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Topics in Heterocyclic Chemistry 41
Series Editor: B.U.W. Maes · Janine Cossy · Slovenko Polanc
Matthias D’hooghe Hyun-Joon Ha Editors
Synthesis of 4to 7-membered Heterocycles by Ring Expansion Aza-, oxa- and thiaheterocyclic small-ring
systems 41 TopicsinHeterocyclicChemistry SeriesEditors:
B.U.W.Maes,Antwerpen,Belgium
JanineCossy,Paris,France
SlovenkoPolanc,Ljubljana,Slovenia
EditorialBoard:
D.Enders,Aachen,Germany
S.V.Ley,Cambridge,UK
G.Mehta,Bangalore,India
R.Noyori,Hirosawa,Japan
L.E.Overmann,Irvine,CA,USA
A.Padwa,Atlanta,GA,USA
AimsandScope TheseriesTopicsinHeterocyclicChemistrypresentscriticalreviewsonpresent andfuturetrendsintheresearchofheterocycliccompounds.Overallthescopeisto covertopicsdealingwithallareaswithinheterocyclicchemistry,bothexperimental andtheoretical,ofinteresttothegeneralheterocyclicchemistrycommunity.
Theseriesconsistsoftopicrelatedvolumeseditedbyrenownededitorswith contributionsofexpertsinthefield.
Moreinformationaboutthisseriesathttp://www.springer.com/series/7081
MatthiasD’hooghe • Hyun-JoonHa
Editors
Synthesisof4to7-memberedHeterocycles byRingExpansion Aza-,oxa-andthiaheterocyclic small-ringsystems
Withcontributionsby
B.Alcaide P.Almendros C.Aragoncillo
A.Bhattacharyya N.Chauhan F.Couty S.Das
O.R.P.David M.K.Ghorai A.F.Khlebnikov J.T.Njardarson M.S.Novikov D.T.Smith J.Xu
Editors MatthiasD’hooghe DepartmentofSustainableOrganic ChemistryandTechnology
FacultyofBioscience
EngineeringGhentUniversity
Ghent
Belgium
Hyun-JoonHa DepartmentofChemistry
HankukUniversityofForeignStudies
Yongin-si Korea(Republicof)
ISSN1861-9282ISSN1861-9290(electronic) TopicsinHeterocyclicChemistry
ISBN978-3-319-24958-2ISBN978-3-319-24960-5(eBook) DOI10.1007/978-3-319-24960-5
LibraryofCongressControlNumber:2015958522
SpringerChamHeidelbergNewYorkDordrechtLondon # SpringerInternationalPublishingSwitzerland2016
Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpartof thematerialisconcerned,specificallytherightsoftranslation,reprinting,reuseofillustrations, recitation,broadcasting,reproductiononmicrofilmsorinanyotherphysicalway,andtransmission orinformationstorageandretrieval,electronicadaptation,computersoftware,orbysimilaror dissimilarmethodologynowknownorhereafterdeveloped.
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Preface Thechemistryofsmall-ringheterocycleshasinspiredmanyscientistsoverthe yearsbecauseoftheremarkablecombinationofringstrain,bondstrength,and chemicalreactivityassociatedwiththesepeculiarcompounds.Althoughsmall-ring heterocyclesaresometimesconsideredtoberatherunpredictableanduncontrollable,seminalexamplesinthechemicalliteraturedemonstratethat,when manipulatedcorrectly,theinherentreactivityofthesesynthonsallowsforthe constructionofaplethoraofvaluableheterocyclesfromsmall-ringprecursors.As editorsofthisspecialvolume,weareverymuchintriguedbythebeautyand richnessofsmall-ringheterocyclicchemistry,andweexplainourfascinationfor thesecompoundsinmoredetailinashortcommentaryentitled“Perceptionsand PerspectivesontheRingExpansionofSmall-RingHeterocycles.”
Thisspecialvolumehastheintentiontointroducethereadertothefascinating worldofsmall-ringheterocycles.Tothatend,leadingexpertshaveacceptedto contributebywritingachapterontheapplicabilityofN-,O-,andS-heterocyclic three-andfour-memberedringsystemsasprecursorsforringtransformations.In particular,CoutyandDavidprovideachapteronringexpansionsofnonactivated aziridinesandazetidinesbearinganelectron-donatinggroupatnitrogen(chapter “RingExpansionsofNonactivatedAziridinesandAzetidines”),whereasGhorai andcoworkersdiscusstheringexpansionoftheiractivatedcounterpartsbearingan electron-withdrawinggroupatnitrogen(chapter“RingExpansionsofActivated AziridinesandAzetidines”).Furthermore,KhlebnikovandNovikovreviewring expansionsofunsaturatedazirinesandazetines(chapter“RingExpansionsof AzirinesandAzetines”),Alcaide,Almendros,andAragoncillodescribethering expansionoffour-memberedbeta-lactamsandbeta-(thio)lactones(chapter“Ring Expansionsof b-Lactamsand b-(thio)lactones”),SmithandNjardarsoncover ringexpansionsoftheoxaheterocyclesoxiranesandoxetanes(chapter“Ring ExpansionsofOxiranesandOxetanes”),andXudemonstratestheapplicabilityof sulfur-containingthiiranesandthietanesinring-expansionreactions(chapter“SynthesisofFour-toSeven-MemberedHeterocyclesbyRingExpansion:Ring ExpansionsofThiiranesandThietanes”).
Thankstothesevaluablecontributions,thisspecialvolumeprovidesathorough andcomprehensiveoverviewofrecentrealizationswithinthefieldofsmall-ring heterocyclicchemistryandclearlydemonstratesthehugesyntheticpotentialof thesecompounds.Wegratefullyacknowledgeandthanktheseauthorsfortheir elaborateinputandefforts.Finally,wearealsoindebtedtotheserieseditorsB. Maes,J.Cossy,andS.Polancforgivingustheopportunitytocompileaspecial volumeforthe TopicsinHeterocyclicChemistry seriesonthisfascinatingchemistry,andwehopethatthisvolumewillbeasourceofinspirationformanycolleagues andfellowchemistsinthefuture.
