ORGANICREACTION MECHANISMS ⋅ 2016
Anannualsurveycoveringtheliterature datedJanuarytoDecember2016
UniversityofUlster NorthernIreland
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Contributors
K.K.BANERJI
C.T.BEDFORD
M.L.BIRSA
J.M.COXON
M.R.CRAMPTON
N.DENNIS
D.A.KLUMPP
P.KO ˇ COVSK ´ Y
M.G.MOLONEY
B.A.MURRAY
K.C.WESTAWAY
DepartmentofChemistry,J.N.V.University, Jodhpur,India
DepartmentofChemistry,UniversityCollege London,London,UK
FacultyofChemistry,‘Al.I.Cuza’UniversityofIasi, Iasi,Romania
DepartmentofChemistry,UniversityofCanterbury, Christchurch,NewZealand
DepartmentofChemistry,UniversityofDurham, Durham,UK
3CamphorLaurelCourt,Stretton,Queensland, Australia
DepartmentofChemistry,NorthernIllinois University,DeKalb,IL,USA
DepartmentofOrganicChemistry,Charles University,CzechRepublicandDepartmentof OrganicChemistry,StockholmUniversity,Sweden
ChemistryResearchLaboratory,Departmentof Chemistry,UniversityofOxford,Oxford,UK
DepartmentofScience,TechnologicalUniversityof Dublin(TUDublin),Dublin,Ireland
DepartmentofChemistryandBiochemistry, LaurentianUniversity,Sudbury,Ontario,Canada
Preface
Thepresentvolume,the52ndintheseries,surveysresearchonorganicreaction mechanismsdescribedintheavailableliteraturedated2016.Inordertolimitthesize ofthevolume,itisnecessarytoexcludeorrestrictoverlapwithotherpublications whichreviewspecialistareas(e.g.photochemicalreactions,biosynthesis,enzymology, electrochemistry,organometallicchemistry,surfacechemistry,andheterogeneous catalysis).Inordertominimizeduplication,whileensuringacomprehensivecoverage, theeditorconductsasurveyofallrelevantliteratureandallocatespublicationsto appropriatechapters.Whileaparticularreferencemaybeallocatedtomorethanone chapter,itisassumedthatreaderswillbeawareofthealternativechapterstowhicha borderlinetopicofinterestmayhavebeenpreferentiallyassigned.
AllthechaptershavebeenwrittenbythemembersofateamofexperiencedORM contributorswhohavesubmittedauthoritativereviewsovermanyyears.Wearenaturallypleasedtobenefitfromsuchcommitmentandconsequentawarenessofdeveloping trendsinthetitlearea.Particularlynoteworthyinrecentyearshasbeenamajorimpact ondirectedorganicsynthesisthroughmechanisticstudieswhichenableoptimizationof liganddesignforhighlyselectivetransitionmetalcatalysts.
Inviewoftheconsiderableinterestintheapplicationofstereoselectivereactionsto organicsynthesis,wenowprovideindication,inthemargin,ofreactionswhichoccur withsignificantdiastereomericorenantiomericexcess(de or ee).
Althougheveryeffortwasmadetoreducethedelaybetweenthetitleyearandthepublicationdate,circumstancesbeyondtheeditor’scontrolagainresultedinthelatearrival ofasubstantialchapterwhichmadeitimpossibletoregainouroptimumproduction schedule.
Stepshavebeentakentoreducetheknock-oneffectofthisoccurrence.
IwishtothankthestaffofJohnWiley&Sonsandourexpertcontributorsfortheir effortstoensurethatthereviewstandardsofthisseriesaresustained.
