuII–amidobondtogiveaRuIIaminohydridecomplex.
Afterwards,theketonebindstothiscomplexinthesecondcoordinationspherebyNHδ+andRuHδ‐
groups,andundergoesahydrogenationprocessinaquasi‐concertedway,togivethealcoholproduct
with theregenerationof theRuamidocomplex.TheoxidationstateofRuremainsunchangedall
alongtheprocess(RuII)andtheketonereductiontakesplacesaccordingtoasocalledouter‐sphere
mechanism.
Scheme1.14MechanismofhydrogenationofketonesbychiralRuIIamidocomplexes.
Amongthevarietyofcomplexesbearingcooperativenon‐innocentligandsreportedinliterature,
pincer complexes derived from bis(di(tert‐butyl)phosphinomethyl)pyridine ligand have found
widespreadapplicationsinsynthesis,bondactivationandcatalysis,andcontinuouslyattracthuge
interestduetotheirhighstability,activityandvariability(Figure1.7).
Figure1.7Milstein’s1stgenerationcatalystprecursorofcomplex[RuIICl(N2)H(tBu‐PNP)].
Pincerligandsaretridentateligandsthatcoordinatetoametalcenterinameridionalfashion.The
firstpincerligandwasintroducedbyShawandco‐workersin1970s.66Duringthepast40years,the
pincerligandhasestablisheditselfasaprivilegedligandinavarietyofresearcharea.(Figure1.8)
Primarily,thepincer‐transitionmetalchemistryconcentratedontheapplicationsofPCP‐andSCS‐
pincerligands(with“soft”P‐orS‐donorsites).Lately,researchersstartedtoapplytheNCN‐pincer
ligands(with“hard”sp3aminedonorgroups).67,68
23
Figure1.8TypicalPincer‐metalplatform.
ParticularlynoteworthyisthepreparationbyMilsteinandco‐workersadecadeagooftheRu(II)
complexeswiththe“pincer” ligandbis(di(tert‐butyl)phosphinomethyl)pyridine(tBu‐PNP).69Since
then,severalanalogouscomplexeshavealsobeenpreparedbystructuralmodulationoftheligand
andthemetal.Theirreactivityandcatalyticactivityhavebeenthoroughlyinvestigated,inparticular
their ability to promote the acceptorless and acid‐free dehydrogenation of alcohols to carbonyl
compounds.70Themainparticularityofthesecomplexesistheirabilitytobedeprotonatedinthe
presence of a base to form a pyridine dearomatized pincer complex. Such kind of dearomatized
complexcanthenactivatechemicalbonds(H‐Y;Y=H,OH,OR,NH2,NR2,C)bycooperationbetween
themetalandtheligand,therebyregainingaromatization.Notably,themetaloxidationstateremains
unchangedduringtheprocess(Scheme1.15).
Scheme1.15Aromatization/dearomatizationofMilsteinpincercomplexes.
The first‐generation catalyst precursor [RuIICl(N2)H(tBu‐PNP)] (Figure1.7)was applied for the
dehydrogenationofsecondaryalcoholsintothecorrespondingketoneswithliberationofdihydrogen.
However,theefficiencyofthistransformationisquitelowevenatelevatedtemperature(>100°C)
and in thepresenceof abase. In addition, theprimary alcohols cannotbe transformedwith this
system,unlessthesterichindranceofthemetalcomplexisreducedbyreplacingthebulkytBugroups
foriPrgroups.Inthisregard,theanalogous[RuIICl(CO)H(iPr‐PNP)]complexwaspreparedandused
to convert 1‐hexanol into the corresponding ester hexyl hexanoate and H2. Nevertheless, the
24
reactivityofsuchmodifiedcomplexwasalsolowforthistransformation(68%conversionat157°C
in24hwithasubstrate/catalyst(S/C)ratioof1000:1).
Lateron,aremarkableimprovementfromthesamegroupwasachieved,byreplacingoneofthe
R’’2PCH2armsinthetridentatePNPligandbyanaminomethylenegroup(Scheme1.16).71Inthiscase,
the complex not onlymaintains the cooperativity, but also profits of the hemilability of the less
stronglyboundaminofunction.Thisnewcomplex1,inthepresenceof1.0equiv.ofbase,efficiently
promotedehydrogenativeesterification,exceedingtheoriginalcomplex(92%conversionat157°C
in24h).Inordertofurtherimprovethereaction,itisdesirabletoavoidtheneedforanexternalbase.
Upontreatmentwith1.0equiv.ofKOtBuat‐32°C,complex1undergoesadearomatizationprocess,
resultinginthedeprotonationatthebenzylicphosphinearm,ratherthanthehydrideligand,toform
ananionicPNNligand.Thedearomatizedcompound2canbeuseddirectlyascatalyst.
Scheme1.16Milstein’s2ndgenerationPNNtypecomplexanditscatalyticactivityinthedehydrogenative
couplingofalcohols.
Byvirtueofthisnovelcooperativemode,alargenumberofdifferenttransformationshavebeen
successfullydeveloped,andsomeofthemwillbepresentedinthefollowingsection.
25
1.3Metal‐LigandCooperativeCatalyticProcesses
Inviewofglobalconcernsregardingtheenvironmentandsustainableenergyresources,thereisa
pressingneedforthedevelopmentofnew,atom‐economicalandenvironmentally‐benigncatalytic
reactions.Inthiscontext,novelapproachesarehighlydesirable.Recentyearshavewitnessedthe
metal‐ligand cooperation emerging as an extremely important concept in catalysis by transition
metalcomplexesbothinsyntheticandbiologicalsystems.72,73Complexesbearingcooperativeligands
haveexhibitedremarkablecatalyticactivitytowardsbondactivations,includingtheH‐H,R‐H(sp2
andsp3),heteroatom‐hydrogen(O‐H,N‐H,etc.)bonds.Theyefficientlypromotetransformationsthat
weresofardifficultorunattainable.74,75
1.3.1Metal‐LigandCooperationuponHydrogenation
Catalytichydrogenation/dehydrogenationprocessesarewidelyusedinthechemicalindustry.The
hydrogenationreactionsareparticularlyimportantinthepreparationofpharmaceuticalsandfine
chemicals.Ligand‐associatedheterolyticactivationofH2isparticularlyattractivesinceitisakeystep
inmosthydrogenationcatalysis.Thepioneeringworkinthisareadatesbackto1980s,byFryzukand
co‐workers, introducing the organometallic amide complexes of rhodium and iridium.76 The
importantconceptofreversiblestorageofH2uponatransitionmetal‐ligandframeworkwaslater
proposed by Crabtree.77,78 Among the most successful catalytic applications are the Noyori’s
hydrogenation65,79(Figure1.9a)andNoyori‐Ikariya’stransfer‐hydrogenationcatalysts(Figure1.9
b).80‐83
Figure1.9NoyoriandIkariya’sfeaturecatalystsforhydrogenationprocesses.
Asdiscussedintheprevioussection,thesecatalystscontainingchelateamineligands,canprovide
aproticN‐Hgroupattheadjacentα‐positionofthemetalcenter.Suchnitrogenligandfunctioneither
asanH‐bonddonortothesubstrateintheprotonatedamineform,orasaninternalBrønstedbase
in the deprotonated amido form, to achieve efficient catalytic transformations. Such discoveries
marked the inception of the rational design of chiral catalysts with unprecedented activity and
selectivityinthereductionofprochiralketonesandimines.
26
In some cases, as in the reduction of α,β‐unsaturated ketones, the chemoselectivity of these
systems isofgreatvalue.Efficientandselectiveasymmetrichydrogenationofcarbonylgroups in
olefinic ketones, especially the α,β‐unsaturated ketones, is a long‐standing problem in organic
chemistry. The resultant chiral allyl alcohol products are important intermediates for further
transformations,suchasClaisenreactionandarangeofSN2'substitutionreactions.84,85Variousmetal
hydride reagents, such as NaBH4 and LiAlH4, can reduce the C=O linkage selectively, but
stoichiometrically.Despiteextensiveefforts,mostreportedcatalystsystemsareselectivefortheC=C
bonds, rather than the C=O bonds. Moreover, some simple enones are very sensitive to basic
conditions,hinderingtheutilityofsomecatalyticsystemsinvolvingbases.Anelegantsolutionwas
reported by Noyori’s group with the XylBINAP/DAIPEN‐ruthenium catalyst (S,S)‐[Ru] a. In the
presence of this complex and K2CO3, a weak base co‐catalyst, benzalacetone can be efficiently
hydrogenatedin2‐propanoltothecorrespondingRalcoholin97%eeunder80atmofH2(Scheme
1.17).86Thiscatalyticsystemcangiveaccesstoavarietyofchiralallylalcohols,fromthestructurally
flexible enones. Some of the allylic alcohol products are the key intermediate for anthracycline
antibiotics.
Scheme1.17SelectiveformationofallylalcoholwiththeXylBINAP/DAIPEN‐rutheniumcatalysta.
Such phosphane/1,2‐diamine‐ruthenium complexes have been intensively investigated by
Noyori’sgroupandwidelyutilizedtocatalyzeasymmetrichydrogenationofalargevarietyofsimple
ketonesefficiently, surpassing theclassicalmethods in termsof substratesscopesand functional
grouptolerance.
Sincethepioneeringworkreportedin1995(Figure1.10),87Ikariyaandco‐workershavedeveloped
aseriesofchiralcatalystsforverypracticalasymmetrictransferhydrogenation,withisopropanolas
27
hydrogensource.Withthesecomplexes,awidespectrumofchiralalcoholsisnowaccessiblewith
excellenteeundermildreactionconditions.80
Figure1.10Ikariya’scatalystsforasymmetrictransferhydrogenation.
SimilartotheNoyori’scomplex,theactivationofisopropanolwiththesesystemsissuggestedto
involvethecontributionoftheamidomoiety,toformcomplexdandacetone.Then,hydrogenation
transfer toaketonesubstratewasproposed tooccur inaconcertedmannerviaasix‐membered
transitionstateTS,fromahydrideoftheRu‐HgroupandaprotonoftheN‐Hgrouptothecarbonyl
group(Scheme1.18).
Scheme1.18ProposedmechanismforRu‐catalyzedofenantioselectivetransferhydrogenation.
28
1.3.2Metal‐LigandCooperationuponDehydrogenation
Noteworthy,dehydrogenationreactionsarerelativelyproblematic,mainlybecausetheyusually
undergoa thermodynamicallyunfavorableprocess, requiring stoichiometricor excess amountof
oxidants,suchasO2,peroxides, iodates,andmetaloxides,orevenasacrificialhydrogenacceptor.
Mostoftheseclassicalstoichiometricmethodsleadtothegenerationofwastefulby‐products,which
obviouslyfrustratesthefuturetrend.Tocircumventsuchdrawbacks,numerousexamples,involving
transitionmetalcomplexes,inparticularthemetal‐ligandcomplexes,havebeenreportedbyseveral
groups.
1.3.2.1DehydrogenationofAlcohols
Aspreviouslymentioned,Milsteinetal.developedarutheniumPNPtypepincercomplexe[2,6‐
bis‐(di‐tert‐butylphosphinomethyl)pyridine].69 The dehydrogenation of secondary alcohols to the
corresponding ketones can be catalyzed in the presence of base,with only low catalytic loading
(Scheme1.19a).Thecatalyticsystemwasmodifiedbytreatmentwithanexcess(5equiv.)ofNaBH4
in2‐propanolfor12h,resultingintheformationofnewPNPRu(II)hydridoborohydridecomplex
f.88Meanwhile,ananalogousPNNRu(II)hydridoborohydridegwasalsoprepared,followingthe
samestrategy.Thesetwocomplexescancatalyzethesamereactionwithoutparticipationofexternal
base,byusingonly0.1mol%ofcatalystloading(Scheme1.19bandc).
Scheme1.19Dehydrogenationofalcoholscatalyzedbycomplexese‐i.
Two other types catalytic systems were later introduced by Yamaguchi and Gelman. In 2007,
Yamaguchiandco‐workersreportedanewCp*Ircomplexhcontaininga2‐hydroxypyridineligand.
It oxidizes various secondary alcohols to ketones under neutral conditions with high turnover
numbers (Scheme1.19h).89 In2010,Gelmanandco‐workersdesignedanewbifunctionalPCsp3P
29
pincercomplexi,whichcatalyzesthedehydrogenationofbothprimaryandsecondaryalcoholsto
affordcarbonylandcarboxyliccompounds(Scheme1.19i).90Thekeystepoftheprocessinvolvesin
bothcasescooperationbetweenthestructurallyremotehydroxylfunctionalityandthemetalcenter
(Scheme1.20).
Scheme1.20Generalmechanismforthedehydrogenationofalcoholscatalyzedbycomplexesdande.
Comparatively, relateddehydrogenationofprimaryalcohols to the correspondingaldehydes is
scarcely reported,mainlydue to thedeactivationof the rutheniumcomplexes resulting from the
decarbonylation of the aldehydes. Recently, Fujita and Yamaguchi reported an iridium catalyst j
whichcanrealizethetransformationofalcoholsintoaldehydes(Scheme1.21).91Afurthermodified
water‐solublecatalystkwasdevelopedthatcancatalyzethe dehydrogenationofbothsecondaryand
primaryalcohols inwater.Mechanistic investigationsdisclosed the crucial involvementofmetal‐
ligandcooperationinthesereactions.92,93
Scheme1.21Iridiumcomplexescatalyzeddehydrogenationofalcoholsintoaldehydesandketones.
30
1.3.2.2DehydrogenativeCouplingofAlcoholstoFormEsters
Esterificationisoneofthemostfundamentalandimportanttransformationsinorganicsynthesis,
inparticularintheproductionoffinechemicalssuchasfragrancesandpharmaceuticals.Herethere
isaparticularinterestinsyntheticroutesthatdonotrequirelargeamountsofcondensingreagents
and activators. Instead of the conventional condensation of alcohols and carboxylic acids (or
derivatives thereof), the direct catalytic transformation of alcohol into esters is very attractive
(Scheme1.22).However,catalyticsystemsinaccordancewithsuchapproachesforestersynthesis
arerarelyreportedwithonlytwopioneeringcontributionssofar.
Scheme1.22Envisageddirectcatalyticesterificationfromalcohols.
In1984,duringtheinvestigationofRu‐catalyzedalcoholtransferdehydrogenation,theruthenium
complex [(η4‐tetracyclone)(CO)2Ru]2 and its analog (η4‐tetracyclone)(CO)3Ruwere discovered by
Shvoandco‐workers(Scheme1.23).94ThisdinuclearRucomplexbearingatetraphenyl‐substituted
hydroxycyclopentadienylligand,hasbeenwidelyusedasastablepre‐catalystforarangeofreactions
involving hydrogen transfer process, such as hydrogenation of carbonyl compounds and imines,
directhydrogenation,alcoholandaminedehydrogenationetc.95
Scheme1.23Shvocomplexanditsdissociationinsolution.
Inthesolidstate,Shvocomplexadoptsthedinuclearstructurel;whileduringthecatalyticprocess,
it dissociates in solution into two part, i.e. the monomeric complexm and the coordinatively
unsaturatedonen,whichareindeedresponsibleforthecatalyticactivity.Thissystemisamongthe
earliestexamplesofhydrogentransfercatalysisinvolvingmetal/ligandcooperativity.Casey96,97and
Backvall98 supported the mechanisms for hydrogenation/dehydrogenation processes through
kineticisotopeeffect(KIE)studies(Scheme1.24).Inanoutersphereprocess,the18e‐complexm
31
simultaneouslytransfersthehydridefromtheRu(II)centerandtheprotonfromtheO‐Hgroupof
theligandtothecarbonylgroup.Complexnpromotesthereverseprocess,namelytheoutersphere
alcoholdehydrogenation.
Scheme1.24ProposedmechanismofhydrogentransferwithShvocomplexesm/n.
Withsuchcomplexes,benzylbenzoateandpentylpentanoatecanbeobtaineddirectlyfromthe
correspondingneatalcoholsat137°‐145°C.Thealdehydeformedbyalcoholdehydrogenationreacts
withtheexcessofalcohol,andtheresultinghemiacetalissubsequentlydehydrogenated.However,
yieldsandreactiontimeswerenotreported.
Asmentionedbefore,Milsteinandco‐workersdiscoveredanovelseriesofPNPandPNNpyridine‐
based ruthenium pincer complexes with a new mode of metal‐ligand cooperation, involving
aromatization‐dearomatizationprocessofthepyridinemoiety,leadingtounusualbondactivation
andtonovel,environmentallybenigncatalysis.71
These complexes canperformdirect catalytic dehydrogenative couplingof primary alcohols to
esterswithhighefficiency(Scheme1.25).Complexeso,p,andrneedacatalyticamountofbase,for
insitugenerationof thecorrespondingdearomatizedcomplexesbydeprotonation,whicharethe
actual catalysts (KOH, 67 %, 24 h; 95 %, 24 h). Complex q itself promotes the reaction and
demonstratesthebestactivity(99%,6h).
32
Scheme1.25CatalyticdehydrogenativecouplingofprimaryalcoholstoesterscatalyzedbyMilstein
complexes.
Remarkably, the direct dehydrogenative cross‐coupling of primarywith secondary alcohols to
formmixedesterswasalsoachievedbyusingarelatedbipyridine‐based,dearomatizedcomplexs
(Scheme1.26).99
Scheme1.26Catalyticdehydrogenativecouplingofprimaryandsecondaryalcoholstomixedesters.
Morespecifically, the intramolecularesterificationwithdiolscanbeused todirectlyobtainthe
corresponding lactones with liberation of H2 (Scheme 1.27). This unique transformation can be
achievedbycomplexg.88
Scheme1.27Catalyticintramoleculardehydrogenativecouplingofprimaryandsecondaryalcoholsinto
lactones.
33
1.3.2.3DehydrogenativeCouplingofAlcoholsandaminestoformamides
Amideformationisafundamentalreactioninchemicalsynthesis.Theimportantroleofamidesin
bothchemistryandbiologyhavebeenlongrecognized,withextensiveinvestigationsoverthepast
century. Similar to other fundamental reactions, approaches that can proceed under neutral
conditionswithgenerationoflesswastes,arealwaysdesirable.Anidealapproachisobviouslythe
directtransformationofalcoholsandaminestothecorrespondingamides,withcleanliberationof
H2.100 However, this reaction is difficult to achieve because of competitive dehydration of the
intermediatehemiaminalsleadingtoimines.
By virtue of complexq, a range of alcohols could readily reactwith alkyl and aryl amines and
diamines to generate amides with liberation of H2, using very low catalyst loadings (0.1mol%)
(Scheme1.28).101Inaddition,undersuchconditions,thereactionsareselectivetowardstheprimary
aminefunctionality.
Scheme1.28Catalyticdehydrogenativecouplingofalcoholsandaminesforamides.
Initially,complexqcatalyzesthedehydrogenationofthealcoholtothecorrespondingaldehydeas
previouslydescribed(Scheme1.29).TheresultantaldehydeAthenreactswiththeaminetoformthe
hemiaminalB,whichthenreactswithcomplexqtoformtargetamideproductCbydehydrogenation.
Noteworthily,thedehydrogenationofthehemiaminalBtoformtheamideismorefavorablethan
thecommonlyoccurringwaterelimination.Onlyatraceamountoftheiminesideproductisobserved
inthiscatalyticsystem.
34
Scheme1.29Proposedmechanismfordirectcouplingofaminesandalcoholsintoamidescatalyzedbyq.
Analternativeapproachemployingestersandaminesinsteadofalcoholsandamineshasalsobeen
reportedtodirectlysynthesizetheamides.Complexqefficientlycatalyzesthistransformationwith
theliberationofH2underneutralconditions(Scheme1.30).102Ethylacetate,whichisacheapand
abundant ester, can be applied as a convenient, atom‐economical acetylation agent of amines,
generatingH2astheonlyby‐product.
Scheme1.30Catalyticdehydrogenativecouplingofestersandaminesintoamidescatalyzedbyq.
35
1.3.3Metal‐LigandCooperationbeyondHydrogenation/Dehydrogenation
As discussed in this section,metal‐ligand cooperation has developed rapidly since the seminal
workofNoyori,Shvo,Milstein,….Mostoftheeffortshavebeenfocusedsofartotransformations
involving H2 activation, H2 transfer, and hydrogenation/dehydrogenation processes. However,
althoughtheyaremuchlessabundant,otherapplicationsinvolvingactivationofX‐HormultipleCC
bondshaverecentlybeenreported.
1.3.3.1Metal‐LigandCooperationInvolvingSi‐HBondActivation
Themetal‐mediatedactivationofSi‐Hbondsiswidelyrecognizedasadirectandefficientstrategy
for the functionalization of organic substrates.103 Recently, Tatsumi, Oestreich et al. reported a
coordinatively unsaturated cationic ruthenium(II) complex t, bearing a tethered thiolate ligand,
capabletopromotethedehydrogenativeC‐Hsilylationofindoles(Scheme1.31)viasequentialSi‐H
bondactivationandSEArprocess.
Scheme1.31RucomplexcatalyzedindoleselectivedehydrogenativeC‐Hsilylation.
TheM‐SbondiscapabletoheterolyticallysplittheSi‐HbondacrosstheRu‐Sbond,toformsulfur‐
stabilized silicon electrophile, while maintaining the Ru‐S interaction (Scheme 1.32).104 This
presumedsulfur‐stabilizedtrivalentsiliconcationofcomplext‐1isthenattackedbytheC‐3position
ofindole,yieldingtheRu‐Hhydridecomplext‐2.Theweaklybasicsulfuratomofcomplext‐2can
abstract the proton from theWheland type intermediateB, resulting in the formationof thenet
product C and complex t‐3. Such complex t‐3 is known to release H2 immediately, with the
regenerationoft.Noteworthily,thesulfurmoietyoftheligandplaysakeyroleinallstepsofthis
catalytictransformation.
36
H-Si
NMe
R
H
H
SRu
Et3P
NMe
R
Si
vacantcoordinationsite
SRu
Et3PH Si
SRu
Et3PH
SRu
Et3PH H
NMe
R
H
H
Si
H H
t
t-1
t-2
t-3
A
B
C
Scheme1.32ProposedmechanismforRucomplexcatalyzedindoleselectiveC‐Hbondfunctionalization.
Another interesting example involving Si‐H and C‐F bond activation promoted by the same
tethered ruthenium thiolate complex t was reported later on by Oestreich and co‐workers.105,169
Following the heterolytic activation of the Si‐H bond across the Ru‐S bond, the sulfur‐stabilized
silyliumformediselectrophilicenoughtoabstractfluoridefromCF3substitutedanilines(Scheme
1.33).
37
Scheme1.33HydrodefluorinationofCF3substitutedanilinescatalyzedbytheRuthiolatecomplext.
1.3.3.2Metal‐LigandCooperationuponHydroamination
Nitrogen‐containingcompoundsareamongthemostimportantcompoundsinchemistry.Theyare
widely found in valuable and commercially important bulk chemicals, specialty chemicals and
pharmaceuticals.106Amongnumeroussyntheticroutes,hydroaminationleadingtodirectformation
ofanewC‐NbondbyadditionofaN‐HbondtoanunsaturatedC‐Cmultiplebond,isobviouslyof
primesignificance.107,108
Anelegantexampleusingmetal‐ligandcooperationforhydroaminationwasreportedbyIkariya
andco‐workers,employinganiridium‐pyrazolecomplexufortheintramolecularhydroaminationof
non‐activatedaminoalkenes(Scheme1.34).109
Scheme1.34Ir‐pyrazolecomplexcatalyzedhydroaminationofalkenes.
Mechanistically,theauthorsproposedtwoplausiblepaths(Scheme1.35).Inpatha,theIrmetal
centeractivatestheolefinbycoordination,favoringthenucleophilicattackoftheamine.Thisstepis
assistedbyasecondaryinteractionbetweentheN‐Hgroupoftheamineandthebasicpyrazolato
ligand.Subsequently,theresultantintermediateu‐3undergoesaprotontransferfromthepyrazole
38
backbone,toreleasethecyclizedproductandtheregeneratecomplexu.Inpathb,complexuandthe
substrateformanamido–pyrazoleintermediateu‐2byactivationoftheN‐Hbond.Theensuingstep
would involve the coordination of the olefin to themetal center and insertion on theM‐N bond
leadingtou‐3,althoughitseemslessplausible.Whateverthepathway,theβ‐nitrogengroupinthe
bifunctionalpyrazole/pyrazolatocomplexesshouldplayanimportantroleinthishydroamination
process.
Scheme1.35Ir‐pyrazolecomplexcatalyzedhydroaminationofalkenes.
Muñizandco‐workersalsoreportedanefficientactivationofN‐Hbonds,byusingawell‐defined
rutheniumamidocomplexv.110Withthiscomplex,anenantioselectivecatalyticaza‐Michaelreaction
ispromotedtogiverisetoindolineβ‐aminoacids(Scheme1.36).
Scheme1.36RucomplexcatalyzedenantioselectiveaminationofacrylatesviaN–Hactivation.
Theauthorsproposedaplausiblemechanismwithdoublecontributionoftheligand(Scheme1.37).
It startswith the crucialmetal‐ligand cooperative activation of theN‐Hbondof the substrateby
39
complexv. Then, addition of the amido group to the olefin via transition statev‐2with a cyclic
arrangementincludinganintramolecularhydrogenbondthatactivatestheolefin,yieldsthecyclized
productandregeneratestheactivecatalystv.
Scheme1.37ProposedmechanismforRucomplexcatalyzedenantioselectiveaminationofacrylatesviaN‐
Hactivation.
40
1.3.4Metal‐LigandCooperationandCycloisomerizationofAlkynoicAcids:Contextof
MyPhDResearchProject
Thelastcatalytictransformationinvolvingmetal‐ligandcooperationthatwillbebrieflydiscussed
inthissectionhasbeendevelopedintheteamwheremyPh.Dhasbeenrealized.Itisattheoriginof
thisPh.Dproject.OurgroupdescribedoriginalindenediidePd(II)pincercomplexes,combiningan
electrophilic Pd center and an electron‐rich ligand backbone (indenediide).111 The non‐innocent
characteroftheindenediideligandwasfirstevidencedbystoichiometricreactionswithorganicand
metallic electrophiles,112,113 and then it was applied to the catalytic intramolecular addition of
carboxylicacidstoalkynes.Thereactionoccursintheabsenceofexternalbase,thankstothemetal‐
ligand cooperative mode of action.114 The lactones were obtained with good yields and high
selectivity.Thereactionisunprecedentedlybroadinscope,inparticularconcerning≥6membered
rings(Scheme1.38).Amoredetailedpresentationofthisreactionwillbeincludedinthefollowing
chapter.
Scheme1.38Catalyticcycloisomerizationofalkynoicacidsbyoriginallydevelopedindenediidecomplexes
ofourgroup.
Despite the good results obtained with this indenediide Pd complex, some limitations were
observedwhenworkingwithcertaininternalalkynesandwithprecursorsofseven‐memberedrings,
suggestingthatthereisroomforimprovement.Inaddition,wewereeagertoextendtheapplication
of this indenediide system to the transformation of more challenging substrates, and the
cycloisomerization of alkynyl amides leading to alkenylidene lactams was chosen as the target
transformation.
Inordertoincreasetheactivityoftheindenediidepincercomplexes,weplannedtotakeprofitof
thestructuralmodularityofthesystem,varyingtheligandstructureatthephosphorussubstituents
and/orthemetalcenter.Thesetwostructuralmodulationsareattheoriginofthetwofollowing
chaptersofthisthesis.
41
1.4Summary
Themetal‐ligandcooperationinvolvingthenon‐innocentligands,eitherredoxorcooperativeones,
hasbeenintensivelyinvestigated.Ithasdemonstratedinterestinalargerangeoftransformations.
Theselectedexamplesgiveageneralideaofthestrategiesfollowedthelastyearstorationallydesign
non‐innocentligands.Thecombinationofatransitionmetalwithanappropriatenon‐innocentligand
canleadtospeciesmoreactivethanthatofthoseinvolvedinclassicaltransitionmetalcatalysis,or
evenenablenewcatalytictransformations,asshownbytheimpressiveresultsofMilstein’sgroup.
Actually, the reactivity of most of these metal‐ligand cooperative complexes has proven
particularly attractive for hydrogenation or dehydrogenation‐related catalysis, involving the
cleavageofH2orasacrificialalcoholasacrucialstep.Moreover,somecomplexeshavebeenshown
to efficiently activate X‐H bonds or unsaturated bonds. From this non‐exhaustive travel around
metal‐ligandcooperativecatalysis,itisclearthatthedevelopmentofnewligandframeworksableto
displaynon‐innocentcharacterwillcontributetomoveforwardandextendtheapproach.
42
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(80) Ikariya, T.; Murata, K.; Noyori, R. Org Biomol Chem 2006, 4, 393. (81) Ito, M.; Ikariya, T. Chem Commun (Camb) 2007, 5134. (82) Ikariya, T.; Blacker, A. J. Acc Chem Res 2007, 40, 1300. (83) Ikariya, T.; Gridnev, I. D. Chem Rec 2009, 9, 106. (84) Wipf, P. Claisen Rearrangements, 1991. (85) Tsuji, J. Palladium Reagents and Catalysts: Innovations in Organic Synthesis, 1996. (86) Ohkuma, T.; Koizumi, M.; Doucet, H.; Pham, T.; Kozawa, M.; Murata, K.; Katayama, E.; Yokozawa, T.; Ikariya, T.; Noyori, R. J Am Chem Soc 1998, 120, 13529. (87) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R. J Am Chem Soc 1995, 117, 7562. (88) Zhang, J.; Balaraman, E.; Leitus, G.; Milstein, D. Organometallics 2011, 30, 5716. (89) Fujita, K.; Tanino, N.; Yamaguchi, R. Org Lett 2007, 9, 109. (90) Musa, S.; Shaposhnikov, I.; Cohen, S.; Gelman, D. Angew Chem Int Ed 2011, 50, 3533. (91) Fujita, K.; Yoshida, T.; Imori, Y.; Yamaguchi, R. Org Lett 2011, 13, 2278. (92) Kawahara, R.; Fujita, K.; Yamaguchi, R. J Am Chem Soc 2012, 134, 3643. (93) Maenaka, Y.; Suenobu, T.; Fukuzumi, S. J Am Chem Soc 2012, 134, 9417. (94) Blum, Y.; Shvo, Y. Isr J Chem. 1984, 24, 144. (95) Karvembu, R.; Prabhakaran, R.; Natarajan, K. Coord Chem Rev 2005, 249, 911. (96) Casey, C. P.; Singer, S. W.; Powell, D. R.; Hayashi, R. K.; Kavana, M. J Am Chem Soc 2001, 123, 1090. (97) Casey, C. P.; Johnson, J. B. Can J Chem 2005, 83, 1339. (98) Johnson, J. B.; Backvall, J. E. J Org Chem 2003, 68, 7681. (99) Srimani, D.; Balaraman, E.; Gnanaprakasam, B.; Ben‐David, Y.; Milstein, D. Adv Synth Catal 2012, 354, 2403. (100) Pattabiraman, V. R.; Bode, J. W. Nature 2011, 480, 471. (101) Gunanathan, C.; Ben‐David, Y.; Milstein, D. Science 2007, 317, 790. (102) Gnanaprakasam, B.; Milstein, D. J Am Chem Soc 2011, 133, 1682. (103) Toutov, A. A.; Liu, W. B.; Betz, K. N.; Stoltz, B. M.; Grubbs, R. H. Nat Protoc 2015, 10, 1897. (104) Klare, H. F.; Oestreich, M.; Ito, J.; Nishiyama, H.; Ohki, Y.; Tatsumi, K. J Am Chem Soc 2011, 133, 3312. (105) Stahl, T.; Klare, H. F.; Oestreich, M. J Am Chem Soc 2013, 135, 1248. (106) Grützmacher, A. T. H. Catalytic Heterofunctionalization; Wiley‐VCH Verlag GmbH, 2001. (107) Muller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem Rev 2008, 108, 3795. (108) Huang, L.; Arndt, M.; Goossen, K.; Heydt, H.; Goossen, L. J. Chem Rev 2015, 115, 2596. (109) Kashiwame, Y.; Kuwata, S.; Ikariya, T. Organometallics 2012, 31, 8444. (110) Muniz, K.; Lishchynskyi, A.; Streuff, J.; Nieger, M.; Escudero‐Adan, E. C.; Belmonte, M. M. Chem Commun (Camb) 2011, 47, 4911. (111) Oulie, P.; Nebra, N.; Saffon, N.; Maron, L.; Martin‐Vaca, B.; Bourissou, D. J Am Chem Soc 2009, 131, 3493. (112) Nebra, N.; Saffon, N.; Maron, L.; Vaca, B. M.; Bourissou, D. Inorg Chem 2011, 50, 6378. (113) Oulié, P.; Nebra, N.; Ladeira, S.; Martin‐Vaca, B.; Bourissou, D. Organometallics 2011, 30, 6416. (114) Nebra, N.; Monot, J.; Shaw, R.; Martin‐Vaca, B.; Bourissou, D. Acs Catal 2013, 3, 2930.
45
Chapter2CycloisomerizationviaPalladiumPincerComplexesThischapterdescribesthenewly‐modulatedPalladiumindenediidepincercomplexes,andtheir
applications upon the challenging cycloamidation reactions of alkynylamides. The catalytic
performance of different Pd complexes will be investigated, as well as the substrate scope. The
mechanism of the reaction processes will also be discussed. But before discussing the obtained
results,asummaryofthepreviousworkofthegroupinthissubjectispresentedhereafter.
2.1Introduction
Cyclopentadienylrings(Cp)andtherelatedindenyl(Ind)andfluorenyl(Flu)systemsareamong
themostcommonlyusedligands,withexamplesoftheircomplexesacrosstheperiodictable.They
coordinatetothemetalmostoftenaccordingtoaη5coordinationmode,butexamplesofη3andη1
coordinationmodesarealsoknown.Inparticular,cyclopentadienyl(Cp)‐typeringshavereceived
considerableinterests,inpartduetotheirabilitytoadopttheseunusualcoordinationmodes.1,2In
contrast, very rare examples of cyclopentadienylidene or indenylidene coordinationmodes have
beenreporteduptonow.Althoughthefirstexampleofcyclopropenylidenecomplexwasreported
nearly 50 years ago,3 it is not until 1997 that the related and to date unique Tantalum
cyclopentadienylidene complex A was structurally authenticated.4 Later on, some other 1‐
indenylideneRutheniumcomplexesoftypeBhavebeenpreparedfromallenylideneprecursorsvia
intramolecular cyclization (Figure 2.1).5,6 These indenylidene complexes are capable to catalyze
olefinmetathesisefficiently,andtopromotetheatom‐transferradicalpolymerization.
Figure2.1Earlyrepresentativeexamplesofcyclopentadienylbasedcomplexes
Earlyinvestigationsinourgroupconcerningzirconiumindenylphosphazenecomplexes,7,8aswell
asthespectacularachievementsofpincercomplexesoverthepastdecades,9‐11promptedustodesign
complexesoftypeC(Figure2.2left),inwhichtwodonorbuttressescansupporttheunprecedented
2‐indenediide coordinationmode to themetal center. In regard to the reports for complexesD
(Figure2.2right)fromCavell,LeFloch...,itiswidelyacceptedthatphosphazeneandthiophosphinoyl
moietiescanactasstronglydonatinggroupsandareeasilyintroduciblesidearms.12‐14
46
Figure2.2Envisaged2‐indenediidecomplexbyourgroupandrelatedcomplexesbyothers
Inlightofallthesepreviousworks,ourgroupfirstreportedtheoriginal2‐indenediidecomplexes
with Zr andPd (Figure 2.3).15 Full characterizationbyNMR andX‐Raydiffraction confirmed the
highlysymmetricstructureofthesecomplexes.