PerceptionsandPerspectivesontheRing ExpansionofSmall-RingHeterocycles MatthiasD’hoogheandHyun-JoonHa
Heterocycliccompounds,accommodatingringstructuresofvarioussizesand bearingdifferenttypesofheteroatoms,enrichtheworldoforganicchemistry significantly.Thekeyroleofheterocyclesinnaturehasalwaysbeenananchor pointforchemistsinthepursuitofnewmoleculesendowedwithpronouncedand diversebiologicalactivities.Nowadays,heterocyclesareattractingattentionfrom peopleinacademiaandindustrymorethaneverduetotheiruniqueproperties, makingthemeligibleandversatilebuildingblocksfortheproductionofvaluable compoundssuchasagrochemicals,pharmaceuticals,andevenmaterials[1]1.
Heterocyclesconstitutethelargestandmostvariedfamilyoforganic compounds,butthesynthesisandelaborationofspecific(classesof)heterocycles canbeaverylaboriousandtediousapproach,oftenassociatedwitharatherlimited scopeintermsofstructuraldiversity.Anelegantwaytoovercomethishurdle comprisestheringexpansionofsmallheterocyclicringsintolargersystems,the latteroftenbearingadditionalhandles(substituentsandfunctionalgroups)for furthersyntheticderivatization.Inourview,thisstrategycanbecomparedwitha “budtoblossom”eventinnature(Fig. 1).Allblossomsbloomfromtheirbuds, which,thoughsmall,havethepotentialtoresultinbeautyandtocreateabroad varietyofflowerswiththerightnumberofpetals,pistil,andstamen.Althoughthe formationof(smallandcondensed)budsisastrenuousanddelicateprocess,itis stillmucheasiertoaccomplishthanthedirectgenerationofcomplexandfullgrownflowersattheendofthebranch.
1 Aftereliminating19biologicsfromthe2010listof200topsellingdrugsintheUS,116ofthe remaining181compoundsincorporateaheterocyclicsystemintheirstructure.
M.D’hooghe(*)
SynBioCResearchGroup,FacultyofBioscienceEngineering,GhentUniversity,CoupureLinks 653,9000Ghent,Belgium
e-mail: matthias.dhooghe@UGent.be
H.-J.Ha
DepartmentofChemistry,HankukUniversityofForeignStudies,Yongin449-791,SouthKorea
e-mail: hjha@hufs.ac.kr
Fig.1 Blossomfromthebud(http://www.flowerandflour.com/wp-content/uploads/2012/10/Budto-Blossom-Flower-and-Flour.jpg) viiiPerceptionsandPerspectivesontheRingExpansionofSmall-RingHeterocycles
Analogously,smallheterocyclesmaybeexpandedintolargerandmore functionalizedheterocycliccompoundsby“bursting”theirbackbonesinacontrolledway.Inprinciple,differenttypesofheterocyclicscaffoldscanbegenerated fromonesmallheterocyclicringsystemuponcarefuldeploymentofitsinherent chemicalreactivity.Inotherwords,afascinatingandversatileworldappearsfor thosewhostudythechemistryofsmall-ringheterocyclesandacquiretheknowledgerequiredto“tame”thepronouncedreactivityofthesesmallrings.Forexample,three-andfour-memberedheterocyclessuchasoxiranesandaziridines, oxetanesandazetidines, b-lactonesand b-lactamsareexcellentsubstratestobe convertedintoadiversityoffive-,six-,andseven-memberedheterocyclesfrequentlyencounteredaskeysubunitsinpharmaceuticalsorotherhigh-value products.Duringtheseconversions,additionalcarbonbackbonesand/ordifferent functionalgroupscanbeintroducedtoculminateinabroadrangeofdecoration patternsandthustoprovideastraightforwardapproachtostructuraldiversity–a principalrequirementinbioactivecompounddevelopment.Therelevanceand chemicalbeautyoftransformationsbasedonringenlargementsstemsfromseminal examplesfoundinnature,suchasthebiosynthesisofthepolyetherantibiotic monensinwhosemajorheterocyclesarederivedfromthecorrespondingoxirane precursors(Fig. 2).
Ofcourse,theremustbeadrivingforcetoelicitthesetransformations.Aswe know,thedelicateinteractionbetweenplanthormones,sunshine(light),andsuitabletemperaturestransformsbudsintobeautifulflowers.Inthesameway,acertain chemical“magic”isrequiredtomakesmallheterocyclesexpandinaselectiveand controlledfashion.Therichnessofknowledgeonsmall-ringheterocyclesgathered inthelastfewdecadesallowsustobetterunderstandtheirchemicalbehaviorandto
Fig.2 Theproposedpathwayformonensinbiosynthesisin Streptomycescinnamonensis [2]
havesufficient“magicalingredients”toaffecttheirselectiveexpansion.Indeed, whenmanipulatedcorrectly,theexquisiteinterplayofringstrain,bondstrength, nucleophilicity,electrophilicity,andsusceptibilitytoreagentsallowsfortheconstructionofaplethoraofvaluableheterocyclesfromsmall-ringprecursors.
Thisspecialvolumehastheintentiontoimmersethereaderintothewonderful worldofsmall-ringheterocyclesandtoarouseinterestintheirchemistry.In particular,weaimatprovidingaoverviewofrecentaccomplishmentsregarding ringexpansionsofsmallheterocyclicringsintolargersystemsandwishtopresent itasatoolboxof“magicalingredients”totacklenewchallengesinheterocyclic synthesis.Thefocusinthespecialvolumeisputontheapplicabilityofaza-(N ), oxa-(O),andthia-(S )heterocyclicthree-andfour-memberedringsystemsas precursorsforringtransformations.Tothatend,leadingexpertshavecontributed differentchaptersontheringexpansionofthree-memberedaziri(di)nes,oxiranes, andthiiranesandfour-memberedazeti(di)nes, b-lactams, b-(thio)lactones, oxetanes,andthiethanes.Wedohopethatthisbookwilltriggerthereader’sinterest insmall-ringheterocyclesandpersuadehim/hertoapplythisremarkablechemistry enroutetothedevelopmentofnewheterocycleswithfascinatingpropertiesand applications.Wearecertainlylookingforwardtolearningmoreonnew developmentsandbreakthroughsinthisfieldofresearchinthenearfuture.
