吡啶-DMFDMA制作方法

RegioselectiveSynthesisof2(1H)-Pyridinonesfrom

󰀁-AminoenonesandMalononitrile.ReactionMechanism

AngelAlberola,LuisA.Calvo,AlfonsoGonza´lezOrtega,M.CarmenSan˜udoRuı´z,*and

PedroYustos

DepartamentodeQuı´micaOrga´nica,UniversidaddeValladolid,Valladolid,Spain

SantiagoGarcı´aGrandaandEstherGarcı´a-Rodriguez

DepartamentodeQuı´micaFı´sicayAnalı´tica,UniversidaddeOviedo,Oviedo,Spain

ReceivedJuly13,1999

Theidentificationofsomeintermediatesofthereactionsbetween󰀁-aminoenonesandmalononitrile

togive2(1H)-pyridinoneshasallowedustoobtainvaluableinformationconcerningitsmechanism.

Thesereactionsbeginwithaconjugatedadditionofthenitriletotheenonefollowedbyelimination.

Thecompoundsthusobtainedcyclizetononisolable2H-pyran-2-imine.Thisafforded2(1H)-

pyridinonesbyringopeningtounsaturatedaminoamidesfollowedbycyclization(Dimroth-type

rearrangement).

Introduction

Thereactionsof󰀁-dicarbonylcompoundsor󰀁-func-

tionalizedR,󰀁-unsaturatedketoneswithmalononitrile

andrelatedcompoundshavebeendescribedasasyn-

theticmethodof2(1H)-pyridinones.1-9Whilethereaction

mechanismwithcyanacetamideseemstobefirmly

established,9-13theprocessbywhichmalononitrileacts

asanucleophilicagenthasbeeninterpretedinaccording

todifferenthypotheticalmechanisms.3,5,7,14-17

Inthispaper,wehaveinvestigatedthereaction

pathwayto2(1H)-pyridinonesfrom󰀁-aminoenonesand

malononitrile,usingtheidentificationoftheirintermedi-

atesasabasicmethodology.

ResultsandDiscussion

Researchhasbeencarriedoutwith󰀁-aminoenones

1a-g,2a,g,and3a,whosereactionswithmalononitrile

(Scheme1)affordedtheresultssummarizedinTable1.

Theprocessesarehighlyregioselective,andeach󰀁-ami-

noenoneregioisomerleadstoitscorresponding2(1H)-

pyridinone(1bf4b,1cf4c,1df4d,1ef4e).

Thereactionratebetween󰀁-aminoenonesandmalono-

nitriledependsonthenatureofR1,R2,andLsubstitu-

entsandexperimentalconditions.Controlofthesefactors

hasallowedustoreducetherateofsomeofthesteps

andtoidentifytherespectiveintermediatesby

spectro-(1)Bergmann,E.D.;Ginsburg,D.;Pappo,R.InOrganicReactions;Adams,R.,Ed.;J.WileyandSons:NewYork,1967;Vol.10,pp258-261.(2)McKillop,A.;Boulton,A.InComprehensiveHeterocyclicChem-istry;Katritzky,A.R.,Rees,C.W.,Eds.;PergamonPress:NewYork,1984;Vol.2,pp460-463.(3)Freeman,F.Chem.Rev.1969,5,591.(4)Rastogi,R.R.;Kumar,A.;Ila,H.;Junjappa,H.J.Chem.Soc.,PerkinsTrans.11978,6,549.(5)Otto,H.H.;Schmelz,H.Arch.Pharm.1982,315,526.(6)Aggarwal,V.;Singh,G.;Ila,H.;Junjappa,H.Synthesis1982,214.(7)Alberola,A.;Andre´s,C.;Gonza´lez-Ortega,A.;Pedrosa,R.;Vicente,M.J.Heterocycl.Chem.1987,24,709.(8)Purkayastha,M.L.;Bhat,L.;Ila,H.;Junjappa,H.Synthesis1995,641.(9)Krstic,V.;Misic-Vukovic,M.;Radojkovic-Velickovic,M.J.Chem.Res.,Synop.1991,82.(10)Bardhan,J.C.J.Chem.Soc.1930,1509.(11)Basu,U.J.IndianChem.Soc.1930,7,481.(12)Dornow,A.Ber.1940,73,153.(13)Fanta,P.E.;Stein,R.A.J.Am.Chem.Soc.1955,77,1045.(14)Basu,U.J.IndianChem.Soc.1930,7,815.(15)Dornow,A.;Neuse,E.Arch.Pharm.1955,288,174.(16)Ivanov,I.C.;Karagiosov,S.K.;Simeonov,M.F.LiebigsAnn.Chem.1992,203.(17)Al-Omran,F.;Al-Awadhi,N.;Khalik,M.M.A.;Kaul,K.;El-Khair,A.A.;Elnagdi,M.H.J.Chem.Res.,Synop.1997,84.Scheme1

Table1.Synthesisof3-Cyano-2(1H)-pyridinones:ReactionConditions

󰀁-aminoenonesolventtime(h)T(°C)pyridinonea(%)

1aTHF2654a(90)1bTHF72204b(80)1cEtOH70804c(90)1dEtOH24204d(70)1eEtOH24804e(35)b,c

1fEtOH120804f(70)d

1gEtOH120804g(76)d

2aTHF2654a(90)2gEtOH120804g(65)d

3aTHF1654a(90)

aIsolatedyield.bBasiccatalysis(NH4OH/Py)isnecessaryforreactiontobeproduced.cOtherisolatedproducts:2-amino-6-tert-butyl-4-methylpyridine-3-carbonitrile13(38%)and2-amino-4-tert-butyl-6-methyl-1,3-benzenedicarbonitrile14(14%).dSeeScheme5.9493J.Org.Chem.1999,64,9493-9498

10.1021/jo991121oCCC:$18.00©1999AmericanChemicalSocietyPublishedonWeb12/03/1999scopicmeansinthereactionmixtureorbypriorisola-

tion.

Monitoringofthereactionsby1HNMRindicatesthat

theprocessbeginswithaconjugatedaddition-elimina-

tionofthemalonicdinitriletothe󰀁-aminoenonetogive

theintermediate5(Scheme2),whoseconcentrationin

thereactionmixturecanreachvaluesofbetween30%

and90%,accordingtothenatureofR1,R2,andL.The

variationsintheconcentrationsofthe󰀁-aminoenone(1),

theintermediate5,andthefinal2(1H)-pyridinone(4)

havebeendeterminedaccordingtotheintensityofthe

signalsduetotheirolefinicprotons,whichwererecorded

atδ)4.87-5.12(for1-3),5.43-5.59(for5),and6.00-

6.21(for4).

Theformationanddisappearanceratesof5dependon

thesizeoftheR2substituent:themorebulkythisis,

themoreslowlytheintermediateisproducedandthe

morequicklyitistransformed.Inthecaseofthe

󰀁-aminoenone1g,inwhichR2)H,thelifetimeof5g

allowsitscompleteidentificationbymeansofits1HNMR

and13CNMRspectra,whichcoincidewiththoseof

sodiumsalt9(Table2),obtainedandisolatedfromthe

reactionofthe󰀁-aminoenones1gor2gwithmalononi-