Closely,fromtheproligand1‐H,the1,3‐bis(thiophosphinoyl)indene,afamilyof2‐indenediidePd
pincer complexes bearing different co‐ligands (Cl, PPh3 …) was readily prepared and fully
characterizedbyNMR,X‐rayanalysis,aswellastheoreticalmethods.Noteworthily,resultsindicated
symmetrical structures of all these complexes, with singlet signal observed in 31P NMR, and Cq
multipletsignalofC2in13CNMR,andthedisappearanceofthesignalofH1.Moreover,X‐rayanalysis
disclosedtheplanarenvironmentsaroundthecarbonatomsC1,C2andC3,andalsoadelocalization
oftheπsystemformedaroundcarbonatomsC1,C2,C3,withtheshortandalmostequalC1C2/C2C3
bondlengths(forcomplexH,1.410(9)and1.435(8)Å).Inaddition,thedifferentcoligandinthetrans
positiontoC2(NHCy2,Cl,orPPh3)barelyhasinfluenceonthegeometricandelectronicpropertiesof
thecomplexes,thatarepredominantlygovernedbytheconjugatedandrigidnatureofthepincer
ligand.
47
Figure2.3Originallydeveloped2‐indenediidecomplexeswithZrandPd
DFT studies, includingNBOandAIManalysis, revealed a similar bonding situation in all these
complexes,withstrongσbondingbutweak(ifany)πinteractionsbetweenC2andM.Thisbonding
situation was further confirmed by computing Wiberg indices, which were consistent with
essentiallysingleC2‐Mbonds.Inaddition,bondordersof1.34‐1.35werefoundbetweenC2C1and
C2C3,indicatingsomemultiplebondcharacter.Theatomicchargesderivedfromnaturalbonding
analyses(NBO) predictednegativeatomicchargesatC1/C3(~–0.60).Allthesedataareconsistent
withasituationinwhichthesecondnegativechargecreatedattheindenefragmentbyabstraction
ofH2isdelocalizedontheligandbackbone,betweenC1‐C3.Thecoordinationmodecanthereforebe
describedasindenediideratherthanindenylidene.
Themolecularorbitalsof thezirconiumandpalladium indenediidecomplexesconfirmed theπ
interactionofC2withC1andC3,andtheabsenceofπinteractionbetweenC2andthemetal.Asan
example,forthepalladiumcomplexG(Figure2.4a),theHOMO‐19andHOMO‐1orbitalsbothdisplay
π interaction between C2 and C1/C3, but they differ in the bonding vs anti‐bonding π overlap
betweenC2andPd(Figure2.4).ThisisconsistentwithessentiallysinglebondcharacteroftheC2Pd
bond.Inaddition,theHOMOiscenteredontheindenediidefragmentanddisplaysstrongcoefficients
onC1andC3,inlinewiththepredictednegativecharges.
48
(HOMO–19)
(HOMO–1)
(HOMO)
a b c
Figure2.4Kohn‐ShamrepresentationsofselectedmolecularorbitalsforcomplexesG.
Thankstothispeculiarelectronicsituation,thesecomplexeswereanticipatedtoexhibitoriginal
behaviorandthegroupstartedtoexploretheirreactivity.Notably,thesecomplexesdemonstrateda
non‐innocentbehavior,duetothenucleophiliccharacterofC1/C3.ThechloropalladatecomplexH
notonlyreactswithelectrophilicmetalprecursorstoformbimetalliccomplexesviametalationof
C1,16,17butalsoundergoeselectrophilicalkylationfromalkylhalides, i.e. iodomethaneandbenzyl
chlorides,tofurnishthe2‐indenylpincercomplexes(Scheme2.1).18
R-X MClLn MLnS
Ph2P Pd
Ph2P
S
Cl
Ph2P S
Ph2P S
Pd
R
X
Ph2P S
Ph2PS
Pd Cl
MLn = Rh(COD), PdCl(PPh3), Ir(COE)2R = Me, Bn
R4N
Scheme2.1Reactivityofchloropalladatebasedonnon‐innocentbehavior
Therefore,theabovestoichiometricreactions,aswellastheanalyticaldataandDFTcalculations
indicated that this kind of complexes is best delineated as indenediide Pd(II) pincer complexes,
consistingofanelectrophilicPdcenterandanelectron‐richligandbackbone(Figure2.5).Withthis
results in hand, our group decided to investigate the catalytic applications of indenediide Pd(II)
pincercomplexesinvolvingmetal‐ligandcooperation.
Pd
S
S
P
P C2
N Pd Pd
S
S P
C2 N
P
49
Figure2.5Bestdescribedformulaasindenediidecomplexes
Thecatalyticadditionofcarboxylicacidstoalkynesattractedourattention,andmorespecifically,
intramolecularadditionofcarboxylicacidstoalkynes,alsoknownascycloisomerizationofalkynoic
acids. This is a particularly interesting process, and recognized as a versatile tool for the direct
preparationoflactoneringsofmanifoldsizeandsubstitution.Thepioneeringworkwasreportedby
Utimotoetal,byusingpalladium(II)inthepresenceoftriethylaminetoafford3‐alken‐4‐olidesin
moderatetoexcellentyields,througharegioselective5‐endo‐digcyclizationfromthecorresponding
3‐alkynoicacids(Scheme2.2).19
Scheme2.2Palladium(II)catalyzedcycloisomerizationofalkynoicacidsbyUtimoto
Lateron,amoreeffectivecatalyticsystemwasintroducedbyHidaietal,byusingofmixed‐metal
sulfideclusterwithacuboidalcore[PdMo3S4(tacn)3Cl](PF6)3(tacn=1,4,7‐triazacyclononane)inthe
presenceoftriethylamine(Scheme2.3).20Notethatsuchsystemperformsthecycloisomerizations
viaexo‐digcyclization, from3‐,4‐,and5‐alkynoicacidstothecorrespondingalkylidene lactones,
underrelativelymildreactioncondition.Theformationof7‐memberedε‐lactonefrom6‐heptynoic
acidappearedasalimitationsinceitwassluggishwithlowyieldobtained.
Scheme2.3Palladium(II)catalyzedcycloisomerizationofalkynoicacidsbyHidai.
50
Anumberof catalytic systems capableof catalyzing such related cycloisomerizationhavebeen
reported.However,mostofthemneedtoproceedinthepresenceofanexternalbase,whichscarcely
restricttheirapplicationsespeciallyonsubstratesbearingbasic‐sensitivefunctionalgroups.Thus,a
systemthatcanproceedinneutralconditionstoefficientlycatalyzesuchtransformationsishighly
desirable.
In this context, the indenediide Pd pincer complexes originally developed by our group were
investigatedforthistransformation.Gratifyingly,thepreliminaryresultsshowedthatsuchkindof
complexescanefficientlypromotethecycloisomerizationofalkynoicacidsintheabsenceofanybase
(Table2.1).21Thetransformationof4‐pentynoicacidcatalyzedby indenediidePdcomplexeswas
firstevaluatedasthemodelreaction.Threecomplexes,namely,chloropalladate1a,iodopalladate1b,
neutraltrimericcomplex1cwereinvestigated.Allthecomplexesaffordedcompleteconversionin1
hourwithonly5mol%ofcatalystloadingatroomtemperatureinCDCl3,devoidofanyexternalbase.
Inaddition,recyclingtestsforuptoat least10timesdemonstratedtherobustnessofthesystem,
withnosighofcatalystdeactivationobserved.
Table2.1EvaluationofthecatalyticpropertiesoftheindenediidePdcomplexes1a‐cinthecyclizationof
4‐pentynoicacid4a.
Entrya Cat. Pdmol% T(°C) Time(h) Conv.(%)b
1 1a 5 25 1 99
2 1b 5 25 1 99
3 1c 5 25 1 99
4 1b 1 25 24 99
5c 1b 0.05 90 6 99
(a)Allcatalytictestswereperformedunderargonatmospherestartingfrom0.2mmolof4‐pentynoicacid(0.1MinCDCl3).(b)Conversionsweredeterminedby1H‐NMRandGC‐MSanalyses.(c)Reactioncarriedoutona2Msolutionof4‐pentynoicacidinCDCl3.
51
Subsequently,thesubstratescopewasextensivelyexamined.Severalanalogouscarboxylicacids
bearingdifferentsubstituentsintheαpositionwereinitiallyassessed(Table2.2).Notably,withn‐
HexandCO2Etgroups,thecyclizationscanproceedreadilyandfasterthanwiththemodelsubstrate
4a.ThisislikelyduetotheThorpe‐Ingoldeffect.TherelatedN‐protectedaminoacid4drequiresto
becatalyzedinaharshercondition(90°C,over12h),becauseofitspoorsolubilityinthereaction
solvent,butstillaffordedquantitativelythecorrespondingγ‐alkylidenelactone5d.Thecyclization
ofpropargyl‐allylsubstrate4eillustratesthecompleteselectivityofthereactioninfavorofalkyne
overalkene,andgivesexclusiveformationof5e.Thenarigidifiedsubstrate4f,containingaPhlinker
between the two reactive moieties, can proceed the cyclization to form the 3‐methylene‐3H‐
isobenzofuran‐1‐one 5f in only 5 min at room temperature. Later, the length of the linker was
enlarged,aimingtoform6‐memberedlactones,whichissignificantlymoredifficulttoachievethan
thatof5‐membered lactones.Thecyclizationof5‐hexynoicacid4gcanbecompletedat90°C, to
affordthecorresponding6‐memberedlactone5ginquantitativeyieldwithin12h.Thisisamongthe
bestresultsobtainedsofarforthistransformation.
Inaddition,theinternalalkynoicacids,whicharemuchmorechallengingthantheterminalones,
areunderinvestigation.3‐pentynoicacid4hreadilyundergoes5‐endo‐digcyclization,tofurnishthe
lactone5hquantitativelywithin3h.Withanotherhomologoussubstrate4i,anelevatedtemperature
at90°Cwasrequiredtoaffordcompleteconversion,while5‐exoand6‐endocyclizationstookplace
competitively,leadingtoa3:1mixtureof5‐and6‐memberedlactones5iexoand5iendo,respectively.
Anothertworigidinternalalkynoicacids4jand4kcanalsobefacilelycyclizedinonly15‐20minat
roomtemperature,toaffordauniquebenzannelatedlactonecompletelyandselectively.Butdueto
thestronginfluenceofthealkynesubstituent,only5‐exocyclizationwithPhand6‐endocyclization
withCywererespectivelyobtained.Last,theformationof7‐memberedlactoneswastargeted.And
gratifyingly,thetwoδ‐alkynoicbenzoicacids4land4mwereconvenientlycyclizedwithin7‐36hat
90°C.
52
Table2.2ScopeofthePd‐catalyzedcyclizationofalkynoicacids(4a‐m).
Control experiments also demonstrated the role of the indenediide Pd complexes (Table 2.3).
Several related2‐indenyl complexes2a and3a,b, inwhich the ligandbackbone isprotonatedor
methylatedatC1,wereemployedforthecyclizationinmodelreactionfrom4a.Thesubstrate4a
remainedintactinthepresenceof2aor3a,whileonly15%conversionafter24hwasobservedwith
3batroomtemperature.Moreover,thecombinedsystemofprecatalyst2‐indenylcomplex3bwith
Et3Nasanexternalbase,wascomparedto1b forthiscyclization.Suchbi‐componentsystemwas
capabletocatalyzethereaction,butproceedednoticeablyslowerthanwith1balone,toafford51%
conversionafter2h.AlltheseresultsstronglysupportthecrucialroleofsuchindenediidePdpincer
complexesinthecycloisomerizationofthealkynoicacids.
53
Table2.3IndenylPdcomplexes2aand3a,bevaluatedinthecyclizationof4‐pentynoicacid4a.
Entrya Cat. Pdmol% T(°C) Time(h) Conv.(%)b
1 2a 5 25 36 0
2 3a 5 25 24 0c
3 3b 5 25 24 15
4 3b+Et3N 5c 25 2 51
(a)Catalytictestswereperformedunderargonatmospherestartingfrom0.2mmolof4‐pentynoicacid(0.1MinCDCl3).(b)Conversionsweredeterminedby1H‐NMRanalyses.(c)Reactioncarriedoutwith5mol%Pdand5mol%Et3N.
A combined theoretical and experimental work, carried out more recently by our group in
collaborationwiththegroupofProfL.Maron,allowedforthepropositionofadetailedmechanism
forthistransformation(Figure2.6).22Thestudydemonstratedthat,inadditiontothecontribution
ofthenon‐innocentligandtotheactivationofthecarboxylicacid,thisindenediidepincercatalyzed
reaction involves theparticipationof twomoleculesof substrate,oneof themactingasaproton
shuttleinthethreedifferentsteps:(i)activationoftheacidpro‐nucleophileviaprotonationbythe
ligandbackboneandactivationoftheCCtriplebondbyside‐onecoordinationtoPd,(ii)nucleophilic
attacktotheactivatedalkyne,and(iii)eliminationofthefinalproduct.
54
Figure2.6ReactionmechanismofthePdindenediidecomplexcatalyzedcycloisomerizationofalkynoicacid:protonshuttlingbythesecondmoleculeofpentynoicacidsubstrate.
In summary, such indenediide Pd pincer complexes 1a‐c were shown to be very efficient
cooperativeall‐in‐onecatalystsforthecycloisomerizationofabroadspectrumofalkynoicacids.As
anextensionofthiswork,wewereeagertoemploysuchcatalyticsystemofindenediidecomplexes
formorevaluable/challengingcatalytictransformations,andthatwastheobjectiveofmyPhD.
55
2.2ResultsDiscussion
Given the success of the previous work21 in our lab with Palladium pincer complex on
cycloisomerizationofalkynoicacids,wemovedonefurtherstepapplyingthiscatalyticsystemon
more challenging reactions. The research scope concerning the substrates was expanded to the
correspondingalkynylamidesforsynthesisoflactams.
LookingatthepKaoftheacids(~5)andthecorrespondingamides(~20)inDMSOsolution,23the
activationoftheN‐Hbondshouldbemoredifficultcomparedtothatofthecarboxylicacid.Canthe
similar reactions for cycloisomerizationhappenwith amides via our current palladium systems?
Besides,wemustkeepinmindthatinadditiontolactamsresultingfromN‐attack,anO‐attackedkind
of isomerproductscanbe formed(Scheme2.4).24Theseare thequestions Iwould like to initially
disclosewithmyproject.
NO RR'
N‐attackedLactamsR
O
N
PPh2Ph2P
S SPd
Cl
NBu4
R O
O
R N
O
HH
R'
pKa: ~ 5 ~ 20
H
?or
ONN
R'
O
R
O‐attackedLactones
R'
RO
N
R
R'
R'nnn n n
Scheme2.4ProposalforcycloisomerizationofalkynylamidesviaPdpincercomplexes.
56
2.2.1PreliminaryStudyandObservedLimitation
ThepreviouslydescribedpalladiumindenediidepincercomplexesIa‐cwerefirstlyemployedhere
as catalysts for cycloisomerization reactions. These complexes, namely monomeric complexes
{Bu4N}{PdCl[Ind(Ph2P=S)2]}(Ia)(δP=44.5ppm),{Bu4N}{PdI[Ind(Ph2P=S)2]}(Ib)(δP=51.3ppm),
and the trimeric complex {Pd[Ind(Ph2P=S)2]}3 (Ic) (δP = 42.7 ppm, s, broad) (Figure 2.7), were
prepared,followingtheformerly‐reportedprocedures,andweresubsequentlycharacterizedby31P,
1H,13CNMR.It’snoteworthythatIcshowsadynamicbehaviorandasinglebroad31PNMRsignalwas
observedinsolution,suggestingthattheSbridgedissociatesorreformsrapidlyontheNMRtime
scale.21
Figure2.7PreviouslydescribedPdindenediidepincercomplexes.
Then, the cycloisomerization of theN‐tosyl alkynylamide1a, was chosen as a model reaction
(Scheme2.5)becausefivememberedringlactamsareknowntobeeasiertoformcomparetolarger
cycles(morethan6carbons).Thefeasibilityofthisreactionwasinitiallyinvestigatedunderexactly
thesameconditionsasthatofacids,0.1molofsubstratedissolvedin0.7mLdeuteratedchloroform,
inpresenceof5mol%ofchloropalladateIb,withoutanyexternalbase,atroomtemperature.The
reactionprocesswasmonitoredby1HNMR,and31PNMR.Toourdelight, thecycloisomerization
reactiondidtakeplacebyourPdcomplexasexpected,butrequiredaratherlongertime(94%,27
h).Itsubstantiatesthatthetransformationofamideswasgoingtobemorechallenging,thanthatof
thecarboxylicacidcounterpartsasexpectedprovidingthepKaofamides,althoughthepKaofN‐tosyl
amidesareprobablylowerthanthetypicalamides.
Inthisregard,thereactionconditionswerefurtheroptimized,especiallythetemperature.Indeed,
increasingat60°Callowsthedecreasingofthealkynesignal(δ=1.9ppm),concomitantlywiththe
appearanceofanewsetoftwomultiplets(δ=4.5&5.4ppm).Thesenewsignalscouldbeattributed
toexocyclicolefinicHofthetargetedlactam2a,ortheisomericform2a’,bycomparisonwiththe
57
literature.21,25 1HNMR spectroscopywas conducted tomonitor the progress of the reaction, and
shownasfollow(Figure2.8):
Scheme2.5Initialinvestigationoncycloisomerizationof1aviaIa.
Figure2.81HNMRstacksdiagramofthereactionprocess.
Throughcolumnchromatography,thecompound2a(or2a’)wasisolatedasawhitesolid(98%
yield),andfullycharacterizedbyNMRandHRMS.Tounambiguouslyassessthestructure,crystals
weregrown(fromaEt2OsolutionwithdropsofDCM)andanX‐raydiffractionwasperformed(Figure
2.9). Thus, the transformation of amide1aproceeded selectively via 5‐exo‐dig cyclization onN‐
58
nucleophilic attack to afford 5‐alkylidene 2‐pyrrolidinone 2a in less than 1 hour, with a 99 %
conversion.
Figure2.9X‐raystructureofcompound2a.
Withapositiveanswertoourinitialexperiment,alltheIndenediidePalladiumpincercomplexes,
includingthemonomericchloropalladate(Ia),Iodopalladate(Ib),andneutraltrimericcomplex(Ic),
wereemployedtoevaluatetheircatalyticpropertiesuponcyclizationofN‐tosylAlkynylamides1a,
aswellas1b,whichisamorechallengingsubstrate(Table2.4).
59
Table2.4EvaluationofthecatalyticpropertiesoftheIndenediidePdcomplexesIa‐c
inthecyclizationofN‐TosylAlkynylamides1aand1b.
Aspreviouslydescribed,withchloropalladateIa,thereactionfrom1acouldgiveanearlycomplete
conversion for2a (Table 2.4, entry 1). Replacement of chloride at palladium (Ia) for iodide (Ib)
inducedaslightdecreaseinactivity(81%conversion,1h,entry2).Withtheneutraltrimericcomplex
Ic,acompleteconversionof1ato2awasachievedwithin50minunderthesameconditions(entry
3).ThesefirstresultsdemonstratedtheabilityofindenediidePdpincercomplexestocatalyzethe
cyclizationofalkynylamides.Amorechallengingsubstrate,namelyN‐tosylhex‐5‐ynamide1b,was
theninvestigated.Inthiscase,thereactiontemperaturehadtobeincreasedto90°Ctoachievethe
cycloisomerizationinareasonablereactiontime.6‐Exoalkylidenelactam2bwasobtainedin67%
conversion after 24 h using Ia as catalyst. After purification, the X‐ray analysis confirmed the
structure(Figure2.10).Increasingthesubstrateconcentration(from0.14to1.0M)allowedusto
increasetheconversionto82%(entry5),butthereactionfailedtoreachcompletionevenaftera
Entry Substrate Cat. T(°C) time(h) Conv(%)
1 1a Ia 60 1h >99
2 1a Ib 60 1h 81
3 1a Ic 60 50min >99
4 1b Ia 90 24h 67
5 1b Ia 90 24h 82c
6 1b Ib 90 24h 49
7 1b Ic 90 20h 92
aAllcatalytictestswereperformedunderanargonatmospherestartingfrom0.1mmolofalkynylamide(0.14MinCDCl3).bConversionsweredeterminedby1HNMR.cReactionconductedat1Malkynylamide.
60
prolongedreactiontime.ThesamebehaviorwasobservedwithiodopalladateIb(entry6),which
wasagain lessactive thanIa.Finally, theneutralcomplexIchereingaveabetter,yet incomplete
conversion(entry7).
Figure2.10X‐raystructureofcompound2b.
Thepreliminaryexperimentssuggestedthecapabilityofthiskindofpalladiumindenediidepincer
systemonsuchmorechallenging cycloisomerizationof amides for lactams,but at the same time
indicatedthatthesystemencounteredsomelimitationsforlargercycleformation.
2.2.2ProbeintotheLimitationofCurrentSystem
Forbetterunderstandingthereactionprocessandfurtherdisclosingtheunderlyingproblemsof
thecurrentcatalyticsystem,31PNMRstudiesweremeticulouslycarriedout.
Theproblematiccyclizationof1bcatalyzedbyIawasmonitoredby31PNMR(Figure2.11).The
reactionmixturewascheckedhourlyfromthebeginning.Thewholeprocessconcerning31Pisshown
below,onceallthereactantsweremingledintheNMRtube,thecomplexIareactedwithsubstrate
1bimmediatelytoformsomeintermediates.Twosetsofnew31Psignals(δ=54.6&51.4ppmandδ
=55.0&50.5ppm)appeareddownfield,comparedtothatofchloropalladateIa(δ=44.5ppm).These
newsetsofsignalswerelaterproventobetheactiveindenylspecies,andwouldbediscussedinthe
mechanism part. As the reactions proceeded, at around 4 hours, another set of doublet signals
appeared,indicatingtheformationofbis(thiophosphinoyl)indene,whichisthefreeligand(δ=45.6
&31.0ppm).Asthereactioncontinuedon,thesignalsoffreeligandcontinuouslyincreaseduntilthe
totalconsumptionof the indenyl intermediate, indicating thateither thecatalyst Iaoroneof the
61
intermediatesdecomposed.Therefore,acontrolexperimentregardingthethermalstabilityoftheIa
wasconductedbytreatmentofthecatalystinCDCl3withoutaddingthesubstrateheatingat90°Cfor
24h,andnodegradationoccurred.Alloftheserevealedaslowdegradationoftheactivecatalytic
speciesratherthanthecatalystitself,andexplainedtheerosionoftheactivityobservedovertimein
thecyclizationof1b.AlthoughabetterconversionwasachievedwithtrimericcomplexIc,again,the
freeligandwasdetectedafter3.5h,indicatingthestabilityissueaswell.
Figure2.1131PNMRstacksdiagramofthereactionprocess.
Thus,acompromiseshouldbereachedbetweenareasonablereactiontime,requiringanelevated
temperatureandastableperformanceofthecatalyticsystem.
62
2.3DesignforStructuralModulation
Facinguptothestabilityissueofthecurrentcatalyticsystem,structuralmodulationoftheligand
was thus designed, aiming to increase the catalyst robustness to overcome the problem. In this
respect,astraightforwardmodulationwasanticipatedtoincreasetheelectrondonatingcharacterof
thethiophosphinoylsidearmsbyvaryingtheRsubstituentsonthephosphorus.
In comparisonwith the phenyl group, the isopropyl group ismore electron‐donating, and the
replacementby this group is supposed to change the interactionbetweenmetal and ligand.Two
aspectsofchangesareexpectedtotakeplace:1)amoreelectron‐richbackbone,whichshouldbe
beneficial for the deprotonation of the N‐H bond of the amide; 2) a stronger metal‐ligand
coordination, whichwould contribute to the robustness of the complexes, and the intermediate
species.
Thetargetedligandwasreadilypreparedfollowingthesamesyntheticstrategy(Scheme2.6).15,26,27
Startingfromindeneskeleton,doublesequenceofdeprotonationwithnBuLifollowedbytheaddition
oftheelectrophileiPr2PClwasappliedforobtainingiPr‐substituenteddonatingarms.Afteroxidation
bysulfuranduponreactionwithPd(PhCN)2Cl2,anoveliPr‐substituented2‐indenylchloropalladium
(IV)complexwasreadilyprepared,in82%yield.ByreactionofIVwithabasemixtureofPS‐DIEA
and tBuOK, in presence of nBu4NCl, the monomeric chloropalladate indenediide complex IIwas
obtained, in 81 % yield. To our delight, another neutral dimeric species III was obtained with
treatmentofNaOAcinToluenewithoutthenBu4NClat90°C,in78%yield.
63
Scheme2.6SynthesisofnewpincercomplexeswithiPrgroups.
Allthesenewly‐developedindenediidepincercomplexeswerefullycharacterizedbyNMR,HRMS,
X‐raydiffraction,andillustratedasfollow(Figure2.12).Fromthe1HNMR,aHsignaloftheindenyl
IV isclearlyshowedat4.66ppm(dd,2JHP=24.0Hz,4JHH=3.0Hz),whereasitdiddisappearwith
complexesIIandIII.
Figure2.12NewlysynthesizedindenediidecomplexeswithiPrgroup.
With respect to the 31P NMR, complex II exhibits a singlet signal at 75.0 ppm, indicating the
symmetricalcoordination,whileIIIindicatedadissymmetricalskeletonwithtwosignals,foundat
78.2and71.2ppm.ItisworthnotingthatasadimericcomplexIIIshowsnodynamicbehaviorin
solution,whereastrimericIcdemonstratesadynamicbehaviorinsolution(s,broad,δP=42.7ppm).
This can be served as a proof that the newly‐modulated complexes have stronger metal‐ligand
64
interaction. To further assess and compare the electronic properties of the new system, the
correspondingcarbonylcomplexwaspreparedfromcomplexIIIasaprecursor.Infraredanalysisof
carbonylcomplexesiswidelyusedtoprobetheelectronicpropertiesof ligands,givinganoverall
estimateofσ–donationandπ‐back‐donation.28ThecomplexVwasquantitativelyformedunder5bar
ofCO(Scheme2.7).ItsFT‐IRspectrumwasrecordedunderaCOatmosphere,andthecharacteristic
νCObandofVwasfoundat2113cm‐1,vsabandat2121cm‐1forthecorrespondingcarbonylcomplex
derived from Ic.21The shift to a lower frequencyupon replacementof thePhwith iPr groupsat
phosphorusisconsistentwithamoreelectron‐donatingandstrongercoordinationoftheSCSpincer
ligandtoPd.
Scheme2.7SynthesisofPdcarbonylcomplexV.
Whether or not this kind of structural modulation can influence their catalytic performance,
cycloisomerizationofalkynylamideswasthusinvestigated.
65
2.4EvaluationoftheNewComplexesinCycloisomerizationofAlkynylamides
With these new complexes in hand, assessment of the impact of the structuralmodulation on
catalyticactivitywasundertaken.ThecyclizationofN‐tosylhex‐5‐yamide1bwasagainchosenasa
benchmarkreaction.UsingeitherIIorIII,the6‐exoalkylidenelactam2bwasobtainedincomplete
conversionwithinonlyonenightat90°C,indicatinganenhancedperformanceofbothmodulated
newcomplexes.
Monitoringofthecyclizationof1bwithIIIby31PNMRshowedquitedifferentobservationofthe
reactionprocesstothatpreviouslydiscussedwithIa(Figure2.13).Atthebeginning,justasbefore,
thesignalsofIIIdisappearedinstantaneously,withanewsetofdoubletsignals(δ=84.7&83.0ppm)
appearingdirectlyinthesameregionofindenylspecies.Itindicatedthequickinteractionbetween
IIIand1b,togenerateanindenylintermediate.Afteraround12hours,acompleteconversioncanbe
achievedwith III. In stark contrastwith the reactions catalyzed by Ia−c, no decompositionwas
observedwithIII,evenbeingcontinuedrunningforaprolongedtimeof1dayaswell.Itisworth
notingthatmostactivespeciesobservedduringtheprocessturnedbacktothecomplexIII,oncefull
conversionwasachieved.
Figure2.1331PNMRstacksdiagramofthereactionprocess.
66
Thus,itcanbeconcludedthat,asimplesubstituentexchangeatphosphorusallowsthesignificant
enhancementoftherobustnessandtherebyabettercatalyticperformanceofindenediidePdpincer
complexes.AssimilarcatalyticactivitieswereobservedbetweencomplexIIandIII,ourfollowing
study was continued by choosing the neutral III as the most potential candidate, devoid of the
presenceofdispensableammoniumsalt.
67
2.5InvestigationuponAmideScope
Avarietyofamideswerethusmeticulouslyenvisionedandpreparedforinvestigationofthenew
Pd system application scope, regarding the Thorpe‐Ingold effect, ring size issue, and impact of
terminal/internalalkyne.
ThecyclizationofN‐tosylpent‐4‐ynamide1a for5‐memberedringwasfirstlyinvestigated.The
reactionproceededreadilyat60°CandwassubstantiallyfasterwithIII thanthatwithIa−c.The
desired5‐exolactam2aisobtainedasuniqueproductinonly10min(table2.5,entry1,98%isolated
yield).ThehigheractivityofIIIpromptedustodecreasethecatalystloading(entry1).At0.2mol%,
alongerreactiontimeandahigherconcentrationwererequiredbutthecyclizationwascompleted
inlessthan7hat1.5M[correspondingtoaturnovernumber(TON)of500].
Table2.5ScopeofthecyclizationofN‐tosylalkynylamides(1a‐i)byindenediidePdcomplexIII.
Substituentshavebeenregularlyintroducedinthelinkingchainofthesubstrates,especiallyfor
the formationof 5‐membered rings.Thisphenomenonhas beenknownand studied fornearly a
century, andwas firstly postulated in 1915 by Thorpe and Ingold.29,30 The theory can be simply
describedbyreplacementofhydrogenatomswithtwomethylorothergroupsinanopencarbon
68
chain,whichwillleadtoanincreaseofangleβ,whileaconcomitantdecreaseofangleα,thusbringing
theterminalgroupsclosertogether(figure2.14).
Figure2.14IllustrativemodeofThorpe‐Ingoldeffect
ThisThorpe‐Ingoldeffectiswidelyusedinorganicsynthesis,especiallyforcyclizationreactions,
tosignificantlyenhancethereactionrate.Andoneofthefirstdemonstrationsofthistheorycanbe
exemplifiedinthecyclizationofchlorohydrinstoformepoxidesasfollow(Table2.6).29
Table2.6ExampleforThorpe‐Ingoldeffectuponthecyclizationofchlorohydrins.
Compound
RelativeRateR1 R2 R3 R4
H H H H 1
H H H CH3 6
CH3 H H H 21
CH3 CH3 H H 248
H H CH3 CH3 252
CH3 CH3 CH3 H 1360
H CH3 CH3 CH3 2040
CH3 CH3 CH3 CH3 11600
Herein,severalamideswithdifferentfunctionalgroupsintroducedattheαpositionoftheamide
functionwereinvestigated.Justastheoreticallypredicted,all thesereactionswereacceleratedby
Thorpe‐Ingoldeffectnotablybyperformingatroomtemperature(comparatively,60°Cfor1a).The
cyclizationofn‐Hexfeaturedamide1cunderwentrapidlyatroomtemperatureinonly30mins,via
5‐exo‐digcyclizationtogiveselectively2c (entry3,99%, isolatedyield).Sameenhancementwas
achievedwithother functionalizedamides, suchas theesters, and theprotectedaminesones, as
exemplifiedwithsubstrates1d(entry4,86%,isolatedyield)and1e(entry5,82%,isolatedyield).
69
Theubiquitousnessofmedium‐ringframeworksinbiologicallyactivenaturalproductsstimulated
fordevelopingmethodsfortheconstructionoflargerrings,like7‐memberedring.31‐33Nevertheless,
onlyahandfulofexamplesforfacilesynthesisof7‐memberedringlactamshavebeendocumented.
Lotsofthemencounteredproblemsmainlylikerequirementofharshconditions,lowconversion,etc.
Thestudyofrateconstantsagainstringsizeforthecyclizationofmalonatesrevealsthatthereactivity
ofmediumsize(7‐and8‐membered)ringsishighlystrainedinthetransitionstateandalsohavea
highentropyofactivation(Figure2.15).34Wearecuriousthatcouldthenewcatalyticsystemhandle
someformationformediumsizerings?
Br(CH2)n-1 CHCOOEt
COOEt
baseBr(CH2)n-1 C
COOEt
COOEtC
COOEt
COOEt
cyclization(CH2)n-1
Figure2.15Rateconstantsvs.ringsizeforthecyclizationofmalonates
Several representative amides for more challenging larger rings formation were prepared, to
furtherevaluate thenewcatalytic system.We firstlyassessedabenzo‐fusedamide, inwhich the
aliphatic linker between the N‐tosyl amide and alkyne moieties was then replaced by an
orthophenylenespacer.Cyclizationof1foccurredat120°Cwithendoinsteadofexoselectivelyto
givethesevenmemberedproduct2f(entry6,95%conversion,51%isolatedyield),comparedtothe
literature.35,36 This transformation opened access to 3‐benzazepin‐2‐ones, which are important
motifsfoundinvariousbiologicallyactivecompounds.37Asmentionedabove,duetotheiPrgroups
atphosphorus,thecatalystisthermallyrobust,whichallowsustotargetchallengingsubstratessuch
70
astheflexiblenonsubstitutedN‐tosylhept‐6‐ynamide1g.Toourdelight,cyclizationof1gcouldbe
achievedwithin6daysat90°Catthisstage,yieldingselectivelythecorrespondinglactam2g(entry
7,70%conv.,53% isolatedyield).And the7‐memberedring lactamwas fullycharacterizedand
furtherconfirmedbyX‐raydiffractionanalysis(Figure2.16).Tothebestofourknowledge,thisisthe
firsttimeamethyleneε‐caprolactamhasbeenpreparedbycycloisomerization.
Figure2.16X‐raystructureofcompound2g.
Then,nonterminalamidesattractedourattention,asitscyclizationisoccasionallyhamperedby
steric repulsion between the terminal substituent and a nucleophile. Thus, to further extend the
scopeof the reaction,wemoved to internalN‐tosyl alkynylamides,whichare substantiallymore
difficult tocyclizethanterminalsubstrates.Gratifyingly,cyclizationof1hwascompleted in24h,
uponheatingat90°C(insteadof60°Cforthecorrespondingterminalalkynylamide1a).Compared
tothatofcarboxylicacid,itunderwentviaa6‐Endocyclizationratherthanthe5‐exooneasbefore,
toaffordtheunsaturated2‐piperidone2h(entry8,83%isolatedyield).Itwasfullycharacterizedby
NMRanalysis.Accordingto the1H,a tripletofdoublets(td)signalappearedat5.5ppm,which is
attributed to newly formed vinyl proton (Figure 2.17). And the X‐ray diffraction analysis
unambiguouslyconfirmedtheendostructure(Figure2.18).
71
Figure2.171HNMRofcompound2h.
Figure2.18X‐raystructureofcompound2h.
Anotherlongerlinearinternalamide1s,inattemptingtoformthelargerC7endolactam,wasalso
investigated.However,thesubstrateremainedintactafter24handevenlongertime,indicatingthat
therearestillsomelimitationsofthenewcomplexsystem.
Rigid internalsubstratessuchas1iand1jwerethen investigated(Table2.7).ComplexIIIwas
foundtoefficientlypromotethecycloisomerizationof1iat50°C.Theconversioniscompletewithin
5handoccursexclusivelyvia6‐endocyclization,toaffordamixtureof2compounds.Onthecontrary
72
towhatwasobservedforthepreviousalkynylamides,bothO‐andN‐cyclizationoccurs.Thesimilar
O‐cyclizationfashionwasreportedbyToste’sandMa’sgroups,24,38fortheirattemptstosynthesize
thecycliccarbamimidates.For1iand1j, theproductderiving fromO‐cyclization ismajor (O‐/N‐
cyclizationratio:84/16for1iand92/8for1j,92%overallyield).
Table2.7InvestigationoncyclizationofN‐tosylalkynylamides1iand1j.
Entrya Sub. Cat. T(°C) Time(h) Conv(%)b O‐/N‐attack
1 1i Ia 50 5 53 92/8
2 1i Ic 50 5 51 93/7
3 1i III 50 5 87 84/16
4 1i III 35 20 >99(89) 86/14
5 1j Ia 50 4d 51 92/8
6 1j III 50 3.5d >99(92) 92/8
(a)Catalyticreactionsperformedunderargonatmosphereusing0.1mmolofthecorrespondingalkynylamide1jor1k(0.2MinCDCl3)and5mol%ofcatalyst.(b)Conversionsweredeterminedby1HNMRanalysis.Isolatedyieldsaregiveninbrackets.
