RANEY NICKEL-ASSISTED SYNTHESISOF HETEROCYCLES
NAVJEETKAUR
DepartmentofChemistryatBanasthaliVidyapith,India
Elsevier
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CONTENTS
Preface vii
Abouttheauthorix
Abbreviationsxi
1Raneynickel-assistednitrogroupreductionforthesynthesisof five-membered N-heterocycles1
1.1 Introduction1
1.2 Nitrogroupreductioninvolvedinthesynthesisofpyrroles2
1.3 Nitrogroupreductioninvolvedinthesynthesisoffusedpyrroles10
1.4 Nitrogroupreductioninvolvedinthesynthesisofindoles14
1.5 Nitrogroupreductioninvolvedinthesynthesisoffusedindoles18
1.6 Nitrogroupreductioninvolvedinthesynthesisofpyrazoles20
1.7 Nitrogroupreductioninvolvedinthesynthesisofimidazolesand benzimidazoles22
1.8 Nitrogroupreductioninvolvedinthesynthesisoftriazoles33 References36
2Raneynickel-assistednitrogroupreductionforthesynthesis of N-, O-,and S-heterocycles43
2.1 Introduction43
2.2 ReductionofNO2 groupforthesynthesisoffive-membered O- and S-heterocycles43
2.3 ReductionofNO2 groupforthesynthesisofsix-membered N-heterocycles45
2.4 ReductionofNO2 groupforthesynthesisofsix-membered N,N-heterocycles55
2.5 ReductionofNO2 groupforthesynthesisofsix-membered N,N,N-heterocycles62
2.6 ReductionofNO2 groupforthesynthesisofsix-membered O-heterocycles62
2.7 ReductionofNO2 groupforthesynthesisofseven-memberedheterocycles66 References74
3Synthesisofheterocyclesfromcyanide,oxime,andazo compoundsusingRaneynickel81
3.1 Introduction81
3.2 Synthesisofheterocyclesfromcyanidecompounds82 v
3.3 Synthesisofheterocyclesfromoximecompounds101
3.4 Synthesisofheterocyclesfromazocompounds107 References111
4Synthesisofheterocyclesfromoxazolesandoxazinesusing Raneynickel119
4.1 Introduction119
4.2 Synthesisoffive-membered N-heterocyclesfromoxazoles120
4.3 Synthesisoffive-membered N-heterocyclesfromoxazines124
4.4 Synthesisoffive-memberedfused N-heterocyclesfromoxazolesand oxazines128
4.5 Synthesisoffive-membered O-heterocyclesfromoxazolesandoxazines141
4.6 Synthesisofsix-memberedheterocyclesfromoxazolesandoxazines142
4.7 Synthesisofhigher-memberedheterocyclesfromoxazolesandoxazines152 References153
5MiscellaneoususeofRaneynickelforthesynthesisofheterocycles159
5.1 Introduction159
5.2 Synthesisoffive-membered N-heterocycles160
5.3 Synthesisoffive-membered N-polyheterocycles161
5.4 Synthesisoffive-memberedfused N-heterocycles162
5.5 Synthesisoffive-membered N,N-heterocycles169
5.6 Synthesisoffive-membered N,N,N-heterocycles170
5.7 Synthesisoffive-membered O-heterocycles171
5.8 Synthesisoffive-membered O,N- and S-heterocycles174
5.9 Synthesisofsix-membered N-heterocycles177
5.10 Synthesisofsix-membered N,N-heterocycles195
5.11 Synthesisofsix-membered O-heterocycles197
5.12 Synthesisofseven-memberedheterocycles200 References202
Conclusion211
Index 213
Preface
Heterocyclicchemistryisaninexhaustiblesourceofnovelcompoundsas anappliedscience.Thecompoundswithmostdiversechemical,physical, andbiologicalpropertiesareprovidedbydesigningawiderangeofcombinationsofcarbon,hydrogen,andheteroatoms.
Heterocyclesareubiquitousinorganicmaterials,pharmaceuticals,variousfunctionalmolecules,andnaturalproducts.The N-, O-,and Sheterocyclesarebeingstudiedforalongtimeduetotheirbiological properties.Theliteratureisenrichedwithadvancedfindingsaboutthe formationandpharmacologicalactivitiesofheterocycles.Therearea numberofheterocyclicnaturalproductssuchasalkaloids,antibiotics,cardiac glycosides,andpesticideshavingalotofimportanceforhumanandanimal health.Therefore,naturalmodelshavebeenfollowedfordesigningand constructingweedkillers,pharmaceuticals,pesticides,rodenticides,and insecticides.