References
1.PozharskiiAF,SoldatenkovAT,KatritzkiAR(1997)Heterocyclesinlifeandsociety.Wiley, Chichester
2.CaneDE,CelmerWD,WestleyJW(1983)Unifiedstereochemicalmodelofpolyetherantibioticstructureandbiogenesis.JAmChemSoc105:3594–3600
RingExpansionsofNonactivatedAziridinesandAzetidines .........1 Franc¸oisCoutyandOlivierR.P.David
RingExpansionsofActivatedAziridinesandAzetidines ............49 ManasK.Ghorai,AdityaBhattacharyya,SubhomoyDas, andNavyaChauhan
RingExpansionsofAzirinesandAzetines .......................143 AlexanderF.KhlebnikovandMikhailS.Novikov
RingExpansionsof b-Lactamsand b-(thio)lactones ...............233 BenitoAlcaide,PedroAlmendros,andCristinaAragoncillo
RingExpansionsofOxiranesandOxetanes ......................281 DavidT.SmithandJonT.Njardarson
SynthesisofFour-toSeven-MemberedHeterocyclesbyRing Expansion:RingExpansionsofThiiranesandThietanes ............311 JiaxiXu
TopHeterocyclChem(2016)41:1–48
DOI:10.1007/7081_2015_146
# SpringerInternationalPublishingSwitzerland2015
Publishedonline:18June2015
RingExpansionsofNonactivatedAziridines andAzetidines Franc¸oisCoutyandOlivierR.P.David
Abstract Ringexpansionspromotedbyringstraininaziridinesandazetidinesare reviewedinthischapter,puttingemphasisonrecentapplicationsfromthelast decade.Thisvastsubjectcannotbesurveyedhereexhaustively,andthereaderwill beguidedtorelevantprecedentreviewsorkeyreports.Rather,specialattention willbeputonselectedexamplesandtheirmechanisticdetails,aimingtodemonstratethathighselectivitycanbereachedinthesereactions.Inthisissue,thisfastgrowingtopichasbeendividedintotwodistinctchapters,thisonedealingwith “nonactivated”aziridinesandazetidines.Therefore,thereaderwillonlyfindhere examplesinvolvingNH-or N-alkylaziridinesand N-azetidinesassubstratesforring expansions,while N-acyl, N-carbamoyl,or N-tosylcompounds,definedas“activated”substrates,willbepresentedinthenextchapter.Thisdistinctioncanappear quitearbitraryatfirstsightbutisamplyjustifiedbythegreatdifferenceinreactivity ofthesedistinctsubstrates.Thefirstpartfocusesontheringexpansionsof nonactivatedaziridinesintouptoseven-memberedringsandisfurtherdivided intoexpansionsinvolvingtheincorporationofone(ormore)heteroatoms,followed byringexpansionsinvolvingonlyincorporationofcarbonatoms.Thesamemodel isthenfollowedforazetidines.
Keywords Azaheterocycles Azetidines Aziridines Ringexpansion
Contents
1Introduction.. .................................................................................2 2RingExpansionofNonactivatedAziridines ................................................3 2.1RingExpansionsInvolvingtheIntroductionofAtLeastOneHeteroatom..........4
F.Couty(*)andO.R.P.David
InstitutLavoisierdeVersaillesUMRCNRS8086,Universite ´ deVersailles,45,avenuedes Etats-Unis,78035VersaillesCedex,France
e-mail: couty@chimie.uvsq.fr
2.2RingExpansionsInvolvingOnlytheIntroductionofCarbonAtoms... .............11 3RingExpansionofNonactivatedAzetidines................................................27
3.1RingExpansionsInvolvingtheIntroductionofAtLeastOneHeteroatom..........27
3.2RingExpansionsInvolvingOnlytheIntroductionofCarbonAtoms... .............32
4Conclusion............ ........................................................................43
1Introduction Beforestartingthistopic,itisimportanttointroducesomebasicfactsregarding aziridinesandazetidines,andthefirstoneistheiravailability.Whileaziridines (derivativesoftheparentmolecule 1),i.e.,saturatedthree-memberednitrogen heterocycles,havebeenextensivelystudiedandappearascornerstones([1–6]; forsomerecentreviewsonaziridines,see[2–6])ofthechemistryofnitrogencontainingcompounds,theirone-carbonhomologues,theazetidines(derivativesof theparentstructure 2),arefarlessstudied,thoughmanynewproceduresfortheir preparationhaveappearedquiterecently(forrecentreviewsonazetidines,includingtheirpreparations,see[7–18];forothersrecentleadingreferencesonthe synthesisofazetidines,see[13–17];forprecedentreviewonringexpansionand openingofazetidinesandazetidiniumions,see[18]).Syntheticaccesstothese heterocyclesfallsoutsidethetopicofthischapter,butitshouldjustbementioned thatrecentadvancesthatcanbefoundintheabovecitedreviewsnowallowsfor easyaccesstothesecompounds,especiallyinenantiomericallypureform.Key pointshoweverdifferinthechemistryoftheseheterocycles.Thefirstoneisthe basicityofthenitrogenatom:adramaticloweringinpKa isobservedforaziridines comparedtoazetidines(Fig. 1),thelatterbeingveryclosetothevaluefor pyrrolidine(pKa 11.31).Ontheotherhand,calculatedringstrain[19]inthese heterocyclesisalmostthesameandcompareswellwithcyclopropane (27kcalmol 1).Thisringstrainisofcoursethekeyparameterforthepromotion ofring-openingandring-expansionreactions,butitiscertainlynottheonlyone, becauseazetidinesappeargenerallylessreactivethanaziridinesinthesereactions. Anillustrationofthiswasrecentlydescribed[20]reportingthehighdifferencein ratesbetweenthenucleophilicopeningofaziridiniumions 3 andazetidiniumions 4 by4-DMAP,thelatterreacting17,000timesmoreslowlydespitesimilarring strains(Fig. 1).
