Enantioselective Direct Mannich Reaction of Functionalized Acetonitrile to NBoc imines Catalyzed byWord文档格式.docx
- 文档编号:16580890
- 上传时间:2022-11-24
- 格式:DOCX
- 页数:23
- 大小:409.40KB
Enantioselective Direct Mannich Reaction of Functionalized Acetonitrile to NBoc imines Catalyzed byWord文档格式.docx
《Enantioselective Direct Mannich Reaction of Functionalized Acetonitrile to NBoc imines Catalyzed byWord文档格式.docx》由会员分享,可在线阅读,更多相关《Enantioselective Direct Mannich Reaction of Functionalized Acetonitrile to NBoc imines Catalyzed byWord文档格式.docx(23页珍藏版)》请在冰豆网上搜索。
AsymmetricMannichreaction,Dual-reagentcatalysis,Quaternaryphosphonium,Organocatalysis
Abstract:
Quaternaryphosphoniumion-pairorsaltsderivedfromaminoacidshasbeendevelopedtocatalyzetheMannich-typereactionof-substitutedethylcyanoacetatesand2-(2-nitrophenyl)acetonitriletoN-Bocimines.Experimentsshownthatmoreactivecyanoacetatescouldbecatalyzedbythegentlephosphoniumion-paircatalysis,while2-(2-nitrophenyl)acetonitrileasthesubstratehastobeactivatedbyquaternaryphosphoniumsaltsandstrongbase.Allthereactionsgavethecorrespondinghighlyfunctionalizedchiral-aminonitrilesproductswithgoodyields,highdiastereo-andenantioselectivitiesinmildconditions.
1.Introduction
Cyanoalkylmoietieshavebeenfoundaspopularstructuralmotifsinseveralnitrile-containingnaturalproductsandimportantdrugs.[1]Oneofthedirectapproachestointroducenitrilegroupintomoleculesthroughthenucleophilicaddition,however,usuallyinneedofgenerationofcarbanionsfromsimplealkylnitrilesbystrongbasesorLewisacids.[2]Recently,alternativemethodtoaccessthiskindofproducts,especiallythechiralspecies,hasbeenachievedbyemployingactivatedfunctionalizedacetonitrileundermildconditions.[3]Sofarasweknow,therelatedwelldevelopedasymmetricreactionsweremajorlylimitedintheconjugatedreactionandwerecatalyzedbymetalliccatalysis.[4]
Duringthepastdecades,organophosphineasaversatilecatalystinenantioselectiveadditionreactionshasbeensuccessfullyappliedinavarietyoforganicsynthesistomakeusefulcompounds.[5]Recently,ourgrouphasdevelopedaminoacid-derivedchiralphosphine[6]tocatalyzeMannich-typereactionsofdimethyl2-fluoromalonateswithN-Bociminesornitroalkaneswithamidosulfone.[7]Thereactionof2-fluoromalonateswithN-Bocimineswasdemonstratedwiththeasymmetricdual-reagentcatalysisbythephosphinecatalystandmethylacrylate.Whilethereactionofnitroalkaneswithamidosulfonerequiredbifunctionalphosphoniumphase-transfercatalysttoachieveexcellentenantioselectivecontrol.Inlightofthiswork,weareveryinterestedintestingalternative
nucleophileslikesubstitutedphenylacetonitrilesintheMannichreactions.[8]Herein,wewouldliketoreportthereactionwithN-Bociminescatalyzedbyquaternaryphosphoniumcatalysis.
2Resultsanddiscussion
Initially,weperformedthecatalystevaluationinthemodelreactionbetweenN-Bocimine1aandethyl2-cyano-2-phenylacetate2a(Table1).Andthefirstcatalyticsystemwetriedwassimilartothereactionof2-fluoromalonateswithN-Bociminesunderdual-reagentcatalysis.WhenthereactionwascarriedoutinCH2Cl2atroomtemperatureinthepresenceofchiralphosphine4f,thedesiredproduct3awasobtainedin5minuteswith1:
1drandonly5%ee(Table1,entry1).Loweringthereactiontemperaturefrom-20Cto-78C,wefoundthatbothdiastereoselectivityandenantioselectivityofthecorrespondingproductcouldbegreatlyincreasedaswellashighyieldachieved(Table1,entries2-3).Itshouldbenotedthatthereactionwasstillveryfastunderprettylowtemperature.WealsoinvestigatedasetofH-bondingtypeofbifunctionalchiralphosphinecatalysts4a-eand4gandrunthesereactionsinCH2Cl2at-78oC(Table1,entries5-10).Amongthesecatalysts,weobservedthethiourea-phosphine4ederivedfromL-phenylalaninegaveabetterresult(Table1,entry9),whereasthecatalysts4c-4dderivedfromotheraminoacidsgaveinferiorselectivities(Table1,entries7-8).ReactionswithsingleH-bonding4aandureacatalyst4balmostgavetheracemicproducts(Table1,entries6-7).Electron-donatingsubstituentsonthethioureahadthebadeffectonthereaction(Table1,entries10).Furtherexaminationofthesolventwasconductedinthepresenceofchiralphosphine4fandshowedthereactionwasbestruninCH2Cl2at-78oC(Table1,11-13).