Amongheterocycliccompounds,aromaticheterocycliccompounds representstructuralmotifsfoundinagreatnumberofbiologicallyactive syntheticandnaturalcompounds,agrochemicals,andmedicines.Moreover, aromaticheterocycliccompoundsareextensivelyutilizedfortheformation ofdyesandpolymericmaterialsofgreatimportance.Inorganicsynthesis, thereareseveralreportsontheuseofaromaticheterocycliccompoundsas intermediates.
Althoughawiderangeofhighlyefficientapproacheshavebeendescribedinthepastfortheformationofaromaticheterocycliccompounds andtheirderivatives,thedevelopmentofnewproceduresisincontinuous demand.Particularly,developmentofnovelsyntheticmethodologiestoward heterocycliccompounds,aimingatattainingbetterlevelsofmolecular complexityandimprovedfunctionalgroupcompatibilitiesinaconvergent andatomeconomicalfashionfromeasilyavailablestartingcompounds undermildreactionconditions,isoneofthemajorresearchactivitiesin syntheticorganicchemistry.
Asaresult,theongoinginterestfordevelopingnewefficientand versatilepreparationofheterocycleshasalwaysbeenathreadinthesynthetic area.Inthelastyearsthecreativeideasofmulticomponentprocedures, dominoreactionsandsequentialreactions,wherecomplexandhighly
diversestructuresareproducedinaone-potmanner,havesignificantly stimulatedbothindustryandacademia.
Significantfocushasbeenpaidtonovelapproachesfortheformation ofheterocycliccompounds.Theheterogeneousnickelcatalystisused inasymmetricsynthesis.Withoutdoubt,Ra-Nicatalysthasbeenthe mostutilizedcatalystinthiscontext.Raneynickelhasbeenutilizedfor abroadrangeofreactionssuchasmethanation,hydrogenolysis,steam reforming,hydrogenation,reductiveamination,anddesulfurization,either onanindustrialscaleorinthelaboratory.Inthisbook,Ihavefocusedon theutilizationofRaneynickelforthesynthesisofheterocycliccompounds.
Abouttheauthor
Dr.NavjeetKaur,daughterofSardarSewak SinghandSardarniHarmeshKaur,wasborn inPunjab,India.Afterattainingherschool education,shereceivedherBScfromPanjab UniversityChandigarh(Punjab,India)in2008. In2010,shecompletedherMScinChemistry fromBanasthaliVidyapith.Shewasawarded withPhDin2014bythesameuniversityunder thesupervisionof Prof.D.Kishore.Being ameritoriousstudent,shewonameritscholarshipforhermaster’sanddoctorate’sdegrees. Presently,sheisworkingasanAssistantProfessorinDepartmentof Chemistry,BanasthaliVidyapithandhasenteredintoaspecializedresearch careerfocusedonthesynthesisof1,4-benzodiazepine-basedheterocyclic compounds(OrganicSyntheticandMedicinalChemistry). Dr.Kaur hasguidedmanyMScdissertationstudentsandiscurrentlyguiding5 researchscholarsastheirPhDsupervisor.With11yearsofteaching experience,shehaspublishedover160scientificresearchpapers,review articles,bookchapters,andmonographsinthefieldoforganicsynthesis innationalandinternationalreputedjournals.Shehaspublishedfive authoredbooks:“PalladiumAssistedSynthesisofHeterocycles”and“Metals andNon-metals:Five-Membered N-HeterocycleSynthesis”withCRC Press,Taylor&Francisgroup;“Metal-andNonmetal-AssistedSynthesis ofSix-MemberedHeterocycles”and“RaneyNickel-AssistedSynthesis ofHeterocycles”withElsevier;“Lawesson’sreagentinheterocyclesynthesis”withSpringerNature.Hernamehasfeaturedconsistentlyfour timesinthe WORLDRANKINGOFTOP2%SCIENTISTS in thesubject-wiseanalysesconductedbyateamofscientistsat Stanford University,USA.Shesecuredherplaceamongtop2%scientistsofthe worldin 2017 (singleyearranking), 2018 (fullcareerwiseranking), 2019 [fullcareerwiserankingwith424worldrank(04inIndia)andsingle yearrankingwith03worldrank(01inIndia)],and 2020 (fullcareer wiserankingwith372worldrankandsingleyearrankingwith126 worldrank).Thisstoryofachievingtoprankinginsuchashortspan (5–6years)ofhercareerwascoveredbynumerousnewspapers.Shewas