Anotherimportantdifferencebetweenthesecompoundsisthevalueofenergy barrierfornitrogeninversion.Thisenergyisveryhighinthecaseoftheaziridines, withatypicalvalueof19.5kcalmol 1 foraziridineitselfandmuchlowerin azetidines(typically10kcalmol 1 for N-Me-azetidine[21]).Thus,whileconformationalequilibriuminaziridinesisrathersimpleandrestrictedtonitrogeninversion,itismorecomplicatedwithazetidinesandinvolvesfourpossibleinvertomers andconformers(Fig. 2).Thispointisofimportanceinthischapter,becausewewill seethattheringenlargementmostoftenimpliespreliminaryactivationofthe
RingExpansionsofNonactivatedAziridinesandAzetidines3
Comparisonbetweenaziridinesandazetidines
Conformers
Most often observable by NMR at room temperature.
Not distinguished by NMR at room temperature.
Fig.2 Conformationalanalysisinaziridinesandazetidines
pseudo equatorial lone pair.
Invertomers
pseudo axial lone pair.
nitrogenatomthroughitslonepair(actingasaLewisbaseorasaBronstedbase). Therefore,comprehensionofthemechanismsatplayinthesereactionsoftengoes withaknowledgeoftheconformationaldynamicsofthereactant,whichallowsan estimationoftheavailabilityofthelonepair.
2RingExpansionofNonactivatedAziridines Unlikethesecondpartofthischapter,devotedtononactivatedazetidines,the literatureonthistopicishugeandcannotbetreatedexhaustively.Representative examples,withafocusonissuesofregio-andstereoselectivityandtheirmechanisticaspectswillthereforebetreatedselectively.
Fig.1
2.1.1ExpansionsintoOxazolidinones Oxazolidin-2-onesareimportantheterocycliccompoundsthathavefoundmany applicationssuchaschiralauxiliariesorasbioactivecompounds.Consequently,the transformationofaziridines 2 intooxazolidin-2-ones 6 isamuchstudiedtopic.This transformationformallyinvolvesinclusionofCO2 intothethree-memberedring, butthisinclusioncannotoccurwithouttheinterventionofanucleophiliccatalyst, becauseaSN2pathwayisnotpossiblefortheintermediatezwitterion 5 (Scheme 1). Wewilltreatthistopic,whichhasbeenmuchexemplifiedinrecentyearsinthe fieldofCO2 valorization,attheendofthissection.Alternatively,chloroformatesor otherCO2 derivativescanbeused,andwewillfirstintroducethismethod.
ArecentandinterestingreportbyLeeandHa[22]outlinesthatissuesofregioandstereoselectivitycanbeperfectlyundercontrolwhennonactivatedaziridines arereactedwithchloroformates.Thus,enantiomericallypureaziridines 7 reactin refluxingacetonitrilewithmethylchloroformatetogivethecorresponding oxazolidinones 10 withoverallretentionofconfigurationandhighregioselectivity (Scheme 2).Releasedchlorideanionactsformallyhereasanucleophiliccatalyst, andregioselectivelyopenstheintermediateaziridiniumion 8.Then,betachlorocarbamate 9 evolvestotheoxazolidinonesthroughintramolecularattackof theoxygenatomandreleaseofchloromethane.Theintermediatechlorocarbamate 9 canbeisolatedandcharacterizedwhenthereactionisrunintoluene.
Di-tert-butyl-dicarbonate(Boc2O)canbeusedinsteadofachloroformateif employedwithamolarequivalentofNaIinrefluxingacetone[23].Themechanism inthiscaseisessentiallythesame,withtheiodideanionplayingtheroleofthe externalnucleophile,with,attheend,releaseofHIandisobutene.Obviously, issuesofregioselectivitycanbeaproblemwhenothersubstituentsarepresenton theaziridinering,duetonon-regioselectiveopeningoftheintermediateaziridinium ionbythehalide.Scheme 3 outlinesonesuchexample(15 leadingto 16 and 17 [24]).Ontheotherhand,since 11 and 13 haveabenzyliccarbon,theyare selectivelyattackedbythehalide,andthesereactionsoccurwithhigh regioselectivitytogive 12 and 14 [23, 25].
Sincethedawnofthiscentury,ahostofdifferentcatalysts,includinghalidesalts [26, 27],iodine[28],zirconylchloride[29],(salen)chromium(III)/DMAP[30], PEGfunctionalizedwithquaternaryammoniumbromides[31], L-histidine[32], orNi-bipycomplexunderelectrochemicalconditions[33],havebeenusedforthe incorporationofCO2 intononactivatedaziridinerings.Someexamplesinvolving
Scheme1 IncorporationofCO2 inaziridinesneedstofollowatwo-stepprocess
R = CO2Et, (-) Menthyl ester, COAr, CH=CH-CO2Et, CH=CH2
Scheme2 Highregioselectivitycanbereachedusingchloroformates
Scheme3 Otherexamplesusingchloroformatesor(Boc)2O
Zr(SO4)2, 4H2O (5%) CO2 (6Mpa), 97% conv.
(0.05%)
(8 Mpa), 36h, 110°C
Scheme4 DirectincorporationofCO2 canbepromotedbyvariouscatalysts
18–28 aredepictedinScheme 4.WorthytonoteisthepossibleinsertionofCS2 leadingto 22. Functionalizedaziridineswithahydroxymethylgroup 29 canbeexpandedto chloromethyloxazolidinones 31 uponreactionwithNaHandphosgene[34].This reactionisofhighsyntheticrelevance,sincethestartingsubstratescanbeprepared quiteeasilyinenantiomericallypureform.Moreover,theintroductionofa
R1 : H, Me, Ph, vinyl
R2 : H, Me, Ph, Bu, t-Bu, Aryl, vinyl
Scheme5 Ring-expansiontofunctionalizedoxazolidinone
chloromethylsubstituentontheoxazolidinoneringallowsforfurtherfunctionalization.Thisreaction,whichisalsooperativeinthecaseofazetidines(videsupra), goesthroughabicyclicaziridiniumion 30,whichisopenedregioselectively attheunsubstitutedcarbonbythechlorideanion(Scheme 5).Notethat theanalogousiodidecanbepreparedfromsimilarsubstratesuponreactionwith 1,10 -carbonyldiimidazoleandTMSI[35].
