DHP THP羟基保护与脱保护方法

e(CuSO4Æ5H2O):amildandetrahydropyranylation/alcChofTecAugue11S.IlartedemarproThetetrahydropyranyl(THP)groupisfrequentlyusedhydrateandsteroidchemistry.Tetrahydropyranylation2involvementofexpensiveandmoisturesensitivecata-lystsandsomeofthemhavetobepreparedpriortouse.4,8,9,14ThereisaneedforagreenercatalyticallyhydropyranylationbecauseofitsmildLewisacidity.Keyword:Protectionofhydroxylcompounds.*Correspondingauthor.Tel.:+913612582305;fax:+913612690762;e-mail:atk@postmark.net12CuSO4.5H2OCH3OHOCH3O/rt/2-6hScheme1.R=alkyl/aryl/sugarresidue/nucleosideresidue.TetrahedronLetters45(2004)7891–7894TetrahedronLettersofalcoholscanbeaccomplishedbyusingp-TSA,BF3ÆOEt23andPPTS.4SomeoftherecentlyusedreagentsthatcancatalyzebothtetrahydropyranylationanddepyranylationareZrCl4,5I2,6LiBr,7acetonyltri-phenylphosphoniumbromide(ATPB),8TBATB,9aluminiumchloridehexahydrate,10In(OTf)3,11dialkylimidazoliumtetrachloroaluminates,12InCl3immobilizedinionicliquids13andbromodimethylsulfo-niumbromide.14Ontheotherhand,manymethodshavealsobeendevelopedbyusingheterogeneouscata-lysts,andthesehavebeenreviewedrecently.15However,someoftheseprocedureshavesomedifficultiessuchasrequirementofmuchlongerreactiontimes,incompati-bilitywithotheracid-sensitivefunctionalgroups,3,9,10,13Inthispaperwedisclosethatcupricsulfatepentahy-dratecanbeusedasanefficientcatalystfortetrahydro-pyranylation/depyranylationofalcoholsandphenolsasshowninScheme1.Whenamixtureof1-hexadecanol1aand3,4-dihydro-2H-pyranwastreatedwith20mol%ofcupricsulfatepentahydrateinacetonitrileassolvent,itwassmoothlyconvertedtothecorrespondingTHPether2awithinCuSO4.5H2OCH3CN/rt/40min-12hOORROHO+fortheprotectionofalcoholsandphenolsduetotheireaseofpreparationandstabilityunderawidevarietyofreactionconditionssuchaswithhydrides,alkylatingreagents,Grignardreagentsandorganometallicreagents.1Inaddition,theyalsoserveasstableprotect-inggroupinpeptide,nucleosideandnucleotide,carbo-efficientmethod,whichmightworkundermildandeconomicallycheaperconditions.Asapartofourongoingresearchprogramtodevelopnewsyntheticmethodologiesinvolvingvariousnewreagents,16,17weperceivedthatcupricsulfatepentahydrate,whichisreadilyavailable,mightbeausefulcatalystfortetra-CupricsulfatepentahydratefficientcatalystfortdepyranylationofAbuT.Khan,*LokmanH.DepartmentofChemistry,IndianInstituteoReceived22July2004;revised15AvailableonlinThispaperisdedicatedtoProfessorHAbstract—Variousalcoholsandphenolscanbesmoothlyconveundermildreactionconditionsatroomtemperature.Someofthgoodyields,lessexpensivecatalystandcompatibilitywithothe�2004ElsevierLtd.Allrightsreserved.0040-4039/$-seefrontmatter�2004ElsevierLtd.Allrightsreserved.doi:10.1016/j.tetlet.2004.08.141oholsandphenolsudhuryandSubrataGhoshhnologyGuwahati,Guwahati781039,Indiast2004;accepted24August2004eptember2004ontheoccasionofher60thbirthdaytothecorrespondingTHPethersusing20mol%CuSO4Æ5H2Ojoradvantagesofthisprocedurearenonaqueouswork-up,verytectinggroups.40minin90%yield