presentedtheProf.G.L.TelesaraAwardin2011byIndianCouncilof Chemists(Agra,UttarPradesh)atOsmaniaUniversity(Hyderabad),and theBestPaperPresentationAwardinNationalConferenceon“Emerging TrendsinChemicalandPharmaceuticalSciences”(BanasthaliVidyapith, Rajasthan).Shehasbeencitedasthemostproductiveanddistinguished authorofBanasthaliVidyapithin“ScientometricsProfileoftheBanasthali Vidyapith:ADeemedUniversityofRajasthan,India”(2020),Library PhilosophyandPractice(e-journal).In2021,Dr.Kaurwaschosenasa candidateformembershipbyRoyalSocietyofResearch,London,England, UKwithfullwaiverofapplicationfees.SheisservingasanEditor-in-Chief for“AdvancedChemicobiologyResearch”journal.Shehasattendedabout 45conferences,workshops,seminars,andrefreshercourses;usingthese platformsshehasdisseminatedherresearchworkthroughoralandposter presentations.Shehasdeliveredmanyinvitedlecturesandradiotalks.She actedasareviewerformanypapersofdifferentjournals.Shehasserved asamemberoforganizingcommitteeofconferencesconductedbyher departmentandactedasamemberofnationaladvisorycommitteeinInternationalConferenceorganizedbyAkalUniversity,Punjabincollaboration withtheIndianChemicalSociety.Apartfromallthis,shehasbeenworking asNSS(NationalServiceScheme)ProgramOfficersince2016andmember ofUBA(UnnatBharatAbhiyan)since2018. Dr.Navjeet findsinterestin Sikhliteratureandhascompleteda2-yearSikhMissionarycoursefrom SikhMissionaryCollege(Ludhiana,Punjab).
Abbreviations
ADMEabsorption,distribution,metabolism,andexcretion
AIBNazobis-isobutyronitrile
BBDM t-butoxybis(dimethylamino)methane
BINOL1,1’-bi-2-naphthol
Boc t-butoxycarbonyl
BOPbenzotriazol-l-yloxytris(dimethylamino)phosphoniumhexafluorophosphate
CANcericammoniumnitrate
Cbzcarboxybenzyl
CDCcross-dehydrogenativecoupling
CMCcomprehensivemedicinalchemistry
CPAcyclopiazonicacid
CSAcamphorsulfonicacid
DABCO1,4-diazabicyclo[2.2.2]octane
DBN1,5-diazabicyclo[4.3.0]non-5-ene
DBU1,8-diazabicyclo[5.4.0]undec-7-ene
DCC N,N’-dicyclohexylcarbodiimide
DCEdichloroethane
DCMdichloromethane
DCP2,4-dichloropheoxyaceticacid
DDQ2,3-dichloro-5,6-dicyanobenzoquinone
DEADdiethylazodicarboxylate
DEAEdiethylethanolamine
DIADdiisopropylazodicarboxylate
DIBAHdiisobutylaluminiumhydride
DIBALdiisobutylaluminiumhydride
DIBAL-Hdiisobutylaluminiumhydride
DIEA N,N-diisopropylethylamine
DIPEA N,N-diisopropylethylamine
DMAdimethylaniline/dimethylacetamide
DMAEdimethylethanolamine
DMAP4-dimethylaminopyridine
DMEdimethoxyethane
DMFdimethylformamide
DMF-DMAdimethylformamidedimethylacetal
DMPDess-Martinperiodinane/dimethoxypyridine/2,9-dimethyl-1,10phenanthroline
DMSOdimethylsulfoxide
Dppf1,1 -bis(diphenylphosphino)ferrocene
EDAC1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride
EDC1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
GABA γ -aminobutyricacid
HATUhexafluorophosphateazabenzotriazoletetramethyluronium
HMPAhexamethylphosphoramide
Abbreviations
HPLChighperformanceliquidchromatography
5-HT1A5-hydroxytryptamine
IBX o-iodoxybenzoicacid
IPAisopropylalcohol
