Citation
Development of a New Class of Atropisomers

Material Information

Title:
Development of a New Class of Atropisomers
Creator:
Cardoso, Flavio
Publisher:
University of Florida
Publication Date:
Language:
English

Thesis/Dissertation Information

Degree:
Doctorate ( Ph.D.)
Degree Grantor:
University of Florida
Degree Disciplines:
Chemistry
Committee Chair:
APONICK,AARON
Committee Co-Chair:
CASTELLANO,RONALD K
Committee Members:
DOLBIER,WILLIAM R,JR
BRUNER,STEVEN DOUGLAS
SLOAN,KENNETH B
Graduation Date:
8/9/2014

Subjects

Subjects / Keywords:
Amines ( jstor )
Catalysis ( jstor )
Chromatography ( jstor )
Imidazoles ( jstor )
Ligands ( jstor )
Nitrogen ( jstor )
Palladium ( jstor )
Phosphines ( jstor )
Room temperature ( jstor )
Solar X rays ( jstor )
asymmetric
atropisomer
biaryl
catalysis
stacking

Notes

General Note:
The design of new chiral ligands is on the cutting edge of organic synthesis. In particular, atropisomeric ligands have been demonstrated to be very successful in asymmetric catalysis; however, the majority of axially chiral biaryl ligands such as BINAP are comprised of sixmembered aromatic rings. The presence of five-membered heteroaromatics in chiral biaryl compounds are rare due to larger bond angles and, in consequence, smaller barriers to rotations. Chiral biaryls with five-membered rings have not been explored in asymmetric catalysis, but should offer significant advantages. In this context, creative new atropisomeric ligand scaffolds with smaller ring sizes should advance the field. In this thesis, a novel strategy towards the design of chiral ligands is described, which allows the synthesis of atropisomeric ligands containing a five membered ring in the chiral biaryl backbone. At the outset, we aimed to design a new system in which the barrier to rotation of a biaryl bond is increased due to the decrease of the ground state energy of enantioconfomers. In general, the presence of sterically demanding groups ortho to the atropisomeric axis are employed to increase the barrier to rotation, but to the best of our knowledge the simple concept of ground state stabilization reported herein has not been explored. Initial studies were aimed at determining the feasibility of this strategy and simple model compounds were designed to undergo intramolecular pi-stacking. The strategy was then applied in the creation of a new axially chiral P,N-ligand comprised of a five-membered imidazole ring in the biaryl backbone. This ligand was prepared as a single enantiomer and evidence of pi-stacking interactions was observed in solution and in the solid state. After developing a method to isolate significant amounts of this P,N-ligand as a single enantiomer, it was necessary to evaluate its performance in enantioselective catalysis. It was found that in the A3-coupling reaction, our ligand furnished the products in 24h at 0C in high yields and enantioselectivies over a broad range of substrates, including alkyl and aryl aldehydes. The method overcomes the limitations in scope associated with QUINAP, the benchmark ligand for this reaction. Moreover, copper-catalyzed acetylide addition to pyridinium ions or Michael acceptors were explored and gave good initial results. The ligand could also be employed in palladium-catalyzed allylic alkylation reaction to give the products in high ee. Research in this area is ongoing in our group and this thesis documents the results obtained during the past five years.

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UFRGP
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All applicable rights reserved by the source institution and holding location.
Embargo Date:
8/31/2016

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Design,Preparation,andImplementationofanImidazole-Based ChiralBiarylP,N-LigandforAsymmetricCatalysisFlavioS.P.Cardoso,KhalilA.Abboud,andAaronAponick *DepartmentofChemistry,UniversityofFlorida,P.O.Box117200,Gainesville,Florida32611,UnitedStates*SSupportingInformationABSTRACT: Anewstrategyforincreasingthebarrierto rotationinbiarylshasbeendevelopedthatallowsforthe incorporationof5-memberedaromaticheterocyclesinto chiralatropisomers.Usingthisconcept,animidazolebasedbiarylP,N-ligandhasbeendesignedandpreparedas asingleenantiomer.Thisligandperformsexceptionally wellintheenantioselectiveA3-coupling,demonstratingthe potentialofthisnewdesignelement.Thechiralbiarylstructuralmotifisanimportant componentfoundinadiversearrayofcatalystsfor enantioselectivesynthesis.1Ligandsbuiltonthebinaphthalene andbiphenylbackbonesareregularlyemployedinavarietyof reactions,withsuchsuccessthatBINAP( 1 )andBINOLare referredtoasprivilegedligands.2Theatropisomericbackbone inthevastmajorityofchiralbiarylligandsiscomprisedof substitutedorfusedbenzenoidaromaticsthatrelyon ortho substitutiontohinderrotationaboutthebiarylbond.3Although reducingthestericdemandbyremovingsubstituentsfromthe 2-or8-positionlowersthebarriertorotationandhence reducescon gurationalstability,4P,N-ligandssuchasQUINAP ( 2 )5andPINAP( 3 )6havesuccessfullybeenpreparedand employedinenantioselectivetransformations.7,8Itiswellknownthatchangingthedihedralandbiteanglesofthebiaryl candrasticallya ectligandperformance,andthesuccessof 2 and 3 canbeattributedtomodifyingtheseparametersaswell aschangingthedonatingpropertiesoftheligand.9AtropisomericP,N-ligandshaveproventobehighly selective,7butmakingstructuralmodi cationsfor ne-tuning oftheligandischallenging,andrelativelyfewderivativesare known.8Incontrasttothesubstitutedorfused6-membered aromaticscommonlyencountered,5-memberedheteroaromaticswouldo eranew,unexploredchemicaldiversityand bemucheasiertoprepareandmodifyusingestablished methods.10Onepotentialproblemisthat ortho -substituentson 5-memberedringsarenotheldascloselyinspacetothe adjacentaromaticgroupduetothemodi edbondanglesofthe ringsystem.Thismayleadtoareducedbarriertorotationand lossofchirality.Inhisseminalwork,Brownencounteredthis di cultywhen 4 ,anindoleversionofQUINAP,wasprepared andfoundnottobecon gurationallystable(Figure1).11While thismaypotentiallybeovercomebytheincorporationof increasinglylarge ortho -substituents,12thecentraldogmafor inducingatropisomerism,wehypothesizedthatafundamental newapproachtoincreasingthebarriertorotationcouldbe developedtoenablenewclassesofhighlyreactiveandselective catalysts.Morespeci cally, wehypothesizedthatthebarrierto rotationinbiarylscanbeincreasedbystabilizingthechiralgroundstateconformationinsteadofdestabilizingtheplanartransition state,leadingtoracemization (Figure1).Surprisingly,tothebest ofourknowledge,thisstrategyhasneverbeenexplored.Herein wereportour ndingsinthisareaincludingthedesign, synthesis,deracemization,andsuccessfulimplementationofa chiralimidazole-basedbiarylP,N-ligandforenantioselective copperacetylideaddition. Thedesignofourligandcentersaroundtheincorporationof a5-memberedelectron-richaromaticheterocyclethatcontains acoordinatingatomandfunctionalelementsthatstabilizethe chiralconformation.Attheoutsetweenvisionedanimidazolebasedsystem,providingabasiccoordinationsiteandasecond nitrogenatomthatcouldbeappendedwithagrouptostabilize thechiralconformation 7 through -stackinginteractions (Figure2).ThiswouldprovideauniqueP,N-ligandwith modi edbiteanddihedralangles. Thesynthesisofracemic 7 wasachievedinseveral straightforwardstepsstartingwith2-hydroxy-1-naphthaldehyde 8 ,wherebytherequisiteheterocycleandphosphinogroups werereadilyintroduced(Scheme1).Intheevent,condensation of 8 withammoniumacetateandbenzilfurnished 9 in80% Received: August6,2013 Published: September17,2013 Figure1. Con gurationallyunstableligand 4 . Communication pubs.acs.org/JACS ©2013AmericanChemicalSociety14548dx.doi.org/10.1021/ja407689a | J.Am.Chem.Soc. 2013,135,14548 14551

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yield.13ThefreealcoholwasthenprotectedastheTBSether, andtheresultingimidazolewasalkylatedwithpenta uorobenzylbromidetoyield 10 .Thealcoholwasthendeprotected, convertedtothetri ate,andcoupled14toproduce rac 7 inca. 33%overallyieldfromcommercialmaterials.Wewere encouragedto ndanABpatternforthebenzylicprotonsin the1HNMRspectrumof rac 7 ,indicatingthattheyare diastereotopicontheNMRtimescale. Withagoodsourceof 7 established,albeitracemic,itseemed prudenttoperformapreliminaryligandacceleratione ect study.Tothisend, rac 7 wasemployedinacopper-catalyzed A3-coupling15ofbutyraldehyde,trimethylsilylacetylene,and dibenzylamine(eq1).Muchtoourdelight,amineproduct 13 wasisolatedin97%yieldafter24hatroomtemperature. Structurally,ligand 7 issigni cantlydi erentthantheknown biarylP,N-ligandssuchasQUINAP,where 13 isobtainedin 88%after120h.6,16Extendedreactiontimesofseveraldaystoa weekarecommonlyobservedusingtheseligands.17With rac 7 , thereactivitywasenhancedtosuchanextentthatthereaction couldevenbeperformedat0 ° C,providing 13 in92%yield after24h(eq1).Thisshouldbeadvantageousforachieving highselectivities,andattemptswerenextmadetoobtainthe ligandasasingleenantiomer. ForQUINAPandderivativescontainingonlyaxialchirality, non-racemicmaterialistypicallyobtainedbyresolution involvingcoordinationtoachiralPdsalt,crystallization,and decomplexation.5,11,18Unfortunately,thisstrategydidnot providesatisfactoryresults,and 7 couldonlybeobtainedin 85 90%ee.Fortunately,insteadofresolving 7 ,afterextensive optimizationitwasfoundthattheracemiccompoundcouldbe convertedtoasingleenantiomerinatwo-stepprocess,ine ect deracemizingit.Toachievethis, rac 7 wastreatedwithcomplex 14 andKPF6inre uxingacetonefor24htoprovide 15 in81% yieldasasinglediastereomerwhosestructurewascon rmedby X-raycrystallography(Scheme2).19,20Thefreeligandwasthen obtainedinhighyieldand98%eeaftertreatmentwithdppe.21Interestingly,theinclusionofKPF6isvitaltothesuccessof thereaction,astwonon-interconvertingdiastereomersare observedintheabsenceofthisadditive.Controlexperiments wereperformedtostudythisissue,andanequalmixtureoftwo diastereomerswasformedwhenKPF6wasomittedbutunder otherwiseidenticalreactionconditions.Additionally,recomplexationof 7 (98%ee)to 14 resultsinasingle diastereomerthatdoesnotreverttothesame1:1mixtureof diastereomersuponheating. Itisimportanttonotethat 7 iscon gurationallystable,and samplesoftheligandhavebeenstoredforseveralmonthswith nolossofopticalpurity.Onefurtherquestionregardingthe structureinvolvestheroleoftheC6F5groupand -stacking. Evidenceof -stackingwasobtainedearlyonwhenX-rayqualitysinglecrystalsweregrownfromasampleof rac 7 and thestructurewassolved(Figure3).19TheF5-phenylgroupis -stackingwiththenaphthaleneringatameandistanceof3.36 Åinaparallel,o setstack.22Thisdemonstratesthat -stacking ispossibleinthesolidstate,butdoesnotnecessarilyindicate thatithasanyin uenceonthebarriertorotationinsolution. Literatureprotocolsusedtostudy -stackinginvolve modi cationofthesubstitutionononeofthearomatic rings.22Toprobethisissue,acomparisonofbarrierheights between 7 andacompoundthatwouldmaintainthesteric Figure2. Stabilizationofthechiralconformationin 7 . Scheme1.SynthesisofRacemicLigand7 Scheme2.DeracemizationofLigand7 Figure3. X-raycrystalstructureshowing -stacking. JournaloftheAmericanChemicalSociety Communicationdx.doi.org/10.1021/ja407689a | J.Am.Chem.Soc. 2013,135,14548 1455114549

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pro lebutperturbtheabilityto -stackwasneeded.Inaccord withliteratureprecedent,thecorrespondingnonuorinated compoundwaschosenbecauseifthee ectwaspurelysteric,no signi cantdi erencewouldbeexpected.If -stackingisindeed involvedinthesolutionphase,asigni cantdi erenceinbarrier heightshouldbeobserved. Tomakethenecessarycomparisons, 7-H5wasprepared from 8 usingtherouteoutlinedabove.19Interestingly,the penultimatenonourinatedpalladiumcomplex 15-H5was con gurationallyunstable,andthe1:1diastereomericmixture ofcomplexespreparedfromracemic 7-H5convergedona singlediastereomeruponstandingatroomtemperaturefor24 h.When 7-H5wasliberatedfromthePdcomplex,itwas obtainedin52%ee,instarkcontrastto 7 whichwasisolatedin 98%ee.Racemizationstudieswereperformed23onboth 7-H5and 7 toobtaintheirbarrierstorotation,anditwasfoundthat 7-H5hasahalf-lifeof22minat75 ° CinDCE,whereas 7 hasa half-lifeof8.70h.19Thiscorrespondsto G75 ° C =2.2kcal/ mol,19avaluethatiswithintherangeofpreviouslyreported valuesfor -stacking,22anddemonstratesthattheelectronic perturbationbysimpleinclusionofthe uorineatoms signi cantlyincreasesthebarriertorotation. Withthenewchiralnon-racemicligand 7 inhand,weturned ourattentiontotestingitsperformanceinanenantioselective transformation.Tothisend, 7 wasemployedinthe enantioselectiveA3-coupling.AscanbeseeninTable1,the reactionswerehighlyenantioselectiveoverarangeof aldehydes.Asmightbeexpected,15withaliphaticaldehydes -substitutionincreasesselectivity(e.g.,entry1vs4).Itisalso noteworthythat,using 7 ,theseconditionsworkwellfor aromaticaldehydes,whicharethemostchallengingsubstrates forthereaction.17Remarkably,thepresenceofelectrondonatingor-withdrawinggroupshaslittlee ectonselectivity (entries5 9),nordoesthereactiontemperature.When 16g wasallowedtoreactat0 ° C,thereactionwasveryslow, yielding 17g inonly15%after4days,butin95%ee(entry8). Increasingthetemperatureto22 ° Crestoredthereactivityto anacceptablelevel(70%yieldafter24h)andhadlittlee ect ontheee(entry9).Incomparison,thepreviousbestyield obtainedwiththiselectron-de cientaldehydewas43%after4 daystoobtaintheproductin63%ee.17aCarreirahasalsodevelopedmodi edconditionstoemploy theamine 19 ,whichisreadilydeprotected.24Withthese conditions,usingthePINAPligand,theyreportthataromatic aldehydesdonotprovidesatisfactoryresults.24Incontrast, ligand 7 enablestheuseofbothaliphaticandaromatic aldehydeswithhighenantioselectivity(Scheme3).These resultsleadtotheconclusionthat 7 isthebestligandforthe enantioselectiveA3-couplingtodate,displayingthehighest levelsofreactivityandselectivityoverthebroadestrangeof substrates.Moreimportantly,theseresultsdemonstratethe potentialofthenewdesignelementexempli edby 7 . Insummary,wehavedevelopedanewconceptforincreasing thebarriertorotationinbiarylswherebythechiralground-state conformationisstabilizedby -stackinginteractions.This strategywassuccessfullyappliedtothedesignofligand 7 ,a Table1.EnantioselectiveA3-CouplingEmploying7a aSeeSupportingInformationforfullexperimentaldetails.bIsolated yieldsofpuri edcompounds.cDeterminedafterdesilyation.dReaction allowedtorunfor4daysat0 ° C.eReactionallowedtorunfor24hat 22 ° C. Scheme3.AlkyneAdditionwith19 JournaloftheAmericanChemicalSociety Communicationdx.doi.org/10.1021/ja407689a | J.Am.Chem.Soc. 2013,135,14548 1455114550

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newchiralbiarylP,N-ligandincorporatinga5-membered electron-richheteroaromatic.Theligandisstraightforwardto prepareandhasbeendemonstratedtobeasuperbcatalystfor theenantioselectiveA3-couplingreaction.Moreimportantly, thisdesignconceptshouldbebroadlyapplicableandenablea newclassof5-memberedheteroaromaticbiarylstobeprepared ascatalystsforarangeofreactions.Furtherstudiesonthisare underwayinourlaboratoriesandwillbereportedindue course.ASSOCIATEDCONTENT*SSupportingInformationFullexperimentalproceduresandspectraldataforallnew compounds.Thismaterialisavailablefreeofchargeviathe Internetathttp://pubs.acs.org.AUTHORINFORMATIONCorrespondingAuthoraponick@chem.u .eduNotesTheauthorsdeclarenocompeting nancialinterest.ACKNOWLEDGMENTSTheauthorsthanktheUniversityofFloridafortheirgenerous supportofourprogramsandProf.JonStewart(UF)forthe loanofHPLCequipment.REFERENCES(1)(a) ComprehensiveAsymmetricCatalysis ,Vols. 1 3 ;Jacobsen,E. 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(19)SeeSIforfulldetails. (20)Anderson,N.G. Org.ProcessRes.Dev. 2005 , 9 ,800 813. (21)Theeeof 7 wasmeasuredbyHPLCafteroxidationtothe correspondingphosphineoxide.SeeSIfordetailedinformation. (22)(a)Meyer,E.A.;Castellano,R.K.;Diederich,F. Angew.Chem., Int.Ed. 2003 , 42 ,1210 1250.(b)Salonen,L.M.;Ellermann,M.; Diederich,F. Angew.Chem.,Int.Ed. 2011 , 50 ,4808 4842.(c)Gung, B.W.;Xue,X.;Zou,Y. J.Org.Chem. 2007 , 72,2469 2475. (23)Muller,C.;Pidko,E.A.;Staring,A.J.P.M.;Lutz,M.;Spek,A. L.;vanSanten,R.A.;Vogt,D. Chem. Eur.J. 2008 , 14 ,4899 4905. (24)Aschwanden,P.;Stephenson,C.R.J.;Carreira,E.M. Org.Lett. 2006 , 8 ,2437 2440. JournaloftheAmericanChemicalSociety Communicationdx.doi.org/10.1021/ja407689a | J.Am.Chem.Soc. 2013,135,14548 1455114551



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DEVELOPMENT OF A NEW CLASS OF ATROPISOMERS By FLÁ VIO SÊGA PEREIRA CARDOSO A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2014

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© 2014 Flávio Sêga Pereira Cardoso

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To my family

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4 ACKNOWLEDGMENTS Firstly, I would like to thank Dr. Aaron Aponick for giving me the opportunity to spend three months as an undergraduate student in his lab. This experience was very important for me to pursue a Ph.D. in his group. As a graduate student, Dr . Aponick taught me how to do research and guided me to achieve results. I am also very grateful to his belief in my ideas and abilities throughout the development of this exciting project. And finally, I acknowledge and admire his ambition s that were cruc ial for me to reach (and to continue reaching) my goals. Additionally, I would like to thank my supervisory committee members for the support throughout my years at the University of Florida. I would like to thank my mentors from my undergradu ate studies: Prof. Carlos Roque Duarte Correia for his advices and for accepting me in his lab when I was an u ndergraduate student; Prof. Angé lica Venturini Moro who taught me how to work in the lab and for her patience; And, Prof. Ronaldo Aloise Pilli who encouraged m e to face a Ph.D. abroad. I thank all the Aponick group members who directly or indirectly contributed to this dissertation . Special thanks go to Nick Borrero, Romain Miotto, John Ketcham, and Berenger Biannic for the friendship. I would also like to expre ss my sincere gratitude to Paulo Paioti for proof reading this dissertation and for being a very good friend in the past ten years. During the past five years at the University of Florida I made many friends and it is impossible to acknowledge everyone. Sp ecial thanks go to Yong Mo Ahn who helped me a lot Brazilian community in Gainesville. Finally I would like to thank my family. Their love and support was extremel y important for me to finish this journey. Trust and faith of my parents on me will always be remembered.

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ ............... 4 LIST OF TABLES ................................ ................................ ................................ ........................... 7 LIST OF FIGURES ................................ ................................ ................................ ......................... 8 LIST OF ABBREVIATIONS ................................ ................................ ................................ ........ 14 ABSTRACT ................................ ................................ ................................ ................................ ... 18 CHAPTER 1 INTRODUCTION ................................ ................................ ................................ .................. 20 1.1 Definition of Atropisomerism ................................ ................................ ........................... 20 1.2 Resolution of Chiral Atr opisomers ................................ ................................ ................... 23 1.3 Heteroaromatic Biaryl Atropisomers ................................ ................................ ................ 26 1.4 Overview of Dissertation ................................ ................................ ................................ .. 29 2 A NEW APPROACH TO ATROPISOMERISM ................................ ................................ .. 30 2.1 Introduction to the Designed Model ................................ ................................ ................. 30 2.2 General Background on Aromatic Interactions ................................ ................................ 33 2.3 Synthesis and NMR Data for Model C ompounds ................................ ............................ 37 2.4 Outcome ................................ ................................ ................................ ............................ 49 3 DESIGN AND PREPARATION OF AN IMIDAZOLE BASED CHIRAL BIARYL P,N LIGAND ................................ ................................ ................................ .......................... 50 3.1 Axially Chiral P,N ligands ................................ ................................ ............................... 50 3.2 Design of a Biaryl P,N Ligand Containing a Five Membered Heteroaromatic ............... 54 3.3 Resolution o f Axially Chiral P,N Ligands ................................ ................................ ....... 62 3.3.1 . Chiral Palladium Complexes ................................ ................................ ................. 62 3.3.2. Separation by C hiral HPLC ................................ ................................ ................... 67 3.3.3. Separation of Diastereomers: the PINAP C ase ................................ ..................... 67 3.3.4. Asymmetric Synthesis of QUINAP ................................ ................................ ....... 68 3.4 Deracemization of the New Chiral Imidazole Based P,N ligand ................................ ..... 72 3.5 Determination of the Absolute Stereochemistry of the P,N Ligand ................................ . 79 3.6 Rationalization of the Two Step Deracemization ................................ ............................. 81 3. 7 Evidence of Stacking in Soluti on ................................ ................................ .................. 88 3. 8 Summary and Conclusions ................................ ................................ ............................... 93

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6 4 APPLICATIONS OF THE NEW P,N LIGAND IN ASYMMETRIC TRANSFORMATIONS ................................ ................................ ................................ ......... 95 4.1. P,N ligands in Asymmetric Catalysis ................................ ................................ .............. 95 4.2. Asymmetric Reactions Catalyzed by Axially Chiral P,N ligands ................................ ... 98 4.2.1. Rhodium Catalyzed Hydroboration of Arylalkenes ................................ .............. 99 4.2.2. Rhodium Catalyzed Diboration of Alkenes ................................ ........................ 100 4.2.3. 1,3 Dipolar Cycloadditions ................................ ................................ ................. 100 4.2.4. Copper C atalyzed A lkynylation of Iminium I ons ................................ ............... 101 4.2.5. Copper Catalyzed Acetylide Addition to Michael Acceptors ............................. 104 4.2.6. Miscellaneous Nickel Catalyzed Reactions ................................ ........................ 106 4.3. Enantioselective Reactions with Imidazole Based P,N ligand ................................ ..... 107 4.3.1. A 3 C oupling R eaction E mploying Imidazole B ase d P,N ligand ........................ 107 4.3.2. Mechanistic Aspects of the Copper C atalyzed A 3 Coupling R eaction ............... 111 4.3.3. Copper Catalyzed Acetylide Addition to Quinolinium Salts .............................. 118 4.3.4. Asymmetric ......... 120 4.3.5 . Palladium Catalyzed Asymmetric Allylic Alkylation ................................ ......... 122 4.4 Outcome and Current Work ................................ ................................ ............................ 125 5 CONCLUSION AND OUTLOOK ................................ ................................ ....................... 126 6 EXPERIMENTAL SECTION ................................ ................................ .............................. 128 6.1 General Remarks ................................ ................................ ................................ ............ 128 6.2 Chemical Procedures ................................ ................................ ................................ ...... 129 6.2. 1 Synthesis of Model Compounds ................................ ................................ ........... 129 6.2.2 Synthesis and Deracemization of 3 1 and 3 111 ................................ .................. 142 6.2.3 A 3 Coupling Reactions ................................ ................................ ......................... 160 6.2.4 Synthesis of (+) C uspareine 4 121 ................................ ................................ ....... 175 6.2.5 Asymmetric A lkynylation of A lkylidene D A cid .......... 177 6.2.6 Palladium Catalyzed Asymmetric Allylic Alkylation ................................ .......... 178 LIST OF REFERENCES ................................ ................................ ................................ ............. 180 BIOGRAPHICAL SKETCH ................................ ................................ ................................ ....... 188

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7 LIST OF TABLES Table page 4 1 Enantioselective A 3 coupling employing 4 1 ................................ ................................ .. 110 6 1 Crystal data and structure refinement for 2 32 ................................ ................................ 133 6 2 Crystal data and structure refinement for 3 1 ................................ ................................ .. 147 6 3 Crystal data and structure refinement for 3 99 ................................ ................................ 150 6 4 Crystal data and structure refinement for 3 99/3 101 . ................................ ..................... 154 6 5 Crystal data and structure refinement for 4 103 ................................ .............................. 174

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8 LIST OF FIGURES Figure page 1 1 Atropisomerism in biphenyl 1 1 and axial chirality in biphenyl 1 3 ................................ . 20 1 2 First report of biaryl atropisomers ................................ ................................ ..................... 21 1 3 Atropisomeric natural products, drugs and catalysts ................................ ......................... 22 1 4 binaphthyl and BINOL ................................ ........... 22 1 5 BINOL resolution employing resolving agent 1 19 ................................ .......................... 24 1 6 1 24 ................................ ........... 24 1 7 General cross coupling towards congested biaryls ................................ ............................ 25 1 8 coupling ................................ ................................ ...... 25 1 9 Stereoselective syntheses of korupensamines A and B ................................ ..................... 26 1 10 Geometrical distinctions between six and five membered rings in a biaryl ...................... 27 1 11 Naturally occurring polybrominated biindoles 1 41 and 1 42 ................................ ........... 27 1 12 Synthes is of murrastifoline F and dixiamycin B ................................ ................................ 28 2 1 Examples of successful biaryl ligands comprised of six membered rings ........................ 30 2 2 Dihedral angle and bite angle on QUINAP/rhodium complex 2 6 and indole based P,N ligand 2 8 ................................ ................................ ................................ .......... 31 2 3 Strategies for increasing barrier height ................................ ................................ .............. 32 2 4 stacking to stabilize the ground state energy of the chiral conformation 2 10 .... 32 2 5 Diastereotopic protons H a and H b in the chiral stacked conformation 2 9 ......................... 33 2 6 Stereocontrol of a reaction using cation interaction and binding mode of anti Alzheimer drug E20202 ................................ ................................ ................................ ..... 34 2 7 Possible arrangements between two arene rings ................................ ................................ 34 2 8 Properties of benzene, hexafluorobenzene, and their dimer ................................ .............. 35 2 9 Geometries and calculated interaction energies of the hexafluorobenzene benzene dimers (the reported distances are the interplanar diastance for 2 20 and intercentroid diastances for 2 21 , 2 22 , and 2 23 , as indicated) ................................ ............................. 36

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9 2 10 interactions ................................ ................................ ................................ ......................... 36 2 11 Pentafluorophenyl phenyl interaction role in ring closing methathesis ............................ 37 2 12 stacking to stabilize the ground state energy of the chiral conformation ............. 37 2 13 Synth esis of compounds 2 10 and 2 32 ................................ ................................ ............. 38 2 14 1 H NMR Spectra of 2 10 and 2 32 at different temperatures ................................ ............ 39 2 15 Calculation of G employing k c and T c ................................ ................................ ............ 40 2 16 Free energy of activation G of 2 10 and 2 32 at the coalescence temperature .............. 41 2 17 Single crystal X Ray analysis of 2 32 ................................ ................................ ............... 42 2 18 General modification on the model system and compounds 2 36 and 2 37 substituted on the naphthalene ................................ ................................ ................................ ............. 42 2 20 Synthesis and analysis of 2 37 ................................ ................................ ........................... 44 2 21 Synthesis and analysis of compounds 2 46 and 2 47 ................................ ........................ 44 2 22 Comparison between pyrrole and indole X ray structures ................................ ................ 45 2 23 ................................ ................................ ...................... 45 2 24 Suggested rationale for the higher barrier to rotation observed ................................ ......... 45 2 25 Synthesis and barriers to rotation of compounds 2 52 and 2 53 ................................ ....... 46 2 26 Comparison between pyrrole and indole biaryls ................................ ............................... 47 2 27 G data for indolic compounds ................................ ................................ ........................ 47 2 28 Potencial functionalization of isoquinolinic compound 2 57 ................................ ............ 48 2 29 Synthesis of 2 57 and C H functionalization to 2 62 ................................ ........................ 48 3 1 New imidazole based chiral biaryl P,N ligand ................................ ................................ .. 50 3 2 C 2 symmetric BINAP 3 3 and C 1 symmetric QUINAP 3 4 and 3 5 ................................ 51 3 3 Synthesis of QUINAP 3 4 ................................ ................................ ................................ . 51 3 4 Palladium catalyzed allylic alkylation employing ( S ) QUINAP 3 12 .............................. 52

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10 3 5 Comparison between ( R ) QUINAP and ( R ) BINAP in the asymmetric Rh catalyzed hydroboration of styrenes ................................ ................................ ................................ .. 53 3 6 Five membered QUINAP analogues proposed by Brown ................................ ................. 54 3 7 Achiral and chiral biaryl P,N ligand containing five membere d rings .............................. 55 3 8 Proposed P,N ligands using our new approach to atropisomers ................................ ........ 56 3 9 Hypothetical rhodium complexes 3 29 and 3 30 . ................................ .............................. 57 3 10 Retrosynthetic analysis of P,N ligands 3 1 and 3 28 ................................ ......................... 58 3 11 Attempted synthesis of P,N ligand 3 28 . ................................ ................................ ........... 58 3 12 Synthesis of triflate 3 44 . ................................ ................................ ................................ ... 59 3 14 Synthesis of racemic P,N ligand 3 1 ................................ ................................ ................. 60 3 15 Reduction of phosphine oxide 3 49 . ................................ ................................ .................. 61 3 16 X ray structure of racemic P,N ligand 3 1 . ................................ ................................ ....... 61 3 17 Comparison between the packing of 3 1 and 3 17 ................................ ............................ 62 3 18 Common palladacyle used to resolve P,N ligands ................................ ............................ 63 3 19 General scheme on the use of chiral palladium complexes to resolve P,N ligands .......... 63 3 20 First generation resolution of QUINAP 3 4 ................................ ................................ ....... 65 3 21 Second generation resolution of QUINAP 3 4 ................................ ................................ .. 65 3 22 QUINAP type ligands that were resolved with chiral palladacycles ................................ . 66 3 23 Use of chiral HPLC for the resolution of pyphos 3 48 ................................ ...................... 67 3 24 Synthesis of PINAP ty pe ligands ................................ ................................ ....................... 68 3 25 R ) QUINAP 3 11 using chiral sulfoxides ................................ ... 69 3 26 R ) QUINAP 3 11 using chiral sulfoxides ................................ ... 69 3 27 Kinetic resolution and dynamic kinetic resolution approaches to QUINAP ..................... 70 3 28 Kinetic resolution of bromide 3 74 . ................................ ................................ ................... 70 3 29 Dynamic kinetic resolution of triflate 3 9 ................................ ................................ .......... 71 3 30 Preliminary test on the reaction of 3 1 and 3 51 ................................ ................................ 72

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11 3 31 Reaction between P,N ligand 3 23 and palladium complex 3 52 ................................ ..... 73 3 32 Preliminary results on the resolution of 3 1 with palladacycle 3 52 ................................ . 73 3 33 Interconversi on of 3 94 to 3 93 under thermodynamic conditions ................................ ... 74 3 34 Synthesis of 3 93 ................................ ................................ ................................ ................ 75 3 35 1 NMR of 1:1 mixture of 3 93/3 94 (top) and single diastereomer 3 93 (bottom) ............. 75 3 36 Oxidation of 3 1 and analysis of the oxide 3 96 by HPLC ................................ ................ 76 3 37 Decomplexation of 3 93 at room temperature ................................ ................................ ... 77 3 38 Optimization of the decomplexation step ................................ ................................ .......... 78 3 39 HPLC chromatograms of 3 96 (racemic) and 3 97 (98% ee) ................................ ............ 79 3 40 X ray crystal structure of 3 99 ( hexafluorophosphate counter anion and hydrogens are omitted for clarity) ................................ ................................ ................................ ....... 80 3 41 Comparison between X ray crystal structures of 3 99 and 3 100 (The pictures present only the core of the structures) ................................ ................................ .............. 81 3 42 Energy and reaction diagram for the two step deracemization process ............................ 82 3 43 X Ray crystal structure of 3 99 / 3 101 (hydrogen atoms are omitted) ............................... 83 3 44 Conformational analysis of 3 59 and 3 60 ................................ ................................ ......... 84 3 45 Attempt of deracemization with 3 51 ................................ ................................ ................ 84 3 46 Palladium complexes 3 100 / 3 102 and 3 102 / 3 104 ................................ ......................... 85 3 47 Control studies with chloride as counter anion ................................ ................................ . 86 3 48 Suggested conformational changes for ne utral and cationic complexes ........................... 86 3 49 Monodentate P,N ligands in complexes 3 108 and 3 109 ................................ ................. 87 3 50 Suggested pathway for the deracemization process ................................ ........................... 87 3 51 Fluorinated and non fluorinated P,N ligands 3 1 and 3 111 ................................ ............. 88 3 52 Synthesis and deracemization of 3 111 ................................ ................................ ............. 89 3 53 Determination of the enantiomeric excess of 3 115 ................................ .......................... 90 3 54 Chromatograms of 3 111 and 3 117 ................................ ................................ .................. 90