Todiscardapotentialcatalysteffect,thecyclizationof1iand1jwithcomplexesIa,cwascarried
out.Lowerconversionswereobserved(∼50%,entries1,2,and5),anddecompositionofIa,cinto
freeligandwasdetectedby31PNMR.However,thereactionproceedsagainexclusivelyvia6‐endo
cyclizationwithcomparableO‐/N‐cyclizationratiotothoseobtainedwithIII,indicatingonlyminimal
influenceofthecatalyststructureonselectivity.Eventually,thestructuresoftheseproductswere
determinedbyX‐raydiffractionanalysis(Figure2.19).
73
O
NS
O
ON
O
SO
O
O
NS
O
O
O
S
N
Figure2.19X‐raystructureofcompounds2i‐N/Oand2j‐O.
74
2.6MechanisticStudy
Chemistsarealwayspassionatetounderstandwhyandhowreactionshappen,inordertobeable
topredictwhatreactionswillhappenwhen facedwithnewcompounds.Variousmechanisms for
reactionswerecontinuouslyproposedeitherbyexperimentsorbytheorystudy.Andthecooperation
betweenexperimentandtheoryisbecomingmoreandmorepowerfulforthestudyofthemechanism
ofcatalytictransformations,tounderstandthefactorsinfluencingtheirefficiencyandselectivity,and
finallytooptimizetheirperformance.
Lately,themechanismofalkynoicacidcycloisomerizationbySCSindenediidePdpincercomplexes
hasbeeninvestigatedexperimentallyandcomputationallyinourlab.Thesestudiesconfirmedthe
cooperation between the Pd center and the backbone of the pincer ligand, and revealed the
involvementofasecondmoleculeofsubstrate.22Itactsasaprotonshuttleintheactivationofthe
acid,itdirectsthenucleophilicattackofthecarboxylicacidontheπ‐coordinatedalkyneanditrelays
theprotonolysisoftheresultingvinylPdspecies.
Apartfromtheobtainedresults,severalcomplementaryexperimentswerecarriedoutforhelping
usbetterunderstandthemechanismofcycloisomerizationofalkynylamideswithindenediidepincer
complexes.
Initially,twocontrolexperimentswerecarriedouttosubstantiatetheroleoftheindenediidePd
complexes(Scheme2.8).Wecheckedthatcyclizationdoesnotoccurspontaneouslyuponheating.In
theabsenceofindenediidePdcomplex,compound1aremainedintactafterheatingfor24hat90°C,
indicating the crucial role of complex III responsible for the cycloisomerization. Another control
experimentwasperformedwiththechloroindenylcomplexIV(theprotonatedformofII).After12
h,noreactionwasobserved,demonstratingthenecessityandactiveroleoftheindenediidemoiety
inthecatalyticcycle.
Scheme2.8ControlexperimentsuponheatingonlyandwithcomplexIV.
75
Manyreactionsproceedinastepwisefashion,andisolationofintermediatespeciesfromreaction
process can serve as a direct “testimony” to rationalize the reactions and disclose the reaction
mechanism.However,itisnotalwaysthateasyorluckytoisolateassomearequitereactiveorwith
trickyskills.Nevertheless,evidencefortheirexistencemaybeobtainedbyothermeans,including
spectroscopicobservation,etc.
Althoughseveraltrialsaimingatisolationofthereactionintermediatesweremindfullycarriedout,
unfortunately,noneofthemweresuccessful.Underthiscircumstance,thereactionprocessinview
of31PNMRwascarefullymonitoredtoprovidesomeinsightsofthemechanism.Incyclizationof1a
byIa,twosetsofnewsignals(δ=54.6&51.4ppmandδ=55.0&50.5ppm)weredetectedinthe
samerangeofindenylspecies(δ=55.9&52.2ppm)duringtheprocess.Itcouldbeproposedasthese
twointermediateAandB,whichwereprobablyformedaftertheactivationofN‐Hbond.Otherwise,
itcouldalsobethealkenylintermediateCaftertheintramolecularnucleophilicattack(Figure2.20).
Figure2.20PlausibleintermediatesinvolvingthePalladiumcatalyzedcycloisomerization.
Inaddition, 31PNMRmonitoringduringcatalysisprovidedsome insights into therestingstate.
Typically,uponcyclizationof1aor1b,thetwosignalsat78.2and71.2ppmassociatedwithcomplex
IIIimmediatelydisappearandanewpairofsignalsat84.4and82.8ppmintegratingina1/1ratiois
observed.Thisisconsistentwiththeformationofanindenylspecies(AorB)byprotonationofthe
indenediidebackbone.Oncethesubstrateisentirelyconsumed,thecharacteristicsignalsat78.2and
71.2ppmreappear,indicatingregenerationofthestartingcomplexIII.Thus,theacidicprotonofN‐
tosylalkynylamidesistemporarilyfixedontheindenediidebackboneandtransferredbacktothe
organicproductaftercyclization.
76
Isotopesarewidelyusedinmechanisticstudiesaslabelsforascertainingthelocationofagiven
atominareaction.Herein,deuteriumsubstituentedsubstrates1a‐D‐Nand1a‐D‐C,respectivelyat
theN‐positionandthealkynylposition,weremeticulouslyprepared.Thecyclizationof1a‐D‐NbyIII
wasfirstlycarriedoutinstandardprocedureasbefore(Scheme2.9).The1HNMRshowedexclusively
incorporationofdeuteriumintransposition(integrationoftheprotonincisposition~100%)with
noscramblingduringD/Hexchangebutalossof~20%ofthedeuteriumlabellingattheposition
transtotheN(Figure2.21).
Scheme2.9Cycloisomerizationofdeuterium‐labelled4‐pentynoicacid1a‐D‐N.
Figure2.21Cycloisomerizationreactionoftheisotopomer[1a‐D‐N].
77
Correspondingly, thecyclizationof1a‐D‐C (C≡CD,93%of isotopic labeling)wassubsequently
carriedout(Scheme2.10).Nodeuteriumscramblingwasdetected,andtheobtainedlactam2a‐D‐C
wasselectivelydeuteratedcistotheNTsgroup(Figure2.22),whichcanbeclearlydistinguishedto
thatof2a‐D‐N.
Scheme2.10Cycloisomerizationofdeuterium‐labelled4‐pentynoicacid1a‐D‐C.
Figure2.22Cycloisomerizationreactionoftheisotopomer[1a‐D‐C].
78
Thus,basedonalltheseexperimentalresultsandthepreviousresultsobtainedforcarboxylicacids,
a plausible simplifiedmechanism (not considering the secondmolecule)was proposed (Scheme
2.11).
Scheme2.11Asimplifiedmechanismproposed.
(i) First, the electron‐rich indenediide backbonewould deprotonate theN‐tosyl amide and the
alkynewouldbeactivatedbyπ‐coordinationtopalladium(intermediateA).
(ii)CyclizationbynucleophilicattackofthenitrogenatomontheC≡Cbondwouldthengivethe
alkenyl complex B. Trans‐addition is supported by the Z stereochemistry of the product2a‐D‐C
obtainedby5‐exocyclizationofthedeuteratedalkyne1a‐D‐C.
(iii)Finally,thealkylidenelactamwouldbereleasedandcomplexIIIwouldberegenerated.
79
2.7Summary
In conclusion, a simple structural modulation of previously described Pd pincer complex had
significantlyenhancedthethermalrobustnessandcatalyticperformanceinthecycloisomerization
reactions.Avarietyofalkynylamidesweremeticulouslypreparedfromthecorrespondingcarboxyl
acid.Withthenewcatalyticsystemapplied,theseamidescanbeactivatedforthecycloisomerization
inarelativelyharderreactionconditions,thanthatofcorrespondingacids.Theamidescopeisquite
broad and ranges from linearC5‐C7, the substituted, benzo‐fused, to internal ones.And finally a
majorityofexolactamproducts,togetherwithsurprisinginternalendolactamcanbepreparedin
excellent yields (most often90%). It is pretty inspiring to obtain the 7‐member ringmethylene
caprolactamforthefirsttime,preparedviaacycloisomerization.
Nevertheless,therearestillplentyofroomforimprovementofourcurrentcomplexsystem,asfull
conversionforC7lactamcannotbeaccomplishedevenafterheatingfordays,noreactionofinternal
C6amidehappenedatall.
Overall,theseresultsunderlinethegreatpotentialofindenediidepincercomplexesincatalysis.
Cooperation between the metal center and the electron‐rich indenediide backbone holds much
promise.Furtherstructuralmodulationofthepincercomplexeswillbepresentedinthefollowing
chapter.
80
2.8ExperimentPart
2.8.1GeneralConsiderations
Allreactionsandmanipulationswerecarriedoutunderanatmosphereofdryargonusingstandard
Schlenktechniques.Dry,oxygen–freesolventswereemployed.Allorganicreagentswereobtained
fromcommercial sourcesandusedas received. 31P, 1Hand 13C spectrawere recordedonBruker
Avance300.31P,1Hand13Cchemicalshiftsareexpressedwithapositivesign,inpartspermillion,
relativetoexternal85%H3PO4andMe4Si.Unlessotherwisestated,NMRspectrawererecordedat
293K.4‐heptynoicacid(5a),5‐hexynoicacid(6b)and6‐heptynoicacid(6f)werepurchasedfrom
Sigma‐Aldrich. 6‐heptynoic acid was dried with molecular sieves overnight and distilled with a
Kugelrohrdistillationapparatus.
2.8.2SynthesisofLigand
Synthesisoftheligand1,3‐(iPr2P=S)2(C9H6)(5):Ina250mLround‐bottomedSchlenkto
a solution of indene (2 mL, 0.017 mol) in diethyl ether (100 mL) at ‐78°C was added
n‐butyllithium(10.7mLofa1.6Mhexanessolutiondilutedwith10mLofdiethylether,
0.017mol)dropwiseovera1hrperiodandfurtheradditionofchlorodiisopropylphosphine
(2.7mLdilutedwith10mLofdiethylether,0.017mol)dropwiseoveraperiodof1hr.The
reactionmixturewaswarmed slowly to room temperature and stirring for 20 hrs. In a
second step, the reaction mixture was cooled down at ‐78°C and was again added n‐
butyllithium(10.7mLofa1.6Mhexanessolutiondilutedwith10mLofdiethylether,0.017
mol)dropwiseovera1hrperiodandfurtheradditionofchlorodiisopropylphosphine(2.7
mLdilutedwith10mLofdiethyl ether, 0.017mol)dropwiseover aperiodof1hr and
stirringatroomtemperaturefor20hrs.Thereactionmixturewasfiltratedandtransferred
viacannulatoanother250mLround‐bottomedSchlenkcontaininganexcessofelemental
sulphur(2.17g,0.068mol)undervigorousstirring,theresiduewasrinsedwith25mLof
diethyletherandagainfiltratedandtransferredviacannula.Theresultingsuspensionwas
81
stirredduring40hrsandevolvedtoaredsuspension.Thefinalproductisnotairsensitive,
afterevaporationofthesolventtheresiduewaspurifiedbysilicagelflashchromatography,
the residual elemental sulphur and the impurities were first eluted with a mixture
pentane/dichlorometane 1:1 and the desire product was eluted with dichloromethane
affordingareddishfraction.Thisfractionwascollected,evaporatedandprecipitatedwith
pentane affording a red powder (5.6 g, yield 79%).M.p. 121.0‐121.8 °C. 31P{1H}–NMR
(CDCl3):δppm71.5and61.9(d,4JPP=3.7).1H{31P}–NMR(CDCl3):δppm8.20(d,3JHH=6.0Hz,
1H,H5),7.79(d,3JHH=6.0Hz,1H,H8),7.54(d,3JHH=3.0Hz,1H,H2),7.38(td,3JHH=9.0,4JHH
=0.6Hz,1H,H6),7.29(td,3JHH=9.0,4JHH=0.6Hz,1H,H7),4.38(dd,3JHH=0.8Hz,4JHH=0.6
Hz,1H,H1),2.66(sep,3JHH=9.0Hz,1H,CH(CH3)2),2.50(sep,3JHH=9.0Hz,1H,CH(CH3)2),
2.32(sep,3JHH=9.0Hz,1H,CH(CH3)2),1.98(sep,3JHH=9.0Hz,1H,CH(CH3)2),1.32(d,3J=9.0
Hz,3H,CH(CH3)2),1.29(d,3J=9.0Hz,3H,CH(CH3)2),1.27(d,3J=9.0Hz,3H,CH(CH3)2),1.14
(d, 3J=9.0Hz,3H,CH(CH3)2),1.09 (d, 3J=9.0Hz,3H,CH(CH3)2),1.06 (d, 3J=9.0Hz,3H,
CH(CH3)2),0.98(d,3J=9.0Hz,3H,CH(CH3)2),0.95(d,3J=9.0Hz,3H,CH(CH3)2).1H–NMR
(CDCl3):δppm8.09(d,3JHH=6.0Hz,1H,H5),7.70(d,3JHH=9.0Hz,1H,H8),7.44(dt,3JHP=9.0
Hz,3JHH=3.0Hz,1H,H2),7.28(t,3JHH=9.0Hz,1H,H6),7.29(t,3JHH=9.0Hz,1H,H7),4.28
(dd,2JHP=24Hz,4JHP=3Hz,1H,H1),2.56(dddd,2JHP=21.0Hz,3JHH=6.0Hz,1H,CH(CH3)2),
2.40(dddd,2JHP=21.0Hz,3JHH=6.0Hz,1H,CH(CH3)2),2.21(dddd,2JHP=21.0Hz,3JHH=9.0
Hz,1H,CH(CH3)2),1.89(dddd,2JHP=21.0Hz,3JHH=9.0Hz,1H,CH(CH3)2),1.26to1.13(m,9H,
CH(CH3)2),1.05to0.83(m,9H,CH(CH3)2).13C{1H}–NMR(CDCl3):δppm147.4(dd,2JCP=9.1
Hz,2JCP=8.3Hz,C2),142.2(dd,2JCP=9.8Hz,3JCP=3.7Hz,C4),141.9(dd,2JCP=8.7Hz,3JCP=
3.0Hz,C9),137.0(dd,1JCP=65.3Hz,3JCP=6.8Hz,C3),127.8(s,C6),126.1(s,C7),126.0(s,
C5),122.6(s,C8),52.2(dd,1JCP=65.3Hz,3JCP=11.3Hz,C1),29.0(d,1JCP=47.5Hz,CH(CH3)2),
28.3(d,1JCP=47.5Hz,CH(CH3)2),28.2(d,1JCP=47.5Hz,CH(CH3)2),27.9(d,1JCP=47.5Hz,
CH(CH3)2), 17.5 (d, 2JCP = 3.0 Hz, CH(CH3)2), 17.3 (d, 2JCP = 3.0 Hz, CH(CH3)2), 17.1 (m,
CH(CH3)2),16.6(d,2JCP=2.3Hz,CH(CH3)2),16.6(d,2JCP=1.5Hz,CH(CH3)2),16.3(d,2JCP=1.5
Hz,CH(CH3)2).MS(EI,m/z(%))413.1(76)[M+H]+,265(100)[(M+H)(iPr2P=S)]+.Anal
CalcdforC21H34P2S2:C,61.13;H,8.31;S,15.54.Found:C,60.89;H,8.23;S,15.35.
82
2.8.3SynthesisofComplexes
Synthesis of {PdCl[(iPr2P=S)2(C9H5)]} (IV): A solution of 1,3‐(iPr2P=S)2(C9H6) (700 mg, 1.2
equiv.,1.7mmol)and[Pd(PhCN)2Cl2](542mg,1.0equiv.,1.4mmol)in20mLofTHFwasstirredat
roomtemperaturefor20h.Ayellowprecipitateappeared,theorangemother‐liquorwasdiscarded
andtheyellowprecipitatewaswashedwithdiethylether(2x20mL).Afterdryingundervacuum
thecomplexwasobtainedasayellowpowder(636mg,yield82%).M.p.203.8‐207.4°C.31P{1H}–
NMR(CDCl3):δppm85.1and83.7(s,slightlybroad).1H{31P}–NMR(CDCl3):δppm7.36(d,3JHH=6.0Hz,
1H,H5),7.26(t,3JHH=6.0Hz,1H,H6),7.18(d,3JHH=6.0Hz,1H,H8),7.11(t,3JHH=6.0,1H,H7),4.61
(s,1H,H1),2.85(sept,3JHH=6.0Hz,1H,CH(CH3)2),2.63(sep,3JHH=6.0Hz,1H,CH(CH3)2),2.58(sept,
3JHH=6.0Hz,1H,CH(CH3)2),1.98(sep,3JHH=6.0Hz,1H,CH(CH3)2),1.55(d,3JHH=6.0Hz,3H,CH(CH3)2),
1.41(d,3JHH=6.0Hz,3H,CH(CH3)2),1.29(d,3JHH=6.0Hz,3H,CH(CH3)2),1.26(d,3JHH=6.0Hz,3H,
CH(CH3)2),1.11(d,3JHH=6.0Hz,3H,CH(CH3)2),0.98(d,3JHH=6.0Hz,3H,CH(CH3)2),0.95(d,3JHH=6.0
Hz,3H,CH(CH3)2).1H–NMR(CDCl3):δppm7.42(d,3JHH=6.0Hz,1H,H5),7.32(t,3JHH=6.0Hz,1H,H6),
7.22(d,3JHH=6.0Hz,1H,H8),7.17(t,3JHH=6.0,1H,H7),4.66(dd,2JHP=24.0Hz,4JHH=3.0Hz,1H,H1),
2.92(m,1HCH(CH3)2),2.66(m,2HCH(CH3)2),2.04(m,1HCH(CH3)2),1.60(dd,3JHP=18.0Hz,3JHH=
9.0Hz,3H,CH(CH3)2),1.48(dd,3JHP=18.0Hz,3JHH=9.0Hz,6H,CH(CH3)2),1.32(m,6H,CH(CH3)2),
1.16(dd,3JHP=18.0Hz,3JHH=9.0Hz,3H,CH(CH3)2),1.02(m,3H,CH(CH3)2).13C{1H}–NMR(CDCl3):
δppm186.9(dd,2JCP=20.8Hz,2JCP=3.7Hz,C2),145.1(dd,2JCP=17.0Hz,3JCP=5.3Hz,C4),140.4(dd,
1JCP=90.6Hz,3JCP=8.3Hz,C3),140.9(d,slightlybroad,2JCP=8.3Hz,C9),128.6(s,C6),124.3(s,C7),
123.6(s,C5),119.05(s,C8),69.6(dd,1JCP=48.0Hz,3JCP=15.8Hz,C1),28.1(d,1JCP=40.8Hz,CH(CH3)2),
27.7(d,1JCP=40.8Hz,CH(CH3)2),25.8(d,1JCP=40.8Hz,CH(CH3)2),24.7(d,1JCP=40.8Hz,CH(CH3)2),
17.6(d,1JCP=2.3Hz,CH(CH3)2),17.5(d,1JCP=2.3Hz,CH(CH3)2),17.3(d,1JCP=2.3Hz,CH(CH3)2),17.2
(d,1JCP=2.3Hz,CH(CH3)2),17.1(d,1JCP=2.3Hz,CH(CH3)2),16.7(d,1JCP=2.3Hz,CH(CH3)2),15.8(d,
1JCP = 2.3 Hz, CH(CH3)2). MS (ESI): m/z [M‐Cl]+ Calcd: 517.1, Found: 517.1. Anal Calcd for
C21H33P2PdS2:C,45.57;H,6.01;S,11.59.Found:C,45.69;H,6.07;S,11.43.
83
Synthesisof[N(n‐Bu)4]{PdCl[(iPr2P=S)2(C9H4)]}(II):Asolutionof{PdCl(iPr2P=S)2(C9H5)}(400mg,
1.0equiv.,0.72mmol),potassiumtert‐butoxide(82mg,1equiv.,0.72mmol)and[N(n‐Bu)4]Cl(241
mg,1.2equiv.,0.86mmol)in20mLofCH2Cl2wasstirredatroomtemperaturefor20h.Theoriginal
yellow solution becomesbrown, the reactionmixturewas filtrated via cannula, and themother‐
liquorwasconcentratedatc.a.4mL.Undervigorousstirringwereadded60mLofdiethylether.A
yellowish‐brown precipitate appears. The mother‐liquor was discarded and the precipitate was
driedundervacuumyieldingayellowish‐brownpowder(460mg,yield81%).Theprecipitatewas
recrystallizedbyslowdiffusionofCH2Cl2/diethyletheraffordingyellowish‐browncrystalssuitable
forX‐raydiffractionanalysis.M.p.216.8‐218.8°C. 31P{1H}–NMR (CD2Cl2):δppm75.0(s).1H{31P}–
NMR(CD2Cl2):δppm7.12(m,broad,2H,H8andH5),6.58(m,broad,2H,H7andH6),3.24(m,8H,
(CH2)3CH3),2.49(sep,3JHH=9.0,4H,CH(CH3)2),1.60(m,8H,(CH2)3CH3),1.38(sex,3JHH=6.0Hz,8H,
(CH2)3CH3),1.17(d,3JHH=6.0Hz,12H,CH(CH3)2),1.10(d,3JHH=6.0Hz,12H,CH(CH3)2),0.91(t,3JHH=
6.0Hz,12H,(CH2)3CH3).1H–NMR(CD2Cl2):δppm7.24(m,2H,H8andH5),6.70(m,2H,H7andH6),
3.36(m,8H,(CH2)3CH3),2.61(dddd,2JHP=21.0,3JHH=9.0Hz,4H,CH(CH3)2),1.49(m,8H,(CH2)3CH3),
1.50(sex,3JHH=6.0Hz,8H,(CH2)3CH3),1.29(dd,3JHP=18.0Hz,3JHH=6.0Hz,12H,CH(CH3)2),1.22(dd,
3JHP=18.0Hz, 3JHH=6.0Hz,12H,CH(CH3)2),1.03 (t, 3JHH=6.0Hz,12H, (CH2)3CH3). 13C{1H}–NMR
(CD2Cl2):δppm168.5(t,2JCP=21.9,C2),145.1(m,C4andC9),116.0(s,C8andC5),115.8(s,C7andC6),
100.1 (dd, 1JCP= 114.0Hz, 3JCP= 15.8Hz, C3 and C1), 59.0 (s, (CH2)3CH3), 27.6 (d, 1JCP= 48.3Hz,
CH(CH3)2), 24.2 (s, (CH2)3CH3), 19.8 (s, (CH2)3CH3), 27.6 (d, 2JCP = 59.6 Hz, CH(CH3)2), 24.2 (s,
(CH2)3CH3).MS(ESI):m/z[M]+Calcd:793.3,Found:793.3,[M–Cl–N(n‐Bu)4]+Calcd:516.0,Found:
516.1.AnalCalcdforC37H68ClNP2PdS2:C,55.91;H,8.62;N,1.76;S,8.07.Found:C,55.20;H,8.42;N,
1.60;S,7.76.
84
Synthesis of the dimeric complex {Pd[(iPr2P=S)2(C9H4)]}2 (III): A solution of
{PdCl(iPr2P=S)2(C9H5)}(200mg,0.36mmol)andpotassiumtert‐butoxide(41mg,0.36mmol)in10
mLofCH2Cl2wasstirredatroomtemperaturefor20h.Theoriginalyellowsolutionbecomesorange;
thereactionmixturewaspouredoverachromatographiccolumnofalumina.Thedimericcomplex
wasfirstelutedwithCH2Cl2affordinganorangefraction.Thisfractionwascollectedandevaporated
untildryness.Theresiduewasprecipitatedwith20mLofdiethyletherrenderingthepuredimmer
likearedpowder(145mg,yield78%).CrystalssuitableforX‐raydiffractionanalysiswereobtained
byslowevaporationofasolutionofthecomplexinamixtureCH2Cl2/diethylether10/90affording
reddish‐orangecrystals.M.p.(decomposition)288°C.31P{1H}–NMR(CDCl3):δppm78.2and71.2(s,
broad).1H{31P}–NMR(CDCl3):δppm7.22(s,broad,2H,H8andH5),6.79and6.76(t,2H,H7andH6),
2.96(s,broad,2H,(CH2)3CH3),2.56(s,broad,2H,CH(CH3)2),1.46(s,broad,6H,CH(CH3)2),1.21(s,
broad,18H,CH(CH3)2).1H–NMR(CDCl3):δppm7.25(s,broad,2H,H8andH5),6.80(m,2H,H7and
H6), 2.97 (s, broad, 2H, CH(CH3)2), 2.58 (s, broad, 2H, CH(CH3)2), 1.46 to 1.20 (m, broad, 24H,
CH(CH3)2).13C{1H}–NMR(CD2Cl2):δppm168.0(t,2JCP=19.6,C2),139.6(m,broad,C4andC9),117.2
(s,broad,C8andC5),116.8and116.4(s,broad,C7andC6),100.5and94.7(dd,broad,1JCP=108.0
Hz,3JCP=16.6Hz,C3andC1),27.9,27.3,26.8,26.2(s,broad,CH(CH3)2),17.0and16.4(s,broad,
CH(CH3)2).MS(ESI):m/z[M2]+Calcd:1032.1,Found:1032.2,[M]+Calcd:516.0,Found:516.1.Anal
CalcdforC42H64P4Pd2S4:C,48.79;H,6.24;S,12.40.Found:C,48.25;H,6.36;S,11.12.
85
Synthesisof{Pd(CO)[(iPr2P=S)2(C9H4)]}(V):Asolutionof{PdCl[(iPr2P=S)2(C9H4)]}2(4)
(25mg,0.024mmol)in0.5mLofCDCl3withinanNMRpressuretubewaspressurizedat5
barofCO.Theredsolutionbecomesslightlylesscolored.Thefullconversionof4tothenew
complexoccursafter20min.IR(CDCl3):νCO=2114cm−1.31P{1H}–NMR(CDCl3):δppm79.7
(s).1H{31P}–NMR(CDCl3):δppm7.28(m,broad,2H,H8andH5),6.82(m,broad,2H,H7and
H6),2.61(sep,3JHH=9.0,4H,CH(CH3)2),1.20(d,3JHH=9.0Hz,12H,CH(CH3)2),1.17(d,3JHH=
9.0Hz,12H,CH(CH3)2).1H–NMR(CDCl3):δppm7.28(m,2H,H8andH5),6.82(m,2H,H7and
H6),2.64(dddd,2JHP=21.0,3JHH=9.0Hz,4H,CH(CH3)2),1.21(dd,3JHP=15.0Hz,3JHH=6.0Hz,
12H,CH(CH3)2),1.15(dd,3JHP=15.0Hz,3JHH=6.0Hz,12H,CH(CH3)2).13C{1H}–NMR(CDCl3):
δppm180.5(t,4JCP=15Hz,CO),176.5(t,2JCP=22Hz,C2),136.2(m,C4andC9),117.5(s,C8
andC5),117.4(s,C7andC6),100.4(dd,1JCP=112.0Hz,3JCP=16Hz,C3andC1),27.5(d,1JCP
=27.5Hz,CH(CH3)2),16.6(d,2JCP=52Hz,CH(CH3)2).
86
2.8.4SelectedCrystalData
Crystallographic data were collected at 193(2) K on Bruker‐AXS APEXII Quazar
diffractometer with Mo Kα radiation (λ = 0.71073 Å) using an oil–coated shock–cooled
crystal. Phi‐ and omega‐ scans were used. Semi‐empirical absorption corrections were
employed.Thestructurewassolvedbydirectmethods(SHELXS‐97),8andrefinedusingthe
least‐squaresmethodonF2.9
Crystallographicdata(excludingstructurefactors)havebeendepositedtotheCambridge
CrystallographicDataCentreassupplementarypublication,complexesII(CCDC1014581)
andIII(CCDC1014580).
Table S1. Crystal Data, Data Collection, and Structure Refinement for [N(n‐
Bu)4]{PdCl[(iPr2P=S)2(C9H4)]}.
Crystaldata
formula C74H68Cl2N2P4Pd2S4(CH2Cl2)
Mr 1674.63
crystalsystem triclinic
spacegroup P‐1
a(Å) 10.2156(3)
b(Å) 16.2747(5)
c(Å) 26.6821(8)
α(°) 91.6030(10)
β(°) 90.239(2)
γ(°) 103.7250(10)
V(Å3) 4307.4(2)
Z 2
ρcalc(gcm‐3) 1.291
(mm‐1) 0.752
F(000) 1772
87
crystalsize(mm3) 0.24x0.18x0.04
DatacollectionandRefinement
T/K 193(2)
measdreflns 85271
Uniquereflns(Rint) 15749(0.0312)
reflnsusedforrefinement 15749
refinedparameters 920
GOFonF2 1.061
R1a[I>2σ(I)] 0.0394
wR2balldata 0.0752
aR1=Σ||Fo|‐|Fc||/Σ|Fo|.bwR2=[Σ[w(Fo2‐Fc2)2]/Σ[w(Fo2)2]]1/2.
Table S2. Crystal Data, Data Collection, and Structure Refinement for
{Pd[(iPr2P=S)2(C9H4)]}2.
Crystaldata
formula C42H64P4Pd2S4(C4H10O)
Mr 1108.01
crystalsystem monoclinic
spacegroup P21/c
a(Å) 18.0562(8)
b(Å) 14.0451(7)
c(Å) 22.0832(9)
α(°) 90
β(°) 113.610(2)
γ(°) 90
V(Å3) 5131.5(4)
Z 4
ρcalc(gcm‐3) 1.434
88
(mm‐1) 1.021
F(000) 2296
crystalsize(mm3) 0.16x0.08x0.04
DatacollectionandRefinement
T/K 193(2)
measdreflns 77988
Uniquereflns(Rint) 9358(0.0421)
reflnsusedforrefinement 9358
refinedparameters 632
GOFonF2 1.102
R1a[I>2σ(I)] 0.0462
wR2balldata 0.1294
aR1=Σ||Fo|‐|Fc||/Σ|Fo|.bwR2=[Σ[w(Fo2‐Fc2)2]/Σ[w(Fo2)2]]1/2.
89
2.8.5SynthesisofN‐tosylAlkynylamidesSubstrates
Fordetails,pleasesee:BenL.Feringa.Org.Lett.,2003,5(3),pp259–261.
N‐tosylpent‐4‐ynamide(1a):Thisproductwaspreparedfollowingtheproceduredescribedinthe
literature.TheproductwascleanlyisolatedbyflashcolumnchromatographywithEthylacetateand
Pentane(v/v,1/2).Theamidewasisolatedasawhitesolidingoodyield(1.13g;85%).
1H–NMR(300.0MHz,CDCl3):δppm8.88(s,1H,NHTs),7.95(d,J=8.3Hz,2H,phenyl),7.34(m,2H,
phenyl),2.51‐2.44(m,7H,CH3(Ts)andCH2CH2),1.97(t,J=2.4Hz,1H,C≡CH).13C{1H}–NMR(75.5
MHz,CDCl3):δppm169.07(C=O),145.32,135.39,129.69,128.41,81.77(C≡CH),69.96(C≡CH),35.08
(CH2CH2C≡CH), 21.71 (CH3(Ts)), 13.67 (CH2CH2C≡CH).HRMS (CH4‐Ionization) calcd for [M+H]
(C12H14NO3S):252.0694;found:252.0687.
N‐tosylhex‐5‐ynamide(1b):Thisproductwaspreparedfollowingtheproceduredescribedinthe
literature.TheproductwascleanlyisolatedbyflashcolumnchromatographywithEthylacetateand
Pentane(v/v,1/2).Theamidewasisolatedasawhitesolidinexcellentyield(1.09g;90%).
1H–NMR(300.0MHz,CDCl3):δppm9.04(s,1H,NHTs),7.94(d,J=8.3Hz,2H,phenyl),7.34(d,J=8.2
Hz,2H,phenyl),2.44‐2.39(m,5H,CH3(Ts)andCH2CH2CO),2.15(td,2H,HC≡CCH2),1.90(t,1H,C≡CH),
1.76(m,2H,CH2CH2CO).13C{1H}–NMR(75.5MHz,CDCl3):δppm170.63(C=O),145.25,135.49,129.70,
128.35, 82.87 (C≡CH), 69.64 (C≡CH), 34.62 (CH2CH2CO), 22.74 (CH2CH2CO), 21.70 (CH3), 17.51
(HC≡CCH2).HRMS(CH4‐Ionization)calcdfor[M+H](C13H16NO3S):266.0851;found:266.0855.
90
2‐(prop‐2‐yn‐1‐yl)‐N‐tosyloctanamide(1c):Thisproductwaspreparedfollowingtheprocedure
describedintheliterature.Theproductwascleanlyisolatedbyflashcolumnchromatographywith
EthylacetateandPentane(v/v,1/3).Theamidewasisolatedasawhitesolidinexcellentyield(0.28
g;86%).
1H–NMR(300.0MHz,CDCl3):δppm8.94(s,1H,NHTs),7.95(d,J=8.3Hz,2H,phenyl),7.33(d,J=8.2
Hz,2H,phenyl),2.43(s,3H,CH3(Ts)),2.33(m,3H,CHCH2C≡CH),1.97(m,1H,C≡CH),1.55(m,2H,
CH2CHCH2C≡CH),1.19(m,8H,CH2CH2CH2CH2CH3),0.84(t,J=6.6Hz,3H,CH3CH2CH2).13C{1H}–NMR
(75.5MHz,CDCl3):δppm172.25(C=O),145.15,135.42,129.55,128.47,80.77(C≡CH),70.98(C≡CH),
46.27 (CHCH2C≡CH), 31.48, 31.40, 29.01, 26.57, 22.46(CH2C≡CH), 21.69 (CH3 (Ts)), 20.88, 14.02
(CH2CH3).HRMS(CH4‐Ionization)calcdfor[M+H](C18H26NO3S):336.1633;found:336.1634.
Ethyl2‐(tosylcarbamoyl)pent‐4‐ynoate(1d):Thisproductwaspreparedfollowingtheprocedure
describedintheliterature.TheproductwascleanlyisolatedbyprecipitationwithEthylacetateand
Pentane.Theamidewasisolatedasawhitesolidingoodyield(0.13g;40%).
1H–NMR(300.0MHz,CDCl3):δppm9.57(s,1H,NHTs),7.95(d,J=8.4Hz,2H,phenyl),7.32(d,J=8.3
Hz, 2H, phenyl), 4.22 (m, 2H, CH3CH2OOC), 3.43 (t, J= 6.6 Hz, 1H, CHCH2C≡CH), 2.74 (m, 2H,
CHCH2C≡CH),2.45(s,3H,CH3(Ts)),1.99(t,J=2.7Hz,1H,C≡CH),1.26(t,J=7.2Hz,3H,CH3CH2O).
13C{1H}–NMR(75.5MHz,CDCl3):δppm168.52(C=O),164.66(COOCH2CH3),145.31,135.21,129.56,
128.58, 78.93 (C≡CH), 71.53(C≡CH), 62.72 (COOCH2CH3), 51.34 (CHCH2C≡CH), 21.70 (CH3 (Ts)),
18.67(CHCH2C≡CH),13.92(COOCH2CH3).HRMS(CH4‐Ionization)calcdfor[M+H] (C15H18NO5S):
324.0906;found:324.0898.
91
2‐acetamido‐N‐tosylpent‐4‐ynamide (1e): This productwas prepared following the procedure
describedintheliterature.TheproductwascleanlyisolatedbyprecipitationwithEthylacetateand
Pentane.Theamidewasisolatedasawhitesolidinmoderateyield(0.06g;20%).
1H–NMR(300.0MHz,(CD3)2CO):δppm10.81(s,1H,NHTs),7.89(d,J=8.3Hz,2H),7.58(s,broad,1H),
7.41(d,J=8.2Hz,2H),4.56(m,1H),2.59(m,2H),2.43(s,3H),2.39(t,J=2.5Hz,1H),1.94(s,3H).
13C{1H}–NMR (75.5 MHz, (CD3)2CO): δppm 170.19 (C=O), 168.51, 144.65, 136.62, 129.34, 128.17,
78.83,71.70,52.36,21.69,20.61.HRMS(CH4‐Ionization)calcdfor[M+H](C14H17N2O4S):309.0909;
found:309.0905.