KHMDSpotassiumhexamethyldisilazide
KMDSpotassiumhexamethyldisilazide
LALewisacid
LDAlithiumdiisopropylamide
LHMDSlithiumhexamethyldisilazide
LiHMDSlithiumhexamethyldisilazide
LPLlipoproteinlipase
MAHTsmalonichalfthioesters
MAPhmethylaluminium-bis(2,6-diphenylphenoxide)
MBO2-methyl-3-buten-2-ol
MOMmethoxymethyl
MVKmethylvinylketone
MWmicrowave
NaHMDSsodiumhexamethyldisilazide
NBS N-bromosuccinimide
NCS N-chlorosuccinimide
NMM N-methylmorpholine
NMO N-methylmorpholine-N-oxide
NMP N-methylpyrrolidinone
NMRnuclearmagneticresonance
NOEnuclearOverhausereffect
OTftrifluoromethanesulfonate
PBDpyrrolobenzodiazepine
PDCpyridiniumdichromate
PEGpoly(ethyleneglycol)
pHTXphilanthotoxin
PIDAphenyliodinediacetate
Pivpivaloyl
PMB p-methoxybenzylamine
PMPpolymethylpentene
PPEpolyphosphoricester
PPTSpyridinium p-tolylsulfonate
PTSA p-toluenesulfonicacid
PZQpraziquantel/pyrazino-isoquinoline
QCSquinoliniumcamphorsulfonate
RCMring-closingmetathesis
SARstructure-activityrelationship
SEM[2-(trimethylsilyl)ethoxy]methyl
SN 2bimolecularnucleophilicsubstitution
TBABtetrabutylammoniumbromide
TBAFtetrabutylammoniumfluoride
TBAItetrabutylammoniumiodide
TBDMS t-butyldimethylsilyl
Abbreviations
TBDPS t-butyldiphenylsilyl
TBS t-butyldimethylsilyl
TBSOTf t-butyldimethylsilyltrifluoromethanesulfonate
TCAtrichloroaceticacid
TCC(cumyl)cyclohexanol
TDSdimethylhexylsilyl
TEAtriethylamine
TEACtetraethylammoniumchloride
TEBACtriethylbenzylammoniumchloride
TEMPO(2,2,6,6-tetramethylpiperidin-1-yl)oxylor(2,2,6,6-tetramethylpiperidin-1yl)oxidanyl
TEStriethylsilyl
TFAtrifluoroaceticacid
TFAAtrifluoroaceticanhydride
THFtetrahydrofuran
THPtetrahydropyran
THSβ Cstetrahydrospiro-beta-carbolines
TIPStriisopropylsilyl
TMEDAtetramethylethylenediamine
TMG1,1,3,3-tetramethylguanidine
TMStrimethylsilyl/tetramethylsilane
TMSCNtrimethylsilylcyanide
TMSItrimethylsilyliodide
TOSMICtoluenesulfonylmethylisocyanide
TPAPtetra-n-propylammoniumperruthenate
TPPtriphenylphosphine/tetraphenylporphyrin
Raneynickel-assistednitro groupreductionforthe synthesisoffive-membered
N-heterocycles
1.1Introduction
The N-containingheterocycliccompoundshaveattractedattentioninthe pastfewdecadesduetotheirhightherapeuticvalues [1].Whethertheyare syntheticornaturalone,theyareelaboratedasimportantconstituentsinbiologicalproceduresduetotheirremarkablebiologicalfeatures [2].Various N-containingheterocycliccompoundsparticularly,inplantkingdomhave madeindeliblemarkasphytochemicalmedicinesliketheophylline,quinine, emetine,procaine,ellipticine,codeine,morphine,andpapaverine [3] Besides,themassivedistributionof N-containingheterocycliccompounds innaturalproducts,theyalsoplayakeyroleinthebiochemicalprocedures inlivingcells.Mostoftheenzymeshavearomaticheterocycliccompounds asmainelementswhilemostofthecoenzymeshavingnonaminoacids functionalitiesarearomatic N-containingheterocycliccompoundsand someimportantvitaminsareformedonaromaticheterocyclicframework [4–6].Additionally, N-containingheterocycliccompoundshavebeenoften foundasanimportantstructuralunitinsyntheticmedicineslikeantipyrine, chlorpromazine,metronidazole,captopril,chloroquinine,barbituricacid, isoniazid,azidothymidine,anddiazepam.Significantfocushasbeenpaid tonovelapproachesfortheformationof N-containingheterocycliccompounds,whicharenaturalbiologicallyactiveorganiccompoundsorpharmacophoricfragments [7–9].