FormationandReactionsofAcetalsandRelatedSpecies
�� ,�� -Unsaturatedaldehydes(e.g. 1)undergo endo-selectivePrinsbicyclizationwith aldehydestogivedioxabicyclo[2.2.2]octanes(2)inhigh de and ee. Glyoxylicesters workwell(i.e.R = COCO2 Et),withinductionbyachiralBINOL-derived N-triflylphosphoramideatambienttemperature.1 (1)(2)
) (S) (S)
(
Organocatalyticenantioselectiveroutestotwoclassesofcyclicacetalshavebeen described.Chiral5,5-fusedtetrahydrofurobenzofurans(bearingtwostereocentres) and5,6-bridgedmethanobenzodioxepines(bearingthree)havebeenpreparedfrom hydroxyarenesand �� -keto-enals.UsingdiphenylprolinolTMSetherascatalyst,very lowloadingsarerequiredfortheseveryefficientiminiumcatalyses.Thepathwayshave beenprobedusingDFT.2 ee
Treatmentof �� -diazo-�� -ketoesters(3)withcyclicketones,lactones,orcarbonates (4;X,Y = CH2 ,O n = 0–3)yieldsspiroketals,orthoesters,ororthocarbonates(5). Thekeyfirststepofdiazodecompositionrequiresacatalystcombinationof1,10phenanthrolineandarutheniumsalt,[CpRu(MeCN)3 ]+ [BAr4 ] ,whereAr = 3,5bis(trifluoromethyl)phenyl.3
Spiroacetalizationoftwoenolethers(6; n = 1or2)hasbeenthesubjectofaQM/ MMstudywhichcomparestwocatalysts:achiralphosphoricacidandachiralimidodiphosphoricacidwithamuchmoreconfined‘activesite’.Forthefirstcatalyst(a BINAP–phosphoricacidwithbuttressinganthracenes),the ee isonly1%fortheformationofthe5,5-spiro-system(7; n = 1):thesubstrateissmall,fitsinside,andinductionis negligible.Inthesecondcatalyst,the ee goesupto92%,reflectingaconfinementeffect. The6,6-reaction(7; n = 2)showsaslightlyhigher ee of95%forthesecondcatalyst.4 ee
Vinylpropynylacetals(8)canberearrangedtoyieldcatecholethers(9)usinggold(I) in1,2-dichloroethane(DCE)at25 ∘ C.Alkyneactivationtriggersnucleophilicaddition ofacetaloxygen,settingupanequilibriummixtureofoxoniumionsofsimilarstability. Thesecanbeconsideredas‘kineticallyself-sorted’bythenextstep:highlyexothermic cyclization.Computationssupportthisview,asthebarriersbetweentheoxoniumions arelow,sothesystemcanbeconsideredasanexampleofdynamiccovalentchemistry (DCC),wherethefastequilibrationactslikean‘error-checking’process.Thealkene ‘linker’inthesubstratecanbereplacedbyanaromatic(orheteroaromatic),resultingin naphthylanalogues,etc.Synthesesofthesubstrateacetals(8)arealsodescribed.5
(8)(9)(10)
Enantiomericacetals(10)showasurprisingdifferenceunderreductivecleavageby diisobutylaluminiumhydride.The �� -acetal(PMPbehind)isconvertedtoaPMBether, whilethe �� -acetalisresistant[butcanbeopenedwithNa(CN)BH3 /TMS–Cl].6
Substitutedbenzothiopheneshavebeenpreparedfromsubstitutedthiophenoxyacetaldehydediethylacetals,X–C6 H4 –S–CH2 –CH(OEt)2 ,inthepresenceofpolyphosphoricacid.Themechanismshavebeenprobedbywayofkineticandcomputational studies.7
Prolinecatalysesreactionofdihydroxyacetoneisopropylideneacetal(11)withenantiopure �� -silyloxyaldehyde(12)togiveasingleisomer(13)cross-aldolproductin 91%yieldinasubstantiallyaqueousmediumatambienttemperature.Thisresulthas nowbeeninvestigatedbyNMRspectroscopy,monitoringindividualsteps,allowing theroleofwatertobebetterunderstood.Itisfoundthatproline‘protects’aldehyde (12)asanoxazolidinone,butthismeansthatthecatalystiseffectively‘trapped’by aldehyde(12) … ,butthehighwatercontenthelpsavoidthis.Wateralsomediates prolylgroupexchanges,andopposesdehydrationofthealdol.NMRalsoalloweddetectionofa‘wanted’intermediate,anenamineoftheadduct(14).Theauthorscounttwo unfavourableeffectsofwatercountervailedbyfourfavourableones.8 de BINOL-basedtrifluoromethylarylketones(15;R = HorCH2 OMe)actasfluorescencesensorsfor1,2-diaminesinorganicsolvents,withadramaticincreaseat375nm andadecreaseat500nm.Littleeffectisseenwithotherdiamines(ormonoamines),so
