SiYmRnjapanese50m咸熟

ISSN1349-4848number166ResearchArticle-InventionofSyntheticReactionsBasedonσ-BondActivationTamejiroHiyamaRDIProfessor,ResearchandDevelopmentInitiative,ChuoUniversityNewProductsInformation:-Nanodiamond-UsefulCopperReagentforCouplingReactions-LigandsforClickChemistry-Non-detergentSulfobetaines-Cyclitol212CONTENTSCECE+catE=Si,Sn,CN,H;cat:Ni(0),Pd(0)No.
1662ResearchArticleResearchArticleInventionofSyntheticReactionsBasedonσBondActivationTamejiroHiyamaRDIProfessorResearchandDevelopmentInitiative,ChuoUniversity1.
IntroductionDuringmystudieswithProfessorHitosiNozaki,wehadweeklydiscussionsaboutthepresentandfutureofourchemistry.
Itmayhavebeeninthesummerof1980thatProfessorNozakisaidoneday"WhenIgavealectureinEurope,Iaskedtheaudience'Doyouknowareactionsystemthatinvolvesbothcarbanionicandcarbocationicspecies'Noonegavemethecorrectanswer.
"Hethensuggestedthereactionofallylicacetatewithtrialkylaluminum,R3Al,wherebyanallyliccationandalanateareproducedandthealanatedeliversanalkylaniontotheallyliccationiccenter.
Theaudiencethenunderstoodhismeaning.
Thereactionoforganoaluminumsiswell-documented,butProfessorNozaki'sviewisquiteuniqueandstraightforward.
Iamconvincedthisnewpointofview,orphilosophy,isessentialfordevisinganddevelopingnovelsyntheticreactions.
Wehaveobservedthatthereactionoftrimethylaluminumwithdiastereometriccyclopropylmethyl-typeacetatesprovidesthesameproduct,endo-methylatednorcarane,andhaveshownthatthereaction1proceedsviaacommoncyclopropylmethyl-typecarbocationicintermediate(Scheme1).
2.
OrganosiliconReagent/FluorideIonItwouldbefascinatingifboththecationicandanionicspeciesweregeneratedbythecleavageofelement–elementbonds.
Ipicturedareactionschemeinwhichdisilaneandafluorideionproduceasilylanionandfluorosilane,withthefluorosilanebehavingsimilartoanelectrophilicsilylcation.
Ifoundthatwhenhexamethyldisilaneandtetrabutylammoniumfluoride(TBAF)aremixedinhexamethylphosophrictriamide(HMPA)inthepresenceofanaldehyde,carbonylattackofthetrimethylsilylanionoccurs,followedbyO-trimethylsilylation.
Afteraqueousworkup,weobtainedanα-silylalcohol,demonstratingthatthedesignedreaction2workswell.
Heterolysisofanelement–elementbondisconceptuallyrewardingandiscloselyrelatedtotherecentlyestablishedactivationofmolecularhydrogenbyafrustratedbasepair(Scheme2).
SiSiHMPA+n-C10H21CHOn-C10H21COSiMe3HMe3Sin-C10H21COHHMe3SiH3OTBAF(5mol%)67%OCOCH3OCOCH3Me3AlMe3AlHH+H3COOAlCH3CH3CH3Al(CH3)3CH3Scheme2.
Scheme1.
No.
1663Duringthisresearch,Dr.
KiyosiKondo,wholaterbecamethepresidentoftheSagamiChemicalResearchCenter(SCRC),oftenvisitedKyoto.
Dr.
KondorepeatedlyandearnestlyinvitedmetomovetoKyoto.
Ifinallyagreed,andin1981startedmyownresearchgroupatSCRCattheageof34.
Dr.
MichioObayashi,oneofmyfirstPhDcoworkers,soondiscoveredthathexamethyldisilane/TBAFreductivelydisilylatesbutadienes.
Forexample,2,3-dimethyl-1,3-butadieneisconvertedto(E)-1,4-bis(trimethylsilyl)-2,3-dimethyl-2-butene.
2Productformationisbelievedtoinvolveatrimethylsilylanionwhichundergoessingleelectrontransfer(SET)tobutadienetogiveatrimethylsilylradicalandabutadieneradicalanion.
CouplingoftheseattheterminalcarbonshouldgiveaTMSCH2-substitutedallylicanion,whichattackshexamethyldisilanetogivetheproductandasilylanion.
InHMPA,SETshouldreadilyoccurfromanaked(i.
e.
,intheabsenceofametalcounter-ion)hardsilylanion.
Regardless,youmayconsiderthenettransformationasaninsertionofbutadienebetweentheSi-Siσ-bondofhexamethyldisilanes(Scheme3).
Wesetaboutgeneralizingthebasicconceptoforganosiliconcompound/fluorideion-basedreactiontogeneratemetal-free(naked)anionicspecies,andfoundthathalomethyl(trimethyl)silanesandtrifluorovinyl(trimethyl)silaneundergoanadditionreaction3withaldehydes,evenatroomtemperature,upontreatmentwithtris(dimethylamino)sulfurdifluoro(trimethyl)silicate(TASF)inHMPAorTHF.
