化學(xué)論文英文版

Jun-KeWang,Ying-XiaoZong,Xi-CunWang,Yu-LaiHu,Guo-RenYue.Synthesisof

N-benzothiazol-2-yl-amidesbyPd-catalyzedC(sp2)-Hfunctionalization[J].CCL,2015,26(11):1376-1380

Synthesisof

N-benzothiazol-2-yl-amidesbyPd-catalyzedC(sp2)-HfunctionalizationJun-KeWanga,b,c,Ying-XiaoZonga,b,Xi-CunWanga,b

,Yu-LaiHua,b

,Guo-RenYuea

a

KeyLaboratoryofHexiCorridorResourcesUtilizationofGansuUniversities,CollegeofChemistryandChemicalEngineering,HexiUniversity,Zhangye734000,China;

b

GansuKeyLaboratoryofPolymerMaterials,CollegeofChemistryandChemicalEngineering,NorthwestNormalUniversity,Lanzhou730070,China;

c

GansuEngineeringLaboratoryofAppliedMycology,HexiUniversity,Zhangye734000,ChinaReceived11May2015,Receivedinrevisedform29June2015,Accepted1July2015,Availableonline10August2015.E-mailaddresses:wangxicun@;huyulai@126.comAbstract:Acatalyticsynthesisof

N-benzothiazol-2-yl-amidesfrom1-acyl-3-(phenyl)thioureaswasachievedinthepresenceofapalladiumcatalystthroughtheC(sp2)-Hfunctionalization/C-Sbondformation.Thissyntheticmethodologycanproducevarious

N-benzothiazol-2-yl-amidesinhighyieldswithgoodfunctionalgrouptolerance.Keywords:

Benzothiazole

Pd-catalyzed

1-Acyl-3-phenylthiourea

C-Hfunctionalization

L-Proline

1.IntroductionThebenzothiazolemoietyisanimportantscaffoldduetoitswidespreadoccurrenceinbioactivenaturalproducts,pharmaceuticals,organicoptoelectronicmaterials,andligandsforphosphorescentcomplexes[1-4].Inparticular,substitutedNbenzothiazol-2-yl-amidesareanimportantclassofheterocycliccompoundsthatexhibitawiderangeofbiologicalproperties[5-9]suchasubiquitinligaseinhibition

[5],antitumor

[6],antirotavirusinfections

[7],modulatingtheadenosinereceptor

[8,

9],andthenuclearhormonereceptor

[9].Forexample,the

N-benzothiazol-2-yl-cyclohexanecarboxamide,asanewanticancerdrug,wasselectedasoneofthemostpromisingscreeninghitcompounds(Fig.1)

[6].Theacylationreactionfrom2-aminobenzothiazole,oneoftheclassicalmethodsforthepreparationofthesemolecules

[5,

6],isknownforthelimiteddiversityofthecommerciallyavailablestartingmaterials.Furthermore,thepreparationof2-aminobenzothiazolealsorequiredtheuseofthetoxicbromine.ThepastseveralyearshavewitnessedthegreatprogressinthedevelopmentoftheC-Sbondformationpromotedbytransitionmetals,whichcanprovidemoreefficient,practical,andstraightforwardapproachestovaluablesulfur-containingcompounds

[10,

11].However,thesemethodshavebeenmainlyfocusedonthe‘‘traditional’’cross-couplingreactionsofArX(X=Cl,Br,I,OTf,andB(OH)2)andsulfides[12-39].ToachievegreenerandmoreatomeconomicC-Sbondformations,transitionmetal-catalyzeddirectoxidativecross-couplingofC-Hbondsandsulfideswouldbeideal[40-47].Inourpreviouswork,wehaveshownthatN-benzothiazol-2-ylamidescanbesynthesizedsmoothlybyCu-catalyzedintramolecularcyclizationofvarioussubstituted1-acyl-3-(2-bromophenyl)thioureas