(12)
(11)
(16)
(13)
diketones(15)canactashighlyselectiveratiometricsensorsfor1,2-diamines,especially ethylenediamine.UVandNMRstudiessuggestformationofahemiaminal(16)atthe electron-deficientcarbonyl,withstabilizationbyhydrogenbondingfromthesecond nitrogen.Suchanon-covalentinteractionisabsentforamonoamine,andwouldbe poorlyoptimizedforalongerdiamine.Jobplotsforthefluorescenceinteractionsuggest anunexpected1:4stoichiometry(ratherthan1:2),indicatingthatthephenolicoxygens canalsohydrogen-bond1,2-diamines.9 (15)
(E -18)(Z-18) (19) (17)
Alkynylhemiaminals(17)canbepreparedfrompropargylaldehydes,oroxidatively frompropargylalcohols.TheMeyer–Schusterreactionwasthenstudiedforstereoselectivesynthesisof �� -enaminones(18).CatalysedbyBrønstedacids,theselectivityof thisrearrangementhasnowbeenfoundtobeverysimplytuneable:benzoicacidgives (Z-18),whiletosicacidgives(E-18).Thekeystepistheprotonationoftheallenolintermediate(19).Themechanismissupportedby 18 O-labellingexperiments.10 de 2-Substituted2H-chromenes(20)havebeenpreparedviaaniline-catalysednucleophilicattackon ortho-hydroxycinnamaldehydes,via N,O-acetals.Thecyclization–substitutioncascadeaccommodatesabroadrangeofnucleophilesincludingindoles, pyrroles,phenols,andsilylenolethers.11
Enantioselectiveaminomethylationof �� ,�� -unsaturatedaldehydes,R–CH=CHCHO, byan N,O-acetal,Bn2 N–CH2 –OMe,togivea �� 2 -aminoester,R–CH2 –*CH(CH2 NBn2 ) –CO2 Me,hasbeenreportedtooccurunderNHC/Brønstedaciddualcatalysis,buta theoreticalinvestigationhassurprisinglyuncoveredaspecificrolefortheBrønstedbase, refiningthemechanismtoanNHC/Brønstedacid/Brønstedbasemulti-catalysis.12 ee
Forareactivityscalefor N,O-acetals,seethe‘�� -Aminations’section.
Abifunctionaltertiary-amidesquaramidecatalystallowshighlyenantioselectiveadditionofmethylthioglycolate(HS–CH2 CO2 Me)to N-Bocaldimines,givingarangeof chiral N,S-acetals.13 ee
3,4,5-Trimethoxybenzaldehydeundergoesreversibledithioacetalformation(21)with 2-phenylethanethiolundermildacidicconditions.SubsequentexchangewithotherthiolsanddisulfidessuggeststhatthemethodologymaybeusefulinDCC.14
Multi-substitutedfurans(22)havebeenpreparedfrom �� -chlorovinyldithianes(23), usingacyclizationwitharomaticaldehydesundermildmetal-freeconditions.Thetactic involvesthedithianeinducingacycloaddition–aromatizationsequence.Thestrong basedehydrochlorinates(23),givinganallenyldithianedonor(separatelyisolable), which–onreactionwithaldehyde–yieldsaspirodihydrofuran(24).Protonationthen drivesaromatization.Thedisulfideside-chainoftheproduct(22)iseasilyremoved,if desired,usingRaneynickel/ethanolreflux.15
(22)(24) (23)
ReactionsofGlucosides
Transition-metalcatalysisofglycosylationisthesubjectofacomprehensivereview(196 references),includingrecentadvancesinstereoselectivesynthesesof O-,N-,C-, and Sglycosides.16 Theuseofasulfoxideasaglycosyldonoris30yearsold,andtheirinitial de useasanomericleavinggroupshasexpandedintootherrolesinglycosylations.Areview examinesthemechanisticaspects(55references).17 Chemicalderivatizationofsulfated de glycosaminoglycanshasbeenreviewed(220references).18
Theoriginof �� -(1,2-cis)selectivityingalactosylandgalactosaminyldonorswitha di-tert-butylsilylene(DTBS)grouphasbeenprobedbyexperimentandcomputation. Themajorfactorsfoundwere(i)generationofanoxocarbeniumionandthrough-space stabilizationthereofbyelectrondonationfromO(4)andO(6),(ii)a4,6-O-silylene structure,and(iii)sterichindrancebybulkysubstituents.19 de Glycosylmethanesulfonatesundergoregio-andstereo-selectivecouplingswithpartiallyprotectedpyranosideandfuranosideacceptors.Inanotableexample,asomewhat �� -selectiveprocess(2:1)isswitchedtobeing �� -selective(10:1)inthepresenceofa rigidbiarylborinicacid(25).ReactionprogresskineticanalysisandEXSY(exchange spectroscopy)NMRhavebeenusedtoprobeuncatalysedandcatalysedmechanisms.20 de
