手性双功能氨基酸酯钛络合物催化醛的不对称硅腈化反应研究百精.docx
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手性双功能氨基酸酯钛络合物催化醛的不对称硅腈化反应研究百精.docx
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手性双功能氨基酸酯钛络合物催化醛的不对称硅腈化反应研究百精
AsymmetricCyanosilylationofAldehydes
CatalyzedbyaChiralBifunctionalAmino
AcidEster-Ti(IVComplex
WangFei,XiongYan,LiuXiaohua,FengXiaoming*
aKeyLaboratoryofGreenChemistry&Technology(SichuanUniversity,MinistryofEducation,College
ofChemistry,SichuanUniversity,Chengdu610064,China
Fax+86(2885418249;E-mail:
xmfeng@
Abstract
Anewchiralbifunctionalcatalysthadbeendevelopedfortheasymmetriccyanosilylation
ofaldehydes.Thecomplexof1dwithTi(OiPr4couldefficientlypromotetheadditionof
trimethylsilylcyanide(TMSCNtoaldehydesinhighyields(upto99%withupto76%
ee.Basedonthepreliminaryinvestigation,apossiblecatalyticcycleviadualactivation
hasbeenproposedtoexplaintheoriginoftheactivationandasymmetricinductivity.
Keywords:
aldehyde;asymmetriccyanosilylation;bifunctionalcatalyst;titanium
1Introduction
Theasymmetriccyanationofaldehydestogivecyanohydrinsisahighlyversatilesynthetictransformation,andtheopticallyactivecyanohydrinsserveasimportantprecursorsofmanyusefulorganiccompounds,suchasα-hydroxyacids,β-aminoalcoholsandtheirderivatives.[1]Overthelasttwodecades,severalefficientenzymaticmethods[2]andchemicalmethods[3],includingavarietyofLewisacidsandLewisbasescatalysishavebeenemployedsuccessfullytopromotethecyanosilylationofcarbonylcompounds.Althoughsignificantadvancesinthisareahavebeenmade,itisstillaveryactiveresearchefforttodevelopnewcatalystsforthisadditionreaction.
Insearchingfornewmethodology,alotofchiralbifunctionalcatalystshavebeendesigned.Obviously,thesecatalystsmustcontainanacidcenterandabasicfunctionalgroupwhichcouldsimultaneouslybindabasicsubstrateandanacidicreactantinapropermanner.Shibasaki’sbifunctionalP-oxidecatalystderivedfromBINOLandnaturalglucose[4],Feng’sbifunctionalN-oxide[3d],[5],[6]andaminoacidsalts[3k]werefoundtobeveryefficientfortheasymmetriccyanosilylationofaldehydes,iminesandketones.KobayashireportedthatanaminemightcoordinatetoTMSCNtoformtheactivehypervalentsilicate[7]andourearlyworksrevealedthattitaniumasaLewisacidcouldefficientlycatalyzedtheasymmetriccyanosilylationofaldehydes[8].Wetiredtodesignanewsimplechiralbifunctionalamine-titaniumcatalystfortheefficientadditionofcyanidetoaldehydes.Herein,wewishtoreportitssynthesisandapplicationintheasymmetriccyanosilylationofaldehydes.
2Resultsanddiscussion
Inourinitialstudies,severalaminoacidesters(Figure1,1a-hwhichcouldbeeasilypreparedfromL-Boc-prolineweremixedwithTi(OiPr4,andthecatalyticpropertyforthecyanosilylationofbenzaldehydewasinvestigated.AsillustratedinTable1,thereactioncatalyzedbytheTi(IVcomplex
of1dgavehigherenantioselectivitythanthatofligands1a,1b,and1c(entry4vs1-3.MorebulkysubstitutesatYgroupoftheligandledtolessenantioselectivity(entry5and6.Ligand1ghadanegativeeffectonthereactivity(entry7.Thetripeptideligand1hexhibitedlowenantioselectivitywhilekeepinghighreactivity(entry8.Notably,TheD-prolineligand2gaveSproductwith46%ee(entry9,whichrevealedthattheconfigurationoftheprolinedominatedthefaceselectivityofthereaction.Therefore,1dwasidentifiedasthemosteffectivecatalysttooptimizethereactionconditions.
Figure1:
TheLigandsEvaluated.
Table1:
AsymmetricCyanosilylationofBenzaldehydeCatalyzedbyLigand-Ti(OiPr4Complex.
EntryLigandYield(%bee(%c
11a9
263(R
21b9062(R
31c9331(R
41d9969(R
51e9060(R
61f8958(R
71g8045(R
81h9340(R
929446(S
aReactionswerecarriedoutona0.2mmolscaleofbenzaldehydein1.0mLofCH
2Cl2with20mol%
ligandand10mol%Ti(OiPr4.bIsolatedyield.cTheeevaluesweredeterminedbyHPLConChiralOD-Hcolumnafterconversiontothecorrespondingacetates.Theabsoluteconfigurationsweredeterminedbycomparisonofthereportedopticalrotation.