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12 3 55 Racemization of optically active phosphines 3 2 and 3 115 ................................ ............. 91 3 56 Plot of the ee (%) versus time for the racemization 3 2 ................................ .................... 91 3 57 Plot of the ee (%) versus time for the racemization 3 115 ................................ ................ 91 3 58 Plot of ln([M] t [M] eq )/([M] 0 [M] eq ) versus time at 75 o C for 3 2 ................................ ..... 92 3 59 Plot of ln([M] t [M] eq )/([M] 0 [M] eq ) versus time at 75 o C for 3 115 ................................ . 92 3 60 Determination of the barriers to rotation of 3 2 and 3 115 at 75 o C ................................ .. 93 4 1 Axially Chiral P,N ligands 4 1 and QUINAP 4 2 ................................ ............................. 95 4 2 Privileged ligand structures (top) and P,N ligands (bottom) ................................ ............. 96 4 3 General P,N ligand structure and properties ................................ ................................ ...... 97 4 4 Tuning the electronic properties of P, N ligand 4 7 ................................ ........................... 98 4 5 Axially chiral P,N ligands ................................ ................................ ................................ . 98 4 6 Examples of sec alcohols 4 19 obtained through rhodium catalyzed enantioselective hydroboration ................................ ................................ ................................ ..................... 99 4 7 Diboration of trans alkene 4 28 with B 2 (cat) 2 ................................ ................................ . 100 4 8 Examples of silver catalyzed [3 + 2] cycloadditions ................................ ....................... 101 4 9 General scheme for the A 3 coupling reaction ................................ ................................ .. 101 4 10 First examples of an enantioselective A 3 coupling ................................ .......................... 102 4 11 Asymmetric A 3 coupling using piperidone 4 54 ................................ ............................. 103 4 12 A 3 coupling reaction as an entry to enantioenriched allenes ................................ ........... 104 4 13 Concise synthesis of homolaudanosine 4 64 ................................ ................................ ... 104 4 14 4 2 ................. 105 4 15 Optimized conditions for the copper derivatives ................................ ................................ ................................ ........................ 105 4 16 Nickel catalyzed regio and enantioseletive annulation reaction ................................ .... 106 4 17 Nickel catalyzed enantioselective synthesis of helicenes ................................ ................ 107 4 18 Copper catalyzed three component reaction ................................ ................................ .... 108

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13 4 19 A 3 coupling employing racemic ligand ra c 4 1 ................................ .............................. 109 4 20 Desilylation of propargylamines 4 86 ................................ ................................ ............. 111 4 21 Alkyne addition with 4 54 ................................ ................................ ............................... 111 4 22 Tentative mechanism for the A 3 coupling ................................ ................................ ....... 112 4 23 X ray structure of 4 95 ................................ ................................ ................................ ..... 113 4 24 Non linear effect observed on the A 3 coupling employing QUINAP ............................. 113 4 25 Tentative mechanism for the enantioselective copper catalyzed A 3 coupling reaction .. 114 4 26 X ray crystal structure and analysis of 4 103 ................................ ................................ .. 115 4 27 X ray crystal structure 4 104 ................................ ................................ ........................... 116 4 28 Proposed formation of complex 4 103 ................................ ................................ ............ 116 4 29 Speculative deprotonation of the terminal alkyne by the imidazole nitrogen ................. 117 4 30 Enantioselective copper catalyzed coupling of quinolines and alkynes .......................... 118 4 31 Enantioselective copper catalyzed coupling of quinolines and alkynes employing P,N ligand 4 1 ................................ ................................ ................................ .................. 119 4 32 Determination of the absolute configuration through the synthesis of (+) cuspareine .... 120 4 33 d derivatives .................... 121 4 34 Concept of electronic differentiation proposed by Pfaltz ................................ ................ 122 4 35 Trans influence on nucleophilic substitution ................................ ................................ ... 123 4 36 Palladium catalyzed allylic alkylation with axially chiral P,N ligands ........................... 123 4 37 Stereoselectivity of the palladium catalyzed allylic alkylation with ligand 4 1 .............. 124 4 38 Enantioselective reactions employing 4 1 ................................ ................................ ....... 125 5 1 New approach to axial chirality in biaryl compounds ................................ ..................... 126 5 2 Copper catalyzed A 3 coupling reaction employing 5 4 ................................ .................. 127

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14 LIST OF ABBREVIATIONS Ac Ar Atm Ax B 2 (cat) 2 BINAP BINOL Bn Boc BOP BSA n Bu Calcd Acetyl Aromatic Atmosphere Axial Dicatechol diborane 2,2' Bis(diphenylphosphino) 1,1' binaphthyl 1,1' Bi 2 naphthol Benzyl tert Butylcarbonyl bis(2 oxo 3 oxazolidinyl)phosphin yl N , O Bis(trimethylsilyl)acetamide Normal/unbranched butyl Calculated Cat Cod Cy d DABCO DART DCE DCM DIPEA DMAP Catalyst 1,5 cyclooctadiene Cyclohexyl Day/Days 1,4 Diazabicyclo[2.2.2]octane Direct Analysis in Real Time Dichloroethane Dichloromethane Dii so propylethylamine 4 D imethylaminopyridine

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15 DME DMF DMSO Dppe Dppp d r E e e ESI E quiv ent Et F 5 h n Hex HPLC HRMS i Pr IR IPA LAH LDA lit Dimethoxyethane Dimethylformamide Dimethylsulfoxide 1,2 Bis(diphenylphosphino)ethane 1,3 Bis(diphenylphosphino)propane Diastereomeric ratio Energy Enantiomeric excess Electrospray Ionization E quivalent E nantiomer Ethyl P entafluoro Hour/Hours Normal/unbranched hexyl High performance liquid chromatography High resolution mass spectrometry iso propyl Infrared Isopropyl alcohol Lithium aluminumhydride Lithium diisopropylamide Literature

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16 M Me m in mol % MS 4 Ã… MP NBD NBS ND NMR Nu OSs Ph PPA R rac R f RT sec QUINAP TBS t Bu temp Metal Methyl M inutes Percent molar equivalents Four angstrom molecular sieves Melting point N orbornadiene N bromosuccinimide Not determined Nuclear magnetic resonance Nucleophile 4 methanesulfonylbenzenesulfonate Phenyl Polyphosphoric acid Group R acemic Retention Factor Room temperature Secondary 1 (2 Diphenylphosphino 1 naphthyl)isoquinoline tert butyldimethylsilyl tert butyl T emperature

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17 Tf THF TLC TMS Tol Ts v s VT X T rifluoromethane sulfonyl Tetrahydrofuran Thin layer chromatography T rimethylsilyl Toluene Tosyl Versus Variable t emperature H alogen

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18 Abstract of Dissertation Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy DEVELOPMENT OF A NEW CLASS OF ATROPISOMERS By Flá vio Sêga Pereira Cardoso August 2014 Chair: Aaron Aponick Major: Chemistry The design of new c hiral ligands is on the cutting edge of organic synthesis. In particular, atropisomeric ligands have been demonstrated to be very suc cessful in asymmetric catalysis; however, the majority of axially chiral biaryl ligands such as BINAP are comprised of six membered aromatic rings. The presence of five membered heteroaromatic s in chiral biaryl compounds are rare due to larg er bond angles and, in consequence, smaller barrier s to rotations. Chiral biaryls with five membered rings have not been explored in asymmetric catalysis, but should offer significant advantages. In this context, creative new atropisomeric ligand scaffolds with smaller ring sizes should advance the field. In this dissertation , a novel strategy towards the design of chiral ligands is described , which allow s the synthesis of atropisomeric ligands containing a five membered ring in the chiral biaryl backbone. At the outset, we aimed to design a new system in which the barrier to rotation of a biaryl bond is increased due to the decrease of the ground state energy of enantioconfo r mers. In general, the presence of sterically demanding groups ortho to the atropisomeric axis are employed to increase the barrier to rotation, but to the best of our knowledge the simple concept of ground state stabilization reported herein has not been explored. Initial studies were aimed at determining the feasibility o f this strategy and simple model compounds were designed to

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19 undergo intramolecular stacking. The strategy was then applied in the creation of a new axially chiral P,N ligand comprised of a five membered imidazole ring in the biaryl backbone. This ligand was prepared as a single enantiomer and evidence of s tacking interactions was observed in solution and in the solid state. After developing a method to isolate significant amounts of this P,N ligand as a single enantiomer, it was necessary to evaluate i ts performance in enantioselective catalysis. It was found that in the A 3 coupling reaction , our ligand furnished the products in 24h at 0 o C in high yields and enantioselectivies over a broad range of substr ates , including alkyl and aryl aldehydes . The me thod overcomes the limitations in scope associated with QUINAP, the benchma rk ligand for this reaction. Moreover, copp er catalyzed acetylide addition to pyridinium ions or Michael acceptors were explored and gave good initial results. The ligand could also be employed in palladium catalyzed allylic alkylation reaction to give the products in high ee . R esearch in this area is ongoing in our group and this dissertation document s the results obtained during the past five years.

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20 CHAPTER 1 INTRODUCTION T he present dissertation will cover from fundamental aspects of atropisomers to the application of an axially chiral P,N ligand for asymmetric catalysis. In Chapter 1, a general introduction to the field will be made with emphasis on biaryl atropisomers whi ch are particularly important for the work presented in chapters 2, 3 and 4. 1.1 Definition of Atropisomerism a means on and trop means turn . 1 IUPAC defines 2 atropisomers as A su bclass of conformers which can be isolated as separate chemical species and which arise from restricted rotation about a single bond . e.g. ortho substituted biphenyl, 1,1,2,2 tetra tert butylethane . As represented in Figure 1 1, the interconversion between the conformers of a tetra ortho substituted biphenyl must pass through a high energy coplanar conformation 1 2 . Due to severe steric interactions between the ortho substituents, this interconversion is not facile. Figure 1 1 . Atropisomerism in biphenyl 1 1 and axial chirality in biphenyl 1 3 In a similar system, 1 3 , with two different pai rs of ortho substituents the same phenomenon is observed. I n this case the conformers are not super im posable mirror images thus

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21 leading to axial chirality in this biaryl system . A tropisomerism is an important topic , d ue to the occurrence of axial chirality in natural products, 3 drug discovery, 4 and catalysis . 5 atropisomer 1 the phenomenon was reported in 1922 by Kristie. 6 In his dinitro diphenic acid 1 6 was resolved by fractional recrystallization using brucine 1 7 and the conformers 1 8 and 1 9 isolated after recrystallization were shown to have opposite optical rotations (Figure 1 2). Since then, the chirality of biaryl systems has been widely studied and applied in different areas. 3 ,4,5 Figure 1 2. First report of biaryl atropisomers T he occurrence of biaryl atropisomers in nature has been well documented . Axially chiral n atural products can appear in either simple or complex structures (Figure 1 3 ). 3 Vancomycin 1 10 is an important example due to its complex molecular architecture and antibiotic activity. 7 This sophisticated glycopeptide contains numerous stereogenic centers including a chir al biaryl unit. Pharmaceutical companies have also been exploring this type of chirality in drug discovery. Recently, medicinal chemists at Pfizer reported that PH 797804 8 1 11 presents higher inhibiting activity against p38 kinase than its mirror image s tructure. Asides from biologically active compounds , axial chirality has been widely utilized in catalysis . 9 Biaryl ligands such as BINOL 10,11 1 12 and BINAP 12,13 1 13 are classified as privileged chiral catalysts 14,15 due to their efficiency in asymmetric reactions.

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22 Figure 1 3 . Atropisomeric natural products, drugs and catalysts An important aspect regarding atropisomers is that the barrier to rotation about a single bond can vary significantly depending on the chosen molecule. Three examples are shown in Figure 1 4. Figure 1 4 . Barriers to rotation of biph binaphthyl and BINOL For instance, biphenyl 1 14 has a very low barrier to rotation which has been calculated to be ~2 kcal/mol in the gas phase. 16 binaphthyl 1 16 was experimentally determined to be 23.5 kcal/mo l and it has a half life (t 1/2 ) of 14.5 min at 50 °C . 17 Interestingly, biaryl 1 16 could be spontaneously resolved from its melt to generate optically

PAGE 23

23 active enantiomers 1 16 or 1 17 . 18 In the chiral auxiliary 1,1' b i 2 naphthol (BINOL) t he enhanced sterics about the biaryl bond leads to a very high barrier to rotation of ~38 kcal/mol (measured at 220 o C in diphenyl ether). 19 Due to this high barrier, enantiomerically pure BINOL is optically stable at 100 o C for 24 hours in dioxane water . 2 0 The analysis of these three examples begs the question: how high does the barrier to rotation of a molecule have to be in order to define it as an atropisomer? In 1983, 21 an arbitrary but useful definition was made by Oki: atropisomers are molecules in w hich an isolated conformer has a half life t 1/2 of at least 1000 seconds (17 minutes) at a specified temperature. At 25 o C, this corresponds to a ~22 kcal/mol barrier to rotation, therefore, biphenyl 1 14 is not considered an atropisomer . By definition bin aphthyl 1 16 (half life t 1/2 is 14.5 minutes) is not considered an atropisomer at 50 o C. BINOL 1 12 has a very high barrier to rotation and is defined as an atropisomer up to at least 100 o C since it is thermally stable at this temperature. It is important to mention that, beyond the arbitrary definition, the racemization rate of axially chiral ligands or catalysts will be crucial when considering their use in asymmetric catalysis. For practical purposes, a useful chiral ligand or catalyst must be configura tionally stable under the reaction conditions in which it is applied. 1.2 Resolution of Chiral Atropisomers Enantiomerically pure atropisomers can be obtained from resolution of racemates using chiral HPLC 22 or resolving agents. 23 The resolution of racemic BINOL rac 1 12 was performed o n a multi gram scale using N benzylcinchonidinium chloride 1 19 as a resolving agent ( Figure 1 5 ). 24 Chiral salt 1 19 selectively forms a complex with ( R ) BINOL to form the insoluble salt 1 20 and ena ntiomerically pure ( S ) BINOL remains in solution. After work up 1 20 is converted to ( R ) BINOL in high enantiomeric excess.

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24 Figure 1 5 . BINOL resolution employing resolving agent 1 19 Another attractive approach to obtain enantiomerically pure atropisomers is the asymmetric synthesis s ince all the starting materials can be converted into a single enantiomer. 25 of many axially chir al natural products. 26 It involves a dynamic kinetic resolution process where a configurationally unstable lactone is opened in a diastereoselective fashion affording optically active biaryls. For example , the biaryl lactone conformers 1 21 a and 1 21 b are stereochemically labile and , when exposed to the chiral oxazaboro lidine borane reagent 1 22 , conformer 1 21b reacts much faster affording product 1 23 in 81% yield and 96% ee ( Figure 1 6). 27 After recrystallization, 1 23 is obtained in > 99% ee and converted to (+) Knipholone 1 24 in several steps. Figure 1 6 . 1 24 With the impressive development of metal catalyzed cross couplings in the past years, 2 8 the enantioselective synthesis of biaryl atropisomers seems to be a very convenient approach ( Figure 1 7). There are many reports on this type of strategy but the substrate scope and

PAGE 25

25 stereoselectivity are still limited. 25 As previously discussed, ortho s ubstituents are necessary for configurational stability of chiral biaryls. However, ortho substituents also raise the energy of the reaction intermediates and, to overcome these effects, high temperatures are usually required to obtain reasonable yields in atropselectivity of the reaction resulting in low enantiomeric excesses. Figure 1 7. General cross coupling towards congested biaryls A successful example of catalytic atropselective cross coupling was developed by Buchwald 29,30 ( Figure 1 8). The palladium catalyzed Suzuki coupling between phenylboronic acid 1 28 and aryl bromides 1 29 provided enantioenriched biaryls in up to 98% yield and 92% ee. Interestingly, the chiral ligand applied was ( S ) KenPhos 1 31 , a C 1 symmetric axially chiral P,N ligand. A drawback of this method is that it requires the ortho phosphite substituted 1 29 to obtain high enantiomeric excesses, leading to limited scope. Figure 1 8 . trop selective Suzuki coupling In 2014, a very efficient Suzuki Miyaura coupling was developed and applied during the first total synthese s of korupensamine s A and B 31 ( Figure 1 9). Boronic acid 1 32 and arylbromide 1 33 were subjected to optimized conditions employing catalytic amounts of bis -

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26 phosphine ligand 1 34 and Pd(OAc) 2 at 35 o C affording biaryl 1 35 in 96% yield and 93% ee. After a few aditional steps, synthesis of korupensamine A 1 3 6 was accomplished. The synthesis of korupensamine B was performed through the same route employing ligand ent 1 34 in the cross coupling reaction. Figure 1 9 . Stereoselective syntheses of korupensamine s A and B 1.3 Heteroaromatic Biaryl Atropisomers The majority of the axially chiral biaryls are comprised of six membered naphthalene or benzenoid rings. In fact, they are the most abundan t in natural 3 and synthetic systems. 25 However, there many important examples in which a heterocycle is present in the chirality axis, 32 such as in the Pfizer drug PH 797804 8 1 11 (Figure 1 3 ). Changing from an all carbon aromatic ring to a nitrogen hetero aromatic can significantly affect the properties of a molecule. This can be exemplified by the interannular distance of C C = 1.48 Ã… in biphenyls, 33 N C = 1.40 Ã… in N phenylazoles 34 and N N = 1.36 Ã… in N,N linked biazoles. 35 It is intuitive that shorter distances in the interannular bond will enhance the steric crowding thus the barrier to rotation. However, the size of the rings will also be decisive. The geometrical distinctions between six and five -

PAGE 27

27 membered rings will affe ct the distances between the interacting groups of an atropisomer and its restricted rotation. As illustrated in Figure 1 10 , the larger bond angles between the substituents in a five membered ring will result in a less restricted biaryl bond. As a result , the vast majority of chiral biaryl atropisomers are comprised of six membered rings whereas five membered rings are less common. Figure 1 10 . Geometrical distinctions between six and five membered rings in a biaryl Examp les of optically active natural products containing five membered heteroaromatic ring. As presented below, they are often dimers of naturally occuring indole or carbazole heteroaromatics. Naturally occurring polybrominated indoles 1 41 and 1 42 have been isolated from Australian algae (Figure 1 11). 36 Figure 1 11 . Naturally occurring polybrominated biindoles 1 41 and 1 42 Whil e C C linked biindole 1 41 did not present optical rotation (probably due to fast racemization as a conseque nce of the 5,5 ring connection), b iindole 1 42 presented a high optical rotation ([ ] 20 D = +71 o ( c 1.00) in CHCl 3 ), suggesting a higher barrier to rotation.

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28 37 an N C linked bicarbazole natural product, required the development of an oxidative C N coupling ( Figure 1 12). The dimerization of murrayafoline A employing Pb(OAc) 4 gave racemic murrastifoline F in 60% yi eld. Resolution by chiral HPLC was performed in order to determine the absolute configuration of the alkaloid. In 2012, Dixiamycins A and B were discovered as the first examples of atropisomerism of naturally occurring N N coupled atrop diastereomers. 38 ,39 Recently, Baran and co workers accomplished the first total synthesis of Dixiamycin B through a new N N coupling. 40 The dimerization of known xiamycin A 1 45 involved a diastereoselective electrochemical oxidative coupling using a carbon anode and furnishe d t he natural product in 28% yield. Figure 1 12 . Synthesis of murrastifoline F and dixiamycin B

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29 1.4 Overview of Dissertation This present dissertation covers the synthesis and applications of biaryls for use in asymmetric catalysis. As described in Chapter 1, five membered biaryl atropisomers are rare and we aim to develop a new family of chiral ligands incorporating this ring size. This task required t he development of a new strategy to increase the barrier to rotation of biaryl molecules. In Chapter 2, this new approach to atropisomers will be described in a fundamental fashion. The strategy involves intramolecular aromatic interactions to stabilize t he chiral ground state conformation of biaryls. Model compounds containing moieties designed for intramolecular stacking interactions were synthesized and analyzed by variable temperature NMR in order to evaluate the feasibility of the proposed strategy. In Chapter 3 the design and synthesis of a new axially chiral ligand incorporating the strategy described in Chapter 2 will be presented. This new P,N ligand was prepared as a single enantiomer through a novel two step deracemization process which will b e described in detail. In Chapter 4, an overview of enantioselective reactions catalyzed by axially chiral P,N ligands will be provided. Testing of the new P,N ligand in different asymmetric transformations will be described and compared to known ligands from the literature. In particular, a full methodological study was performed in the so called A 3 coupling reaction in which our new P,N ligand excelled.

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30 CHAPTER 2 A NEW APPROACH TO ATROPISOMERISM 2.1 Introduction to the Designed Model The design of new c hiral ligands is on the cutting edge of organic synthesis. In particular, atropisomeric ligands have been shown to be very successful in asymmetric catalysis. 5 However, the majority of axially chiral biaryl ligands are comprised of six membered aromatic r ings (Figure 2 1). 9,41 In this context, creative new atropisomeric ligand scaffolds should advance the field and one way this could be accomplished is by using other ring sizes. Figure 2 1 . Examples of successful biaryl ligands comprised of six membered rings When coordinated to a metal, t hese bidentate ligands have two important properties: the dihedral angle and the bite angle . 42,43,44 As an example, the dihedral angle and the bite angle in QUINAP/rhodium comple x 2 6 45 are graphically represented in Figure 2 2. QUINAP performs extremely well in the asymmetric hydroboration of arylalkenes 46 and it is believed that these angles in their optimal position are associated with this success (this topic will be discussed in more detail in chapters 3 and 4). In order to change the properties of QUINAP, Brown and co workers attempted to modify the dihedral and bite angle s by substituting the naphthalene ring to a five membered indole heteroaromatic. 47 This ring contraction would generate a new ligand 2 8 in enantioselective reactions. Unfortunately 2 8 is not configurationally stable (probably due to reduce steric congestion arou nd the biaryl bond) and biaryl ligands of this type have not been explored in asymmetric catalysis. In addition to the changes in the dihedral angle and bite

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31 angle t here are other advantages on employing electron rich five membered heteroaromatics i n b iaryl ligands. Their synthese s are well known, which reduces the difficulty in their preparation and exploration of analogues for fine tuning. 48,49 Figure 2 2. D ihedral angle and bite angle on QUINAP/rhodium complex 2 6 and indole based P,N ligand 2 8 In regards to the problem of conformational stability described for ligand 2 8 , a fundamental question arose: how can the ring sizes of a chiral biaryl be contracted without losing their configurationally stabili ty? Is there any strategy other than steric obstruction of rotation that can be used to increase the barrier to rotation? As described in Chapter 1, the usual strategy to increase the barrier to rotation in biaryls involves the employment of larger groups ortho to the chiral axis, which can be graphically represented as going from a to b in Figure 2 3. In contrast, we sought to introduce a new strategy in which the barrier to rotation of a biaryl bond is increased due to the decrea se of the ground state en ergy of chiral confo r mers. Graphically, this could be described as going from a to c in F igure 2 3. Surprisingly the simple concept of ground state stabilization presented herein has not been explored in the context of atropisomerism .

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32 Figure 2 3. Strategies for increasing barrier height Fundamentally, the proposed approach could be explored with any type of intramolecular inte raction (eg. stacking interactions, cation interactions, hydrogen bonding interactions etc.). T he proposed model system is a biaryl structure comprised of three aromatic units A, B , and C designed to stack intramolecularly ( Figure 2 4 ). The presence of a heteroaromatic ring B allows easy functionalization or structure modification for the synthes is of chiral ligands or catalysts. Before this application, it was necessary to study model systems in order to test the feasibility of this intramolecular interaction. As represented in Figure 2 4, the proposed structure will be in equilibrium between a stacked conformation 2 9 and a conjugated coplanar conformation 2 10 . Our hypothesis is that stacking interactions will be the main factor governing the energy minima of this system rendering 2 9 to be the lowest energy conformation . Figure 2 4 . Using stackin g to stabilize the ground state energy of the chiral conformation 2 10 In addition, t his system is designed for the easy calculation of the b arrier to rotation using variable temperature NMR. 21,50 T he methylene protons in the chiral conf ormation 2 9 are diastereotopic allowing for differentiation between H a and H b on the NMR time scale (Figure 2 5). On the other hand, other conformation such as 2 10 would display H a and H b as a singlet

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33 since they are enantiotopic . Also, this method does not require the isolation of enantiomerically pure samples or chiral probes to measure the racemization rates and/or barriers to rotation of the compounds. As long as the compound has diagnostic peaks that coalesce below the NMR te mperature limits, the barrier to rotation can be measured. This would allow us to compare different model compounds and quickly evaluate our hypothesis. Figure 2 5 . Diastereotopic protons H a and H b in the chiral stacked conformation 2 9 Despite the fact that intramolecular stacking interactions have been widely studied, 51,52 the system proposed here remains unexplored. Due to the importance of this non covalent interaction in our system, a brief introduction on the topic will be given herein . 2.2. General Background on Aromatic Interactions Intra and intermolecular interactions involving aromatic units play an important role in the properties of not only biological but also chemical systems (Figu re 2 6) . 51,52 In organic transformations, these interactions often explain stereoselectivity in reaction outcomes. 53,54 For 55 on the nucleophilic addition of malonate to the pre organized pyridinium ion 2 12 involved the design of an intramolecular cation interaction to give product 2 13 in excellent regio and diastereoselectivities. The biologically relevance of many compounds are also rationalized with structure/activity studies involving aromatic interactions. For example, in the binding mode 2 14 of anti Alzheimer drug E20202 to the enzyme acetylcholine sterase 56,57 aromatic rings are stacking in three different sites, demonstrating the diversity of this interaction.

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34 Figure 2 6 . Stereocontrol of a reaction using cation interaction and binding mode of anti Alzheimer drug E20202 In general, the interaction between two benzene rings can adopt three configurations: parallel displaced, T shaped edge to face, and eclipsed face to face (Figure 2 7). 51,52 The strength of the interaction will vary depending on many factors such as substituents on the aromatic ring and nature of the solvent. Figure 2 7 . Possible arrangements between two arene rings There are different theoretical and experimental models designed to study the interactions between aromatic rings. In a broad sense, the theories are divided into either London dispersions or polar electrostatic interactions and there is still a debate as to wh ich is dominant in the overall energetics of these interactions. 51,52 Regardless of the nature of the interaction, there are many models that demonstrate their existence and those were very valuable to the development of our

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35 project. In this context, we w ere interested in a strong stacking energy and the analysis of known models directed us to the arene perfluoroarene interactions that we used in the end ( vide infra ) . Perfluoroaromatics are well known to bind strongly to other arenes and this behavior has been explored in many areas such as supramolecular chemistry and catalysis. 51,52 The strength of this interaction is well illustrated by formation of a solid when benzene and hexafluorobenzene are combined (Figure 2 8). These two compounds are liquids in their pure forms but a 1:1 mixture of benzene and hexafluorobenzene forms a solid with a melting point of 23.7 o C. 58 a X ray crystallography showed that the crystals are constituted of alternating molecules of benzene and hexafluorobenzene. Studies on this type of interaction reveals that the inverted quadrupole moment of 2 19 (+ 32 x 10 40 C m 2 ) when compared to 2 18 ( 29 x 10 40 C m 2 ) is essential for the strong binding. 59 Figure 2 8 . Properties of benzene, hexafluorobenzen e , and their dimer Tsuzuki and co workers performed theoretical studies on the system and determined that the arrangement of the interaction can be parallel displaced, face to face, T shaped and inverse T shaped (Figure 2 9). 60 Among them, the first case is predicted to be the strongest with an energetic stabilization of 5.38 kcal/mol. Their studies conclu ded that dispersion interaction is predominant in this system, although electrostatic interaction als o contributes to the att raction .

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36 Figure 2 9 . Geometries and calculated interaction energies of the hexafluorobenzene benzene dimers ( the reported distances are the interplanar diastance for 2 20 and intercentroid diastances for 2 21 , 2 22 , and 2 23 , as indicated ) Experimental models were also explored to study perfluorinated aromatic rings. Cozzi and Siegel have studied the 1,8 diarylnapht h alene system 2 23 illustrated below ( Figure 2 10) . 61 In this work, the effect s of a variety of substituents o n the phenyl groups on the face to face stacking interactions was studied . For example, increasing the number of fluorin e atoms on the phenyl ring enhances the barrier to rotation due to stronger intramolecular stacking. It was observed that for each fluorine atom added, the barrier to rotation increased by approximately 0.5 kcal/mol. Figure 2 10 . (left (right) model s to study intra molecular aromatic interacti ons More recently, Gung and co workers designed another model which, in contrast to the former, the intramolecular stack ing occurs in a parallel displaced arrangement (Figure 2 10). 62

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37 Their studies involve the equilibrium between a folded syn 2 24 and un folded anti 2 25 conformation, being the stacking syn 2 24 favored. This strong interaction was also useful in the macrocyclization depicted in Figure 2 11. 63 The pentafluorobenzyl moiety in 2 26 shields one side of the aromatic ring forcing the olefins to cyclize through a ring closing metathesis reaction. The absence of the pentafluoro moiety in the substrate resulted in no reaction with the recovery of starting material and undesired oligomers. Figure 2 11 . Pentafluorophenyl phenyl interaction role in ring closing methathesis 2.3 Synthesis and NMR Data for Model C ompounds Based on these precedents, we decided to prepare compounds 2 10 and 2 31 hoping that the latter would undergo a strong intramolecular interaction favoring conformation 2 32 (Figure 2 12). The easy analysis of the methylene protons H a and H b by 1 H NMR in each molecule would quickly give insight if the equilibrium below favors t he stacked conformation 2 32 . Figure 2 12 . Using stackin g to stabilize the ground state energy of the chiral conformation

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38 The syntheses of 2 10 and 2 32 began with a Suzuki cross coupling between 1 bromonaphthalene 2 33 and N B oc pyrrole 2 boronic acid 2 34 64 to give 2 aryl pyrrole 2 35 in 59% over two steps after deprotection 65 ( Figure 2 1 3). Benzylation using benzyl bromide gave 2 10 in 84% yield. Employing pentafluorobenzylbromide , compound 2 32 was readily prepared i n 57% yield. Figure 2 13 . Synthesis of compounds 2 10 a n d 2 32 To our delight, it was found by 1 H NMR that the methylene group of 2 10 showed a broad singlet while 2 32 exhibited an AB system ( Figure 2 14, 2 10 and 2 32 1 H NMR in CDCl 3 ). This behavior could be explained by the fact that, in the perfluorinated molecule, the intramolecular interaction restricts rotation about the biaryl bond due to intramolecular stacking interactions and, by consequence, the methylene proton s are diastereotopic o n the 1 H NMR time scale. With this in mind, we decided to measure the barriers to rotation of 2 10 and 2 32 using the coalescence method. 66 As shown in Figure 2 14, the coalescence method requires 1 H NMR analysis of 2 10 a n d 2 32 at different temperatures. The diagram in Figure 2 14 shows the 1 H NMR (expanded in the

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39 methylene peak region) for compounds 2 10 a n d 2 32 at different temperatures. As expected, the AB system observed for the methylene peak of 2 32 gradually coalesced to a broad single t at a higher temperature. On the other hand, the broad singlet observed for 2 10 at room temperature gradually separated into an AB system when the sample was cooled to 15 o C. The coalescence temperature T c is the lo west temperature where there is no minimum between the two coalescing peaks of the AB system. Careful analysis of the spectra provided a coalescence temperature of 9 o C and 57 o C for 2 10 a n d 2 32 , respectively. Figure 2 14 . 1 H NMR Spectra of 2 10 a n d 2 32 at different temperatures Although the coalescence temperatures observed demonstrate a higher barrier to rotation in the biaryl bond of compound 2 32 , calculations are needed to obtain the actual free energy of activation G for interconversion of H a and H b between the two sites. As an example, compound 2 32 will be used to demonstrate how these energy values can be obtained. First, a 1 H

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40 NMR analysis has to be performed at a temperature where no change in the peak shape is observed (low enough that the AB pattern is constant at this temperature and below). For compound 2 32 the 1 H NMR spectrum at 10 o C was used (Figure 2 15). The exchange rate constan t k c is given by equation 1 derived for AB systems and employs J AB (coupling constant in each site of the AB system) and (chemical shift between the two sites). 21,50 For compound 2 32 , the exchange rate constant was calculated to be 145 s 1 . The free en ergy of activation G at the coalescence temperature (T c = 57 o C = 330 K) is calculated using the Eyring equation (eq. 2). Employing k c and T c in equation 2, the free activation energy G at the coalescence temperature for compound 2 32 is found to be 16.1 kcal/mol. It is important to mention that there is a minimum error associated with these experiments. Raban and co workers 67 studied the error on these types of approximations and it was found that even if error of 100% in the exchange rates would be observed, this would only translate to an error of 0.4 kcal/mol in the free energy of activation. In other words, this simple method allows for a n useful determination of the barrier to rotation in these biaryl compounds. Figure 2 15 . Calculation of G employing k c and T c

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41 By analogy, u sing the coalescence temperature for biaryl 2 10 we determined the activation energy as 13.7 kcal/mol . The activation energies of compounds 2 10 a n d 2 32 are shown in Figure 2 16, along with the coalescence temperature and solvent employed in the analysis. Figure 2 16 . F ree energy of activation G of 2 10 a n d 2 32 at the coalescence temperature These results verified that there is a higher barrier to rotation in compound 2 32 . Comparing the calculated energies required for bond rotation in compounds 2 10 a n d 2 32 gives a G of 2.4 kcal/mol for compound 2 32 . By analogy to the previously described models, this energy can be attributed to intramolecular stacking interactions 66b and t his value is in agreement with other stacking energies involving pentafluoroaromatic moieties. 51,52 In addition, compound 2 10 is an oil and compound 2 32 is a white solid. This provid ed the opportunity to grow good quality single crystals , and to use X ray diffraction to obtain a crystal structure of compound 2 32 (Figure 2 17 ). W hat seems to be involved is an arene arene interaction in the parallel displaced arrangement. The two arenes are parallel to each other with the center of one arene (benzyl) on top of the edge of the other. The dihedral angle that defines the planes of the A and B rings is 88° and the A and C stacked with a n interplanar distance of 3.26 Å . Si nce the two stacked aromatic rings are not perfectly in parallel, 3.26 Å is th is distance between the averaged planes of each of the rings. Interestingly, this is closer than the i nterplanar distance of 3.4 Å between C 6 H 6 and C 6 F 6 in the well known co crys tal. 58 b In t he

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42 packing of the structure there is also intermolecular stacking interactions between alternating naphthalenes and pentafluorobenzene rings. Figure 2 17 . Single crystal X Ray analysis of 2 32 The synthetic versatility of our model system enabled the systematic study of the influence of substituents o n rings A, B or C (Figure 2 18). This was important to understand how electronic and steric factors affect the system. Initially, substitution on t he naphthalene ring C was studied with compounds 2 3 6 and 2 3 7 . Figure 2 18 . General modification on the model system and compounds 2 3 6 and 2 3 7 substituted on the naphthalene The synthetic routes to prepare 2 3 6 and 2 3 7 are analogous to the previous compounds. To prepare 2 3 6 , the hydroxyl group on 2 38 was converted to a triflate in 85% yield. Next, a Suzuki coupling between 2 39 and 2 3 4 followed by deprotection gave 2 40 in 26% yield over two steps. The low yield obtained in this two step process is probably due to the instability 68 of boronic acid 2 3 4 leading to low conversion in the Suzuki cross coupling. To complete the