(25)(26)
Anomericsulfoniumionscanactasglycosyldonorsforstereoselectiveinstallationof 1,2-cis glycosides,buttheirmechanismisnotwellcharacterized.Derivatization,NMR kinetics,andcomputationhaveexaminednon-sulfuranaloguestohelppindowntherole ofsulfur.Itappearsthatasulfoniumionisformedasa trans-decalinringsystemthatcan undergoglycosylationthroughabimolecularmechanism,withthesulfoniumionformingahydrogen-bondedcomplexwiththeacceptorthatundergoes SN 2-likeglycosylation togive �� -anomericproduct.21 de
Apopularureaorganocatalyst, N,N’-bis[3,5-bis(trifluoromethyl)phenyl]urea,hasbeen employedinstereoselectiveKoenigs–Knorrglycosylations,avoidingmethodsinvolving heavymetals.Fordealingwiththelow �� -selectivityfoundwithperbenzylateddonors, additionoftris(2,4,6-trimethoxyphenyl)phosphine(TTMPP)greatlyimprovedresults. Theeffectofbothadditiveshasbeenascribedinparttohydrogen-bondingeffects,supportedby 1 HNMRstudies.22
Nucleophile-directedstereocontroloverglycosylationshasbeendevelopedusing geminallydifluorinatednucleophilessuchasHO–CH2 –CF2 –CH2 –NBnCbz.The twofluorineslowertheoxygennucleophilicityandreversethestereoselectivityto preferentiallyform cis-glycosides.23 de 1-O-Acetylfuranosesandpyranose1,2-orthoestersactasexcellentglycosyldonors whenactivatedbyagold(III)/phenylacetylenerelay,withapreferencefor1,2-transglycosideproducts.24 de Iodoniumions,generatedfrom N-iodosuccinimideandtriflicacid,promoteglycosylationofdisarmedglycosylbromide,avoidingtheneedforheavy-metalsalts.25
Anewstereoselectivesynthesisof �� -mannopyranosidesemploysanomericOalkylationofmannopyranoside-derivedlactols,exploitingakineticanomericeffectand chelationbycaesium.26
RadicamineAandBareazasugars,andtheirfluorinatedderivativeshavebeen preparedfromad-arabinose-derivedcyclicnitrone.Theirabilitytoinhibitglycosidases hasbeentested.27
Stereoselectivityofchiralphosphoricacid-catalysedspiroketalizationofdeuteriumlabelledcyclicenolethers(e.g. 26 → 27)hasbeenprobedbyexperimentand computation.Long-livedoxocarbeniumintermediateswereruledout,andHammett analysisofthekineticsrevealedaccumulationofpositivechargeatthetransition state.Secondarykineticisotopeeffects(KIEs)arereported.Computations,including moleculardynamicsimulations,suggestanasynchronousconcertedroutewithaTS lifetimeofabout500fs.28
Reactiveboronspeciesareusefulinsensingapplicationsofd-fructose.Akinetic studyexaminedphenylboronicacidandits2-methyland2-isopropylderivatives,plus 1-hydroxy-3H-2,1-benzoxaborole.Bothboronicacidsandboronateionswerereactive towardsd-fructose,thelattermoreso.29
OxidativeNHCcatalysishasbeenusedforregio-andchemo-selectivefunctionalizationofcarbohydrates.30
Thevaluablefeedstock,furfural(furan-2-carboxaldehyde),canbegeneratedfrom xyloseunderhydrothermalconditions.ADFTstudyidentifiesxyluloseasalikely intermediate,withwaterloweringtheTSbarrierby12.8kJmol 1 comparedtothe gasphase.Explicitparticipationofawatermoleculeresultsinthereplacementof four-memberedtransitionstatesforseveralstepswithless-strainedsix-membered ones.31
DFThasbeenusedtostudytheiridium-catalysedchemoselectiveC(1)–Oreduction ofglucosewithsilene.32
ReactionsofKetenesandRelatedCumulenes
Thefirstketene N,S-acetalwasreportedin1956,andtheirchemistryisthesubjectofa comprehensivereview(234references).33