2‐(2‐ethynylphenyl)‐N‐tosylacetamide(1f):Thisproductwaspreparedfollowingtheprocedure
describedintheliterature.Theproductwascleanlyisolatedbyflashcolumnchromatographywith
EthylacetateandPentane(v/v,1/2).Theamidewasisolatedasawhitesolidingoodyield(0.35g;
55%).
1H–NMR(300.0MHz,CDCl3):δppm8.23(s,1H),7.88(m,2H),7.53(m,1H),7.36‐7.27(m,4H),7.22‐
7.19(m,1H),3.75(s,2H),3.21(s,1H),2.42(s,3H).13C{1H}–NMR (75.5MHz,CDCl3):δppm167.58
(C=O),145.08,135.26,134.91,133.28,130.20,129.79,129.47,128.54,128.14,122.07,82.96,81.36,
42.58,21.68.HRMS(CH4‐Ionization)calcdfor[M+H](C17H16NO3S):314.0851;found:314.0854.
92
N‐tosylhept‐6‐ynamide(1g):Thisproductwaspreparedfollowingtheproceduredescribedinthe
literature.TheproductwascleanlyisolatedbyflashcolumnchromatographywithEthylacetateand
Pentane(v/v,1/2).Theamidewasisolatedasawhitesolidinexcellentyield(1.06g;96%).
1H–NMR(300.0MHz,CDCl3):δppm8.97(s,1H),7.94(d,J=8.3Hz,2H),7.34(d,J=8.3Hz,2H),2.44(s,
3H),2.29(t,J=7.2Hz,2H),2.12(td,J=7.0HzandJ=2.6Hz,2H),1.91(m,1H),1.69(m,2H),1.45(m,
2H).13C{1H}–NMR(75.5MHz,CDCl3):δppm170.80(C=O),145.21,135.53,129.68,128.32,83.74,68.81,
35.58, 27.43, 23.27, 21.70, 18.04 (CH3).HRMS (CH4‐Ionization) calcd for [M+H] (C14H18NO3S):
280.1007;found:280.0996.
N‐tosylhex‐4‐ynamide(1h):Thisproductwaspreparedfollowingtheproceduredescribedinthe
literature.TheproductwascleanlyisolatedbyflashcolumnchromatographywithEthylacetateand
Pentane(v/v,1/2).Theamidewasisolatedasawhitesolidingoodyield(0.43g;81%).
1H–NMR(300.0MHz,CDCl3):δppm8.96(s,1H),7.95(d,J=8.4Hz,2H),7.34(m,2H),2.47‐2.36(m,
7H) , 1.73 (m, 3H). 13C{1H}–NMR (75.5MHz, CDCl3): δppm 169.56 (C=O), 145.17, 135.54, 129.62,
128.40, 77.82, 76.58, 35.72, 21.69, 14.12, 3.39. HRMS (CH4‐Ionization) calcd for [M+H]
(C13H16NO3S):266.0851;found:266.0859.
93
N‐tosylhept‐5‐ynamide(1r):Thisproductwaspreparedfollowingtheproceduredescribedinthe
literature.TheproductwascleanlyisolatedbyflashcolumnchromatographywithEthylacetateand
Pentane(v/v,1/3).Theamidewasisolatedasawhitesolidinexcellentyield(0.98g;89%).
1H–NMR(CDCl3):δppm9.10(s,broad,1H,NHTs),7.96(d,2H,Ph),7.35(d,2H,Ph),2.45(s,3H,PhCH3),
2.40 (t, 2H, CH2CO), 2.11 (m, 2H, CH2C≡C), 1.73 (m, 5H, CH2CH2CO and C≡CCH3). 13C{1H}–NMR
(CDCl3):δppm170.9(C1),145.2(C11),135.6(C8),129.7(C10,C10’),128.3(C9,C9’),77.6(C5),77.0
(C6), 34.9 (C2), 23.4 (C3), 21.7 (C12), 17.9 (C5), 3.4 (C7). HRMS (ESI): m/z calcd for [M+H]
(C16H20NO5S)Calcd:280.1007,Found:280.1009.
2‐(phenylethynyl)‐N‐tosylbenzamide (1i): Thisproductwasprepared following theprocedure
describedintheliterature.Theproductwascleanlyisolatedbyflashcolumnchromatographywith
EthylacetateandPentane(v/v,1/2).Theamidewasisolatedasawhitesolidingoodyield(2.00g;
90%).
1H–NMR(300.0MHz,CDCl3):δppm10.50(s,1H),8.08‐8.01(m,3H),7.75‐7.71(m,2H),7.63(m,1H),
7.61(m,1H),7.46‐7.38(m,4H),7.31(d,J=8.4Hz,2H),2.41(s,3H).13C{1H}–NMR(75.5MHz,CDCl3):
δppm162.92(C=O),145.11,135.66,133.98,132.58,131.85,131.44,130.93,139.82,129.56,129.11,
128.78, 128.74, 121.14, 120.37, 98.70, 86.69, 21.70. HRMS (CH4‐Ionization) calcd for [M+H]
(C22H18NO3S):376.1007;found:376.1016.
94
3‐cyclohexyl‐2‐tosylisoquinolin‐1(2H)‐one (1j): This product was prepared following the
procedure described in the literature. The product was cleanly isolated by flash column
chromatographywithEthylacetateandPentane(v/v,1/5).Theamidewasisolatedasawhitesolid
ingoodyield(1.08g;64%).
1H–NMR(300.0MHz,CDCl3):δppm10.79(s,1H),8.08‐8.02(m,3H),7.50‐7.42(m,2H),7.38‐7.33(m,
3H),2.77(m,1H),2.42(s,3H),2.03(m,2H),1.80(m,2H),1.67(m,3H),1.41(m,3H).13C{1H}–NMR
(75.5MHz,CDCl3):δppm162.84(C=O),144.97,135.88,134.19,132.50,130.93,130.89,129.52,128.70,
128.46, 125.44, 121.10, 105.13,78.96,32.12, 30.11, 25.67,25.08, 21.69.HRMS (CH4‐Ionization)
calcdfor[M+H](C22H23NO3S):382.1477;found:382.1479.
95
2.8.6CatalysisforLactams
GeneralprocedureforthecatalyticcycloisomerizationofYnamide:InaNMRpressuretube,
thedriedcorrespondingYnamide(0.1mmol)andtheiPrPd2dimer(2.6mg,5mmol%)in0.7mLof
CDCl3washeatedat90°C,underargonatmosphere.Theprogressofthereactionwasmonitoredboth
by1HNMRand31PNMR.Flashcolumnchromatographyrenders the lactams ingoodtoexcellent
yields. Crystallographic data (excluding structure factors) have been deposited to the
Cambridge Crystallographic Data Centre as supplementary publication, 2a (1446628), 2b
(1446630),2g(1446625),2h(1438982),2i‐O‐endo(1446629),2i‐N‐endo(1446628),and2j‐O‐endo
(1446626).
5‐methylene‐1‐tosylpyrrolidin‐2‐one(2a):Aftercompleteconversion(10minsheatingat60°C),
theproductwascleanlyisolatedbyflashcolumnchromatographywithEthylacetateandPentane
(v/v,1/3).Thelactamwasisolatedasawhitesolidinexcellentyield(25.0mg;99%).
1H–NMR(300.0MHz,CDCl3):δppm7.94(m,2H),7.35(m,2H),5.47(m,1H),4.56(m,1H),2.67(m,2H),
2.48‐2.43 (m, 5H). 13C{1H}–NMR (75.5 MHz, CDCl3): δppm 173.65 (C=O), 145.53, 141.01, 135.34,
129.66,128.09,94.31,29.92,25.90,21.72.HRMS(CH4‐Ionization)calcdfor[M+H](C12H14NO3S):
252.0694;found:252.0692.
6‐methylene‐1‐tosylpiperidin‐2‐one(2b):Aftercompleteconversion(heatingovernightat90°C),
theproductwascleanlyisolatedbyflashcolumnchromatographywithEthylacetateandPentane
(v/v,1/3).Thelactamwasisolatedasawhitesolidinexcellentyield(26.0mg;98%).
1H–NMR(300.0MHz,CDCl3):δppm7.91(m,2H),7.31(m,2H),5.26(m,1H),5.12(m,1H),2.50(t,J=
7.4and7.3Hz,2H),2.43(s,3H),2.37(t,J=7.0Hz,2H),1.77(m,2H).13C{1H}–NMR(75.5MHz,CDCl3):
96
δppm170.65(C=O),144.84,138.99,136.55,129.41,128.56,111.19,33.71,30.52,21.67,17.84.HRMS
(CH4‐Ionization)calcdfor[M+H](C13H16NO3S):266.0851;found:266.0852.
Ethyl5‐methylene‐2‐oxo‐1‐tosylpyrrolidine‐3‐carboxylate(2c):Aftercompleteconversion(30
minsatroomtemperature),theproductwascleanlyisolatedbyflashcolumnchromatographywith
EthylacetateandPentane(v/v,1/3).Thelactamwasisolatedaspaleoilingoodyield(27.5mg;86%).
1H–NMR(500.0MHz,CDCl3):δppm7.93(d,J=8.5Hz,2H),7.33(d,J=8.0Hz,2H),5.53(m,1H),4.62
(m,1H),4.15(m,2H),3.48(m,1H),3.05(m,1H),2.86(m,1H),2.43(s,3H),1.21(t,J=7.2Hz,3H).
13C{1H}–NMR(125.8MHz,CDCl3):δppm168.67,167.39,145.83,138.64,134.86,129.74,128.18,95.06,
62.26,47.47,30.10,21.74,13.96.HRMS(CH4‐Ionization)calcdfor[M+H](C15H18NO5S):324.0906;
found:324.0901.
3‐hexyl‐5‐methylene‐1‐tosylpyrrolidin‐2‐one(2d):Aftercompleteconversion(30minsatroom
temperature),theproductwascleanlyisolatedbyflashcolumnchromatographywithEthylacetate
andPentane(v/v,1/9).Thelactamwasisolatedaspaleoilingoodyield(33.0mg;99%).
1H–NMR(500.0MHz,CDCl3):δppm7.93(d,J=8.4Hz,2H),7.32(d,J=8.1Hz,2H),5.47(m,1H),4.56
(m,1H),2.78(m,1H),2.47(m,1H),2.43(s,3H),2.34(m,1H),1.71(m,1H),1.33(m,1H),1.22(m,
10H),0.85(t,J=7.0Hz,3H).13C{1H}–NMR(125.8MHz,CDCl3):δppm175.97,145.40,140.03,135.40,
129.62, 128.02, 94.18, 41.10, 32.88, 31.54, 30.63, 28.92, 26.45, 22.50, 21.71, 14.02.HRMS (CH4‐
Ionization)calcdfor[M+H](C18H25NO3S):336.1633;found:336.1637.
97
N‐(5‐methylene‐2‐oxo‐1‐tosylpyrrolidin‐3‐yl)acetamide (2e): After complete conversion (30
minsatroomtemperature),theproductwascleanlyisolatedbyflashcolumnchromatographywith
AcetoneandPentane(v/v,1/2).Thelactamwasisolatedaspaleoilingoodyield(25.0mg;82%).
1H–NMR(300.0MHz,CDCl3):δppm7.90(d,J=8.4Hz,2H),7.34(d,J=8.3Hz,2H),6.43(m,1H),5.49(m,
1H),4.64(s,1H),4.46(m,1H),3.09(m,1H),2.60(m,1H),2.43(s,3H),1.97(s,3H).13C{1H}–NMR
(125.8MHz,CDCl3):δppm171.88,170.65,145.96,137.51,134.78,129.84,128.04,95.89,50.51,34.75,
22.78,21.77.HRMS(CH4‐Ionization)calcdfor[M+H](C14H17N2O4S):309.0909;found:309.0906.
3‐tosyl‐1H‐benzo[d]azepin‐2(3H)‐one(2f):Aftercompleteconversion(12hheatingat120°C),the
productwascleanlyisolatedbyflashcolumnchromatographywithEthylacetateandPentane(v/v,
1/3).Thelactamwasisolatedasawhitesolidinmoderateyield(32.0mg;51%).
1H–NMR(500.0MHz,CDCl3):δppm7.82(m,2H),7.32‐7.30(m,3H),7.25‐7.23(m,2H),7.19(m,1H),
7.12(d,J=9.6Hz,1H),6.61(d,J=9.6Hz,1H),3.54(s,2H),2.37(s,3H).13C{1H}–NMR(125.7MHz,
CDCl3):δppm166.77(C=O),145.28,135.32,132.45,130.81,129.44,129.42,129.03,128.72,127.77,
123.03, 119.53, 44.50, 21.67.HRMS (CH4‐Ionization) calcd for [M+H] (C17H16NO3S): 314.0851;
found:314.0842.
98
7‐methylene‐1‐tosylazepan‐2‐one (2g): After 70% conversion (3 days heating at 120 °C), the
productwascleanlyisolatedbyflashcolumnchromatographywithEthylacetateandPentane(v/v,
1/2).Thelactamwasisolatedaswhitesolidsingoodyield(19.4mg,67%).
C5lactam:1H–NMR(300.0MHz,CDCl3):δppm7.92(m,2H),7.30(m,2H),5.44(m,1H),5.28(s,1H),
2.48(m,2H),2.41(m,5H),1.71(m,4H).13C{1H}–NMR(75.5MHz,CDCl3):δppm172.60(C=O),144.78,
144.00,136.31,129.33,128.88,119.53,37.50,35.04,29.90,22.94,21.66.HRMS(CH4‐Ionization)
calcdfor[M+H](C14H18NO3S):280.1007;found:280.1017.
6‐methyl‐1‐tosyl‐3,4‐dihydropyridin‐2(1H)‐one(2h):Aftercompleteconversion(5daysheating
at60°C),theproductwascleanlyisolatedbyflashcolumnchromatographywithEthylacetateand
Pentane(v/v,1/4).Thelactamwasisolatedasalightbrownsolidingoodyield(64.0mg;83%).
1H–NMR(300.0MHz,CDCl3):δppm7.96(m,2H),7.31(m,2H),5.50(m,1H),2.42(t,5H),2.23(t,3H),
2.17‐2.10 (m, 2H). 13C{1H}–NMR (75.5 MHz, CDCl3): δppm 172.72 (C=O), 144.74, 137.21, 136.80,
129.38, 128.40, 115.32, 35.15, 21.65, 20.89, 18.65. HRMS (CH4‐Ionization) calcd for [M+H]
(C13H16NO3S):266.0851;found:266.0846.
99
(Z)‐4‐methyl‐N‐(3‐phenyl‐1H‐isochromen‐1‐ylidene)benzenesulfonamide(O‐attack2i‐endo):
Aftercompleteconversion(20hheatingat35°C),thetwoproductswerecleanlyisolatedbyflash
columnchromatographywithEthylacetateandPentane(v/v,1/4).The lactamswere isolatedas
whitesolidsinexcellentyield(C5lactam,15.0mg;C6lactam,52mg,89%).
C5lactam:1H–NMR(300.0MHz,CDCl3):δppm8.19(m,1H),7.86(m,2H),7.66(m,1H),7.54‐7.51(m,
2H),7.46‐7.40(m,5H),7.28‐7.25(m,2H),6.48(s,1H),2.41(s,3H).13C{1H}–NMR(75.5MHz,CDCl3):
δppm163.33(C=O),145.13,141.16,137.77,136.30,135.69,134.13,129.34,129.17,128.52,128.41,
128.23, 127.79, 127.37, 126.46, 125.96, 112.94, 21.71.HRMS (CH4‐Ionization) calcd for [M+H]
(C22H18NO3S):376.1007;found:376.1013.
3‐phenyl‐2‐tosylisoquinolin‐1(2H)‐one (N‐attack2i‐endo): 1H–NMR (300.0MHz, CDCl3): δppm
8.32(m,1H),8.00(m,4H),7.71(m,1H),7.48(m,5H),7.27(m,2H),7.04(s,1H),2.40(s,3H).13C{1H}–
NMR(75.5MHz,CDCl3):δppm159.35(C=O),153.45,143.05,139.37,135.71,135.39,130.90,130.44,
129.29, 129.06, 128.94, 128.81, 126.95, 126.13, 125.66, 120.65, 103.08, 21.54. HRMS (CH4‐
Ionization)calcdfor[M+H](C22H18NO3S):376.1007;found:376.1012.
100
(Z)‐N‐(3‐cyclohexyl‐1H‐isochromen‐1‐ylidene)‐4‐methylbenzenesulfonamide (O‐attack 2j):
After complete conversion (3.5 days heating at 50°C), the product was cleanly isolated by flash
columnchromatographywithEthylacetateandPentane(v/v,1/10).Thelactamwasisolatedasa
whitesolidinexcellentyield(70.0mg;92%).
1H–NMR(300.0MHz,CDCl3):δppm8.32(d,J=8.1Hz,1H),7.96(d,J=8.2Hz,2H),7.66(t,J=7.5Hz,
1H),7.42(t,J=7.6Hz,1H),7.33(d,J=8.2Hz,1H),7.29(d,J=8.6Hz,2H),6.30(s,1H),2.41(s,3H,‐
CH3),2.37(m,1H),1.88(m,4H),1.74(m,1H),1.34(m,4H),1.24(m,1H).13C{1H}–NMR(75.5MHz,
CDCl3): δppm 161.75 (C=O), 160.07 (CTs), 142.88, 139.64, 135.73, 135.28, 129.24, 128.87, 128.31,
127.11,125.44,120.33,102.55,41.29(CH),30.35,25.91,25.75,21.55(CH3).HRMS(CH4‐Ionization)
calcdfor[M+H](C22H24NO3S):382.1471;found:382.1485.
101
1‐Deuterio‐N‐tosylpent‐4‐ynamide: A dried Schlenk was charged with N‐tosylpent‐4‐ynamide
(125mg,0.5mmol).To thiswasaddedTHF (dry,10mL)and thesolutionwas cooled to ‐78 °C.
HexanesolutionoftBuLi(1.5M,0.65mL,1.1mmol,2equiv.)wasaddeddropwiseoveraperiodof10
min.afterbeingstirredfor30minat‐78°C,theD2Osolution(0.04mL,2.2mmol,4equiv.)wasadded
andstirredforanother10min.Thenthemixturewasslowlywarmeduptoroomtemperature.The
mixturewaswashedby2NHCl,andextractedwithEthylAcetate.Thecombinedorganiclayerwas
driedoveranhydroussodiumsulfate.Filtrationandevaporationofthesolventgive1‐deuterio‐N‐
tosylpent‐4‐ynamide(90mg,72%yield)asacolourlessoil.
1H–NMR(300.0MHz,CDCl3):δppm8.45(s,1H,NHTs),7.97(d,J=8.7Hz,2H,phenyl),7.37(d,J=7.9
Hz,2H,phenyl),2.50(m,4H,CH2CH2),2.47(s,3H,CH3(Ts)).
N‐Deuterio‐N‐tosylpent‐4‐ynamide:AdriedSchlenkwaschargedwithN‐tosylpent‐4‐ynamide(50
mg,0.2mmol).TothiswasaddedD2OandCDCl3atrt,stirringovernight.Afterdecantationanddrying
overNa2SO4,andtheisotopiclabellingwasdeterminedby1HNMRtobearound99%.
1H–NMR(300.0MHz,CDCl3):δppm7.96(d,J=8.3Hz,2H,phenyl),7.36(d,J=7.9Hz,2H,phenyl),2.52‐
2.47(m,4H,CH2CH2),2.46(s,3H,CH3(Ts)),1.99(t,J=2.5Hz,1H,C≡CH)
102
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104
105
Chapter3WhenPtOutperformsPdinCatalytic
CycloisomerizationThischapterwill introduceanewcatalyticsystembasedon the indenediidepincerplatformin
which Palladium was switched for Platinum. The synthesis and characterization of the new Pt
complexes will be reported, followed by the evaluation of their performance in the catalytic
cycloisomerization of N‐tosyl alkynylamides and alkynoic acids. Comparisons will clearly
demonstratethatthePtcomplexessignificantlyoutperformtheirPdanalogs, inparticularforthe
challenging medium‐size ring formation (6‐/7‐membered rings). In the light of in‐depth
understandingofthemechanism,severalcatecholcandidatesaremeticulouslychosenasH‐bonding
additivesandappliedtofurtherenhancethecycloisomerizationinanimpressiveway.
3.1Introduction
PlatinumwasdiscoveredinancientEgyptmorethan3,000yearsago,andthefirstknownreference
wasdescribedinthewritingsoftheItalianphysicianJuliusCaesarScaliger,in1557.Rudimentarily,
Platinumwasusedmainlyinjewelryandornamentsinatime,asitappearedscarcelyandvalued
becauseitdidnottarnishlikesliver.However,nowadaysoneofthemostimportantusesofPlatinum
isobviouslycatalysis.Withthedevelopmentofera,applicationsofPlatinumhadbeensignificantly
extendedtomanyareasbothinindustryandacademia.
FirstreportsoftheuseofPtincatalytictransformationsdatebacktotheXIXthcenturyandconcern
elementalPt.Theearliesthydrogenation reported in1823usedPt as catalyst for the reactionof
hydrogenwith oxygen in the Döbereiner’s lamp, a device developed for lighting fires and pipes
(Scheme3.1).1Since thispioneeringprocess,hydrogenationreactionshavebeenoneof themost
important catalytic application of Pt. Later, in 1831, England chemist P. Philips developed a
Pt/asbestossystemtocatalyzetheoxidationofsulfuricdioxide,asaresponsetothehugedemandof
sulfuricacidoftheindustrialrevolution.2
Scheme3.1Philips’shydrogenationusingPtascatalyst.
LaterinthedawnoftheXXthcentury,theGermanchemistW.Ostwaldindustrializedtheproduction
ofnitricacidbyoxidationofammoniainpresenceofPt‐plate(Scheme3.2),whichearnedhimthe
Nobelprizein1909.2
106
NH35/4 O2 NO 3/2 H2O
NO 1/2 O2 NO2
2 NO2 N2O4
3 NO2 H2O 2 HNO3 NO
Scheme3.2IndustrializationofNitricacidbyW.Ostwald.
Inourdailylife,themostknownuseofPlatinumasacatalystisincars,asacatalyticconvertor,
fertilizingthecompletecombustionoftheunburnedhydrocarbon,andreducingtheamountofthe
pollutantsreleasedtotheair.
Lookingbacktoacademia,in1827,theprominentDanishorganicchemistW.C.Zeisedescribed
thefirstorganometalliccompound,namely“Zeise’ssalt”,K[Pt(C2H4)Cl3]·H2O(Figure3.1a).3Thiswas
aremarkablediscoveryfororganometallicchemistry,andalsoforPlatinumchemistry.Sincethen,a
greatdealofplatinum‐olefincomplexesandotherPtorganometalliccomplexeshavebeenreported.
These complexes have found versatile applications in different fields. In addition to catalysis, Pt
complexeshaveinparticularreceivedincreasingresearchinterestbecauseoftheirpotentialutility
in gas‐sensingdevices,4,5 organometallic supramolecular structure building,6,7 anddesign of anti‐
cancerprodrugs.8,9
Figure3.1RepresentativeexamplesofPtcomplexes.
Pt complexes have demonstrated diverse catalytic activities in a relatively large range of
transformations. One of themost impressive catalytic applications of Pt complexes is the olefin
hydrosilylation. Pt complexes, such as theKarstedt’s catalyst (Figure 3.1 b) are among themost
efficient catalysts for this transformation, and have found industrial applications.10 However, in
107
comparisonwithpalladiumcomplexes,platinumcatalystsseemsomewhatoverlooked,probablydue
totheintrinsicpropertiesofPt.11,12ComparedtoPd,PtformsstrongerM‐Cbonds,withstrengths
closetoC‐Cbonds.Asaresult,whereasforPdcomplexesreductiveeliminationtoformC‐Cbondsis
typically a favored process, for Pt complexes both reductive elimination/oxidative addition have
large activation barriers, making C‐C formation slower (Table 3.1).11 In addition, Pt complexes
possesshigherkinetic inertness,whichresults inmuchslower ligandsubstitutionprocess (up to
severalordersofmagnitude).ThesefactsmakePtcomplexeslesssuitableforC‐Ccouplingprocess,
in which Pd complexes occupy a forefront position. However, thanks to their low reactivity, Pt
complexesarevaluabletoolsfortheisolationandcharacterizationofcatalyticintermediates.That,
andthefactthatPthasanactiveisotopeinNMR(195Pt,33%abundance)contributestotheimportant
roleofPtcomplexesintheinvestigationofthemechanismofreactions.
Table3.1StrengthofM‐Cbonds,andactivationandreactionenergiesofC‐CREandOAprocess.(kcal/mol)
BDE ΔE≠(RE) ΔE(RE) ΔE≠(OA) ΔE(OA)
C‐C 87.4
Pd‐C 43.3‐55.2 24.9 ‐19.0 43.9 19.0
Pt‐C 60.8‐66.5 45.8 ‐3.5 49.3 3.5
Fromanotherpointofview,Ptisknownasoneofthesoftestmetals,asaresult,itformsstronger
bondswithsoft ligands,suchassulfur ligands,orunsaturatedsystemsviaπ‐coordination.Pthas
indeedagreataffinityforC‐Cdoubleandtriplebonds,andrecentyearshavewitnessedanupsurge
ofinterestsforPtcatalyzedprocessesinvolvingelectrophilicactivationofmultipleC‐Cbonds.
As for theprocess involving electrophilic activationof alkenes followedbyadditionof aprotic
nucleophiletotheC=C,PtcomplexesarenormallylessreactivethanthoseofPd,especiallyinM‐C
bondcleavagetoreleasetheproductbyβ‐Helimination.Nevertheless,thelowerreactivityinligand
substitutionofPtpreciselyfacilitatesalternativecatalyticprocessesforM‐Cbondcleavage,suchas
protonolysis, cyclopropanation, or cation rearrangement, giving access to different product.13 An
illustrative example is intramolecular hydroalkoxylations of δ and γ‐hydroxyolefins catalyzed by
[PtCl2(C2H4)]2/2P(4‐C6H4CF3)3 (Scheme 3.3 a). The final step, namely Pt‐C bond protonolysis,
contrastswith thePdcatalyzedsystem,which tends togiveoxidizedproductsviaaWacker‐type
oxypalladation/β‐eliminationmechanism.Additionally,Ptcationiccomplexescanbeefficientforthe
108
activationofnon‐activatedalkynesandpromotenucleophilicadditionofwaterormethanoltoyield
thecorrespondingketone,afterhydrolysis(Scheme3.3b).14
Scheme3.3ProcessesinvolvingPtelectrophilicactivationofalkenesandalkynes.
AnotherimportantprocessinvolvingPtactivationofalkynesisthecycloisomerizationofenynes,
inwhichtheC‐Cbondreactswiththeactivatedalkynes.Eventheverysimplecatalystprecursor,
PtCl2, iswidely used in a variety of such reactions. The transitionmetal catalyzed cyclization of
enynesanddiynesisamongthemostimportantstrategyfortheconstructionoffunctionalizedcyclic
structures. The cycloisomerization of 1,6‐ and 1,7‐enynes is one of the most investigated
transformations.Pt,togetherwithAu,isparticularlypowerful.MuraietalfirstreportedthePtCl2‐
catalyzedenynemetathesis.15Thetreatmentof1,6‐and1,7‐enyneswithacatalyticamountofPtCl2
intolueneat80°Cresultedinskeletalreorganizationoftheenynestogive1‐vinycycloalkenesinhigh
yields(Scheme3.4).
Scheme3.4PtCl2‐catalyzedconversionof1,6‐enynesto1‐vinycyclopentens.
In2000,Trostreportedtheapplicationofthisreactiontothesynthesisofabicyclicnaturalproduct,
viacycloisomerizationfollowedbyaring‐expansionprocess.16Intheapproachtotheconstructionof
109
roseophilin,onekindofprodigininefamilyofalkaloids,thecriticalstepentailedthetransformation
of the enyne to bicyclic diene (Scheme 3.5). PtCl2 can reliably catalyze the reaction at ambient
temperaturetoafford99%yield,whichisextremelyimportantforsuchtedioustotalsynthesis,while
Pdcatalysisprovedtobeinefficientuponthisreaction.
Scheme3.5Synthesisofroseophilinintermediateviaenynemetathesis.
Themechanismproposedforthesereactionsisreminiscentoftheoneproposedinchapter2for
the cycloisomerization of alkynoic acids: nucleophilic addition of a protic reagent/alkene to the
alkyneactivatedbyπ‐coordinationtoPt.Takingintoaccounttheefficiencyofthetransformations
discussed above, some ofwhich are superior to those catalyzed by analogous Pd complexes,we
decidedtoinvestigatetheimpactofchangingthePdatomoftheindenediidepincercomplexesbyPt.
110
3.2ResultsDiscussion
Aspreviouslydiscussed,ourformerindenediidepincercatalyticsystembasedonPddemonstrated
itsabilitytowardscycloisomerizationreactions.Afacileligandstructuralmodulationsignificantly
enhanced its thermal robustness and thereby its catalytic performance.Nevertheless, limitations
werestillobservedregardingseveralchallengingsubstrates.17Thecycloisomerizationstargeting7‐
memberedringlactonesandlactamscappedbothataround70%conversion,andC6amidesbearing
internalalkynesremainedintactafterdays.Thus,furtherimprovementswerehighlydesirable.To
theseends,webecameextremelyinterestedtomodulatethepincersystembyreplacingPalladium
byPlatinum,whichisknowntobeefficienttoactivatetheC‐Cmultiplebonds,inparticularthetriple
bonds.13Inaddition,Platinumhasscarcelybeenusedtocatalyzethecyclizationofalkynoicacidsand
relatedamides.18‐20
3.2.1DesignandSynthesisofPtComplexes
Thetargetedplatinumindenediidecomplexesweresynthesizedaccordingtoasimilarroutetothat
reportedforthePdcomplexes,21,22intwostepsstartingfromthebis(thiophosphinoyle)indenepro‐
ligandsIa,band[Pt(C2H4)Cl2]2asmetalprecursor(Scheme3.6).TheindenylcomplexesIIa,bwere
firstformedbyC–Hactivation(85%yieldforbothofthem).
Scheme3.6SynthesisofPtIndenediidecomplexesIII‐IV
111
Inregardto31PNMRspectra,bothcomplexesdisplaytwosingletsignals,respectivelyat56.8&
52.0ppm(IIa),and85.9&84.9ppm(IIb)(comparedto45.6&31.0ppmand71.5&61.9ppm,for
thecorrespondingfreeligands),accompaniedbysatellitesforthelowfieldsignal(JP‐Pt=81.0and
66.8Hzrespectively).Thechemicalshiftvariations forthetwoP=SgroupsandtheP‐Ptcoupling
observedforoneofthemareconsistentwiththecoordinationofthetwoP=Ssidearmsandwitha
dissymmetricalligandskeleton.Inaddition,doubletsignalsassociatedtoH1wereobservedinthe
1HNMR spectra at 4.96 and 4.05 ppm respectively, and no signal corresponding toH2 could be
observed.TheseobservationsareconsistentwiththeformationoftheindenylpincercomplexesIIa,b.
ThechloroplatinatecomplexesIVa,bwerepreparedreacting the indenylcomplexesIIa,bwith
polystyrene‐supported DIEA (diisopropylethylamine) in the presence of tetrabutylammonium
chloride(IVa:88%andIVb:84%).Withrespecttothe31PNMR,bothplatinatecomplexesexhibita
singletsignal,respectivelyat45.9ppmand75.4ppm(onlyforIVasatelliteswereobserved,JP‐Pt=45
Hz),indicatingthesymmetricalstructureoftheindenediidepincerligand.Additionally,the1HNMR
spectradenotedthedisappearanceofthesignalsattributedtoH1(observedinthecaseoftheindenyl
typecomplexes)confirmingtheformationoftheindenediideskeleton.
Inordertodiscardthenon‐crucialammoniumsaltasdonepreviouslyforthePdcomplexes,the
neutraltrimeric/dimericcomplexesIIIa,bwerepreparedreadilybyusingsodiumacetateintoluene
at90°C,andwereobtainedinpureformandgoodyield(IIIa:78%andIIIb:87%).The31PNMR
spectrumofIIIadisplaystwobroadsignalsat43.8&38.4ppm,consistentwithastrongerassociation
oftheindenediideplatinumfragmentsthanitsPdanalogueIc,whichshowedabroadsingletsignal
(δP=42.7ppm).Thiscanberegardedasaproofofastrongermetal‐ligandinteractionofPlatinum
trimerthanthatofPalladium.AsforIIIb,thesituationissimilartothatofthePdanalog,withtwo
singletsat68.9and79.8ppm.Again,the1HNMRspectrumconfirmstheabstractionofH1.These
data are consistentwith the formation of the indenediidePt fragment, but no conclusion canbe
drawnconcerningthedegreeofassociation.
Allthecomplexeshavealsobeencharacterizedbythe13CNMR,andmostdiagnosticarethesignals
forthecentralcarbonatomoftheSCSpincerwhichappearslightlyupfield(ataround160ppm),
comparedtothoseoftherelatedPdcomplexes(by~10ppm)withtheexpectedmultiplicity(tordd
duetoP‐Ccoupling).
ThestructureofcomplexesIIb,IIIaandIVawereunambiguouslyconfirmedbyX‐raydiffraction,
whichthecrystalswereobtainedbyslowdiffusionofCH2Cl2/Et2O(IIb,IIIa)orfromaCHCl3solution
(IVa)(Figure3.2).ThesolidstructuresdeterminedforcomplexesIIbandIVaareconsistentwith
112
thoseproposedinsolution.ThetrimericstructureofIIIawasunambiguouslyconfirmedbyX‐ray
diffraction.AsforIIIb,thedimericstructurewasproposedaccordingtothestructureofitsPdanalog.
Inallcases,theSCSligandformsaquasi‐perfectsquare‐planarpincercomplex(SPtS=174‐178°)and
thePtcenterdeviatesonlymarginallyfromtheindenyl/indenediideplane(bylessthan0.5Å, in‐
planecoordination).InlinewiththeverysimilarsizeofPtandPd(covalentradiiof1.36and1.39Å,
respectively),23 the geometric features of the Pt complexes are quasi‐identical to those of the
correspondingPdcomplexes.
IIb
IVa
IIIa
Figure3.2EllipsoiddrawingsofthemolecularstructuresofIIb,IIIaandIVa(Hatomsofthethree
complexesandnBu4N+groupofIVaareomittedforclarity)
113
3.2.2EvaluationoftheCatalyticActivityofthePtComplexes
A rapid evaluation of the catalytic performances was first led on the cycloisomerization of 5‐
hexynoicacid1atodiscriminateamongthefournewlydevelopedPtcomplexesIII‐IV(Table3.2).
Withthesamereactionconditionsapplied,thebestresultwasobtainedwiththeplatinumdimerIIIb.
Completeconversionwasachievedwithin3hat50°Cinchloroformwith1mol%Ptloading(entry
2),whichrepresentsasignificantimprovementovertherelatedPddimerIII(10hat90°Cand5mol%
Pdwererequiredinthiscase).6‐exocyclizationwasidentifiedinallcasesby1HNMR,denotedin
particularbyasetoftwomultipletsofolefinicHobservedat4.60&4.20ppmfortheexocyclic=CH2
group(seeexperimentalpartofchapter2).ThereactioncatalysedbythetrimericcomplexIIIabarely
showedactivityduemostlikelytoitspoorsolubility,andonlyatraceamountofthetargetlactone
product was observed after 3 h. Cycloisomerization reactions catalysed by the two monomeric
chloroplatinatecomplexesIVa,bwentrelativelysluggish(27%and44%yieldrespectively)under
suchconditions,andrequiredmoretime,orhighertemperature.ComplexIIIbwasselectedforthe
restofthestudy.
Table3.2EvaluationofthecatalyticperformancesofcomplexesIII‐IV.