2.1.2ExpansionsintoImidazolidinones Byanalogywiththeprecedentsection,isocyanates,insteadofchloroformates,can beincorporatedintononactivatedaziridines,leadingtoimidazolidinones.Two distincttypesofsubstrateshavebeenstudiedinthisreaction:aziridinesfitted withanalkenylmoietyonthethree-memberedring,whichcanbeactivatedwith palladiumcatalysts,andaziridinesdevoidofthissubstituent,which,inthiscase, needtheinterventionofaLewisacid.Thislattercaseisillustratedbythereportof HaandLee[36],whichparallelstheirworkwithchloroformiates.Thus,when( )menthol-derivedaziridine 32 isreactedwithdifferentisocyanatesinthepresenceof 10mol%ofMgBr2,thecorrespondingimidazolidinones 33 areproducedwith retentionofthestereocenter(Scheme 6),throughamechanismsimilartotheone depictedinScheme 2
Itisnoteworthythat,whenNiI2 isusedasacatalystinthisreaction, 2-iminooxazolidines 35 areproduced[37].Inthecaseofphenyl-substituted aziridine 34 (R1¼Bu,R2¼Ph),thiscompoundisomerizestothecorresponding imidazolidinone 36 uponheating(Scheme 7).
Morerecently,HaandLeereported,inanalogywiththeaboveScheme 5,that aminomethylaziridines 39 preparedthroughreductiveaminationofthe correspondingaldehyde 37 canbering-expandeduponreactionwithNaHand triphosgenetogivefunctionalizedimidazolidinones 39 [38].Thisreaction sequencewasexploitedforthepreparationofaminoacyltRNAsynthetaseinhibitors 40 (Scheme 8).
Asmentionedatthebeginningofthissection,2-alkenylaziridinessuchas 41 are aspecialkindofsubstratesfortheincorporationofisocyanates.Boththermaland metal-catalyzedreactionshavebeenstudiedandcompared[39],andthethermal couplingwasshowntoproceednonselectively,leadingtomixturesofregioisomers
R : Aryl, alkyl, Bn,Ts, COCCl3
Scheme6 MgBr2-catalyzedexpansiontoimidazolidinones
R1 : Alkyl, Benzyl, Phenyl R2 : H, Ph
Scheme7 NiI2-catalyzedexpansiontoimidazolidinones
(R1 = Bu R2 = Ph)
Scheme8 Ring-expansiontoafunctionalizedimidazolidinone
42–44.Interestingly,theissueofchemoselectivitywasfoundtodependuponthe stereochemistryofthestartingalkene.Ontheotherhand,theNi-catalyzedreaction wasfoundtogiveselectivelytheimidazolidinone 44 (Scheme 9).
Palladiumisthemetalofchoicetopromotesuchtransformations.Theearlier reportinthisfieldcamefromthegroupofAlper([40];seealsoreferencescited thereinforsimilarreactionswithaziridinesunsubstitutedbyanalkenylgroup)who reportedthepalladium-catalyzedringexpansionofaziridinessuchas 45 with differentheterocumulenes,includingisocyanatesandisothiocyanates.Thisreactionishighlychemoselectiveandafford 46,providedthatsufficientcatalyst(2%Pd (OAc)2)ispresent.Iflowcatalystloadingisused(0.2mol%),substantialamounts ofregioisomeric2-iminooxazolidineareproduced(Scheme 10).
Scheme9 Ring-expansiontoimidazolidinoneinvolvingalkenylaziridines
Scheme10 Pd-Catalyzedexpansiontoimidazolidininones
R1 = Bn
R2 = H, Me
R3 = Ph, Bn, Ar
Scheme11 Anenantioselectiveversionofthisringexpansion
AninterestingdevelopmentofthisreactionwasdevisedbyTrostin2003 [41].Byintroducingachiralligand 49 inthepalladiumcatalyst,itispossibleto producethecorrespondingvinyloxazolidinones 48 from 47 withhighyieldand enantiomericexcess(Scheme 11).Thisdynamickineticasymmetrictransformation (DYKAT)processwaslateronemployedasakeysteptoproduceimidazolidinone 50,whichservedasthekeybuildingblockforthesynthesisof(+)-pseudodistomin D 51,analkaloidofmarineoriginshowingpotentcytotoxicityagainstcancercell lines[42](Scheme 11).
Scheme12 Ringexpansiontovariousfivememberedrings
2.1.3ExpansionsintoOtherFive-MemberedRings Numerousotherring-expansionprocessesleadingtofive-memberedringshave beenreported.Scheme 12,(compounds 52–59)outlinessomeexamples,featuring ineachcasethetypeofobtainedheterocycle,thestartingaziridine,andthe conditionsforthereaction[43–46].
2.1.4ExpansionsintoSix-andSeven-MemberedRings Expansionsofnonactivatedaziridinesleadingtolargerringsarescarce.Inhis ongoingstudyonDYKATprocesspresentedabove(Scheme 11),Trostdescribed thePd-catalyzedannulationofvinylaziridineswithpyrrole 60 [47].Thisreaction affordedpyrrolopiperazinone 63 withexcellentyieldsandenantioselectivity,and theproducedcompoundcouldthenbefurtherelaboratedintoepimericpyrrolic alkaloidcompoundsAgesamidesAandB 64 (Scheme 13).Itisworthytonotehere theabsenceofanyadditivenecessaryforoptimizationofthecatalyticreaction.
Recently,aringexpansionofaziridine2-carboxylicacidsuponactivationwith oxalylchloridewasreportedbyWulff[48].Theoutcomeofthisreactiondepends ondifferentparameters,includingthenatureofthesolvent(presence/absenceof DMF),thebulkinessoftheprotectinggrouponthenitrogenatom,andthedegreeof substitutionoftheC-2carbonontheaziridinering.Forexample,whenaziridine 65 wasreactedfollowingconditionsinScheme 14,thenmorpholinetrione 66 was exclusivelyformed.