Severalcandidatesforprebioticinterstellarchemistryhavebeenexamined.Ketenimineandmethyleneimine,identifiedininterstellarspace,havebeenproposedas precursorsofprebioticspecies.Second-orderMoller–Plessetperturbationtheory (MP2)hasbeenemployedtoinvestigatetheirreactivity,withpericyclicreactionsgiving risetofive-memberedcycliccarbeneintermediates,leading–throughsubsequent hydrogentransfers–topyrazolesandimidazoles.34 Insimilarstudies,thecycloadditionofketeniminewithvariousunsaturatedcompoundsshowsthatfive-membered cycliccarbenesappearachievablewithacetonitrile,leadingto3-methylpyrazole and2-methylimidazole,35 whilereactionwithhydrogencyanidecangivepyrazoleand imidazoleviasimilarprocesses,36 andreactionwithethyneorethenegivespyrrolesor pyrrolines,respectively.37
O-Silylcyanohydrins(28)canbeconvertedtosilyloxy-N-silylketenimines(29) insitu, buttheseinturnconvertto �� -ketoamides(30)onbriefexposuretoair.A3-imino-1,2dioxetane(31),formedspontaneouslybytripletoxygen,ispostulatedtoexplainthe facileoxidationof(29).ThecasesreportedinvolveRbeinganarylorvinylsubstituent.38
(28)(29)
31)
30)
OrganicReactionMechanisms2016 (32)
�� -Additionofaldehydes(e.g.Pr–CHO)acrossallenamides,H2 C=C=CH–N(R)Ts, givesaldehyde–enaminederivatives(32).39 Catalysisisbygold(I)andadiarylprolinol silylether:theformeractivatestheallenamide,andthelatterthealdehyde.Suchcatalysts alsorenderthereactionenantioselective.40
FormationandReactionsofNitrogenDerivatives
Imines:Synthesis,andGeneralandIminiumChemistry
A‘new’synthesisof N-sulfonylarylaldimines,Ar–CH=N–SO2 R,hasbeenreported41a … ithaving‘failed’in1960.41b Simplyheatinganarylaldehydewithasulfinylisocyanate,RO2 S–N=C=O(neat,orinasolvent),givesthesulfinylimine,withlossofCO2 drivingtheprocess.Neithercatalystnoradditiveisrequired.Fortheexampleof paratolualdehydeandtosylisocyanate,refluxinginDCEat90 ∘ Cfor40mindelivers93% yield(afterrecrystallization).2 + 2-Cycloadditionviaacycliccarbonate-typeintermediate(33)isdiscussed.41a
Thekineticsofcondensationof4-methoxybenzaldehydewith2-aminobenzamide havebeenmeasuredusingformicacidasbothcatalystandsolvent.42
Benzimidazoles(34;X = NH)areeasilypreparedbycondensationof ortho-phenylenediaminewitharylaldehydesusingTiCl3 OTfinethanolatambienttemperature.Similarly, ortho-aminophenolyieldsbenzoxazoles(34;X = O).43
Adehydrogenativecross-couplingstrategyconverts1,2,3,4-tetrahydroquinolines (35)into3-benzylquinolines(36),usinganaldehyde,asimplerutheniumcatalyst, andoxygen.Thetransformationisequivalentto �� -benzylationofquinolines.Control experimentshelpedestablishthemechanism:radicalswereruledoutasscavengers
hadnoeffect,andquinolinewouldnotreactwithbenzaldehydes(orbenzylalcohols). Critically,enamine(37) would,identifyingitasanintermediate,andshowingthat reactionwithbenzaldehydeprecedestheseconddehydrogenationofthering.44
[RuCl2(p-cymene)]2
O2/120 °C
36) (35)
37)
Trifluoromethylketimines,R–C(CF3 )=N–CH2 –Ar,havebeenenantioselectivelyisomerizedviasymmetricprotontransfer,usingachiralcinchoniumbetainecatalyst.The tautomericproducts,R–CH(CF3 )–N=CHAr,affordaccesstoopticallyactivetrifluoromethylatedamines,45 withtheoverallprocessmimickingtransamination. ee 2-Methoxyimidoyl-oxiranes(38)havebeenprepareddiastereoselectivelybytrapping �� -phosphonyloxyenolateswithaldehydes(Ar2 –CHO).Dimethylphosphiteinitiates couplingofan �� -keto N-tert-butylsulfinylimidate,Ar1 –CO–C(OMe)=NS(O)–But , initiatingacascadesequence.A[1,2]-phospha-Brookrearrangementfollows,togive the �� -phosphonyloxyenolate.ThisDarzens-typeprocessforpreparingepoxidesvia �� -phosphonyloxyenolatesandaldehydescanbeviewedastheoxygenanalogueofthe correspondingreactionwithaldiminestogiveaziridines.46 de
(39) (38)