Thisfindingisremarkablegiventhathalomethyllithiumsandtrifluorovinyllithiumarebothunstableorganometallicspeciesandwerethoughtonlytobegeneratedatextremelylowtemperatures.
Thus,theideathatremovalofametalcounter-ionfromcarbenoids(i.
e.
,organometalswithaleavinggroupontheα-carbon)togeneratenakedcarbanionicspecieswithaleavinggroupontheα-carbonledtothediscoveryofusefulsyntheticreactionsthatcanbeconductedatambienttemperature.
Wefurtherextendedtheconceptoforganosiliconreagents/fluorideion-basedreactiontohydrosilane/fluorideioninthehopeofgeneratinganakedhydride.
Dr.
MakotoFujita,currentlyaprofessorattheUniversityofTokyo,carriedoutreactionsofα-chiralketoneswithdimethylphenylsilane/fluorideionandobservedthreo-selectivereduction.
3WeexpectedthatapentacoordinatehydrosilicateshouldbesufficientlybulkytostereoselectivelyreduceketonecarbonylsaccordingtotheFelkin-Ahnmodeltransitionstate.
Itisreasonabletoassumethathydridoandelectronegativefluorogroupsintrigonalbipyramidalpentacoordinatesilicateshouldbebothapical,andorganicsubstituentslocatingatequatorialpositions.
SincethebondanglesofH–Si–organicgroupsinthetrigonalbipyramideare90°,thepentacoordiantehydrideislikelybulkierthantetrahedral(109.
5°)borohydrides.
Consequently,carbonylgroupsarereducedwithahighlevelofstereoselectivity.
Inanyevent,wefailedtoproduceanakedhydride(Scheme4,5).
4PhSiMeMeHFbulkyreductantH+PhSiMe2Fnakedhydridecounterion:Bu4Nor(Et2N)3SPhSiMe2-H+FRZOHMeMeOZRRZOHMeZ=OR',NR'2,CONR'2HSiMe2PhHSiMe2PhF–H+>95:5>93:7SiSiSiSi+81%,99:1TBAFHMPAScheme5.
Scheme4.
Scheme3.
No.
16643.
Cross-CouplingReactionwithOrganosiliconCompoundsWenextenvisagedwhatwouldhappenifatransitionmetalcatalystwaspresentintheorganosilicon/fluorideionsystem.
Istheorganicgrouponsiliconsuccessfullytransferredtothetransitionmetal,ordoesthefluorideionsimplyattackthetransitionmetalcentertogivemetalfluorideandlosecatalyticactivityTofindout,Dr.
YasuoHatanaka,whoiscurrentlyaprofessoratOsakaCityUniversity,mixedPd(II)complex,TASFasafluoridesource,trimethylvinylsilaneand1-iodonaphthaleneinHMPA,andisolated1-vinylnaphthaleneinanearlyquantitativeyield.
5Hisfindingsdemonstratethatourworkinghypothesiswascorrect;thisnewsilicon-basedcross-couplingreactionwaslaternamedHiyamaCoupling.
TheTASFfluoridesourcemaybereplacedwithTBAForKF.
Tooursurprise,KOHcouldalsoactivatetheC–Sibond.
However,attemptstoextendthisapproachtosubstitutedvinylsilaneswereunsuccessful.
Thislimitationwasovercomebyintroducingafluorineoralkoxygrouponsilicon:thiseffectivelyextendedthescopeofthecross-couplingreactionanddemonstratedthataheteroatomonsiliconassistsformationofpentacoordiatesilicates,anessentialspeciesforsuccessfulreaction.
Atheoreticalstudy6andourintuitionbothsuggestedafour-memberedcyclictransitionstateforthetransmetalationfromSitoPd.
Fluorideisbelievedtoplayakeyroleinthetransmetalation.
Thefollowingschemesummarizesthesilicon-basedcross-couplingreaction(Scheme6).
Halosilanesandalkoxysilanesaresensitivetomoistureandarethusincompatiblewithchromatographicpurification,socross-couplingwiththeseorganosiliconreagentsislessaccessiblecomparedtoSuzuki-Miyauracoupling.
Accordingly,whileProfessorKyokoNozakiwasworkingwithmeinKyoto,sheshowedthatoneorganicgroupontetraorganosilanescanbeinsituconvertedtoahalo-oralkoxygroupbytheactionofafluorideion.
WerecentlyfoundthatC–Ncoupling7isconvenientlyachievedwithtrimethylsilylaminesandallowseasysynthesisoftriarylamineswhichdisplayacharacteristicreactivityprofiledifferentfromthatobtainedusingHartwig–Buchwaldcoupling(Scheme7).
In2004,Dr.
YoshiakiNakao,whoiscurrentlyaprofessoratKyotoUniversity,suggestedusingHOMSi(dimethyl(o-hydroxymethylphenyl)silane)tetraorgansilanereagents8,predictingthattheywouldbeconvertedtoapentacoordinatestructurebyintramolecularnucleophilicattackofthehydroxylgroup.
