et discipline ou spécialité

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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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

2.9References

  (1)  Jutzi, P.; Redeker, T. Eur. J Inorg Chem 1998, 1998, 663.   (2)  Siemeling, U. Chem Rev 2000, 100, 1495.   (3)  Öfele, K. Angew Chem Int Ed 1968, 7, 950.   (4)  Briggs, P. M.; Young, V. G.; Wigley, D. E. Chem Commun 1997, 791.   (5)  Dragutan, V.; Dragutan, I.; Verpoort, F. Platinum Metals Review 2005, 49, 33.   (6)  Boeda, F.; Clavier, H.; Nolan, S. P. Chem Commun (Camb) 2008, 2726.   (7)  Freund, C.; Barros, N.; Gornitzka, H.; Martin‐Vaca, B.; Maron, L.; Bourissou, D. Organometallics 2006, 25, 4927.   (8)  Oulié, P.; Freund, C.; Saffon, N.; Martin‐Vaca, B.; Maron, L.; Bourissou, D. Organometallics 2007, 26, 6793.   (9)  Jensen, D. M.‐M. C. The Chemistry of Pincer Compounds; Elsevier Science, 2007.   (10)  Albrecht, M.; van Koten, G. Angew Chem Int Ed 2001, 40, 3750.   (11)  van der Boom, M. E.; Milstein, D. Chem Rev 2003, 103, 1759.   (12)  Cavell, R. G.; Kamalesh Babu, R. P.; Aparna, K. J Organomet Chem 2001, 617‐618, 158.   (13)  Jones, N. D.; Cavell, R. G. J Organomet Chem 2005, 690, 5485.   (14)  Cantat, T.; Mezailles, N.; Auffrant, A.; Le Floch, P. Dalton Trans 2008, 1957.   (15)  Oulie, P.; Nebra, N.; Saffon, N.; Maron, L.; Martin‐Vaca, B.; Bourissou, D. J Am Chem Soc 2009, 131, 3493.   (16)  Nebra, N.; Saffon, N.; Maron, L.; Vaca, B. M.; Bourissou, D. Inorg Chem 2011, 50, 6378.   (17)  Nebra, N.; Ladeira, S.; Maron, L.; Martin‐Vaca, B.; Bourissou, D. Chem Eur J 2012, 18, 8474.   (18)  Oulié, P.; Nebra, N.; Ladeira, S.; Martin‐Vaca, B.; Bourissou, D. Organometallics 2011, 30, 6416.   (19)  Lambert, C.; Utimoto, K.; Nozaki, H. Tetrahedron Lett 1984, 25, 5323.   (20)  Wakabayashi, T.; Ishii, Y.; Ishikawa, K.; Hidai, M. Angew Chem Int Ed 1996, 35, 2123.   (21)  Nebra, N.; Monot, J.; Shaw, R.; Martin‐Vaca, B.; Bourissou, D. Acs Catal 2013, 3, 2930.   (22)  Monot, J.; Brunel, P.; Kefalidis, C. E.; Espinosa‐Jalapa, N. Á.; Maron, L.; Martin‐Vaca, B.; Bourissou, D. Chem Sci 2016, 7, 2179.   (23)  F. G. Bordwell, H. E. F., David L. Hughes, Tsuei Yun Lynch, A. V. Satish, Young E. Whang J Org Chem 1990, 55.   (24)  Campbell, M. J.; Toste, F. D. Chem Sci 2011, 2, 1369.   (25)  Cannizzo, L. F.; Grubbs, R. H. J Org Chem 1985, 50, 2316.   (26)  Nebra, N.; Lisena, J.; Saffon, N.; Maron, L.; Martin‐Vaca, B.; Bourissou, D. Dalton Trans 2011, 40, 8912.   (27)  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.   (28)  Tolman, C. A. Chem Rev 1977, 77, 313.   (29)  Jung, M. E.; Piizzi, G. Chem Rev 2005, 105, 1735.   (30)  Kostal, J.; Jorgensen, W. L. J Am Chem Soc 2010, 132, 8766.   (31)  Kantorowski, E. J.; Kurth, M. J. Tetrahedron 2000, 56, 4317.   (32)  Cao, H.; Vieira, T. O.; Alper, H. Org Lett 2011, 13, 11.   (33)  Fujita, K.; Takahashi, Y.; Owaki, M.; Yamamoto, K.; Yamaguchi, R. Org Lett 2004, 6, 2785.   (34)  Casadei, M. A.; Galli, C.; Mandolini, L. J Am Chem Soc 1984, 106, 1051.   (35)  Hu, T.; Li, C. Org Lett 2005, 7, 2035. 

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  (36)  Takeuchi, K.; Holloway, W. G.; Mitch, C. H.; Quimby, S. J.; McKinzie, J. H.; Suter, T. M.; Statnick, M. A.; Surface, P. L.; Emmerson, P. J.; Thomas, E. M.; Siegel, M. G. Bioorg Med Chem Lett 2007, 17, 6841.   (37)  Ritter, S.; Horino, Y.; Lex, J.; Schmalz, H. G. Synlett 2006, 3309.   (38)  Bian, M.; Yao, W.; Ding, H.; Ma, C. J Org Chem 2010, 75, 269.

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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;ordeposit@ccdc.cam.ac.uk).

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. 

158

  (35)  Hong, L.; Sun, W.; Yang, D.; Li, G.; Wang, R. Chem Rev 2016, 116, 4006.   (36)  Vogl, E. M.; Gröger, H.; Shibasaki, M. Angew Chem Int Ed 1999, 38, 1570. 

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.