Novelchiralpyridoxaminescatalyseenantioselectivetransamination.Thebiometric processconverts �� -ketoacids(R1 –CO–CO2 H)to �� -aminoacidsinupto87% ee,using amino-diphenylaceticacid[2,2-diphenylglycine,Ph2 C(NH2 )CO2 H]asaminedonor, drivenbylossofCO2 ,withbenzophenoneastheotherby-product,inaqueousmethanol atambienttemperature.Thepyridoxaminecatalystisproposedtocondensewiththe �� -ketoacidtogiveaketiminewhichundergoesasymmetric1,3-protontransfertautomerizationtoanaldimine.Hydrolysisthengivesthe �� -aminoacid,withapyridoxal asby-product.Theprotontransfermayinvolveapyridinium-stabilizedazaallylanion (39).47 ee
Copper(I)couplingofaketone,R1 –CO–CH2 –CH2 –(CH2 )n –Cl(n = 1,2),aprimary amine,R2 –NH2 ,andaterminalalkyne,H–C≡C–R3 ,yields2-alkynyl N-heterocycles
40)(41)
(40)inupto98%yield,via insitu generationofacyclicketiminiumspecies(41),which ismorereactivetowardsalkynylationthanacyclicanalogues.48
Asalicylaldehydederivativehasbeenusedinanoxidativekineticresolutionof indolineswithachiralphosphoricacidcatalyst.Aself-redoxprocessoftheiminium intermediateisdescribed.49
ADFTstudyhasexaminedJorgensen–Hayashi-typeaminesascatalystsofiminiumtypeadditionsof �� -keto-sulfoxidesand-sulfonestoenals.Highenantio-anddiastereoselectivityisobservedforthesulfoxides,butthe de dropsforthesulfones.50
Phosphate-mediatedPictet–SpenglercyclizationhasbeenstudiedbyDFTand abinitio methods invacuo andinacetonitrile.Examiningthereactionsofphenethylamineandits3-hydroxyderivativewithformaldehydetogivethecorresponding tetrahydroisoquinolinewas,withlowerbarriersinsolution.51
Mannich,Mannich-type,andNitro-MannichReactions
Freefluorinatedamideenolates(42;R = H,alkyl,aryl)derivedfrom3-fluoroindolin-2 -onehavebeengenerated insitu bylithium-promoteddetrifluoroacetylationofan �� -fluoro-�� -ketoamidehydrate(43).SubsequentMannichadditionswithsulfinylaldiminesbearingfluoroalkylgroupsareveryclean,withupto97%yieldand >96% de ofprotectedamine(44).Bothstepstake5minat0 ∘ C.Deprotectionthengivesan �� -fluoro-�� -(fluoroalkyl)-�� -aminoindolin-2-one.52 de (43)(44) (42)
ThefirstorganocatalyseddirectMannichreactionofunactivated �� -styrylacetates addsthemto N-tosylbenzaldiminestogive N-tosyl �� -aminoesters.Thecinchona alkaloid–ureacatalystemployedgivesyields/de/ee upto84/92/97%.53 de ee
�� -FluoroketonesundergoMannichreactionwith N-tert-butylsulfinyliminesinupto 98% de. 54 de
AdiastereoselectiveMannichreactionofanaromaticaldimineandaphenyloxazolidinepromotedbyTiCl4 /R3 Nstopsatthetitaniumenolatestageunlessaprotonsource isadded.Theprocesshasbeenexaminedbylow-temperatureNMR,withaceticacid provingthebestadditive.Theprotocol,runslowlyat 50to 40 ∘ C,hastostrikeafine balance,asdirectprotonationoftheenolaterevertsittothereactant.55 de Azinc–proline–phenolcatalystgiveshigh de and ee inMannichreactionsof �� -branchedketoneswith N-Bocaldimines,giving �� -aminoketoneswithanall-carbon quaternarystereocentreinthe �� -position.56 de ee
Adiastereo-andenantio-selectiveMannichaddition/cyclizationreactionof ��substitutedisocyanoacetateesterpronucleophileswithketiminesemploysabinary catalystsystemofsilveracetateandacinchona-derivedaminophosphine.AnX-ray crystalstructureoftheaminophosphine/silveracetatecomplex,aswellas 1 Hand 31 P NMRstudies,helpssupportamechanisticproposal.Theproductimidazolinescanbe hydrolysedtogivefullysubstituted �� ,�� -diaminoacids.57 de
�� ,�� -Tetrasubstitutedimidazolines(45)arepreparedfrom �� -substituted �� -isocyanoacetates[R4 –CH(CO2 R5 )–N+ ≡C ]andketimines(R1 R2 C=N–R3 )viaaMannich reactioncatalysedbyacinchonaalkaloid/nickel(II)/Cs2 CO3 combination:typical yields/de/ee areinthe90s.58 de
46)