Protectionofthehydroxylgroupwithacommonprotectinggroupsignificantlystabilizesthesiliconreagentsunderchromatographicseparationandcommonreactionconditions;upondeprotection,thereagentsbecomecoupling-active.
Afterthereaction,thesiliconresidueisrecoveredasacyclicsilylether,whichisreconvertedbacktotheHOMSireagentbyreactionwithorganolithiumor–magnesiumreagents.
Recently,directC–Hsilylationof(hetero)aromaticsandterminalalkeneshasbeendemonstratedstartingwithaTHP-protectedHOMSihydridereagentandaniridiumcatalyst(Scheme8).
Cross-couplingreactionwithHOMSireagentshasrecentlybeenappliedtopolymersynthesisundermildconditions.
Theresultingπ-conjugatedpolymersfindimportantapplicationsaslight-emittingandsolar-cellmaterials(Scheme9).
9Ar–Br+NSiMe3NArPhp-Tolylp-Ph2N-C6H42-Naph90%97%95%99%Ar=Pd(dba)2(1mol%)XPhos(2mol%)CsF(1.
1eq)DMI,100°CPXphostransmetalationreductiveeliminationoxidativeadditionPd(0)FXPdR2SiR1YFYYR1SiSiYFYYXR1R2R2R2XR2PdcatR1–+R1—+FSiYmRnSiYmRn:SiMe3SiMe2F,SiMe2ORSiF2RSiF3R1:vinyl,alkynyl,silyl,NR2alkenyl,arylaryl(R=Et,n-Pr,Cy)allyl(R=Ph)alkyl,allylR1PdR2SiR1YFYYR2XX=FetcPdSiXYmRn–XScheme7.
Scheme6.
No.
16654.
ConjugateadditionofHOMSiReagentsOncewediscoveredthattransmetalationfromSitoPdispossible,weassumedthatthesametransformationfromSitoRhcouldbeachieved.
Indeed,Rh-catalyzedconjugateadditionoforganosiliconreagentshadsomeprecedents.
WecollaboratedwithProfessorTamioHayashi,thenatKyotoUniversityandcurrentlyaprofessoratSingaporeNationalUniversity,andwithDr.
RyoShintani,currentlyaprofessorattheUniversityofTokyo.
Together,weshowedthatHOMSireagentsundergoconjugateadditiontoenones,α,β-unsaturatedesters,andamideswithhighenantioselectionusingachiraldieneligand.
10Hereagain,thecogeneratedcyclicsilyletherisreadilyrecoveredandconvertedbacktothecorrespondingHOMSireagent(Scheme10).
5.
CarbostannylationReactionofAlkynesandDienesIn1997,IwasinvitedbacktoKyotoUniversitytoheadtheresearchgroupofthelateProfessorHidemasaTakaya,andtobeginresearchwithDr.
EijiShirakawa,currentlyaprofessoratKwanseiGakuinUniversity.
Dr.
ShirakawahadbeenexaminingtheMigita-Kosugi-StillecouplingreactionmechanismandhadevidenceforanovelcatalyticcycleinvolvingoxidativeadditionofPd(0)totheC–Snbond,followedbytransmetalationwithorganichalides.
Iwassurprisedathisproposedmechanism,andsuggestedthatinvolvementoftheoxidativeadductC–Pd(II)–SnmayleadtotheinsertionofanunsaturatedC–CbondbetweentheC–PdorPd–Snbond;ifthiswasindeedthecase,thenanewsyntheticreactionmightberealized,leadingtoinsertionofan+[RhCl(C2H4)2]2(1.
5mol%)(R,R)-Ph-bod(3.
3mol%)1.
0MKOHaq.
(15mol%)THF,50°C,5–10hHOSiMe2(R,R)-Ph-bodOMe85%,96%eePhPhMeO1.
5:1Pd[P(o-tolyl)3]2(5.
0mol%)DPPF(5.
3mol%)CuBr·SMe2(7.
5mol%)OSiMe2quantSiSiOctOctYOctOctBrBrNSNNSNXX=Br,H;Y=Si,HMw=2.
3x103;PDI=2.
97Cs2CO3(4.
0mmol)MS3Atoluene/DME50°C,24h++OSiMe2HOSiMe2RTHPOSiMe2RCH3COOSiMe2Rt-BuPh2SiOSiMe2RPdCl2cat.
(CuIcat.
)ligandK2CO3DMSOR,R'=alkenyl,arylR'RR'IMgX/H2ORorLiAlH4,alkyne,Ptcat.
OSiMeRMeOrthogonallyprotectedHOMSireagentsDeprotectionPPTS/MeOHOH,HAI(i-Bu)2FKScheme10.
Scheme9.
Scheme8.
No.
1666alkynebetweentheC–Snbond.
Thisreactionproceededwellandwasnamed'transitionmetal-catalyzedcarbostannylation'.
11Variousorganostannanereagents,andalkynesordienesareapplicabletothetransformation.
Atypicalexample,shownbelow,istheadditionofalkynylstannanetoethynetogive(Z)-but-3-yn-1-enyl(tributyl)stannane.