[48].ThismethodcanprovidemorediversiformNbenzothiazol-2-yl-amidesthroughthecarbon-heteroatomformationunderrelativelymildconditionsandavoidtheuseofthetoxicbromine.However,thedrawbackofthisprocedureisthelimiteddiversityofthecommerciallyavailablestartingmaterialsduetotheuseofsubstitutedortho-haloarylamines.InordertofurtherextendthediversityofN-benzothiazol-2-yl-amides,wehaverecentlydemonstratedanefficientintramolecularcyclizationofsubstituted1-acetyl-3-(2-phenyl)thioureacatalyzedbyironthroughC-Hfunctionalization

[49].ThismethodcanprovidemorediversiformN-benzothiazol-2-yl-amidesunderrelativelymildconditions.However,thepurificationofthetargetcompoundsischallengingusingthecolumnchromatographyorrecrystallization,sinceitisinescapabletoobtain1-acetyl-3-phenylureawhosepolarityissimilartothatof1-acetyl-3-(2-phenyl)thiourea.Recently,Doi’sgroup

[46]

reportedaPd-catalyzedsynthesisof2-substitutedbenzothiazolesviaaC-HFunctionalizationreaction.Therefore,weenvisionedthatPd-catalyzedcyclizationof1-acyl-3-(2-phenyl)-thiourea

1wouldrepresentaviablemethodfortheformationandpurificationofsubstitutedN-benzothiazol-2-yl-amides

2(Scheme1).mol%),CuI(20mol%),Cs2CO3

(2equiv.),L-proline(20mol%)inDMSO(4mL)within8hat100℃.Inresponsetothisencouragingresult,weusedarangeofsubstituted1-acetyl-3-(phenyl)thioureastoinvestigatethescopeandlimitationofthisreaction.Thecorrespondingproductswereobtainedinexcellentyields(88%-98%).Theresultsobtainedundertheoptimizedconditionsarelistedin

Table2.Initially,thesubstituentsofphenylwerescreened.Theresultsdemonstratethatlittleeffectofthesubstitutedgroupsonthebenzeneringwasobservedforthistransformation.Furthermore,substituentsatdifferentpositionsofthephenylringdonotsignificantlyaffecttheefficiency(Table2,entries1-8).Itisnoteworthythatthehalosubstitutedbenzenessurvivedleadingtohalo-substitutedproducts,whichcanbeusedforfurthertransformations(Table2,entries2,7,8and11).InordertomakethenewSankyoinvestigationaldrugs,theRgroupwasselectedasacyclohexyltogivethecorrespondingproducts(Table2,entries10-12).Althoughextensivestudiesonreactionmechanismhavenotyetbeencarriedout,theproposedmechanismcanbeproposedaccordingtothesimilarpalladium-catalyzedprocesses

[51]

(Scheme3).1-Acetyl-3-(phenyl)thioureawasconvertedtothethioenolateinthepresenceofCs2CO3.Pre-associationofthesulphuratominthethioenolatetoPd(OAc)2facilitatestheorthopalladationprocesswiththeconcomitantreleaseofchlorideion.Theformationofthesix-memberedpalladacycleandthesubsequentreductiveeliminationleadstoN-benzothiazol-2-yl-amideandPd(0).ThePd(0)speciesarereoxidizedtoPd(II)byCuI,thuscompletingthecatalyticcycle.4.ConclusionInconclusion,wehaveachievedanefficientintramolecularcyclizationofsubstituted1-acetyl-3-(2-phenyl)thioureascatalyzedbypalladium(II)catalyststhroughC(sp2)-Hfunctionalization.ThismethodcanprovidemorediversiformN-benzothiazol-2-yl-amidesefficientlyandquicklyinhighyieldsunderrelativelymildconditions.Thecombinationofthegeneralitywithrespecttothesubstratescopeandfacileaccessibilitytothestartingmaterialsmaygeneratenumeroussyntheticpossibilities.Furthermechanisticanalysisofthesereactionswillbethesubjectoffuturework.AcknowledgmentsThisworkwassupportedbytheNationalNaturalScienceFoundationofChina(Nos.21462016,21262010),NaturalScienceFoundationofGansuProvinceandtheAdvancedResearchFundofJinchuanGroupCo.,Ltd.References[1]R.S.Keri,M.R.Patil,S.A.Patil,S.Budagumpi,Acomprehensivereviewincurrentdevelopmentsofbenzothiazole-basedmoleculesinmedicinalchemistry,

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