Functionalizedpropargylicamineshavebeenpreparedinhigh de and ee viaa synselectiveMannichreactionofenolizablealdehydesand C-alkynylimines,catalysedby prolineandanachiralaminal/ureaco-catalyst.59 de ee
TheenantioselectivedirectMannichadditionofethylacetoacetatetoarylideneureas, Ar–CH=NCONH2 ,hasbeenusedtoexplorenon-covalentorganocatalysisbynetworks ofcooperativehydrogenbonds.60 ee
�� -Fluoroaromaticketonesundergozinc-catalysedMannichreactionswith N-Bocbenzaldiminestogiveprotected �� -fluoroamines(e.g. 46)with ee/de upto99/95%.61 de ee
A syn-selectivedirectMannichadditionuses �� -iodothioesters(47)andsulfinylimines toproduce �� -aminothioesters.Enolateformationisachievedbyreductivesoftenolization.The �� -iodothioesterisashelf-stablelatentenolate.62 de 2,2,2-Trifluoroethanol(TFEA;pKa = 12.40)activatesaone-potreactionof �� -nitroenamine(48),benzaldehyde,andpiperidinetogiveaMannich-likeproduct(49).TFEA isbelievedtoactivatethealdehydeviaitsacidityandhydrogen-bondingability,allowing ittoreactwithpiperidinetoformaniminiumion,whichthenreactswiththeiminium zwitterionictautomerofenamine(48).ControlexperimentsandMSdetectionofthe firstiminiumintermediatesupportthemechanism.63
N-Aryl-3-hydroxyisoindolinones(50;R = OH)reactwithalkylarylketonesunder Lewisacid-catalysedanhydrousconditionstogivethecorrespondingsubstituted
(48)(49)
isoindolinones(50;R = CH2 COPhforthecaseofacetophenone).Evidenceforan N-acyliminiumionintermediateispresented.64
51)
50)(52)(53)
Simplecyclicamideswithanelectron-withdrawinggrouponnitrogen(51; n = 1–3) undergodirectcatalyticasymmetricMannich-typereactionwith N-Bocaldimines.An electron-withdrawinggroupisnotrequiredatthe �� -position.Mannichadductscanthen befurthermodifiedattheamideposition,includingremovalofthe7-aza-indolemoiety ifdesired.Catalysisisprovidedbycopper(I)andBarton’sbase(2-tert-butyl-1,1,3,3tetramethylguanidine),withchiralphosphinesbeingemployedforstereoselectivity.65
�� ,�� -Dichloro-�� -aminonitriles(52)havebeenpreparedviaanenantioselective Mannich-typereactionofdichloroacetonitrilewithprotectedaldimines,RCH=N–PG, usingchiralbis(imidazoline)catalysts‘pincing’palladium.Silveracetateandpotassium carbonatearealsoemployedinaprocesswhichgiveshighyieldsand eesinTHF at0 ∘ C.Atfirstsight,astrongbasemightappeartobeindicated,but �� ,�� -dichloro carbanions(includingthecurrentone, CCl2 CN)areunstable.Soaweakbaseand palladiumactivationisthemoreeffectivestrategy.Theproducts(52)canbeconverted to �� -amino-nitrilesor-amideswithoutlossofenantiopurity.66 ee
Asimple �� ,�� -unsaturated �� -butyrolactam(53)undergoesadirectcatalyticasymmetric Mannich-typeadditionreactionwithan �� -ethoxycarbonyl N-thiophosphinoylketimine, Ph–C(CO2 Et)=N–P(=S)Ph2 .Usingcopper(I)catalysis,achiraldiphosphineinducer, andtriethylamine, ee upto91%isachieved.67 ee
DirectMannich-typereactionsgeneratingboth �� -and �� -aminoestersfromarange ofcarbonylcompoundsandaldimineshavebeendescribed.UsingastericallyfrustratedLewisacid/Brønstedbasepair,B(C6 F5 )3 /1,2,2,6,6-pentamethyl-piperidine,high deshavebeenachievedundermildconditions.68 de
AldiminesofglycinatesundergocatalyticenantioselectiveMannich-typereaction with N-sulfonylimines,usingachiralguanidinecatalyst,ingoodyieldandfair ee, providingarouteto �� ,�� -diaminoacids.Previousexamplesfeatured ketimines of glycinates.69 de Enoldiazoacetamides(e.g. 54)undergocatalyst-controlleddivergentreactionswith nitrones:(i)aCuBF4 –bisoxazolinecomplexfavours3 + 3-cycloaddition,whereas(ii) CuOTfcatalysesnearlyexclusiveMannichadditioninhighyields. 1 HNMRandother evidencesuggeststhatthefirstcatalystfavoursmetalcarbenegenerationwithinafew minutes,whereastheenoldiazoacetamide(54)isrelativelyinertinthepresenceofcoppertriflateonthistimescale.70