Inordertoclosethissection,arecentreportfromSaitoetal.[49]deservestobe presented.Wepreviouslymentionedthethermalreactionofphenylisocyanatewith 2-alkenylaziridines(Scheme 8),whichisnotselective.Adifferentbehaviorcanbe seenwiththemoreelectrophilic N-sulfonylisocyanate.Inthatcase,notonlydoes ringexpansionoccurmuchmorerapidlywithoutheating,butitleadsselectivelyto
Scheme13 Enantioselectiveringexpansionintopyrrolopiperazinone
Scheme14 Ringexpansiontomorpholinetrione
= DMB, Bu, Cy
Scheme15 Ringexpansiontoseven-memberedring
theseven-memberedurea 68 startingfrom 67 (Scheme 15).Theoutcomeofthis reactionwasfoundtoheavilydependontherelativestereochemistryofthe substituentinthestartingaziridine,because trans-69 gaveseven-memberedurea 70 inexcellentyield,whilethe cis-compound 71 reactedsluggishlytogiveurea 72 inlowyield.Thiscouldbeexplainedbyananalysisoftheconformationalequilibriuminthereactingaziridines:inthe cis-isomer,themorestableinvertomeris 73,inwhichthelonepairofthenitrogenatomisshieldedbytheadjacentsubstituentsandcannotleadtotheproductivezwitterion 74 forringexpansion.
ReactionthereforeproceedsviaaSN1process,whichismoreenergeticandleadsto five-memberedureaasshowninScheme 15.
2.2RingExpansionsInvolvingOnlytheIntroduction
ofCarbonAtoms 2.2.1ExpansionintoAzetidinesandAzetidinones
Themostsimplehomologationconceivablefromaziridinesleadstoazetidinesand wasillustratedonlyrecentlybyDeKimpe[50, 51]inanintramolecularfashion (Scheme 16).
N-Benzylaziridines 75,appendedwithbothamethylandabromomethylarmon theC-2position,canundergoanucleophilicbromidedisplacementtoproducea bicyclicazetidiniumion 76,whichisthenregioselectivelyringopenedattheC-3 positionbyvariousanionicnucleophilestodeliverazetidines 77.Thepresenceof themethylgroupwasproventobeindispensabletoobserveringexpansion,which wasinterpretedasaThorpe–Ingoldeffectcriticaltoformthestrainedazetidinium ion.Thisworkallowedtherationalizationofpreviouslyobservedsidereactions involving2-(halomethyl)azetidines[52, 53].
Thesametypeofrearrangement(Scheme 17)canbeappliedtothepreparation ofazetidinonesfromaziridinecarboxylatesasshownbyCloughin1974[54]and reinvestigatedmorethan30yearslaterbySharma[55]andveryrecentlyoptimized byCroussewithtrifluoro-substitutedaziridines[56].
Inthisreaction,thecarboxylateatC2ofaziridine 78 istransformedintoan activatedcarbonylgroup,usingvarioushalogenatingreagents(SOCl2,oxalyl chloride,POCl3,PPh3Br2),thelatterbeingthemostefficient,probablyleadingto averyuncommonandreactivequaternary N-acylaziridiniumion 79,
stereoselectivelyopenedbytheliberatedchloride/bromideaniontogiveexclusivelythe cis-azetidinone 80.
Thisbringsustothemostreportedreactionconvertingaziridinesinto azetidinones,thecarbonylationprocessinvolvingcarbonmonoxideinsertioninto aC–Nbondofthereactant.TheprominentinvestigatorinthatfieldwasAlper,who reportedin1983thefirstexampleofcarbonylativetransformationofaziridineof type 81 into β-lactam 82 usingarhodium(I)catalyst(Scheme 18)[57].
Carbonylationoccurredexclusivelybetweenthemostsubstitutedcarbonandthe nitrogenatomswithoutproductionof 83.Thesamecatalystwaslateremployedfor thecarbonylationofenantioenrichedaziridinesleading,withoutlossofoptical purity,tothecorresponding β-lactams.Aremarkableenantioselectivekinetic resolutionprocesswasdeveloped((rac 84 leadingto(S)-85 and(R)-86),usinga mixedsystemrhodium(I)/menthol[58](Scheme 19).
Thistransformationwasveryefficientlyconductedusingasolid-supportedand dendriticrhodium(I)catalystbythesameauthor[59].Notethatonlyaziridineswith aryl-substituentsarereactivetowardrhodium,andthiswasrationalizedin2006by Sordo[60],whopresentedcomputationalresultsalsoexplainingthe regioselectivityofthiscarbonylationprocess.In2-arylaziridines,asignificant hyperconjugativeeffectweakensthemoresubstitutedC–Nbondandthusfacilitatesrhodiuminsertionintothatbond.Inparallel,Alpercircumventedthislackof reactivityofnonactivatedaziridines 87 byusingdicobaltoctacarbonylascatalyst, andyielding 88,asdepictedinScheme 20 [61].
Thismoreactivecatalystalsoinducesareversalofregioselectivityforcarbonylation,sincenowthelesssubstitutedpositionispreferredfortheCOinsertion.
Scheme18 Rh-catalyzed COinsertion
20 atm, PhH
[Rh(CO)2Cl]2 5% quant.
Scheme19 Enantio selectiveRh-catalyzedCO insertion
Scheme20 Co-catalyzed COinsertion
20 atm, PhH
[Rh(COD)Cl]2 5% (-)-menthol 3 equiv.
(rac) 84 (S)-85, 25 %
(R)-86, 56 % 85 % ee
33 atm, DME
8% 24 h, 100°C
, 94%
Scheme21 Regioselective Co-catalyzedCOinsertion
33 atm, DME
Co2(CO)8 8% 16 h, 100°C
Scheme22 Stereo specificityoftheCocatalyzedCOinsertion
Scheme23 Ringexpansiontoapolycyclic β-lactam
cis-91 trans-93,95%
-92
33 atm, DME
Co2(CO)8 8% 16 h, 100°C
Co2(CO)8 1 eq. rt, 18h 61 %
-94, 40%
Thismethodologywasappliedtofunctionalizedsubstratesbearingtwosubstituents ina cis-relationship(Scheme 21).