.Similarly,4-methoxybenzylalcohol1bwasconvertedtothecorrespondingTHPether2bwithin40minunderidenticalreactionconditions.Althoughdichloromethanecanalsobeused,weemployedacetonitrileassolventbecausedichlorometh-aneisahalogenatedsolventandharmful.Thetetra-hydropyranylationcouldbeachievedonalargescalebetween10and100mmolwithoutanydifficulty.Fol-lowingthetypicalreactionprocedure,18variousbenz-ylic,allylicandsecondaryalcohols1c–iaswellasphenols1j–kweresmoothlytransformedtothecorre-spondingTHPethers2c–k,respectively,inverygoodyields.Remarkably,variousdiolsweretransformedtomonoTHPethers2l–nalongwith5–8%di-THPetherbyusing20mol%catalystinsteadof40mol%catalyst.Thediolscouldbeconvertedtothedi-THPethers2o–pingoodyieldsinasimilarmanner.Invarioussub-stratescontainingotherfunctionalgroupssuchasacetyl,TBDMSandTBDPSethers,isopropylideneprotecteddiolsandbenzylethersweresmoothlycon-vertedtothedesiredTHPethers2q–wingoodyieldsasshowninTable1.AlltheproductswerefullyTable1.TetrahydropyranylationofalcoholsandphenolsinpresenceofacatalyticamountofCuSO4Æ5H2OEntrySubstrate1Time(min)Product2aYieldb(%)aOHnn=1340nOTHPn=1390bOHMeO40MeOOTHP89cOH40OTHP91dClOH45OTHPCl92eOOH40OOTHP90fOH55OTHP87gOH60THPO89hOH55OTHP91iC8H17OH80C8H17THPO85jOHCl95ClOTHP87kOHMeO90OTHPMeO89lOHOH45THPOOH70mOHOHn12hOHOTHPn83c7892A.T.Khanetal./TetrahedronLetters45(2004)7891–7894n=4nOHOH60oOHOH90pOHOHnn=412hqOHOAc40rOHOTBDMS40sOHOTBDPS40n=4OTHPOH55OTHPTHPO92THPOOTHPnn=493THPOOAc84THPOOTBDMS82THPOOTBDPS82min)sis.ronLTable1(continued)EntrySubstrate1Time(tOHOO50uOOOOOOH85vOBnOBnOOBnOHOMe90wOOHNNOOOO45aAllproductswerecharacterizedbyIR,1HNMRandelementalanalybIsolatedyields.cYieldbasedonstartingmaterialrecovery.Table2.Tetrahydropyranylationof4-methoxybenzylalcohol1busingA.T.Khanetal./TetrahedcharacterizedbyIR,1HNMRspectroscopyandbyele-mentalanalyses.ThemostinterestingfeatureisthattheTHPether2aundergoescleavagewithin5husingsamecatalyst(20mol%)inmethanolin85%yield.19OtherTHPethers2b,2c,2fand2kwereconvertedtotherespectivehydroxylcompounds1b,1c,1fand1kwithin2–6hin80–85%yieldsunderidenticalreactionconditions.Thetetrahydropyranylationof4-methoxybenzylalcohol1bwasinvestigatedwiththevariousformsofcupricsul-fatetofindouttherelativeefficiencies(Table2).Cupricsulfatepentahydrateshowedthehighestcatalyticactiv-ityintermsofreactiontimeandyield.Insummary,thepresentmethodologydemonstratesCu-SO4Æ5H2Oasaneffectivecatalystfortetrahydropyranyl-ation/depyranylationofalcoholsandphenols.Themainadvantagesofourprotocolare:mild,clean,environ-mentallybenignreactionconditionsaswellasgoodyields.Inaddition,ourmethodologymightbeusefulforthesubstratescontainingacid-sensitiveprotectinggroupsbecauseofthealmostneutralreactioncondi-tions.Furthermore,thismethodisalsoexpectedtohavebetterapplicabilityinorganicsynthesisduetothelowcostofthereagent.Webelievethisprotocolwillbeausefuladditiontothemodernsyntheticmethodologies.A.T.K.thankstheDST,NewDelhiforafinancialgrant(GrantNoSP/S1/G-35/98),L.H.C.andS.G.aregratefulvariousformsofcupricsulfateaRunCatalystConversion(%)Time(min/[h])1CuSO4Æ5H2O100452CuSO480[3]3CuSO4ÆSiO290[2.5]4SiO20[3]aReactionsweremonitoredbyGC.toIITGfortheirresearchfellowships.Theauthorsarealsogratefultotherefereeforhisvaluablecommentsandsuggestions.ReferencesandnotesAcknowledgementsProduct2aYieldb(%)OTHPOO85OOOOOOTHP83OBnOBnOOBnTHPOOMe81OTHPONNOOOO90etters45(2004)7891–789478931.Greene,T.W.;Wuts,P.G.M.ProtectiveGroupsinOrganicSynthesis,3rded.;JohnWiley&Sons:NewYork,1999;p49.2.(a)Corey,E.J.;Niwa,H.;Knolle,J.J.Am.Chem.Soc.1978,100,1942;(b)Bernady,K.F.;Floyd,M.B.;Poletto,J.F.;Weiss,M.J.J.Org.Chem.1979,44,1438.3.Alper,H.;Dinkes,L.Synthesis1972,81.4.Miyashita,M.;Yoshikoshi,A.;Grieco,P.A.J.Org.Chem.1977,42,3772.5.Rezai,N.;Meybodi,F.A.;Salehi,P.Synth.Commun.2000,30,1799.6.Deka,N.;Sarma,J.C.Synth.Commun.2000,30,4435.7.Reddy,M.A.;Reddy,L.R.;Bhanumathi,N.;Rao,K.R.Synth.Commun.2000,30,4323.8.Hon,Y.-S.;Lee,C.-F.TetrahedronLett.1999,40,2389.9.Naik,S.;Gopinath,R.;Patel,B.K.TetrahedronLett.2001,42,7679.10.Namboodiri,V.V.;Varma,R.S.TetrahedronLett.2002,43,1143.11.Mineno,T.TetrahedronLett.2002,43,7975.12.Namboodiri,V.V.;Verma,R.S.Chem.Commun.2002,342.13.Yadav,J.S.;SubbaReddy,B.V.;Gnaneshwar,D.NewJ.Chem.2003,202.14.Khan,A.T.;Mondal,E.;Borah,B.M.;Ghosh,S.Eur.J.Org.Chem.2003,4113.15.Sartori,G.;Ballini,R.;Bigi,F.;Bosica,G.;Maggi,R.;Righi,P.Chem.Rev.2004,104,199.16.Khan,A.T.;Mondal,E.;Ghosh,S.;Islam,S.Eur.J.Org.Chem.2004,22,2002.17.Khan,A.T.;Ghosh,S.;Choudhury,L.H.Eur.J.Org.Chem.2004,2198.18.Typicalprocedureofprotection:Intoamixtureof3,4-dihydro-2H-pyran(1.1mmol)andalcoholorphenol(1mmol)inacetonitrile(2mL)wasaddedcupricsulfatepentahydrate(0.05g,0.2mmol)atroomtemperatureandthemixturestirreduntilcompletionofthereactionwasascertainedbythedisappearanceofthealcoholspotonTLC.TheproductwasisolatedinalmostpureformfromthereactionmixturebysimplyfilteringthroughaWhat-man42filterpaperwithoutaqueouswork-up.Thepureproductwasobtainedfromthereactionmixturebypassingitthroughashortcolumnofbasicalumina.Compound2a:IR(Neat):2919,2854,1469,1354,1228,1122,1071,1037;1HNMR(CDCl3):0.85(t,3H,J=6.6Hz),1.22–1.32(m,26H),1.47–1.81(m,8H),3.32–3.38(m,1H),3.44–3.49(m,1H),3.65–3.73(m,1H),3.81–3.87(m,1H),4.54(m,1H).Elementalanalysis:calcdfor,C21H42O2(326.56);C77.24,H12.96,foundC77.08,H12.87.19.Typicalprocedureofdeprotection:ToasolutionofTHPether2a(0.325g,1mmol)inmethanol(5mL)wasaddedcupricsulfatepentahydrate(0.05g,0.2mmol)andthemixturestirredatroomtemp.Thereactionwascompletedwithin5handthesolidcupricsulfatewasfilteredoff.Thesolidresiduewaswashedwithdrymethanol(2·5mL).Afterconcentrationofthecombinedfiltrate,thecruderesiduewaspurifiedthroughashortsilicagelcolumn.Thedesiredcetylalcohol1awasobtained0.206gin85%yield.7894A.T.Khanetal./TetrahedronLetters45(2004)7891–7894 Cupricsulfatepentahydrate(CuSO4middot5H2O):amildandefficientcatalystfortetrahydropyranylation/depyranylationofalcoholsandphenols Acknowledgements Referencesandnotes