Versatile Reagent for the Synthesis of Bis(indolyl) Methanes under Solvent-Free

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Versatile Reagent for the Synthesis of Bis(indolyl) Methanes under Solvent-Free

SyntheticCommunicationsw,38:1760–1767,2008

ISSN0039-7911print/1532-2432online

DOI:

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10.1080/00397910801982118

Lanthanum(III)NitrateHexahydrate:A

VersatileReagentfortheSynthesisof

Bis(indolyl)MethanesunderSolvent-Free

Conditions

J.JonPaulSelvam,M.Srinivasulu,N.Suryakiran,V.Suresh,

S.MallaReddy,andY.Venkateswarlu

OrganicChemistryDivisionI,NaturalProductsLaboratory,Indian

InstituteofChemicalTechnology,Hyderabad,India

Abstract:Amildandef?cientsynthesisofbis(indolyl)methanesbythereactionofindoleswithvariousaldehydesatroomtemperatureinthepresenceofacatalyticamountofaLa(NO3)3.6H2Oaffordedthecorrespondingbis(indolyl)methanesinexcellentyieldsundersolvent-freeconditions.

Keywords:Aldehydes,bis(indolyl)methanes,electrophilicsubstitution,indolesINTRODUCTION

Bis(indolyl)alkanesareabiologicallyusefulclassoforganiccompounds,andalargenumberoftheseindolylmethaneshavebeenisolatedfromterrestrialandmarinenaturalsourcessuchastunicatesandsponges.[1]Forexample,vibrindoleA(3,30-diindolylethane)exhibitsantibacterialactivityand3,30-diindolylmethanehaspotentcarcinogenicproperties.[2]Becauseoftheirwideoccurrenceasnaturalproductsandvariousbiologicalactivities,synthesisofthesebis(indolyl)methaneshaveattractedattention.Recently,oxidizedbis(indolyl)methanescontainingaconjugatedbis(indolyl)skeletonhaveactedascolorimetricsensorsandchromogenicsensors.[3]Inaddition,AddresscorrespondencetoY.Venkateswarlu,OrganicChemistryDivisionI,NaturalProductsLaboratory,IndianInstituteofChemicalTechnology,Hyderabad500007,India.E-mail:luchem@iict.res.in

1760

SynthesisofBis(indolyl)Methanes17611,1-bis(30-indolyl)-1-(p-substitutedphenyl)methanescontainingp-tri?uoro-methyl(DIM-C-p-CF3Ph),p-t-butyl(DIM-C-p-tBuPh),andp-phenyl(DIM-C-p-C6H5Ph)substituentshavebeenidenti?edasanewclassofperoxisomeproliferator-activatedreceptors(PPAR)agoniststhatexhibitantitumorigenicactivity.[4]VariousmethodshavebeendevelopedfortheirsynthesisusingLewisacidcatalystssuchasLiClO4,[5]In(OTf)3,[6]Dy(OTf)3,[7]Sc(OTf)3,[8,9]CAN,[10]ZrOCl2,[11]InCl3,[12]andAlPW12O40,[13]ionicliquids,[14]trichloro-1,3,5-triazine,[15]andpotassiumhydrogensulphate.[16]However,manyofthesereportedmethodssufferfromoneormoredisadvan-tagessuchasharshexperimentalprocedureandreagentsthatareexpensive,moisturesensitive,orhighlytoxicinnature.Amildandef?cientcatalystforthesynthesisofbis(indolyl)methanesishighlydesirable.Inviewofcurrentinterestincatalyticprocesses,thereisameritindevelopingofsynthesisofbis(indolyl)methanesusinginexpensive,mild,http://wendang.chazidian.comanicreactionsusingmildandwater-tolerantcatalystshavereceivedmuchattentioninrecentyearsbecausetheycanconvenientlybehandledandremovedfromthereactionmixture,makingtheexperimentalproceduresimpleandecofriendly.[17]Inthecourseofourongoingsearchforchemoselectivereagentsinthemultistepsynthesisofnaturalproducts,weexploredLa(NO3)3.6H2Oasamildandef?cientcatalystinvariousorganictransformations.[18]Incontinuationofourwork,hereinwereportthesynthesisofbis(indolyl)methanesusingLa(NO3)3.6H2Oundersolvent-freeconditions.