Withtheseconditions,carbonylationoccursin 89 atthemethyl-bearingposition (only8%oftheotherregioisomerisobserved),andtherelativeconfigurationinthe finalproductascertainsastereospecificnucleophilicringopeningbythecobalt catalystsinceonly trans isomer 90 isobserved[62, 63].Later,Prati[64]conducted amoreextensivestudyontheinfluenceofringsubstituentsontheregioselectivity ofcarbonylationreactionswiththesamecobaltcatalyst,additionallydemonstrating thestereospecificityofthereactionstartingfromboth cis-91 and trans-92 substrates andyielding trans-93 and cis-94 respectively(Scheme 22).
Pratithenemployedthismethodologytopreparebicyclic β-lactams[65].An isolatedexamplewitha2-silylatedaziridinewasdescribedbyAggarwal[66],while Coatesreportedtheuseofawell-definedbimetalliccatalyst[Cp2Ti(thf)2]+[Co (CO)4] forthesecarbonylationsofnonactivatedaziridines[67]andlaterreviewed thistopic[68].Finally,dicobaltoctacarbonylwasveryrecentlyemployedinCO insertionreactionswithafascinatingclassofcompounds,2,6-diazasemibullvalenes 95 (Scheme 23).Here,Xi[69]describedthespontaneousformationof β-lactam 96 undertheactionofoneequivalentofdicobaltoctacarbonylatroomtemperature.
Inparallel,Alperrecognized[70]thepotentialofferedbynonactivated 2-vinylaziridinesinthesecarbonylationreactions.Theseparticularsubstrates engagedveryefficientlyin β-lactamformationundertheactionofdiiron nonacarbonyl.Inthisfield,Ley[71]showedthataziridine 97 canbetreatedwith
Scheme24 COinsertionintoanalkenylaziridine
Scheme25 COinsertionintoabicyclicalkenylaziridine
1 atm, CH2Cl2
10 mol%
40mol%
Scheme26 COinsertionleadingtoa α-methylene β-lactam
diironnonacarbonylundersonicationtooffer π-allyltricarbonylironcomplex 98 for whichitwasdemonstratedthatketonereductionwaspossibletogive 99.Final decomplexationusingtrimethylamine N-oxidedelivered β-lactam 100.Moreover, thisreactantallowedtheinterceptionofareactionintermediateinthecarbonylative process(Scheme 24).
Thevinylaziridinemotifcanbeembeddedinabicyclicstructure 101 asreported byBurger[72].Inthiscase,finalirondecomplexationfrom 102 wasperformed withceriumammoniumnitratetogive β-lactam 103 ingoodyield(Scheme 25).
Methylene-aziridinessuchas 104 arealsoviablesubstratesforcarbonylation reactions,asAlper[73]reportedin1987theformationof β-lactamswithan exomethyleneusingthistimeacatalyticprocessbasedonpalladium(0).Insertion occursherebycleavageofthenitrogen–sp2 carbonbondleadingexclusivelyto α-methylene-β-lactam 105 (Scheme 26).
Thesemethylene-aziridines 106 canalsoleadto β-lactamderivativesthrough otherunconventionalprocesses.Thus,Shipmandevisedareactionsequence allowingforthepreparationofaverydiversearrayof β-lactamsbysequential nucleophilic/electrophilicfunctionalizationofamethylene-aziridine 106,deliveringanimine 108 via 107 whichisthenengagedina[2+2]Staudingercycloaddition withaketene[74].Thissequential,one-potfour-componenttransformationgives
= PMB, Bn, CyH)
Scheme27 Stepwiseringexpansionleadingtoa β-lactam
Scheme28 Ringexpansionintoimino-β-lactam
accessto β-lactams 109 bearingaquaternarycenteringoodoverallyields(46–58%)(Scheme 27).
Toclosethissection,anintriguingtransformationreportedbyDeKimpeupon reactionofmethylene-aziridineswithsulfonylazidesleadingtocyclicfourmemberedamidinesdeservesamention[75].Uponcycloadditionbetweenthe alkenemoietyof 110 andasulfonylazide,intermediate 111 isformedthat decomposestodipole 112,thenevolvinginasemipinacol-typerearrangementto delivertheimino-β-lactamderivative 113 inexcellentyields(Scheme 28).
2.2.2RingExpansiontoPyrrolidines,Pyrroles,Pyrrolines, andPyrrolidinones Insertionofatwo-carbonfragmentintotheaziridinebackbonecanberealizedin twodifferentways,followingtheclassicalinsertionintotheintuitivelyweakestC–Nbond,asshownpreviously,althoughamoreintriguingC–Cbondscissionofthe three-memberedringcanalsooperate.Wewillbeginthissectionwithsuch processes,whereaziridinesareconvertedintoazomethineylidesandthenreact through1,3dipolarcycloadditionswithtwo-carbondipolarophilesleadingto pyrrolidineandpyrrolederivatives.
Althoughnotrecognizedassuch,thefirstexampleofazomethineylidegenerationfromanaziridinedatesbackto1965,whenHeine[76]heatedamixtureof 114 withdiethylacetylenedicarboxylate(DEAC)andobservedtheformationof 116, whichwasconvertedintopyrrole 117 forauthenticationpurposes.Underthermal conditions,azomethineylide 115 canbegeneratedandtrappedbythealkyne (Scheme 29).
Inthefollowingyears,Huisgen[77, 78]brilliantlydemonstratedthevalidityof thenewlyintroducedWoodward–HoffmannruleswiththestereospecificcycloadditionofDEAContotheisomericylidesgeneratedfrom cis-or trans-aziridines 118 (Scheme 30).
