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

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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