O
O
Cat. 1 mol% [Pt]
CDCl3, 50°C, 3h
OH
O
1a 2a
Pt
iPr2P PiPr2SS
Pt
PiPr2iPr2P
S S
IIIb
PR2R2P
S SPt
Cl
PPh2Ph2P
S SPt3
IVa (R = Ph)IVb (R = iPr)
NBu4
IIIa
Entry Cat. Conv. (%)
1 IIIa Trace
2 IIIb >99
3 IVa 27
4 IVb 44
114
With these results in hands, the twodimeric complexes III and IIIbwere employed for direct
comparisonof their catalyticperformance inmodel cycloisomerization reactions, leading to5/6‐
memberedlactones/lactams(Table3.3).
Table3.3EvaluationofthecatalyticpropertiesoftheindenediidePtcomplexIIIb.
Entry Sub. Cat.
(mol% [M]) T
(°C) t (h) Conv (%)b
1 1a III (5) 90 10 >99
2 IIIb (1) IIIb (0.05)
50 3 97
3 90 12 >99c
4 1b III (5) 90 12 >99 (98)
5 IIIb (5) 90 0.4 >99
6 IIIb (2) 90 3 >99c
7 IIIb (0.4) 90 18 >99d
8 1c III (5) 25 0.5 >99
9 IIIb (5) 25 0.5 >99
10 1d III (5) 60 0.16 >99 (98)
11 IIIb (5) 60 1 >99 (88) a)Catalytic reactions performed under argon atmosphere using 0.1 mmol of substrate (0.14 M in CDCl3).b)Conversions were determined by 1H NMR analysis. Isolated yields are given in brackets. c)Substrateconcentrationof2M.d)Substrateconcentrationof0.83M.
115
Comparedwiththecyclizationof1abythePddimericcomplexIII(99%conv.,5%cat.,90°C,10
h), the Pt dimeric complex IIIb demonstrated better catalytic performance by carrying out the
reactionunderrelativelymilderreactionconditions,namelylowercatalystloadingwithonly1.0mol%
[Pt],lowertemperatureat50°Candinonly3h(entries1and2).Inaddition,thecatalystloadingcan
be lowered down to 500 ppm (0.05 mol% [Pt]). Correspondingly, the temperature should be
increased from 50 to 90°C to accomplish the reaction in a reasonable time. To our delight, the
performanceofIIIbwaswithoutdetrimentaleffectatsuchlowloading,leadingtoafullconversion
within12h,correspondingtoturnovernumber(TON)andturnoverfrequency(TOF)of2000and
167h–1,respectively(entry3).Theverygoodresultobtainedwith5‐hexynoicacid1aencouragedus
totestthecyclizationoftherelatedN‐tosylamide1bwhichisnotoriouslymorechallenging.Aslight
increase of the reaction temperature (from50 to 90°C) enabled to achieve complete conversion
within25minwithIIIb(5mol%ofPt,entry5).The1HNMRspectrumofthereactiondisplayedhas
alsotwosignalsforthecharacteristicolefinicprotonsoftheexocyclic=CH2group(δ=5.56&5.12
ppm, see experimental part chapter 2), consistent with 6‐exo cyclization. Comparatively, the
formationofthealkylidenelactam2bismuchfaster(~30times)withIIIbthanwiththePdcomplex
III(whichrequired12hofreactionunderthesameconditions,entry4).Giventheveryhighactivity
of IIIb, the catalytic loading was again reduced. Using 2, or even only 0.4 mol% of Pt, the
cycloisomerizationsmoothlywenttocompletionwithin3and18h,respectively(entries6and7),
demonstratingtherobustnessofthePtcomplex.
Then,asimilarstudywascarriedoutfortheformationof5‐memberedringproducts.Incontrast
withwhatwasobservedfortheδ‐lactoneandlactam2a,b,PtdoesnotoutperformPdforthesmall
ringformation.Thecyclizationofpentynoicacid1cproceedsequallywellwithIIIbthanwithIII(30
min at 25°C, Table 3.3, entries 8 and 9) to form 2a via 5‐exo cyclization. Moreover, for the
correspondingN‐tosylamide1b,IIIbdemonstratedalowerefficiencycomparedtoIII(1hvs10min
at60°C,entries10and11).
AlthoughthePtcomplexIIIbbehaveddifferentlyupontheformationfor5‐memberedrings,the
resultsobtainedfortheformationof6‐memberedringspermittedustobeoptimistconcerningits
catalyticperformanceuponmorechallengingsubstrates,suchasthoseleadingtomedium‐sizerings,
orbearinginternalalkynes.
116
3.2.3SubstrateScope:Medium‐SizeRingFormation
Awidearrayofsubstratesaimingtoformmorechallengingmedium‐sizeringsweresubsequently
preparedandsubmittedtocyclization.Asexpected,thePtdimerIIIbprovedmuchmoreactivethan
itsPdanalogIIIfortheformationof7‐memberedrings(Table3.4).
Table3.4ScopeofthecycloisomerizationbyindenediideIIIb.
a)Catalyticreactionsperformedunderargonatmosphereusing0.1mmolofsubstrate(0.14MinCDCl3)andcatalystloadingof1and5mol%forthealkynoicacidsandtheN‐tosylalkynylamides,respectively.b)Conversionsweredeterminedby1HNMRanalysiswithmesityleneasinternal standard. Isolated yields are given in brackets. c)Substrate concentration of 0.5 M. d)Intermolecular addition products weredetectedby1HNMRinthecrudereactionmixture.e)Unidentifiedproducts(19%)weredetectedby1HNMRinthecrudereactionmixture.f)Mixtureofproducts.g)Substrateconcentrationof1M.h)Phthalicanhydride(57%)wasdetectedby1HNMRinthecrudereactionmixture.
The first testswereperformedwith thesimplest linearsubstrates1e and1f.Here, the flexible
unsubstituted backbonesmake the cyclizationmore challenging. Using IIIb (1mol% of [Pt]), 6‐
heptynoicacid1ewascompletelyconsumedafteronly21hat90°C.Thecorrespondingalkylidene
‐lactone2ewasobtainedinpureformandverygoodyield(84%)afterdistillation.Thestructure
wasconfirmedby1HNMR,andinparticular7‐exocyclizationwasconfirmedbytheolefinicsignals
at δ 4.75 & 4.64 ppm attributed to the exocyclic =CH2 group. A small amount (~12 %) of
intermolecular addition product was detected by 1H NMR in the reaction crude, but it can be
discarded by distillation. This outcome represents a significant improvement of the result we
recentlyreportedwiththePdcomplexIII(51%isolatedyieldafter22hat120°Cusing5mol%of
117
[Pd]),whichwasatthattimethemostefficientsystemtocyclize1einto2e.24‐27ThePtcomplexIIIb
also gave excellent result in the cycloisomerization of theN‐tosyl amide1f. Full conversionwas
achievedin22hat90°Cusing5mol%ofPt(entry2)toform2fvia7‐exocyclization(frommsignals
on1HNMRatδ=5.44&5.28ppm,seechapter2).Previously,2fwasobtainedonlyinmoderateyield
(53%)afterextremelylongtimeof130hat90°CwiththePdcomplexIII.ByreplacingPdforPt,the
reactiontimeisconsiderablyshortened(by~6times)andpurealkylidene‐lactam2fwasisolated
inexcellentyield(93%).
ToillustratethegeneralityofthePtcomplexIIIb,theformationofother7‐memberedringswas
then explored. The α‐substituted substrates 1g,h were efficiently cyclized (entries 3 and 4),
demonstratingthecompatibilitywithestergroups.For2g,twosignals(δ=4.75&4.63ppm)were
observedinthe1HNMR,nearlyatthesamerangeasfor2e,consistentwith7‐exocyclization.Besides,
formationof2gwasaccompaniedbysomeintermolecularaddition(lessthan10%).Notethatonly
7hwerenecessarytoconvert1hinto2h.Thisisasignificantspeedup,whencomparedwiththe
parentsubstrate1f(whichrequired22hofreaction),whichmaybeattributedtoThorpe‐Ingold
effectaspreviouslydiscussedandacidificationoftheN‐tosylamide.The1HNMRspectrumof2h
displaystwosetsofsignals(δ=5.52&5.40ppm),similartothatofitsnon‐substitutedanalogue.X‐
raydiffractionstudyof2hunambiguouslyconfirmeditsexostructure(Figure3.3)and,inparticular,
theformationofthelactamviaN‐attack.
Figure3.3X‐raystructureoflactam2h.
Veryfacileandrapidreactionswerealsoobservedwiththeo‐benzoicsubstrates1i,j(entry5and
6).Their7‐exocyclizationswerecompletewithinonly30min/1hat90°C. Incomparison, the
cyclizationof1iwiththePdindenediidecomplexIIIrequired9.5htoreach95%conversion.Again,
1HNMRspectroscopyshowsthepresenceof=CH2signalsconsistentwithexocyclization.Moreover,
X‐Raydiffractionstudywasperformedon2j (figure3.4),unambiguouslyconfirming themodeof
118
cyclization(7‐exovs6‐endoandNvsOattack).28‐31UsingIIIbascatalyst,theε‐lactonesandlactams
2g‐jwerereadilyformedandisolatedingoodtoexcellentyields(57‐92%).
Figure3.4X‐raystructureoflactam2j.
Theverygoodresultsobtainedwith7‐memberedringspromptedustoenvisionthentheformation
of8‐memberedlactonesandlactams.Asdiscussedbefore,theformationof8‐memberedringwould
beevenmorechallengingcomparetothepreparationof7‐memberedring.Ourfirstexperimentwith
linear7‐octynoicacidtoforma8‐memberedringlactoneshowedthatinsteadoftheintramolecular
cyclization, the intermolecular reaction leading to a mixture of oligomers was observed.32 The
correspondinglinearalkynylamide1kwasthentestedandremainedunaffectedafter24h(entry7).
Whenprolongingthereactiontimefor7days,itturnedouttobecomplicatedandmessyinviewof
1HNMRforthecrudewitharound30%ofconsumptionofthestartingmaterial,andfinallyonlya
smallamountofthetargetproductaltogetherwithlotsofside‐products.
To favour the cyclization, the rigid substrates 1l,m deriving from phthalic anhydride were
prepared.Gratifyingly, inviewofthe1HNMRspectrum,thecharacteristicsignalsofolefinic=CH2
protons(m,4.69ppm&m,4.30ppm)wereclearlyobserved.The8‐memberedlactone2lcouldbe
preparedin43%isolatedyield(21hofreactionat60°C,entry8),although1lconcomitantlyconverts
back intophthalicanhydride(retro‐acylation)under theseconditions.ThecorrespondingN‐tosyl
amide1mwasalsoconvertedbyIIIbintothetargeted8‐memberedlactam.Inthe1HNMRspectrum
of the crude reaction, several sets of olefinic =CH2 signals were observed in the same range
preventingtheidentificationoftheproducts.Lateron,byconductingafastcolumnchromatography,
followingwiththeprep‐HPLC,twopurecompoundswereisolated(86%yield,86:14ratio,entry9).
ThestructuresofbothproductswereelucidatedbyX‐raydiffractionstudies.Insteadofthetargeted
8‐memberedlactam,twospiro‐typedstructuresof2m‐N‐spiroand2m‐O‐spirowereestablished
(Figure3.5).
119
Figure3.5X‐raystructuresoflactam2m‐N‐spiroandlactone2m‐O‐spiro.
The formationof twospirocompoundsfrom1m turnedouttobesurprisingandinteresting. It
apparentlyresults fromintramolecularcascadecyclizations.Atentativemechanismforthesetwo
spirocompoundsisdescribedasfollow(Scheme3.7).Fortheformationof2m‐N‐spiro,thecomplex
IIIbfirstreactswith1m,bydeprotonationofitsN‐Hbond,andactivationofitstriplebondviaπ‐
coordinationtoPt,togeneratetheintermediate.Later,itundergoesanintramolecularreaction.The
nucleophilic ‐NTs attacks the carbonyl of the ester,which subsequently leads to thenucleophilic
attackoftheOtotheactivatedalkyne.Finally,thespiroproductisformedwithregenerationofIIIb.
A similar process is proposed for the formation of2m‐O‐spiro, after an initialmigration of the
propargylgrouptotheNatom.
120
NHTs
O
O
O
N-H activationand
C-C -activation
IIIb NTs
O
O
O
[Pt]
NTs
OO
O
2m-N-spiro
trans-propargylation
N
O
OH
O
Ts
O-H activationand
C-C -activation
IIIb
N
O
O
O
Ts
O
ONTs
O
2m-O-spiro
[Pt]
1m
Scheme3.7Proposedmechanismsfortheformationof2m‐N‐spiroand2m‐O‐spiro.
As shownabove, although very efficient for ε‐lactones and lactams, thePt complex IIIb shows
limitationstowards8‐memberedringsandside‐reactionsprevail.Afterexploringtheperformance
ofPtcomplexregardingthemedium‐sizeringformation,wedecidedtofurtherstudyitsperformance
towardssubstratesbearinginternalalkynes.
121
3.2.4SubstratesBearingInternalAlkynes
Carboxylic acids and N‐tosyl amides bearing internal alkynes are particularly challenging
substratesforcycloisomerizationreactions,intermsofactivityaswellasexo/endoselectivity.Given
theefficiencyofthePtcomplexIIIb(andsuperiorityoverthePdcomplexIII)intheformationof6
and7‐memberedrings,wewereeagertoevaluateitsbehaviourtowardssubstratesraisingissuesof
5‐exo/6‐endoand6‐exo/7‐endoselectivity(Table3.5).
Accordingly,compounds1n,owerecyclizedat90°Cusing5mol%ofPt(entriesIandII).Inboth
cases,theuseofIIIbspectacularlyshortenedthereactiontime(byupto28times)comparedwith
III.Animpressivespeedupisalsoobservedwiththeα‐substitutedsubstrates1p,q(byupto18times,
entriesIIIandIV).Completeconversionoftheacid1prequiresonly5minwithIIIb(vs1.5hwith
III).
Table3.5Cycloisomerizationof1n‐sbearinginternalalkynescatalyzedbyPtComplexIIIb.
Entrya t (h) Conv (%)b
I
II
III
Substrate Product t (h) Conv (%)b
5 min >99
Entrya
V
Substrate Product
IV
18 6
4 >99 36 38
24 901 >99
exo/endo: 24/1
exo/endo: 1/4.9
OHO 1n
OO
OO
2nexo
2nendo
NHTsO 1o
NTsO
NTs
O
2oexo
2oendo
OHE
O
Et
1p
E = CO2Me
OO
EEt
EtOO
E
2pendo
2pexo
NHTsE
O
Et
1q
E = CO2Me
NTsO
EEt
EtNTs
O
E
2qendo
2qexo
1r
OH
O
MeO
O
Me
2rexo
O
O2rendo
NHTs
O
Me
1s
NTs
O
Me
2sexo
NTs
O2sendo
exo/endo: 1/1.6
exo/endo: >1/99
exo/endo: >1/99
exo/endo: n.d.
VI
a)Catalytic reactions performed under argon atmosphere using 0.1 mmol of substrate (0.14 M in CDCl3) and catalyst loading of 1 and 5 mol% for
the alkynoic acids and the N-tosyl alkynylamides, respectively. b)Conversions were determined by 1H NMR analysis with mesitylene as internal
standard. Isolated yields are given in brackets. c)Substrate concentration of 0.5 M. d)Intermolecular addition products were detected by 1H NMR in
122
the crude reaction mixture. e)Unidentified products (19%) were detected by 1H NMR in the crude reaction mixture. f)Substrate concentration of 1
M. g)Phthalic anhydride (57%) was detected by 1H NMR in the crude reaction mixture.
Besidesremarkablerateenhancement,replacingPdforPtalsoinfluencesexo/endoselectivity.As
glimpsedpreviouslyuponcyclizationofhexynoicandpentynoicsubstrates1a‐d,thePtcomplexIIIb
displays a noticeable preference over its Pd analog III for the formation of 6‐membered rings.
Accordingly,the6‐endocyclizationof1nwasslightlypredominantwithPt(exo/endo1:1.6)while
the5‐exocyclizationwasfavouredwithPd(exo/endo1.5:1),asdeducedfromtherelativeintegration
ofthemultipletolefinicsignalsat5.21ppm(exo)and5.00ppm(endo)inthe1HNMRspectra.17An
increasein6‐endovs5‐exoselectivityisalsoobservedwiththeα‐substitutedacid1p(from1.2with
V,to4.9withIIIb,entryIII)asdeducedfromtherelativeintegrationofthettolefinicsignalsat4.62
ppm (exo) and 5.02 ppm (endo) in the 1H NMR spectra. Gratifyingly, the correspondingN‐tosyl
amides1o,q underwent exclusively 6‐endo cyclization. From the 1HNMR, both2o,q displayed a
diagnostictripletsignalasdescribedinthepreviouschapter,at5.45ppm&5.60ppm,respectively,
associatedtotheendocyclicolefinicprotons.Theensuingalkylideneδ‐lactams2o,qareobtainedin
pureformandveryhighyields(entriesIIandIV).Inaddition,themolecularstructureofcompound
2q,andinparticularN‐nucleophilicattackmodewasunambiguouslyconfirmedbyX‐raydiffraction
study(Figure3.6).
Figure3.6X‐raystructureoflactam2q.
TheabilityofIIIbtoformefficiently6aswellas7‐memberedringsisuniqueandraisestheissue
of6‐exo/7‐endoselectivity.Totrytoanswerthisquestion,westudiedthecyclizationoftwotypesof
very challenging substrates: internal 5‐alkynoic acids, that have been very rarely engaged in
cycloisomerization so far, and their relatedN‐tosyl amides, whose cyclisation is unprecedented.
Accordingly,prolongedheatingof5‐heptynoicacid1rinthepresenceofIIIbinducedcyclization,and
amultipletsignalofamajorproductwasobservedat4.56ppmwiththesignalofatraceamountof
123
aminoroneat5.20ppm.Althoughtheconversionremainedmodest(38%after36hat90°C,no
reactionatallwasdetectedwiththePdcomplexIII),thereactionisselectivefor6‐exocyclization
andtheδ‐lactone2rexowasformedin24:1ratiowithrespecttothecorrespondingε‐lactone2rendo
(entryV).Themajorproduct1rwascharacterizedbycomparisonwiththeliterature.25Asimilartest
wasperformedwith thecorrespondingN‐tosylamide1s(entryVI).ThePtcomplexIIIb showed
some activity but the conversion of1swas too low (6% after 18 h at 90°C) to characterize the
cyclizationproductsandevaluatetheirratio.
ComparingtheperformancesofPdandPtcomplexes,thePtdimerdemonstratesoverwhelming
advantagesupon the substrate scope.6‐ and7‐membered ring couldbeefficientlyobtained (full
conversions)aswellashighselectivities for6‐memberedsubstitutedringsstartingfrominternal
alkynes.Moreover,thePtcomplextriggeredcyclizationofsubstratesbearinginternalalkynesthat
werenotreactivewith thePdcatalyst,even though insomecases theconversionswerenot that
promising so far. Furthermore, the complicated reaction mixture obtained for 8‐member ring
formation indicated that there are still some limitations of this complex system. The question
whetherisitpossibleornottoincreasefurthertheactivityofcurrentsystempromptedusfordeeper
investigation,inparticularmechanisticinvestigations.
124
3.2.5MechanisticStudy
To substantiate the contribution of the indenediide ligand, the catalytic activity of IIIb was
compared to these of its precursors, [PtCl2(ethylene)]2 and of the indenyl derivative IIb. In the
presenceof[PtCl2(ethylene)]2,thealkylidenelactone2aformsbutrapidlydegradesintoamixture
ofunidentifiedproducts.Inthecaseofthealkynylamide1b,noreactionoccurredafterheatingfor
24hat90°C(Table3.6).AsfortheindenylcomplexIIb,verylowconversionsofboth1aand1b
(traces)wereobservedevenafterprolongedreactiontimes(24h).
Table3.6Blankreactiononthecycloisomerizationof1aand1b.
Entry Sub. [Sub] Cat. mol% [Pt] T (°C) t (h) Conv (%)
1 1a 0.1 [PtCl2(ethylene)2] 1 25 5.5 mixture of unidentified products
3 1a 0.1 IIb 1 50 24 Traces
4 1b 0.5 [PtCl2(ethylene)2] 5 90 24 n.r.
5 1b 0.1 IIb 5 90 24 Traces
In addition, the cyclizations of1a,b catalysed by IIIbweremonitored by 31PNMR: during the
process,thecleanformationofaindenylspeciesisobserved,concomitantlytotheconsumptionof
IIIb,andtheindenediidecomplexIIIbisregeneratedattheendofthereaction(Figure3.7and3.8).
NodecompositionofIIIbleadingtothefreeligand(δ=71.5&61.9ppm)wasobservedattheendof
thereaction.
125
Figure3.731PNMRmonitoringofthecycloisomerizationof5‐hexynoicacid1abyIIIb.
Figure3.831PNMRmonitoringofthecycloisomerizationofN-tosyl hex-5-ynamide 1b byIIIb.
Pt
iPr2P PiPr2SS
Pt
PiPr2iPr2P
S S
Complex IIIb
ComplexIIIb
Indenylspecies
5 mins during the reaction
Complex IIIb
End of the reaction
15 mins during the reaction
Complex IIIb
End of the reaction
ComplexIIIb
Indenylspecies
126
Altogether, theseresultssupportanactiveparticipationof the indenediide ligand(metal‐ligand
cooperativity).Inlinewithwhathasbeendiscussedinthepreviouschapter,thiscooperationvery
likelytakesplaceforeachstepofthemechanism:(i)activationoftheacid/amidepro‐nucleophileby
deprotonationbytheligandbackboneandactivationoftheCCtriplebondbyside‐onecoordination
toPt,(ii)nucleophilicattacktotheactivatedalkyne,and(iii)eliminationofthefinalproduct(see
chapter2,section2.6).
Asdisclosedinacombinedtheoreticalandexperimentalworkrecentlyreportedbyourgroup,33in
additiontothecontributionofthenon‐innocentligand,thisindenediidepincercatalyzedreaction
involvestheparticipationoftwomoleculesofsubstrate,oneofthemactingasaprotonshuttleinthe
threedifferentsteps(Figure3.9).Fromthisobservation,itwasdemonstratedthatbyaddinganH‐
bondingadditive,thecyclizationreactionefficiencycouldberemarkablyenhancedbothintermsof
activityandselectivity.Since thePt systemvery likelyacts in thesame fashionas thatofPd,we
envisionedthatthepreviouslyusedadditivescanalsobebeneficialforthissystem.
Figure3.9Protonshuttlingmechanismdisclosed.
127
3.3AdditiveImpact
3.3.1Introduction
Thepursuitofhighlyefficientcatalyticsystemsisofconstantinterestforallchemists.Inaddition
to arduously seekingnewpotential catalytic systems, the introductionofproper additives to the
provisionallywell‐establishedcatalyticsystemshasbecomemoreandmoreubiquitousandproved
efficient.34‐36 Generally, the additives enhance reactions, by promoting the reactivity or/and the
selectivity (including chemo‐, regio‐, diastereo‐, and enantioselectivity), or in some cases by
modifyingthereactionpathway.Amongthenumerousadditive‐assistedreactions,theuseofacids,
alcohols,andevenwaterisquitecommon.Oneofthemainrolesforsuchkindofadditivesisthat
theymayfunctionasaprotonshuttleinthereactionprocess.
Asmentionedabove,ourmechanisticinvestigationsonthecycloisomerizationreactionscatalyzed
byindenediidePdcomplexeshaverecentlypointedouttheimportanceofprotonshuttling.33Awide
array of H‐bonding additives were investigated in the model cyclization of 4‐pentynoic and 5‐
hexynoicacid(Table3.7).Herein,theformalPddimericcomplexIIIwasemployed.
Table3.7Investigationofadditiveseffectuponcyclizationreactions.
Cat. (0.2 mol% [Pd])CDCl3, RT
O
O
OH
O
additive (30 mol%)
OH
OOH
O
OH
OOH
O
S
O
O
OHH3C
OP
O
O OH
OH OH
OH
OH
OH
OH
OHR
Carboxylic acids Stronger acids
ab
c d
e
f
g h ij
10 catechols
n n
n= 1, 2
Pd
iPr2P PiPr2SS
Pd
PiPr2iPr2P
S S
128
The initial studies beganwith aliphatic and aromatic carboxylic acids (a‐d),which showed no
obviouseffect.Usingstrongeracidssuchasmethanesulfonicacidanddiphenylphosphoricacidcan
even completely inhibited the reaction (e and f), probablydue toprotonationof the indenediide
backbone, giving inactive indenyl species. Subsequent studieswere focused on awide variety of
alcohols, diols, and triolswith aliphatic and aromatic skeletons. Simple alcoholshave little orno
impact (g), while diols and triols were found to improve the conversion (h‐j), in particular the
aromaticones.Themostefficientadditivesarethosefeaturingproximalhydroxylgroups,toensure
optimal proton transfer, especially the catechols (j). By adding the simple catechol (without any
substituents),thecyclizationof4‐pentynoicacidcanbesignificantlyspeededup,requiringonly30
mins,insteadof5hwithoutadditive.Inparallel,thecompletecyclizationof5‐hexynoicacid(which
ismuchlessreactive)canagainbeachievedin30minsinsteadof10h.Thesimplifiedprotontransfer
modescanbeillustratedasfollows:theprotontransfermayinvolvethetwohydroxylgroups(proton
shuttlingviaH‐bonding, Scheme3.8 a) oronlyone (Scheme3.8b, theotherhydroxyl group can
participateinadjacentH‐bonding).
Scheme3.8Schematicrepresentationoftwodifferentmodesofprotontransferwithcatechol.
Similarimpactofcatecholhasbeenobservedinother’sworkdealingwithorganocatalysis.Rovis
et al. investigated the asymmetric intermolecular Stetter reaction of enals with nitroalkenes
catalyzedbychiralN‐heterocycliccarbene(Table3.8).
Table3.8EffectofBrønstedacidadditivesuponStetterreactionofenalswithnitroalkenes.
129
entry additive time(h) yield(%) ee(%)
1 none 8 5 93
2 8 8 93
3 8 15 93
4 2 80 93
5 8 9 93
Intheabsenceofadditive,thecatalyticsystemdisplayedlowactivity,withonlyatraceamountof
thetargetproduct(8h,5%yield)observed.Optimizingthereactionbyadding1.0equiv.ofcatechol,
aremarkableincreaseofbothactivityandisolatedyieldwasachieved(2h,80%yield).Aplausible
mechanismwasproposedthatthecatecholmayserveasaprotonshuttletoassistingeneratingthe
acyl anion through a synchronous transition state (Scheme 3.9). And its general effect was
demonstratedbythesimilarimprovementsobservedintheothersubstitutedsubstrates.
Scheme3.9Proposedmodeofactivationwithcatechol.
130
3.3.2EvaluationoftheAdditivesImpactontheEfficiencyofthePtPincerComplex
IIIb
GiventhedistinctimpactofcatecholuponthecycloisomerizationobservedwiththePdcomplex
III,3potential catechol candidateswereselected (Figure3.10) to further improve thescopeand
efficiencyofthePtcomplexIIIb.
Figure3.10Potentialcatecholcandidates.
Asillustratedintable3.9,theimpactoftheseadditivesonthecycloisomerizationof1sasamodel
substratewasfirstinvestigated.Asareminder,IIIbalonecantriggerthisreaction,butendedina
verypoorconversionof6%after18h.Gratifyingly,thanktotheseadditives,thissubstratecanbe
efficiently cyclized for the first time. In the presence of 4‐nitrocatechol, the cyclization was
remarkablyacceleratedandinonly6h,acompleteconversionwasachieved(Table3.9,entry2).A
mixturewith6‐exo/7‐endoratiosat58/42.Meanwhile,aslightlylongertimeof18hwasrequired
bytreatmentofpyrogallol,buttheratiobetween6‐exo/7‐endoselectivelyshiftedto68/32(entry3).
With tetrachlorocatechol, thereactiongavea fullconversionwith53/47of6‐exo/7‐endo in15h
(entry4).
131
Table3.9Additiveimpactuponthecycloisomerizationof1s.
Entry Additive Time (h) Conv. (%) Exo/endo
1 none 18 6 n.d.
2
6 99 58/42
3
18 99 68/32
4
15 99 53/47
The6‐exo/7‐endorationwasdeterminedfromtherelativeintegrationofthesignalsassociatedto
theexoandendoolefinicprotons(qat5.69ppmandtat5.88ppm,respectively).Thestructuresof
both 6‐exo and 7‐endo products were fully characterized by 1H & 13C NMR spectra, and later
unambiguouslyconfirmedbyX‐raydiffractions(Figure3.11).
Figure3.11X‐raydiffractionof2sexo(left)and2sendo(right).
After this first success, we decided to tempt a challenging linear amide in order to form a 8‐
membered ring lactam.The alkynyl amide1t derived fromsuccinic anhydridewas subsequently
132
tested(Scheme3.10).However,withorwithouttheseadditives,alltheexperimentsturnedouttobe
complicated and messy. So, 8‐membered ring lactams remain non achieved target even in the
presenceofadditives.
Scheme3.10AdditiveImpactontheCycloisomerizationof1tfor8‐memberringlactam.
133
3.3.3PyrogallolImpactuponInternalSubstrates
Theinfluenceofpyrogallol(1,2,3‐benzenetriol,chosenasthebestcompriseintermsofactivityand
solubility)was then extensively studiedon the cyclizationof substratesbearing internal alkynes
(Table3.10).
Table3.10Cycloisomerizationofsubstrates1m‐rbearinginternalalkynesbyIIIb.
Entrya
t (h) Yield (%)b
I
II
III
Substrate Productsexo/endo
5 min >99
exo/endo
V
t (h) Yield (%)b
IV
18 6
4 >99
36 38
24 90
1 >99OH
O 1m
OO OO
2mexo 2mendo
NHTsO 1n
NTsO
NTs
O
2nexo 2nendo
OHE
O
Et
1o
E = CO2Me
OO
EEt
EtOO
E
2oendo2oexo
NHTsE
O
Et
1p
E = CO2Me
NTsO
EEt
EtNTs
O
E
2pendo2pexo
1q
OH
O
Me
O
O
Me
2qexo
O
O2qendo
NHTs
O
Me
1r
NTs
O
Me
2rexo
NTs
O2rendo
VI
1/1.6
>1/99
1/4.9
>1/99
24/1
n.d.
Without additive With Pyrogallol
1/4.30.5 >99 (99)
1/245 min >99
>1/99<2 >99 (78)
32.3/16 >85c
2.1/118 >99 (91)
1/35 min >99
a)Catalytic reactions performed under argon atmosphere using 0.1 mmol of substrate (0.14 M in CDCl3), 5 mol% of Pt and 0 / 30 mol% of pyrogallol at 90°C. b)Yields were determined by 1H NMR analysis with mesitylene as internal standard. Isolated yields are given in brackets. c)15% of ethyl ketone side-product (5-oxo-heptynoic acid)
Accordingly, the addition of 30 mol% of pyrogallol was found to spectacularly speed up the
cyclizationof1n‐q(byupto12times,entriesI’‐IV’).Thecorrespondingδ‐lactonesandlactamsare
obtainedinhigh,oftenimprovedselectivitieswith5‐exo/6‐endoratiosrangingfrom1:3to>1:99.
134
TheH‐bonddonoradditivealsoprovedverybeneficialtothecyclizationof5‐alkynoicderivatives.
Thecarboxylicacid1rwasfullyconvertedinlessthan2h(entryV’)andtheδ‐lactoneZ‐2rexowas
obtainedwithexcellentselectivity(6‐exo/7‐endo32:1,onlytheZisomerisdetected).Onceagain,Pt
isremarkablymoreactivethanPd,IIIbachievingfullconversion30timesfasterthanVinthesame
conditions.19 In addition, cyclization occurs selectively, while 30% of the methyl ketone
correspondingtothehydrationof1rwasobservedwithV.Finally,asmentionedabove,theresult
obtainedwiththecorrespondingN‐tosylamide1sisevenmorestriking.Whilenoconversionwas
observedwithV,fullconversionisobservedin18hwithIIIbandpyrogallol.
Ptcomplex IIIbdemonstrates furtherenhancedperformanceespeciallyupon thesechallenging
substrates bearing internal alkynes. However, it still revealed its limitations upon cyclization of
substratesoflongerchain,targetingforlargerrings(≥8),aswellassomeinternalones.
135
3.4Conclusion
Insummary, thePtpincercomplex IIIbwas found tocompleteandoutperformtherelatedPd
complex III in the catalytic cycloisomerization of alkynoic acids and N‐tosyl alkynylamides. In
particular,Ptcomplexisveryefficientfortheformationof6and7‐memberedrings.Thereaction
rateandtheselectivityfor6‐endo(vs5‐exo)aswellas6‐exo(vs7‐endo)cyclizationsissignificantly
improvedbyusingpyrogallolasH‐bonddonoradditive.Forthefirsttime,alargevarietyofand‐
lactones/lactamscouldbepreparedwithhighselectivitiesandinverygoodyields.
TheseresultsemphasizetheuniquepropertiesofSCSindenediidepincercomplexesandextend
further their catalytic applications. Future work will seek to increase the non‐innocent of the
indenediidepincerligand,inordernotonlytoovercomelimitationsrevealedinthisworkbutalsoto
achieve activation ofmore challenging substrates as alcohols and alkenes, enlarging thereby the
scopeoftransformationsinwhichthesecomplexescanbeperformed.
Inaddition,thisefficientpreparationofε‐alkylidenelactonesgivesaccesstothepreparationof
substitutedε‐lactones,whicharetypicalmonomersfortheconstructionofbiodegradablepolyesters
viaringopeningpolymerization(ROP).Afterreadilyscalingupthereactiontomulti‐gram‐level,we
planinthenearfuturetotakeadvantageoftheε‐alkylidenelactonestopreparesuchmonomersvia
derivatizationof theexocyclicdoublebond,eitherbyhydrogenation,orbyaddition reaction like
thiol‐enereaction.Subsequentpolymerizationoftheselactoneswithε‐caprolactonewillleadtothe
preparationofpolyestersofmodulatedproperties,thankstotheintroductionofthelateralfunctional
groupalongthepolymerchain.
136
3.5ExperimentPart
Allreactionsandmanipulationswerecarriedoutunderanatmosphereofdryargonusing
standardSchlenktechniques.Dryoxygen–freesolventswereemployed.Allorganicreagents,
includingsubstrates1a,c,e,wereobtainedfromcommercialsources.Substrates1b,1d,1f,
1i, 1m‐o and 1q were prepared following the literature procedures.S1‐3 31P, 1H and 13C
spectrawererecordedonBrukerAvance300,400and500.Chemicalshiftsareexpressed
withapositivesign,inpartspermillion,relativetoexternal85%H3PO4andMe4Si.Unless
otherwisestated,NMRspectrawererecordedat293K.
3.5.1SynthesisofComplexesII‐IV
Synthesisof {PtCl[(Ph2P=S)2(C9H5)]} (IIa):1,3‐(Ph2P=S)2(C9H6) (440mg, 1.2 equiv.,0.8
mmol)and[Pt(CH2CH2)2Cl2](214mg,0.5equiv.,0.36mmol)weresuspendedin15mLof
tolueneandstirredat100°Cfor20hrs.Awhiteyellowishprecipitateappeared,theyellow
mother‐liquorwasdiscardedandthewhiteyellowishprecipitatewaswashedwithdiethyl
ether(2x20mL).Afterdryingundervacuumthecomplexwasobtainedasawhiteyellow
powder (480 mg, yield 85%). M.p. 345.0 – 345.9 °C. 31P{1H}–NMR (CDCl3 +
DMSO‐d6):δppm56.8(s,satellitesJPPt=81.0Hz)and52.0(s,slightlybroad).1H{31P}–NMR
(CDCl3+DMSO‐d6):δppm7.88–7.02(m,24H,Ph,H5,H6,H8,H7),4.96(s,1H,H1).1H–NMR
(CDCl3+DMSO‐d6):δppm7.88–7.02(m,24H,Ph,H5,H6,H8,H7),4.96(dd,2JHP=25.0Hz,4JHP
=5.0Hz,1H,H1).13C{1H}–NMR(CDCl3+DMSO‐d6):δppm171.2(dd,2JCP=27.6Hz,2JCP=6.3
Hz,C2),147.2(dd,2JCP=17.6Hz,3JCP=5.0Hz,C4),138.8(dd,2JCP=6.3Hz,3JCP=2.5Hz,C9),
138.2(dd,1JCP=108.1Hz,3JCP=7.5Hz,C3),133.9,133.3,132.9,132.6,132.5,131.5,131.4,
129.8,129.7,129.2,129.0,(s,Ph),128.1(s,C6),127.0,126.4,125.4,125.0(s,Ph),124.1(s,
C7),123.6(s,C5),118.1(s,C8),70.2(dd,1JCP=55.3Hz,3JCP=16.3Hz,C1).MS(ESI):m/z[M]+
Calcd:777.0,Found:777.0.AnalCalcdforC33H25ClP2PtS2:C,50.93;H,3.24;S,8.24.Found:
C,50.84;H,2.96.