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43 synthesis, the alkylation of 2 40 furnished 2 3 6 . This compound was prepared with the intent ion of add ing an electron donating group ( OMe) in a position away from the axis, in order to combine an electron rich n aphthalene ring and an electron poor pentafluorobenzyl group. Based on the X ray structure of 2 32 , the substitution at 5 position of th e naphthalene would increase the electron density to provide a more electron rich ring where the stacking takes place. Unfortunately, the barrier to rotation in 2 36 was very similar ( G = 16.3 kcal/mol and T c = 61 o C) to compound 2 32 suggesting that the pentafluorobenzyl moiety dominates the interaction regardless of the nature of the naphthalene ring. It is important to note that Gung and co workers also observed the same trend when studying stacking interactions involving strongly electron deficient aromatic rings. 62 Figure 2 19 . Synthesis and analysis of 2 3 6 The methoxy group was also placed on c ompound 2 42 by a similar route using from bromide 2 41 . 69 B enzylation afforded compound 2 37 containing a methoxy group ortho to the biaryl bond, which presented a very high barrier to rotation. As previously stated, the presence of a bulky group close to the axis would increase the restriction on the biaryl bond due to more severe steric interac tions. In this case, the variable temperature NMR required the use of a solvent with a higher boiling point and 1,1,2,2 tetrachloroethane d 2 ( C 2 D 2 Cl 4 , BP = 145 146 o C ) was the solvent of choice. 1 H NMR analysis in C 2 D 2 Cl 4 at 120 o C showed an AB system and the

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44 barrier could not be determined since that temperature was above the upper limit of the equipment . Figure 2 20 . Synthesis and analysis of 2 37 Having successfully synthesized and studied pyrro le derivatives we proceeded to investigate other heteroaromatic analogues. Among the different heterocycles that could be explored, we chose to analyze indole derivatives 2 46 and 2 47 ( Figure 2 21 ). Compound 2 45 was readily prepared through a Fischer ind ole synthesis according to a literature procedure . 70 B enzylations of 2 45 gave 2 46 and 2 47 in very good yields. Figure 2 21 . Synthesis and analysis of compounds 2 46 and 2 47 Unexpectedly, the barrier to rotation for the indole pair ( 2 46 and 2 47 ) increased considerably in comparison to the corresponding pyrrole structures 2 10 and 2 32 . The changes were from 13.7 to 15.3 kcal/mol for the non fluorinated pair and from 16.7 to 17.3 kcal/mol for the fluorinated pair. Th ese data show that the nature of the heterocyclic ring B affects the barrier to rotation of these biaryl compounds. After careful analysis , two explanations for this result (or a combination of both) emerged. Firstly, the geometries of these heteroaromatic s were studied

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45 and we were encouraged to compare the X ray structure of our pyrrole 2 32 to a similar indole structure 2 48 from the literature. 71 As shown in Figure 2 22, a slightly larger N C C bond angle and a shorter biaryl bond is observed for the ind ole compound. These subtle factors could be leading to a larger barrier to rotation on indolic compounds. Figure 2 22 . Comparison between pyrrole and indole X ray structures Additionally, the buttressing effect should also be considered. 72 This effect is observed in biaryls when a meta substituent is present in a biaryl structure. For instance, rotation in tetraiodobiphenyl 2 50 ( G = 30.1 kcal/mol at 25 o C) is more difficult than in diiodoanalogue 2 49 ( G = 23.4 kca l/mol at 25 o C) by a significant energy amount (Figure 2 23). 73 Figure 2 23 . Example of a buttressing effect By analogy, the presence of a n extra benzenoid ring on the indole (when compared to pyrrole) could be buttress ing up towards the naphthalene ring resulting in a higher barrier to rotation in the biaryl bond ( Figure 2 24 ). Figure 2 24 . Suggested rational e for the higher barrier to rotation observed

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46 To further investigate this rational e we turned our attention into a pyrrole analogue in which the system would be the same but 5 position of the pyrrole would be substituted with a methyl group (Scheme 6). To this end, diketone 2 51 74 was submitted to standard Paa l Knorr conditions 75 to give the desired compounds 2 52 and 2 53 in 74 and 51% yields, respectively. The observed barriers to rotation were increased in comparison to 2 10 and 2 32 (13.7 and 16.1 kcal/mo l , respectively) suggesting that a buttressing effe ct might be involved and in this case the extra methyl group could be buttressing the benzyl groups causing the barrier to increase. Figure 2 25 . Synthesis and barriers to rotation of compounds 2 52 and 2 53 In Figure 2 26, the graph summarize s the data of the three pairs of compounds . Interestingly, the introduction of the methyl group to the pyrrole ring increases the barrier to rotation in 0.8 kcal/mol (13.7 to 14.5 kcal/mol) in the non fluorinated compounds whereas the fluorinated analogues increases in only 0.4 kcal/mol (16.1 to 16.5 kcal/mol). This could also be explained by a greater stacking between the pentafluorobenzyl group and the naphthalene diminishing the buttressing effect. Another observation is that the G in the indolic ( 2 46 and 2 47 ) and 5 methylsubstituted ( 2 52 and 2 53 ) pairs were found to be 2.0 kcal/mol which is slightly smaller than in the pyrrole analogues but still a significant stabilization energy.

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47 Fig ure 2 26 . Comparison bet ween pyrrole and indole biaryls Furthermore, three additional indolic derivatives 2 54 , 2 55 , and 2 56 , containing different benzyl groups , were easily prepared from 2 45 . As presented in Figure 2 27, no significant difference in the biaryl bond rotation was observed for any of the compounds. Even 2 54 containing a fluorine in the para position presented similar energy barrier which indicates that perfluorinated analogues results in higher stabilization . Also, e ither an electron r ich para methoxyphenyl or a heterocyclic pyridine ring did not resulted in significant energy differences when compared to non fluorinated indole 2 47 . Figure 2 27 . G data for indolic compounds Having identified the highest barrier to rotation for compound 2 46 containing a pentafluorobenzyl ring C and an indole ring B, we decided to investigate an isoquinolinic analogue 2 57 (Figure 2 28) . This compound is a potential precursor for atropisomeric ligands or

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48 catalysts with an indole 3 position available for functionalization along with a coordenating nitrogen. In the next Chapter studies towards P,N ligand 2 59 will be presented. Figure 2 28 . Potencial functionalization of isoquinolinic compound 2 57 The preparation of 2 57 begins with a Fischer indole synthesis 76 employing ketone 2 60 and phenylhydrazine to give 2 61 in 75% yield (Figure 2 29) . Subsequent pentafluorobenzylation furnished 2 57 . Unfortunately, the isoquinoline derivative 2 57 presented a very low barrier to rotation, probably due to minimized steric demand on the nitrogen. When 2 57 was cooled down to 0 o C in CDCl 3 the methylene peak still appeared as a sharp singlet and its barr ier to rotation was not determined. In order to restore a reasonably high barrier to rotation, a palladium catalyzed C H funcionalization 77 was performed giving acetate 2 62 in 68 % yield. VT NMR studies on this 3 substituted indole gave a higher barrier of 15.4kcal/mol although still too low to attempt the isolation of an optically active atropisomer. Studies on the functionalization of 2 57 are ongoing in the laboratory with the goal of the synthesis of an N oxide such as 2 58 (Figure 2 29) which can be a potential chiral organocatalyst for asymmetric synthesis. Figure 2 29 . Synthesis of 2 57 and C H functionalization to 2 62

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49 2.4 Outcome In summary, a new concept to increase the barrier to rotation in atropisomers was demonstrated. A variety of compounds were synthesized with different rings A, B and C and it was shown that when ring C is perfluorinated a stabilization of 2.0 2.4 kcal/mo l is observed. It was also found that rings A and B can affect the barrier to rotation depending on their steric and/or eletronic properties . The absolute G values ranged from 13.7 to 17.3 kcal/mol. It is important to remind that, b y definition, an atro pisomer presents at least a barrier of ~22 kcal/mol, which means that sterics will usually be the main component for the occurrence of the magnitude of the barrier to rot ation. Indeed the next Chapters will show that a stabilization of ~2 kcal/mol can be crucial when developing new ligands for asymmetric catalysis. W e believe that these studies provide a new strategy when desiring to increase the barrier to rotation in bia ryl atropisomers. This concept can also be expanded to other non covalent interactions or even covalent bonds. Studies along these lines are underway in our laboratory .

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50 CHAPTER 3 DESIGN AND PREPARATION OF AN IMIDAZOLE BASED CHIRAL BIARYL P,N LIGAND Chap ter 3 will describe the work on the design and preparation of P,N ligand 3 1 (Figure 3 1). Part of this work was published in the Journal of the American Chemical Society: Cardoso, F. S. P.; Abboud, K. A.; Aponick, A. J. Am. Chem. Soc. , 2013 , 135 , 14548 14551. 79 Initially, how we became interested in this area will be presented, which was sparked by our desire to apply the studies from Chapter 2 for the creation of a new family of P,N ligands. Then, an overview of the methods used to resolve axially chiral P,N ligands will be required to explain our approach to the preparation of optically active 3 2 . It involved a novel two step deracemization approach which allows convertion of the racemic ligand 3 1 into a single enantiomer, 3 2 . Figure 3 1 . New imidazole based chiral biaryl P,N ligand 3.1 Axially Chiral P,N ligands In the early 1990s, Brown and co workers started their work on the development of previously unexplored axially chiral P,N ligands. 80 Aware of the succ ess of chiral bidentate C 2 symmetric ligands, 41 they became interested to prepare a BINAP parent ligand in which one phosphine would be substituted with a basic nitrogen atom (Figure 3 2). The targeted C 1 symmetric ligand would have structure 3 4 containing an isoquinoline ring, and this is the reason for the chosen name for this ligand: QUINAP. 80

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51 Figure 3 2 . C 2 symmetric BINAP 3 3 and C 1 symmetric QUINAP 3 4 and 3 5 Interestingly, it was revealed by the Brown group that the initial goal was to apply these novel P,N ligands in cross coupling reactions but we will see that things did not go this way. 80a In a first attempt, difficulties were encountered in preparing QUINAP 3 4 and a similar P,N ligand 3 5 was prep ared (Figure 3 2). Unfortunately, 3 5 was stereochemically labile precluding any application in asymmetric catalysis. 80a Figu re 3 3 . Synthesis of QUINAP 3 4 Next, Brown and co workers prepared and resolved QUINAP 3 4 which was considered, since the beginning, the best heterocyclic analogue of BINAP 3 3 . The synthesis was accomplished employing a Suzuki cross coupling between 3 6 and 3 7 to build the biaryl moiety in 3 8 (Figure 3 3). Methoxy deprotection and triflatio n gave the substrate 3 9 for a C P coupling. A nickel catalyzed coupling followed by reduction of the phosphine oxide gave QUINAP 3 4 . 80 b The resolution of QUINAP involved the use of a chiral palladium complex

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52 which will be discussed in detail in Section 3 .3 .1 . Alternatively, nickel catalyzed C P coupling of Ph 2 PH gave QUINAP 3 4 in a single step from the triflate 3 9 , but this method was developed several years later. 81 With enantiomericall y pure QUINAP in hand , they explored two asymmetric reactions: pall adium catalyzed allylic alkylation 82 and rhodium catalyzed hydroboration of styrenes. 45,46 The success achieved in these two reactions opened a new avenue in ligand design and reaction discovery that has been continuously going until these days. 83 The fi rst application of ( S ) QUINAP 3 12 was in the palladium catalyzed asymmetric allylic alkylation between 3 13 and 3 14 (Figure 3 4). After some optimization, they were able to obtain product 3 15 in 98% enantiomeric excess overcoming previous results with C 2 symmetric ligands, such as BINAP. 45,46 Although this result was excellent, at about the same time, three groups independently reported 84,85,86 the preparation of PHOX type ligands 3 16 which proved to be an even better P,N ligand for this type of reacti on. In light of this, the exploration of QUINAP on allylic alkylation was not substantially explored. Figure 3 4 . Palladium catalyzed allylic alkylation employing ( S ) QUINAP 3 12 On the other hand , QUINAP stands out as one of the best ligands for t he asymmetric rhodium catalyzed hydroboration of styrenes . 45,46 The rhodium catalyzed hydroboration/oxidation of arylalkenes delivers the Markovnikov product allowing for an enantioselective reaction. The reaction requires a cationic source of rhodium (usually [Rh(COD) 2 ] BF 4 ) and catecholborane, followed by an oxidation step. A comparison between ( R ) -

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53 QUINAP 3 11 and ( R ) BINAP 87 3 17 is displayed in Figure 3 5 , illustrating that in general QUINAP yields better enantioselectiviti es. For styrene 3 18 the better performance of QUINAP is impressive giving high selectivities at ambient temperature (95% ee versus 57% ee with BINAP). With substituted styrene 3 19 the superiority is even more significant. The use of QUINAP furnishes the product 3 21 in 95% ee at room temperature whereas with BINAP it requires a very low temperature to give only 42% ee . Figure 3 5 . Comparison between ( R ) QUINAP and ( R ) BINAP in the asymmetric Rh cata lyzed hydroboration of styrenes To interpret these results, Brown analyzed the X ray crystal structures of BINAP and QUINAP in metal complexed environments (Figu re 3 5, the metal is palladium in both structures). The proposed rationale postulates that the less sterically demandi ng isoquinoline ring allows more sterically demanding substrates to undergo the reaction in high enantioselectivities. 26 In other words, switching from BINAP to QUINAP, a 6 membered chelate is formed (instead of 7 to accommodate larger substrates. It is important to mention that this is probably only one of the factors involved since

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54 there are other differences that could be postulated, such as the electronic properties of the bidentate ligands (P,P versus P,N ligan ds). These were the earliest examples in which QUINAP excelled. Nowadays, QUINAP is th ese ligands in asymmetric metal catalyzed reactions will be summariz ed in Chapter 4. 3.2 Design of a B iaryl P,N L igand Containing a Five Membered H etero aromatic Since its first appearance, a variety of QUINAP type ligands have been synthesized and explored in asymmetric catalysis. 44 AP 3 23 (discussed in Chapter 2) has been studied by Brown and co workers . 47 In this report it was stated that the naphthalene (e.g. modifying to an indole) sh ould permit some appraisal of the effects on reactivity and selectivity of varying the bite angle 47 These variations are presented in Figure 3 6. Figure 3 6 . Five membered QUINAP analogues proposed by Brown As described in Chapters 3 and 4, the isolation of these biaryl structures as a singl e enantiomer could be difficult because of the less steric ally demanding five membered ring. Although the benzpyrazole analogue 3 22 QUINAP 3 23 was prepared and its resolution attempted. 47 Unfortunately, t his system is stereochemically labile precluding application in asymmetric catalysis. Such type of C 1 symmetric axially chiral P,N -

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55 ligands (containing a biaryl system with a 5 and 6 membe red rings) have not been explored in asymmetric catalysis. Recently, a few examples of achiral biaryl P,N ligands, such as 3 24 89 and 3 25 , 90 were reported proving their importance in catalysis. Their application in cross coupling reactions have attracted many research groups. On the other hand, there is only one example of an axially chiral P,N ligand comprised of a five membered ring: BIMNAP 91 3 26 . Although 3 26 was prepared and resolved there are no reports of its use in asymmetric catalysis. The fact t hat no other examples of such type of P,N ligands exist is probably related to the challenges of preparing configurationally stable biaryls with smaller ring sizes. Figure 3 7 . Achiral and chiral biaryl P,N ligand containing five membered rings In this context, we were encouraged to approach this issue applying our strategy to five membered biaryl atropisomers described in Chapter 2. By analogy to the structures proposed by Brown, P,N ligands 3 1 and 3 28 were envis ioned. Based on our studies on model compounds, we hypothesized that an extra stabilization by stacking interactions c ould increase the barrier to rotation of these biaryls and allow for the isolation of conformationally stable ligands (Figure 3 8).

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56 Figure 3 8 . Proposed P,N ligand s using our new approach to atropisomers As described in Chapter 2, the d ihedral angle and bite angle of ligands when coordinated to a metal play an important role in their performance in catalytic reactions. In a recent review, 44 Guiry and Brown collected all X ray crystal structures of P,N ligands chelated to a metal and analyzed their properties. Although single crystal X ray analysis might not be the most appropriate representation o f the catalyst in solution, they suggested that the analysis of many structures can provide good trends on the performance of a type of ligand in a specific reaction. For instance, axially chiral P,N ligands in chelate complexes exhibit a rigid backbone wi th dihedral angles between ~55 and ~75 o while, for example, PHOX type P,N ligands are more flexible and this property ranges from ~20 to ~55 o . 44 In Figure 3 9, there are hypothetical rhodium complexes of the targeted P,N ligand structures 3 29 and 3 3 0 . T aking QUINAP/rhodium 45 complex 3 3 1 as a reference, it is evident that changing the size of a ring in the biaryl moiety will affect the geometries of the complexes. In addition, the electronic properties of the coordinating sites will be different. In P,N ligand 3 28 , the phosphine will be linked to the 3 position of an indole ring enhancing the electron density at the phosphorus (when compared to QUINAP). Along the same lines, in the imidazole based P,N ligand 3 1 there is a more electron rich heteroaroma t ic than the isoquinoline ring of QUINAP 3 4 .

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57 Figure 3 9 . Hypothetical rhodium complexes 3 29 and 3 3 0 . These conformational and electronic modifications would allow for a new family of chiral ligands that were unexplored in asymmetric catalysis before. For these reasons, we were encouraged to plan the syntheses of 3 1 and 3 28 (Figure 3 10) . For synthesis o f the indole analogue 3 28 , it seemed apparent to employ intermediate 3 36 w hich is readily available from a Fischer indole synthesis between ketone 3 35 and phenylhydrazine 3 34 (this reaction was shown in Chapter 2). Benzylation and phosphination would p rovide P,N ligand 3 28 . Synthesis of biaryl 3 1 would employ a one pot imidazole synthesis using diketone 3 37 , aldehyde 3 38 and ammonia. Benzylation and nickel catalyzed P C coupling delivers P,N ligand 3 1 . An advantage of incorporating five membered ar omatic heterocycles such as imidazole into these new ligands is the well known array of methods to prepare these type of rings. 48 The biaryl core structure of the ligands are constructed in the first step of their synthesis which are well established metho ds and can be performed on a large scale.

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58 Figure 3 10 . Retrosynthetic analysis of P,N ligands 3 1 and 3 28 The attempted synthesis of P,N ligand 3 28 began with a bromination at 3 position of indole 3 4 0 using N bromosuccinimide in 84% yield (Figure 3 11) . Next, the phosphine synthesis was planned through a lithiation of bromoindole 3 41 with n butyllithium followed by the addition of chlorodiphenylphosphine , 9 2 but this reaction was not successful. In the analysi s of the crude reaction mixture t he reduced compound 3 40 and decomposition products were observed. Figure 3 11 . Attempted synthesis of P,N ligand 3 28 . In parallel, the synthesis of 3 1 was also explored. The preparation of racemic 3 1 was achieved in several straightforward steps starting with 2 hydroxy 1 naphthaldehyde 3 38 , whereby the requisite heterocycle was readily introduced ( Figure 3 12 ). In the event,

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59 condensation of 3 38 with benzil 3 37 and ammonium acetate as a source of ammonia furnished 3 39 in 80% yield. 93 This reaction is very efficient and can be done on a deca gram scale. The free alcohol was then protected as the TBS ether in 78% yield , and the resulting imidazole was alkylated with penta fluorobenzyl bromide to yield 3 42 . The benzylation step required an unusually low temperature of 78 o C otherwise the reaction was not consistent and desilylated products were often observed. The alcohol was then easily deprotected an d converte d to the triflate 3 44 using reagent 3 4 3 in 95% yield over two steps . Figure 3 12 . Synthesis of triflate 3 44 . Next, we explored the nickel catalyzed C P coupling needed for the formation of 3 1 . The most prevalent methods to convert a triflate to a phosphine are listed in Figure 3 13. The first method (Method A), developed by Merck, uses Ni(dppe)Cl 2 , diphenylphosphine and DABCO. 94 Chemists at Monsanto developed a similar method (Method B) employing Ni(dppe )Cl 2 and Zn/PPh 2 Cl. 95 These two methods were used in the synthesis of BINAP 3 3 and related phosphines. Although P,N ligands, such as QUINAP 3 4 , were also prepared by methods A and B, our attempts to convert 3 44 to 3 1 were not successful. Kwong and co w orkers reported the same results when trying to prepare p yphos 3 48 , a pyridine base P,N ligand from triflate 3 47 . 96 They suspected that the more coordinating pyridine nitrogen could be chelating to nickel causing a retarding effect in the phosphination r eaction. To overcome that, a new catalyst

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60 system was developed (Method C) employing a monodentate triphenylphosphine ligand and they were able to isolate p yphos 3 48 in 41% yield. Figure 3 13 . Methods to convert a triflate 3 45 to a n aryl phosphine 3 46 The imidazole nitrogen of triflate 3 44 could cause the same retarding effect and when we employed the method C on a small scale the desired phosphine 3 1 was isolated in similar yield (30 40 %). This reaction employs a relatively inexpensive source of nickel catalyst Ni(PPh 3 ) 2 Cl 2 and activated zinc. After optimization, i t was found that large scale reactions would provide the desired phosphine in 60% yield after two days (Figure 3 14) . A procedure starting with ~6g of triflate 3 44 provided ~4g of P,N ligand 3 1 after column chromatography and this procedure was repeated several times. A drawback of the method is the utilization of 0.5 equivalents of the nickel catalyst and efforts are being made t o optimize this coupling reaction. Figure 3 14 . Synthesis of racemic P,N ligand 3 1

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61 In these reaction s , full conversion of the triflate is observed and the desired product is formed along with phosphine oxide 3 49 and reduced product 3 50 . The yields of these byproducts vary from 10 20% each. Fortunately, p hosphine oxide 3 49 can be reduced 97 back to 3 1 using HSiCl 3 in 77% yield (Figure 3 15) . Figure 3 15 . Reduction of phosphine o xide 3 49 . Racemic P,N ligand 3 1 is a very non polar compound and its crystallization was challenging. After exposing many solvent systems, it was found that 3 1 crystallizes from acetonitrile at room temperature over the course of several hours. An X r ay structure of 3 1 was obtained and it is shown in Figure 3 16. Importantly, the expected stacking interactions were observed in the solid state . Figure 3 16 . X ray structure of racemic P,N ligand 3 1 . Interestingly, the coordinating atoms of the free ligand are pointing in opposite directions and this will be different when coordinated to a metal. The dihedral angle of the biaryl bond is 84.9 o . In contrast to the pyrrolic structure 3 17 discussed in Chapter 2, there is n o intermolecular stacking and the crystals contain alternating enantiomers in the packing (Figure 3 17).

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62 Figure 3 17 . Comparison between the packing of 3 1 and 3 17 3.3 Resolution of Axially Chiral P,N L igands At this p oint, P,N ligand 3 1 was prepared as a racemate, but whether or not the compound was configurationally stable needed to be determined. In other words, it needed to be determined if this compound could be chiral and therefore potentially useful for asymmetr ic catalysis. In order to evaluate this the resolution of 3 1 needed to be performed . In this section, the usual methods to re solve atropisomeric P,N ligands will be presented . There are four different approaches: 1) use of chiral palladium complexes as auxiliaries ; 2) installation of a second chiral center in order to separate diastereomers of the P,N ligand; 3) separation by preparative chiral HPLC; 4) enantioselective synthesis. F inally, the method developed to deracemize our new P,N ligand , in con trast to a traditional resolution, will be described. 3.3.1 Chiral Palladium Complexes The use of chiral metal complex es to resolve ligands for asymmetric catalysis has been known for decades. 98 In the case of axially chiral P,N ligands, there are many exa mples in which a chiral palladacycle was used. 99 The most common palladacycles are shown in F igure 3 18 .

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63 Their preparation involves an Eschweiler Clarke methylation of commercially available chiral amines followed by cyclopalladation with Na 2 PdCl 4 and trie thylamine to form the C Pd bond. 100 Figure 3 18 . Common palladacyle used to resolve P,N ligands The general three step resolution process is depicted in Figure 3 19. It involves the complexation of the racemic P,N ligand 3 54 with, for example, palladacyle 3 52 to give a 1:1 mixture of diastereomers which are easily differentiated by NMR. Then, diastereomers are separated by fractional recrystallization or column chromatograph. A pure diastereomer 3 55 or 3 56 is decomplex ed using a stronger ligand (usually dppe) to deliver the free, optically active, P,N ligands 3 57 or 3 58 , respectively . Figure 3 19 . General scheme on the use of chiral palladium complexes to resolve P,N ligands

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64 It is im portant to describe a few important drawbacks to the method. Firstly, it requires one equivalent of palladium and another equivalent of an expensive chiral amine 3 50 . Besides the price , the separation of diastereomers formed after complexation with the ch iral ligand are known to be very tedious . 99 Nevertheless, this method has proven to be efficient for many axially chiral P,N ligands. In fact, it is quite amazing how well this method works across a broad range of ligands. The method described above is use d for resolution of QUINAP 3 4 . QUINAP 3 4 is synthesized as a racemate and this requires resolution since the molecule contains only the axis of chirality. In the first appearance of QUINAP 3 4 related compounds, but in no case was there any evidence for the selective formation of a single diastereomeric salt . 80 b Although QUINAP type P,N ligands contain a basic site at the nitrogen heterocycle, no reports on its protonation with a chiral acid exists in the context of ligand resolution. After many attempts to resolve QUINAP, it was found that chiral palladium complex dimer 3 52 was the most successful. Initially, Brown and co workers prepared an equimolar mixture of diastereomers and separate d them by fractional crystallization (Figure 3 20) . In this case, one of the diastereomers 3 59 crystallized from chloro form leaving the diastereomer 3 60 in solution. A fter decomplexation of 3 59 with ethylenebis( diphenyl phosphine ) 3 61 , a stronger bidentate ligand , it was obtained enantiomerically pure ( S ) QUINAP 3 12 in 88% yield for this step and an overall yield of 41% . 80 b It is important to mention that this process was not possible with Pd complex 3 51 . When 3 51 was mixed with racemic QUINAP 3 4 a diastereomeric mixture was observed but the fractional crystallization was unsuccessful.

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65 Figure 3 20 . First generation resolution of QUINAP 3 4 After optimization, they found that mixing 3 52 with QUINAP 3 4 in a 1:4 ratio a single diastereomer would be predominantly formed along with optically active free ligand 3 11 after heating the mixture in acetone for 2h . 81 Upon cooling this solution, diastereomer 3 5 9 precipitates and optically active ( R ) QUINAP 3 11 remains in solution. Ten years after the first synthesis of QUINAP 3 4 , Brown and co workers reported a resolution of ~40g of QUINA P employing this strategy (Figure 3 21) . 81 Figure 3 21. Second generation resolution of QUINAP 3 4

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66 Careful analysis of this process showed that it initially generates a 1:1 mixture of diastereomers and one equivalent of racemic free ligand 3 4 . When a 1:1 mixture of 3 59 and 3 60 in dichloromethane was allowed to stand at room temperature it was observed, after 24h, the formation a single diastereomer 3 5 9 . This is possible through an extensive number of complexation/deco mplexation events in which the most stable diastereomer 3 5 9 becomes predominant over the time. This was a very significant improvement because employing this method requires only half of an equivalent of palladium and avoid s the fractional crystallization step. After the discovery of QUINAP, a few groups prepared similar type P,N ligands containing different nitrogen heterocycles and/or carbon backbones (Figure 3 22) . 101 Guiry and co workers developed a related class of ligands called Quinazolinap 3 6 3 . 102 Kwong and co workers developed p yphos 3 48 containing a pyridine heterocyclic ring. 103 All these P,N ligands were resolved using chiral palladium complexes . Figure 3 22 . QUINAP type ligands that were resolved with chira l palladacycles The success of QUINAP in many enantioselective reactions encouraged many research groups to develop better syntheses and resolution methods for this ligand. An improvement in the synthesis strategy would provide an entry to different analog ues of QUINAP , which are rare. In addition, t he development of new methods to resolve QUINAP would avoid the use of chiral

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67 palladium complex in the resolution of this type of ligand. In the following Sections it will be describe d alternative methods to pre pare optically active P,N ligands. 3.3.2. Separation by C hiral HPLC Kwong et al . explored p yphos 3 48 , 103 a pyridine analogue of QUINAP. The report included the fractional recrystallization of a mixture of palladium complexes diastereomers , as described for QUINAP, and racemic 3 48 was achieved with success . As an alternative , they also investigated separation of p yphos 3 48 using preparative chiral HPLC which ultimately proved to be unsuccessful. To overcome that, an oxidation to the more polar phosphine oxide 3 63 was performed and they were able to separate the enantiomers by HPLC (Figure 3 23) . The drawback of this process is that optically active phosph ine oxide s 3 64 or 3 66 have to be converted back to the phosphine requiring two extra steps for thi s type of resolution. Additionally, although the barrier to rotation of these ligands are relatively low, they did not observe racemization of the optically active p yphos 3 48 under the harsh reaction conditions for reduction of the oxide. Figure 3 23 . Use of chiral HPLC for the resolution of p yphos 3 48 3.3.3 . Separation of Diastereomers: the PINAP C ase Carreira and co workers identified ( S ) QUINAP 3 1 2 as the best ligand for the copper catalyzed alkyny lation acid alkylidenes 104,105 (This topic will be discussed in Chapter 4). Although the enantiomeric excess was only 42%, that was the best result among 25

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68 ligands tested in the reaction. It is known that structural modification on QUINAP is not well explored s o the improvement of the enantioselectivity of this reaction required the development of a new family of ligand s . Along with this, Carreira group decided to adopt a different strategy to obtain the optically active P,N ligand. Instead of using a chiral pal ladium complex, they designed a ligand that would incorporate a chiral center allowing for the separation of diastereomers. The chiral center would be away from the axis as in the diastereomeric structures 3 72 and 3 73 (Figure 3 24). This new family of li gands was named PINAP ( P hthalaz I ne NAP phtha lene in analogy to QUINAP). A 1:1 diastereomeric mixture of triflate 3 71 was prepared in three steps from 3 68 , 2 naphthol 3 69 and enantiopure alcohol or amine 3 70 . A nickel catalyzed C P coupling gives the P,N ligand as a 1:1 mixture of diastereomers of 3 72 and 3 73 . The diastereomers can be separated by chromatography on silica gel or fractional crystallization. This method was an important contribution since it avoids the use of chiral palladium complexes and it allows the synthesis of analogues by the use of other chiral groups (other chiral alcohols or amines were employed instead of 3 70 ). Figure 3 24 . Synthesis of PINAP type ligands 3.3.4 . Asymmetric Synthesis of QUINAP Knochel and co workers took a different approach to the synthesis of QUINAP (Figure 3 25) . They separated diastereomeric sulfoxide intermediates 3 76 and 3 77 and then converted them , after separation via column chromatography, to enantiopure QUINAP in 4 a dditional

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69 steps. 106 They considered this protocol comparable to the conventional preparation in terms of yields, time and effort. Figure 3 25 . R ) QUINAP 3 11 using chiral sulfoxides In a related rep ort, Clayden and co workers 107 stu died the equilibration of the same atropdiastereomeric sulfoxides 3 78 and 3 79 and, upon heating, it was observed a predominant formation of 3 79 (Figure 3 26) . They were able to isolate 3 79 in 77% yield . Sulfoxide 3 79 is his characterized a dynamic thermodynamic route to QUINAP. Figure 3 26 . R ) QUINAP 3 11 using chiral sulfoxides More recently, in 2013, Stoltz an d Virgil reported a very relevant advance in the field. 108 The synthesis of optically active QUINAP was performed employing a ki netic resolution (KR) and dynamic kinetic resolution (DKR). This work represents the state of the art for the synthesis of QUINA P and will be briefly described here. The dynamic behavior of QUINAP and its precursors in a cross coupli ng between Ar X (X = Br, OTf, OS s) and diphenylphoshine were

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70 analyzed. In Figure 3 27 , the main possibilities are depicted. Employing a palladium catalyzed coupling, the presence of an optically active chiral ligand would generate diastereomeric intermediates 3 81 / 3 83 . Figure 3 27 . Kinetic resolution and dynamic kinetic resolution approaches to QUINAP For instance, an atroposelective oxidative addition wi th a chiral palladium catalyst c ould favor the formation of either aryl Pd 3 81 or 3 83 and, ideally, the final product would be ( R ) or ( S ) QUINAP in 50 % yield. This would require conditions in which the aryl Pd intermediate and QUINAP do not rotate about the axis of chirality. After extensive optimization, this KR was achieved employing ligand 3 85 at 70 o C in dioxane giving ( S ) QUINAP 3 12 in 45% yield and 99.5% ee (Figure 3 28). The remaining bromide 3 84 was recovered in 44% yield and 99.7% ee . Figure 3 28 . Kinetic resolution of bromide 3 74 .

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71 During the course of their work, they also explored a more elegant DKR in which a single enantiomer of QUINAP would be obtained in higher than 50% yield (hypothetically in 100% yield) . After an extensive optimization of different chiral ligands , it was found tha t this DKR was possible (Figure 3 29) . Now utilizing a triflate 3 9 and Josiphos type ligand 3 89 at 80 o C in dioxane the Stoltz group was able to convert all the starting material to enantioenriched product (90% ee). Fig ure 3 29 . Dynamic kinetic resolution of triflate 3 9 Under these reaction conditions both enantiomers of triflate 3 9 ( 3 86 and 3 87 ) undergo oxidative addition to give palladium intermediates 3 83 and 3 81 . As represented in Figure 3 29 , the key for the success of this process was to find reaction conditions in which the equilibration between diastereomeric intermediates 3 83 and 3 81 was facile favoring 3 81 which undergo es reductive elimination giving optically active 3 12 as the major product .

