Table Of ContentAzaheterocycles Based on
(cid:2),(cid:3)-Unsaturated Carbonyls
(cid:2) (cid:2)
Valentin A. Chebanov Sergey M. Desenko
Thomas W. Gurley
Azaheterocycles Based
on (cid:2),(cid:3)-Unsaturated
Carbonyls
ValentinA.Chebanov SergeyM.Desenko
StateScientificInstitution‘‘Institute StateScientificInstitution‘‘Institute
forSingleCrystals’’ofNational forSingleCrystals’’ofNational
AcademyofSciencesofUkraine AcademyofSciencesofUkraine
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Ukraine Ukraine
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Preface
This book is devoted to heterocyclizations of aliphatic and aromatic
(cid:2),(cid:3)-unsaturated carbonyls with various binucleophiles leading to three-,
five-, six and seven-membered partially hydrogenated nitrogen-containing
heterocycles. During the last decade interest in these classes of organic com-
poundshasbeenexperiencingascientificrenaissanceowingtotheirsignificant
role in biological processes in living cells and diverse effects on physiological
activities.Inaddition,suchcompoundsarealsomoreprevalentfromtheview-
point of ‘‘classical’’ problems of organic chemistry, among them reactivity,
chemo-andregioselectivity,tautomerism,conformationalanalysisandfeatures
of their electronic structure. The character of these problems in the case of
partiallyhydrogenatedheterocyclesdifferssufficientlyfromthatforheteroar-
omatized and perhydrogenated heterocyclic compounds and investigations in
thisfieldveryoftenleadtointerestingandunusualresults.
Extensivelycharacterizedcyclocondensationsof(cid:2),(cid:3)-unsaturatedcarbonyls,
theirsyntheticequivalentsandtheirprecursorsarethemostwidespread,facile
and generally valid pathway to dihydroazaheterocycles. The popularity and
significance of this synthetic approach is based on the high reactivity and
availability of unsaturated carbonyl compounds and the precise selectivity of
theheterocyclizationreactionsincomparisonwiththatinvolving(cid:3)-dicarbonyls.
Therecentdevelopmentofcombinatorialhigh-throughputmethodsandtheuse
ofnewenergysourcessuchasmicrowavesandultrasoundtoenhancereactions
havealsoincreasedinterestin(cid:2),(cid:3)-unsaturatedcarbonylsandtheirreactions.
Themainaimofthismonographisacomprehensivereviewandorganization
of the known literature data devoted to the reactions of (cid:2),(cid:3)-unsaturated
ketones,theirsyntheticequivalentsandtheirprecursorsutilizedinthesynthesis
of nitrogen-containing heterocycles. The book is separated into four chapters
andanAddendum,andcontainsnearly900literaturereferences.Eachchapter
describes the synthesis and chemical and other interesting properties and fea-
turesofcertainclassesofheterocycliccompounds.
The first chapter is devoted to the formation and subsequent modifica-
tion of three-membered heterocycles—aziridines. Synthesis and properties
of aziridinyl ketones, bi- and tricyclic aziridine derivatives, cycloaddition
and photochemical reactions are described. The second chapter deals with
v
vi Preface
five-membered heterocycles. Heterocyclizations of unsaturated ketones leading
to six-membered heterocycles are the topic of the third and largest chapter
of the book. Besides the reactions of unsaturated ketones with diverse 1,3-
binucleophilesandthechemicalpropertiesofthepartiallyhydrogenatedazines
that are formed, the problem of tautomerism is addressed as well. The last
chapterincludesdataonthereactionsof1,2-diamineswithunsaturatedcarbo-
nylswhichoccurina‘‘classical’’mannerwiththeformationofdiazepinesand
exhibitsomeunusualdirections.ThebookalsocontainsanAddendumdescrib-
inggeneral aswell asspecialsynthetic proceduresrelating tothechemistryof
(cid:2),(cid:3)-unsaturatedcarbonylcompounds.
We are very thankful to many scientists who have taken an active role in
thewritingofthisbook.Thechapterswerepreparedinveryclosecollabora-
tion with Valery Orlov, Nadezhda Kolos, Fedor Yaremenko and Alexander
Zbruyev.Theirefforts,remarks,correctionsandadditionswereveryusefulin
enhancingthequalityofthebook.AlargepartoftheAddendumwaswrittenby
SergeyKomykhov.Alotofhelpwasobtainedfromourcolleaguesworkingin
theDepartmentofHeterocyclicCompoundsChemistryoftheStateScientific
Institution ‘‘Institute for Single Crystals’’ NAS of Ukraine as well as from our
friends around the world—Nikolay Gorobets, Eugeny Gladkov, Vyacheslav
Saraev,YanaSakhno,KirillKobzar,BogdanKhanetsky,KaterinaGura,Dmitry
Sysoev and many others. We also would like to thank the Karl Franzens
University of Graz (Austria) and the University of Constance (Germany) and
personallyGertKollenz,OliverKappeandUlrichGrothforallowingustoaccess
theirextensivescientificdatabasesandelectronicanduniversitylibraries.