Thiscarbostannylationreactionhasmadevariousπ-conjugatedorganostannanesaccessible(Scheme11,12).
6.
CarbocyanationReactionofAlkynesandAlkenesIn2002,ProfessorKyotoNozakimovedtotheUniversityofTokyoasafullprofessorandDr.
YoshiakiNakao,currentlyaprofessoratKyotoUniversity,joinedmyresearchgroup.
OnedayhevisitedmetodiscusstheworkofProfessorW.
D.
JonesatRochesterUniversityonthesyntheticpotentialofoxidativeadditionofNi(0)toC–CNbonds.
Iimmediatelysuggestedexaminingthereactioninthepresenceofunsaturatedsubstrates,aswedidforthecarbostannylationreaction.
Toourdelight,acoupleofweekslaterDr.
Nakaotwitteredthatthisapproachwouldbefeasible.
However,theinitialprotocolneeded10mol%ofNi(0)catalystandrequireda1or2daystoachievesyntheticallymeaningfulyields.
Althoughthecatalystwaslazy(theturnovernumberwasroughly6~7),wecalledthenewreactioncarbocyanation(Scheme13).
11Afterwepublishedthefirstpaperonthenewreaction,weimprovedthecatalyticefficiencybyaddingamildLewisacidsuchasorganoaluminum,-borane,or-zinctomakethereactiontrulycatalytic.
12Underthesenewconditions,notonlyarylcyanides,butallylandalkenylcyanideswerealsoapplicable,aswereacetonitriles:CH3–CNwascleavedintoCH3andCNfragmentsandaddedtointernalalkynesinasynmanner(Scheme14).
RCNPrPrPrCNPrRNi(cod)2(1mol%)PMe2Ph(2mol%)AlMe2Cl(4mol%)tolueneR=MeO:Me2N:96%(50°C,16h)87%(80°C,21h)54%(111h)noreactionNi/PMe3(10mol%)at100°C(1.
0mmol)(1.
0mmol)CNPrPr+Ni(cod)2(10mol%)PMe3(20mol%)toluene,100°C,30hCNPrPr(pin)B(pin)B61%1:1PhSnBu3HHSnBu3Ph[PdCl(π-C3H5)]2,L(5mol%)+THF,50°C1atmNPhPPh281%L=Scheme14.
Scheme13.
Scheme12.
CNHexSiMe3CH3CH3CN74%,E/Z=91:9HexSiMe3toluene,80°C,12~21hNi(cod)2(5mol%)PCy2Ph(10mol%)AlMe2Cl(20mol%)+1:1RSn+RSnRSnRSnSnRPdorNicatSn=orSnBu3SnMe3R=acyl,alkynylallyl,vinylScheme11.
No.
16677.
Hydro(hetero)arylationofAlkynesandAlkenesWhilestudyingthecarbocyanationofN-protected3-cyanoindolesundertheoriginalconditions,weobservedtheformationofasmallamountofbyproductandattributedittoC(2)–Hactivationfollowedbyalkyneinsertion.
TuningtheprotectinggroupandligandresultedinC–Hactivationoccurringuniformlywithheteroaromaticsandpolyfluoroaromaticcompounds.
13ThemostsyntheticallysignificantdiscoverywasC(4)-selectivenormalalkylation14ofpyridineswithterminalolefinsusingNi(cod)2/iPrligandandanaluminumLewisacidMAD.
GiventhatpyridineanditshomologsareinerttowardsFriedel-Craftsreaction,site-selectiveheteroarylationwithterminalolefinsprovidesanewroutetothen-alkylationofpyridines(Scheme15).
Theobservedregioselectivityisunderstoodinsofaras(1)thebulkyMADiscoordinatedbythepyridinenitrogen,(2)Ni-Iprinteractswiththepyridineringπ-electrons,(3)stericrepulsionbetweenthemetalcenterscausesNitolocatefarfromthenitrogenandinteractatC(4),(4)Ni(0)isoxidativelyaddedtoC(4)–H,(5)hydronickelationoftheterminalolefinsoccurs,and(6)quickreductiveeliminationiscausedbythetwobulkyligands.
Accordingly,thebulkinessoftheNiligandsandthealuminummetalarekeytoselectivealkylation(Scheme16).
TheconceptofNi(0)/LewisacidisapplicabletoN,N-dimethylformamide(DMF),whoseformylC–HbondoxidativelyaddstoNi(0).
TheresultingNi–Hbondundergoesregioselectiveadditiontoterminalolefins,thensubsequentreductiveeliminationtoproducealkanamideunderone-carbonhomologationofolefin(Scheme17).
15PolyfluorobenzenesundergoC–HactivationbyNi(0)intheabsenceofaLewisacid;itispossiblethatthemostelectrophilicpositionisactivatedtoeffecthydroarylation.
16Accordingly,polyfluorobenzonitrilesfirstundergocarbocyanationandthenhydroarylationoftheinternalalkynestogiveextensivelyπ-conjugatedpolyfluorobenzenes.
17ThestructureoftheoxidativeadductoftheC–CNbondtoNi(0)canbeunambiguouslydeterminedbyX-raycrystallography(Scheme18).