Scheme29 Ringexpansionintoapyrrole
CO2Et cis-119 cis-120
Scheme30 Ringexpansionsintopyrrolines
Hence,theconrotatorythermalprocessofringopeninggivesa trans-ylide 119 from cis-aziridine 118,whichthenrapidlyreactswithDEACtogive transpyrroline 120.Conversely, trans-aziridine 118 produces cis-ylide 119 thenleading to cis-pyrroline 120.Itwasrecognizedthatylides cis/trans 119 couldinterconvert, butthatthisequilibriumisfarslowerthanthe1,3-dipolarcycloadditionprocess, henceallowingtheisolationofvirtuallypurepyrrolinediastereomers 120. Sincethen,numerousstudieshaveexploitedthefacilegenerationofazomethine ylidesfromaziridines,whichtheneasilyengageincycloadditionreactionswith unsaturatedmoieties.Thistopicwasreviewedin2005byColdham([79]; azomethineylidesgeneratedfromaziridinesaretreatedinpages2797–2795).In particular,manychemistsfocusedtheirattentiononintramolecular 1,3-cycloadditions,involvingageneratedylideandanappendedcarbon–carbon doubleortriplebond.Wewillillustratethistopicwithtwoexampleswherethe attachedunsaturationcanbeeitherlinkedtotheaziridinenitrogenatomoralternativelyonthecarbonofthering.Thefirsttypeofthesesituationshasbeenvery seldomlystudied,butPadwa[80]reportedaninterestingexample(Scheme 31). Whenaziridinecis-121,fittedwithanalkenoatemoietyattachedtothenitrogen atomoftheheterocyle,isheatedunderrefluxintoluene,itcangiverisetoylide 122,whichisinrapidequilibriumatthistemperaturebetweenthe cis and trans forms;intramolecularcycloadditionthendeliversbicyclicstructures 123 with endo/exo isomerismforthearomaticsubstituent.Almostequimolaramountsof theseisomersareobtainedstressingthat,inthiscontext,interconversionbetween twoylidesisrapidcomparedtocycloaddition;moreover,heatingof trans-aziridine 121 resultsinexactlythesameproductratio.
Scheme31 Intramolecularcycloadditionleadingtobicyclicadduct
1. H2, Pd(OH)2 2. LiOH
DPPA
1. EtSH, BF3.Et2O
2. I2, PPh3
3. DBU
%
HCl 2. Ac2O, NEt3 then H2O2, TFAA
Scheme32 Intramolecularcycloadditionleadingtoapyrrolidine
Alternatively,theunsaturatedchaincanbeattachedtoacarbonoftheaziridine ring.Toillustratethatarrangement,wewillexaminethetotalsynthesisofanecine basebyOgasawaradepictedinScheme 32 [81].Aziridine 124 ispreparedintwo stepsfrombenzyl-protectedenantiopureglycidolandcanundergoanintramolecularcycloadditionuponquickheatinginrefluxingdiphenylethertogivethe bicyclicadduct 125 asthemajorisomer.Remarkably,sincethisreactionproceeds throughaplanarazomethineylide,thestereochemistryoftheaziridineringis unimportant,onlythechiralcenterontheoxygenatedchaincontrolsthestereochemicaloutcomeofthecyclization.Fromthisbicycliccompound 125,thetotal synthesisofdihydroheliotridane 126 wasachievedin11steps.
Inthemostrecentadvances,chemistshaveturnedtheirattentiontoaziridines withlesselectron-withdrawinggroups.Hence,Khlebnikov[82]reportedthegenerationofazomethineylidesfromaziridine 127 toreactitwithDMDA(dimethyl acetylenedicarboxylate)orevenfullerene(Scheme 33).Inthelattercase,as fullereneisapoorpartnerincycloadditionreactions,theauthorsfounditadvantageoustoperformthesynthesisundermicrowaveirradiation.Inalldipolarcycloadditionsinvolvingylidesoftype 128,only cis-pyrrolinederivatives 129 or pyrrolidinofullerene 130 wereobserved.
More“conventional”ylideswereusedbyPinhoeMelo[83],thenoveltyofthis studylyingintheuseofallenoatepartnersasdipolarophiles.Thus,microwave heatingofketoaziridine 131 generatesanylidethatreactsregio-andstereoselectivelywiththeconjugateddoublebondofallenoatestogivestereoselectively pyrrolidine 132 (Scheme 34).
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“In this condition of mind and body he remained in the city for some time, wandering about here and there; until one day, while standing at the Worsham House corner, he became involved in a quarrel with one James Dolan, a member of the Eighth Missouri Regiment, a large and powerful man, while Black was a man of medium height and stature. Words between the parties waged furious, and finally Dolan struck Black with a cane which he had with him; but quickly warding off the blow, Black wrenched the cane from his adversary and dealt him a blow, which so fractured the skull of Dolan as to cause death within a short time thereafter Black effected his escape from the city, and with a couple of accomplices, began a system of wholesale murder and robbery on the Hernando road. The atrocity and boldness of these acts created the greatest excitement in Memphis.
“Several parties were robbed of sums varying from one to as high as ten thousand dollars, and, in one instance, a speculator was compelled to disgorge to the amount of five thousand dollars in gold. Of course, these rascals, of whom Black was the leader, often met with men who would make resistance rather than give up their money; and in this way no less than three or four fell victims to the fiendish spirit exhibited by these scoundrels. It was finally agreed upon by the military commanders of the district, on both sides, that means should be taken which would insure their capture. Accordingly a squad of Blythe’s battalion, of the rebel army, were sent in pursuit, and succeeded in capturing, about ten miles out of the city, Black and his companion, a fellow young in years, named Whelan. They were placed in the guard-house in Hernando, we believe, and at a pre-concerted signal attacked the guard, and mounting some horses belonging to the soldiers, made off at a rapid rate. The guard immediately started in pursuit, and coming upon Whelan, who was some distance behind Black, shot and killed him. Black again escaped, and applied himself with more vigor than ever to the plundering, stealing and robbing of everybody and everything that came within his reach. He would frequently ride into this city at night, passing through the lines at will; and, as an instance of his audacity, on one occasion rode down Adams street, and fired several shots into the station house. It was reported that he had
accumulated large sums of money, and the report proved correct. As his business became either too tiresome or too dangerous, he came to the city, disguised, and took passage on a boat for the North. Since that time, and until recently, nothing has been heard from him. It seems that after leaving Memphis, he went to St. Paul, Minnesota, and embarked in the staging and saloon business, under his proper name, John Keene. His restless spirit could not stand the monotony of such a dull business (to him), and, organizing a band of some twenty men, he started for the Territories.”
CHAPTER XXIX.