RESULTSANDDISCUSSION

Inthisreport(Scheme1),wedescribeanef?cientmethodforsynthesisofbis(indolyl)methanes.Thismethoddoesnotneedexpensivereagentsorspecialcaretoexcludemoisturefromthereactionmedium.Thereactionproceededef?cientlyandsmoothlyatroomtemperature,andtheproductswereobtainedinexcellentyields.Furthermore,http://wendang.chazidian.com(NO3)3.6H2Oishighlyoxophilic,formsalabilebondwithcarbonyloxygen,andinitiatestheformationofaC-Cbondwithcarbonylcompounds.Thisfeatureoftenallowsasubstoichiometricamountofthecatalysttobeusedtopromoteareaction.We?rstexaminedthereactionofbenzaldehyde(1mmol)

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with

Scheme1.

1762J.J.P.Selvametal.indole(1mmol)inthepresenceofLa(NO3)3.6H2O(5mol%)atroomtemp-eraturetogivethecorrespondingbis(indolyl)methanein96%yield(Table1,Entry1).Tooptimizethereactionconditions,wecarriedoutthereactioninvarioussolventssuchasEtOH,MeOH,CH3CN,CHCl3,andCH2Cl2.However,wefoundthatusing5mol%ofLa(NO3)3.6H2Oundersolvent-freeconditionswasmosteffectiveintermsofreactiontimesaswellasyieldsoftheproducts(Table1).Intheabsenceofthecatalyst,thereactiondoesnotyieldthecorrespondingproductevenafteralongreactiontime(12h).EncouragedbythesuccessofthisreactionusingacatalyticamountofLa(NO3)3.6H2O,wecarriedoutthereactionofvariousaromaticandaliphaticaldehydeswithindolestoaffordthecorrespondingproductinexcellentyields.TheresultsaresummarizedinTable1,clearlyindicatingthatthescopeofthereactionwithrespecttovarioussubstitutedaldehydeswithindolesreactedunderthesereactionconditions.Theeffectofelectronde?ciencyandnatureofthesubstituentsonthearomaticringshowedsomeeffectonthisconversion.Thenitrosubstitutedarylaldehydesrequiredlongerreactiontimestoproducecomparableyieldsthanthoseoftheirsimpleandelectron-richcounterparts.Electron-richaldehydessuchasanisal-dehyde,piperonal,andveratraldehydereactedrapidlywithindoleandsubsti-tutedindolestogivecorrespondingproductsinexcellentyieldswithin2h(Table1,entries2,17,and18)respectively.Further,aliphaticaldehydessuchasn-hexanalandcyclohexanecarboxaldehydetookslightlongerreactiontimes(Table1,entries12and16).Inthiscondensationreaction,indoleformsazafulveniumsaltwithaaldehydes,whichundergofurtheradditionwithasecondmoleculeofindoletoaffordbis(indolyl)methanes.Promptedbythissuccess,weextendedthereactionwithdifferentsubstitutedindolesundersimilarconditionsatroomtemperatureinexcellentyields(Table1).

CONCLUSION

Inconclusionwehavedescribedamildandhighlyef?cientprocedureforthepreparationofbis(indolyl)methanesusingLa(NO3)3.6H2Oundersolvent-freeconditions.

EXPERIMENTALSECTION

GeneralExperimentalProcedure

La(NO3)3.6H2O(5mol%)wasaddedtoaneatmixtureofindole(2mmol)andaldehyde(1mmol),andthereactionwasstirredforanappropriatetime(Table1).Aftercompletionofthereactionasmonitoredbythin-layerchrom-atography(TLC),waterwasaddedandtheproductwasextractedintoethyl

SynthesisofBis(indolyl)Methanes1763Table1.Synthesisofbis(indolyl)methanesusinglanthanum(III)nitratehexahydrate

Yield

Time(%)b

(min)[Ref.]

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4596[5]

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Entry1AldehydeIndolesProducta

26597[5]

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33099[6]

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