The book was written with partial support from the National Academy of
Sciences ofUkraine,INTASand theUSFulbrightScholarProgram, andthe
GermanandAustrianAcademicExchangeServices(DAADandOeAD).
Thebookisorientedtochemistsworkinginthefieldofsynthesisandboth
inexperimentalandintheoreticalinvestigationsofnitrogen-containinghetero-
cycles,universitylecturersandbothgraduateandundergraduatestudents.
June2008 ValentinA.Chebanov
SergeyM.Desenko
ThomasW.Gurley
Contents
Introduction................................................ 1
1 Three-MemberedAzaheterocycles............................ 5
1.1 SynthesisofAziridinylKetonesandTheir
ChemicalProperties.................................. 5
1.2 SynthesisofBi-andTricyclicAziridineDerivatives ......... 15
1.3 ChemicalPropertiesofBi-andTricyclicAziridines ......... 20
References.............................................. 33
2 Five-MemberedAzaheterocycles ............................. 37
2.1 ReactionswithDiazoalkanes........................... 37
2.2 ReactionsofHydrazinesandHydroxylamines ............. 41
2.3 Structure,ChemicalandPhysicochemicalPropertiesofPyrazolines 50
References.............................................. 55
3 Six-MemberedAzaheterocyclesBasedon1,3-Binucleophiles........ 61
3.1 ReactionsofEnamines................................ 62
3.2 ReactionsofUreaandItsAnalogues .................... 65
3.3 ReactionsofMalonicAcidDerivatives................... 76
3.4 ReactionsofAminoazoles ............................. 83
3.5 ReactionsofAnilinesandAminoazines................... 100
3.6 ChemicalPropertiesofDihydroazines.................... 108
3.7 TautomerismofPyridineandPyrimidineDihydroDerivatives 130
References.............................................. 136
4 Cyclocondensationsof1,2-Diamines .......................... 149
4.1 Synthesisof1,5-Dihydroazepines........................ 149
4.2 Three-ComponentCondensationof1,2-DiamineswithKetones 157
4.3 ReactionsofDihydrobenzodiazepines.................... 163
4.4 Five-andSix-MemberedHeterocyclesBasedonortho-Diamines 170
References.............................................. 176
Addendum:SelectedSyntheticProcedures......................... 181
Index..................................................... 205
vii
Introduction
Specificquestionsofthechemistryof(cid:2),(cid:3)-unsaturatedcarbonylcompoundsare
describedinseveralpublications,includingtwobooks.Propertiesofchalcones
arediscussedinthemonographofDhar[1].However,thesynthesesofazahe-
terocycles in this book are described only occasionally since it was published
beforesystematicinvestigationsintheappropriatefieldsbegan.Anotherbook
[2],written inRussian, devoted to azaheterocyclesbased onaromaticunsatu-
rated ketones is inaccessible for the most part to many scientists as well as
containingout-of-dateandincompletedata.Someaspectsoftheapplicationof
(cid:2),(cid:3)-unsaturatedketonesinsyntheticorganicchemistry,partiallyinthesynth-
esis of certain classes of nitrogen-containing heterocycles, are described in
several summary reviews [3, 4, 5, 6, 7, 8]. There are also reviews dealing with
propertiesandfeaturesoftargetazaheterocycles[9,10,11,12,13].
The presence of two electrophilic reaction centers in the molecule of
(cid:2),(cid:3)-unsaturated carbonyls is responsible for their ability to participate in the
synthesisofheterocycles.Suchcompoundscanreactasambidentelectrophiles
owing to delocalization of electron density in a C¼C–C¼O system. The
addition of nucleophiles to these molecules can proceed in one of two main
directions—via attack of the carbonyl group (1,2-addition) or involving the
(cid:3)-carbon(1,4-addition).
Featuresofambidentbehaviorofenonesandenalesandtheirtreatmentwith
CH-acidshavebeendiscussedinareview[14].Therelativereactivityofcarba-
nionsin1,2-and1,4-additionreactionsisconsideredfromtheviewpointofthe
V.A.Chebanovetal.,AzaheterocyclesBasedon(cid:2),(cid:3)-UnsaturatedCarbonyls, 1
(cid:2)Springer-VerlagBerlinHeidelberg2008
2 Introduction
perturbationofthemolecularorbitalstheory[15].Onthebasisofthistheory,
considering the electronic structure of the enone fragment (the maximum
effectivepositivechargeisonthecarbonylgroup,whilethemaximumlocaliza-
tionofLUMO(lowestunoccupiedmolecularorbital)isonthe(cid:3)-carbon[16])
for the case of 1,2-addition charge control of the reaction takes place. Corre-
spondingly, 1,4-addition occurs under orbital control. Consequently, with all
things being equal, localization of the charge at the nucleophilic group and
decreasing of the HOMO (highest occupied molecular orbital) energy favor
additionofthenucleophiletothecarbonylgroup.Ontheotherhand,increas-
ing of the charge delocalization and increasing of the HOMO energy causes
orbitalcontrolofthe1,4-addition[14,17].