Theirsynthesisneedsanincorporationof N-containingfunctionality viaC–CandC–Nbondformationprocesses.TheNO2 compounds actasimportantbuildingblocksintheformationofnitrogen-containing heterocycliccompoundsbecauseoftheirhighchemicalreactivity [10].
Theheterogeneousnickelcatalystisusedinanasymmetricsynthesis. Heterogeneouscatalyticreactions,ascomparedtotheirhomogeneous
RaneyNickel-AssistedSynthesisofHeterocycles.
Copyright c 2022ElsevierInc.
DOI: https://doi.org/10.1016/B978-0-323-99492-7.00001-9 Allrightsreserved. 1
equivalents,havesomespecificpropertiesbecausetheyproceedonasolid surface [11].
1.2Nitrogroupreductioninvolvedinthesynthesisof pyrroles
Differentreactionconditionswereappliedinanefforttoachieve thisreactionstartingwith10%Pd/Cunderhydrogenatmospherein CH3 COOC2 H5 ,whichgiverisetonoreaction.Theconditionswere modifiedtosomeextentbychangingthereactionsolventto1Mhydrochloricacidandtheresultsforthereactionwereinconclusiveinthis case.Then,NaBH4 wasincorporatedintoreactionwith10%Pd/Cin tetrahydrofuranbutonlystartingcompoundwasfound.Theunreacted compoundfromthisreactionwasthenrecycledandreactedwithRaneyNiinEtOH/tetrahydrofuransolutionundernitrogenatmosphere,which wasinconclusiveagain(Scheme1.1).However,itwasdecidedthatthe Raney-Nimaynothavebeenveryactive,therefore;thereactionwascarried outinMeOHunderhydrogenatmosphere.Simultaneousintramolecular aminolysisofacetalundertheseconditionsprovided γ -lactamsviacyclizationofamine,whichledtoeliminationofpivalaldehyde(Scheme1.2) [12]
Scheme1.1
Nocarbamate-protectedanalogueshadbeendescribedintheliterature [13].The N-Boc-piperidone(commerciallyaccessibleonbulkscale) wastransformedtoitsoximeandfurtheroxidizedwithtrifluoroacetic anhydride/hydrogenperoxide [14] toaffordthe4-nitropiperidinein55% yield.Undermildconditions,thenitroesterintermediatewasprepared byaMichaeladditionofnitropiperidinetomethylacrylate.Theamino intermediate,obtainedbythereductionofNO2 groupbycatalytichydrogenationoverRaney-Ni,wascyclizedtospirolactam.Theformation ofnitroesterwasmoredifficult,requiredtetra-n-butylammoniumfluoride asabaseandincreasedreactiontimeinrefluxingtetrahydrofuran.Both spirolactams(Scheme1.3)wereformedingoodoverallyield(morethan 80%overthreesteps) [15]
InnovativeeffortwasdescribedbyLietal. [16] inwhichtheadduct wastransformedtosyntheticallybeneficialchiral 1 -pyrrolidinebyaneasy hydrogenationreaction(Scheme1.4).