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72 3.4 Der acemization of the N ew Chiral Imidazole Based P,N ligand With our imidazole based P,N ligand 3 1 in hand, our next task was to obtain the ligand as a single enantiomer. At this point we did not have any evidence that ligand 3 1 was configurationally stable. The only evidence in this regard was the fact that it shows an AB pattern for the benzylic protons in the 1 H NMR spectrum of 3 1 , indicating that they are diastereotopic on the NMR time scale, however, according to our studie s from Chapter 2, this information does not translate to a configurationally stable chiral compound. As expected , the AB system of this compound did not coalesce up to 120 o C and this method could not be used. Actually, if coalesce nce occuried at that tempe rature or lower , the barrier to rotation would not be considerably high enough to result in a useful atropisomer for asymmetric catalysis. Then we turned our attention to the reaction of 3 1 with palladium complex 3 5 1 . For that, P,N ligand 3 1 and 3 5 1 w ere dissolved in deuterated methanol in an NMR tube and analyzed. The result was satisfying since we observed the formation of two diastereomers 3 90 and 3 91 in a 1:1 ratio (Figure 3 30). Figure 3 30 . Preliminary test on the reaction of 3 1 and 3 51 An unsatisfactory result could have been something similar to what was observed with 3 23 (Figure 3 31). The reaction between 3 23 and palladium complex 3 52 led to a single diastere omer 3 92 at room temperature. 47 This indicates that under these reaction conditions, the biaryl bond was stereochemically labile. Upon treatment with dppe 3 61 , an optically inactive ligand was recovered confirming that 3 23 is achiral.

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73 Figure 3 31 . Reaction between P,N ligand 3 23 and palladium complex 3 52 Our next step was to attemp t the fractional crystalization of the diastereomeric mixture 3 90 / 3 91 . Many attempts using different solvent systems did not lead to a s elective crystallization. Next, use of the analogous palladium complex 3 52 was attempted. As expected, upon treatment of 3 1 with complex 3 52 at room temperature, a 1:1 mixture of diastereomers was formed (Figure 3 32). Unfortunately, only one di astereomer selectively crystalli zed but in very poor yields and the conditions were not reproducible. The selective formation of a single diastereomer described for the resolution of QUINAP 3 4 (Figure 3 21) employing four equivalents of ligand to palladiu m complex (2 equivalent of ligand in relation to palladium atoms) was also attem pted but the same trend was observed. This method seemed to work better, since we could get the pure diastereomer 3 93 in satisfactory yields of 30 40%. Figure 3 32. Preliminary results on the resolution of 3 1 with palladacycle 3 52

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74 Over the course of the optimization of this process, it was realized that during the recrystallization procedures the ratio of diastereomers would slightly change. This observation was made when conditions higher than ambient temperatures were employed and begged the 3 23 readily gives one diastereomer when treated with chiral pallad ium complex 3 92 at room temperature (Figure 3 31), but QUINAP complexes 3 59 / 3 60 do not interconvert even at relatively higher temperatures (Figure 3 21). It seemed possible that in terms of activation energy for rotation about the biaryl bond, complexes 3 9 3 / 3 94 could be somewhere in between complexes 3 92 and 3 59 / 3 60 . In other words, these data suggests a simple question: what would happen if we submit our diastereomeric complexes 3 9 3 / 3 94 to a higher temperature? Would both complexes be converted 3 92 did at room temperature? To probe this, a 1:1 mixture of diastereomers 3 9 3 / 3 94 in deuterated acetone was heated at 60 o C in an NMR tube. To our delight, after 24h a single diastereomer was observed as judged by 1 H and 31 P NMR (Figure 3 33). Figure 3 33. Interconversion of 3 94 to 3 93 under thermodynamic conditions To evaluate the practical ity of this process, the experiment was performed on a larger scale by mixing racemic phosphine 3 1 with palladium complex 3 52 and KPF 6 in acetone. After refluxing the mixture for 24 hours the solution was filtered off , the solvent removed , and a single d iastereomer was observed in the NMR of the crude reaction mixture. A single recrystallization gives the pure diastereomer 3 93 as a yellow solid in 81% yield (Figure 3 34).

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75 Figure 3 3 4 . Synthesis of 3 93 In Figure 3 3 5 , the 1 H NMR of the 1:1 mixture of diastereomers 3 93 and 3 94 formed at room temperature is shown and the single diastereomer 3 93 after heating in acetone for 24h. Figure 3 3 5 . 1 NMR of 1:1 mixture of 3 93 /3 94 (top) and single diastereomer 3 93 (bottom) With a single diastereomer in hand, it was likely that one enantiomer of the ligand 3 2 would b e isolated after decomplexation. Many research groups working in this area assume that after the decomplexation event the free ligand is obtained in >99% ee. This is likely because most of the ligands have such a high barrier that they will not racemize. 99,101 Since the biaryl axis of complexes 3 93/3 94 was converted to a single diastereomer 3 93 it could be possible that

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76 under the decomplexation conditions it could partially epimerize back. So a careful analysis of the enantiomeric excess of free ligand 3 2 was needed after decomplexation. The most accurate method of analysis to determine the enantiomeric excess of 3 2 would be using a HPLC with a chiral column. However, all attempts to separate the racemic ligand 3 1 by HPLC were unsuccessful. A s previ ously described for p yphos, 103 oxidation of 3 1 to phosphine oxide 3 96 was encouraged in hopes to obtain a more polar material and a better separation by HPLC . This oxidation could be performed in quantitative yields using hydrogen peroxide in dichlorome tha n e and was usually in an analytical fashion (1 5 mg of material). As expected, t he racemic phosphine oxide 3 96 exhibit s very good baseline separation using the CHIRALPAK® 1A chiral column on the HPLC. The conditions employed are displayed in Figure 3 36 . Although this procedure was not as easy as the direct analysis of 3 1 , it allowed for the precise determination of the ee of phosphine 3 2 implicit that the enantiomeric excess was determined by this method. Figure 3 36 . Oxidation of 3 1 and analysis of the oxide 3 96 by HPLC As previously described, the decomplexation is performed using one equivalent of dpp e 3 61 , a stronger bidentate bisphosphine. The experiment was run at room temperature in dichloromethane and 3 2 was recovered in high yield after column chromatograph. This procedure was repeated a few times and the enantiomeric excesses determined using the method

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77 described in Figure 3 36. In t erestingly, the enantiomeric excess of 3 2 would range from 88 to 92% among different experiments . Figure 3 37 . Decomplexation of 3 93 at room temperature S tate of the art ligands for asymmetric catalysis require a single enantiomer of the chiral ligand, so clearly this procedure needed improvement. However, many important experiments were able to be performed with these enantioenriched samples: 1) several enantioselective reactions were evaluate d with optically active ligand 3 2 in order to decide if there was promise that this ligand would work well and whether it was worthwhile to continue working on it. Fortunately, very promising results were obtained with ~90% ee ligand and wil l be discussed in detail in Chapter 4; 2) ligand 3 2 was stored in the refrigerator for a period of time and analyzed for loss of the enantiomeric excess after months. It was found that the ligand does not racemize and this is essential when developing a l igand for enantioselective catalysis. In light of that, our attention turned to improving the enantiomeric excess of the free ligand 3 2 . Three possible reasons for this relatively low enantiomeric excess were envisioned : 1. The free ligand 3 2 is racemizing at some point after the decomplexation. This hypothesis was ruled out since it was found that it is config urationally stable for months with no loss of optical purity at the temperature of the experiment . 2. There is ~ 4 6% of the minor diastereomer ( 3 94 ) present in the starting material samples of 3 93 . This possibility was very unlikely since there was a single peak in the 31 P. 3. The axial chirality is being slightly scrambled during the decomplexation or oxidation step.

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78 The third possibility seemed most likely since it is known that a 1:1 mixture of diastereomers 3 93/3 94 equilibrates to a single diastereomer 3 93 . This dynamic behavior of the system could be allowing the formation of a small amount of 3 94 during the decomplexation. Also, bisphosphine 3 61 could be coordinating to the palladium complex in a random fashion releasing the undesired phosphine 3 95 to a small extent . In order to avoid this, different temperatures were explored for the decomplexation (Figure 3 38). A d ecomplexation at 0 o C was performed and no improvement was observed n either in terms of yield nor enantiomeric excess . Next, we attempted an experiment at very low temperature ( 78 o C ) but there was no reaction due to low solubility of 3 61 in dichloromethane. Finally , it was foun d that adding 3 61 as a solid to a solution of 3 93 at 78 o C and quickly transferring the mixture to 0 o C ice bath would release the ligand in 98% enantiomeric excess after one hour. Figure 3 38. Opt i mization of the decomplexation step The HPLC chromatograms of the corresponding oxides 3 96 (racemic) and 3 97 (98% ee) are represented in Figure 3 39. This procedure was repeated many times and has also been repeated by other PhD students in our group proving to be a rel iable protocol. Usually, the decomplexation reaction gives about 100 mg of 3 2 in a single experiment.

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79 Figure 3 39. HPLC chromatograms of 3 96 (racemic) and 3 97 (98% ee) It is important to mention that the decomplexation using 3 61 at room temperature has been the standard procedure in the resolution process of many P,N ligands 99,101 and usually it is assumed that the ligand is enantiomerically pure based on the NMR of the single diastereomer prior to decomplexation . However, for ligands presenting relatively low barrier to rotation s about the chiral axis, the decomplexation step can compromise the entire effort spent to obtain a single diastereomer of the palladium complex . In our case, this was avoided by checking the enantiomeric excess of the final ligand 3 2 through derivatization to its oxide 3 96 . 3.5 Determination of the Absolute Stereochemistry of the P,N Ligand The absolute stereochemistry of P,N ligand 3 2 was determined by X ray crystallography of palladium complex 3 99 (Figure 3 40). 3 99 is the enantiomer of 3 92 and was prepared using palladium complex 3 53 under the same conditions as in Figure 3 38. The single crystal was obtained by vapor diffusion o f diethyl ether into a concentrated solution of 3 99 in dichloromethane. Since we know the stereochemistry at the benzylic position to be ( S ) we can define unambiguously that in 3 99 the P,N ligand is ( R ). And, by analogy, t he configuration in ligand 3 2 i s ( S ) obtained from 3 93 .

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80 Figure 3 40 . X ray crystal structure of 3 99 ( hexafluorophosphate counter anion and hydrogens are omitted for clarity) It is important to mention that in the solid state, the pentafluorobenzyl group is pointed away from the naphthalene ring. Indeed, the fluorinated aromatic ring is stacking with the phenyl ring at 5 position of the imidazole. A possible explanation for t his is that the small dihedral angle of 54.3 o observed in the biaryl moiety is required to bind to the metal. Consequently , it positions the pentafluorophenyl too close to the naphathalene and this results in repulsive interactions. In other words , rotatio n decreases the dihedral angle preventing the stacking interaction observed in the free phosphine 3 1 . In the case of the free ligand 3 1 ( dihedral angle: 84.9 o ) , without metal binding, there is no need for such a small dihedral angle and the stacking interaction occurs with the naphthalene ring. The fact that this interaction is not with the naphthalene ring in the complex does not compromise the objectives of the project for a few reasons. Firstly, in the free ligand these interactions are happening as expected and this is probably contributing to the barrier to rotation (this topic will be discussed in Section 3. 7 ). In addition, it will be shown in Chapter 4 that using different metals (copper, for example) stacking can indeed occur with the naphth alene ring.

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81 Figure 3 41 . Comparison between X ray crystal structure s of 3 99 and 3 100 (The pictures present only the core of the structures) For a point of comparison with QUINAP 3 4 , the X ray crystal structure of palladium complex 3 100 109 was analyzed. Both structures ( 3 99 and 3 100 ) are displayed in Figure 3 4 1 and they have the same stereochemistry in all respects. The dihedral angles and bite angles are listed for both struct ures . Although the bite angle is slightly smaller in 3 99 , the dihedral angle is significantly smaller (>10 o difference) probably due to the smaller five membered imidazole ring. The metal environments with either P,N ligands are shown. The chiral auxi liaries and counter anions were removed for clarity. The selected views demonstrate that a significant difference in the steric profile of the complexes is present at the nitrogen binding site. It appears that the phenyl rings of the imidazole generate a b ulky chiral environment at this area. 3.6 Rationalization of the Two Step Deracemization With regards to the two step deracemization process , it can be viewed as a dynamic thermodynamic resolution . 1 10,111 A general energy diagram can be drawn to illustrate the two step process (Figure 3 42).

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82 Figure 3 42 . Energy and reaction diagram for the two step deracemization process The racemic mixture of ligand 3 1 is represented by L S and L R in Figure 3 42. Complexation of 3 1 with the chiral palladium complex 3 52 at room temperature gives an equimolar mixture of 3 93 and 3 94 . At this point, 3 93 and 3 94 are equimolar and have different energies, they are diastereomers. The decomplexation of this mixture using dppe 3 61 prov ides a racemic mixture of ligand 3 1 . In order to obtain optically active 3 2 , a fractional crystallization can , in principle, be performed to separate 3 93 and 3 94 and decomplexation of 3 92 provides 3 2 . However, as previously discussed this did not provide satisfactory results. On the other hand, exposure of the mixture to acetone at 60 o C causes equilibration and the less stable diastereomer 3 94 converts to the most stable diastereomer 3 93 . Fortunatel y, under

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83 thermodynamic conditions, the final material contains essentially a single diastereomer 3 93 and decomplexation gives enantioenriched 3 2 (L S ) . In order to understand the difference in stability between the two diastereomers 3 99 and 3 101 , the is olation of crystals for X ray analysis of the unobserved and presumably less stable diastereomer 3 101 was attempted but this proved to be difficult . As an alternative, X ray quality crystals of the equimolar mixture of diastereomers 3 9 9 / 3 1 0 1 were obtain ed (prepared as in Figure 3 32) and the structure solved. Figure 3 43 . X Ray crystal structure of 3 9 9 / 3 1 0 1 (hydrogen atoms are omitted) The X ray structure of the crystals revealed a 1:1 packing of the two diastereomers (Figure 3 43). This structure was useful because a conformational analysis of each diastereomer became possible and insight into the favored and dis favored interactions on each structure was gained . The str uctures of each diastereomer are depicted separately in Figure 3 44. The most relevant difference between the two structures is the conformation of the highlighted five membered ring. In the more stable isomer 3 9 9 mation whereas it is flattened in 3 101 suggesting a more strained system. It is believed that this difference is directly associated with the relative stereochemistry of each diastereomer which

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84 will be discussed in the next paragraphs. Figure 3 44 . Conformational a nalysis of 3 59 and 3 60 Another important feature of this deracemization is that the naphthalene ring from 3 52 is required for the feasibility of this process. A control experiment employing palladium complex 3 51 was performed and a 1:1 mixture of diastereomers is obtained under the same conditions described before (Figure 3 45). Figure 3 45. Attempt of deracemization with 3 51 A very similar trend was observed by Brown while studying the diastereomer ic palladium complexes 3 100 / 3 102 and 3 102 / 3 10 4 formed from QUINAP 3 4 (Figure 3 46) . 109 He suggests that the presence of an extra benzene ring in 3 100 / 3 102 is important and a more strained system results . Consequently , a greater difference in energy for the pair of diastereomers is observed making the fractional crystallization more facile in this napththyl Pd system. In the

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85 case of 3 10 3 / 3 10 4 , the methyl group on the benzylic position has more deg rees of freedom dimin ishing the energy difference between the diastereomers. Indeed, when Brown and co workers tried to fractionally crystalli ze 3 103 / 3 10 4 a quasiracemate was formed in which each diastereomer would adopt very similar conformations. 109 On the other hand, for 3 100 and 3 102 the benzylic methyl group s are locked peri H of the naphthalene resulting in a more strained system and a greater energy difference between diastereomers. The se results are consistent with our observations when trying to deracemize palladium complexes 3 90 and 3 91 . Figure 3 46 . P alladium complexes 3 100 / 3 102 and 3 102 / 3 10 4 Studies on the importance of the counter anion hexafluorophosphate was also performed. Interestingly, the inclusion of KPF 6 is vital to the success of the deracemization reaction, as two non interconverting diastereomers are observed in the absence of this additive. Control experiments were performed to study this issue, and an equal mixture of two diastereom ers 3 105 / 3 10 6 was formed when KPF 6 was omitted but under otherwise identical reaction conditions. Additionally, recomplexation of 3 2 in the absence of KPF 6 results in a single diastereomer 3 105 that does not revert to the same 1:1 mixture of diastereom ers upon heating.

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86 Figure 3 47. Control studies with chloride as counter anion The different behavior of the palladium complexes 3 105 / 3 10 6 in the absence of hexafluorophosphate suggests that a cationic palladium is neede d for the epimerization process to occur. As discussed previously, careful analysis of the X ray structure of palladium complex 3 99 shows that the pentafluorobenzyl group rotated in order to stack with a phenyl group at 5 position of the imidazole. As described in Chapter 2, this directly affects the barrier to rotation around the biaryl bond. In other words, if the stacking is not occuring on the naphthalene ring, a reduced barrier to rotat ion might be expected. Actually, if the chloride is acting as a ligand instead of the imidazole nitrogen, as in 3 10 7 , the barrier to rotation around the biaryl bond would be expected to be higher (Figure 3 48). Therefore, switching to a less coordinating PF 6 counteranion decreases the electron density on the palladium, forcing the nitrogen to coordinate in a bidentate fashion and the energy barrier for rotation about the biaryl bond decreases. The results shown in Figure 3 47 are consistent with this expl anation. Figure 3 48 . Suggested conformational changes for neutral and cationic complexes

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87 There are reports of P,N ligand in the literature in which the square planar palladium complex has a chloride coordinated instead of the nitrogen of the heterocycle (Figure 3 49). Figure 3 49 . Monodentate P,N ligands in complexes 3 108 and 3 109 Palladium complexes 3 108 112 and 3 109 113 were isolated by other groups and the structures confirmed by X ray crystallography. Interestingly, in both cases there is a sterically demanding group next to the potentially coordinating nitrogen which could be one of the factors favoring the coordinati on of the chloride instead. In 3 1 07 , there is also a phenyl group adjacent to the imidazole nitrogen and an analogy can be drawn with 3 108 and 3 109 . Figure 3 50 . Suggested pathway for the deracemization process A suggested pathway for the deracemization process is illustrated in Figure 3 50. The complexation of racemic ligand 3 1 with chiral palladium complex 3 53 generates two diastereomers 3 107 / 3 110 . In the presence of KPF 6 , the nitrogen coordinates to pallad ium and

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88 the pentafluorobenzyl group stacks on the phenyl group on the other side of the biaryl axis thereby lowering its barrier to rotation. Consequently, the less stable diastereomer 3 101 then converts to the observed diastereomer 3 99 by rotating abo ut the biaryl bond. 3. 7 Evidence of Stacking in Solution stacking was obtained early on when X ray analysis of racemic P,N ligand 3 2 was performed stacking with the naphthalene ring in a parallel displaced fashion. Besides this data, further evidence stacking interactions in solution was needed . As described in Chapter 2, model systems employed stacking interactions are well known. 51,52 Usually, the feasibility of a n intramolecular stacking interaction is studied by modifying one of the aromatic rings in a model system and analyzing the impact on the barrier to rotation . Figure 3 51 . Fluorinated and non fluorinated P,N ligands 3 1 an d 3 111 In our case, a direct comparison of the barrier to rotation about the biaryl bond s in fluorinated 3 1 and 3 111 , a non fluorinated analogue , would be appropriate (Figure 3 51) . Based on our studies described in Chapter 2, c ompound 3 111 would not h ave the same level of stacking ability as 3 1 . The presence of an AB system for the methylene protons of both compounds suggested the use of VT NMR to calculate the rotational barr iers but, as mentioned before, the AB systems of both compounds did not coalesce up to 120 o C. Since the coalescence method was not appropriate to determine barriers above approximately 2 5 kcal/mol , a different approach was needed . Compound 3 2 was obtain ed in

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89 98% enantiomeric excess, therefore kinetic studies on the racemization of this compound would give the barrier to rotation. To make the desired comparison , the preparation of optically active 3 111 was essential and this compound was prepared by a si milar route (Figure 3 52). Although the synthesis of racemic 3 111 occurred as expected, the two step deracemization process presented a different behavior. T he equilibration event employing palladium complex 3 52 was feasible at room temperature, suggesti ng a lower barrier for the biaryl bond of 3 114 . The reaction of 3 52 and 3 111 in the presence of KPF 6 gave 3 114 as a single diastereomer in 58% yield a fter 24h . T reatment of 3 114 with 3 61 at 78 to 0 o C released optically active 3 115 in 88% yield, however, the ee of 3 115 was observed to be only 52%. This is probably due to a more facile epimerization during the decomplexation event. Figure 3 52 . Synthesis and deracemization of 3 111 The enantiomeric exce ss was determined analogously to 3 2 by oxidation of 3 11 1 using hydrogen peroxide in dichloromethane (Figure 3 53 ).

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90 Figure 3 53 . Determination of the enantiomeric excess of 3 115 The HPLC chromatograms for the phosphine oxides 3 116 (racemic) and 3 117 ( optically active ) are presented in Figure 3 5 4 . Figure 3 54 . Chromatograms of 3 11 1 and 3 117 With optically a ctive 3 2 and 3 115 in hand, the racemization studies were performed (Figure 3 55) . To make the right comparisons both compounds were submitted to the same conditions employing dichloroethane (DCE) as a solvent. Solutions (2 mM) of 3 2 (98% ee) or 3 115 (52% ee) in DCE were heated in a 75 ºC oil bath. The enantiomeric ratio was measured by chiral HPLC (after oxidation of aliquots containing the phosphines to the corresponding oxides). The decay in enantiomeric excess of 3 2 and 3 115 over time are shown in the graphs below (Figures 3 56 and 3 57).

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91 Figure 3 55 . Racemization of optically active phosphines 3 2 and 3 115 Figure 3 56 . Plot of the ee (%) versus time for the racemization 3 2 Figure 3 57 . Plot of the ee (%) versus time for the racemization 3 115 98 96 91 85 74 66 60 0 20 40 60 80 100 120 0 200 400 600 800 1000 1200 1400 ee (%) Time (min) 52 36 30 22 16 0 10 20 30 40 50 60 0 10 20 30 40 50 60 70 ee (%) Time (min)

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92 Figure 3 58 . Plot of ln([M] t [M] eq )/([M] 0 [M] eq ) versus time at 75 o C for 3 2 Figure 3 59 . Plot of ln([M] t [M] eq )/([M] 0 [M] eq ) versus time at 75 o C for 3 115 A plot of ln([M] t [M] eq )/([M] 0 [M] eq 11 4 resulted in the graphs shown in Figures 3 58 and 3 59 . Where [M] t is the enantiomeric ratio at a certain time and [M] eq = 0.5. Using the slope of these lines and the Eyring

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93 equation, the free activation energy ( G T ) and the half lives (t 1/2 ) for compounds 3 2 and 3 115 were determined (Figure 3 60) . It was found that 3 115 has a half life of 22 min at 75 °C in DCE, whereas 3 2 has a half life of 8.70 h. The absolute free activation energies to rotation were calculated to be: 28.37 and 26.18 kcal/mol for compounds 3 2 and 3 115 , respectively. This corresponds to G ( 75 °C ) = 2.2 kcal/mol, a value that is within the range of previously stacking, 51,52 and demonstrates that the electronic perturbation by simple inclusion of the fluorine atoms significantly increases the barrier to rotation of these biaryls . Figure 3 60 . Determination of the barriers to rotation of 3 2 and 3 115 at 75 o C 3. 8 Summary and Conclusions In summary, the design and preparation of an imidazole based chiral biaryl P,N ligand 3 2 was accomplished. The presence of the pentafluorobenzyl moiety enhances the barrier to rotation of the P,N ligand allowing it to be useful for asymmetric catalysis. The method to obtain optically active 3 2 appears as the first example of a deracemization process to obtain enantiomerically pure axially chiral P,N ligands. The main drawback of this method is the use one equivalent of palladium and efforts are being made towards the exploration of other metals and chiral auxiliaries for the deracemization. However, w ith a reli able protocol for obtaining this ligand as single enantiomer, the evaluation of 3 2 in different enantioselective reactions was

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94 possible. Chapter 4 will describe the importance of P,N ligands in metal catalyzed asymmetric transformations and show the perfo rmance of 3 2 in these reactions.

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95 CHAPTER 4 APPLICATIONS OF THE NEW P,N LIGAND IN ASYMMETRIC TRANSFORMATIONS The success of P,N ligands in asymmetric c atalysis has been reported in several reviews. 101,115,116 The most recent update, published in 2014 by Carroll and Guiry, 83 shows how these type of ligands are continuing to be developed. Very recently, an interesting Perspective article appeared in the Journal of Organic Chemistry covering exclusively axially chiral P,N ligands. 117 Although P,N ligands have been known for decades, the number of axially chiral structures with this moiety is relatively small. Unfortunately, the present state of asymmetric catalysis does not allow predictions into the performance of a new ligand in a reaction. The incorpor ation of a five membered heterocycle in the chiral axis might offer advantages. This motivated us to evaluate 4 1 in known and new transformations. As an obvious strategy, reactions in which QUINAP performs well were selected to be tested first. Figure 4 1 . Axially Chiral P,N ligands 4 1 and QUINAP 4 2 It is important to mention that the extensive efforts for the preparation of a single ligand described in Chapter 3 was motivated by early data obtained in the application of 4 1 in asymmetric transformations. These preliminary data are presented herein. In addition, a full methodological study of the copper catalyzed A 3 coupling employing 4 1 will be given. 4.1. P,N ligands in Asymmetric Catalysis New chiral ligands for asymmetric catalysis are reported very frequently and the number of ligands that catalyze specific reactions in high enantiomeric excess are extensive. However, the number of ligands that catalyze a number of diverse reactions are limited. 15 These ligand

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96 s chirality in various transformations. 14 ter covers a privileged scaffold. 15 The top row of Figure 4 2 shows three examples: bisoxazoline 4 3 , BINAP 4 4 and Josiphos 4 5 type structures. These structures were selected to illustrate the three types of chirality discussed by Cahn, Prelog, and Ingold: central, axial, and planar chirality. 118 Figure 4 2 . Privileged ligand structures (top) and P,N ligands (bottom) In general, the current state of the art for the development of new chiral ligands relies upon modification of a previous family of ligands. In this context, the first P,N ligands were inspired by P,P or N,N ligands. The success of th e latter ligands encouraged many chemists to switch a phosphorus to a nitrogen and vice versa. Interestingly, the most successful P,N ligands were derived from privileged structures (Figure 4 2). Indeed, PHOX type ligands 4 6 were designed as an extension of bisoxazolines 4 3 and now are also considered privileged. PHOX ligands appear frequently in metal catalyzed asymmetric reactions and this topic will be revisited in Section 4.3. 5 . As stated in the previous chapters, axially chiral QUINAP 4 2 was inspire d by

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97 the success of BINAP 4 4 . JOSIPHOS type P,N ligands are exemplified by pyrazole based ligands 4 7 , 119 but there can be other nitrogen donors. This is an important class of ligands that was suggested based on JOSIPHOS 4 5 , but they will not be covered in detail. In Figure 4 3, a general P,N ligand structure is illustrated. The main distinction of a P,N ligand, if compared to a N,N or P,P, is the presence of two chemically different binding sites. When coordinated to a metal, the soft phosphorus atom ha s acceptor and donor properties whereas the hard nitrogen acts primarily as a donor. This allows for very subtle tuning of the electronics at the metal center by changing the nature of the substituents at phosphorus and nitrogen atoms. In the majorit y of P,N ligands , the phosphorus atom is part of a triaryl phosphine but alkyl groups also exist . On the other hand, the nitrogen donor appears in many different functionalities, such as amines, imines, heterocycles , etc. The nitrogen donor atoms of axially chiral P,N ligands are usually sp 2 hybridized nitrogens such as in 4 1 and 4 2 Figure 4 3 . General P,N ligand structure and properties 119 on the pyrazole based ferrocenyl ligands 4 7 is a representative example of how tuning the electronics of a P,N ligand can be effective (Figure 4 4). While studying the rhodium catalyzed asymmetric hydroboration/oxidation of styrene 4 8 , it was found that the combination of an electron po or phosphine (Ar = 3,5 (CF 3 ) 2 Ph) and an electron rich pyrazole ring (R = CH 3 ) in ligand 4 13 would deliver sec alcohol 4 9 in 98.5% ee. Switching or changing the electronic properties of the P,N ligand would result in a poor enantiomeric excess (See result s with 4 10 , 4 11 , and 4 12 ).

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98 Figure 4 4 . Tuning the electronic properties of P,N ligand 4 7 4.2. Asymmetric Reactions Catalyzed by Axially Chiral P,N ligands The aim of this section is to present the main asymmetric transformations in which axially chiral P,N ligands stand out. After the seminal reports by Brown on the discovery of QUINAP, many groups developed new asymmetric reactions employing QUINAP and/or new axially chiral P,N ligands. 83,101 The most important ex amples of ligand variations are presented in Figure 4 5. Figure 4 5 . Axially chiral P,N ligands Guiry and co workers developed a new family of ligands 4 1 5 , 102,113 named Quinazolinap, comprised of a quinazoline heterocyc le in the biaryl backbone. The advantage of these ligands is the possibility for variation at 2 position of the nitrogen heterocycle allowing for tuning of the electronic and steric factors on this side of the structure. Pyphos 4 1 6 , 96,103 discussed in Chapter 3 (Section 3.3.2), is a pyridine analogue of QUINAP that was developed by

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99 Kwong. PINAP ligands 4 1 7 104,105 were developed by Carreira and co workers during the course of their studies on alkynylation reactions. The main advantage of P INAP is the introduction of a chiral center to facilitate resolution (Section 3.3.3). Additionally, access to other PINAP analogues is facile. There are many reactions in which axially chiral P,N ligands were employed with success. A few examples will be d escribed to show the highlights of each reaction and it should be noted that this is not a comprehensive review on the field. 4.2.1. Rhodium Catalyzed Hydroboration of Arylalkenes As described previously, axially chiral P,N ligands appear to be the best li gand choice for the rhodium catalyzed h ydroboration of arylalkenes , furnishing the sec alcohols 4 19 in extremely high enantioselectivity for a wide range of substrates. The success of P,N ligands from Figure 4 5 in this reaction is summarized and the resu lts from each ligand is presented below (Figure 4 6). The chirality on the axis of the ligand correlates to the configuration of the product so that ( S ) ax gives ( S ) sec alcohol and ( R ) ax gives ( R ) sec alcohol in all cases. Figure 4 6 . Examples of sec alcohols 4 19 obtained through rhodium catalyzed enantioselective hydroboration

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100 4.2.2. Rhodium Catalyzed Diboration of Alkenes In 2003, Morken and co workers developed the first asymmetric diboration of alkenes employing rhodi um catalyst 4 29 and dicatechol diborane 4 30 . 120 In their studies, QUINAP 4 2 was shown to be a superior ligand in comparison to BINAP 4 4 . For instance, in the reaction with trans alkene 4 28 , a syn addition product is observed and retained through the o xidation to give the syn diol 4 32 in high ee (Figure 4 7). Figure 4 7 . Diboration of trans alkene 4 28 with B 2 (cat) 2 4.2.3. 1,3 Dipolar Cycloadditions Although 1,3 Dipolar Cycloadditions have been extensively explored, 121 the development development of a silver catalyzed reaction between azomethine ylides and electron poor alkenes revealed QUINAP as the best ligand. 122 The reactions w ere carried out at 20 o C in THF to give the tetrasubstituted pyrrolidines in good yields and good enantioselectivities. As an example, the cycloaddition between iminoester 4 3 4 and tert butyl acrylate 4 3 3 yielded the cyclic product 4 35 as a single diast ereomer in 84% ee and 97% yield (Figure 4 8). Reisman and co workers extended this type of reaction to a double cycloaddition process. 123 The first [3 + 2] 4 37 . In the same pot , a reaction between 4 37 and cinnamaldehyde 4 38 generates an iminium salt which can equilibrate to a new azomethine. Reaction between the new ylide and alkene 4 36 gives the

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101 bicyclic product 4 39 in 90% ee and 74% yield. It is important to mention that t he second step does not require the silver / QUINAP catalyst , giving the product in a diastereocontrolled manner. Figure 4 8 . Examples of silver catalyzed [3 + 2] cycloadditions 4.2.4. Copper Catalyzed Alkynylation of Iminium I ons The three component reaction between an aldehyde 4 40 , an amine 4 41 and a terminal alkyne 4 42 gives a propargylic amine 4 43 in one pot in a very efficient manner (Figure 4 9). This reaction is the so called A 3 coupling and can be catalyzed by different metals with copper, gold, and silve r complexes being the most preva lent. 124,125 In general, this transformation tolerates aliphatic and aromatic aldehydes, primary and secondary amines and a variety of alkynes (Figure 4 9). The reaction is a v ery efficient way to access propargylic amines from simple substrates generating water as only byproduct. Figure 4 9 . General scheme for the A 3 coupling reaction

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102 In 2003, Knochel and co workers reported the first enantios elective copper catalyzed A 3 coupling reaction. 126 The method employed a QUINAP/CuBr catalytic system providing enantioenriched propargylic amines 4 44 (Figure 4 10). Figure 4 10 . First examples of an enantioselective A 3 coupling In general the reaction times were extremely long varying from 2 6 days. In a full report of their studies, 127 a broad range of substrates were explored. Secondary aldehydes, such as cyclohexanecarboxaldehyde 4 45 , furnished the propargylamines i n excellent enantioselectivity. On the other hand, the lower reactivity of aromatic aldehydes had an impact on the yield and enantioselectivity of these reactions. For instance, the A 3 coupling of aldehyde 4 49 , phenylacetylene 4 50 and diallylamine 4 51 g ave propargylamine 4 52 in 43% yield and 63% ee after five days. This specific reaction was explored with P,N ligand 4 1 and will be discussed in more detail further in this chapter. Although the elegant reaction developed by Knochel was the first example of an asymmetric A 3 coupling, important drawbacks emerged. For instance, the reaction only worked with dibenzyl or diallyamines generating propargylic tertiary alkyl amines that are difficult to

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103 deprotect. The selective amine deprotection of dibenzylamin e products is not possible without reduction of the alkyne and the diallylamine cleavage requires the use of excess of palladium catalysts (eight equivalents). 128 In view of this, Carreira and co workers developed an alternative in which 4 piperidone 4 54 was used as the amine component and ( R , R ) PINAP 4 5 5 /CuBr as a catalyst to deliver propargylic amines in high yields and enantioselectivities (Figure 4 11) . 128 Using a polymer supported scavenger the amine products, such as 4 5 6 , were deprotected throug h a double retro Michael addition, with concurrent desilylation, to give the amine hydrochloride 4 5 7 as a single enantiomer. Figure 4 11 . Asymmetric A 3 coupling using piperidone 4 54 The potential application of these reactions was demonstrated early on by Knochel on the synthesis of ( S ) coniine. 127 Recently, Ma and co workers used the method as an entry to disubstituted allenes (Figure 4 12). 12 9 The two step process generates the propargylic amines using ( R , R ) PINAP 4 5 5 /CuBr and, after filtration of the copper catalyst, the reaction mixture is treated with half an equivalent of ZnI 2 and NaI to provide enantioenriched allenes 4 60 in a

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104 stereospecific fashion. Figure 4 12 . A 3 coupling re action as an entry to enantioenriched allenes to isolated dihydroisoquinoline iminium ions was explored. 130 In this case, with the ( S ) QUINAP 4 2 /CuBr cyclic propargylic amines were obtained in good yields and enantioselectivities. The iminium salts were prepared and submitted to the reaction conditions to give the cyclic tertiary amines in excellent yields and enantiomeric excesses. The efficiency of the procedure is exemplified in a concise synthesis of the neuroactive alkaloid homolaudanosine 4 64 (Figure 4 13). Figure 4 13 . Concise synthesis of homolaudanosine 4 64 4.2.5. Copper Catalyzed Acetylide Addition to Michael Acceptors of ligand design and reaction discovery. 105 The reaction employed phenylacetylene 4 50 and alkylidene 4 65 to give product 4 66 (Figure 4 14) . The reaction was performed in a biphasic medium between water and phenylacetylene 4 50 . Also, although a source of copper(II) is initially added to the flask, this reaction is catalyzed by an in situ generated copper(I) species. This is easily done by mixi ng Cu(OAc) 2 with (+) sodium ascorbate which acts as a reducing

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105 agent. At the outset, they tested ~25 commercially available chiral ligands which would ligate copper and induce chirality in the reaction. 105 Among them, QUINAP gave the best enantioselectivit y of 42% although this is not high enough to have any practical synthetic utility (Figure 4 14). Figure 4 14 . 4 2 QUINAP derivatives for optimization were scarce and Carreira and co workers proposed the design of a new family of ligands, which would allow the synthesis of analogues. The idea behind the design of PINAP ligands was previously discusse d (Section 3.3.3 ). With approximately 10 15 PINAP analogues in hand, extensive optimization studies were conducted, to achieve a high enantiomeric excess for product 4 66 . Figure 4 15 . Optimized conditions for the copper catalyzed acetylide addition to Meldrum derivatives

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106 As shown in Figure 4 15, the highest yields and enantioselectivities were obtained with PINAP ligand 4 68 , (94% yield, 95% ee). Interestingly, the atropdiastereomer 4 69 gave low yield and enantio selectivity . 131 As a consequence, besides the axial chiralit y, the other chiral center present in the ligand proved to be influential on the stereosele ctivity outcome of the reactions. 4.2.6. Miscellaneous Nickel Catalyzed Reactions There are two very recent examples in which QUINAP was the preferred ligand in nick el catalyzed reactions. The first involves an annulation reaction between heterocycle 4 70 and allene 4 71 to furnish sulfonamide 4 72 in 87% yield and 96% ee (Figure 4 16). 132 The proposed pathway of this novel reaction involved a nitrogen extrusion of 4 70 with concurrent oxidative addition of nickel(0). An insertion at the central carbon of the allene followed by a reductive elimination provides 4 72 . The product could be manipulated to methylphenethylamine 4 73 with high diastereoselectivity . Figure 4 16 . Nickel catalyzed regio and enantioseletive annulation reaction Another example, published in 2013, is a nickel catalyzed [2 + 2 + 2] cycloaddition to furnish enantioenriched helicenes. 133 For instance, when tr ialkyne 4 77 was treated with ( R ) QUINAP/Ni(COD) 2 catalyst, product 4 79 was obtained in 80% yield and 85% ee .