Tooptimizethereaction,molarratioofligand1dtoTi(OiPr4,solventeffect,thereactiontemperature,andcatalystloadingwereexamined.AlltheresultsweresummarizedinTable2.Theenantioselectivitywasmarkedlyinfluencedbythemolarratioofligand1dtoTi(OiPr4.Theoptimalmolarratiowas4:
1,whileincreasingordecreasingthemolarratioledtotheloweree(entry2vs1,3.ItwasfoundthatthereactioninCH2Cl2proceededbetterthaninothersolvents(entry2vs6-8.Whenthereactionwascarriedoutat-20oC,theproductwasobtainedwithalmostsimilaree(entry4.Moreover,increasingthecatalystloadingdecreasedtheee(entry5.
Table2:
OptimizationoftheReactionConditions.
Entry1d(mol%
Ti(Oi-Pr4(mol%SolventTemp(oC
Time(hYield(%bee(%c
120
10CH2Cl20oC109769(R
2205CH2Cl20o
C109976(R
3202CH2Cl20o
C108720(R
420
5CH2Cl2-20o
C2090
74(R54010CH2Cl20o
C109953(R
6205THF0o
C109016(R
7205PhCH30o
C109238(R
820
5Et2O0o
C1094
20(Ra
Thereactionwascarriedoutona0.2Mscaleofbenzaldehyde,TMSCN(1.5eq.bIsolatedyield.cThe
eevaluesweredeterminedbyHPLConChiralOD-Hcolumn.
Undertheoptimizedconditions,theasymmetricadditionsofTMSCNtoarangeofaromaticaldehydeswereinvestigated.AsdeliveredinTable3,aromaticsubstratesincludingdifferentsubstitutedonesaffordedthedesiredproductsinexcellentyieldsandwithupto76%ee.Ingeneral,alkyl,alkoxyatthepara-positionofaromaticringand2-Naphthaldehydeweretoleratedwellasthemodelreaction(entries2,5and7,subsitituentsatthemeta-position,ortho-positionand1-Naphthaldehydegaveloweree’s(entries3,4,6,8.
Table3:
GeneralityofSubstrates.
EntryAldehydeTime(hYield(%bee(%c1Benzaldehyde109976(R24-Methylbenzaldehyde30866833-Methylbenzaldehyde128520(R42-Methylbenzaldehyde12753254-Methoxylbenzaldehyde128272(R61-Naphthaldehyde129524(R72-Naphthaldehyde309275(R83-Chlorobenzaldehyde12865894-Fluorobenzaldehyde159740(R
a
Reactionswerecarriedoutona0.2mmolscaleofaldehydein1.0mLofCH2Cl2with20mol%1dand
10mol%Ti(OiPr4.bIsolatedyield.cTheeevaluesweredeterminedbyHPLCorGCafterconversiontothecorrespondingacetates.
Basedonthepreliminarystudiesandstericandelectronicconsiderations[7],apossibledualactivationmechanismwasproposed,inwhichthetitaniumactivatedthealdehydesasaLewisacidandthebasicnitrogenofthepyrrolidineactivatedtheTMSCNasaLewisbase,respectively.Weconsideredherethatduetothestrongcoordinationabilityofcarbonylgrouptotitanium,aldehydeisactivatedtogenerateapossiblecomplex.Hypervalentsilicate[9],formedfromamineandTMSCN,isassumedtobeanactivecyanidesourcewithnucleophilicityenhancedbytheelectrondonationlewisbase,andreadilyattacktheactivatedaldehyde.
3Conclusion
Insummary,theasymmetriccyanosilylationofaldehydeshasbeenachievedbythebifunctionalcatalysisof5mol%ofchiralaminoacidester-titaniumcomplexgivingthecorrespondingO-TMS
ethersofcyanohydrinsinhighyields(upto99%withupto76%eeundermildconditions.Meanwhile,theligand1dwasreadilypreparedfromaninexpensiveandreadilyavailablechiralaminoacid.Furtherinvestigationsshouldbedevotedtooptimizationofthecatalysttoenhanceenantioselectivityandreactivity,andclarifythemechanismofthereaction.
Acknowledgments
TheauthorsthanktheNationalNaturalScienceFoundationofChina(Nos.202252206,20390055and20472056,theMinistryofEducation,China(Nos.104209andtheSpecializedResearchFundfortheDoctoralProgramofHigherEducation(Nos.20030610021forfinancialsupport.
References
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