A Novel Substitution Process for the Preparation ofAlkoxy-,

J.Am.Chem.Soc.1997,119,245-246245

ANovelSubstitutionProcessforthePreparationofAlkoxy-,Aryloxy-,andAcyloxy-Substituted1,2-Dioxetanes

HashemZahraArghavani,Akhavan-Tafti,*andA.RobertPaulSchaap

A.Eickholt,Lumigen,Inc.,Southfield,24485WestMichiganTenMile48034

Rd.

ReceiVedJuly2,1996

Stabilized1,2-dioxetaneswhichareenzymaticallytriggeredtoundergochemiluminescentdecompositionarewidelyusedinnumerousapplicationsincludingimmunoassays,geneexpres-sionstudies,Westernblotting,Southernblotting,DNAsequenc-ing,andtheidentificationofinfectiousagents.1Thedioxetane4-methoxy-4-(3-phosphoryloxyphenyl)spiro[1,2-dioxetane-3,2′-tricyclo[3.3.1.13,7]decane],disodiumsalt,http://doc.guandang.netmonstructuralfeaturesofthesedioxetanesincludeanalkoxygroup,aspiroadamantylgroup,andaprotectedaryloxidegroup.

Thepreparationofthesealkoxy-substituteddioxetaneshasgenerallybeenaccomplishedbyphotooxygenationofthecorrespondingvinylether.2Othermethodsforpreparingdioxetaneswithalkoxysubstituentsfromthecorrespondingvinylethersareknown,e.g.electron-transferoxidationwithoxygenandtriarylaminiumcationradicalsalts,3oxidationbyCr(VI)orMo(VI)oxidediperoxides,4andoxidationwithtriethylsilylhydrotrioxide.5Nevertheless,thereisnogeneralmethodforsynthesizingdioxetanesincorporatingothertypesofgroupsinplaceofthealkoxymoiety.Syntheticmethodsareneededtopreparetriggerabledioxetanesbearinggroupswhichwouldbeadverselyaffectedduringtheoxidationofthevinyletherorwhichwoulddeactivatethevinylethertoward1Oreportageneralmethodforthepreparationofa2.Wenowvarietyofalkoxy-,aryloxy-,andacyloxy-substituteddioxetanesfromacommondioxetaneintermediate.Thisprocessdoesnotrequirethepreparationofeachinpidualvinyletherprecursor.

ThekeyfeatureofthismethodisthereplacementofathiolgroupSR1ofanalkylthio-orarylthio-substituteddioxetanebyoneofvariousoxygennucleophiles(Scheme1).OxidationofvinylsulfideIwith1O2attemperaturesbetween0and-78°Cproducesthesulfur-substituteddioxetaneII.TreatmentofIIwithastoichiometricamountofaLewisacidoxidantsuchasN-chlorosuccinimide(NCS),Hg(OAc)2,orH2Ooxygencompoundleadsto2/Iformation2andanexcessofanucleophilicofoxygen-substituteddioxetanesIIIinmoderateyields.

Thedirectreplacementofagrouponthedioxetaneringwithanothergroupiswithoutprecedentindioxetanechemistry.Further,noreactioninvolvingthedirectintroductionofsub-stituentsonapre-formeddioxetaneringhasbeenreported.ThisnovelreactionsequenceisbestexplainedbyanSN1mechanisminvolvingadioxetanecarbocation(Scheme2).Reactionofthe

A.(1)S.;P.;(a)Akhavan,Schaap,A.P.Photochem.Photobiol.1988,47S,50S.(b)Schaap,J.;(e)Pelletier,Ko¨ster,H.H.;Romano,L.J.Clin.Chem.1989,35,1863.(c)Beck,J.-P.;AnalColman,.Chem.1990R.;Adam,,62,2258.A.(d)Legris,F.;Martel-Pelletier,B.;Bronstein,I.;Olesen,C.E.M.;Martin,J.C.Immun.Meth.1994,168,111.FundamentalsSparks,A.;P.E.,andVoyta,AppliedJ.AspectsC.BioluminescenceS.;Schneider,G.;Edwards,;Campbell,A.andChemiluminescence935.