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107 Figure 4 17 . Nickel catalyzed enantioselective synthesis of helicenes 4.3. Enantioselective Reactions with Imidazole B ased P,N ligand of different reactions catalyzed by the metal complexes of these ligands is impressive. As mentioned before, with enantioenriched P,N ligand 4 1 in hand, a few of these enantioselective transformations were tested. Preliminary experiments on the rhodium catalyzed hydroboration/oxidation were not successful due to regioselectivity issues and attention was directed to copper and palladium catalyze d reactions. O ur work focused mainly on copper catalyzed acetylide additions which perform exceedingly well with ligand 4 1 . In addition, Acid derivatives are pres ented. The palladium catalyzed asymmetric allylic alkylation was investigated for a direct comparison with QUINAP and will be discussed at the end of this chapter. 4.3.1. A 3 Coupling R eact ion Employing Imidazole B ase d P,N ligand As described in Chapter 3 d uring the optimization of the ligand synthesis we obtained samples of ent 4 1 in 87 92% enantiomeric excess. Early data was obtained on the copper catalyzed A 3 coupling reactions employing enantioenriched P,N ligand ent 4 1 (87% ee). For a direct compariso n with QUINAP, the alkynylation of in situ generated iminium ions between aromatic aldehydes, phenylacetylene 4 50 and diallylamine 4 51 were evaluated (Figure 4 18). The desired propargylic amines were obtained in excellent yields and good enantioselectivities.

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108 It is worth mentioning that Knochel encountered difficulties when employing QUINAP for these exact reactions. 126,127 Although aliphatic aldehydes performed very well, aromatic aldehydes proved to be more challenging in terms of yields and enantioselectivities. Figure 4 18 . Copper c at alyzed three component reaction In addition, as depicted in Figure 4 18, our reaction times were much shorter giving good to excellent yields for benzaldehyde 4 8 0 , p methoxybenzaldehyde 4 81 , and p trifluoromethanebenzaldehyde 4 49 in only 24 hours. Furthermore, using the 87% ee ligand ent 4 1 , the enantioselecitivities were higher than those observed when QUINAP was employed as a single enantiomer (>99% ee). In p articular, electron poor aldehyde 4 49 gave only 43% yield and 63% ee with QUINAP ent 4 2 after five days 126 whereas with imidazole based ligand ent 4 1 ( 87% ee ligand) the yield was 94% and a respectable ee of 73% after 1 day. As pointed out , three main improvements were observed when employing ligand ent 4 1 instead of QUINAP ent 4 2 in the copper catalyzed A 3 coupling: 1) shorter reaction times; 2) higher yields; 3) higher enantioselectivities for aromatic aldehydes. These results encouraged us to explo re the reaction in more detail with a close eye on reactivity and stereoselectivity. Knochel reported that reactions catalyzed by a CuBr/QUINAP complex took between 1 6 days for completion. 126,127 As an example, when employing butyraldehyde 4 84 , TMS acetylene

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109 4 46 and dibenzylamine 4 47 at room temperature the product was obtained in 88% yield after 5 days. 134 With racemic ligand rac 4 1 , a much shorter reaction time of 1 day was observed, furnishing the product in 97% yield. In order to explore the reactivity of our catalytic system, the same experiment was performed at 0 °C and the product was found in 92% yield. 79 These results were encouraging since reactions at lower temperatures often provide better selectivities. 5 Figure 4 19 . A 3 coupling employing racemic ligand rac 4 1 With this motivation, we expended every effort to obtain 4 1 as a single enantiomer (Chapter 3). With this ligand in hand (98% ee), efforts were directed towards the enantioselectivity of the reaction with different substrates. As can be seen in Table 4 1 , the reactions were highly enantioselective over a range of al dehydes. 79 As might be expected, with substitution increases selectivity (e.g., entries 2 vs 4 ). It is also noteworthy that, using 4 1 , these conditions work well for aromatic aldehydes, which are the most challengin g substrates for the reaction. Remarkably, the presence of electron donating or temperature. When 4 49 was allowed to react at 0 °C, the reaction was very slow, yielding 4 97 in only 15% after 4 days, but in 95% ee (entry 8). Increasing the temperature to 22 °C restored the reactivity to an acceptable level (70% yield after 24 h) and had little effect on the ee ( 92% ee, entry 9). In comparison, the previous best yield obtained with th is electron deficient aldehyde was 43% after 4 days to o btain the product in 63% ee. 126

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110 Table 4 1 . Enantioselective A 3 coupling employing 4 1 . Due to the very low polarity of the products, a deprotection of the silyl group was needed in order to separate the enantiomers in the HPLC. That was done using a methanolic KOH solution which readily provided the desylilated products in quantitative yield s (Figure 4 20).

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111 Products 4 92 and 4 96 did not require this procedure since they were readily separable by HPLC. Figure 4 20 . Desilylation of propargylamines 4 86 Carreira and co workers have also developed modified condi tions to employ amine 4 54 , which can be readily deprotected. 128 With these conditions, using the PINAP ligand, it was reported that aromatic aldehydes do not provide satisfactory results. In contrast, ligand 4 1 enables the use of both aliphatic and aromatic aldehydes with high enantioselectivity ( Figure 4 21 ). 79 Figure 4 21 . Alkyne addition with 4 54 These results lead to the conclusion that 4 1 is the best ligand for the enant ioselective A 3 coupling to date, displaying the highest levels of reactivity and selectivity over the broadest range of substrates. 79 More importantly, these results demonstrate the potential of the new design element exemplified by 4 1 . 4.3.2. Mechanisti c Aspects of the Copper C atalyzed A 3 Coupling R eaction The mechanism of the copper catalyzed A 3 coupling reaction is not fully understood to date . 124,125 A tentative mechanism for the racemic version of the reaction is depicted in Figure 4 22. The coordination of the copper species to the triple bond of 4 42 enhances the acidity of the

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112 terminal proton favoring the formatio n of copper acetylide species . Coo rdination of the metal to the terminal alkyne is important due to the absence of a strong base in the reaction medium ( 4 41 and 4 43 are not strong enough to deprotonate a terminal alkyne). The nucleophilic attack of the copper acetylide to an in situ form ed iminium ion furnishes the propargylamine products 4 43 and regenerates the catalyst. Figure 4 22 . Tentative mechanism for the A 3 coupling Preliminary aspects of the mechanism for the enantioselective A 3 coupling reactio n were discussed by Knochel. 126,127 In his seminal report employing QUINAP, the mechanism was proposed based on two observations: a dimeric X ray structure of [CuBr{( R ) QUINAP}] 2 4 9 5 135 (Figure 4 23) and a strong positive non linear effect on the reaction (Figure 4 24). The dimeric structure of [CuBr{( R ) QUINAP}] 2 complex 4 9 5 has a distorted planar four membered Cu 2 ( Br) 2 ring. Although there are P Cu bonds, the distances between copper and nitrogen are longer than usual, resulting in a weak Cu N bond and a distorted tetrahedral geometry in both copper atoms.

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113 Figure 4 23 . X ray structure o f 4 9 5 Mechanistic studies by Knochel and co workers shows a strong positive nonlinear effect (Figure 4 24) . For instance, employing 10% ee QUINAP, propargylic amine 4 97 was obtained in 68% ee. This suggests that diastereomeric dimers are formed in solution and the heterochiral [Cu 2 Br 2 {( R )/( S ) QUINAP}] 2 complex reacts much more slowly than the homochiral [CuBr{( R ) QUINAP}] 2 complex. Figure 4 24 . Non linear effect observed on the A 3 coupling employing QUINAP 50 68 80 82 92 96 0 20 40 60 80 100 120 0 20 40 60 80 100 120 %ee catalyst ent 4 2 %ee product 4 97

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114 Based on these observations, a mechanism involving a dimeric complex 4 98 was proposed . 126,127 The first step would be the activation of the alkyne system by the copper complex resulting in a complex 4 99 . Aminal 4 100 generated by a reaction between the secondary amine 4 41 and aldehyde 4 40 would form an adduct with 4 99 resulting in 4 101 . Deprotonation of the alkyne, followed by water elimination, would form complex 4 102 between an iminium ion and copper acety lide. Nucleophilic attack on the prochiral face of the iminium ion by the chiral copper acetylide complex leads to the product 4 44 and regenerates the catalyst 4 98 . In this last event, in which the chiral center is formed, one diastereomeric transition s tate is favored leading to a high enantiomeric excess. Figure 4 25 . Tentative mechanism for the enantioselective copper catalyzed A 3 coupling reaction In order to obtain insight into the mechanism of the reaction with lig and 4 1 , X ray crystal structure analysis of rac 4 2 /CuBr complex was desired. For this, different solutions of rac 4 1 and CuBr were dissolved in several solvent mixtures and recrystallization attempted. After optimization, white crystals were formed by t he vapor diffusion of diethyl ether into a

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115 yellow solution of rac 4 2 /CuBr in toluene/dichloromethane as solvent system. The optimized recrystal l ization conditions were employed with enanti o pure ligand 4 1 to the formation of enantiomerically pure homochiral complex [CuBr{( S ) 4 1 }] 2 4 103 . Analysis of the X ray crystal structure revealed that the connectivity of the dimeric heterochiral complex [CuBr{( S ) 4 1 }] 2 4 103 greatly differed from that of the QUIN AP analogue 4 95 . The two P,N ligands in 4 103 are clearly different because one of them is bidentate and the other is monodentate. Interestingly, the bidentate P,N ligand is coordinated to two different copper atoms that are bridged with a bromine atom, f orming an eight membered ring (Figure 4 26). 136 The formation of this large ring allows for an enlarged dihedral angle of 89.9 o in the biaryl moiety. Consequently, the intramolecular stacking interaction between the pentafluorobenzyl moiety and naphthale ne is feasible because they are not forced too close together. The monodentate P,N ligand is also stacking and the dihedral angle is 78.4 o . Figure 4 26 . X ray crystal structure and analysis of 4 103 4 104 137 (Figure 4 27) in which the P,N ligands are monodentate forming a chlorine bridged dimeric structure. In

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116 4 95 , in this case the coppe r atoms are purely trigonal planar. Figure 4 27 . X ray crystal structure 4 104 By analogy to complexes 4 95 and 4 104 , an analogous structure 4 105 was hypothesized (Figure 4 28). The final connectivity obtained in the cry stal structure of 4 103 could come from the coordination of an imidazole nitrogen of 4 105 to copper and displacement of a bromine atom as shown below. This is a reasonable pathway to explain how this specific structure is formed and could be supported by the fact that imidazole nitrogens are more basic/nucleophilic than isoquinolines 135 or quinazolines. 137 Figure 4 28 . Proposed formation of complex 4 103 With the X ray structure of 4 103 solved, attention was given to a possible mechanism of the A 3 coupling reaction employing 4 1 . Since the crystal structure of 4 103 is dimeric, as in QUINAP/CuBr structure 4 95 , the same mechanism suggested by Knochel could be proposed. However, results f rom Figure 4 18, in which ligand ent 4 1 was used in 87% ee, suggests that

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117 the reaction with imidazole based P,N ligand does not present a non linear effect and a monomeric copper complex could be catalyzing the reaction. Therefore, it is difficult at this moment to draw any conclusion with respect to the mechanism of the copper catalyzed A 3 coupling reaction employing 4 1 . Regarding the more basic imidazole nitrogen in 4 1 , a comparison to the isoquinoline nitrogen of QUINAP was considered. The shorter rea ction times observed with 4 1 could be related to a faster deprotonation of the terminal alkyne during the A 3 coupling reaction. If a nitrogen of the imidazole is in close proximity to the metal alkyne complex 4 106 during the reaction, it could deproton ate the alkyne and accelerate the transformation (Figure 4 29). Interesting evidence for this possibility could be obtained by studying the P,N ligand copper alkyne complex 4 107 . To this end, racemic P,N ligand rac 4 1 , phenylacetylene 4 50 and CuBr were mixed in CDCl 3 in hopes to observe a deprotonation of the terminal alkyne by 1 H NMR, but it was difficult to analyze the spectrum due to very broad peaks. Figure 4 29 . Speculative deprotonation of the terminal alkyne by the imidazole nitrogen In summary, the mechanism of the copper catalyzed enantioselective A 3 coupling is still poorly understood. Efforts still need to be directed towards the investigation of which copper complexes (monomeric, dimeric, etc.) are involved in the reaction. In addition, studying the

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118 difference between imidazole based ligand 4 1 and QUINAP 4 2 in the A 3 coupling will be important. 4.3.3. Copper Catalyze d Acetylide Addition to Quinolin ium Salts The functionalization of pyridine aromatic rings through the formation of pyridinium salts is a very important tool for the synthesis of nitrogen heterocycles. 138 In 2008, Arndsten and co workers reported the copper catalyzed coupling between quinolinium salts and terminal alkynes to give cyclic proparg ylcarbamates (Figure 4 30). 138b The reaction requires the in situ formatio n of the iminium salt from quinoli ne 4 108 and ethylchloroformate 4 109 which reacts smoothly with the copper phenylacetylide to furnish 4 110 . They observed higher reactivity for qu inolines when compared to simple pyridines and the chosen catalyst system was CuCl along with a PINAP ligand 4 113 . Interestingly, the introduction of an electron donor methoxy group on the 7 position of the naphthalene ring increased significantly the ena ntioselectivity of the reaction from 53% to 81% (Compare results with ligands 4 112 vs 4 113 ). The optimized conditions employed catalytic 4 113 /CuCl, CH 2 Cl 2 /CH 3 CN as the solvent system at 78 o C and Figure 4 30. Enantioselective copper catalyzed coupling of quinolines and alkynes During the course of our work on copper catalyzed acetylide addition with imidazole based P,N ligand 4 1 , the reaction developed by Arndsten appeared to be a good candidate to

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119 study as the reported enantioselectivities were not high enough to be synthetically useful, leaving room for improvement. At the outset, an experiment using the optimal conditions from the A 3 coupling was performed. Q uinoline 4 108 , ethylchloroformate 4 109 , an d TMS acetylene 4 46 were exposed to ligand 4 1 provided the product in 55% yield (Figure 4 31). Although the conversion was not ideal, to our delight the product 4 114 was isolated in exc ellent 95% enantiomeric excess. Isoquinoline 4 115 was also used as starting material under the same conditions providing the product in lower enantiomeric excess of 82%, but still higher than the 72% observed by Arndtsen with the same substrate. 138b Figure 4 31. Enantioselective copper catalyzed coupling of quinolines and alkynes employing P,N ligand 4 1 The present method allows for the synthesis of alkaloids 4 117 , 4 118 and 4 119 in only three steps from commerciall y available materials (Figure 4 32) . These natural products were isolated from the bark of Galipea offininalis Hancock in Venezuela. 139,140,141 Despite the interesting biological activities of these compounds, 139,140,141 we were interested in preparing th em so that the absolute configuration of the products of our reaction could be determined . The use of arylalkyne 4 62 in the three component reaction gave the product 4 120 in 86% yield and

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120 95% ee using reaction conditions optimized by our group member Muk esh Pappoppula . The higher yield obtained in this reaction was probably due to better solubility of the catalyst in dichloromethane, when compared to toluene. Global hydrogenation of 4 1 20 using Pd/C and H 2 , followed by LAH reduction of the carbamate furnished ( + ) cuspareine 4 1 21 , the unnatural version of the natural product, in 77% yield over two steps. The observed positive value for the optical rotation allowed for the assignment of the absolute configuration of the product by comp arison to the known value for the natural ( ) cuspareine. 142 This work is being further developed by graduate students Mukesh Pappoppula and Owen Garrett. Figure 4 32 . Determination of the absolute configuration through the synthesis of (+) cuspareine 4.3.4. Asymmetric A lkynylation of Alkylidene D A cid The a was discussed in Section 4.2.5 . The employment of PINAP type ligands in t he reaction was widely studied for a variety of substrates. 105,131

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121 In view of the success of ligand 4 1 in copper catalyzed acetylide additions, an evaluation of 4 1 in this powerful carbon carbon bond formation reaction was performed . Since PINAP type li gands possess one chiral center and one chiral axis, the examination of a purely axially chiral ligand such as 4 1 was worthwhile . The preparation of substrate 4 123 was done through a Knoevenagel 4 122 and p anisaldehyd e 4 80 (Figure 4 33) . By 2 , (+) sodium ascorbate , and ligand 4 1 were employed. The reaction is performed in water and with excess of phenylacetylene ( 10 molar equivalents ) generating a biphasic medium. After 18 hours of vigorous stirring at 0 o C , an excellent yield of 95% and a good 80% enantiomeric excess were obtained. In a patent, 143 C arreira and co workers report 27% yield and 80% ee for the same reaction. This represents a very good preliminary result since QUINAP gave only 42% ee in a similar reaction (Figure 4 14). For pratical matters, the product is submitted to a n amidation/decarboxylation reaction using aniline in DMF to give amide 4 125 , which can be separated by HPLC. Figure 4 33 . The higher reactivity observed with our ligand calls attention to the fact that this substrate presents an aromatic ring substituted on the electroph i lic carbon. This i s somewhat similar to the higher reactivity observed for the aromatic aldehydes in the A 3 coupling. This preliminary result

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122 is encouragi ng since a good enantiomeric excess was observed with a xially chiral ligand 4 1 , showing that the biaryl moiety dictates stereoinduction in this re a ction and there is no requirement for the additional stereocenters as in PINAP . Studies on this reaction are ongoing in the laboratory. 4.3.5 Palladium Catalyzed Asymmetric Allylic Alkylation In the beginning of Chapter 3, the a pplication of QUINAP in palladium catalyzed asymmetric allylic alkylations was briefly discussed. In parallel to the first appearance of QUINAP , PHOX 85,86,87 and Trost ligands 144 were discovered and were also found to be excellent for this reaction. All th ese examples represent an important improvement for this reaction since well known C 2 symmetric ligands were not as successful. 145 The approach adopted in the development of QUINAP and PHOX have some similarities. The success of PHOX in the asymmetric ally lic alkylation was rationalized by Helmchen and Pfaltz 146 using the electronic differentiation concept which can also be applied to other P,N ligands such as QUINAP (Figure 4 34) . Figure 4 34 . Concept of electronic differentiation proposed by Pfaltz Inspired by previous work on C 2 symmetric BOX type N,N ligands, Pfaltz thought that changing one of the hard nitrogens to a soft phosphorus donor would be useful, giving rise to a P,N ligand. At tha t time, C 1 symmetric ligands were not widely explored because reduced

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123 symmetry increases the number of possible reaction intermediates and predicting the reaction outcome can be more difficult. Interestingly, the differentiation proposed by Pfaltz was extr emely successful as exemplified by the reaction in Figure 4 34. To gain insight into the mechanism of the reaction catalyzed by PHOX ligands, a combination of NMR and X ray studies were performed. 146 X ray structure of a PHOX allyl complex 4 132 reveals a longer Pd C bond trans to the phosphorus atom ( trans influence), when compared to the Pd C bond trans to the nitrogen atom , which illustrates the electronic differentiation governed by the P,N ligand. As a consequence, it is believed that this d irects the nucleophilic attack trans to the phosphorus, controlling the regioselectivity of the reaction (Figure 4 35). Figure 4 35 . Trans influence on nucleophilic substitution Although there are excellent ligands for the palladium catalyzed allylic alkylation, a test with ligand 4 1 was desired in order to analyze the feasibility of this ligand with other metals. For direct comparison with QUINAP, 82 the same conditions that were optimized by Brown and co workers were employed. Figure 4 36 . Palladium catalyzed allylic alkylation with axially chiral P,N ligands

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124 The observed enantioselectivity was 94%, lower than the 98% obtained with QUINAP (Figure 4 36). Although this results is not excellent, it shows the compatibility of ligand 4 1 with palladium catalysis. Studies on the optimization of this reaction as well as the development of other palladium catalyzed transformations are ongoing. By analogy to PHOX and QUINAP, P,N ligand 4 1 should also present an electronic differentiation. To rationalize the stereoselectivity observed in the reaction, the X ray structure of complex 4 134 , obtained during the deracemization studies (Chapter 3) was used. The conformation of the P,N ligand and palladium (in the absence of the chiral auxiliary) is shown in structure 4 135 . Using that structure, transition states 4 136 and 4 137 can be suggested (note the opposite ligand enantiomer) . In each structure, the all yl approaches the metal in a different orientation and transition state 4 136 leads to the observed product 4 133 , so presumably it should be favored . This reaction outcome can be rationalized by possible steric interactions between the phenyl groups of th e allyl and of the imidazole ring. Figure 4 37 . Stereoselectivity of the palladium catalyzed allylic alkylation with ligand 4 1

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125 In summary, product 4 133 was obtained in very good yield and excellent enantiomeric excess in the asymmetric palladium catalyzed allylic alkylation with 4 1 . Although there are many ligands that can catalyze this reaction, this result shows that this reaction is also feasible wit h imidazole based P,N ligand 4 1 . Current work is focused on expanding the substrate scope of this reaction. 4.4 Outcome and Current Work In summary, the set of experiments presented in Chapter 4 illustrates the utility of P,N ligand 4 1 . For instance, in the A 3 coupling reaction our ligand furnished the products in 24h at 0 o C with high yields and enantioselectivies for a broad range of substrates (alkyl and aryl aldehydes), whereas when QUINAP 4 2 was employed the reaction times were much longer and the less reactive aryl substrates were more challenging to achieve high enantioselectivities. This higher reactivity of our catalytic system might be related with the electron rich five membered imidazole heteroaromatic. Moreover, copper catalyzed acetylide ad ditions to pyridinium ions or Michael acceptors were explored giving good results. The ligand can also be employed in palladium catalyzed allylic alkylations. The research in this area is still in progress in our group towards the expansion of these method ologies and also development of analogues of ligand 4 1 . Figure 4 38. Enantioselective reactions employing 4 1

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126 CHAPTER 5 CONCLUSION AND OUTLOOK The development of new chiral ligands for enantioselective catalysis has been an important topic in organic synthesis because the preparation of chiral molecules as single enantiomers plays an important role in the fields of pharmaceuticals, agriculture and materials science. 5 Therefore, discovery of new reaction methodologies and chiral catalysts is an ongoing research topic. 9,41 Among the chiral ligands for metal catalyzed reactions, the existence of axially chiral P,N ligands comprised of five membered heteroaromatics in the biaryl backbone is rare, probably due to difficulti es in isolating enantiopure materials. 32 The work described in this dissertation focused on the development of a new strategy to increase the barrier to rotation in axially chiral compounds. The approach was based on intramolecular stacking interactions that would stabilized the ground state conformation of biaryls. The synthesis and NMR studies of many compounds showed a significant stabilization (2.0 2.4 kcal/mol) when a pentafluorinated benzyl ring was employed, as in 5 2 . Figure 5 1 . New approach to axial chirality in biaryl compounds In light of this, our new approach to atropisomers was applied to the design and preparation of an imidazole based P,N ligand 5 4 . The invention of 5 4 allows for the exploration of a new class of ligands that were previously unexplored in asymmetric catalysis. In fact, ligand 5 4 proved to be very efficient in copper catalyzed acetylide additions, as exemplified by the results obtained in the A 3 coupling reaction (Fig ure 6 2).

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127 Figure 5 2 . Copper catalyzed A 3 coupling reaction employing 5 4 Although the employment of 5 4 for asymmetric reactions gave very good results there are many aspects to be improved. The synthesis and deracemization to provide 5 4 as a single enantiomer are not ideal, and efforts have to be made to provide a more efficient and less expensive method. In addition, the preparation of analogues of 5 4 for fine tuning will be crucial when developing new enantioselective reactions. From a broader perspective, this previously unexplored class of compounds in asymmetric catalysis encourages for the development of other types of chiral ligands or catalysts. The expansion of this new design element to the synthesis of new ligands and catalysts has emerged in our group along with the investigation of new organic reactions. Therefore, new reports along t hese lines will be reported in due course.

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128 CHAPTER 6 EXPERIMENTAL SECTION 6.1 General Remarks All reactions were carried out under an atmosphe re of nitrogen unless otherwise specified. Anhydrous solvents were transferred via syringe to flame dried glassw are, which had been cooled under a stream of dry nitrogen. Anhydrous tetrahydrofuran (THF), acetonitrile, ether, dichloromethane, and pentane were dried using a m Braun solvent purification system. Analytical thin layer chromatography (TLC) was performed us pre coated plates (EMD Chemicals Inc.). Flash column chromatography was performed using 230 400 Mesh 60Å Silica Gel (Whatman Inc.). The eluents employed are reported as volume/volume percentages. Melting points were recorded o n a MEL TEMP® capillary melting point apparatus and are uncorrected. High performance liquid chromatography (HPLC) was performed on a Shimadzu LC 20AT . Gas Chromatography analyses were obtained using a Hewlett Packard HP 5890 Series II FID Detector. Prot on nuclear magnetic resonance (1H NMR) spectra were recorded using Varian Unity Inova 500 MHz and Varian Mercury 300 MHz spectrometers. Chemical shift ( ) is reported in parts per million (ppm) downfield relative to tetramethylsilane (TMS, 0.0 ppm) or CDCl 3 (7.26 ppm). Coupling constants ( J ) are reported in Hz. Multiplicities are reported using the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; Carbon 13 nuclear magnetic resonance ( 13 C NMR) spectra were rec orded using a Varian Unity Inova 500 MHz and Varian Unity Mercury 300 spectrometer at 75 MHz. Chemical shift is reported in ppm relative to the carbon resonance of CDCl 3 (77.00 ppm). Phospho rus 31 ( 31 P NMR) and Fluorine 19 ( 19 F NMR) nuclear magnetic resona nce spectra were recorded using Varian Unity Mercury 300 spectrometer at 121 MHz, and 281 MHz, respectively. The 31 P NMR chemical shifts were calibrated using an external reference sample of

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129 85% H 3 PO 4 in D 2 O. The 19 F NMR chemical shifts were calibrated usi ng an external reference sample of CCl 3 F in CDCl 3 ( 0.0 ppm). Specific Optical ro tations were obtained on a JASCO P 2000 Series Polarimeter (wavelength = 589 nm). Infrared 111 spectra were obtained on a Perkin Elmer Spectrum RX 1 at 0.5 cm 1 resolution and are reported in wave numbers. High resolution mass spectra (HRMS) were obtained by The Mass Spectrometry Core Laboratory of University of Florida, and are reported as m/e (relative ratio). Accurate masses are reported for the molecular ion (M+) or a suitable fragment ion. 6.2 Chemical Procedures 6.2.1 Synthesis of Model Compounds 5 methoxynaphthalen 1 yl trifluoromethanesulfonate (2 39) . A solution of Tf 2 O (0.73 mL, 4.32 mmol) in DCM (5 mL) was added dropwi se to a solution of pyridine (0.6 mL, 7.2 mmol) and 2 38 147 (625 mg, 3.6 mmol) in DCM (10 mL) at 0 o C. After complete addition, the mixture was warmed to room temperature and allowed to stir for 1 hour the mixture was then diluted with Et 2 O (20 mL) , quench ed with 10% HCl (10 mL) and washed with NaHCO 3 (2 x 10 mL) saturated solution and twice with brine (2 x 10 mL) . After drying this solution with MgSO 4 , the solvent was removed and a column run at 20% EtOAc/Hexanes gave the triflate 2 39 as a yellow solid (9 21 mg , 84 %); MP = 47 48 o C. 1 H NMR (300 MHz, CDCl 3 ): 8.28 (d, J = 9Hz, 1H), 7.25 (d, J = 9Hz, 1H), 7.53 7.38(m, 3H), 6.87 (d, J = 6Hz, 1H), 3.96 (s, 3H). 13 C NMR (75 MHz, CDCl 3 , 124.4 , 123.0, 121.1, 118.5, 116.8, 114.4, 112.9, 105.4, 104.7, 55.9 . HRMS (DART) Calcd for C 12 H 10 F 3 O 4 S (M+H) + 307.0246, found 307.0519.