NNi0AlHNAlNiIILHNAlNiIIHLRNAlNiIILRNRHNHRL=IPr;Al=MADNNi0HAlNNi0HAlLLLNAlNiIILHNNOMeAlMe2IPrR2+Ni(cod)2(5mol%)IPr(5mol%)MAD(20mol%)toluene,130°Cmajorminor+NR1NR1R2HNR1HR261%(23h,90:10)91%(10h,>95:5)NHO3NH87%(5h,95:5)NHC11H23t-BuO1:1.
5MADScheme16.
Scheme15.
No.
16688.
ortho-C–HActivationofPhenylSilylethynylEthersandCromaneRingFormationwithAlkynesIretiredfromKyotoUniversityin2010andimmediatelymovedtomypresentpositionattheResearchandDevelopmentInitiative(RDI),ChuoUniversity.
Dr.
YasunoriMinamijoinedmesoonafterreceivinghisPhDfromOsakaUniversity.
Westartedstudyingtheinteractionoftransitionmetalcomplexeswithp-methoxyphenylTIPS-ethynyletherinthepresenceof4-octyne,withtheintentionofcleavingeitheroftheetherealC–Obonds.
However,tooursurprise,theortho-C–HbondwasfoundtobeselectivelyactivatedbyPd(0),allowingincorporationof4-octynetogive2-(TIPS-methylene)benzochromene.
ThisreactionisattributedtonucleophilicattackofPd(0)ontheα-carbonoftheethynyloxygrouptogiveaPd(II)intermediate,whichthenoxidativelyaddstotheortho-C–Hbondtomediatechromeneannulation.
18WorthyofnoteisthesilylethynoxygroupbehavedasanacceptorofPd(0)toproducePd(II)temporalilybeforeoxidativeadditiontoanortho-C–Hbond.
Thisisanewtypeofdirectinggroupofortho-C–Hactivation(Scheme19).
+OTIPSHOPrPrPrPrPd(OAc)2(5mol%)PCy3(10mol%)Zn(5mol%)toluene,90°C(1.
1equiv.
)HTIPSMeOMeO84%NHRROONNi(cod)2(5mol%)IAd(5mol%)AlEt3(20mol%)toluene,100°CMeMeMeMe+1:1.
5NN.
.
IAdR=n-C10H21:84%R=n-C5H11:51%R=CH2CH2OTBS:77%R=CH2CH2OPiv:59%OMe2N90%HHCNFFHF+PrPrFFHFPrCNPrFFNi(cod)2(3mol%)DPEPhos(3mol%)BPh3(12mol%)CPME,100°C,8hNi(cod)2(7mol%)PCyp3(10mol%)72%overallyieldtoluene,80°C,15hSiMe3Me3SiFFFPrCNPrFMe3SiMe3SiScheme19.
Scheme17.
Scheme18.
No.
1669Conductingthereactionusinganalleneinlieuofaninternalalkyneproduced2,3-bismethylenechromane.
19aThisreadilyunderwentDiels–Alderreactiontostereoselectivelyprovidethetetracyclicringstructure.
Isocyanatesalsoreactwiththesamealkynylethertogivesolidbenzoxazine19bwhichemitslightuponUVirradiation,eveninthesolidstate(Scheme20).
ThePd(II)/Zncatalystpromotescyclizationof2,6-dimethylphenylTIPS-ethynylethertogive2-(TIPS-methylene)dihydrobenzofuran.
Thus,γ-C–Hbondactivationismadefeasible(Scheme21).
20Undersimilarconditions,2-(TIPS-ethynyloxy)-2-biphenylunderwentδ-C–Hactivationtoformanoxatricyclicproduct21whichwasreadilyconvertedtothe10,10-disubstituted9-oxaphenanthreneframework,oftenusedaspotentelectroncarriermaterials(Scheme22).
Insummary,thisisthestorytodateofhowIhaveinventedsyntheticreactionsforC-Cformation.
I,ofcourse,encounteredproblemsduringmyresearch;nowreadersknowhowIanalyzedtheproblems,howIconstructedworkinghypotheses,andhowIsolvedtheproblems.
Inventionofreactionsdescribedhereinwouldsuggesthowitisessentialtounderstandreactionmechanismandpayattentiontorelatingscienceandtechnology.
AcknowledgmentsTheauthorisdeeplyindebtedtoKyotoUniversity,SagamiChemicalResearchCenter,TokyoInstituteofTechnology,andChuoUniversity:allkindlyprovidedresearchlaboratoriesandfinancialsupport.
Inaddition,theMinistryofEducation,Culture,Science,Sports,andTechnology,theJapanSocietyforthePromotionofScience,theJapanScienceandTechnologyAgency,andSumitomoChemicalsLtd.
aregratefullyacknowledgedforfinancialsupport.
Isincerelythankallmycollaborators,whosenamesarelistedintheliteraturecitedbelow,fortheirdedicationtohelpingmediscoverandconfirmthechemistryIdescribedabove.
Pd(OAc)2(5mol%)PCy3(10mol%)Zn(5mol%)toluene(0.