Isoindolin-1-one-3-phosphonates(e.g. 55)areeasilypreparedatambienttemperature in40minundersolvent-andcatalyst-freeconditionsfromthreecomponents:2-formyl benzoicacid,benzylamine,andtrimethylphosphite(inthiscase).Thisversionofthe Kabachnik–Fieldsreactionshows de >94%forthe �� -methylbenzylaminecase.71 de Aredox-annulationofacyclicamine(56)anda �� -keto-aldehyde(57)yieldsa benzo[a]quinolizine-2-one(58)inrefluxingaceticacid/toluenewithmoderatetogood de.Thenewintramolecularredox-Mannichprocessprobablyinvolvesazomethine ylidesasintermediates.Productssuchas(58)areknowntobeinequilibriumwiththe correspondingring-openedisoquinoliniumions,sothediastereoselectiveratioofthe productslikelyrepresentstheequilibriumratio.Inasamplecase,thediastereomers wereseparatedandbothsubjectedtothereactionconditions,resultinginidentical de. 72 de
57)
56)(58)
3-En-1-ynamides(e.g. 59)undergogold-catalysedimination/Mannichcascadesina one-potreactionwithbenzaldehydeandaniline,giving1,5-iminoamines(60)withsome diastereoselectivity.Controlexperimentsshowthatgold-catalysedaminationsofthe
enynamides(59)yield �� -iminoallylgoldintermediates.Substratessuchas(59)give (anti-60) products,whereasifthealkeneiscyclic, syn-selectivityisobtained.73 de
Other‘Name’ReactionsofImines
Aza-Henryreactionofanitroalkanewithanisatin-derived N-Bocketimineiscatalysed byaquininederivative,givinghigh ee. DFThasbeenusedtoprobetheorigin oftheselectivity.C–Cbondformationisfoundtobeboththerate-determiningand thestereo-controlledsteps.Multiplenon-covalentinteractions,includingclassical andnon-classicalhydrogenbondsandanion �� interactions,actcooperativelyto givethehighreactivityandhigh ee. 74 DFThasbeenusedtoprobechiralhydrogen- ee bondingcatalystsofaza-Henryreactions.Theresultshighlighttheroleofcooperative effectsarisingfromnon-covalentattractionsasavitalfactorgoverningstereoinduction,whereasunfavourablestericinteractionswerethedominantfactorcontrolling diastereoselection.75 de ee
Aself-catalysedaza-Henryreactionofethylnitroacetateonchiraltrifluoromethyl aldimines,F3 C–CH=N–R*,workswithoutsolvent.Theproduct �� -amino �� -nitrotrifluoromethylestersareeasilyreducedto �� ,�� -diaminoacidesters.Thereactionscanalso becatalysedbyLewisacidssuchasZrCl4 orAlCl3 . 76 de
Newrecyclablepolymer-supportedchiralthioureashavebeentestedinsolvent-free aza-Henryandnitro-Michaeladditions,givinggood eesatlowcatalystloading.77 ee
Animiniumactivationofaromaticaldehydeshasbeenexploitedinanorganocatalytic dominoaza-Michael–Henryreactionof N-(2-formylphenyl)sulfonamideswith trans-��nitroolefins,togive3-nitro-1,2-dihydroquinolines(61)inhighyieldsandupto88% ee atambienttemperature.78 ee
Inanexplorationofcarbenecatalysis‘beyondNHCs’,acyclopropenylidenehasbeen testedinaza-Morita–Baylis–Hillman(aza-MBH)reactions,usinganumpolungstrategy. Bis(dialkylamino)cyclopropenylidenes(‘BAC’s, 62),firstisolatedin2006,areeasily synthesizedandstable,andareamongtheleasthinderedcarbenesasthebulkydialkylaminosareneverthelessfarfromthecarbenecentre.Theyarestronger �� -donorsthan NHCs,andcomparable �� -donors.Inamodelaza-MBHtestof N-tosylbenzaldimine andcyclopent-2-enonewithDBUasbase,BAC(62;R = Pri )indeedprovedsuperior toNHCs,CAACs[cyclic(alkyl)(amino)carbenes],and P-or N-centredLewisbases.79
Sulfonatedbenzaldimineswithan ortho-alkynylmoietyundergoenantioselectiveazaMBHreactionswithenonesinonepot,usingacombinedchiralphosphine/goldcatalysis,togivedihydroisoquinolines.80 ee
MO6-2Xcalculationsonamodelaza-MBHreactionhaveidentifiedapathwaywith explicitinvolvementofformicacidintherate-determiningstep.Substrateandmedium