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130 2 (naphthalen 1 yl) 1H pyrrole (2 35) . N Boc pyrrole 2 boronic acid 2 34 64 ( 0.0912 g, 0.432 mmol ), 1 bromonaphthalene 2 33 ( 30 L, 0.216 mmol ), Pd(PPh 3 ) 4 ( 0.05 g, 0.0432 mmol ) and LiCl ( 0.018 g, 0.432 mmol ) were added sequentially to a test tube that then evacuated and refilled with argon. Degassed DME was then added and the mixture was heated at 80 o C before the degassed 2M Na 2 CO 3 ( 0.5 mL ) was added dropwise. The mixture was stirred for 1h and cooled to room temperature. The mixture was diluted with CHCl 3 and NaHCO 3 (saturated solution) was added. The aqueous phase was washed with CHCl 3 twice. T he organ ic phase was dried with MgSO 4 and concentrated under vacuum . The crude mixture was filtrated through a short plug of silica using 20% EtOAc/h exanes. After the short column, the solution was concentrated and dissolved in THF (6 mL). MeONa 25% in MeOH (0.25 mL) was added dropwise at room temperature and let to stir for 12 hours. After dilution in water (1 0 mL), the crude produ ct was extracted with Et 2 O (2x1 0 mL), the combined organic layers were dried over MgSO 4 and the solvent removed by vacuum. Flash chroma tography ( gradient 5 20 % EtOAc/hexanes) afforded the product as a colorless oil that crystalizes upon standing ( 25 mg, 59 % yield over two steps ) . Compound 2 35 148 has been described in the literature and when prepared here satisfactorily matched all previously reported data. 2 (5 methoxynaphthalen 1 yl) 1H pyrrole (2 40). The typical Suzuki coupling procedure was followed with triflate 2 39 (0.236 g, 0. 77 mmol) to give the title compound as a

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131 white solid ( 45 mg, 26% yield over two steps) ; MP = 114 115 o C. 1 H NMR (300 MHz, CDCl 3 8.36 (s, 1H), 8.25 (ddd, J = 7.6, 2.2, 0.9 Hz, 1H), 7.83 (dt, J = 8.6, 1.0 Hz, 1H), 7.57 7.28 (m, 3H), 6.92 (td, J = 2.7, 1.5 Hz, 1H), 6.83 (dd, J = 7.6, 0.9 Hz, 1H), 6.48 (ddd, J = 3.9, 2.6, 1.5 Hz, 1H), 6.38 (dt, J = 3.5, 2.7 Hz, 1H), 4.00 (s, 3H). 13 C NMR (75 MHz, CDCl 3 131.3, 131.1, 127.1, 126.42, 126.4, 124.9, 121.6, 118.5, 118.2, 109.6, 109.6, 104.1, 55.8. HRMS (DART) Calcd for C 15 H 14 NO (M+H) + 224.1070, found 224.1081. 2 (2 methoxynaphthalen 1 yl) 1H pyrrole (2 42). The typical Suzuki coupli ng procedure was followed with bromide 2 41 69 (0.280 g, 1.18 mmol) to give the title compound as a colorless oil ( 90 mg, 34 % yield over two steps) ; 1 H NMR (300 MHz, CDCl 3 ) 8.76 (s, 1H), 8.20 (ddt, J = 8.6, 1.4, 0.8 Hz, 1H), 7.86 7.74 (m, 2H), 7.48 7.27 (m, 3H), 6.98 (td, J = 2.7, 1.5 Hz, 1H), 6.53 6.37 (m, 2H), 3.88 (s, 3H). 13 C NMR (75 MHz, CDCl 3 129.6, 129.2, 128.1, 126.8, 125.8, 125.5, 123.97, 117.9, 116.82, 113.7, 111.1, 10 8.7, 56.5 . HRMS (DART) Calcd for C 15 H 14 NO (M+H) + 224.1070, found 224.1074. 1 benzyl 2 (naphthalen 1 yl) 1H pyrrole ( 2 10). A solution of 2 35 (0.025 g, 0.13 mmol) in DMF (3 mL) was added dropwise to a suspension of NaH ( 5 mg, 0.208 mmol ) in DMF (2 mL) at 0 o C. After 15 minutes, benzylbromide ( 15 L, 0.13 mmol ) was added at 0 o C and the reaction was allowed to warm to room temperature over 1 hour . The mixture was diluted with Et 2 O (10 mL) and washed with water (2 x 10mL) and brine (10 mL) . The organic layer was dried

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132 with MgSO 4 and concentrated under vacuum. The crude was purified by flash chromatography ( 10% EtOAc/Hexanes) giving the title compound as a colorless oil (31 mg, 84%) . 1 H NMR ( 300 MHz, CDCl 3 ) 7.92 7.71 (m, 3H ), 7.52 7.31 (m, 4H), 7.21 7.08 (m, 3H), 6.88 6.74 (m, 3H), 6.35 (t, J = 3.1 Hz, 1H), 6.30 (dd, J = 3.5, 1.7 Hz, 1H), 4.83 (s, 2H). 13 C NMR (75 MHz, CDCl 3 ) 138.9, 133.8, 133.6, 132.3, 131.2, 129.2, 128.6, 128.5, 128.3, 127.4, 127.1, 126.5, 126.4, 126.0, 125.3, 121.9, 110.6, 108.4, 51.1. HRMS (APCI) Calcd for C 21 H 18 N (M+H) + 284.1434, found 284.1444. 2 (naphthalen 1 yl) 1 (pe rfluorobenzyl) 1H pyrrole ( 2 32). The typical benzylation procedure was followed with 2 35 (0.025 g, 0.13 mmol) and pentafluorobenzylbromide ( 20 L, 0.13 mmol ) to give the title compound as a white solid ( 28 mg, 57 %) ; recrystallization from chloroform gave white needles that were submitted to X Ray crystallography. MP = 89 90 o C; 1 H NMR (300 MHz, CDCl 3 ): 7.89 (t, J = 6 Hz, 2H), 7.54 7.35 (m, 5H), 6.87 (s, 1H), 6.33 (t, J = 3Hz, 1H), 6.26 6.24 (m, 1H), 4.92 (ABq, J = 15Hz, = 52 Hz, 2H). 19 F NMR (282 MHz, CDCl 3 ) 142.3 (dd, J = 22.5, 8.2 Hz), 155.1 (t, J = 20.9 Hz), 162.7 (td, J = 22.0, 7.7 Hz). HRMS (APCI) Calcd for C 21 H 13 F 5 N (M+H) + 374.0963, found 374.0972. Crystal structure 2 32: Data were collected at 173 K on a Siemens SMART PLATFORM equipped with A CCD area detector and a graphite monochromator utilizing MoK radiation ( = 0.71073 Ã…). Cell parameters were refined using up to 8192 reflections. A full sphere of data (1850 frames) was collected using the scan method (0.3 frame width). The first 50 frames were re measured at the end of data collection to monitor instrument and crystal

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133 stability (maximum correction on I was < 1 %). Absorption corrections by integration were applied based on measured index ed crystal faces. The structure was solved by the Direct Methods in SHELXTL6, and refined using full matrix least squares. The non H atoms were treated anisotropically, whereas the hydrogen atoms were calculated in ideal positions and were riding on thei r respective carbon atoms. A total of 244 parameters were refined in the final cycle of refinement using 3078 reflections with I > 2 (I) to yield R 1 and wR 2 of 3.58% and 9.42%, respectively. Refinement was done using F 2 . Table 6 1 . Crystal data and struc ture refinement for 2 32 . Empirical formula C21 H12 F5 N Formula weight 373.32 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P2 1 c Unit cell dimensions a = 7.1612(7) Å = 90°. b = 20.2521(19) Å = 97.324(5)°. c = 11.1873(11) Å = 90°. Volume 1609.2(3) Å 3 Z 4 Density (calculated) 1.541 Mg/m 3 Absorption coefficient 0.131 mm 1 F(000) 760 Crystal size 0.28 x 0.12 x 0.07 mm 3

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134 Table 6 1 . Continued Theta range for data collection 2.01 to 27.48°. Index ranges Reflections collected 18678 Independent reflections 3691 [R(int) = 0.0534] Completeness to theta = 27.48° 99.8 % Absorption correction Numerical Max. and min. transmission 0.9904 and 0.9638 Refinement method Full matrix least squares on F 2 Data / restraints / parameters 3691 / 0 / 244 Goodness of fit on F 2 1.075 Final R indices [I>2sigma(I)] R1 = 0.0358, wR2 = 0.0942 [3078] R indices (all data) R1 = 0.0434, wR2 = 0.0988 Largest diff. peak and hole 0.285 and 0.216 e.Å 3 2 (5 methoxynaphthalen 1 yl) 1 (perfluorobenzyl) 1H pyrrole ( 2 36) . The typical benzylation procedure was followed with 2 36 (0.018 g, 0.08 mmol) and pentafluorobenzylbromide ( 12 L, 0.08 mmol ) to give the title compound as a colorless oil ( 30 mg, 92 %). 1 H NMR (300 MHz, CDCl 3 ) 8.26 (dd, J = 8.3, 1.6 Hz, 1H), 7.53 7.33 (m, 2H), 7.28 7.12 (m, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.85 6.65 (m, 2H), 6.22 (td, J = 3.3, 1.3 Hz, 1H),

PAGE 135

135 6.13 (dt, J = 3.4, 1.7 Hz, 1H), 4.82 (ABq, J = 15Hz, = 47.89 Hz, 2H), 3.93 (s, 3H). 19 F NMR (282 MHz, CDCl 3 ) 142.8 (dd, J = 22.4, 8.6 Hz), 154.8 (t, J = 20.8 Hz), 162.5 (td, J = 21.9, 8.0 Hz). HRMS (DART) Calcd for C 22 H 15 F 5 NO (M+H) + 404.1068, found 404.1068. 1 benzyl 2 (2 methoxynaphthalen 1 yl) 1H pyrrole (2 37). The typical benzylation procedure was followed with 2 42 (0.029 g, 0.13 mmol) and benzylbromide ( 15 L, 0.13 mmol ) to give the title compound as a colorless oil ( 28 mg, 70 %). 1 H NMR (300 MHz, CDCl 3 ) 7.86 (d, J = 9.0 Hz, 1H), 7.81 7.74 (m, 1H), 7.63 7.55 (m, 1H), 7.41 7.19 (m, 3H), 7.11 (dtd, J = 4.7, 3.4, 2.7, 1.7 Hz, 2H), 6.97 6.86 (m, 1H), 6.83 (dd, J = 2.8, 1.6 Hz, 1H), 6.39 (ddd, J = 3.7, 2.7, 1.0 Hz, 1H), 6.23 (dd, J = 3.5, 1.7 H z, 1H), 4.76 (ABq, J = 15Hz, = 9.95 Hz, 2H) , 3.72 (s, 3H). 13 C NMR (75 MHz, CDCl 3 127.5, 127.2, 126.8, 125.6, 123.8, 121.4, 116.1, 113.2 , 1 10.5, 108.3, 56.4, 51.1 . HRMS (EI) Calcd for C 22 H 19 NO (M) + 313.1467, found 313.1469. 2 (naphthalen 1 yl) 1H indole (2 45). P henylhydrazine 2 44 ( 5.91 mL, 60 mmol) was added dropwise to a solution of 2 acetylnaphthalene 2 43 ( 7.61 g, 50 mmol) in phosphoric acid 85% ( 10 mL ). Th e resulting mixture was stirred at 40 o C for one hour. Polyphosphoric acid (50 g) was carefully added to the mixture. The viscous mass was mixed while temperature was increased from room temperature to 12 0 o C (keep for 1 hour) . The black reaction mixture w as poured into crushed ice ( ~ 150 mL) and the product extracted with EtOAc (3 x 50 mL) . The

PAGE 136

136 organic layer was dried with MgSO 4 and concentrated under vacuum. The crude was purified by flash chromatography ( 10% EtOAc/Hexanes) giving the title compound as a light brown solid (8.9 g, 73%) . Compound 2 45 14 9 has been described in the literature and when prepared here satisfactorily matched all previously reported data. 2 (naphthalen 1 yl) 1 (perfluorobenzyl) 1H indole (2 46). Th e typical benzylation procedure was followed with 2 45 ( 0.19 g, 0. 7 8 mmol) and pentafluorobenzylbromide ( 0. 12 mL, 0. 7 8 mmol) to give the title compound as a white solid ( 0.314 g, 9 5 %). MP = 157 158. 1 H NMR ( 300 MHz, CDCl 3 ) 8.01 7.76 (m, 2H), 7.68 (dd, J = 7.8, 1.2 Hz, 1H), 7.60 7.12 (m, 8H), 6.64 (s, 1H), 5.16 (ABq, J = 15Hz, = 38 Hz, 2H). 19 F NMR (282 MHz, CDCl 3 ) 142.3 (dd, J = 22.4, 8.1 Hz), 155.1 (t, J = 20.9 Hz), 162.7 (td, J = 22.6, 8.5). HRMS (APCI) Calcd for C 25 H 15 F 5 N (M+H) + 424.1119, found 424.1138. 1 benzyl 2 (naphthalen 1 yl) 1H indole (2 47). The typical benzylation procedure was followed with 2 45 (0.21 g, 0.863 mmol) and benzylbromide ( 0.1 mL, 0.863 mmol ) to give the title compound as a colorless oil ( 0.24 g, 84 %). 1 H NMR ( 300 MHz, CDCl 3 ): 8.06 (d, J = 4.8 Hz, 2H), 7.99 (d, J = 3.0 Hz, 1H), 7.93 (d, J = 5.1 Hz, 1H), 7.66 7.56 (m, 4H), 7.48 (d, J = 3.0 Hz, 1H), 7.40 7.38 (m, 2H), 7.28 (s, 3H), 6.99 6.98 (m, 2H), 6.91 (s, 1H), 4.54 (bd, J = 18Hz, 2H). 13 C NMR (75 MHz, CDCl 3 ) 139.3, 138.1, 137.4, 133.7, 133.2, 130.4, 129.2, 129.2, 128.6,

PAGE 137

137 128.6, 128.4, 127.2, 126.8, 126.4, 126.3, 126.2, 125.3, 122. 0, 120.8, 120.2, 110.7, 104.2, 47.9. HRMS (APCI) Calcd for C 26 H 19 N (M+H) + 334.1590, found 334.1603. (perfluorophenyl)methanamine hydrochloride (6 1). Pd/C (200 mg) was added to a solution of pentafluorobenzonitrile (1.0 g, 5.18 mmol) in a mixture of MeOH (10 mL) and 37% HCl (1 mL). The reaction mixture was stirred overnight under H 2 (1 atm). Filtration over a plug of cotton and removal of the solvent afforded 37 as a white solid (1.077 g, 89%). Compound 6 1 150 has been described in the literature and when prepared here satisfactorily matched all previously reported data. 2 methyl 5 (naphthalen 1 yl) 1 (perfluorobenzyl) 1H pyrrole (2 52). Diketone 2 51 74 (0.039 g, 0.172 mmol) and 2, 3,4,5,6 pentafluorobenzylamine hydrochloride 6 1 (0.040 g, 0.172 mmol) were added to toluene (3 mL) and the resulting mixture was refluxed overnight. The mixture was cooled to room temperature, water (10 mL) was added and the mixture was extracted with EtO Ac (3 x 5 mL). The organic layers were dried over MgSO 4 and then purified by flash chromatography (5% EtOAc in Hexanes) to give the title compound as a white solid (0.067 g, 74%). MP = 174 175 o C. 1 H NMR ( 300 MHz, CDCl 3 ) 7.90 7.75 (m, 2H), 7.55 7.27 (m, 5H), 6.15 (d, J = 3.4 Hz, 1H), 6.07 (dd, J = 3.4, 1.0 Hz, 1H), 4.94 (ABq, J = 15Hz, = 39.00 Hz, 2H), 2.38 (s, 3H). 19 F NMR (282 MHz, CDCl 3 ) 143.7 (dd, J = 22.1, 8.0 Hz), 155.9

PAGE 138

138 (t, J = 20.8 Hz), 163.5 (td, J = 2 1.7, 7.7 Hz). HRMS (DART) Calcd for C 22 H 15 F 5 N (M+H) + 388.1119, found 388.1128. 1 benzyl 2 methyl 5 (naphthalen 1 yl) 1H pyrrole (2 53). The typical Paal Knorr procedure was followed with 2 51 (0.665 g, 2.94 mmol) and benzylamine ( 0.32 mL, 2.94 mmol ) to give the title compound as a colorless oil ( 0.446 g, 51 %). 1 H NMR (500 MHz, CDCl 3 ) 7.89 7.86 (m, 1H), 7.81 7.78 (m, 1H), 7.74 (ddt, J = 7.3, 2.2, 0.6 Hz, 1H), 7.46 7.30 (m, 4H), 7.17 7.05 (m, 3H), 6.72 (ddt, J = 7.2, 1.3, 0.7 Hz, 2H), 6.25 (d, J = 3.4 Hz, 1H), 6.13 (dq, J = 3.3, 0.9 Hz, 1H), 5.08 4.55 (m, 2H), 2.18 (s, 3H). 13 C NMR (12 5 MHz, CDCl 3 ) 139.0, 133.8, 133.6, 131.8, 131.7, 129.8, 129.0, 128.6, 128.3, 128.1, 126.9, 126.4, 126.3, 126.0, 125.9, 125. 3, 109.7, 107.2, 48.0, 13.0. HRMS (DART) Calcd for C 22 H 20 N (M+H) + 298.1590, found 298.1604. 1 (4 fluorobenzyl) 2 (naphthalen 1 yl) 1H indole (2 54). The typical benzylation procedure was followed with 2 45 (0.1 g, 0.42 mmol) and 4 fluorobenzylbromide ( 0.079 g, 0.42 mmol ) to give the title compound as a colorless oil ( 0.1 g, 71 %). 1 H NMR (500 MHz, CDCl 3 ) 7.94 7.86 (m, 2H), 7.77 7.66 (m, 2H), 7.53 7.37 (m, 4H), 7.31 7.26 (m, 1H), 7.24 7.17 (m, 2H), 6.82 6.71 (m, 4H), 6.69 (d, J = 0.8 Hz, 1H), 5.08 (ABq, J = 15Hz, = 119.10 Hz, 2H) . 13 C NMR (125 MHz, CDCl 3 134.3, 134.2, 133.6, 130.9, 129. 8, 129.7 , 129.1, 128.9, 128.7, 128.6, 127.3, 126.8, 126.6, 125.8, 122.6, 121.4, 120.8,

PAGE 139

139 116.0, 115.9, 111.0, 104.8, 47.7 . HRMS (DART) Calcd for C 25 H 19 FN (M+H) + 352.1496, found 352.1500. 1 (4 methoxybenzyl) 2 (naphthalen 1 yl) 1H indole ( 2 55). The typical benzylation procedure was followed with 2 45 (0.1 g, 0.42 mmol) and 4 methoxybenzylbromide ( 0.084 g, 0.42 mmol ) to give the title compound as a colorless oil ( 0.073 g, 48 %). 1 H NMR ( 300 MHz, CDCl 3 ) 8.02 7.83 (m, 2H), 7.79 7.64 (m, 2H), 7.53 7.10 (m, 7H), 6.78 6.57 (m, 5H), 5.10 (ABq, J = 15Hz, = 70.42 Hz, 2H) , 3.67 (s, 3H). 13 C NMR (75 MHz, CDCl 3 ) 158.8, 139.3, 137.3, 133.7, 133.2, 130.6, 130.2, 129.2, 129.2, 128.6, 128.4, 127.8, 126.8, 126.3, 126.2, 125.3, 121.9, 120.8, 120.1, 114.0, 110.7, 104.1, 55.4, 47.4. HRMS (DART) Calcd for C 26 H 22 NO (M+H) + 364.1696, found 364.1706. 2 (naphthalen 1 yl) 1 (pyridin 4 ylmethyl) 1H indole (2 56). The typical benzylation procedure was followed with 2 45 ( 0.613 g, 2.52 mmol) , 4 (bromomethyl)pyridine hydrobromide (0. 637 g, 0.42 mmol) and NaH (0.121 g, 5.02 mmol) to give the title compound as a yellow solid (0. 447 g, 53 %). MP = 60 62 o C. 1 H NMR (500 M Hz, CDCl 3 ) 8.38 (bs, 2H), 7.98 7.80 (m, 2H), 7.79 7.65 (m, 2H), 7.55 7.32 (m, 4H), 7.29 7.14 (m, 3H), 6.71 (m, 3H), 5.07 (ABq, J = 15Hz, = 70.42 Hz, 2H) . 13 C NMR (12 5 MHz, CDCl 3 ) 149.4, 147.5, 139.0, 137.1, 133.6, 132.8, 129.7, 129.4, 129.1, 128.5, 128.4, 126.9, 126.3, 125.7, 125.2, 122.3,

PAGE 140

140 121.5, 121.0, 120.6, 110.1, 104.6, 46.7. HRMS (DART) Calcd for C 24 H 19 N 2 (M+H) + 335.1543, found 335.1559. 1 (1 H indol 2 yl)isoquinoline ( 2 61 ). This compound was prepared according to a modified procedure from the literature. 76 Phenylhydrazine 2 44 (3.0 mL, 30 mmol) was added to a solution of 1 (isoquinolin 1 yl)ethan 1 one 2 60 ( 5.1 g, 30 mmol) in ethanol ( 20 mL ). 3 drops of glacial acetic acid was added and the mixture was refluxed for 2 hours. A yellow solid precipitated when the solution was cooled to 0 o C and it was filtrated. Polyphosphoric acid (20 g) was mixed with the solid. The viscous mass was mixed whi le temperature was increased from room temperature to 10 0 o C forming a homogeneous red solution . After 1 hour at this temperature, the mixture was cooled to room temperature and water (300 mL) was added. The formed yellow solid was filtered and washed with 25% NaOH aqueous solution. The crude was purified by flash chromatography ( 5% EtOAc/Hexanes) giving the title compound as a yellow solid (5.5 g, 75%). 1 H NMR (500 MHz, CDCl 3 ) 9.92 (s, 1H), 8.85 (d, J = 8.4 Hz, 1H), 8.53 (d, J = 5.6 Hz, 1H), 7.87 (dd, J = 8.0, 1.5 Hz, 1H), 7.71 (dddd, J = 22.5, 8.3, 6.8, 1.4 Hz, 3H), 7.63 7.55 (m, 1H), 7.47 (dq, J = 8.2, 1.0 Hz, 1H), 7.34 7.22 (m, 2H), 7.15 (ddd, J = 8.1, 7.0, 1.0 Hz, 1H).

PAGE 141

141 1 (1 (perfluorobenzyl) 1H indol 2 yl)isoquinoline (2 57). The typical benzylation procedure was followed with 2 61 ( 0.50 g, 2.05 mmol) and pentafluorobenzylbromide ( 0.32 mL, 2.05 mmol) in THF to give the title compound as a white solid ( 0.696 g, 80 %). MP = 173 174 o C 1 H NMR ( 300 MHz, CDCl 3 ) 8.63 (d, J = 5.7 Hz, 1H), 8.32 (d, J = 8.5 Hz, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.77 7.62 (m, 3H), 7.56 (t, J = 7.7 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.19 (t, J = 7.4 Hz, 1H), 6.88 (s, 1H), 5.84 (s, 2H). 19 F NMR (282 MHz, CDCl 3 ) 142.2 (dd, J = 22.5, 8.4 Hz), 155.2 (t, J = 20.9 Hz), 162.4 (td, J = 22.5, 8.5). HRMS (DAR T) Calcd for C 24 H 14 F 5 N 2 (M+H) + 425.1072, found 425.1087. 2 (isoquinolin 1 yl) 1 ((perfluorophenyl)methyl) 1H indol 3 yl acetate (2 62). Pd(OAc) 2 (12 mg, 0.518 mmol), PhI (OAc) 2 ( 0.334 g, 1.0 mmol), indole 2 57 ( 0.220 g, 0.5 18 mmol), and KOAc ( 51 mg, 0.5 18 mmol) were loaded into a Schlenk tube equipped with a Tefl on coated magnetic stir bar. A cetonitrile (5 .0 mL) was then added with stirring at room temperature for several minutes. The tube was then placed into a preheated oil bath (70 o C ) and stirred for 1 h . After completion of the reaction as judged by TLC analy sis, the reaction tube was allowed to cool to room temperature and quenched with sodium bisulfate saturated solution (5 mL) and water (5 mL) . EtOAc (10 mL) was then added for dilution. The organic layer was separated, and the aqueous layer was washed with EtOAc (2 x 10 mL) . The organic layers were

PAGE 142

142 dried over MgSO 4 and then pur ified by flash chromatography (10% EtOAc/h exanes) to give the title compound as a yellow ish oil (0.170 g, 68%). 1 H NMR (500 MHz, CDCl 3 ) 8.71 (d, J = 5.6 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.79 7.67 (m, 2H), 7.56 (t, J = 7.7 Hz, 1H), 7.50 (t, J = 8.3 Hz, 2H), 7.35 (t, J = 7.6 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 5.70 (ABq, J = 15Hz, = 134.36 Hz, 2H), 1.97 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) 168.8, 150.4, 145.2 (d, J = 250.0 Hz), 142.6, 140.9 (d, J = 255.3 Hz), 137.3 (d, J = 253.0 Hz), 136.7, 135.5, 130.7, 130.5, 128.1, 127.9, 127.2, 125.9, 124.2, 121.1, 121.0, 120.6, 119.0, 111.1 (t, J = 17.0 Hz), 110.0, 36.0, 20.6. 19 F NMR (282 MHz, CDCl 3 ) 141.9 (dd, J = 22.7, 8.1 Hz), 154.8 (t, J = 20.9 Hz), 162.3 (td, J = 22.1, 8.0 Hz). HRMS (DART) Calcd for C 26 H 16 F 5 N 2 O 2 (M+H) + 483.1126, found 483.1127. Variable temperature 1 NMR: The variable temperature 1 H NMR spectra were collected in C 2 D 2 Cl 4 ( = 5.91 ppm) or CDCl 3 ( = 7.26 ppm). Samples were prepared in a 0.05M concentration allowed to equilibrate for ~5 min at each set temperature. The recorded NMR data were analyzed as described in Chapter 2. 6.2.2 Synthesis and Deracemization of 3 1 and 3 111 1 (4,5 diphenyl 1H imidazol 2 yl)naphthalen 2 ol ( 3 3 9) . Prepared according to a modified procedure by Eseola et al. 93 To a flask containing benzyl 3 37 (6.1 g, 29 mmol), 2 hydroxynaphthalene 1 carbaldehyde 3 38 (5 g, 29 m mol) and ammonium acetate (45 g, 584 mmol) was added glacial acetic acid (40 mL). The mixture was heated from room temperature to 140 ºC over 1 hour when a yellow solid was formed. After cooling to room temperature, the mixture was filtered and washed with excess of water. The remaining residue was recrystallized

PAGE 143

143 from ethanol to give 8.4 1 g (80%) of the title compound as a yellow solid. MP: 202 203 ºC. 1 H NMR (500 MHz, DMSO d6) 12.04 (s, 1H), 8.21 (d, J = 8.6 Hz, 1H), 7.88 (dd, J = 11.3, 8.5 Hz, 2H), 7.5 8 (d, J = 7.1 Hz, 4H), 7.48 (td, J = 6.8, 3.3 Hz, 1H), 7.44 7.25 (m, 8H), 3.42 (s, 1H). 13 C NMR (125 MHz, DMSO d6) 154. 6, 143.02, 132.3, 130.6, 128.5, 128.1, 128.0, 127.7 , 127 .1, 127.0, 124.5, 123.0, 118.4, 109.2 . IR (Neat): 3392, 2098, 1643 cm 1 . HRMS (DART) Calcd for C 25 H 18 N 2 O (M+H) + 363.1492, found 363.1489. 2 (2 (tert butyldimethylsilyloxy)naphthalen 1 yl) 4,5 diphenyl 1H imidazole ( 3 112 ) . To a suspension of 3 39 (7.5 g, 20.7 mmol) and triethylamine (2.9 ml, 2 0.7 mmol) in DCM (90 mL) was added TBSCl (3.2 g, 20.7 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1.5 hours and quenched with H 2 O (30 mL). The crude product was extracted with DCM (2 x 20 mL), dried over MgSO 4 and th e solvent removed under reduced pressure. The residue was purified by flash chromatography (5 20% EtOAc/Hexanes, gradient) to yield 7.7 g (78%) of the title compound as a white solid. R f = 0.59 (20% EtOAc/hexanes). MP: 145 146 ºC. 1 H NMR (500 MHz, CDCl 3 ) 9.58 (s, 1H), 8.79 (d, J = 8.6 Hz, 1H), 7.87 7.73 (m, 4H), 7.50 (ddd, J = 8.5, 6.8, 1.3 Hz, 2H), 7.45 7.25 (m, 8H), 7.13 (d, J = 8.9 Hz, 1H), 0.84 (s, 9H), 0.09 (s, 6H). 13 C NMR (125 MHz, CDCl 3 ) 151.9, 142.4, 133. 5, 130.9, 130.1 , 130.0 , 128.0, 128.0 , 127.6, 126.3, 124.6, 121.2, 116.4, 110.2, 25.7, 18.3, 4.3 . IR (Neat): 3059, 2858, 1594, 1462, 1361, 1244, 991, 837, 696 cm 1 . HRMS (DART) Calcd for C 31 H 32 N 2 OSi (M+H) + 477.2357, found 477.2360.

PAGE 144

144 2 (2 (tert butyldimethylsilyloxy)naphthalen 1 yl) 1 (perfluorobenzyl) 4,5 diphenyl 1H im idazole (3 42) . A solution of the silyl ether 3 112 (7.43 g. 15.6 mmol) in THF (30 mL) was added dropwise to a suspension of sodium hydride (413 mg, 17.2 mmol) in THF (20 mL) at 78 ºC. The mixture was stirred for 10 min and pentafluorobenzyl bromide (2.4 mL, 15.9 mmol) was added in a dropwise fashion. The reaction was allowed to warm up to room temperature over 18h at which point the solution was cooled to 0 ºC and wat er was added. The organic phase was separated and the aqueous phase was extracted with EtOAc (2 x 50 ml). The combined organic layers were dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by flash chromatography (5 20% EtO Ac/Hexanes, gradient) to yield 9.63 g (94%) of the title compound as a colorless oil that crystallizes upon standing. R f = 0.68 (20% EtOAc/hexanes). MP: 148 149 ºC. 1 H NMR (500 MHz, CDCl 3 ) 7.77 (d, J = 8.9 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.54 7.43 (m, 6H), 7.31 (dt, J = 15.1, 6.6 Hz, 2H), 7.21 (t, J = 7.4 Hz, 2H), 7.18 7.08 (m, 2H), 4.95 (ABq, J = 15.4 Hz, = 109.55 Hz, 2H) , 0.94 (s, 9H), 0.30 (s, 3H), 0.07 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) 152.8, 144.7 (d, J = 253 Hz), 142.9, 140.2 (d, J = 255 Hz), 137.7, 136.6 (d, J = 252 Hz), 134.9, 133.8 , 131.5 , 131.3, 129.8, 129.4, 129.2, 129.1, 128.2, 127.6, 127.0, 126.4, 124.5, 124.4, 120.8 , 116.8 , 110.2 (t, J = 15 Hz), 36.7, 25.7, 18.2, 3.9 , 4.6. 19 F NMR (282 MHz, CDCl 3 ) 142.1 (dd, J = 22.2, 7.5 Hz), 156.1 (t, J = 20.7 Hz), 163.5 (td, J = 21.2, 6.7 Hz). (Neat): 3061, 2859, 2361, 1595, 1506, 1249, 1132, 1020, 838, 701 cm 1 . HRMS (DART) Calcd for C 38 H 33 F 5 N 2 OSi (M+H) + 657.2355, found 657.2345.

PAGE 145

145 1 (1 (perfluorobenzyl) 4,5 diphenyl 1H imidazol 2 yl)naphthalen 2 yl trifluoromethanesulfonate (3 44) . To a solution of compound 3 42 (6.50 g, 9.89 mmol) in MeOH (100 ml) was added K 2 CO 3 (2.73 g, 19.78 mmol) at room temperature. After 30 minutes, the mixture was filtered and concentrated under reduced pressure to ~10ml. The residue was dissolved in EtOAc (50 ml) and poured into water (50 ml). The organic phase was separated and the water phase was extracted with EtOAc (2 x 50 ml). The combined organic layers were dried over MgSO 4 and concentrated under reduced pressure to give the deprotected product as a white solid that was used in the next step without further purification. To a solutio n of the free alcohol obtained above and DMAP (121 mg, 0.989 mmol) in DCM (100 mL) was added triethylamine (1.38 mL, 9.89 mmol) followed by N phenyl bis(trifluoromethanesulfonimide) 3 43 (3.68 g, 9.89 mmol) at room temperature. The resulting solution was s tirred at room temperature for 6h and concentrated under reduced pressure. The residue was purified by flash chromatography (20% EtOAc/Hexanes) to yield 5.34 g (95%, 2 steps) of the triflate 3 44 as a white solid. R f = 0.51 (20% EtOAc/hexanes). MP: 163 164 o C. 1 H NMR (500 MHz, CDCl 3 J = 9.1 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.62 7.41 (m, 10H), 7.21 (t, J = 7.5 Hz, 2H), 7.16 (d, J = 7.2 Hz, 1H), 4.96 (ABq, J = 15Hz, 2H) . 13 C NMR (125 MHz, CDCl 3 , 144.8 (d, J = 250.9 Hz), 140. 7 (d, J = 255 Hz), 139.1 , 138.6 , 136.8 (d, J = 254 Hz), 134.2, 133.1, 132.6, 132.3, 131.3, 130.8, 130.5, 129.5, 128.4, 128.3, 128.1, 127.6, 127.0, 126.9, 126.1 , 121.2 , 119.3, 118.6 (q, J = 321 Hz), 109.7 (t, J = 16 Hz), 37. 0 . 19 F NMR (282 MHz, CDCl 3 74.5 , 142.2 (dd, J = 21.2, 7.0

PAGE 146

146 Hz), 154.4 (t, J = 20.8 Hz), 162.7 (td, J = 20.7, 6.6 Hz). IR (Neat): 3056, 1521, 1510, 1211, 1138, 1021, 944, 829, 745, 702 cm 1 . HRMS (DART) Calcd for C 33 H 19 F 8 N 2 O 3 S (M+H) + 675.0983, found 675.0968. (±) 2 (2 (diphenylphosphino)naphthalen 1 yl) 1 (perfluorobenzyl) 4,5 diphenyl 1H imidazole (3 1) . To a solution of 3 44 (6.34 g, 9.4 mmol), NiCl 2 (PPh 3 ) 2 (3.08 g, 4.7 mmol) and Ph 2 PCl (2.10 ml, 11 .4 mmol) in anhydrous DMF (40 ml) was added activated Zn (1.23 g, 18.8 mmol) in three portions at room temperature which resulted in a brown solution ( Zinc dust was activated by washing the solid with aqueous HCl, water, ethanol and dry ether) . The mixture was heated to 110 °C for 48h, cooled to room temperature, diluted with EtOAc and filtered through a short plug of silica. The resulting solution was washed with water (3 x 50 ml) and brine (50 ml), dried over MgSO 4 , and concentrated under reduced pressure . Flash chromatography (5 20% EtOAc/Hexanes, gradient) afforded 4.00 g (60%) of the phosphine 3 1 as a white foam. R f = 0.57 (20% EtOAc/hexanes). MP = 88 90 o C. 1 H NMR (500 MHz, CDCl 3 ) 7.81 (d, J = 8.8 Hz, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.62 7.19 (m, 20 H), 7.19 7.10 (m, 4H), 5.00 (ABq, J = 15Hz, = 144.22 Hz, 2H) . 13 C NMR (125 MHz, CDCl 3 ) 144.9 (d, J = 248 Hz), 144.3, 144.3 , 140.4 (d, J = 255 Hz), 138.7, 138.6, 137.5, 136.7 (d, J = 254 Hz), 136.6 , 136.5 , 135.8, 135.7, 134.7, 134.7, 134.5, 134.4, 13 4.4, 134.3, 134.2 , 133.12, 133.10, 133.05, 131.9 , 131.2, 129.9, 129.8, 129.3, 129.2, 129.0, 128.9, 128.7, 128.6, 128.6, 128.0 , 127.7 , 127.1 , 126. 9, 126.8, 126.4, 125.6, 125.6 , 109.9 (t, J = 16 Hz), 37.3, 37.2 . 19 F NMR (282 MHz, CDCl 3 ) 141.2 (dt, J = 22. 1, 6.6 Hz), 155.4 (t, J = 20.8 Hz), 163.1 (td, J = 21.8, 7.6 Hz). 31 P NMR (121 MHz, CDCl 3 ) 7.69 (t, J = 5.8 Hz). IR

PAGE 147

147 (Neat): 3056, 1522, 1509, 1434, 1379, 1213, 1146, 1020, 746, 696 cm 1 . HRMS (DART) Calcd for C 44 H 28 F 5 N 2 P (M+H) + 711.1983, found 711.1965. Crystal structure 3 1: X Ray Intensity data were collected at 100 K on a Bruker DUO diffractometer using CuK radiation ( = 1.54178 Ã…), from an ImuS power source, and an APEXII CCD area detector. Raw data frames were read by program SAINT 1 and integrated using 3D profiling algorithms. The resulting data were reduced to produce hkl reflections and their intensities and estimated standard deviations. The data were corrected for Lorentz and polarization effects and numerical ab sorption corrections were applied based on indexed and measured faces. The structure was solved and refined in SHELXTL6.1, using full matrix least squares refinement. The non H atoms were refined with anisotropic thermal parameters and all of the H ato ms were calculated in idealized positions and refined riding on their parent atoms. In the final cycle of refinement, 5959 reflections (of which 5586 are observed with I > 2 (I)) were used to refine 469 parameters and the resulting R 1 , wR 2 and S (goodness of fit) were 2.89 %, 7.69 % and 1.057 , respectively. The refinement was carried out by minimizing the wR 2 function using F 2 rather than F values. R 1 is calculated to provide a reference to the conventional R value but its function is not minimized. Table 6 2 . Crystal data and structure refinement for 3 1 . Empirical formula C44 H28 F5 N2 P Formula weight 710.65 Temperature 100(2) K Wavelength 1.54178 Ã… Crystal system Triclinic Space group P 1

PAGE 148

148 Table 6 2 . Continued Unit cell dimensions a = 12.2489(1) Å = 70.19°. b = 13.0230(1) Å = 72.89°. c = 13.1871(1) Å = 63.27°. Volume 1742.24(2) Å 3 Z 2 Density (calculated) 1.355 Mg/m 3 Absorption coefficient 1.227 mm 1 F(000) 732 Crystal size 0.14 x 0.05 x 0.04 mm 3 Theta range for data collection 3.61 to 66.49°. Index ranges Reflections collected 26825 Independent reflections 5959 [R(int) = 0.0233] Completeness to theta = 66.49° 96.9 % Absorption correction Numerical Max. and min. transmission 0.9503 and 0.8489 Refinement method Full matrix least squares on F 2 Data / restraints / parameters 5959 / 0 / 469 Goodness of fit on F 2 1.057 Final R indices [I>2sigma(I)] R1 = 0.0289, wR2 = 0.0769 [5586] R indices (all data) R1 = 0.0308, wR2 = 0.0782 Largest diff. peak and hole 0.279 and 0 .290 e.Å 3

PAGE 149

149 ( S , R ) cis [Dimethyl(1 ( Naphthyl)Ethyl)Aminato C 2 , N ) [2 (2 (diphenylphosphino)naphthalen 1 yl) 1 (perfluorobenzyl) 4,5 diphenyl 1H imidazole] Palladium (II) Hexafluorophosphate ( 3 93 ). Acetone (12 mL) was added to a flask containing 3 1 (500 mg, 0.704 mmol), (+) Di µ chlorobis[( R ) dimethyl(1 (1 naphthyl)ethyl)aminato C 2 , N ]dipalladium (II) 100 3 52 (240 mg, 0.352 mmol) and potassium hexafluorophosphate (130 mg, 0.704 mmol). The resulting m ixture was stirred at 60 ºC for 12 h. The mixture was then cooled, concentrated under reduced pressure, and filtered through a plug of celite washing with dichloromethane. The resulting yellow solution was concentrated under vacuum and dissolved in acetone (12 mL) before stirring for an additional 12 h at 60 ºC. The solution was then concentrated under vacuum to give a yellow solid. Recrystallization from ether/dichloromethane gave 662 mg of the palladium complex 3 93 as a light yellow powder (81% yield). [ 27 D = 205.4 ( c 1.00, CHCl 3 ). MP: 212 214 ºC (dec.). 1 H NMR (500 MHz, CDCl 3 J = 8.7 Hz, 1H), 8.11 (t, J = 7.9 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.93 (d, J = 8.6 Hz, 1H), 7.88 (d, J = 7.9 Hz, 2H), 7.78 (t, J = 7.7 Hz, 1H), 7.72 (t, J = 7.4 Hz, 1H), 7.67 7.62 (m, 2H), 7.58 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.39 7.19 (m, 12H), 7.09 (td, J = 8.7, 2.0 Hz, 2H), 6.89 (d, J = 8.5 Hz, 3H), 6.82 (dd, J = 11.7, 7.7 Hz, 2H), 6.56 (ddd, J = 8.1, 6.1, 1.8 Hz, 1H), 4.96 (ABq, J = 1 5.9 Hz, 204.45 Hz, 2H) , 4.01 (p, J = 6.5 Hz, 1H), 2.40 (d, J = 3.6 Hz, 3H), 1.67 (d, J = 6.4 Hz, 3H), 1.36 (d, J = 2.5 Hz, 3H). 31 P NMR (121 MHz, CDCl 3 144.23 (hept, J = 712.7 Hz). IR (Neat): 3056, 2881, 1573, 1438, 841, 746, 700 cm 1 . HRMS (ESI) Calcd for C 58 H 44 F 5 N 3 PPd (M PF 6 ) + 1014.2242, found 1014.2239.