Table1.Optimizationofconditionsandevaluationofchiralcatalystsa
aReactionswerecarriedoutwith1a(0.15mmol),2a(0.1mmol),andmethylacrylate(0.01mmol)inthepresenceofchiralphosphine4(0.01mmol)insolvent(1.0mL)atthespecifiedtemperature.bIsolatedyield.cThediastereomericratiowasdeterminedby1HNMRspectroscopicanalysisofthecrudemixtures.dTheeevaluewasdeterminedbychiralHPLCanalysis.eThereactionwascarriedoutwith5mol%of4fand5mol%ofmethylacrylate.Boc=tert-butoxycarbonyl,Bn=benzyl.
entry
catalyst
solvent
temperature/oC
t/min
Yield(%)b
drc
ee(%)d
1
4f
CH2Cl2
rt
5
96
50:
50
2
-20
90:
10
70
3
-78
94:
6
99
4e
93
81
4a
95
49:
51
4b
71:
29
7
4c
83:
17
15
8
4d
74
9
92:
87
4g
75
11
toluene
93:
92
12
Et2O
94
13
THF
64:
36
Withtheoptimizedconditioninhand,wethenexaminedthegeneralityofthisreactionwithavarietyofN-Bocprotectedaldiminesandalkylnitriles.AsshowninTable2,allthereactionswerecompletewithin10minutes.Thedesiredproducts3wereobtainedinhighyieldsandexcellentdiastereoselectivities(90:
10-98:
2).Regardlessoftheelectronicnatureandstericeffectsofthesubstituentsonthearylgroups,goodtohighenantioselectivitiesof3werealsoobtained(Table2,3a-3j).Ethylesterreplacedbymethylorbenzylgroupsalsogavegoodresults(Table2,3l,3m)andreplacementofthephenylofalkylnitrileswithbenzylorallylhadlittleeffectontheselectivity(Table2,3n,3o).Moreover,goodyieldandselectivitywerealsopresentwhenweusedcyclohexylinsteadofphenylaldimine(Table2,3k).
Table2.ScopeoftheMannichReactionCatalyzedbytheDual-ReagentCatalysisa
Duringourinvestigationofthegeneralityofthereaction,wealsoevaluatedseverallessactivatedacetonitrilessuchasphenylacetonitriletotestthecatalyticabilityofthesystem.However,noneofthemgavesatisfiedyieldsorenantioselectivitiesexcept2-nitrophenylacetonitrilewhichgavethecorrespondingproductrac-6awithanacceptable60%yield(table3,entry1).Furthereffortstoimprovetheselectivityofthereactionbetween1aand5awiththeabovedual-reagentcatalyticsystemwerenotsatisfactory(table3,entry2,fordetailsseetheSupportingInformation).Wepresumedthattheactivityof2-nitrophenylacetonitrilewasmuchclosetothenitroalkanewhichwehavestudiedinthereactionwithamidosulfonebybifunctionalphosphoniumphase-transfercatalyst.[x]Inspiredbythiswork,wethententativelyscreenedanumberofconditionsincludingthecatalysts,solvents,temperatureandbasesandfinallywegottheproduct6ainhighyieldandgoodenantioselectivityinthepresenceofphosphoniumcatalyst4k.Thediastereoselectivitywasalsoimprovedto82:
18(table3,entries3-6,fordetailsseetheSupportingInformation).Undertheseoptimizedconditions,varioussubstitutedN-Bocprotectedaldiminesweretestedwith2-nitrophenylacetonitrile.Allthereactionstookplacesmoothlyandaffordedthecorrespondingadditionproducts6ingoodyieldsandhigh-to-excellentenantioselectivitiesirrespectiveoftheelectronicnatureofthesubstituentsorsubstitutiontypes(Table4,6a-6r).Littleeffectontheyieldandselectivitywasobservedwhencyclohexylgroupwasintroducedinsteadofphenylinaldimine(Table4,6r).Althoughboth3-nitrobenzylcyanideand4-nitrobenzylcyanidealsogavetheproductswithgoodyields,poorenantioselectivitieswereobtainedforthesetwosubstrateswhichdemonstratedthenitrogroupattheorthopositionnotonlyactivatethemethyleneintheacetonitrilebutalsodirectedthereactiontocontroltheenantioselectivity(Table5,6s-6t).
Table3.ChiralcatalystsfortheasymmetricMannichReactionof1aand5aa
T(oC)
base
t(h)
Yield(%)c
dr(%)d
Ee(%)e
1b
-
60
2b
4h
55
68:
32
60/52
4i
K2CO3
90
62:
38
74/50
4
4j
85
4k
66:
34
77/53
24
80
82:
18
96/74
aReactionswerecarriedoutindichloromethane(1.0mL)with1a(0.15mmol)and5a(0.1mmol)inthepresenceof5mol%ofcatalyst.bReactionwascarriedoutwithmethylacrylate(0.01mmol).cIsolatedyield.dThediastereomericratiowasdeterminedby1HNMRspectroscopicanalysisofthecrudeproduct.eTheeevaluewasdeterminedbychiralHPLCanalysis.
Table4.ScopestudywithdifferentN-Bocprotectedaldiminesa
Althoughthemechanismofthisnovelcatalystsystemisnotcompletelyclear,apossibletransitionstatecanbeconsidered(Figure1A,1Bforthetwosubstrates).Withthemoreactivatedcyanoacetate,thereactionispreferablycatalyzed
- 配套讲稿:
如PPT文件的首页显示word图标,表示该PPT已包含配套word讲稿。双击word图标可打开word文档。
- 特殊限制:
部分文档作品中含有的国旗、国徽等图片,仅作为作品整体效果示例展示,禁止商用。设计者仅对作品中独创性部分享有著作权。
- 关 键 词:
- Enantioselective Direct Mannich Reaction of Functionalized Acetonitrile to NBoc imines Catalyzed by
![提示](https://static.bdocx.com/images/bang_tan.gif)
链接地址:https://www.bdocx.com/doc/16580890.html