1M)90°C,6hOiPr3SiHOSiiPr3Hαδ88%OTIPSCH3HOTIPSHOTIPSHtoluene90°C,18hPd(OAc)2(5mol%)PCy3(10mol%)Zn(5mol%)HH>99%(NMR)98%AcOHMeOOHexTIPSHOTIPSHexMeONOOPhDCE100°C12h(3.
0eq)HHMeOOTIPSPd(OAc)2(5mol%)PCy3(5mol%)Zn(5mol%)toluene100°C,2hHHexone-potsynthesis74%overallyield(3.
0eq)+N-Ph-MIScheme22.
Scheme21.
Scheme20.
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11)Y.
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12)(a)Y.
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(b)Y.
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15)Y.
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16)(a)K.
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(b)Y.
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Introductionoftheauthor:TamejiroHiyamaRDIProfessorResearchandDevelopmentInitiative,ChuoUniversity[Education]1965-1969:BachelorofEngineeringatKyotoUniversity1969-1972:Master(&1yearforPhD)ofEngineeringatKyotoUniversity1975.
9.
23PhDofEngineeringatKyotoUniversity(Prof.
HitosiNozaki,mentor)1975-1976:PostdoctoralFellowatHarvardUniversity(Prof.
YoshitoKishi)[AcademicCareer]1972-1981:AssistantProfessoratFac.
Engineering,KyotoUniversity1981-1983:ResearchFellow&GroupLeaderatSagamiChemicalResearchCenter1983-1988:SeniorResearchFellow&GLatSCRC1988-1992:ExecutiveResearchFellow&GLatSCRC1992-1997:ProfessoratRes.
Lab.
ResourcesUtilization,TokyoInstituteofTechnology1997-2010:ProfessoratGraduateSchoolofEng.
,KyotoUniversity2010-present:RDIProfessoratChuoUniversity10No.
16611TCIRelatedProductsChapter2H0638Hexamethyldisilane10mL100mLT1125TBAF(ca.
1mol/LinTetrahydrofuran)25mL100mLT1037TBAFHydrate25g100gU0009Undecanaldehyde25mL250mLD11482,3-Dimethyl-1,3-butadiene10mL25mLD2196Dimethylphenylsilane25mLChapter3B1374Pd(dba)21g5gC2204CesiumFluoride25g100gD1477DMI25mL100mL500mLD42431,1-Dimethyl-1,3-dihydrobenzo[c][1,2]oxasilole1g5gD38424,7-Dibromo-2,1,3-benzothiadiazole1g5g25gB20271,1'-Bis(diphenylphosphino)ferrocene1g5g25gC2160CesiumCarbonate25g100gChapter4C2461[RhCl(C2H4)2]2200mgChapter5A1479[PdCl(p-C3H5)]2500mg1gChapter7M1211MAD(=MethylaluminumBis(2,6-di-tert-butyl-4-methylphenoxide)(0.
4mol/LinToluene)50mLB3465IPr(=1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene)1g5gT0925Triethylaluminum(15%inToluene,ca.
1.
1mol/L)100mLB2867DPEphos5g25gT2248Tricyclopentylphosphine1g5gChapter8A1424Palladium(II)Acetate1g5gP2161Palladium(II)Acetate(Purified)1gT1165Tricyclohexylphosphine(ca.
18%inToluene,ca.
0.
60mol/L)25mL[Honors]1980TheChemicalSocietyofJapanAwardforYoungChemists2004TheJapaneseLiquidCrystalSociety(JLCS)Award2007TheSyntheticOrganicChemistryAward,Japan2008TheChemicalSocietyofJapan(CSJ)Award2012TheHumboldtResearchAward[ResearchInterests]NovelOrganometallicReagentsandReactionsforSelectiveOrganicSynthesis,OrganofluorineandOrganosiliconChemistry,SynthesisofBiologicallyActiveSubstances,DesignandSynthesisofNovelFunctionalityMoleculesandMaterials.
[Achievements]SyntheticReactionswithCarbenoidReagents,Carbon-CarbonBondFormingReactionswithCr(II)reagents(Nozaki-Hiyama-KishiReactionorNHKReaction),CondensationofEsterMagnesiumEnolateswithNitriles(HiyamaReaction),Silicon-BasedCross-CouplingReaction(HiyamaCoupling),PolysilacageCompoundsfors-ConjugationMaterials,Oxidative-Desulfurization-FluorinationReactions,CarbostannylationReactionofAlkynesandDienes,CarbocyanationReactionofAlkynesandAlkenes,Hydro(hetero)arylationReactionofAlkynesandAlkenes,DesignandSynthesisofLiquidCrystalandLight-EmittingMaterials,SynthesisofBiologicallyActiveCompounds.
[E-mail]thiyama@kc.
chuo-u.
ac.
jp[Website]http://www.
chem.
chuo-u.
ac.
jp/~omega300/index.
htmlNo.
16612NanodiamondN0962Nanodiamond(particlesize:<10nm)(1)1g5gN0968Nanodiamond(particlesize:<10nm)(Amine-modified)(2)1gN0969Nanodiamond(particlesize:<10nm)(Carboxyl-modified)(3)1gDiamond,anallotropeofcarbon,hasexcellenthardness,coefficientoffriction,thermalconductivity,insulationcharacteristics,andrefractiveindex.