PAGE 150

150 Crystal structure 3 9 9 : X Ray Intensity data were collected at 100 K on a Bruker DUO diffractometer using MoK radiation ( = 0.71073 Å) and an APEXII CCD area detector. Raw data frames were read by program SAINT 1 and integrated using 3D profiling algorithms. The resulting data were reduced to produce hkl reflections and their intensities and estimated standard deviations. The data were corrected for Lorentz and polarization effects and numerical absorption corrections were applied based on indexed and measured faces. The structure was solved and refined in SHELXTL6.1, using full matrix least squares refinement. The non H atoms were refined with anisotropic thermal parameters and all of the H atoms were calculated in idealized positions and refined riding on their parent atoms. In the final cycle of refinement, 11122 reflections (of which 10515 are observed with I > 2 (I)) were used to refine 679 parameters and the resulting R 1 , wR 2 a nd S (goodness of fit) were 2.18 %, 5.21 % and 1.039 , respectively. The refinement was carried out by minimizing the wR 2 function using F 2 rather than F values. R 1 is calculated to provide a reference to the conventional R value but its function is not mini mized. Table 6 3 . Crystal data and structure refinement for 3 99 . Empirical formula C58 H44 F11 N3 P2 Pd Formula weight 1160.30 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P2 1 Unit cell dimensions a = 14.2312(15) Å = 90°. b = 12.8462(14) Å = 112.251(2)°. c = 14.9347(16) Å = 90°.

PAGE 151

151 Table 6 3 . Continued Volume 2527.0(5) Å 3 Z 2 Density (calculated) 1.525 Mg/m 3 Absorption coefficient 0.514 mm 1 F(000) 1176 Crystal size 0.20 x 0.17 x 0.10 mm 3 Theta range for data collection 1.47 to 27.50°. Index ranges Reflections collected 48946 Independent reflections 11122 [R(int) = 0.0283] Completeness to theta = 27.50° 100.0 % Absorption correction Integration Max. and min. transmission 0.9513 and 0.9063 Refinement method Full matrix least squares on F 2 Data / restraints / parameters 11122 / 1 / 679 Goodness of fit on F 2 1.039 Final R indices [I>2sigma(I)] R1 = 0.0218, wR2 = 0.0521 [10515] R indices (all data) R1 = 0.0243, wR2 = 0.0527 Ab solute structure parameter 0.026(9) Largest diff. peak and hole 0.607 and 0.398 e.Å 3

PAGE 152

152 ( ) 2 (2 (diphenylphosphino)naphthalen 1 yl) 1 (perfluorobenzyl) 4,5 diphenyl 1H imidazole ( 3 2 ) . 1,2 bis(diphenylphosphino)ethane 3 61 (60 mg, 0.151 mmol) was added as a solid to a solution of 3 93 (170 mg, 0.147 mmol) at 78 ºC. After 5 minutes, the solution was warmed up to 0 ºC and allowed to stir for 1 hour at the same temperature. The mixture was submitted directly to flash chro matography (20% EtOAc/Hexanes) to give 101 mg (97% yield) of 3 2 as a white foam. R f = 0.57 (20% EtOAc/hexanes). 23 D = 73.5 ( c 3.03, CHCl 3 ). The ee was determined after oxidation to phosphine oxide 3 97 . ( ) 2 (2 (diphenylphosphoryl)naphthalen 1 yl) 1 (perfluorobenzyl) 4,5 diphenyl 1H imidazole (3 97) . Phosphine 3 2 (7 mg, 0.01 mmol) was dissolved in dichloromethane (2 mL) followed by the addition of hydrogen peroxide (0.05 mL), and the solution was stirred at room temperature for 5 min. The mixture was diluted with dichloromethane, washed with water and dried over MgSO 4 . The solvent was removed under reduced pressure, and the residue was purified using a plug of silica gel (hexane/ethyl acetate 1:1) to yield 3 97 as a white solid (7 mg, 96% yield). R f 23 D = 5.1 ( c 0.60, CHCl 3 ). MP: 265 266 ºC. 1 H NMR (500 MHz, CDCl 3 ) 7.91 7.86 (m, 3H),7.79 (d, J = 8.3 Hz, 1H), 7.69 7.43 (m, 11H), 7.43 7.31 (m, 3H), 7.25 7.05 (m, 8H), 5.94 (d, J = 15.5 Hz, 1H), 4.86 (d, J = 15.4 Hz, 1H). 13 C NMR (125 MHz, CDCl 3 ) 145.0 (d, J = 248 Hz), 142.3, 142.3, 140.3 (d, J = 249 Hz), 137.2, 136.6 (d, J = 253 Hz), 134.7, 134.7, 134.5, 134.4, 133.7, 133.56, 133.5, 133.4, 132.9 , 132.5 , 132.1, 131.7 , 131.6 ,

PAGE 153

153 131.6, 131.4, 131.3, 131.2, 131.0, 130.4, 129.6, 129.5 , 129.2 , 129.0, 128.9, 128.8, 128.5, 128.4, 128.4 , 128.3 , 128.3 , 127.8 , 127.7, 127.3, 127.0, 126.4, 126.2 , 110.3 (t, J = 18 Hz), 37.4 . 19 F NMR (281 MHz, CDCl 3 ) 140.9 (dd, J = 22.4, 7.8 Hz), 155.8 (t, J = 20.7 Hz), 163.3 (td, J = 21.5, 7.1 Hz). 31 P NMR (121 MHz, CDCl 3 ) 27.37. IR (Neat): 3058, 1652, 1521, 1508, 1438, 1192, 1118, 1022, 700 cm 1 . HRMS (DART) Calcd for C 44 H 28 F 5 N 2 OP (M+H) + 727.1932, f ound 727.1920. Enantiomeric excess was deter mined by HPLC with a Chiralpak IA column (90:10 n hexane:isopropanol, 1 mL/min, 215 nm); major t r = 13.77 min; minor t r = 25.59 min; 98% ee . Crystal structure 3 99/3 101: X Ray Intensity data were collected at 100 K on a Bruker DUO diffractometer using MoK radiation ( = 0.71073 Ã…) and an APEXII CCD area detector. Raw data frames were read by program SAINT 1 and integrated using 3D profiling algorithms. The resulting data were reduced to produce hkl reflections and their intensities and estimated stand ard deviations. The data were corrected for Lorentz and polarization effects and numerical absorption corrections were applied based on indexed and measured faces. The structure was solved and refined in SHELXTL6.1, using full matrix least squares refin ement. The non H atoms were refined with anisotropic thermal parameters and all of the H atoms were calculated in idealized positions and refined riding on their parent atoms. The asymmetric unit consists of two Pd Complex cations and two hexafluorophosp hate anions. The correct enantiomer are refined as can be seen from the value of the Flack x parameter of 0.02(3). In the final cycle of refinement, 43677 reflections (of which 13112 are observed with I > 2 (I)) were used to refine 1339 parameters and t he resulting R 1 , wR 2 and S (goodness of fit) were 5.61 %, 12.25 % and 1.143 , respectively. The refinement was carried out by minimizing the wR 2 function using F 2 rather than F values. R 1 is calculated to provide a reference to the conventional R value but i ts function is not minimized.

PAGE 154

154 Table 6 4 . Crystal data and structure refinement for 3 99/3 101 . Empirical formula C58 H44 F11 N3 P2 Pd Formula weight 1160.30 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P2 1 Unit cell dimensions a = 15.2517(15) Å = 90°. b = 13.1262(12) Å = 91.281(2)°. c = 25.466(3) Å = 90°. Volume 5097.0(8) Å 3 Z 4 Density (calculated) 1.512 Mg/m 3 Absorption coefficient 0.510 mm 1 F(000) 2352 Crystal size 0.14 x 0.10 x 0.09 mm 3 Theta range for data collection 1.34 to 27.50°. Index ranges Reflections collected 43677 Independent reflections 19981 [R(int) = 0.0545] Completeness to theta = 27.50° 98.3 % Absorption correction Integration Max. and min. transmission 0.9560 and 0.9343

PAGE 155

155 Table 6 4 . Continued Refinement method Full matrix least squares on F 2 Data / restraints / parameters 19981 / 1 / 1339 Goodness of fit on F 2 1.143 Final R indices [I>2sigma(I)] R1 = 0.0561, wR2 = 0.1225 [13112] R indices (all data) R1 = 0 .1151, wR2 = 0.1427 Absolute structure parameter 0.02(3) Largest diff. peak and hole 1.650 and 1.546 e.Å 3 1 (1 benzyl 4,5 diphenyl 1H imidazol 2 yl)naphthalen 2 ol ( 3 113 ). A solution of the silyl ether 3 112 (3.43 g. 7.2 mmol) in THF (15 mL) was added dropwise to a suspension of sodium hydride (190 mg, 7.92 mmol) in THF (10 mL) at 78 ºC. The mixture was stirred for 10 min and benzyl bromide (0.94 mL, 7.90 mmol) was added in a dropwise fashion. The reaction was allowed to warm up to room temperature over 18h at which point the solution was cooled to 0 ºC and water was added. The organic phase was separated and the aqueous phase was extracted with EtOAc (2 x 25 ml). The organic layers were dried over MgSO 4 and the crude product was recovered as a colorless oil which was used for the next step without further purification. To a solution of the silane obtained above in MeOH (50 ml) was added K 2 CO 3 (2.0 g, 14.4 mmol) at room temperature. After 30 minutes, the mix ture was filtered and concentrated under reduced pressure to ~10ml. The residue was dissolved in EtOAc (25 ml) and poured into water (25 ml). The organic phase was separated and the water phase was extracted with EtOAc

PAGE 156

156 (2 x 25 ml). The combined organic lay ers were dried over MgSO 4 and concentrated under reduced pressure to give 2.51g of 3 113 as a white solid (70%, 2 steps). R f = 0.29 (20% EtOAc/hexanes). MP: 227 228 o C. 1 H NMR (500 MHz, CDCl 3 J = 8.4 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 6.9, 2.2 Hz, 2H), 7.42 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 7.35 7.20 (m, 7H), 7.15 (t, J = 7.7 Hz, 2H), 6.79 (t, J = 7.4 Hz, 1H), 6.70 (t, J = 7.6 Hz, 2H), 6.53 (d, J = 7.4 Hz, 2H), 6.42 (d, J = 8.8 Hz, 1H), 6.15 (d, J = 7.6 Hz, 2H), 4.74 (ABq, J = 15 .6 Hz, 97.98 Hz, 2H). 13 C NMR (125 MHz, CDCl 3 131.2, 130.7, 129.9, 129.2, 128.8, 128.5, 128.0, 127.9, 127.0, 127.0, 126.8, 126.7, 126.6, 124.3, 123.3, 120.6, 48.6 . HRMS (DART) Calcd for C 32 H 25 N 2 O (M+H) + 453.1961, found 453.1959. 1 (1 benzyl 4,5 diphenyl 1H imidazol 2 yl)naphthalen 2 yl trifluoromethanesulfonate (6 2). To a solution of the free alcohol 3 113 (2.07 g, 4.57 mmol) and DMAP (56 mg, 0.46 mmol) in DCM (50 mL) was added triethylamine (0.64 mL, 4.57 mmol) followed by N phenyl bis(trifluoromethanesulfonimide) (1.70 g, 4.57 mmol) at room temperature. The resulting solution was stirred at room temperature for 6h and concentrated under reduced pressure. The resi due was purified by flash chromatography (20% EtOAc/Hexanes) to yield 2.54 g (95%) of the triflate 6 2 as a white solid. R f = 0.41 (20% EtOAc/hexanes). MP: 63 64 o C. 1 H NMR (500 MHz, CDCl 3 ) 7.95 (d, J = 8.9 Hz, 1H), 7.84 (dd, J = 21.5, 7.3 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.54 7.31 (m, 7H), 7.25 7.10 (m, 3H), 7.07 6.98 (m, 1H), 6.97 6.71 (m, 3H), 6.48 (d, J = 7.6 Hz, 2H), 4.86 (s, 2H). 13 C NMR (125 MHz, CDCl 3 ) 146.2, 139.8, 139.0, 136.1, 134.4 , 133.7, 132.5, 131. 3, 130. 9, 130.7, 129.2, 12 9 .0 , 128 .4, 128.3, 128.2, 127.5, 127.2, 126.9,

PAGE 157

157 126.7, 124.3 , 121.5 , 119.0, 48. 8. HRMS (DART) Calcd for C 33 H 24 FN 2 O 3 S (M+H) + 585.1454, found 585.1461. 1 benzyl 2 (2 (diph enylphosphino)naphthalen 1 yl) 4,5 diphenyl 1H imidazole ( 3 111). To a solution of triflate 6 2 (2.3 g, 3.93 mmol), NiCl 2 (PPh 3 ) 2 (1.29 g, 1.97 mmol) and Ph 2 PCl (0.87 ml, 4.72 mmol) in anhydrous DMF (20 ml) was added activated Zn (0.51 g, 7.86 mmol) in three portions at room temperature which resulted in a brown s olution ( Zinc dust was activated by washing the solid with aqueous HCl, water, ethanol and dry ether) . The mixture was heated to 110 °C for 48h, cooled to room temperature, diluted with EtOAc and filtered through a short plug of silica. The resulting solution was washed with water (3 x 25 ml) and brine (25 ml), dried over MgSO 4 , and concentrated under reduced pressure. Flash chromatography (5 20% EtOAc/Hexanes, gradient) afforded 1.29 g (53%) of the phosphine 3 111 as a white foam. R f = 0.47 (20% EtOAc /hexanes). MP = 68 69 o C 1 H NMR (500 MHz, CDCl 3 J = 8.5 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.41 7.25 (m, 19H), 7.16 7.06 (m, 5H), 6.96 6.82 (m, 6H), 6.55 (d, J = 7.5 Hz, 2H), 4.63 (ABq, J = 15 Hz, Hz, 2H). 13 C NMR (125 MHz, CDCl 3 136.9, 136.3, 135.5, 135.2, 134.5, 134.4, 134.2, 134.0, 134.0, 133.9, 133.6, 133.6, 131.5 , 131.3 , 130.0, 129.8 , 129 .5, 129.2 , 128.9 , 128.8, 1 28.8, 128.7, 128.7, 128.7, 128.6, 128.6, 128.5, 128.1, 128.0, 128.0, 127.4, 127.4, 127.3, 127.3, 127.2, 127.2, 126.9, 126.6, 126.4, 124.2, 121.2, 49.0, 49.0 . 31 P NMR (121 MHz, C 2 D 2 Cl 4 10.07. Calcd for C 44 H 34 N 2 P (M+H) + 621.2454, found 621.2459.

PAGE 158

158 ( S , R ) cis [Dimethyl(1 ( Naphthyl)Ethyl)Aminato C 2 , N ) [1 benzyl 2 (2 (diphenylphosphino)naphthalen 1 yl) 4,5 diphenyl 1H imidazole] Palladium (II) Hexafluorophosphate ( 3 114 ). Acetone (12 mL) was added to a flask containing 3 111 (410 mg, 0.661 mmol), (+) Di µ chlorobis[( R ) dimethyl(1 (1 naphthyl)ethyl)aminato C 2 , N ]dipalladium (II) 100 14 (225 mg, 0.331 mmol) and potassium hexafluorophosphate (121.3 mg, 0.659 mmol). The resulting mixture was stirred at room temperature for 12 h. Th e mixture concentrated under reduced pressure, and filtered through a plug of celite washing with dichloromethane. The resulting yellow solution was concentrated under vacuum and dissolved in acetone (12 mL) before stirring for an additional 12 h at room t emperature. The solution was then concentrated under vacuum to give a yellow solid. Recrystallization from ether/dichloromethane gave 410 mg of the palladium complex 3 114 as a light yellow powder (58% yield). [ ] 23 D = 75.44 ( c 2.00, CHCl 3 ). MP: 214 216 ºC (dec.). 1 H NMR (5 00 MHz, CDCl 3 ) 8.46 (d, J = 8.5 Hz, 1H), 8.10 (t, J = 7.8 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.84 7.73 (m, 4H), 7.70 7.49 (m, 4H), 7.48 7.04 (m, 14H), 7.01 6.71 (m, 8H), 6.62 (dd, J = 8 .4, 5.8 Hz, 1H), 5.66 (d, J = 7.6 Hz, 2H), 4.98 (ABq, J = 15.0 Hz, = 64.3 Hz, 2H) , 4.02 (p, J = 6.5 Hz, 1H), 2.38 (d, J = 3.7 Hz, 3H), 1.92 (d, J = 6.3 Hz, 3H), 1.37 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) 152.3, 149.5, 143.3, 143.3, 138.1, 136.6, 136.5, 13 5.7, 135.2, 134.78, 134.3, 133.6, 133.5, 132.5, 132.2 , 132. 0, 132.0, 131.7 , 131.6 , 131.5, 131.3, 131.2, 130.9, 130.9, 130.6, 130.1, 130.1, 129.7, 129.2, 129.1, 129.0, 128.8, 128.8, 128.7, 128.6, 128.4, 128.3, 128.2, 128.2, 127.9, 127.7, 127.5, 127.2 , 127.0 , 126.7, 126.4, 126.3, 126.1, 126.0, 125.9, 125.3, 125.3, 124.6, 123.1, 122.6 , 73.6, 51.0, 50.7, 47.9, 24.0 . 31 P NMR (121

PAGE 159

159 MHz, CDCl 3 ) 34.03 , 141.16 (h, J = 712.9 Hz). HRMS (ESI) Calcd for C 58 H 49 N 3 PPd (M PF 6 ) + 924.2713, found 924.2720. ( ) 1 benzyl 2 (2 (diphenylphosphino)naphthalen 1 yl) 4,5 diphenyl 1H imidazole ( 3 115 ) . 1,2 bis(diphenylphosphino)ethane 3 61 (49.4 mg, 0.124 mmol) was added as a solid to a solution of 3 114 (132.4 mg, 0.124 mmol) at 78 ºC. After 5 minutes, the solution was warmed up to 0 ºC and allowed to stir for 1 hour at the same temperature. The mixture was submitted directly to flash chromatography (20% EtOAc/Hexanes) to give 68 mg (88% yield) of 3 115 as a white foam. R f = 0.47 (20 % EtOAc/hexanes). 23 D = 19.0 ( c 1.09, CHCl 3 ). The ee was determined after oxidation to phosphine oxide 3 117 . ( ) 1 benzyl 2 (2 (diphenylphosphoryl)naphthalen 1 yl) 4,5 diphenyl 1H imidazole (3 117) . Phosphine 3 115 (10.9 mg, 0.017 mmol) was dissolved in dichloromethane (2 mL) followed by the addition of hydrogen peroxide (0.05 mL), and the solution was stirred at room temperature for 5 min. The mixture was diluted with dichloromethane, washed with water and dried ove r MgSO 4 . The solvent was removed under reduced pressure, and the residue was purified using a plug of silica gel (hexane/ethyl acetate 1:1) to yield 3 117 as a white solid (10 mg, 90% yield). R f = 0.10 (20% EtOAc/hexanes). [ ] 25 D = 25.4 ( c 1.00, CHCl 3 ). M P: 89 90 ºC. 1 H NMR (500 MHz, CDCl 3 J = 11.4, 7.9, 1.6 Hz, 2H), 7.89 (dd, J = 8.7, 2.2 Hz, 1H), 7.82 7.70 (m, 3H), 7.62 7.44 (m, 6H), 7.44 7.34 (m, 5H), 7.33 7.20 (m, 3H), 7.20 7.06 (m, 5H),

PAGE 160

160 7.02 (t, J = 7.4 Hz, 1H), 6.78 (t, J = 7. 2 Hz, 1H), 6.71 (t, J = 7.5 Hz, 2H), 6.39 (d, J = 7.4 Hz, 2H), 5.18 (ABq, J = 15.0 Hz, 2H). 13 C NMR (125 MHz, CDCl 3 136.7, 135.0, 134.9, 134.9, 134.9, 134.5, 134.0, 133.9 , 1 33.9, 133.0, 132.3, 132.1, 132.0, 131.8, 1 31.8, 131.5, 131.5, 131.3, 131.2, 131.2 , 131.13, 131.05 , 130.7, 129.6, 129.5, 129.4, 129.0, 128.8, 128.7, 128.6, 128.5, 128.3, 128.3, 128.3, 128.1, 128.0, 127.7, 127.7, 127.7, 127.6 , 1 27.6, 127.3, 127.1, 126.8, 126.0 , 49.7. 31 P NMR (121 MHz, CDCl 3 26.91. Calcd for C 44 H 34 N 2 OP (M+H) + 637.2403, found 637.2397. Enantiomeric excess was determined by HPLC with a Chiralpak IA column (97:3 n hexane:isopropanol, 1 mL/min, 254 nm); major t r = 66.43 min; minor t r = 80.49 min; 52% ee . 6.2.3 A 3 Coupling Reactio ns N , N dibenzyl 1 (trimethylsilyl)hex 1 yn 3 amine (4 85). CuBr (5.5 mg, 0.03834 mmol, 5 mol%), and activated MS 4Å sieves (450 mg) were added to a test tube in a glove box. The tube was fitted with a septum before being t aken from the glove box and placed directly under dry nitrogen. rac 4 1 (30.0 mg, 0.0 422 mmol, 5.5 mol %) in toluene (3 mL) was added to the tube and the mixture was stirred for 30 minutes at room temperature. The mixture was cooled to 0 ºC and trimethylsi lylacetylene 4 46 (0.767 mmol, 0.11 mL), butyraldehyde 4 84 (0.767 mmol, 0.069 mL), and dibenzylamine 4 47 (0.767 mmol, 0.15 mL) were added via syringe. The reaction mixture was stirred at 0 ºC for 24 hours, filtered and subjected to flash column chromatography on silica gel (hexanes) giving the product as a colorless oil (247.2 mg, 92%) that matched previously reported spectral data. 134 1 H NMR (500 MHz, CDCl 3 ) 7.37 (d, J = 7.5 Hz, 4H), 7.29 (t, J = 7.6 Hz, 4H), 7.21 (t, J = 7.3 Hz, 2H), 3.78 (d, J = 13.8 Hz, 2H), 3.44 3.22 (m, 3H), 1.67 (dtd, J = 13.7, 8.9, 5.4 Hz, 1H), 1.62 1.48 (m, 1H), 1.49 1.30 (m, 2H), 0.77 (t, J = 7.4 Hz, 3H), 0.23 (s, 9H). 13 C

PAGE 161

161 NMR (125 MHz, CDCl 3 ) 140.1, 129.0, 128.4, 127.0, 104.9, 89.2, 55.0, 52.3 , 36.0 , 19.7, 13. 9, 0.7 . General procedure (A) for enantioselective copper acetylide addition: ( R ) N , N dibenzyl 1 (trimethylsilyl)hex 1 yn 3 amine (4 93 ). CuBr (1.8 mg, 0.0125 mmol, 5 mol%), and activated MS 4Å sieves (150 mg) were added to a test tube in a glove box. The tube was fitted with a septum before being taken from the glove box and placed directly under dry nitrogen. Phosphine 4 1 (9.7 mg, 0.0141 mmol, 5.5 mol%) in toluene (1 mL) was added to the tube and the mixture was stirred for 30 minutes at room temperature. The mixture was cooled to 0 ºC and trimethylsilylacetylene 4 46 (0.25 mmol), butyraldehyde 4 84 (0.25 mmol), and dibenzylamine 4 47 (0.2 5 mmol) were added via syringe. The reaction mixture was stirred at 0 ºC and monitored by TLC. T he reaction mixture was directly subjected to flash column chromatography on silica gel. General procedure (B) for desilylation: The propargylamine obtained above was dissolved in MeOH (0.5 ml), and (KOH 1M in MeOH, 0.3 mL, 0.3 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 12 h, quenched with water (2 mL), and extracted with Et 2 O (3 x 3 mL). The combined organic laye rs were dried over MgSO 4 , concentrated under reduced pressure and purified by flash column chromatography. ( R ) N,N dibenzyl 1 cyclohexyl 3 (trimethylsilyl)prop 2 yn 1 amine ( 4 90 ). The following compound was prepared via procedure A, with trimethylsilylacetylene 4 46 (35 µL, 0.25

PAGE 162

162 mmol), cyclohexanecarboxaldehyde 4 45 (30 µL, 0.25 mmol) and dibenzylamine 4 47 (48 µL, 0.25 mmol) at 0 ºC for 24h. Purification by flash column chromatogra phy (hexanes) yielded the product as a colorless solid (92.5 mg, 95%) that satisfactorily matched previously reported data. 126 The ee was determined after desilylation (below). [ ] 24 D = +180.5 ( c 0.77 , CHCl 3 ). MP = 83 84 o C. 1 H NMR (300 MHz, CDCl 3 ) 7.48 (s, 4H), 7.42 7.34 (m, 4H), 7.34 7.25 (m, 2H), 3.89 (d, J = 13.6 Hz, 2H), 3.45 (d, J = 13.7 Hz, 2H), 3.13 (d, J = 10.4 Hz, 1H), 2.37 (d, J = 13.1 Hz, 1H), 2.09 (d, J = 12.6 Hz, 1H), 1.87 1.55 (m, 4H), 1.44 1.02 (m, 3H), 1.03 0.65 (m, 2H), 0 .35 (s, 9H). 13 C NMR (75 MHz, CDCl 3 ) 140.0, 129.0, 128.4, 127. 0, 103.7 , 90.3, 58.8, 55.1, 39.7, 31.5, 30.5, 26.9, 26.4, 26.2, 0.8 . The absolute configuration was determined by comparing the sign of the optical rotation to that of a known sample. 126 ( R ) N,N dibenzyl 1 cyclohexylprop 2 yn 1 amine . The following compound was prepared via procedure B, with 4 90 (41 mg, 0.105 mmol), KOH (0.3 mmol) and MeOH (0.5 mL). Purification by flash column chromatography (hexanes) yielded the product as a colorless solid (32 mg, 96%) that satisfactorily matched previously reported data. 126 24 D = +156.6 ( c 0.51 , CHCl 3 ). MP = 75 76 o C. 1 H NMR (300 MHz, CDCl 3 ) 7 .31 (d, J = 7.4 Hz, 4H), 7.21 (t, J = 7.3 Hz, 4H), 7.13 (t, J = 7.2 Hz, 2H), 3.73 (d, J = 13.8 Hz, 2H), 3.29 (d, J = 13.8 Hz, 2H), 2.95 (dd, J = 10.5, 2.2 Hz, 1H), 2.30 2.13 (m, 2H), 1.92 (d, J = 13.5 Hz, 1H), 1.71 1.42 (m, 4H), 1.29 0.86 (m, 3H), 0. 86 0.50 (m, 2H). 13 C NMR (75 MHz, CDCl 3 73.7 , 57.8 , 55.0, 39.7, 31.4, 30.4, 26.8, 26.3, 26.1 . Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (100:0 n hexane:isopropanol, 0.1 mL/min, 215 nm); minor t r = 66.22 min; major t r = 71.90 min; 97% ee . The absolute configuration was determined by comparing the sign of the optical rotation to that of a known sample. 126

PAGE 163

163 ( R ) N,N dibenzyl 4 methyl 1 (trimethylsilyl)pent 1 yn 3 amine (4 91). The following compound was prepared via procedure A, with trimethylsilylacetylene 4 46 (35 µL, 0.25 mmol), isobutyraldehyde 4 53 (23 µL, 0.25 mmol) and dibenzylamine 4 47 (48 µL, 0.25 mmol) at 0 ºC for 24h. Purification by flash column chromatography (hexanes) yielded the product as a clear colorless oil (80.0 mg, 92%) that satisfactorily matched previously reported data. 126 The ee was etermined after desilylation (below). [ ] 24 D = +263.6 ( c 0.67 , CHCl 3 ). 1 H NMR (500 MHz, CDCl 3 ) 7.42 7.37 (m, 4H), 7.33 7.27 (m, 4H), 7.24 7.19 (m, 2H), 3.79 (d, J = 13.7 Hz, 2H), 3.34 (dd, J = 13.8, 0.8 Hz, 2H), 2.88 (dd, J = 10.4, 0.9 Hz, 1H), 1.95 1.80 (m, 1H), 0.97 (dd, J = 10.1, 6.9 Hz, 6H), 0.24 (s, 9H). 13 C NMR (125 MHz, CDCl 3 0, 129.1, 128.4, 127.0, 104.0, 90.1, 60.1, 55.2, 30.8, 21.1, 20.1, 0.7 . The absolute configuration was determined by comparing the sign of the optical rotation to that of a known sample. 126 ( R ) N,N dibenzyl 4 methylpent 1 yn 3 amine . The following compound was prepared via procedure B, with 4 91 (30 mg, 0.097 mmol), KOH (0.3 mmol) and MeOH (0.5 mL). Purification by flash column chromatography (hexanes) yielded the product as a clear colorless oil (22 mg, 92%) that satisfactorily matched previously reported data. 126 24 D = +232.1 ( c 0.90 , CHCl 3 ). 1 H NMR (500 MHz, CDCl 3 ) 7.56 7.50 (m, 4H), 7.46 7.40 (m, 4H), 7.38 7.31 (m, 2H), 3.95 (d, J = 13.7 Hz, 2H), 3.50 (d, J = 13.8 Hz, 2H), 3.03 ( dd, J = 10.6, 2.2 Hz, 1H), 2.47 (d,

PAGE 164

164 J = 2.3 Hz, 1H), 2.05 (dp, J = 10.6, 6.6 Hz, 1H), 1.12 (dd, J = 11.8, 6.6 Hz, 6H). 13 C NMR (125 MHz, CDCl 3 . Enantiomeric excess was determined by HP LC with a Chiralcel OD H column (100:0 n hexane:isopropanol, 0.2 mL/min, 215 nm); minor t r = 32.45 min; major t r = 36.71 min; 95% ee . The absolute configuration was determined by comparing the sign of the optical rotation to that of a known sample. 126 ( R ) N,N dibenzyl 1 (1 tosylpiperidin 4 yl) 3 (t rimethylsilyl)prop 2 yn 1 amine. (4 92). The following compound was prepared via procedure A, with trimethylsilylacetylene 4 46 (35 µL, 0.25 mmol), 1 tosylpiperidine 4 carbaldehyde 4 88 151 (67 mg, 0.25 mmol) and dibenzylamine 4 47 (48 µL, 0.25 mmol) at 0 ºC for 24 hours. Purification by flash column chromatography (20% EtOAc/Hexanes) yielded the product as a colorless sol id (128.0 mg, 94%). [ ] 24 D = +88.1 ( c 0.73 , CHCl 3 ). MP = 128 129 o C. 1 H NMR (500 MHz, CDCl 3 ) 7.59 (d, J = 8.2 Hz, 2H), 7.39 7.15 (m, 12H), 3.72 3.64 (m, 4H), 3.30 (d, J = 13.8 Hz, 2H), 3.00 (d, J = 10.5 Hz, 1H), 2.40 (s, 3H), 2.22 (td, J = 11.6, 2.9 Hz, 2H), 2.13 (td, J = 11.9, 2.7 Hz, 1H), 1.96 (d, J = 13.5 Hz, 1H), 1.54 1.36 (m, 1H), 1.14 (dtd, J = 49.0, 13.4, 12.7, 3.9 Hz, 2H), 0.21 (s, 9H). 13 C NMR (125 MHz, CDCl 3 ) 143.5, 139.3, 133.1, 129.7, 128.9, 128.5, 127.9, 127.3, 102.1 , 91.3 , 57.4, 55.1, 46.5, 46.4, 37.5, 29.7, 29.0, 21.7, 0.5 . HRMS (DART) Calcd for C 32 H 41 N 2 O 2 SSi (M+H) + 545.2653, found 545.2646. Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (95:5 n hexane:isopropanol, 0.5 mL/min, 215 nm); minor t r = 13.13 mi n; major t r = 15.05 min; 91% ee . The absolute configuration was determined by analogy.