Developinganefficientandselectivecatalyticprocedurewasthebest solutionwhenasymmetryarosefromprochiralstartingcompounds.The synthesisofendothelin-AantagonistABT-546wasanexcellentinstance [17,18].AlthoughracemicpyrrolidinecoreofABT-546wasconstructed bydevelopingasyntheticpathway(Scheme1.5),itneededsubsequent resolutionwithD-tartaricacid.Thisprocedurestillneededmanyrecrystallizationsandtheresolvedtartratesaltwasformedinonly40%oftheory. Thisinspiredasearchforanasymmetricsynthesisofpyrrolidinecoreto affordthesufficientmaterialtosupportupcomingscientifictrials [19]
Scheme1.2
Scheme1.3
Scheme1.4
Scheme1.5
Easilyenolizablecompoundslike β -ketoesterswerereactedwithnitroalkenesusingNMM(N-methylmorpholine)andcatalyticamountsof chiralbis-oxazoline-magnesiumtriflatecompoundascocatalyst(Scheme 1.6) [17].The β -Hresiduepresentinadductwastooacidictoallow configurationalstabilityatthecorrespondingcarbon,ontheotherhand,the selectivitywasgoodattheotherstereocenter.Thisprocesswasamenable toscalingupto13molesandwasusedfortheformationofendothelinA antagonistABT-546,(R)-rolipram,andphosphodiesterase-type4IC86518 [18,19].Thefinalcompoundwassynthesizedbyreactinganappropriate βketoesterwithnitroalkenetogivethedesiredadductswith88%selectivity. ThereductionofNO2 groupfurtherprovidedpyrrolinealongwithparent
Scheme1.6
Scheme1.7
nitroneinsmalleramounts.Thestereoselectivereductionofthismixture wasbesteffectedwithNaBH(OAc)3 underacidicconditions,providinga pyrrolidinesystemwhichwastransformedtoABT-546byeasysynthetic operations.
Thereductivecyclizationofsubstrates,preparedbyconjugateaddition of2-nitropropaneto α ,β -unsaturatedketones,providedpyrrolidineswhich weretransformedto2H-pyrrolesbydehydrogenationwithDDQ(2,3dichloro-5,6-dicyano-1,4-benzoquinone)(Scheme1.7)[20,21].
Thefirstdeliberatelyusednitro-Mannichreactionwaspublished,when Tsuritanietal. [22] describedtheformationofastrong κ -opioidagonist, i.e.,ICI-199441 [23].Thesynthesisstartedwithnitro-Mannichreaction of N-phosphinoylimineandCH3 NO2 inthepresenceofheterobimetallic catalyst.ThepyrrolidinewassynthesizeduponhydrogenationoverRaneyNifollowedbyanintramolecular.Then,acidicdeprotectionofphosphinoyl group,reductivemethylation,andacylationdeliveredICI-199441in35% overallyieldandonlysixsteps(Scheme1.8).
Thediastereoselectivitywasnotimprovedbyadding20mol%(S)proline [24] orthechiralamineorganocatalystsdevelopedbyMacMillan etal.[25,26].Therefore,thispathwaywasnotfurtherpursued,although disubstitutednitroalkanesaffordedhighlyfunctionalizedpyrrolidinebuildingblocksafterhydrogenationanddeprotection(Scheme1.9).
TheuseofenantioselectivedecarboxylativereactionofMAHTs(malonichalfthioesters)fortheformationoftherapeutictargetswasexemplified bythesynthesisofGABAreceptorantagonistsutilizingorganocatalysts (Scheme1.10).The γ -nitrothioesterseasilyaccessibleviatheseorganocatalyticmethodologiesoccurringundermildconditionsandtoleratingboth airandmoistureareversatilebuildingblocksforadditionalmodifications. Amongthemthesynthesisof γ -butyrolactamsbythereductionofNO2 groupfollowedbyanintramolecularcyclizationledtointermediatesforthe synthesisofantidepressant(R)-rolipram [27] andtogramscaleformation andtransformationto(S)-baclofen HCl,aGABAreceptorantagonist utilizedtocurespasticity[28,29].
Scheme1.8
Scheme1.9
Analternativemetal-catalyzedsystem [18] wherethepotentialforscaleupwasclearisdepictedin Scheme1.11 andseemedtobehighlycompetitive withanorganocatalyzedmethod.ThechiralLewisacid-catalyzedMichael additionofdiethylmalonatetonitrostyreneprovidednitroester,whichon reductionandsaponificationledtodesiredrolipram.Bothenantiomersof rolipramwereobtainedintotalsixstepsandat10gscalewithexcellent overallyields(76%)andwithoutchromatography [29].
Theazabornaneskeletonispresentinanumberofcompounds,i.e., Pantagonistsandacommonapproachforitsformationincludedan intramolecularring-closureofappropriatederivativesofpyrrolidine.Tandemdoubleconjugateadditionsof4-benzylaminoenoatewithnitroalkenes afforded3-nitropyrrolidines,featuringa3,4-cis-relationship(Scheme1.12)
Scheme1.10 [30].The3,4-trans-isomerswerepreparedsmoothlybyequilibrationof 4-benzylaminoenoateunderbasicconditions.Thereductionofesterand NO2 groupsviareactionwithdifferentreagentsprovidedaminoalcohols, whichweresubsequentlyprotectedwith N-Boc.TheconcurrentnucleophilicdisplacementsoccurredonthemesylationofOHgroupstoproduce theNH4 + saltsofazabornanesystems,whichgavefreeaminoderivatives byhydrogenolyticdebenzylation.