137
Synthesisof {PtCl[(iPr2P=S)2(C9H5)]} (IIb):1,3‐(iPr2P=S)2(C9H6) (590mg, 1.2 equiv.,1.4
mmol) and [Pt(CH2CH2)2Cl2] (350mg, 0.5 equiv.,0.6mmol)were suspended in 15mLof
toluene and was stirred at 100°C for 20 hrs. A brown precipitate appeared, the red
mother‐liquorwasdiscardedandthebrownprecipitatewaswashedwithdiethylether(2x
20mL).Afterdryingundervacuumthecomplexwasobtainedasabrownpowder(660mg,
yield 85%). The precipitatewas recrystallized by slow diffusion of CH2Cl2/diethyl ether
affording yellow crystals suitable for X‐ray diffraction analysis.M.p. 205.4 – 209.8 °C.
31P{1H}–NMR (CD2Cl2):δppm85.9 (s, satellites, JPPt=66.8Hz)and84.9 (s, slightlybroad).
1H{31P}–NMR(CD2Cl2):δppm7.32(d,3JHH=6.0Hz,1H,H5),7.20(m,2H,H6,H8),7.10(t,3JHH
=6.0,1H,H7),4.05(s,1H,H1),2.87(sep,3JHH=6.0Hz,1H,CH(CH3)2),2.61(m,2H,CH(CH3)2),
2.04(sep,3JHH=6.0Hz,1H,CH(CH3)2),1.54(d,3JHH=6.0Hz,3H,CH(CH3)2),1.39(d,3JHH=6.0
Hz,3H,CH(CH3)2),1.35(d,3JHH=6.0Hz,3H,CH(CH3)2),1.22(m,6H,CH(CH3)2),1.11(d,3JHH
= 6.0Hz, 3H, CH(CH3)2), 0.99 (d, 3JHH= 6.0Hz, 3H, CH(CH3)2), 0.95 (d, 3JHH= 6.0Hz, 3H,
CH(CH3)2).1H–NMR(CDCl3):δppm7.43(m,1H,H5),7.34(m,2H,H6,H8),7.22(m,1H,H7),
4.17(d,2JHP=25.0Hz,1H,H1),2.97(m,1HCH(CH3)2),2.75(m,2HCH(CH3)2),2.16(m,1H
CH(CH3)2),1.67(dd,3JHP=15.0Hz,4JHP=5.0Hz3H,CH(CH3)2),1.49(m,6H,CH(CH3)2),1.35
(m, 6H, CH(CH3)2), 1.16 (dd, 3JHP = 15.0 Hz, 3JHH = 5.0 Hz, 3H, CH(CH3)2), 1.09 (m, 6H,
CH(CH3)2).13C{1H,31P}–NMR(CDCl3):δppm176.6(s,satellitesJCPt=1040Hz,C2),147.1(s,
satellitesJCPt=71.7Hz,C4),138.7(s,satellitesJCPt=42.8Hz,C3),133.3(s,satellitesJCPt=
147.1Hz,C9),128.8(s,C6),124.4(s,C7),123.4(s,C5),118.6(s,C8),67.6(s,satellitesJCPt=
154.7HzC1),28.0(s,CH(CH3)2),27.7(s,CH(CH3)2),26.2(s,satellitesJCPt=20.1Hz,CH(CH3)2),
24.0 (s, satellites JCPt=32.7Hz,CH(CH3)2),17.6 (s,CH(CH3)2),17.2 (s,CH(CH3)2),17.1 (s,
CH(CH3)2),17.0(s,CH(CH3)2),16.8(s,CH(CH3)2),16.6(s,CH(CH3)2),16.1(s,CH(CH3)2),16.0
(s, CH(CH3)2). MS (ESI): m/z [M – Cl]+ Calcd: 606.1, Found: 606.1. Anal Calcd for
C21H33P2PtS2:C,39.28;H,5.18.Found:C,39.18;H,4.91.
138
Synthesis of the trimeric complex {Pt[(Ph2P=S)2(C9H4)]}3 (IIIa): A suspension of
{PtCl[(Ph2P=S)2(C9H5)]}(200mg,1equiv.,0.25mmol)andsodiumacetate(84mg,4equiv.,
1.00mmol)in10mLofCHCl3wasstirredat90°Cfor12hrs.Theoriginalcolourlesssolution
becomesyellowwithabundantyellowprecipitate.Thereactionmixturewasconcentrated
byslowevaporation.Thecomplexprecipitates fromthemother‐liquorasyellowcrystals
suitableforX‐raydiffractionanalysis.Theprecipitatewasrecoveredfromthemother‐liquor
andwashedwithmethanol(144mg,yield78%).M.p.(decomposition)320°C.31P{1H}–NMR
(CD2Cl2):δppm46.1(d,broad,J=6.0),42.8(s,broad),38.4(s,broad),29.4(d,broad,J=4.9).
1H–NMR (CD2Cl2):δppm7.87(m,broad,4H,Ph),7.66–7.20(m,broad,16H,Ph),6.81(m,
broad,2H,H8andH5),6.53(m,2H,H7andH6).MS(ESI):m/z[M3]+Calcd:2225.2,Found:
2252.2,[M2]+Calcd:1484.1,Found:1484.1,[M]+Calcd:742.1,Found:742.1.AnalCalcdfor
C99H72P6Pt3S6:C,53.44;H,3.26;S,8.65.Found:C,51.23;H,3.29,S,7.91.
139
Synthesis of the dimeric complex {Pt[(iPr2P=S)2(C9H4)]}2 (IIIb): A suspension of
{PtCl[(iPr2P=S)2(C9H5)]}(200mg,1equiv.,0.31mmol)andsodiumacetate(102mg,4equiv.,
1.24mmol)in10mLoftoluenewasstirredat90°Cfor1hrs.Theoriginalcolourlesssolution
becomes yellow; the reaction mixture was poured over a pad of celite and eluted with
tolueneaffordingayellowfraction.Thisfractionwascollectedandevaporateduntildryness.
Theresiduewasprecipitatedwith15mLofpentanerenderingthepuredimmerlikeayellow
powder(165mg,yield87%).M.p.292.2–294.0°C.31P{1H}–NMR(CDCl3):δppm79.8and
68.9(s,satellites JPPt=47.0).1H{31P}–NMR(CDCl3):δppm7.38(m,broad,1H,H8andH5),
7.31(m,broad,1H,H5),6.88(m,2H,H7andH6),3.10(sept,3JHH=5.0Hz,2H,CH(CH3)2),
2.69(sept,3JHH=5.0Hz,2H,CH(CH3)2),1.57(d,3JHH=5.0Hz,6H,CH(CH3)2),1.35(d,3JHH=5.0
Hz,6H,CH(CH3)2),1.32(d,3JHH=5.0Hz,6H,CH(CH3)2),1.26(d,3JHH=5.0Hz,6H,CH(CH3)2).
1H–NMR(CDCl3):δppm7.38(m,broad,1H,H8),7.32(m,broad,1H,H5),6.88(m,2H,H7and
H6),3.10(dddd,2JHP=20.0,3JHH=5.0Hz,2H,CH(CH3)2),2.69(dddd,2JHP=20.0,3JHH=5.0Hz,
2H,CH(CH3)2),1.57(dd,3JHP=20.0Hz,3JHH=5.0Hz,6H,CH(CH3)2),1.34(m,12H,CH(CH3)2),
1.26(dd,3JHP=20.0Hz,3JHH=5.0Hz,6H,CH(CH3)2).13C{1H,31P}–NMR(CD2Cl2):δppm160.5
(s,C2),138.2(s,C4),137.8(s,C9),117.3(s,C8),117.3(s,C5),117.2(s,C7),116.6(s,C6),
97.8(s,C3),92.4(s,C1),27.6,and26.4(s,broad,CH(CH3)2),17.15,17.1,16.6and16.3(s,
CH(CH3)2).MS(ESI):m/z[M2]+Calcd:1211.2,Found:1211.2.AnalCalcdforC42H64P4Pt2S4:
C,41.58;H,5.48.Found:C,42.30;H,5.23.
140
Synthesisof[N(n‐Bu)4]{PtCl[(Ph2P=S)2(C9H4)]}(IVa):{PtCl[(Ph2P=S)2(C9H5)]}(440mg,
1.0equiv.,0.56mmol),PS‐DIEA(376mg,2equiv.,1.13mmol)and[N(n‐Bu)4]Cl(188mg,1.2
equiv.,0.67mmol)weresuspendedin15mLofCH2Cl2andstirredatroomtemperaturefor
20hrs.Theoriginalcolorlesssolutionbecomesyellow,thereactionmixturewasfiltratedvia
cannula,andthemother‐liquorwasconcentratedatc.a.4mL.Undervigorousstirringwere
added60mLofdiethylether.Ayellowprecipitateappears.Themother‐liquorwasdiscarded
andtheprecipitatewasdriedundervacuumyieldingayellowpowder(506mg,yield88%).
TheprecipitatewasrecrystallizedbyslowdiffusionofCH2Cl2/diethyletheraffordingyellow
crystalssuitableforX‐raydiffractionanalysis.M.p.260.2–263.9°C.31P{1H}–NMR(CD2Cl2):
δppm 45.9 (s, satellites JPPt = 45.0 Hz).
1H–NMR(CD2Cl2):δppm7.89(m,8H,Ph),7.48(m,12H,Ph),7.10(m,2H,H8andH5),6.10(m,
2H,H7andH6),3.16(m,8H,(CH2)3CH3),1.48(m,8H,(CH2)3CH3),1.30(sex,3JHH=6.0Hz,8H,
(CH2)3CH3),0.86(t,3JHH=6.0Hz,12H,(CH2)3CH3).13C{1H}–NMR(CD2Cl2):δppm158.2(t,2JCP
=58.0Hz,C2),139.2(t,2JCP=31.7Hz,C4andC9),134.5(s,Ph),133.4(s,Ph),132.0(m,Ph),
131.2(s,Ph),128.4,(m,Ph),117.3(s,C8andC5),115.8(s,C7andC6),102.2(dd,1JCP=129.8
Hz,3JCP=16.6Hz,C3andC1),58.7(s,(CH2)3CH3),24.0(s,(CH2)3CH3),19.6(s,(CH2)3CH3),
13.4(s,(CH2)3CH3).MS(ESI):m/z[M–N(n‐Bu)4]‐Calcd:777.0,Found:777.0.AnalCalcd
forC49H60ClNP2PtS2:C,57.72;H,5.93;N,1.37.Found:C,57.45;H,5.49;N,1.24.
141
Synthesis of [N(n‐Bu)4]{PtCl[(iPr2P=S)2(C9H4)]} (IVb): A solution of
{PdCl[(iPr2P=S)2(C9H5)]}(200mg,1.0equiv.,0.31mmol),potassiumtert‐butoxide(35mg,
1.0equiv.,0.31mmol),PS‐DIEA(103mg,1.0eq,0.31mmol)and[N(n‐Bu)4]Cl(104mg,1.2
equiv., 0.37mmol) in 10mL of CH2Cl2was stirred at room temperature for 20 hrs. The
originalclearbrownsolutionbecomesdarkbrown,thereactionmixturewasfiltratedvia
cannula,andthemother‐liquorwasconcentratedatc.a.3mL.Undervigorousstirringwere
added60mLofdiethylether.Abrownprecipitateappears.Themother‐liquorwasdiscarded
andtheprecipitatewasdriedundervacuumyieldingabrownpowder(230mg,yield84%).
TheprecipitatewasrecrystallizedbyslowdiffusionofCH2Cl2/diethyletheraffordingbrown
crystals.Insolution,atroomtemperaturethenewcomplexisinequilibriumwiththedimeric
specie.Thisequilibriumslowlyshiftstothedimericspecies(monomer/dimer1.0:3.0after
20h).M.p.210.6–215.4°C.31P{1H}–NMR(CDCl3):δppm75.4(s).1H{31P}–NMR(CDCl3):δppm
7.27(m,broad,2H,H8andH5),6.71(m,broad,2H,H7andH6),3.40(m,8H,(CH2)3CH3),
2.60 (sep, 3JHH = 10.0, 4H, CH(CH3)2), 1.67 (m, 8H, (CH2)3CH3), 1.53 (d, 3JHH = 10.0, 3H,
CH(CH3)2),1.43(sex,3JHH=10.0Hz,8H,(CH2)3CH3),1.30(d,3JHH=10.0Hz,3H,CH(CH3)2),
1.27(d,3JHH=10.0Hz,3H,CH(CH3)2),1.23(d,3JHH=10.0Hz,6H,CH(CH3)2),1.23(d,3JHH=
10.0Hz,3H,CH(CH3)2),1.19(d,3JHH=10.0Hz,6H,CH(CH3)2),0.95(t,3JHH=10.0Hz,12H,
(CH2)3CH3).1H–NMR(CDCl3):δppm7.27(m,2H,H8andH5),6.74(m,2H,H7andH6),3.40
(m, 8H, (CH2)3CH3), 2.58 (dddd, 2JHP = 25.0, 3JHH = 10.0 Hz, 4H, CH(CH3)2), 1.67 (m, 8H,
(CH2)3CH3),1.43(sex,3JHH=10.0Hz,8H,(CH2)3CH3),1.31(dd,3JHP=20.0Hz,3JHH=10.0Hz,
12H,CH(CH3)2),1.22(dd,3JHP=20.0Hz,3JHH=10.0Hz,12H,CH(CH3)2),0.96(t,3JHH=10.0Hz,
12H,(CH2)3CH3).13C{1H,31P}–NMR(CDCl3):δppm159.4(s,C2),138.4(s,C4andC9),115.9(s,
C8andC5),115.5(s,C7andC6),97.5(s,C3andC1),58.9(s,(CH2)3CH3),27.8(s,CH(CH3)2),
24.3 (s, (CH2)3CH3), 19.8 (s, (CH2)3CH3), 17.3 (s, CH(CH3)2), 16.4 (s, CH(CH3)2), 13.8 (s,
(CH2)3CH3).MS(ESI):m/z[M]+Calcd:884.4,Found:884.4,[M–Cl–N(n‐Bu)4]+Calcd:606.1,
Found:606.1.AnalCalcdforC37H68ClNP2PdS2:C,50.30;H,7.76;N,1.59.Found:C,49.83;H,
7.74;N,1.56.
142
3.5.2SynthesisofAmideandAcidSubstrates
Dibenzyl2‐(pent‐4‐yn‐1‐yl)malonate.Dibenzylmalonate(5.72g,1.2equiv.,20.0mmol)
wasaddeddropwisetoasuspensionofNaH(0.60g,1.5equiv.,25.1mmol)inTHF(40mL)
at 0°C. The suspentionwas stirred at room temperature for 30minutes and then under
vigorous stirring the 4‐pentyn‐1‐yl tosylate (4.00 g, 1 equiv., 16.0mmol), KI (1.67 g, 0.6
equiv.,10.0mmol)andDMF(40mL)wereadded.Thereactionmixturewasheated100°C
andafterwardsquenchedwithsaturatedNH4Cl(aq)(40mL)andextractedwithdiethylether
(3x50mL).Thecombinedorganicextractswerewashedwithbrine(2x50mL)driedwith
MgSO4,concentratedunderreducepressureandpurifiedbyflashcolumnchromatography
(petroleumether/ethylacetate95:5)toaffordacolorlessoil(3.86g,yield69%).1H–NMR
(CDCl3):δppm7.37(m,10H,OCH2Ph),5.22(s,4H,CH2OPh),3.54(t,3JHH=6.0Hz,1H,CHR3),
2.25(td,2H,3JHH=6.0Hz,3JHH=3.0Hz,2H,CH2),2.13(m,2H,CH2),2.01(t,3JHH=3Hz,C≡CH),
1.61(m,2H,CH2).13C{1H}–NMR(CDCl3):δppm168.9(C2),135.4(C4),128.6(C5,C5’),128.4
(C7),128.2(C6,C6’),83.4(C11),69.1(C12),67.2(C3),51.6(C1),27.8(C8),26.1(C10),18.2
(C9).
143
2‐((benzyloxy)carbonyl)hept‐6‐ynoic acid (1g).KOH (249mg, 4.45mmol) was dried
undervacuumheatingseveralminuteswithheatgun.Theresiduewassuspendedin10mL
of benzyl alcohol and added to a stirred solution of dibenzyl 2‐(pent‐4‐yn‐1‐yl)malonate
(1.30g,3.71mmol) in5mLofbenzylalcohol.Thereactionmixturewasstirredat room
temperaturefor48handextractedwithwater(3x15mL).Theorganiclayerwasdiscarded;
to the combined aqueous layer was added dichloromethane (20 mL) and the pH was
adjustedto2–3withaqueousHCl(2M).Afterextractingwithdichloromethane(3x20mL)
thecollectedorganiclayersweredried(MgSO4)andconcentratedunderreducepressure.
The residuewas dried a room temperature in high vacuum (3 x 10‐5mbar) in order to
remove residual benzyl alcohol. The final residue was purified by flash column
chromatography(CH2Cl2/MeOH95:5) toprovide1gasapalecolorlessoil (410mg,yield
35%).1H–NMR (CDCl3):δppm10.32(s,broad,1H,OH),7.37(m,5H,OCH2Ph),5.23(s,2H,
CH2OPh),3.50(t,3JHH=6.0Hz,1H,CHR3),2.24(td,2H,3JHH=6.0Hz,3JHH=3.0Hz,2H,CH2),
2.09(m,2H,CH2),1.98(t,3JHH=3Hz,C≡CH),1.60(m,2H,CH2).13C{1H}–NMR(CDCl3):δppm
174.5(C1),168.9(C3),135.2(C5),128.7(C6,C6’),128.5(C8),128.2(C7,C7’),83.2(C12),
69.1(C13),67.5(C4),51.2(C2),27.9(C9),25.9(C11),18.1(C10).HRMS(ESI):m/zcalcdfor
[M+H](C15H15O4)Calcd:259.0970,Found:259.0973.
144
2‐((prop‐2‐yn‐1‐yloxy)carbonyl)benzoic acid (1l).Procedure inspired by thework of
Breitetal,withpropargylalcoholasthereactant.Afterovernightreaction,theproductwas
cleanlyisolatedbyprecipitationfromDCMandPentane.Theamidewasisolatedasawhite
solidingoodyield(2.08g;72%).1H–NMR(CDCl3):δppm11.62(s,1H,OH),7.99(m,1H,Ph),
7.73(m,1H,Ph),7.64(m,2H,Ph),4.97(d,2H,JHH=2.4Hz,CH2C≡CH),2.59(t,1H,JHH=2.5
Hz,C≡CH).13C{1H}–NMR(CDCl3):δppm172.3(C1),167.4(C4),132.9(C3),132.5(C9),131.1
(C10),130.0(C8),129.7(C2),128.7(C11),76.9(C7),75.6(C6),53.3(C5).HRMS(ESI):m/z
calcdfor[M+H](C11H9O4)Calcd:205.0501,Found:205.0508.
Ethyl2‐(tosylcarbamoyl)hept‐6‐ynoate (1h).Thisproductwasprepared following the
procedure described in the literature. The productwas cleanly isolated by flash column
chromatographywithEthyl acetate andPentane (v/v,1/3).Theamidewas isolatedasa
whitesolidingoodyield(0.42g;54%).1H–NMR(CDCl3):δppm9.61(s,broad,1H,NHTs),7.96
(d,2H,Ph),7.35(d,2H,Ph),4.20(m,2H,CH3CH2O),3.26(t,1H,CH),2.45(s,3H,PhCH3),2.03
(m,2H,CH2C≡CH),1.98(m,2H,CHCH2),1.97(t,1H,C≡CH),1.47(m,2H,CHCH2CH2),1.26(t,
3H,CH2CH3).13C{1H}–NMR (CDCl3):δppm170.9(C3),166.0(C5),145.2(C14),135.3(C11),
129.6(C13,C13’),128.5(C12,C12’),83.0(C9),69.2(C10),62.4(C2),52.4(C4),29.5(C6),
25.5(C7),21.7(C15),17.9(C8),14.0(C1).HRMS(ESI):m/zcalcdfor[M+H](C17H22NO5S)
Calcd:352.1219,Found:352.1215.
145
2‐(but‐3‐yn‐1‐yl)‐N‐tosylbenzamide (1j): This product was prepared following the
procedure described in the literature. The productwas cleanly isolated by flash column
chromatographywithEthylacetateandPentane(v/v,1/4).Theamidewasisolatedasalight
yellowsolidingoodyield(0.11g;73%).1H–NMR(CDCl3):δppm8.89(s,1H,NHTs),8.03(d,
2H,JHH=8.4Hz,PhCH3),7.43(m,2H,Ph),7.38(d,2H,JHH=8.6Hz,PhCH3),7.31(m,1H,Ph),
7.26(m,1H,Ph),2.86(t,2H,JHH=7.2Hz,PhCH2),2.47(s,3H,PhCH3),2.39(m,2H,CH2C≡CH),
1.96 (t, 1H, JHH=2.6Hz,CH2C≡CH). 13C{1H}–NMR (CDCl3): δppm 166.2 (C1), 145.3 (C15),
139.8(C3),135.5(C12),132.5(C2),131.8(C10),131.2(C11),129.7(C14,C14’),128.5(C13,
C13’),127.5(C8),126.8(C9),83.6(C6),69.8(C7),31.6(C4),21.7(C16),20.3(C5).HRMS
(ESI):m/zcalcdfor[M+H](C18H18NO3S)Calcd:328.1007,Found:328.0991.
Prop‐2‐yn‐1‐yl2‐(tosylcarbamoyl)benzoate(1m):Thisproductwaspreparedfollowing
theproceduredescribedintheliterature.Theproductwascleanlyisolatedbyflashcolumn
chromatographywithEthyl acetate andPentane (v/v,1/2).Theamidewas isolatedasa
whitesolidingoodyield(0.80g;56%).1H–NMR(CDCl3):δppm9.27(s,broad,1H,NHTs),7.96
(d,2H,PhCH3),7.35(d,2H,PhCH3),7.88(d,1H,Ph),7.51(m,3H,Ph),4.62(d,2H,CH2C≡CH),
2.50(t,1H,C≡CH),2.46(s,3H,PhCH3).13C{1H}–NMR(CDCl3):δppm166.2(C1),165.1(C4),
145.1(C15),135.3(C12),135.2(C3),132.7(C10),130.9(C9),130.5(C11),129.5(C14,C14’),
128.7(C13,C13’),128.1(C8),128.0(C2),77.2(C6),75.5(C7),52.9(C5),21.7(C16).
146
HN
O
S
O
O
O
O1234
56
7 89
10
1112
13 141112
Methyl2‐(tosylcarbamoyl)hept‐4‐ynoate(1q):Thisproductwaspreparedfollowingthe
procedure described in the literature. The productwas cleanly isolated by flash column
chromatographywithEthyl acetate andPentane (v/v,1/4).Theamidewas isolatedasa
whitesolidingoodyield(0.53g;55%).1H–NMR(CDCl3):δppm9.60(s,1H,NHTs),7.95(d,
2H,Ph),7.32(d,2H,Ph),3.73(s,3H,OCH3),3.40(t,1H,CH),2.70(m,2H,CHCH2),2.43(s,3H,
PhCH3),2.08(m,2H,CH2CH3),1.05(t,3H,CH2CH3).13C{1H}–NMR(CDCl3):δppm169.6(C3),
165.3(C1),145.3(C13),135.4(C10),129.6(C12,C12’),128.6(C11,C11’),86.0(C7),73.8
(C6),53.2(C4),51.9(C2),21.8(C14),19.7(C5),14.0(C9),12.4(C8).HRMS(ESI):m/zcalcd
for[M+H](C16H20NO5S)Calcd:338.1062,Found:338.1063.
N‐tosylhept‐5‐ynamide (1s): This product was prepared following the procedure
described in the literature. The product was cleanly isolated by flash column
chromatographywithEthyl acetate andPentane (v/v,1/3).Theamidewas isolatedasa
whitesolidinexcellentyield(0.98g;89%).1H–NMR(CDCl3):δppm9.10(s,broad,1H,NHTs),
7.96 (d, 2H,Ph), 7.35 (d, 2H,Ph), 2.45 (s, 3H, PhCH3), 2.40 (t, 2H, CH2CO), 2.11 (m, 2H,
CH2C≡C),1.73(m,5H,CH2CH2COandC≡CCH3).13C{1H}–NMR(CDCl3):δppm170.9(C1),145.2
(C11),135.6(C8),129.7(C10,C10’),128.3(C9,C9’),77.6(C5),77.0(C6),34.9(C2),23.4(C3),
21.7 (C12), 17.9 (C5), 3.4 (C7).HRMS (ESI):m/z calcd for [M+H] (C16H20NO5S) Calcd:
280.1007,Found:280.1009.
147
3.5.3CatalysisforLactamsandLactones
7-Methylene-oxepan-2-one8 (2e): In a sealed Schlenk under stirring was performed the catalysis
in a bigger scale (252 mg of heptynoic acid in 4 mL of CDCl3). The reaction mixture was dropped
in a round Schlenk and the solvent removed under vacuum, to the flask was adapted a cold finger
and the residue was distillated under vacuum (10-3 mPa). At RT the lactone slowly volatizes but it
condenses in the cold finger faster when it is cold down with liquid nitrogen. Once the cold finger
is saturated the cold finger was rinsed with CH2Cl2 in order to recover the pure lactone 2e. This
procedure was repeated two times more and were recovered 221 mg of 1e (84%). 1H–NMR
(CDCl3): δppm 4.75 and 4.64 (m, 2H, C=CH2), 2.54 (m, 2H, CH2), 2.30 (m, 2H, CH2), 1.74 (m, 2H,
CH2). 13C{1H}–NMR (CDCl3): δppm 172.6 (C7), 157.6 (C2), 102.2 (C1), 33.65 (C6), 32.6 (C3),
29.0 (C5), 22.9 (C4). HRMS (CH4-Ionization) calcd for [7f+1H](C7H11O2): 127.0759; found:
127.0759. Anal Calcd for C7H10O2: C, 66.65; H, 7.99. Found: C, 66.93; H, 7.94.
benzyl 7-methylene-2-oxooxepane-3-carboxylate (2g). The reaction mixture was dried under
vacuum and the residue purified in PLC (Silica gel, 60-F254, Pentane/AcOEt 80:20, rf. 0.4). Cat
0.5 M, 130 mg of alkynoic acid, were recovered 75 mg of the lactone 2g as a colorless oil (yield
58%). The lactone also can be purified by distillation and condensation in a cold finger (40°C, 10-
5 mPa). 1H–NMR (CDCl3): δppm 7.27 (m, 5H, OCH2Ph), 5.11 (s, 2H, CH2OPh), 4.75 (m, 1H,
C=CH2), 4.63 (m, 1H, C=CH2), 3.71 and 3.70 (d, 1H, 3JHH = 9.6 Hz, 1H, R3CH), 2.41 (m, 1H,
CH2), 2.17 – 1.87 (m, 4H, CH2CH2), 1.59 (m, 1H, CH2). 13C{1H}–NMR (CDCl3): δppm 168.7 (C3),
168.5 (C5), 156.7 (C2), 135.3 (C7), 128.6 and 128.5 (Ph), 103.7 (C1), 67.5 (C6), 49.7 (C4), 32.2
(C8), 26.8 (C10), 25.7 (C9). HRMS (ESI): m/z calcd for [M+H] (C15H17O4) Calcd: 261.113,
Found: 261.1119. Anal Calcd for C15H16O4: C, 69.22; H, 6.20. Found: C, 69.14; H, 6.02.
148
GeneralProcedureofthecycloisomerizationofN‐tosylalkynylamides:InaNMRpressure
tube,thedriedcorrespondingsubstrate(0.1M)andcomplexIIIb(5mol%[Pt])in0.7mLof
CDCl3washeatedatthecorrespondingtemperature,underargonatmosphere.Theprogress
ofthereactionwasmonitoredbothby1HNMRand31PNMR.Afterevaporation,theresidue
waspurifiedbyflashcolumnchromatographytoaffordthecorrespondinglactones/lactams
ingoodtoexcellentyields.
Ethyl 7‐methylene‐2‐oxo‐1‐tosylazepane‐3‐carboxylate (2h). After complete
conversion, theproductwascleanly isolatedby flashcolumnchromatographywithEthyl
acetateandPentane(v/v,1/6).Thelactamwasisolatedasawhitesolidingoodyield(72
mg;70%).1H–NMR(CDCl3):δppm7.94(d,2H,Ph),7.33(d,2H,Ph),5.52(s,1H,C=CH2),5.40
(s,1H,C=CH2),4.15 (m,2H,CH2CH3),3.71 (m,1H,CH),2.45 (s,3H,PhCH3),2.44 (m,2H,
CH2C=CH2),1.95(m,2H,CHCH2),1.77(m,2H,CHCH2CH2),1.23(t,3H,CH2CH3). 13C{1H}–
NMR(CDCl3):δppm168.8(C3),168.7(C5),145.2(C14),142.9(C9),135.9(C11),129.6(C13,
C13’),129.1(C12,C12’),121.1(C10),61.7(C2),52.4(C4),34.4(C8),27.1(C7),25.6(C6),
21.8(C15),14.1(C1). HRMS(ESI):m/zcalcdfor[M+H](C17H22NO5S)Calcd:352.1219,
Found:352.1223.
149
3‐methylene‐2‐tosyl‐2,3,4,5‐tetrahydro‐1H‐benzo[c]azepin‐1‐one(2k).Aftercomplete
conversion, theproductwascleanly isolatedby flashcolumnchromatographywithEthyl
acetateandPentane(v/v,1/4).Thelactamwasisolatedasawhitesolidingoodyield(26
mg;80%).1H–NMR(CDCl3):δppm8.10(d,2H,JHH=8.4Hz,PhCH3),7.65(m,1H,Ph),7.41(m,
1H,Ph),7.38(m,2H,PhCH3),7.29(m,1H,Ph),7.14(m,1H,Ph),5.15(s,1H,C=CH2),5.10(s,
1H,C=CH2),2.95(s,4H,CH2CH2),2.47(s,3H,PhCH3).13C{1H}–NMR(CDCl3):δppm168.2(C1),
145.1(C15),141.9(C6),138.8(C2),136.0(C12),133.4(C3),132.5(C9),129.8(C8),129.5
(C14,C14’),129.2(C13,C13’),128.9(C11),127.3(C10),120.5(C7),37.9(C5),30.1(C4),21.7
(C16)HRMS(ESI):m/zcalcdfor[M+H](C18H18NO3S)Calcd:328.1007,Found:328.1000.
3‐methylene‐3,4‐dihydrobenzo[f][1,4]dioxocine‐1,6‐dione (2l). After complete
conversion, theproductwascleanly isolatedby flashcolumnchromatographywithEthyl
acetateandPentane(v/v,1/9).Thelactonewasisolatedasacolorlessoilinmoderateyield
(44mg;43%).1H–NMR(CDCl3):δppm7.92(m,1H,Ph),7.75(m,3H,Ph),4.92(m,2H,CH2),
4.69(m,1H,C=CH2),4.30(m,1H,C=CH2).13C{1H}–NMR(CDCl3):δppm165.3(C1),153.6(C4),
140.5(C2),134.9(C9),132.4(C11),128.4(C3),125.3(C8),124.3(C6),123.4(C10),82.6(C7),
67.5(C5).HRMS(ESI):m/zcalcdfor[M+H](C11H9O4)Calcd:205.0501,Found:205.0490.
150
4‐methylene‐2'‐tosylspiro[[1,3]dioxolane‐2,1'‐isoindolin]‐3'‐one (2m‐N‐spiro) and
5'‐methylene‐3'‐tosyl‐3H‐spiro[isobenzofuran‐1,2'‐oxazolidin]‐3‐one (2m‐O‐spiro).
After complete conversion, the mixture products were isolated by flash column
chromatography firstly with Ethyl acetate and Pentane (v/v, 1/9), and followed by
separationofpre‐HPLC.Theproductswereisolatedaswhitesolidsinexcellenttotalyield
(2l‐N,135mg,71%;2l‐O,29mg,15%).
2m‐N‐spiro:1H–NMR(CDCl3):δppm8.02(d,2H,JHH=8.4Hz,PhCH3),7.67(m,2H,Ph),7.50
(m,2H,Ph),7.30(d,2H,JHH=8.1Hz,PhCH3),5.29(dt,1H,JHH=11.3Hz,JHH=2.1Hz,CH2),
4.93(dt,1H,JHH=11.3Hz,JHH=1.8Hz,CH2),4.65(q,1H,JHH=2.3Hz,C=CH2),4.24(m,1H,
C=CH2),2.39(s,3H,PhCH3).13C{1H}–NMR(CDCl3):δppm163.8(C1),155.1(C6),145.2(C15),
142.5(C3),136.1(C12),135.1(C10),131.6(C9),129.5(C14,C14’),128.6(C13,C13’),127.5
(C2),124.1(C8),122.3(C11),118.4(C4),80.7(C7),69.4(C5),21.7(C16).HRMS(ESI):m/z
calcdfor[M+H](C18H16NO5S)Calcd:358.0749,Found:358.0742.
2m‐O‐spiro:1H–NMR(CDCl3):δppm7.93(d,1H,JHH=7.4Hz,Ph),7.78(m,1H,Ph),7.69(m,
2H,Ph),7.64(d,2H,JHH=8.4Hz,PhCH3),7.35(d,2H,JHH=8.0Hz,PhCH3),4.59(m,1H,C=CH2),
4.53(dt,1H,JHH=12.4Hz,JHH=1.7Hz,CH2),4.24(m,1H,C=CH2),4.18(dt,1H,JHH=12.4Hz,
JHH=2.2Hz,CH2),2.45(s,3H,PhCH3).13C{1H}–NMR(CDCl3):δppm165.7(C1),151.9(C6),
145.2(C15),143.2(C3),135.1(C10),133.5(C12),132.0(C9),129.9(C14,C14’),128.5(C13,
C13’),127.2(C2),125.3(C8),123.6(C11),114.7(C4),85.3(C7),48.2(C5),21.7(C16).HRMS
(ESI):m/zcalcdfor[M+H](C18H16NO5S)Calcd:358.0749,Found:358.0750.
151
Methyl6‐ethyl‐2‐oxo‐1‐tosyl‐1,2,3,4‐tetrahydropyridine‐3‐carboxylate(2qendo).After
completeconversion,theproductwascleanlyisolatedbyflashcolumnchromatographywith
DCMonly.Thelactamwasisolatedasawhitesolidingoodyield(52mg;78%).
1H–NMR(CDCl3):δppm7.96(d,2H,JHH=8.4Hz,Ph),7.33(d,2H,JHH=8.6Hz,Ph),5.60(t,1H,
JHH=6.1Hz,CH2CH=C),3.69(s,3H,OCH3),3.40(t,1H,JHH=6.4Hz,COCHCO),2.74(m,1H,
CH2CH3),2.61 (m,1H,CH2CH=C),2.55 (m,1H,CH2CH3),2.44 (s,3H,PhCH3),2.36 (m,1H,
CH2CH=C),1.03(t,3H,JHH=7.4Hz,CH2CH3)13C{1H}–NMR(CDCl3):δppm168.7(C1),168.4
(C8),145.1(C13),144.0(C5),136.8(C10),129.5(C12,C12’),128.5(C11,C11’),113.2(C4),
52.8(C9),51.7(C2),27.4(C6),22.1(C3),21.8(C14),13.1(C7).HRMS(ESI):m/zcalcdfor
[M+H](C16H20NO5S)Calcd:338.1062,Found:338.1058.