PAGE 165

165 ( R ) N,N dibenzyl 1 (trimethylsilyl)hex 1 yn 3 amine ( 4 93 ). The following compound was prepared via procedure A, with trimethylsilylacetylene 4 46 (35 µL, 0.25 mmol), butyraldehyde 4 84 (22 µL, 0.25 mmol) and dibenzylamine 4 47 (48 µL, 0.25 mmol) at 0 ºC for 24h. Purification by flash column chromatography (hexanes ) yielded the product as a clear colorless oil (80.4 mg, 92%) that satisfactorily matched previously reported data. 134 The ee was determined after desilylation (below). [ ] 24 D = +169.2 ( c 1.00 , CHCl 3 ). 1 H NMR (500 MHz, CDCl 3 ) 7.37 (d, J = 7.5 Hz, 4H), 7. 29 (t, J = 7.6 Hz, 4H), 7.21 (t, J = 7.3 Hz, 2H), 3.78 (d, J = 13.8 Hz, 2H), 3.44 3.22 (m, 3H), 1.67 (dtd, J = 13.7, 8.9, 5.4 Hz, 1H), 1.62 1.48 (m, 1H), 1.49 1.30 (m, 2H), 0.77 (t, J = 7.4 Hz, 3H), 0.23 (s, 9H). 13 C NMR (125 MHz, CDCl 3 129.0, 128.4, 127.0, 104.9, 89.2, 55.0, 52.3, 36.0, 19.7, 13.9, 0.7 . The absolute configuration was determined by comparing the sign of the optical rotation to that of a known sample. 134 ( R ) N,N dibenzylhex 1 yn 3 amine . T he following compound was prepared via procedure B, with 4 93 (34 mg, 0.097 mmol), KOH (0.3 mmol) and MeOH (0.5 mL). Purification by flash column chromatography (hexanes) yielded the product as a clear colorless oil (25 mg, 93%) that satisfactorily matched previously reported data. 134 24 D = +159.5 ( c 0.73 , CHCl 3 ). 1 H NMR (500 MHz, CDCl 3 ) 7.41 (d, J = 7.5 Hz, 4H), 7.32 (t, J = 7.5 Hz, 4H), 7.24 (t, J = 7.3 Hz, 2H), 3.84 (d, J = 13.8 Hz, 2H), 3.47 3.31 (m, 3H), 2.32 (d, J = 2.3 Hz, 1H), 1.80 1.69 (m, 1H),

PAGE 166

166 1.62 (ddt, J = 13.3, 8.9, 6.6 Hz, 1H), 1.44 (dtdd, J = 38.1, 13.5, 10.9, 6.7 Hz, 2H), 0.81 (t, J = 7.4 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 , 129. 0, 128.4 , 127.1, 82.4 , 72.6 , 55.0, 51.4, 36.1, 19.7, 13.9 . Enantiomer ic excess was determined by HPLC with a Chiralcel OD H column (100:0 n hexane:isopropanol, 0.1 mL/min, 215 nm); major t r = 84.62 min; minor t r = 104.20 min; 89% ee . The absolute configuration was determined by comparing the sign of the optical rotation to that of a known sample. 134 ( R ) N,N dibenzyl 1 phenyl 3 (trimethylsilyl)prop 2 yn 1 amine ( 4 94 ) . The following compound was prepared via procedure A, with trimethylsilylacetylene 4 46 (35 µL, 0.25 mmol), benzaldehyde 4 79 (25 µL, 0.25 mmol) and dibenzylamine 4 47 (48 µL, 0.25 mmol) at 0 ºC for 24 hours. Purification by flash column chromatography (hexanes) yielded the product as a colorless solid (76.7 mg, 80%). The ee was determined after desilylation (below). [ ] 23 D = +75.2 ( c 1.00 , CHCl 3 ). MP = 100 101 o C. 1 H NMR (500 MHz, CDCl 3 ) 7.68 7.59 (m, 2H), 7.42 7.36 (m, 4H), 7.35 7.26 (m, 6H), 7.26 7.18 (m, 3H), 4.70 (s, 1H), 3.70 (d, J = 13.5 Hz, 2H), 3.41 (d, J = 13.5 Hz, 1H), 0.32 (s, 9H). 13 C NMR (125 MHz, CDCl 3 ) 139.8, 139.1, 129.1, 128.5, 128.5, 128.3, 127.6, 127.2, 101.1, 93.4, 56.5, 54.7, 0.7 . HRMS (DART) Calcd for C 26 H 30 NSi (M+H) + 384.2142, found 384.2128. The absolute configuration was determined by analogy.

PAGE 167

167 ( S ) N,N di benzyl 1 phenylprop 2 yn 1 amine . The following compound was prepared via procedure B, with 4 94 (26 mg, 0.078 mmol), KOH (0.3 mmol) and MeOH (0.5 mL). Purification by flash column chromatography (hexanes) yielded the product as a clear colorless oil (19.7 mg, 93%). [ ] 24 D = +28.9 ( c 0.50 , CHCl 3 ). 1 H NMR (500 MHz, CDCl 3 ) 7.66 (d, J = 8.1 Hz, 2H), 7 .39 (d, J = 7.3 Hz, 4H), 7.36 7.27 (m, 6H), 7.27 7.18 (m, 3H), 4.72 (s, 1H), 3.72 (d, J = 13.4 Hz, 2H), 3.44 (d, J = 13.5 Hz, 2H), 2.64 (d, J = 2.3 Hz, 1H). 13 C NMR (125 MHz, CDCl 3 ) 139.6, 138.8, 129.1, 128.5, 128.4, 128.3, 127.7, 127.3, 79.0, 76.3, 55.6, 54.6 . HRMS (DART) Calcd for C 23 H 22 N (M+H) + 312.1747, found 312.1747. Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (100:0 n hexane:isopropanol, 0.4 mL/min, 215 nm); minor t r = 27.50 min; major t r = 35.34 min; 94% ee . The abs olute configuration was determined by analogy. ( S ) N,N dibenzyl 1 (thiophen 2 yl) 3 (trimethylsilyl)prop 2 yn 1 amine ( 4 95 ) . The following compound was prepared via procedure A, with trimethylsilylacetylene 4 46 (35 µL, 0.25 mmol), 2 thiophenecarboxaldehyde 4 89 (23 µL, 0.25 mmol) and dibenzylamine 4 47 (48 µL, 0.25 mmol) at 0 ºC for 4 days. Purification by flash column chromatography (hexanes) yielded the product as a colorless solid (58.4 mg, 60%) that satisfac torily matched previously reported data. 127 The ee was determined after desilylation (below). [ ] 24 D = +415.5 ( c 0.12 CHCl 3 ). MP = 89 90 o C.

PAGE 168

168 1 H NMR (300 MHz, CDCl 3 ) 7.54 7.47 (m, 3H), 7.40 7.31 (m, 3H), 7.30 7.23 (m, 4H), 6.96 (ddd, J = 5.1, 3.5, 0.8 Hz, 1H), 4.85 (d, J = 1.2 Hz, 1H), 3.86 (d, J = 13.7 Hz, 2H), 3.46 (d, J = 13.7 Hz, 2H), 0.34 (s, 9H). 13 C NMR (75 MHz, CDCl 3 ) 144.7, 139.5, 128.9, 128.5 , 12 7.3, 126.4, 126.2, 125.7, 100.5, 92.1, 54.6, 53.1, 0.5 . The absolute configurati on was determined by comparing the sign of the optical rotation to that of a known sample. 127 ( S ) N,N dibenzyl 1 (thiophen 2 yl)prop 2 yn 1 amine . The following compound was prepared via procedure B, with 4 95 (20 mg, 0.051 mmol), KOH (0.3 mmol) and MeOH (0.5 mL). Purification by flash column chromatography (hexanes) yielded the product as a clear colorless oil (12.0 mg, 74%) that satisfactorily matched previously reported data. 6 [ ] 24 D = +143.5 ( c 0.11 , CHCl 3 ). 1 H NMR (300 MHz, CDCl 3 ) 7.52 (d, 3H), 7.37 (t, 4H), 7.31 7.27 (m, 3H), 6.97 (dd, J = 5.0, 3.6 Hz, 1H), 4.90 (t, J = 1.5 Hz, 1H), 3.90 (d, J = 13.7 Hz, 2H), 3.51 (d, J = 13.7 Hz, 2H), 2.64 (d, J = 2.3 Hz, 1H). 13 C NMR (75 MHz, CDCl 3 ) 144.2, 139.3, 128.9, 128.6, 127.3, 126.4, 126.3, 125.8, 78.7, 75.0, 54.6, 52.3 . Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (100:0 n hexane:isopropanol, 0.5 mL/min, 215 nm); minor t r = 14.23 min; major t r = 18.66 min; 94% ee . T he absolute configuration was determined by comparing the sign of the optical rotation to that of a known sample. 127

PAGE 169

169 ( R ) N,N dibenzyl 1 (4 methoxyphenyl) 3 (trimethylsilyl)prop 2 yn 1 amine (4 96). The following compound was prepared via procedure A, with trimethylsilylacetylene 4 46 (35 µL, 0.25 mmol), p anisaldehyde 4 80 (30 µL, 0.25 mmol) and dibenzylamine 4 47 (48 µL, 0.25 mmol) at 0 ºC for 4 days. Purification by flash column chromatography (5% EtOAc/Hexanes) yielded the product as a clear colorless oil (79.6 mg, 77%). [ ] 22 D = +34.3 ( c 0.99 , CHCl 3 ). 1 H NMR (500 MHz, CDCl 3 ) 7.58 (d, J = 8.9 Hz, 2H), 7.42 (s, 4H), 7.33 (t, J = 7.6 Hz , 4H), 7.26 (d, J = 9.8 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 4.68 (s, 1H), 3.82 (s, 3H), 3.73 (d, J = 13.5 Hz, 2H), 3.43 (d, J = 13.5 Hz, 2H), 0.36 (s, 9H). 13 C NMR (125 MHz, CDCl 3 ) 159.1 , 139.8, 131.1, 129.5, 129.1, 128.4, 127.1, 113.6, 101.4, 93.0, 55.8 , 5 5.5, 54.5, 0.6 . HRMS (DART) Calcd for C 27 H 32 NOSi (M+H) + 414.2248, found 414.2230. Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (100:0 n hexane:isopropanol, 0.8 mL/min, 254 nm); minor t r = 9.53 min; major t r = 13.96 min; 94% ee . The absolute configuration was determined by analogy. ( R ) N,N dibenzyl 1 (4 (trifluoromethyl)phenyl) 3 (trimethylsilyl)prop 2 yn 1 amine ( 4 97 ). The following compound was prepared via procedure A, with trimethylsilyl acetylene 4 46 (35 µL, 0.25 mmol), p trifluoromethylbenzaldehyde 4 49 (39 µL, 0.25 mmol) and dibenzylamine 4 47 (48 µL, 0.25 mmol) at room temperature for 24 hours. Purification by flash column chromatography (hexanes) yielded the product as a clear colorless oil (79.0 mg, 70%). The ee was

PAGE 170

170 determined after desilylation (below). [ ] 22 D = +54.5 ( c 1.50 , CHCl 3 ). 1 H NMR (500 MHz, CDCl 3 ) 7.75 (d, J = 9.8 H z, 2H), 7.57 (d, J = 9.3 Hz, 4H), 7.36 (d, J = 8.7 Hz, 4H), 7.30 (t, J = 7.6 Hz, 2H), 7.24 7.19 (m, 2H), 4.69 (s, 1H), 3.66 (d, J = 13.4 Hz, 2H), 3.40 (d, J = 13.5 Hz, 2H), 0.32 (s, 9H). 13 C NMR (125 MHz, CDCl 3 ) 143.3, 139.3, 130.0, 129.8, 129.1, 128.7 , 128.6, 127.4 , 125.2 (q, J = 4 Hz), 100.0, 94.3, 56.3, 54.9, 0.6 . HRMS (DART) Calcd for C 27 H 29 F 3 NSi (M+H) + 452.2016, found 452.2006. The absolute configuration was determined by analogy. ( S ) N,N dibenzyl 1 (4 (trifluoromethyl)phenyl)prop 2 yn 1 amine . The following compound was prepared via procedure B, with 4 97 (35 mg, 0.078 mmol), KOH (0.3 mmol) and MeOH (0.5 mL). Purification by short flash column chromatography (hexanes) yielded the pro duct as a clear colorless oil (21 mg, 70%). [ ] 23 D = +7.1 ( c 1.00 , CHCl 3 ). 1 H NMR (500 MHz, CDCl 3 ) 7.79 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 7.4 Hz, 4H), 7.32 (t, J = 7.5 Hz, 4H), 7.27 7.19 (m, 2H), 4.74 (s, 1H), 3.70 (d, J = 13.5 Hz, 2H), 3.45 (dd, J = 13.4, 1.7 Hz, 2H), 2.69 (d, J = 2.3 Hz, 1H). 13 C NMR (125 MHz, CDCl 3 ) 143.0, 139.2, 130.2, 129.9, 129.1, 128.7, 128.6, 127.5, 125.5, 125.3 (q, J = 4 Hz), 123.3, 78.9, 77.1, 55.4, 54.8 . HRMS (DART) Calcd for C 24 H 21 F 3 N (M+H) + 380.1621, found 380.1617. Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (100:0 n hexane:isopropanol, 0.5 mL/min, 215 nm); minor t r = 16.08 min; major t r = 23.19 min; 92% ee . The absolute configuration was determined by analogy.

PAGE 171

171 ( R ) 1 (1 phenyl 3 (trimethylsilyl)prop 2 ynyl)piperidin 4 one ( 4 90 ). CuBr (1.8 mg, 0.0125 mmol, 5 mol%), and activated MS 4Å sieves (150 mg) were added to a test tube in a glove box. The tube was fitted with a septum be fore being taken from the glove box and placed directly under dry nitrogen. Phosphine 4 1 (9.7 mg, 0.0141 mmol, 5.5 mol%) in dichloromethane (1 mL) was added to the tube and the mixture was stirred for 30 minutes at room temperature. The mixture was cooled to 0 ºC and triethylamine (56 mg, 0.55 mmol, 2.2 equiv) was added via syringe. 4 piperidone hydrochloride monohydrate (38.4 mg, 0.25 mmol, 1.0 equiv) was added as a solid, followed by phenylacetylene (55 µL, 0.5 mmol, 2.0 equiv) and isobutyraldehyde (46 µ L, 0.50 mmol, 2.0 equiv) via syringe. After addition of an additional 1 mL of dichloromethane the reaction was stirred at 0 °C for 24 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (3 mL) and tranfered to a separatory funnel containing dichloromethane (5 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (3 x 5 mL). The combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure. Purification of the crude material by flash column chromatography on silica gel (20% EtOAc/Hexanes) afforded the product (51.2 mg, 80%) as a yellowish solid that satisfactorily matched previously reported data. 128 [ ] 25 D = +15.7 ( c 1.00 , CHCl 3 ). MP = 69 70 o C. 1 H NMR (500 MHz, CDCl 3 ) 7.44 7.35 (m, 2H), 7.31 7.26 (m, 3H), 3.18 (d, J = 10.0 Hz, 1H), 2.98 (dt, J = 11.8, 6.2 Hz, 2H), 2.76 (dt, J = 11.5, 6.0 Hz, 2H), 2.48 (ddt, J = 22.0, 14.8, 8.0 Hz, 4H), 1.91 (dt, J = 9.8, 6.5 Hz, 1H), 1.10 (dd, J = 33.1, 6.6 Hz, 6H ). 13 C NMR (125 MHz, CDCl 3 ) 209.7, 131.9, 128.5, 128.2, 123.4, 86.7, 86.4, 64. 7, 49.7 , 41.8, 31.4,

PAGE 172

172 20.9, 20.1 . Enantiomeric excess was determined by HPLC with a Chiralcel OJ H column (99:1 n hexane:isopropanol, 0.5 mL/min, 254 nm); minor t r = 31.60 min; major t r = 39.09 min; 93% ee . The absolute configuration was determined by comparing the sign of the optical rotation to that of a known sample. 128 ( R ) 1 (4 methyl 1 phenylpent 1 yn 3 yl)piperidin 4 one ( 4 91 ). CuBr (2.7 mg, 0.0188 mmol, 7.5 mol%), and activated MS 4Å sieves (150 mg) were added to a test tube in a glove box. The tube was fitted with a septum before being taken from the glove box and placed directly under dry nitrogen. Phosphine 7 (14.2 mg, 0.02 m mol, 8 mol%) in dichloromethane (1 mL) was added to the tube and the mixture was stirred for 30 minutes at room temperature. The mixture was cooled to 0 ºC and triethylamine (56 mg, 0.55 mmol, 2.2 equiv), 4 piperidone monohydrate (38.4 mg, 0.25 mmol, 1.0 e quiv) was added as a solid, followed by trimethylsilylacetylene 4 46 (55 µL, 0.5 mmol, 2.0 equiv) and benzaldehyde (25 µL, 0.25 mmol, 1.0 equiv) via syringe. After addition of an additional 1 mL of dichloromethane the reaction was stirred at room temperatu re for 48 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (3 mL) and tranfered to a separatory funnel containing dichloromethane (5 mL). The layers were separated and the aqueous layer was extracted with dic hloromethane (3 x 5 mL). The combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure. Purification of the crude material by flash column chromatography on silica gel (20% EtOAc/Hexanes) afforded

PAGE 173

173 the product (49.0 mg, 69%) as a yellowish oil. [ ] 25 D = 27.4 ( c 1.00 , CHCl 3 ). 1 H NMR (500 MHz, CDCl 3 ) 7.61 (d, J = 7.6 Hz, 2H), 7.37 (t, J = 7.5 Hz, 2H), 7.31 (t, J = 7.3 Hz, 1H), 4.80 (s, 1H), 2.80 (t, J = 6.2 Hz, 4H), 2.46 (dtd, J = 20.9, 14.7, 7.1 Hz, 4H), 0.23 (s, 9H). 13 C NMR (125 MHz, CDCl 3 ) 209.4, 138.0, 128.4, 128.4, 128.0, 100.4, 93.5, 61.4, 49.3, 41.7, 0.4 . HRMS (DART) Calcd for C 17 H 24 NOSi (M+H) + 286.1622, found 286.1628. Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (99:1 n hexane:isopropanol, 1 mL/min, 215 nm); minor t r = 21.31 min; major t r = 26.57 min; 92% ee . The absolute configuration was determined by analogy. Crystal structure 4 103 : X Ray Intensity data were collected at 100 K on a Bruker DUO diffractometer using CuK radiation ( = 1.54178 Ã…), from an ImuS power source, and an APEXII CCD area detector. Raw data frames were read by program SAINT 1 and integrated using 3D profiling algorithms. The resulting data were reduced to produce hkl reflections and their intensities and est imated standard deviations. The data were corrected for Lorentz and polarization effects and numerical absorption corrections were applied based on indexed and measured faces. The structure was solved and refined in SHELXT2013, using full matrix least squares refinement. The non H atoms were refined with anisotropic thermal parameters and all of the H atoms were calculated in idealized positions and refined riding on their parent atoms. The asymmetric unit consists of the Cu dimer and a significantly disordered molecule. The latter is significantly disordered and could not be modeled properly, thus program SQUEEZE, a part of the PLATON package of crystallographic software, was used to calculate the solvent disorder

PAGE 174

174 area and remove its contribution to the overall intensity data. The molecules exhibit five disordered phenyl rings. Those are located on C26, C79, C86, and P2. The latter are C101 C106 and C201 C206 and their disordered counter parts. The final cycle of refinement, 14276 reflections (of w hich 12641 are observed with I > 2 (I)) were used to refine 822 parameters and the resulting R 1 , wR 2 and S (goodness of fit) were 4.88 %, 12.32 % and 1.065 , respectively. The refinement was carried out by minimizing the wR 2 function using F 2 rather than F v alues. R 1 is calculated to provide a reference to the conventional R value but its function is not minimized. Table 6 5 . Crystal data and structure refinement for 4 103 . Empirical formula C89 H58 Br2 Cl2 Cu2 F10 N4 P2 Formula weight 1793.13 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Orthorhombic Space group P 21 21 21 Unit cell dimensions a = 12.0023(2) Å = 90°. b = 24.3165(4) Å = 90°. c = 27.2759(4) Å = 90°. Volume 7960.6(2) Å 3 Z 4 Density (calculated) 1.496 Mg/m 3 Abs orption coefficient 3.442 mm 1 F(000) 3608 Crystal size 0.350 x 0.075 x 0.058 mm 3

PAGE 175

175 Theta range for data collection 2.434 to 67.999°. Table 6 5 . Continued Index ranges Reflections collected 52658 Independent reflections 14276 [R(int) = 0.0431] Completeness to theta = 67.679° 99.3 % Absorption correction Empirical Max. and min. transmission 0.8946 and 0.5691 Refinement method Full matrix least squares on F 2 Data / restraints / parameters 14276 / 0 / 822 Goodness of fit on F 2 1. 065 Final R indices [I>2sigma(I)] R1 = 0.0488, wR2 = 0.1232 [12641] R indices (all data) R1 = 0.0551, wR2 = 0.1265 Absolute structure parameter 0.025(10) Extinction coefficient n/a Largest diff. peak and hole 0.683 and 0.629 e.Å 3 6.2.4 Synthesis of (+) C uspareine 4 121 Ethyl ( S ) 2 ((3,4 dimethoxyphenyl)ethynyl)quinoline 1(2H) carboxylate (4 120). A solution of 4 1 (9.7 mg, 0.0141 mmol, 5.5 mol%) and alkyne 4 62 ( 41 mg , 0.25 mmol) in dichloromethane (1.0 mL) was added to CuBr (1.8 mg, 0.0125 mmol, 5 mol%) and stirred at

PAGE 176

176 room temperature for 30 min. Quinoline 4 115 (30 µL, 0.25 mmol) and ethyl chloroformate 4 109 (24 µL, 0.25 mmol) were mixed in DCM (1.0 mL) for 5 min. at ambient te mperature. Then the quinoline salt was added to the above reaction mixture at 0 °C followed by EtN i Pr 2 ( 60 µL, 0. 35 mmol) and the reaction mixture was allowed to warm to room temperature. The reaction was stirred for three hours and directly subjected to f lash column chromatography using dichloromethane. The solvent was removed under reduced pressure and the title product was obtained as a white solid (86%, 95% ee). Enantiomeric excess was determined by HPLC w ith a Chiralcel OD H column (90 : 1 0 n hexane:isop ropanol, 1.0 mL/min, 2 54 nm); minor t r = 14 . 54 min; major t r = 18 . 22 min . 1 H NMR (500 MHz, CDCl 3 7.16 (m, 1H), 7.17 7.00 (m, 2H), 6.88 (dd, J = 8.3, 1.9 Hz, 1H), 6.77 (d, J = 1.9 Hz, 1H), 6.67 (d, J = 8.3 Hz, 1H), 6.60 6.48 (m, 1H), 6.16 6.00 (m, 2H), 4.44 4.15 (m, 2H), 3.80 (s, 3H), 3.77 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H). ( R ) 2 (3,4 dimethoxyphenethyl) 1 methyl 1,2,3,4 tetrahydroquinoline (4 121). A solution of 4 120 (23 mg, 0.0633 mmol) in EtOH/EtOAc (1:1) (2.0 mL) was added 10% Pd C (5 mg). The reaction vessel was evacuated and refilled with hydrogen three times using vacuum pump. The reaction was stirred under hydrogen balloon at ambient temperature for 16 h. The reaction mixture was diluted with EtOAc and filtered through a celite bed. The filtrate was collected and the solvents were distilled off to afford a crude mixture which was forwarded to the next step without any further purification. To a suspension of LAH ( 24 mg, 0.633 mmol) in anhydrous THF (3.0 mL) at 0 °C was added a solution of the material obtained above in THF (3.0 mL) in a dropwise fashion . The

PAGE 177

177 suspension was stirred at 55 °C for three hours. The reaction mixture was cooled to 0 °C and quenched according to Fieser workup. After drying this solution with MgSO 4 , the solvent was removed and a column run at 20% EtOAc/Hexanes gave the title compound 2 39 as a yellow oil ( 14 mg, 71% over to steps); [ ] D 24 = +26.2 (c = 1.00, CHCl 3 ) {For ( ) cuspareine: lit. 142 [ ] D 25 = 22.8 (c = 1.00, CHCl 3 )}. 1 H NMR (500 MHz, CDCl 3 ) 7.11 (dd, J = 8.5, 6.8 Hz, 1H), 7.01 (d, J = 7.5 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 6.78 6.71 (m, 2H), 6.62 (t, J = 7.3 Hz, 1H), 6.56 (d, J = 7.8 Hz, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 3.31 (dt, J = 8.7, 4.3 Hz, 1H), 2.94 (s, 3H), 2.88 (ddd, J = 17.5, 12.1, 6.1 Hz, 1H), 2.77 2.65 (m, 2H), 2.56 (ddd, J = 14.0, 10.1, 6.4 Hz, 1H), 2.04 1.89 (m, 3H), 1.83 1.70 (m, 1H). 13 C NMR (125 MHz, CDCl 3 ) 149.1, 147.4 , 145.5 , 134.8, 128.9, 127.3 , 121.9 , 120.3, 115.6, 111.8, 111.5, 110.8, 58.6, 56.2, 56.1 , 38.3 , 33.3, 32.1, 24.6, 23.8 . 6.2.5 cid ( R ) 5 (1 (4 methoxyphenyl) 3 phenylprop 2 yn 1 yl) 2,2 dimethyl 1,3 dioxane 4,6 dione (4 124). Sodium (L) ascorbate (5 mg, 0.025 mmol) was added to test tube containing a 0.3M solution of Cu(OAc) 2 in water (0.04 mL, 0.012 mmol). Water (0.12 mL) was added and the mixture was stirred until the mixture turned bright orange. Subsequently, 4 1 (9 mg, 0.0126 mmol) and phenylacetylene 4 50 (0.14 mL, 1.27 mmol) were added, the resulting mixture was stirred 10 min at 23 °C, cooled to 0 °C, stirred for 5 min and treated with 4 123 (33 mg, 0.126 mmol) . The reaction mixture was stirred vigorously at 0 °C for 18 hours, diluted with dichloromethane (2 ml) and subjected directly to flash column chromatography (30 % EtOAc/hexanes) to yield the title compound as a white foam (44 mg, 95%). Enantiomeric excess: 80%. [ ] D 24 = +20.0 (c = 1.00, CHCl 3 ). 1 H NMR (500 MHz, CDCl 3 ) 7.46 (d, J = 8.6 Hz, 2H),

PAGE 178

178 7.44 7.37 (m, 2H), 7.23 (dd, J = 5.1, 1.9 Hz, 3H), 6.81 (d, J = 8.7 Hz, 2H), 5.04 (d, J = 2.6 Hz, 1H), 3.89 (d, J = 2.7 Hz, 1H), 3.73 (s, 3H), 1.66 (s, 3H), 1.54 (s, 3H). 13 C NMR (125 MHz, CHCl 3 ) 163.8 , 163.4, 159.3, 131.9, 130.1, 129.1 , 128.4, 128.3 , 122.9, 113.9, 105.3, 86.8, 85.3, 55.4, 53.0, 36.5, 28.4, 27.9 . Determination of the ee: 10 mg of 4 124 was heated in 1.1 ml of DMF/aniline (10:1) at 100 °C for 1 hour, cooled to room temperature, the reaction mixture was extracted with Et 2 O and washed three times with 1 M HCl, the organic phase was filtered through a plug of silica gel, eluted with hexane/EtOAc 3:1 to give the pure anilide 4 125 . Enantiomeric excess was determined by HPLC with a Chiralcel OD H column (87:13 n hexane:isopropanol, 0.7 mL/min, 215 nm); minor t r = 22.76 min; major t r = 24.54 min. The absol ute configuration was determined by analogy. 105,131 6.2.6 Palladium Catalyzed Asymmetric Allylic Alkylation D imethyl ( R , E ) 2 (1,3 diphenylallyl)malonate (4 133). Dimethyl malonate 4 127 (4 6 µL , 0. 405 mmol) was added dropwise to another flask containing a suspension of NaH (10 mg, 0.405 mmol) in acetonitrile (0.3 mL) at 0 o C. 15 crown 5 (0.08 mL, 0.405 mmol) was then added and it was cooled to 20 o C. A solution of 1,3 diphenyl 2 propenyl acetate 4 126 ( 34 mg, 0. 135 mmol) and 4 1 (5 mg, 0.00675 mmol) in acetonitrile (0.1 ml) was added via syringe to a flask containing [ PdC l( 3 C 3 H 5 )] 2 (1 mg, 0.0027 mmol) and stirred for 10 minutes at room temperature. The resulting yellow solution was added via syringe to the sodium dimethylmalonate suspension at 20 o C and the mixture was let to stir for 7 hours at this temperature. The reaction mixtur e was poured into water ( 10 ml), extracted into diethyl ether ( 10 ml), then washed with water ( 10 ml) and saturated brine ( 10 ml). The solution was dried over

PAGE 179

179 MgSO 4 , then the solvent removed under reduced pressure. The residue was purified by flash column chromatography (gradient hexanes to 5% EtOAc/hexanes ) to yield the title compound as a clear oil (34 mg, 77%). Enantiomeric excess was determined by HPLC w ith a Chiralcel OJ H column (95 : 5 n hexane:isopropanol, 0.7 mL/min, 2 54 nm); minor t r = 36.81 min; major t r = 30.99 min. The absolute stereochemistry was determined by comparison of the HPLC retention time to these reported in the literature data . 152

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180 LIST OF REFERENCES (1) Kuhn, R. Stereochemie (Ed.: K. Freudenberg), 1933 , 803. (2) http://goldbook.iupac .org/A00511.html (3) Bringmann, G.; Gulder, T.; Gulder, T. A. M.; Breuning, M. Chem. Rev . 2011 , 111, 563. (4) Clayden, J.; Moran, W. J.; Edwards, P. J.; LaPante S. R. Angew. Chem. Int. Ed. 2009 , 48 , 6398. (5) Comprehensive Asymmetric Catalysis, Vol. 1 3 (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer, Berlin, 1999 . (6) Christie, G. H.; Kenner, J. H. J. Chem. Soc. 1922 , 121, 614. (7) Hubbard, B. K.; Walsh, C. T. Angew. Chem., Int. Ed. 2003 , 42 , 730. (8) Xing, L.; Devadas, B.; Devraj, RV.; Selness, S. R.; Shieh, H.; Walker, J. K.; Mao, M.; Messing, D.; Samas, B.; Yang, J. Z.; Anderson, G. D.; Webb, E. G.; Monahan, J. B. ChemMedChem 2012 , 7 , 273. (9) McCarthy, M.; Guiry, P. J. Tetrahedron 2001 , 57 , 3809. (10) Brunel, J. M. Chem. Rev. 2005 , 105 , 857. (11) Chen, Y.; Yekta, S.; Yudin, A. K. Chem. Rev. 2003, 103, 3155. (12) Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23 , 345. (13) Berthod, M.; Mignani, G.; Woodward, G.; Lemaire, M. Chem. Rev. 2005, 105 , 1801. (14) Yoon, T. P.; Jacob sen, E. N. Science 2003 , 299 , 1691. (15) Qi Lin Zhou (Ed.), Privileged Chiral Ligands and Catalysts, Wiley VCH, Weinheim, 2011 . (16) Almenningen, A.; Bastiansen, O.; Fernholt, L.; Cyvin, B. N.; Cyvin, S. J.; Samdal, S. J. Mol. Struct. 1985 , 128 , 59. (17) Cooke, A. S.; Harris, M. M. J. Chem. Soc. 1963 , 2365 (18) Pincock, R.; E.; Perkinsm, R. R.; Ma, A,; S.; Wilson, K. R. Science 1971 , 174 , 1018. (19) Meca, L.; Reha, D.; Havlas, Z. J. Org. Chem. 2003 , 68 , 567 7. (20) Kyba, E. P.; Gokel, G. W.; de Jong, F., Koga, K.; Sousa, L. R.; Siegel, M.G.; Kaplan, L.; Sogah, G. D. Y.; Cram, D. J. J. Org. Chem. 1977 , 42 , 4173.

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188 BIOGRAPHICAL SKETCH Flávio S. P. Cardoso was born in São José dos Campos, São Paulo, Brazil. He was raised in the same city and graduated from high scho ol in the end of 200 4 . Subsequently, he moved to Campinas to begin his studies in chemistry at the State University of Campi nas (UNICAMP). He performed undergraduate research under the supervision of Prof. Carlos Roque Duarte Correia for a period of nearly three years. His research at UNICAMP focused on the palladium catalyzed Heck Matsuda reaction. In the Summer of 2009, upon graduation with a B.S in Chemistry , Flavio started his graduate studies at the University of Florida . U nder the guidance of Prof. Aaron Aponick, his PhD studies involved the development of a new class of atropisomers which was ultimately applied in asymmet ric catalysis.