(2)Eds.;Schaap,Wiley:A.P.;Chichester,K.,Kricka,L.J.,Stanley,Handley,R.1994;S.;Giri,pp269B.-P.272.

TetrahedronLett.1987,Tetrahedron(3)(a)Curci,R.;Lopez,L.;Troisi,L.;Rashid,TetrahedronLett.1987,28,5319.(b)Lopez,L.;S.M.Troisi,K.;Schaap,L.;Mele,A.P.Tetrahedron(4)Curci,LettR.;.Lopez,1991,32L.;,117.

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Nelson,W.M.;Kishimoto,T.;Seliger,S0002-7863(96)02245-7CCC:$14.00Scheme1

Scheme2

electrophileatsulfurconvertsthethioalkylorthioarylsubstituentintoagoodleavinggroupwhichionizestoabenzyliccarbo-cation.Itseemslikelythatthecationiccenterisalsostabilizedbyoverlapwithalonepaironoxygen.Noproductsresultingfromcarbocationicrearrangementswereobserved,althoughthepresenceofunidentifiedminorreactionproductspreventsusfromdefinitivelyexcludingtheirformation.Thelackofsignificantamountsofrearrangedproductscanbeattributedtothethermodynamicstabilityoftheadamantylringsystem.AnSN2mechanismwouldappearunlikelyonstericgrounds.Recently,thenucleophilicsubstitutionofachlorideleavinggrouponanozonidehasbeenreported.6Fluoride-,methoxy-,andacetoxy-substitutedozonidesaccompaniedbyring-openedproductswereformedbyanScasethatN1reaction.Itisparticularlysignificantinthepresenttheadditionalringstrainofthefour-memberedringdoesnotprecludesubstitutioninfavorofringfragmentationasisthecasewithepoxides.7

VinylsulfidesI(R1)C2HpreparedbyTiCl5,CH2CF3,orp-C6H4F)canbe4-initiatedreactionofthecorrespondingaryladamantylketonewiththerequisitemercaptan.8Wehavediscoveredthatvinylsulfidescanalsobeformedbycouplingadamantanoneandathioesterwithalow-valenttitaniumreagentpreparedfromTiCl3andLiAlH4inthepresenceofEt3NinTHF.Thelatterreactionachievesthedirectformationofbothcarbon-carbonbondsofthevinylsulfide.AlthoughtheformationofvinylsulfidesbyreductionofvinylsulfoneswithLiAlH4-TiCl4,9andthereductiveeliminationof -halosulfoxideswithZn-TiCl410havebeenreported,neitherofthesemethodsinvolvesthedirectformationofthesulfur-substitutedC-Cdoublebondfromtwocarbonylcompounds.

PhotooxygenationofvinylsulfideIinthepresenceofeithermethyleneblueorRoseBengalisreadilymonitoredbythinlayerchromatography(TLC)or1HNMRspectroscopybyobservingthedisappearanceofthevinylsulfide.Additionally,heatingasmallportionofthereactionsolutionleadstoeasilydetectablechemiluminescenceindicatingformationofthesulfur-substituteddioxetane.Treatmentofsulfur-substituteddioxe-tanesIIwithF-inDMSOproducesyellowororange-redchemiluminescence.Sulfur-substituteddioxetanesofrelativelylowerthermalstability(Rat-781)C°C2Hwith5)arenotisolatedatthispointbutinsteadreactedacompoundcontainingahydroxylgrouporitssalt.Sulfur-substituteddioxetanesofhigherthermalstability(R1)CH2CF3andp-C6H4F)canbeisolatedfirstorreactedat0to-78°C.ALewisacidoxidant

(6)(7)Griesbaum,K.;Schlindwein,http://doc.guandang.net.Chem.1995,60,8062.(8)Keul,Commun(9)Mukaiyama,H.;Pfeffer,B.;Griesbaum,K.Chem.Ber.1984,117,2193.Akgun,.1994E.;,6,Mahmood,T.;Saigo,K.761.

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