152
(Z)‐3‐ethylidene‐2‐tosylcyclohexanone (2sexo) and7‐methyl‐1‐tosyl‐4,5‐dihydro‐1H‐
azepin‐2(3H)‐one(2sendo).Aftercompleteconversion,themixtureproductswereisolated
by flash column chromatography firstly with Ethyl acetate and Pentane (v/v, 1/4), and
followedbyseparationofpre‐HPLC.Theproductswereisolatedaswhitesolidsinexcellent
totalyield(2rexo,32mg,72%;2rendo,16mg,28%).
2sendo: 1H–NMR (CDCl3): δppm7.91 (d, 2H, JHH=8.4Hz,PhCH3), 7.32 (d, 2H, JHH=7.8Hz,
PhCH3),5.69(q,1H,JHH=6.9Hz,C=CHCH3),2.48(m,2H,CH2CO),2.44(s,3H,PhCH3),1.88(d,
3H,JHH=7.0Hz,C=CHCH3),1.27(s,broad,2H,CH2CH2CO).13C{1H}–NMR(CDCl3):δppm171.9
(C1),144.8(C11),136.3(C8),132.2(C5),129.3(C10,C10’),128.8(C9,C9’),125.9(C6),33.5
(C2), 29.9 (C4), 21.7 (C12), 17.2 (C3), 14.8 (C7). HRMS (ESI): m/z calcd for [M+H]
(C14H18NO3S)Calcd:280.1007,Found:280.1021.
2sendo:1H–NMR (CDCl3): δppm7.97 (d, 2H, JHH=8.3Hz,PhCH3), 7.33 (d, 2H, JHH =8.1Hz,
PhCH3),5.88(t,1H,JHH=7.5Hz,CH=CCH3),2.45(s,3H,PhCH3),2.36(s,broad,2H,CH2CO),
2.27(s,3H,CH=CCH3),2.04(t,2H,JHH=6.9Hz,CH2CH=C),1.96(s,broad,2H,CH2CH2CO).
13C{1H}–NMR(CDCl3):δppm173.0(C1),144.9(C11),137.0(C8),136.7(C6),129.2(C10,C10’),
129.1(C9,C9’),125.9(C5),34.8(C2),27.2(C3),22.8(C4),22.0(C7),21.7(C12).HRMS(ESI):
m/zcalcdfor[M+H](C14H18NO3S)Calcd:280.1007,Found:280.1004.
153
3.5.4SelectedCrystalData
Crystallographic data were collected at 193(2) K on Bruker‐AXS APEXII Quazar
diffractometer with Mo Kα radiation (λ = 0.71073 Å) using an oil–coated shock–cooled
crystal. Phi‐ and omega‐ scans were used. Semi‐empirical absorption corrections were
employed.Thestructurewassolvedbydirectmethods(SHELXS‐97),8andrefinedusingthe
least‐squaresmethodonF2.9
Crystallographicdata(excludingstructurefactors)havebeendepositedtotheCambridge
CrystallographicDataCentreassupplementarypublicationno.xxxxxx.Thesedatacanbe
obtainedfreeofchargeviawww.ccdc.cam.uk/conts/retrieving.html(orfromtheCCDC,12
UnionRoad,CambridgeCB21EZ,UK;fax:(+44)1223‐336‐033;[email protected]).
154
Table S1. Crystal Data, Data Collection, and Structure Refinement for{PtCl[(iPr2P=S)2(C9H4)]}(IIa)
Crystaldata
formula C21H33ClP2PtS2
Mr 642.07
crystalsystem monoclinic
spacegroup P21/n
a(Å) 13.2086(4)
b(Å) 14.2069(4)
c(Å) 13.9678(4)
α(°) 90
β(°) 107.990(2)
γ(°) 90
V(Å3) 2492.96(13)
Z 4
ρcalc(gcm‐3) 1.711
(mm‐1) 6.037
F(000) 1264
crystalsize(mm3) 0.240x0.150x0.120
DatacollectionandRefinement
T/K 173(2)
measdreflns 28700
Uniquereflns(Rint) 9045(0.0291)
reflnsusedforrefinement 9045
refinedparameters 252
GOFonF2 1.161
R1a[I>2σ(I)] 0.0272
wR2balldata 0.1045
aR1=Σ||Fo|‐|Fc||/Σ|Fo|.bwR2=[Σ[w(Fo2‐Fc2)2]/Σ[w(Fo2)2]]1/2.
155
TableS2.CrystalData,DataCollection,andStructureRefinementfor
{Pt[(Ph2P=S)2(C9H4)]}3(IIIa)
Crystaldata
formula C99H72P6Pt3S62·(CH2Cl2)
Mr 1108.01
crystalsystem triclinic
spacegroup P‐1
a(Å) 14.0054(6)
b(Å) 14.5896(6)
c(Å) 25.4903(9)
α(°) 76.122(2)
β(°) 80.256(2)
γ(°) 65.066(2)
V(Å3) 4571.4(3)
Z 2
ρcalc(gcm‐3) 1.740
(mm‐1) 4.986
F(000) 2340
crystalsize(mm3) 0.140x0.030x0.020
DatacollectionandRefinement
T/K 173(2)
measdreflns 38424
Uniquereflns(Rint) 22345(0.0478)
reflnsusedforrefinement 22345
refinedparameters 1076
GOFonF2 1.090
R1a[I>2σ(I)] 0.0595
wR2balldata 0.2091
aR1=Σ||Fo|‐|Fc||/Σ|Fo|.bwR2=[Σ[w(Fo2‐Fc2)2]/Σ[w(Fo2)2]]1/2.
156
TableS3.CrystalData,DataCollection,andStructureRefinementfor
[N(n‐Bu)4]{PtCl[(Ph2P=S)2(C9H4)]}(IVa)
Crystaldata
formula C49H60ClNP2PtS2(CH2Cl2)
Mr 1104.52
crystalsystem orthorhombic
spacegroup Pbca
a(Å) 17.7935(10)
b(Å) 21.1387(12)
c(Å) 26.6659(15)
α(°) 90(10)
β(°) 90(2)
γ(°) 90(10)
V(Å3) 10029.9(10)
Z 8
ρcalc(gcm‐3) 1.463
(mm‐1) 3.139
F(000) 4480
crystalsize(mm3) 0.40x0.08x0.04
DatacollectionandRefinement
T/K 193(2)
measdreflns 170112
Uniquereflns(Rint) 10164(0.0719)
reflnsusedforrefinement 10164
refinedparameters 536
GOFonF2 1.111
R1a[I>2σ(I)] 0.0455
wR2balldata 0.0644
aR1=Σ||Fo|‐|Fc||/Σ|Fo|.bwR2=[Σ[w(Fo2‐Fc2)2]/Σ[w(Fo2)2]]1/2.
157
3.6References
(1) John Meurig Thomas, W. J. T. Principles and Practice of Heterogeneous Catalysis, 1996. (2) Muroi, T. Role of Precious Metal Catalysts, Noble Metals, 2002. (3) Forniés, J.; Martín, A.; Martín, L. F.; Menjón, B.; Tsipis, A. Organometallics 2005, 24, 3539. (4) Albrecht, M.; Lutz, M.; Spek, A. L.; van Koten, G. Nature 2000, 406, 970. (5) Albrecht, M.; Hovestad, N. J.; Boersma, J.; van Koten, G. Chem Eur J 2001, 7, 1289. (6) Rodríguez, G.; Albrecht, M.; Schoenmaker, J.; Ford, A.; Lutz, M.; Spek, A. L.; van Koten, G. J Am Chem Soc 2002, 124, 5127. (7) Albrecht, M.; van Koten, G. Angew Chem Int Ed 2001, 40, 3750. (8) Wang, D.; Lippard, S. J. Nat Rev Drug Discov 2005, 4, 307. (9) Johnstone, T. C.; Suntharalingam, K.; Lippard, S. J. Chem Rev 2016, 116, 3436. (10) Meister, T. K.; Riener, K.; Gigler, P.; Stohrer, J.; Herrmann, W. A.; Kühn, F. E. Acs Catal 2016, 6, 1274. (11) Ananikov, V. P. Acs Catal 2015, 5, 1964. (12) Clarke, M. L. Polyhedron 2001, 20, 151. (13) Chianese, A. R.; Lee, S. J.; Gagne, M. R. Angew Chem Int Ed 2007, 46, 4042. (14) Kataoka, Y.; Matsumoto, O.; Tani, K. Organometallics 1996, 15, 5246. (15) Chatani, N.; Furukawa, N.; Sakurai, H.; Murai, S. Organometallics 1996, 15, 901. (16) Trost B. M., Doherty G. A. J. Am. Chem. Soc. 2000, 122, 3801 – 3810. (17) Espinosa‐Jalapa, N. Á.; Ke, D.; Nebra, N.; Le Goanvic, L.; Mallet‐Ladeira, S.; Monot, J.; Martin‐Vaca, B.; Bourissou, D. Acs Catal 2014, 4, 3605. (18) Aleman, J.; del Solar, V.; Navarro‐Ranninger, C. Chem Commun (Camb) 2010, 46, 454. (19) Girard, A. L.; Enomoto, T.; Yokouchi, S.; Tsukano, C.; Takemoto, Y. Chem Asian J 2011, 6, 1321. (20) Tsukano, C.; Yokouchi, S.; Girard, A. L.; Kuribayashi, T.; Sakamoto, S.; Enomoto, T.; Takemoto, Y. Org Biomol Chem 2012, 10, 6074. (21) Oulie, P.; Nebra, N.; Saffon, N.; Maron, L.; Martin‐Vaca, B.; Bourissou, D. J Am Chem Soc 2009, 131, 3493. (22) Nebra, N.; Lisena, J.; Saffon, N.; Maron, L.; Martin‐Vaca, B.; Bourissou, D. Dalton Trans 2011, 40, 8912. (23) Cordero, B.; Gomez, V.; Platero‐Prats, A. E.; Reves, M.; Echeverria, J.; Cremades, E.; Barragan, F.; Alvarez, S. Dalton Trans 2008, 2832. (24) Jiménez‐Tenorio, M.; Carmen Puerta, M.; Valerga, P.; Javier Moreno‐Dorado, F.; Guerra, F. M.; Massanet, G. M. Chem Commun 2001, 2324. (25) Harkat, H.; Dembelé, A. Y.; Weibel, J.‐M.; Blanc, A.; Pale, P. Tetrahedron 2009, 65, 1871. (26) Wakabayashi, T.; Ishii, Y.; Ishikawa, K.; Hidai, M. Angew Chem Int Ed 1996, 35, 2123. (27) Lumbroso, A.; Abermil, N.; Breit, B. Chem. Sci. 2012, 3, 789. (28) Campbell, M. J.; Toste, F. D. Chem Sci 2011, 2, 1369. (29) Gimeno, A.; Cuenca, A. B.; Medio‐Simón, M.; Asensio, G. Adv Synth Catal 2014, 356, 229. (30) Preindl, J.; Jouvin, K.; Laurich, D.; Seidel, G.; Furstner, A. Chem Eur J 2016, 22, 237. (31) Espinosa‐Jalapa, N. Á.; Ke, D.; Nebra, N.; Le Goanvic, L.; Mallet‐Ladeira, S.; Monot, J.; Martin‐Vaca, B.; Bourissou, D. Acs Catal 2016, 6, 1565. (32) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem Rev 2004, 104, 3079. (33) Monot, J.; Brunel, P.; Kefalidis, C. E.; Espinosa‐Jalapa, N. Á.; Maron, L.; Martin‐Vaca, B.; Bourissou, D. Chem Sci 2016, 7, 2179. (34) DiRocco, D. A.; Rovis, T. J Am Chem Soc 2011, 133, 10402.
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159
GeneralConclusion
This thesis fits into the area of cooperative catalysis, and in particularmetal / ligand cooperation.
Inspiredbynature,cooperativecatalysishasbeenwidelyinvestigatedinthelastdecadesanditsefficiency
overthestandardsingle‐sitecatalysishasbeendemonstrated.Inthiscontext,ourgrouphasdeveloped
originalindenediidePdpincercomplexesthatexhibitnon‐innocentbehavior.Recently,suchPdcomplexes
weresuccessfullyappliedtothecatalyticcycloisomerizationofalkynoicacidstoformlactones.These
encouraging results, as well as an in‐depth understanding of the mechanism by experimental and
theoretical investigations, prompted us to further develop the catalytic applications of such pincer
complexes.Thiswastheobjectiveofthisthesis.
CycloisomerizationofN‐tosylalkynylamides,closetothatofalkynoicacidsbutmorechallenging,first
attractedourattention.PreliminaryresultswiththefirstreportedfamilyofindenediidePdcomplexes
disclosedtheirabilitytocompleteformationof 5‐memberedlactams,butrevealedlimitationsforthe
formationof6‐membered lactams.31PNMRmonitoring indicateddegradationof thecatalyticspecies
during reaction. A structural modulation of the ligand skeleton aiming at improving the catalyst
robustnesswasthereforeenvisioned,byexchangingthePhsubstituentsatphosphorusformoreelectron‐
donating iPr groups. Two new complexes were readily prepared following the synthetic strategy
previouslyreportedandfullycharacterized(NMR,IR,XRD).Toourdelight,thenewcomplexesbearing
iPrgroupsledtobetterperformancesthantheirPh‐substitutedcounterparts.Thankstothismodulation,
the substrate scope of amides could be expanded, from linear non‐substituted C5‐C7 amides, to
substituted, benzo‐fused, and finally to internal‐alkyne ones. Notably, the 7‐membered exo‐
methylenecaprolactamwasobtained for the first timeviacycloisomerization,butwithmoderate
yield.Therefore,therewasstillroomforformationofmedium‐sizerings,suchas7‐memberedrings,
butalsoforthecyclizationofamidesbearinginternalalkynes.
Inresponsetosuchchallenges,amoreactiveindenediidesystemwaslookedafter.Knowingthat
platinum efficiently activates C‐C multiple bonds, in particular triple bonds, a straightforward
strategytoswitchthemetalcenterfromPdtoPtwasenvisioned.Tothisend,fourPtcomplexeswere
prepared and fully characterized (NMR, IR, XRD). A rapid evaluation showed that the new Pt
complexes,inparticularthedimericonefeaturingiPrgroupsonP,outperformedtheirPdanalogs.
Subsequentinvestigationswerefocusedonthechallengingformationofmedium‐sizeringlactones
/ lactams, including from substrates featuring internal alkynes. Gratifyingly, with the new Pt
complexes, complete conversions in the formation of 7‐membered lactones/lactams from the
160
corresponding linear acid and amidewere achieved.The generality of such catalytic systemwas
supported by the successful formation of other diversely substituted 7‐membered rings. Several
substratesbearinginternalalkynes,whicharechallengingforsuchcycloisomerizationreactionsin
terms of activity and exo/endo selectivities, were also investigated. The reaction times were
remarkablyshortenedinmostcases. Inaddition,althougha lowconversionwasobserved,thePt
dimertriggeredthecyclizationofC6amidefeaturinganinternalalkyne,whichwasimpossiblewith
thePdindenediidecomplexes.
On the basis of amechanistic study carried out in the group, the use ofH‐bond additiveswas
envisionedtofurtherimprovetheperformancesoftheindenediidePtcatalyst.Catecholwasusedfor
anumberofcandidates.Itwasshowntoshortensignificantlythereactiontimesandtoincreasethe
exo/endoselectivities(infavortotheendoproduct)inmostcases.Notably,theinternal‐alkyneC6
amidecouldbeutterlycyclizedinthepresenceoftheadditive.
Insummary,byvirtueoftwosimplestructuralmodulationsoftheindenediidesystem,firstlyexchange
of theP substituent for themoreelectron‐donating iPrgroupand then replacementofPdbyPt, the
catalyticperformancesoftheindenediidepincersystemforthecycloisomerizationofalkynoicacidsand
relatedamideshavebeenremarkablyenhanced.Inthepresenceoftheseindenediidepincercomplexes,
awidespectrumof5‐,6‐,7‐memberedlactones/lactamshavebeenefficientlypreparedwithoutusingany
externalbases,inmostcasesundermildconditions.Theseresultsdemonstratetheefficiencyofmetal‐
ligandcooperationandhighlightthepivotalinfluenceofstructuralmodulationincatalystdesign.Inthe
future,weseektoapplyourpincercomplexestoothertransformations,inparticularintramolecularand
intermolecularhydro‐elementationofalkynesandalkenes.
Inaddition,theefficientpreparationofε‐alkylidenelactones,whichcanbescaleduptomulti‐gram
level,openstheroutetothepreparationofsubstitutedε‐caprolactonesbyderivationoftheexocyclic
double bond. These products are interesting monomers for the preparation of functionalized
biodegradable polyesters via ring‐openingpolymerization (ROP), andwill be investigatedby the
groupinthenearfuture.
161
INTRODUCTIONGENERALE
Les applications de la catalyse organometalliques se sont developpe tout long du XXeme siecle grace a la
modulationdeleursproprietesstereoelectroniquesenvariantlesligands.Ceciestbienillustreparl’amelioration
del’efficacitedesystemespermettantla(co)polymesisationd’olefinespolaires:lessystemesCGC(Constrained
GeometryComplexes)danslesannees80sd’abord,puislescomplexesdiimineduPd(II)etNi(II)dixansplustard
pourfiniraveclescomplexescomportantlesligandsphosphine‐sulfonate.1,2
Maislecontroledeproprietesstereoelectoniquesdumetaln’estpasl’uniquerolepossiblepourunligand.
Au cours de 20 dernieres annees, les systemes catalytiques dans lesquels un des ligands participe
directement a l’activationdusubstrat(exhibantcequiestconnucommecaracterenon‐innocent)sesont
fortementdeveloppesapreslestravauxpionniersdeNoyorietShvo.3,4Cetteactionconcerteeentrelemetalet
leliganddansl’activationdessubstratsestconnuecommecooperationmetal/ligand,etpermetlarealisationde
transformations dans des conditions douces. Plus particulierement, elle permet l’activation / formation de
liaisonssansvariationdel’etatd’oxydationdumetaletrepresenteainsiunealternativeauxetapesd’addition
oxydanteeteliminationreductrice.5,6
Lestravauxdecritsdanscemanuscrits’inscriventdansledomainedelacooperativitemetal/ligand.Plus
particulierement,ilsconcernentl’applicationcatalytiquedecomplexespincedePdetPtcomportantleligand
bis(thiophosphinoyl)indenediide dans la reaction de cycloisomerization d’acides alcynoıques et de N‐
alcynylamides.Lemanuscritestdiviseentroischapitres:
Lepremierchapitreenglobeunerevisionbibliographiquenon‐exhaustivedelacooperativiteencatalyse.
Apres une presentation rapide des systemes catalytiques duals (organo‐organo, metal‐metal et organo‐
162
metal),lacooperativitemetal/ligandestdecriteplusendetail.Desexemplesrepresentatifsbasessurles
systemes amido‐Ru de Noyori pour l’hydrogenation et sur les complexes pince de Milstein a pyridine
desaromatiseesontdiscutesavantlapresentationdequelquesexempleschoisisd’applications.
LedeuxiemechapitrepresentelesresultatsobtenusaveclecomplexeindenediidedePd,prepareselonune
modulationstructuralduligand(remplacementdessubstituantsPhsurlePpariPr)visantaaugmenterla
robustesse du catalyseur.8,9 Les resultats montrent la pertinence de la modulation puisque des N‐
alcynylamides ont pu etre transformees en lactames demaniere efficace. Cependant, dans certains cas,
commelessubstratsaalcyneinterneouceuxconduisantadelactamesa7‐chaınons,lesresultatsontete
moinsbonsmaisneanmoinsprometteurs.
LetroisiemechapitreresumelesresultatsobtenuslorsquedescomplexessimilairesabasedePt(metal
connu par sa capacite a activer les alcynes) ont ete prepares et utilises. Grace a ces complexes la
cycloisomerisation des N‐alcynylamides problématiques a pu être mené avec succès avec des bons
rendementsetsélectivitésexo/endo.Deplus,lacombinaisonducomplexesindenediidedePtavecunadditif
donneurdeliaison‐H(typecatéchol)9apermisd’améliorerlesrésultatsetdanscertainscasd’inverserla
sélectivitéexo/endo.
Enconclusion,lestravauxréalisésmontrentquelessystèmespinceindenediidedePdetPtsontdebons
catalyseurspourlacycloisomerisationd’acidesalcynoïquesetdeN‐alcynylamides,grâceàlacoopération
métal/ligand.Deplus,cestravauxmettentenévidencel’intérêtdelamodulationstructuraledescatalyseurs
à l’heured’incrémenter l’activitécatalytique,ainsique lerôleclé jouépar lesétudesmécanistiquespour
réalisercesajustements.
1.Catalysecooperative
1.1.Introduction
Lacatalysejoueunrôleprimordialdanslapréparationd’unegrandequantitédecomposésetattireune
attentioncroissanteaussibiendanslemondeacadémiquequ’industriel.Lacatalyse«classique»implique
uneinteractionsimpleducatalyseuravecunsubstratpourgénérerl’espèceactivéequiréagitàsontouravec
d’autressubstrats.C’estcequ’onappellelacatalysemono‐site.Maisilexistedeplusenplusd’exemplesde
systèmes catalytiquesmulti‐centres. Inspirésde systèmesbiologiques, ces systèmespossèdentplusieurs
sitesactifscapablesd’activersimultanémentplusd’unsubstratoud’activerdoublementunsubstrat.10‐13
163
Lessystèmesmulti‐centrespeuventêtreclassésselonquatremodèles(Figure1.1):(I)lepremier,appelé
Catalysepardouble activation’, consiste en l’activationd’undes substratspardeux sites catalytiquesde
manière simultanée; (II) dans le deuxième, l’activation d’un substrat par un des sites conduit à un
intermédiaire,lequelactivéàsontourparledeuxièmessitecatalytiqueréagitavecledeuxièmesubstrat.Les
deuxautrescatégoriesimpliquentunesynergieoucoopérativitédesdeuxsitescatalytiques,chacund’eux
activantundessubstrats.Onpeutfaireladifférenceentrelessystèmesoulesdeuxsitesappartiennentà
deux catalyseurs différents (III) et ceux ou les deux sites sont placés sur unemêmemolécule (III’). Ces
dernierssontappeléssystèmesbifonctionnels.
Figure1.1Classificationdessystèmescatalytiquesmulti‐sites.
Lessystèmescatalytiquesétudiésaucoursdecettethèseappartiennentàcederniergroupedecatalyse
bifonctionnelle.Eneffet,ils’agitdecomplexesmétalliquesdanslesquelsundesligandsneselimitepasà
modulerlespropriétésstéréoélectroniquesdumétalmaisparticipeactivementàl’activationdessubstrats.
C’estcequ’onappelleunligandnon‐innocentetonparlealorsdecatalysecoopérativemétal/ligand.
1.2CoopérativitéMétal‐Ligand
La catalyse coopérative métal / ligand est devenue un concept important en catalyse grâce au
développementdesligandsnon‐innocents.
Les termes innocent / non‐innocent furent introduits initialement dans le domaine de la chimie de
coordinationparJørgensenen1966.14Unligandinnocentpermetdedéterminerdemanièrecertaineledegré
d’oxydationdumétal.Aucontraire,unligandnon‐innocentpossèdeunsystèmedélocaliséquirenddifficile
cettedétermination.Unexemplereprésentatifd’uncomplexesàligandnon‐innocentestlecomplexesneutre
deNiglyoxalbis(2‐mercaptoanil)Ni(gma)2caratériséparlaprésenced’unsystèmeconjuguéétendu(Figure
164
1.2).15 Ce compose peut être considéré comme un complexe de Ni(II) à 16‐électrons avec un ligand
diiminodithiolate(1a)oudi(imino‐thiosemiquinonate)(1b),commeuncomplexedeNi(IV)à14‐électrons
(1c)ou,alternativement,commeuncomplexedeNi(0)à18‐electron(1d).Engénéral,laformedélocalisée
(1e)estconsidéréecommelameilleurereprésentationdelasituationélectroniqueducomplexe.
Figure1.2ComplexedeNicomportantunligandnon‐innocentN2S2.
Audébutdesannées1990leconceptdenon‐innocenceestgénéralementacceptéetestétenduensuiteaux
ligandsimpliquésdirectementdansl’activation/formationdeliaisonschimiques(ligandscoopératifs).Dans
lesdeuxcas,lacontributionduligandpermetderéaliserdestransformationsenévitantlesétapesd’addition
oxydante/élimination réductive sur le métal. Des transformations chimiques sont ainsi rendues plus
accessiblesvoirpossibles.Nousallonsnousfocalisersurquelquesexemplesreprésentatifsdécritsavecdes
ligandscoopératifs.
1.3.Ligandscoopératifsnon‐innocents
Les ligandsdetypeamidoontété lespremiersàêtreextensivementappliquésencatalysecoopérative
métal ligand. Ils sont connus depuis longtemps comme coopératifs aussi bien dans des réactions
stoechiométriques16‐18 que catalytiques, notamment dans des réactions d’hydrogénation catalytiques de
substratsinsaturés.19
En2001,NoyorireçuleprixNobeldechimiepoursestravauxsur l’hydrogénationasymétrique.20Plus
particulièrement,songroupeacontribuédemanièreremarquableaudéveloppementde lacoopérativité
métal / ligand, grâce à leur complexe chiral amido de Ru(II). Ce dérivé a des excellentes activités et
sélectivités (turnover frequency (TOF)>200 000 h‐1; turnover numbers (TON)>2 × 106; ee>98%). Le
165
mécanismegénéralementreconnupourcettetransformationpeutêtreillustrécommesuit(schéma1.1):la
moléculedeH2secoordineàl’atomedeRuviauneliaisonetensuitelaliaisonH‐Hestactivéedemanière
hétérolytique par l’unité amido‐Ru pour conduire à un composé amino‐Ru‐hydrure. La cétone interagit
ensuiteavecladeuxièmesphèredecoordinationdececomplexeparlebiaisdesliaisonspolariséesNHδ+et
RuHδ‐,poursubirleprocessusd’hydrogénation.L’étatd’oxydationdel’atomedeRuresteinvariabletoutau
longdelatransformationetlaréductiondelacétonealieuparcequ’onappelleunmécanismedesphère
externe.
Schéma1.1Mécanismed’hydrogénationdecétonespascomplexes chirauxRuIIamido.
Depuisledébutdesannées2000lescomplexesdetypepinceontconnuungrandessoretparmieuxnous
pouvonsdistinguerlescomplexesdécritspasl’équipedeD.Milsteincomportantunligandpinceàcaractère
non‐innocent.Ils’agitduligandbis(di(tert‐butyl)phosphinomethyl)pyridine,lequelpardéprotonationd’un
des CH2 des bras latéraux conduit à une désaromatisation de la pyridine (Figure 1.3). Ce système
désaromatisé est alors capable d’active des liaisons H‐X (X = H, O, N…) grâce à la force motrice de la
réaromatisationdelapyridine(schéma1.2).21
Figure1.31èregénérationdecomplexespincedeMilstein
166
N
L1
L2
MLn- H+base N
L1
L2
MLnH-Y
Y = H, OH, OR, NH2, NR2, C
N
L1
L2
MLn
H
Y
pyridinedearomatization
pyridinerearomatization
Schéma1.2Aromatisation/désaromatisationdanslescomplexespincedeMilstein.
Cessystèmesontétéappliquésavecsuccèsdansdesprocessusd’hydrogénation(directeoupartransfert
d’hydrogène) de dérivés carbonylés et de déshydrogénation d’alcools. D’autres transformations plus
complexesimpliquantcesétapesd’hydrogénationoudéshydrogénationontétéensuitedécritestelquele
couplage déshydrogénant d’alcools pour conduire à des esters.22 Dans cette transformation, la
déshydrogénationd’unemoléculed’alcoolconduitàundérivécarbonyléquiréagitavecuneautremolécule
d’alcoolpourformerundérivédetypehémiacétal.Cethémiacétalestàensuitedéshydrogénéluiaussipour
formerl’ester(schéma1.3).Surlabasedecettedésaromatisation‐réaromatisationd’autretransformations
telles que le couplage déshydrogénant alcool‐amines…ont été réalisées avec succès dans les dernières
années.23‐24
Schéma1.3Couplagedéshydrogénantd’alcoolscatalyséparuncomplexepincedécritparMilstein.
167
MaiscesystèmedécritpasMilsteinn’estpasleseulsystèmedetypepincemontrantunecoopérativité
métal / ligand.D’autres systèmes ont été décrits dans la dernière décennie et certains d’entre eux sont
appliquésdansdeprocessuscatalytiquesn’impliquantpasd’étaped’hydrogénationoudeshydrogénation.
Lescomplexespinceindendiidedéveloppésparnotreéquipeetfocusdecettethèsefontpartiedecesdérivés.
Ces composés se caractérisent par unmétal (Pd) électrophile et un squelette carboné riche en densité
électrophile à caractère non‐innocent (schéma 1.4). Nous avons cherché à exploiter ces complexes
indèndiide en catalyse de cyclisationdes d’acides carboxyliques ‐acétyléniques,méthodede choix pour
accéderaux‐méthylènelactones.Notresystèmes’estavérétrèsefficacepourcettetransformation(TON
jusqu’à2000)etrecyclablejusqu’à10foissanspertenotabled’activité.Ilnenécessitepasdebaseexterneet
permetlacyclisationd’unevariétédesubstratssansprécédent(alcynesterminauxetinternes;formation
de lactones à 5, 6 et même 7 chaînons). Une étude conjointe expérimentale (marquage isotopique,
comparaison d’activité des différentes espèces…) et théorique a confirmé la contribution du caractère
basiqueduligandàlatransformation.
Scheme1.4Cycloisomerisationd’acydesalcynoïquescatalyséeparlescomplexesindendiidedePddevelopésdans
l’équipe.
Cependant,malgré lesbonsrésultatsobtenus,des limitationsontaussiété identifiées lorsquecertains
alcynesinternesoulesprécurseursdecyclesà7chaînonssontvisés.Deplus,nousavionshâted’étendre
l’application de ce système coopératif métal / ligand à de transformations à enjeu majeur comme la
cycloisomerisationd’alcynylamidesconduisantàdelactames.
Lebutdecettethèseétaitdetirerprofitdelamodularitéstructuraledecescomplexesindendiidepour
optimiserleursperformancescatalytiquesetadressercesdeuxproblématiques.
2.CycloisomerisationcatalyseedescomplexespincedePdCe chapitre décrit la synthèse de nouveaux complexes pince indenediide de palladium et leur
applicationcatalytiquepourlacyclisationd’alcynylamides.Lesperformancescatalytiquesdecesdifférents
complexes ont été évaluées et la structure des substrats a été variée. Lemécanisme de la réaction est
168
égalementdiscutédanscettepartie.Maistoutd’abord,unrésumédestravauxantérieursdel’équipesurle
sujetestprésenté.
Lesréactionsdecycloisomérisationssontdestransformationsàhautesvaleursajoutéesquidonnentaccès
àunlargeéventaildecomposéscycliquesavecuneparfaiteéconomied’atomesetd’étapes.Enparticulier,
deshétérocyclespeuventêtrefacilementpréparésàpartirderéactifsinsaturésprésentantunefonctionpro
nucléophile(fonctionnalitésO‐H,N‐H).Uncertainnombredecomplexesdemétauxdetransitionscatalysent
ces transformations. L’activation de la liaison carbone‐carbone insaturée par le centre métallique
électrophile est suivie d’une attaque du pro nucléophile permettant ainsi la cyclisation. Ces réactions
nécessitent bien souvent la présence d’additifs tels qu’une base pour activer simultanément le pro
nucléophile.
Commenousl’avonsvudanslechapitre1,desprogrèsspectaculairesontétéréaliséscesvingtdernières
annéesencatalysebifonctionnelleimpliquantlacoopérativitémétal/ligand.3,4Enparticulier,lescomplexes
pinceprésentantuncaractèrenon‐innocentontétélargementutilisésdansdestransformationsfaisantappel
au processus d’hydrogénation/déshydrogénation.23 Cependant, la coopérativitémétal/ligand a aussi été
appliquéoccasionnellementàd’autresprocessusincluantlacycloisomérisation.
C’estdanscecontextequenotreéquipeadéveloppéunenouvellefamilledeligandpinceSCSàpartirdu
squelette indène incorporant deux bras thiophosphinoyle en position 1 et 3.25,26 Ces deux bras Ph2P=S
permettentunecoordinationducentremétalliqueàl’instard’unecoordinationfacialpluscommune.Des
étudesDFT,incluantdesanalysesNBOetAIM,ontrévéléuncaractèretrèsfortpourlaliaisonC2‐métal
maisuntrèsfaiblecaractère.L’étudedesorbitalesmoléculairedecescomplexesaégalementrévéléune
densitéélectroniqueimportantesurlescarbonesC1etC3.Cesdonnéessontenaccordaveclaprésenced’une
densitéélectroniqueimportantesurcesdeuxatomesdecarbone,préditeégalementparlescalculsDFT.Ceci
résulteenuncaractèrenon‐innocentquiapuêtredémontrépardesréactionsstœchiométriquesenprésence
d’électrophilesorganiquesetmétalliquesdonnantlieurespectivement,àl’alkylationélectrophileduligand
etàlaformationdecomplexesbimétalliques(Schéma2.1).27,28
Schéma2.1Réactivitéduchloropalladatedémontrantsoncaractèrenoninnocent
169
CesétudesstœchiométriquesainsiquelescalculsDFT,indiquentdoncquecescomplexespeuventêtre
définiscommedescomplexespinceindenediidedePalladium,présentantuncentremétalliqueélectrophile
etunsitebasiquesurlepro‐ligand(Figure2.1).
Figure2.1Formuledécrivantlemieuxlescomplexesindènediide
CescomplexesSCSindènediide(Figure2.2)ontétéensuiteappliquésavecsuccèsencatalysecoopérative
métal/ligandpour la cycloisomérisationd’acidesalcynoïques.29Cette réactionnenécessitepas l’ajoutde
base externe, contrairement à d’autres systèmes métalliques, et a été appliquée à un large éventail de
substrats.C’estdanscecontextequelestravauxdecettethèseontcommencé.Nousavonschoisid’appliquer
les complexes indènediidesdePalladiumà une transformationplusdifficile, la cycloisomérisationdeN‐
Tosylalcynylamideenalkylidènelactames.7
Figure2.2ComplexespinceSCSindènediideprécédemmentdécrits.
Uneétudepréliminaireadoncétéréaliséemettanten jeu lescomplexesSCS indènediidedePalladium
disponiblesauseindel’équipe(Tableau2.1).Cescatalyseurssesontmontrésefficacespourl’obtentionde
lactames à 5 chainons avec des conversions quantitatives en 1 h. Cependant, une baisse de l’activité
catalytiqueaétéobservéelorsquelaformationducycleà6chainons2baététestée.Après24hderéaction,
lesconversionsnedépassentpas92%(entrées4‐7).Afindedéterminerlescausesdecettebaissed’efficacité,
un suivi RMN 31P a été réalisé (Figure 2.3). Lors du mélange de 1a avec le catalyseur Ic, on observe
directement la formation d’espèces intermédiaires de type indényle provenant très probablement de la
déprotonationdelafonctionamide(CONHTs)parlesitebasiqueducomplexe.Aprèsquelquesheuresde
réaction,l’apparitiond’unetroisièmeespèceestdétectée.Cecomposéaétéformellementidentifiécomme
étantleligandlibre(45.6et31.0ppm)résultantdeladécompositionducatalyseur(44.5ppm).CesuiviRMN
31P permet de mettre en évidence un problème de stabilité de notre catalyseur dans les conditions de
cycloisomérisationd’alcynylamide.
170
Tableau2.1EvaluationdespropriétéscatalytiquesdescomplexesindènediidedePdIa‐c
DanslacyclisationdeN‐tosylAlcynylamides1aet1b.