Nanodiamond(ND,1)isananoparticlehavingthecrystalstructureofdiamond,anditisanartificialdiamondwiththeexcellentpropertiesofanormaldiamond.
NDisusefulforpolishingtoolsandadditivesofengineoil.
Amine-modifiedND(2)andcarboxyl-modifiedND(3)arealsoknown.
ThesegroupsarefurtherconvertedbyachemicalmodificationtointroduceanewfunctionalitytotheND.
1-3)NDcanbedispersedinwater,butcoheresinorganicsolvents.
Ontheotherhand,afunctionalizedNDparticlewithalkylgroupscanbedispersedinorganicsolvents.
Inaddition,wecanmodifyaglasssurfacewithNDthatisfunctionalizedwithasilanecouplingreagent.
4)References1)NanodiamondnanofluidsforenhancedthermalconductivityB.
T.
Branson,P.
S.
Beauchamp,J.
C.
Beam,C.
M.
Lukehart,J.
L.
Davidson,ACSNano2013,7,3183.
2)WetchemistryroutetohydrophobicbluefluorescentnanodiamondV.
N.
Mochalin,Y.
Gogotsi,J.
Am.
Chem.
Soc.
2009,131,4594.
3)Functionalizationofdiamondnanoparticlesusing"Click"chemistryA.
Barras,S.
Szunerits,L.
Marcon,N.
Monfilliette-Dupont,R.
Boukherroub,Langmuir2010,26,13168.
4)FluorinatednanodiamondasawetchemistryprecursorfordiamondcoatingscovalentlybondedtoglasssurfaceY.
Liu,V.
N.
Khabashesku,N.
J.
Halas,J.
Am.
Chem.
Soc.
2005,127,3712.
Nanodiamond,ND(1)SOCl2C18H37NH2NDNH2HO2CN3N3Nanodiamond,Carboxyl-modified(3)Nanodiamond,Amine-modified(2)NDHNOCNDCO2HNDCONHC18H37No.
16613UsefulCopperReagentforCouplingReactionsC2312Copper(I)2-Thiophenecarboxylate(=CuTC)(1)1g5gCuTC(1)isusedasausefulcopperreagentforvariousreactionsinorganicsynthesis.
Forexample,Stillecross-coupling1)andUllmanncoupling2)efficientlyproceedatroomtemperaturebyusing1.
InLiebeskind-Sroglcross-coupling,thiolestersreactwithboronicacidsundermildconditionsbyusingthepalladiumcatalystand1,affordingthecorrespondingunsymmetricalketones.
3)Thisreactioncanbeappliedtohighlyfunctionalizedandbase-sensitivecompounds,becauseitproceedsundernonbasicreactionconditions.
References1)Copper-mediatedcross-couplingoforganostannaneswithorganiciodidesatorbelowroomtemperatureG.
D.
Allred,L.
S.
Liebeskind,J.
Am.
Chem.
Soc.
1996,118,2748.
2)Ambienttemperature,Ullmann-likereductivecouplingofaryl,heteroaryl,andalkenylhalidesS.
Zhang,D.
Zhang,L.
S.
Liebeskind,J.
Org.
Chem.
1997,62,2312.
3)Thiolesterboronicacidcoupling.
AmechanisticallyunprecedentedandgeneralketonesynthesisL.
S.
Liebeskind,J.
Srogl,J.
Am.
Chem.
Soc.
2000,122,11260.
4)Othercouplingreactionsa)C.
Savarin,L.
S.
Liebeskind,Org.
Lett.
2001,3,2149.
b)H.
Prokopcová,C.
O.
Kappe,J.
Org.
Chem.
2007,72,4440.
c)Z.
Zhang,Y.
Yu,L.
S.
Liebeskind,Org.
Lett.
2008,10,3005.
d)Y.
Yu,L.
S.
Liebeskind,J.
Org.
Chem.
2004,69,3554.
1[C2312]SCuOO+NMP,23°C,30min1(1.
5eq.
)NO2Y.
74%NO2ISn(n-Bu)31)IOCH31(2.
5-3eq.
)NMP,23°C,1hY.
97%2)OCH3CH3OOOOOS+1(1.
6eq.
)THF,50°C,18h1%Pd2dba33%TFPY.
93%CF3OCF33)TFP:Tris(2-furyl)phosphineCH3B(OH)2StilleCross-CouplingUllmannCouplingLiebeskind-SroglCross-CouplingNo.
16614LigandsforClickChemistryT2993Tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine(=TBTA)(1)1g5gT3170Tris(2-benzimidazolylmethyl)amine[=(BimH)3](2)200mg1gTris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine(1)andtris(2-benzimidazolylmethyl)amine(2)areextremelyusefulligandsforclickchemistry(Hüisgen1,3-dipolarcycloadditionreaction).
IntheHüisgenreaction,coppercatalystsaregenerallyrequiredforreactionacceleration.