Scheme1.11
Scheme1.12
1.3Nitrogroupreductioninvolvedinthesynthesisoffused pyrroles
TheCH3 NO2 afforded meso-diphenylpyrrolizidineinthreesteps(Scheme 1.13).TheCH3 NO2 wasreactedwithsodiumhydroxide,andtheformed anionwasutilizedtodisplacethechloridefrom3-chloro-1-phenylpropan1-onetoprovidethenitroketonein90%yield.Two-directionalformation ofdiketoneinthismannernotprovedtobefeasible;however,itwas obtainedingoodyieldbyMichaeladditionofnitroketoneanionto phenylvinylketone.ExposingdiketonetohydrogengasandRaney-Ni furtherreducedtheNO2 groupandaffectedthedoublereductiveamination toprovidethe meso-diphenylpyrrolizidinein30%yield.Itisprobablethat thescopeofthissequencecanbeextendedtoincludequinolizidineand indolizidineframeworks,andthereforeofferedanalternativepathwayto thesescaffolds,insteadofthedoubleMichaeladditionapproach [31].
TheselectionofLewisacidpromoterforthesereactionschanged thesenseofasymmetricinduction [32–36].Forinstance,tandem [3+2]/[4+2]-cycloadditions(Scheme1.14)assistedbyTi(Oi-Pr)2 Cl2 ,followedbyhydrogenolysisprovidedtricyclic(-)-α -hydroxylactamwith 98%enantiomericexcessanduseofMAPh(methylaluminium-bis-2,6diphenylphenoxide)inthesimilarreactionprovided(+)-α -hydroxylactam with93%enantiomericexcess.Thechiralauxiliarydidnotaffectthe selectivity.Rather,itwasduetoahighly endo-selectivecycloadditionin thecaseoftitaniumascomparedtohigh exo-selectivityinthecaseof methylaluminium-bis-2,6-diphenylphenoxide [5]
Scheme1.13
Scheme1.14
The α -hydroxylactamswereobtainedinnonracemicformbytandem cycloadditionwithchiralvinylandpropenylethers(Scheme1.15)[5, 37,38]. Inthisprocedure,astandardsetofreactionsconditionswasutilized,exposureofasolutionofdienophileandnitroalkenetoTiCl2 (Oi-Pr)2 at-78°C, togivethenitronateintermediate.Thethermalcycloadditionoccurred overtheperiodof2–3hatrt.Theformednitrosoacetalswereimmediately subjectedtohydrogenolysiswithRaney-NiinCH3 OHtogivethelactams in76%and89%yield(threesteps)withhighenantioselectivity(96:4enantiomericratio) [39].Theepimeric α -hydroxylactamwaseasilyobtainedin 63%yieldfollowingthestandardprocedure(96:4enantiomericratio).
The7,8-dihydro-5(6H)-quinolonewasusedasastartingpointfor theformationofnicotine.Animportantcharacteristicwastheuseof nitroethylene,asynthonforconstructingpyrrolidineringofnicotine,as shownin Scheme1.16.Thereactionof7,8-dihydro-5(6H)-quinolonewith LDA(lithiumdi-i-propylamide)intetrahydrofuranat-70°Cfollowedby additionofnitromethyleneaffordednitroketonein63%yield.Nodinitro side-productwasformed.ThereductionofnitroketonewithH2 (50psi) andRaney-NiinC2 H5 OHdirectlydeliveredbridgedmyosminein76% yield,apparentlyincludinganintermediateaminoketonewhichunderwent anintramolecularSchiffbasecyclization.ThereductionofbridgedmyosminewithNaCNBH3 inCH3 OHproceededeasilytogivethebridged nornicotinein53%yield.Theprotonnuclearmagneticresonancestudy ofbridgednornicotine(at80and500MHz)showedthepresenceofonly oneofthetwopossiblering-junctureepimers.Thereductivemethylation