Afin de résoudre ce problème de stabilité, des modulations structurales sur le ligand, telles que la
substitutiondugroupementPhsurlephosphoreparungroupementisopropyle,ontétéenvisagées.Cette
modificationpermettraituneaugmentationducaractèredonneurdesbras thiophosphinoylesetainsiun
renforcementdel’interactiondusoufreaveclemétal.Onpeutanticiperdeuxchangementsprincipaux:1)
une augmentation de la densité électronique sur les carbone C1 et C3 qui devrait être bénéfique pour
l’activationdelaliaisonNHdel’amide;2)unecoordinationmétal/ligandplusfortequidevraientcontribuer
àplusgranderobustesseducatalyseuretdesintermédiairesréactionnels.
Entry Substrate Cat. T(°C) time(h) Conv(%)
1 1a Ia 60 1h >99
2 1a Ib 60 1h 81
3 1a Ic 60 50min >99
4 1b Ia 90 24h 67
5 1b Ia 90 24h 82c
6 1b Ib 90 24h 49
7 1b Ic 90 20h 92
aTouslestestscatalytiquesontétéréaliséssousatmosphèred’argonenpartantde0.1mmol
d’alcynylamide(0.14MdansCDCl3).bLesconversionsontétédéterminéeparRMN1H.cLa
réactionesteffectuéeà1Md’alcynylamide.
171
Figure2.3SuiviRMN31PmontrantladegradationducomplexeIaaucoursdutempslorsdelacycloisomérisation
de1b.
Leproligandcibleaétépréparéselonlamêmestratégiedesynthèsedécritepourlesprécédentproligand
(Schéma 2.2).26,29 Une double séquence de déprotonation avec le n‐butyllithium suivi de l’ajout de la
chlorodiisopropylphosphineaétéappliquéeàl’indène.Aprèsoxydationaveclesoufreélémentaire(S8)et
réactionenprésencedePd(PhCN)2Cl2,lecomplexeindényleIVestobtenuavecunrendementde82%.Après
déprotonation avec un mélange de deux bases, PS‐DIEA et de tBuOK, en présence de nBu4NCl, le
chloropalladate II est isolé avec 81% de rendement. L’espèce dimère III est, quant à elle obtenue par
déprotonationdeIVenprésencedeNaOAcdansleToluèneà90°C(78%derendement).Touscesnouveaux
complexesontétécaractérisésparRMN,HRMSetdiffractionparrayonsX.
172
Schéma2.2SynthèsesdenouveauxcomplexespinceavecgroupementsiPr.
Pourévaluer l’impactdecettemodulationstructurale(iPrà laplacedePh)sur l’activitécatalytique, la
cyclisationduN‐Tosylhex‐5‐ynamide1baétéchoisiecommeréactionmodèle.EnutilisantIIouIII,le6‐exo
alkylidène lactame2b est obtenu avec un rendement quantitatif en une nuit à 90°C. Ce résultat est en
contraste total avec ceux obtenus en présence des complexes Ia‐c. Aucun signe de décomposition n’est
observéenRMN31Paucoursdelaréaction,mêmeenlaissantlemilieuréactionnelà90°C6haprèslafinde
laréaction.Unsimpleéchangedesubstituantsurlephosphorepermetdoncuneaugmentationimportante
delarobustesseetparconséquentdesperformancescatalytiquesdescomplexesindènediidesdePalladium.
LesrésultatsobtenusaveclecomplexeIIetIIIétanttrèssimilaires,lasuitedel’étudeaétéréaliséeen
présenceducomplexedimèreneutreIII.LacyclisationduN‐Tosylpent‐4‐ynamide1aaensuiteétéévaluée.
Lacyclisationa lieubeaucoupplusrapidementqu’enprésencedeIa‐cà60°C.Eneffet, le lactame2aest
obtenuavecuntrèsbonrendement(98%)enseulement10min.Cerésultatnousaencouragéàdiminuerla
charge catalytique jusqu’à 0.2 mol%. Dans ces conditions, un temps de réaction plus long (7 h) et
l’augmentationdelaconcentration(1.5M)ontéténécessaires.Leproduitdecyclisationestquandmême
obtenuavecunrendementquantitatifcequicorrespondàunturnovernumberde500.
Tableau2.2CyclizationdeN‐tosylalcynylamides(1a‐i)catalyséeparIII.
173
Entrya T (ºC) t (h) Conv (%)b
160
2
3
4
Alkynylamide Lactam
NHTsO
NTsO
2c1c
T (ºC) t (h) Conv (%)b
25 30 min 99 (99)
25 30 min 99 (86)
Entrya
7
1a 2a
Alkynylamide Lactam
NHTsO
NO
Hexn
Hexn
NHTsO NO
EtO2CEtO2C
6d
NHTsO
1h
90 24 h 99 (83)fMe
1d 2d
NHTsO
N
O
HNTs
O
NH
O
25 30 min 99 (82)
1e 2e
2b1b
90 12 h 99 (98)NHTs
O
NTs
ONTs
O
NHTs
O
5
90 130 h 70 (53)e
Ts
Ts
NHTs
O
8
1f 2f
1g 2g
120 12 h 95 (51)e
2h
10 min7 hc
99 (98)99c NTs
O
9
2sendo1s
90 24 h 0NHTs
O
Me
Me
NTs
O
NTs
Me
O
(a)Touslestestscatalytiquesontétéréaliséssousatmosphèred’argonenpartantde0.1mmold’alcynylamide1a‐h(0.14MdansCDCl3)enprésence
de5mol%dePd.(b)LesconversionsontétédéterminéeparRMN1H.Lesrendementsisoléssontentrecrochets.(c)Lachargecatalytiqueaété
diminuéeà0.2mol%etlaconcentrationdusubstrataétéaugmentéeà1.5M.(d)LaRéactioneffectuéeà0.2Md’alcynylamide.(e)l’analyseRMN1H
dubrutindiquelaformationd’unseulisomère.Lesdifférencesentreconversionetrendementrésultentdeproblèmesdepurifications.(f)Laréaction
aétéréaliséavecuneconcentrationde0.3Md’alcynylamide.
Nousavonsensuiteexplorélatolérancefonctionnelleetladiversitéstructurelledesubstratspourle
systèmecatalytiqueIII(tableau2.2).Différentssubstituantsontétéintroduitsenpositionαdelafonction
amide. La réaction est accélérée de manière significative par l’effet Thorpe‐Ingold comme le montre la
cyclisationrapidede1c(comportantungroupenHex)àtempératureambianteenseulement30min(entrée
3). Les très bons résultats obtenus avec les substrats 1d et 1e démontrent que l’introduction de
groupementsfonctionnelstelsquedesestersetdesaminesprotégéessontcompatiblesavecnotresystème.
LelienaliphatiqueentrelaN‐Tosylamideetlafonctionalcyneaensuiteétéremplacéparungroupement
benzyle.La cyclisationde1f a lieuà120°Cavecunesélectivitéendo au lieud’exopourdonneraccès au
produità7chainons2favecunrendementisoléde51%(conversion95%).Cettetransformationouvrela
voieaux3‐benzazepin‐2‐onesquisontdesmotifsimportantsquel’onretrouvedansdenombreuxcomposé
biologiquementactifs.
Larobustessethermiquedecenouveaucatalyseurnousapermisdeciblerdessubstratsambitieuxtel
queleN‐Tosylhept‐5‐ynamide1g.Cettecyclisationestachevéeen6joursà90°Cetdonnesélectivementle
174
lactame2g correspondantavecunrendementde53%Anotreconnaissance,c’est lapremière foisqu’un
méthylène‐caprolactameestobtenueparcycloisomérisation.
Nousnoussommesensuiteintéressésauxalcynylamidesinternesquisontconnuspourêtrebeaucoup
plusdifficileàcycliserqueleurshomologuesterminaux.Lacyclisationde1hestréaliséeen24hà90°C.Par
rapportàl’acidealcynoïquecorrespondant,1hsubitdanscecasunecyclisation6‐endopourdonnerla2‐
piperidone2h.CeproduitaététotalementcaractériséparRMNetpardiffractiondesrayonsX.
Enfin, lacyclisationdesubstratscontraintscomme1iet1jaétéétudiée(tableau2.3).LecomplexeIII
permetlacyclisationefficacede1i.Après5h,onobtientlaconversioncomplètede1iendeuxproduitsvia
6‐endocyclisationexclusivement.Al’inversedecequiaétéobservépourlesautresalcynylamides,dansce
cas, laO‐ et laN‐cyclisation ont lieu. Pour1i et1j, le produit deO‐cyclisation est lemajoritaire (O‐/N‐
cyclisation:84/16pour1iet92/8pour1j).Lastructuredechacundesdeuxproduitsaétéconfirméepar
diffractiondesrayonsX.
Tableau2.3EtudedelacyclisationdesN‐tosylalcynylamides1iet1j.
Entrya Sub. Cat. T(°C)Time
(h)
Conv
(%)b
O‐/N‐
attack
1 1i Ia 50 5 53 92/8
2 1i Ic 50 5 51 93/7
3 1i III 50 5 87 84/16
4 1i III 35 20 >99(89) 86/14
5 1j Ia 50 4d 51 92/8
6 1j III 50 3.5d >99(92) 92/8
(a) Tous les tests catalytiques ont été réalisés sous atmosphère d’argon en partant de 0.1 mmol
d’alcynylamide (0.14 M dans CDCl3) en présence de 5 mol% de Pd. (b)Les conversions ont été
déterminéeparRMN1H.Lesrendementsisoléssontentrecrochets.
175
Pourvérifierunpotentiel effetde catalyseur, la cyclisationde1i et1j a été réaliséeenprésencedes
complexesIa‐c.DefaiblesconversionsontétéobservéesetladécompositiondeIa‐cenligandlibreaencore
étédétectéepar31PRMN.Cependant,lacyclisationestexclusivementdetype6‐endoavecdesratiosdeO‐
/N‐cyclisationcomparablesàceuxobtenuavecIII.Ceciindiqueuneabsenced’influencedelastructuredu
catalyseursurlasélectivité.
Nousavonsproposéuncyclecatalytiquepourlacycloisomérisationdesalcynylamidescatalyséeparle
complexeIII(Schéma2.3).
Schéma2.3Mécanismesimplifiéproposé.
(i) LadensitéélectroniqueprésentesurleligandindènediidepermetladéprotonationdelaN‐Tosyl
amide, et l’électrophilie du palladium permet l’activation de l’alcyne par coordination
(intermédiaireA).
(ii) Lacyclisationparl’attaquenucléophiledel’atomed’azotesurlatripleliaisoncarbone‐carbone
donne lecomplexeB.L’additionen trans estsuggéréepar lapositioncisdudeutériumsur le
produit2a‐Dprovenantdelacyclisationduproduit1a‐Ddeutéréenpositionterminal(CCD,
93%demarquageisotopique,voirschéma2.4).
(iii) Enfin,l’alkylidènelactameestlibéréetlecomplexeIIIestrégénéré.
Schéma2.4Cycloisomérisationdel’acide4‐pentynoïquedeutéré1a‐D‐C.
176
LedoublerôleducomplexeindènediidedePalladiumaétéconfirmépardesblancs.Toutd’abord,nous
avonsmontréquelaréactionn’avaitpaslieusousactivationthermiqueenl’absenceduIII.Unautrecontrôle
aétéréaliséenprésenceduchloroindényledePalladiumIV (la formeprotonéede II).IV est totalement
inactif pour la cyclisation de 1a ce qui démontre la nécessité du centre métallique électrophile et de
l’activationvialesitebasiqueduligandpourréaliserlatransformation.
Pourconclure,unemodulationsimplesurlepro‐ligandapermisd’augmenterdemanièreimportantela
stabilitéthermiqueetparconséquentl’activitécatalytiquedescomplexesSCSindènediidedePalladiumpour
la cycloisomérisationd’alcynylamides.Une largediversité structuralede substrats apuêtre cyclisé (des
composés aliphatique à 5‐7 chainons jusqu’aux alcynes internes). Dans lamajorité des cas de très bons
rendementsetsélectivitésontétéobtenus(supérieursà90%).
Cependant, il reste encorequelques améliorationsà apporter au système catalytiquenotammentpour
atteindredemeilleuresconversions/rendementspourlescyclessupérieursà6chainons.
3.QuandlePtsurpasselePdencyclosiomerisationcatalytique
Comme nous l’avons vu dans le chapitre 2, l’utilisation d’un complexe pince SCS indènediide de
palladiumapermis lapréparationdelactonesetde lactamesdansdesconditionsdoucesavecunehaute
tolérancefonctionnelleetsansl’ajoutd’unebaseexterne.Descyclesà6et7chaînonsontpuêtreformésà
températuresélevées(90‐120°C)avecdestempsderéactionsimportants(10‐120h).
Malgrécesavancées,laformationdecyclesà6àpartird’alcynesinternesetcelledecyclesà7chainons
restentdeuxchallengesimportants.Deplus,uneaméliorationdelasélectivitéexo/endoestaussihautement
souhaitable.C’estpourcelaquenousavonschoiside remplacer lePalladiumpar lePlatine.Ace jour, le
Platineaétépeudécritpourlacyclisationd’acidesalcynoïquesetd’amides.Cependant,sacapacitéàactiver
lesliaisonsmultiplescarbone‐carbone(alcynes,alcènesetallènes)estlargementdécriteetenparticulier,le
selPtCl2s’estmontrétrèsefficacepourlesréarrangementsd’énynes.
LapréparationdescomplexesSCSindènediidedePlatineainsiqueleurapplicationencatalysepourla
cycloisomérisationd’acidesalcynoïquesetdeN‐tosylalcynylamidessontdécritesdanscechapitre3.8Pour
lapremièrefois,unlargeéventaildeδ‐et‐lactones/lactamesontainsiétépréparésavecdetrèsbonnes
sélectivitésetd’excellentsrendements.
177
Schéma3.1SynthèsedescomplexesindénediidesdePtIII‐IV
Lescomplexesindènediidedeplatineciblésontétésynthétisésen2étapesàpartirdespro‐ligandsIa,b
décritsdanslechapitre2(Schéma3.1).LescomplexesindénylesIIa,bsontdansunpremierlieuforméspar
C‐Hactivationpuisdéprotonés.L’utilisationd’acétatedesodiumdansletoluèneà90°Cpermetlaformation
des espèces dimère et trimère IIIa,b avec de bons rendement (IIIa: 78%et IIIb: 87%). Les complexes
chloroplatinate IVa,b sont, quant à eux, obtenus en utilisant la diisopropyléthylamine supportée sur
polystyrène (PS‐DIEA) en présence de chlorure de tétrabutylammonium (IVa: 88% et IVb: 84%). La
structuredechaquecomplexeaétéconfirméesansambiguïtéparspectroscopieRMNmulti‐noyaux(31P,1H
et13CRMN)etdiffractiondesrayonsX.
Tableau3.1EvaluationdespropriétéscatalytiquesducomplexeindènediidedePlatineIIIb.
Entrée Sub.Cat.
(mol%[M])T(°C) t(h)
Conv
(%)b
178
1 1a III(5) 90 10 >99
2 IIIb(1)
IIIb(0.05)
50 3 97
3 90 12 >99c
4 1b III(5) 90 12 >99(98)
5 IIIb (5) 90 0.4 >99
6 IIIb(2) 90 3 >99c
7 IIIb(0.4) 90 18 >99d
8 1c III (5) 25 0.5 >99
9 IIIb(5) 25 0.5 >99
10 1d III(5) 60 0.16 >99(98)
11 IIIb (5) 60 1 >99(88)
(a)Touslestestscatalytiquesontétéréaliséssousatmosphèred’argonenpartantde0.1mmoldesubstrat(0.14MdansCDCl3).(b)Lesconversions
ontétédéterminéeparRMN1H.Lesrendementsisoléssontdonnéeentrecrochets(c)Laconcentrationdusubstratestde2M.(d)Laconcentration
desubstratestde0.83M.
Dansunpremiertemps,uneévaluationrapidedesperformancescatalytiquesdes4complexesIII‐IVaété
réaliséeenprenantlacycloisomérisationdel’acide5‐hexynoïque1acommeréactionmodèle(Tableau3.1).
LedimèredePlatineIIIbdonnelesmeilleursrésultatsavecuneconversioncomplètede1aaprèsseulement
3h à 50°C dans le chloroforme avec 1 mol% de charge en Pt. Ce résultat représente une amélioration
significativeparrapportaucomplexeVaveclequelilfallait10hà90°Cenprésencede5mol%dePdpourle
mêmerésultat.Parconséquent,lecomplexeIIIbaétéutilisépourlerestedel’étude.Letrèsbonrésultat
obtenuavecl’acide5‐hexynoïquenousaencouragéàtesterlacycloisomérisationdelaN‐tosylamide1bqui
estbeaucoupplusdifficileàcycliser(cfchapitre2).Danscecas,uneaugmentationdelatempérature(de50
à 90°C) est nécessaire pour obtenir une conversion complète en 25 min avec IIIb (5 mol% de Pt). La
formationdel’alkylidènelactame2bestbienplusrapideavecIIIb(environ30foisplusrapide)qu’avecle
complexedePd correspondantV (qui nécessite 12hde réactiondans lesmêmes conditions). Grâce aux
performancescatalytiquesdeIIIb,nousavonspudiminuerlachargecatalytiqueà1puis0.2mol%dePlatine
etréaliserlacycloisomérisationen3et18hrespectivement,démontrantainsilarobustessedescomplexes
dePlatine.Lamêmeétudeaétémenéepourlaconversionde1aen2a.Danscecas,lachargecatalytiquea
étéprogressivementdiminuéejusqu’à500ppmdePtetparallèlementlatempératureaétéaugmentéede
50à90°Csanseffetnéfastesurlesperformancescatalytiques:conversioncomplèteen12hcorrespondant
àunturnovernumber(TON)de2000etunturnoverfrequency(TOF)de167h‐1.
Pourjustifierlacontributionduligandindènediide,l’activitécatalytiquedeIIIbaétécomparéaveccelle
desesprécurseursdesynthèse.Enprésencede[PtCl2(éthylène)]2,lalactone1aestforméemaissedégrade
179
rapidementpourdonnerunmélangedeproduitsnonidentifiés.Danslecasdel’amide1b,aucuneréaction
n’alieuaprès24hdechauffageà90°C.LemêmeconstatestfaitenprésenceducomplexeindènylIIb,detrès
faiblesconversionssontobservéespour1aet1baprès24h.
Lesréactionsdecyclisationde1a,benprésencedeIIIbontétésuiviesparRMN31P:laformationd’une
espèceindényleestobservéeaucoursdelatransformationetlecomplexeIIIbestrégénéréàlafindela
réaction.Toutescesobservationsétayentlaparticipationactiveduligandindènediideetdelacoopérativité
métal/ligand (activation de la fonction pro nucléophile acide/amide par déprotonation, activation de la
liaisontriplecarbone‐carbonevialacoordinationduplatine).Ceciesttotalementcohérentaveccequiavait
étédécritpourlesespècespalladiumcorrespondantes.
L’influencedelatailledecycleaensuiteétéétudiée.Paradoxalementàcequiavaitétéobservépourlesδ‐
lactonesetlactames2a,b,LePlatinenesurpassepaslePalladiumpourlaformationdecyclesà5chainons.
La cyclisation de l’acide pentynoïque1c est aussi efficace en présence de IIIb que deV. Cependant, la
conversiondel’alcynylamidecorrespondante1destbeaucouppluslenteavecIIIbqu’avecV(1haulieude
10minà60°C).Cependant,ledimèredePlatineIIIbdémontreuneactivitébeaucoupplusimportantequeV
pourlaformationdecycleà7.Dansunpremiertemps,nousavonstestélessubstrats1eet1fpossédantun
espaceurflexiblenonsubstitué.L’acide6‐heptynoïque1eestcomplétementconsuméaprèsseulement21h
à90°CenprésencedeIIIb(1mol%dePt).L’‐lactonecorrespondante2eestobtenuepureavecuntrèsbon
rendementde84%aprèsdistillation.Cerésultatreprésenteuneaméliorationsignificativeparrapportau
résultatobtenuavecV(cfchapite2).Eneffet,danscecas,leproduit2eestobtenuavecunrendementmoyen
de51%après22hà120°Cenprésencede5mol%dePd.Acejour,lesystèmeSCSindènediidedePtestle
plus efficace pour former l’‐lactone 2e. IIIb a donné également d’excellents résultats pour la
cycloisomérisation de laN‐tosylamide 1f. La conversion complète de 1f est achevée en 22h à 90°C en
présencede5mol%dePt.Aucoursduchapitre2,nousavonsvuque2fétaitobtenuavecunrendementde
seulement 53% après 130h de réaction à 90°C lorsque le complexe de Palladium V était utilisé. Le
remplacementduPdparlePtpermetunediminutionconsidérabledutempsderéaction(d’unfacteur6)et
l’obtentionde‐lactame2favecunexcellentrendementde93%.
Tableau3.2Cycloisomérisationd’acidesalcynoïqueetdeN‐tosylamidecatalyséeparlecomplexeIIIb.
180
(a)Tous les tests catalytiquesont été réaliséssous atmosphèred’argonenpartantde0.1mmolde substrat (0.14MdansCDCl3).La charge
catalytiqueestde1mol%pourlesacidesalcynoïquesetde5mol%pourlesN‐tosylalcynylamides.(b)LesconversionsontétédéterminéeparRMN
1Haveclemésitylènecommestandardinterne.Lesrendementsisoléssontdonnéeentrecrochets(c)Laconcentrationdusubstratestde0.5M.(d)
lesproduitsd’additionintermoléculairespntdétectésparRMN1Hdanslebrutdelaréaction.(e)unmélangedeproduitsnonidentifiés(19%)aété
détectéparRMN1Hdanslebrutdelaréaction.(f)Mélangedeproduits.(g)Laconcentrationdusubstratestde1M.(h)L’anhydridephtalique(57%)
estdétectéparRMN1Hdanslebrutdelaréaction.
Pourillustrerlelargedomained’applicationducomplexeIIIb,laformationd’autrescyclesà7chaînonsa
ensuiteétéexplorée(Tableau3.2).Lessubstratsα‐substitués1g,hontétécyclisésefficacementdémontrant
ainsilacompatibilitédesgroupementsestersaveclesystème.Ilestàsoulignerqueseulement7hsuffisent
pourconvertir1hen2h.Cetteaccélérationsignificative(lorsqu’oncomparelerésultatà1f)estàmettreau
créditdel’effetThorpe‐ingoldetdel’acidificationdelaN‐tosylamide.Unecyclisationrapideetfacileaaussi
étéobservéeaveclessubstratsorthobenzoïque1i,j.Leurcyclisationestcomplèteenseulement1‐2hà90°C.
Parcomparaison,lacyclisationde1ienprésenceducomplexeindènediidedePdVdemande9.5hderéaction
pouratteindre95%deconversion.AvecIIIbcommecatalyseur,les‐lactonesetlactames2g‐jsontisolées
avecdebons rendements (57‐92%).Desétudesdediffractionsdes rayonsX sur2h et2j ontpermisde
confirmersansambigüitélemodedecyclisation(7‐exovs6‐endoetattaque‐Nvs‐O).
Lestrèsbonsrésultatsobtenusaveclescyclesà7chaînonsnousontmotivésàtesterensuitelaformation
de lactones/lactames à 8 chainons. Cependant, la réaction intermoléculaire conduisant à une mixture
d’oligomèresaétéobservéeavecl’acide7‐octynoïqueetaucuneréactionn’aétédétectéeavecl’alcynylamide
correspondanteaprès24h.Pourfavoriserlacyclisation, lessubstratsrigides1k,ldérivantdel’anhydride
181
phtaliqueontétésélectionnés.Danscecas,lalactoneà8chaînons2kapuêtreréparéeavecunrendement
isoléde43%,cependant,laréactionderétro‐acylationaégalementlieuenmêmetemps.LaN‐tosylamide1l
correspondanteaégalementétéconvertieenprésencedeIIIb.Maisaulieudulactameà8chainonsciblé,
deuxnouveauxcomposésspiroontétéisolé(96%derendementratio:86:14).Lesstructuresde2l‐N‐spiro
et2l‐O‐spiroontétédéterminéspardiffractiondesrayonsX.leurformationrésulteprobablementd’une
cyclisation intramoléculaire en cascade. Bien que le complexe de Pt IIIb soit très efficace pour les ‐
lactones/lactames,l’obtentiondecycleà8resteunelimitations.
Tableau3.3Cycloisomérisationdessubstrats1m‐rcomportantunalkyneinterneenprésenceIIIbetdepyrogallol.
(a)Tous les testscatalytiquesontétéréaliséssousatmosphèred’argonenpartantde0.1mmoldesubstrat(0.14MdansCDCl3).Lacharge
catalytiqueestde5mol%dePtet0/30mol%depyrogallol.(b)LesconversionsontétédéterminéeparRMN1Haveclemésitylènecommestandard
interne.Lesrendementsisoléssontdonnéeentrecrochets(c)15%d’acide5‐oxoheptynoïque(produitssecondaire).
Les acides carboxyliques et le N‐tosylamides possédant des alcynes internes sont des substrats
particulièrement difficiles en réaction de cycloisomérisation aussi bien en termes d’activité et que de
sélectivitéexo/endo(Tableau3.3).Aveclestrèsbonsrésultatsobtenuspourlescyclesà6et7chaînons,nous
182
avonstestélecomportementdudimèreIIIblorsquedesquestionsdesélectivité5‐exo/6‐endoet6‐exo/7‐
endoseposaient.Lescomposés1m,nontdoncétécyclisésà90°Cavec5mol%dePt.Danslesdeuxcasune
diminutionspectaculairedutempsderéaction(jusqu’à28foisplusrapide)estobservéeenutilisantIIIbau
lieudeV.Uneaccélérationimpressionnanteaégalementétéobservéeaveclessubstratsα‐substitués1o,p
(parunfacteur18).Enseulement5minutes,l’acideesttotalementconvertiavecIIIb(contre1.5havecV).
Enplusd’uneaugmentationimpressionnantedelavitessederéaction,leremplacementduPdparlePt
influencelasélectivitéexo/endo.Commementionnépourlacyclisationdessubstrats1a‐d,lecomplexedePt
IIIbdémontreunepréférencenotablepourlaformationdecycleà6parrapportàsonhomologuePd.Cette
caractéristique est encore une fois observée avec la cyclisation 6‐endo de 1m qui est légèrement
prédominantedanslecasduPt(exo/endo1:1.6)alorsqu’avecVlacyclisation5‐exoestfavorisée(exo/endo
1.5:1).Uneaugmentationdelasélectivitéexo/endoestégalementdétectéeaveclesubstratα‐substitué1o
avec une sélectivitéexo/endo de 1/4.9. LesN‐tosylamide correspondantes1n,p, quant à elles, subissent
exclusivement une cyclisation de type 6‐endo et les δ‐lactames correspondant sont obtenus avec des
rendementtrèsélevés.
LapropensiondeIIIbàformerefficacementdescyclesà6et7chaînonsestuniqueetsoulèvelaquestion
delasélectivité6‐endo/7‐exo.Pouressayerderépondreàcettequestion,nousavonsétudiélacyclisationde
deux types de substrats difficiles: les acides 5‐alcynoïque interne qui ont rarement été testés en
cycloisomérisation jusqu’à ce jour, et leurs homologues N‐tosylamides dont la cyclisation n’avait aucun
précédent.Après36hà90°CenprésencedeIIIb,laconversionde1qrestemodeste(38%).Cependant,la
réactionesthautementsélectiveenfaveurdela6‐exocyclisationpuisquelaδ‐lactone2qexoestforméede
manièreprépondéranteavecunratiode24:1parrapportàl’‐lactone2qendo.Untestsimilaireaétéréalisé
avec la N‐tosylamide correspondante 1r. Dans ce cas, le complexe IIIb a montré une faible activité ne
permettantpasdecaractériserlesproduitsdecylisations(6%après18h).
Nosprécédentstravauxsurlemécanismedelaréactiondecycloisomérisationcatalyséeparlescomplexes
indènediidedePdapermisdemettreenévidencel’importancedurôledenavetteàprotonsjouéparune
secondemoléculedesubstrat.9L’ajoutd’unadditifsdonneurdeliaisonhydrogène,enparticulierdedérivés
de catéchol, a montré une augmentation significative de l’activité et de la sélectivité. Afin d’améliorer
l’applicationetl’efficacitéducomplexedePtIIIb,l’influencedupyrogallolaétéétudiéesurlacyclisationde
substrats internes.L’ajoutde30mol%depyrogallolaentrainéuneaugmentation impressionnantede la
vitesse de cyclisation (par un facteur 12) pour1m‐p (Tableau 3.3). De plus, les δ‐lactones et lactames
correspondantsontétéobtenusavecdessélectivitésamélioréesenfaveurdela6‐endocyclisation(ratio5‐
exo/6‐endode1:3à>1/99).L’ajoutdudonneurdeliaisonhydrogènesemontreaussitrèsbénéfiquepourla
183
cyclisationdedérivés5‐alcynoïques.L’acidecarboxylique1qesttotalementconvertien6hetlaδ‐lactoneZ‐
2qexoestobtenueavecuneexcellentesélectivité(6‐exo/7‐endo32:1).Encoreunefois,l’indènediidedePtest
remarquablementplus actif que celuidePd, IIIb converti 10 foisplus rapidement1q queV.Deplus, la
cyclisationestpluspropreenprésencede IIIb avecunediminutiondemoitiéduproduit secondaire.Le
résultatobtenuaveclaN‐tosylamide1rsontencoreplusremarquables.Pourlapremièrefoiscesubstrat
peutêtreefficacementcyclisé.Après18hà90°C,1resttotalementconvertietunratio6‐exo/7‐endode2.1/1
estobservé.
En conclusion, nous avons démontré que le complexe SCS indèndiide de Paltine IIIb catalyse la
cycloisomérisationd’acidesalcynoïquesetdeN‐tosylalcynylamidesetmêmequ’ilsurpassaitsonhomologue
PalladiumV.Notamment,lePlatineestplusefficacepourlaformationdecycleà6et7chaînons.Lavitesse
de réaction et la sélectivité pour la cyclisation 6‐endo ou 6‐exo ont été significativement améliorées en
utilisantlepyrogallolcommeadditifdonneurdeliaisonhydrogène.Pourlapremièrefois,unegrandevariété
deδ‐et‐lactones/lactamesontpuêtrepréparéesavecdehautessélectivitésetdetrèsbonsrendements.
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Abstract
This work contributes to the study of new indenediide pincer complexes, including their
synthesis, characterization, and finally their activity in metal-ligand cooperative catalytic
cycloisomerization of a range of alkynoic acids and N-tosyl alkynylamides.
The 1st chapter compiled a non-exhaustive bibliographical survey of the field of metal-ligand
cooperation in catalysis, from the pioneering work of Noyori using amido-Ruthenium complexes for
hydrogenation, to the recent work of Milstein with pincer complexes based in dearomatized
pyridine.
The 2nd chapter of this thesis is dedicated to the development of the newly-tuned Pd indenediide
pincer complexes and their application in metal-ligand cooperative catalysis. A structural
modulation, by varying the R substituents Ph at phosphorus with iPr, was performed in attempt to
increase the robustness of the Pd pincer complexes and enhance thereby their catalytic
performance. Thus, two novel complexes were successfully synthesized and fully characterized
(NMR, IR, XRD). Initial study demonstrated a better performance of the new complexes than their
predecessor, as the cycloisomerization of N-tosyl alkynyl amides can be efficiently achieved.
Moreover, the N-tosyl alkynyl amide scope was extensively studied, from linear non-substituted C5-
C7, then substituted, benzo-fused, and finally to internal alkyne ones. Eventually, a majority of exo
lactams products, together with the unusual internal endo lactam can be prepared in excellent
yields (most often 90 %). Note that the obtaining for the first time of 7-member ring methylene
caprolactam via a cycloisomerization was pretty inspiring. Nevertheless, improvements for the
current catalytic system remain.
The 3rd chapter of this thesis is devoted to further modulation of the pincer complexes, in
particular the switching of metal center from Palladium to Platinum. The newly-synthesized Pt
complexes were evaluated in the cycloisomerization of N-tosyl alkynylamides and alkynoic acids,
and the dimeric complex with iPr groups at the P atoms exhibited the best performance. The
substrate scope was further extended to more challenging ones. In most cases, reactions were
remarkably accelerated. Direct comparisons upon amides and acids bearing internal alkyne further
indicated that the Pt complex outperformed its Pd analogue. In particular, the Pt pincer complex is
extremely efficient for the formation of 6 and 7-membered rings. In light of in-depth understanding
of the mechanism, several selected additives were employed as H-bond donor, to reinforce the
cyclization. The reaction rate and selectivity for 6-endo (vs 5-exo) as well as 6-exo (vs 7-endo)
cyclizations was greatly improved by using pyrogallol. For the first time, a large variety of and -
lactones/lactams could be prepared with high selectivities and in very good yields.
These results emphasize the unique properties of SCS indenediide pincer complexes and extend
further their catalytic applications.
Key words: pincer complex, metal-ligand cooperation, catalysis, cycloisomerization
Résumé de thèse
Cette thèse décrit l’étude réalisée sur des complexes portant le ligand pince indendiide, incluant
leur synthèse et caractérisation ainsi que leur activité en catalyse coopérative métal/ligand de
cycloisomérisation d’acide alcynoïques et N-tosyl alkynylamides.
Le premier chapitre fait un point bibliographique non-exhaustif du domaine de la catalyse
coopérative métal/ligand, des premiers travaux précurseurs de Noyori sur les processus
d’hydrogénation avec des complexes amido de ruthénium aux récents travaux de Milstein avec des
complexes pince à base de pyridine déaromatisée.
Le deuxième chapitre porte sur le développement de nouveaux complexes pince indendiide du Pd
et leur application en catalyse coopérative métal/ligand. La modification structurale réalisée,
remplacement des substituants Ph sur l’atome de phosphore par des iPr, visait à augmenter la
robustesse des complexes et améliorer ainsi leur performance en catalyse. Deux nouveaux
complexes ont été préparés et entièrement caractérisés (RMN, IR, DRX). Les premières évaluations
d’activité catalytique ont en effet révélé une meilleure activité de ces nouveaux complexes
comparés à leurs prédécesseurs, puisqu’ils sont capables de cycloisomériser de manière efficace les
N-tosyl alkynyl amides. Une large gamme de substrats a été étudiée, incluant N-tosyl alkynyl amides
linéaires non-substituées et substituées, d’autres à base de squelette phénylène, et même celles à
alcyne en position interne. De manière générale, une majorité d’exo-lactames est formée avec des
très bons rendements (~90%) sauf lorsque l’alcyne est en position interne, cas dans lequel l’endo-
lactame est formée préférentiellement. Il est important de souligner que le résultat phare de ce
chapitre est la préparation pour la première fois de methylène lactames à 7-chainons par
cycloisomérisation. Malgré les avancées notables atteintes dans ce chapitre, la grand modularité
des complexes pince étudiés permet d’espérer des améliorations du système catalytique.
Ces améliorations sont présentées lors du troisième chapitre. Il s’agit ici de remplacer l’atome de Pd
par le Pt. Les nouveaux complexes préparés ont été évalués dans la cycloisomérisation de acides
alcynoïques et N-tosyl alcynyl amides et le meilleur d’entre eux a été identifié (dimère à
groupement iPr sur l’atome de P). A nouveau une large gamme de substrats, acides et amides, a été
étudiée faisant varier la taille de cycle et la position de l’alcyne. La stratégie s’est avérée fructueuse
puisque de manière générale ce complexe de Pt s’est montré plus actif que l’équivalent à base de Pd.
En particulier, ce complexe présente une activité remarquable pour la transformation d’alcynes
internes et la formation de cycles à 6 et 7-chaînons. La connaissance approfondie du mécanisme de
la réaction a conduit aussi à l’utilisation d’additifs donneurs de liaison H afin de favoriser la réaction
de cyclisation. Grâce à l’utilisation du pyrogallol, la vitesse de réaction et la sélectivité 6-endo (vs 5-
exo) et 6-exo (vs 7-endo) ont été améliorées de manière significative. Pour la première fois, une
grande variété de δ et ε-lactones et lactames ont pu être préparées avec des très bonnes sélectivités
et rendements.
L’ensemble de ces résultats souligne les propriétés uniques de ces complexes pince indendiide et
étend leurs applications catalytiques.