SharplessandFokinetal.
havereportedthat1hasapowerfulbindingabilitytocopper(I),therebyenhancingitscatalyticactivity.
1)Especially,Finnetal.
havereportedthatwhenusing2,thereactioneffectivelyproceedsevenunderlowercatalystloadingconditions.
2)References1)Polytriazolesascopper(I)-stabilizingligandsincatalysisT.
R.
Chan,R.
Hilgraf,K.
B.
Sharpless,V.
V.
Fokin,Org.
Lett.
2004,6,2853.
2)BenzimidazoleandrelatedligandsforCu-catalyzedazide–alkynecycloadditionV.
O.
Rodionov,S.
I.
Presolski,S.
Gardinier,Y.
-H.
Lim,M.
G.
Finn,J.
Am.
Chem.
Soc.
2007,129,12696.
NNHNHNNNHNTBTA(1)(BimH)3(2)NNNNNNNNNNNN+Cu(I)(cat.
)NNNNNo.
16615Non-detergentSulfobetainesB4030NDSB256-4THydrate(1)1gH1399NDSB211(2)1g5gS0813NDSB201(3)5g25gNon-detergentsulfobetains(NDSBs)havebeenutilizedforsolubilizationandcrystallizationofproteins.
1,2)Inaddition,NDSBshavebeenemployedtopreventproteinaggregationandtorenaturedenaturedprotein.
3,4)Thesesulfobetainecompoundsarezwitterioniccompounds.
1,3)Compounds,1~3,shownherearefrequently-usedNDSBs.
References1)Non-detergentsulfobetaines:AnewclassofmildsolubilizationagentsforproteinpurificationL.
Vuillard,C.
Braun-Breton,T.
Rabilloud,Biochem.
J.
1995,305,337.
2)AnewadditiveforproteincrystallizationL.
Vuillard,T.
Rabilloud,R.
Leberman,C.
Berthet-Colominas,S.
Cusack,FEBSLett.
1994,353,294.
3)Physical–chemicalfeaturesofnon-detergentsulfobetainesactiveasprotein-foldinghelpersN.
Expert-Bezanon,T.
Rabilloud,L.
Vuillard,M.
E.
Goldberg,Biophys.
Chem.
2002,100,469.
4)Non-detergentsulphobetaines:AnewclassofmoleculesthatfacilitateinvitroproteinrenaturationM.
E.
Goldberg,N.
Expert-Benzanon,L.
Vuillard,T.
Rabilloud,Fold.
Des.
1996,1,21.
xH2O.
Nt-BuSO3HONSO3CH3CH3NSO3NDSB256-4T(1)NDSB211(2)NDSB201(3)CyclitolP2219D-Pinitol(1)100mg1gD-Pinitol(1)isoneofcyclitolsoccurringinvariousplants,Leguminosae(Fabaceae),Pinaceaeetc.
1)1suppressesincreasingblood-sugarlevelsinnormalanddiabetes-inducedmice2)andthemechanismofactionof1doesnotaugmenttheeffectofinsulinbutmightinvolveaninteractionwithpartofacellularsignalingpathwaythatlinksinsulinwithglucosetransport.
3)Ontheotherhand,Itwasreportedthat,inpolycysticovarysyndrome,D-chiro-Inositol,de-methyl-moietyof1,reducescirculatinginsulin,decreasesserumandrogens,andamelioratessomeofthemetabolicabnormalitiesofsyndromeX.
4)Inaddition,itwasreportedthat1isaccumulatedinplantandfunctionsasanosmolyteunderthesaltstressconditionincludingwaterdeficit.
5,6)Thisproductisforresearchpurposeonly.
References1)AreviewoninsulinomimeticpinitolfromplantsG.
Poongothai,S.
K.
Sripathi,Int.
J.
Pharm.
BioSci.
2013,4(2),992.
2)Pinitol–anewanti-diabeticcompoundfromtheleavesofBougainvilleaspectabilisC.
R.
Narayanan,D.
D.
Joshi,A.
M.
Mujumdar,V.
V.
Dhekne,Curr.
Sci.
1987,56,139.
3)Insulin-likeeffectofpinitolS.
H.
Bates,R.
B.
Jones,C.
J.
Bailey,Br.
J.
Pharmacol.
2000,130,1944.
4)EffectsofD-chiro-inositolinleanwomenwiththepolycysticovarysyndromeM.
J.
Iuorno,D.
J.
Jakubowicz,J.
-P.
Baillargeon,P.
Dillon,R.
D.
Gunn,G.
Allan,J.
E.
Nestler,Endcr.
Pract.
2002,8,417.
5)SaltstressperceptionandplantgrowthregulatorsinthehalophyteMesembryanthemumcrystalliumJ.
C.
Thomas,H.
J.
Bohnert,PlantPhysiol.
1993,103,1299.
6)PinitolaccumulationinmatureleavesofwhitecloverinresponsetoawaterdeficitM.
T.
McManus,R.
L.
Bieleski,J.
R.
Caradus,D.
J.
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2000,43,11.
RelatedProductI06321D-chiro-Inositol200mgHOHOCH3OHOOHOH1