Sufficient differences in the nature of these two electrophilic centers of
enones are reflected in the high regioselectivity of their reactions with mono-
and binucleophiles. This fact clearly discriminates (cid:2),(cid:3)-unsaturated carbonyls
fromotherbielectrophiliccompounds,forinstance,(cid:3)-diketones.However,the
application of this advantage requires the determination and subsequent
systematizationofthefactorsinfluencingthedirectionsofthereactions.
Itshouldbenotedthatinthecaseofthereactionof(cid:2),(cid:3)-unsaturatedketones,
1,4-additionismorepreferable.Itisknown[1,18,19,20,21,22,23]thattheir
treatment with aromatic, secondary and most primary amines leads to the
formation of the appropriate (cid:3)-adducts. Unsaturated aldehydes, in contrast,
usually react with primary and aromatic amines, forming the appropriate
azomethines[24,25,26,27,28,29,30].
On the other hand, reactions of (cid:2),(cid:3)-unsaturated ketones with hydrazines
andhydroxylaminesinvolve,inthefirststage,acarbonylgroup[13,31,32,33,
34, 35, 36, 37, 38, 39, 40] (see Sect. 2.3 for more details). This fact is usually
explainedbyenhancingthenucleophilicityofthehydrazineandhydroxylamine
derivatives owing to the presence of an unshared pair being adjacent to the
attacking atom ((cid:2)-effect) [41, 42, 43]. However, N-amino-substituted hetero-
cyclesalsohaveenhancednulcleophilicityrelativetocarbonyls,althoughinthis
casethe(cid:2)-electronpairisincorporatedintheheteroaromaticsystem[44].
The conditionsinfluencethedirectionofthereactionsbetween thenucleo-
phileandunsaturatedcarbonylcompoundsaswell.Forexample,thereaction
ofhydrazidesofsomeorganicacidswithchalconeinthepresenceofaceticacid
involves the carbonyl group of the unsaturated ketone, while basic catalysis
(piperidine)promotes(cid:3)-addition[45].Ananalogousinfluenceoftheacidityon
thedirectionisobservedinreactionswithbinucleophiles[46].Numeroussimi-
larexamplesaregivenintheappropriatechaptersofthisbook.
The problems of (cid:3)-amination of aromatic unsaturated ketones and their
mechanismaredescribedin[31,47,48].Themultistagecharacterofthisprocess
and high sensitivity both tothe nature of thereactioncomponents and tothe
reaction conditions should be noted. For the same reactions in the literature,
differentdataconcerningkineticsaredescribedowingtotheinfluenceoftrace
contaminantsinthereactionmixture[47,48].
Introduction 3
(cid:2),(cid:3)-Unsaturated ketones may have a trans and cis structure with S-trans
orS-cisconformationoftheenonefragment.
When the reactivity of the (cid:2),(cid:3)-unsaturated carbonyls is considered, their
stereochemistry is very important. However, literature data concerning this
problemareveryrarebecauseofthehighrateofisomerizationandconforma-
tionalprocessesinenones.Someexamplesofsuchaninfluencearediscussedin
thismonographaswell.
References
1. Dhar,D.N.TheChemistryofChalconesandRelatedCompounds,Wiley-Interscience:
NewYork,1981.
2. Desenko,S.M.;Orlov,V.D.AzaheterocyclesBasedonAromaticUnsaturatedKetones,
Folio:Kharkov,1998.
3. Sausins,A.;Duburs,G.Khim.Geterotsikl.Soedin.,1992,4,435.
4. Sausins,A.;Duburs,G.Heterocycles,1988,27,269.
5. Insuasty,B.;Quiroga,H.;MeierH.TrendsHeterocycl.Chem.,1997,5,83.
6. Desenko,S.M.Khim.Geterotsikl.Soedin.1995,147.
7. Chebanov,V.A.;Desenko,S.M.Curr.Org.Chem.,2006,10,297.
8. Druzhinin,S.V.;Balenkova,E.S.;Nenajdenko,V.G.Tetrahedron,2007,63,7753
9. Sausins,A.;Duburs,G.Heterocycles,1988,27,291.
10. Sausins,A.E.;Dubur,G.Y.Khim.Geterotsikl.Soedin.,1993,579.
11. Sausins,A.E.;Dubur,G.Y.Khim.Geterotsikl.Soedin.,1992,781.
12. Weis,A.L.;VanderPlas,H.C.Heterocycles,1986,24,1433.
13. Levai,A.Khim.Geterotskl.Soedin.,1997,579.
14. Yanovskaya,L.A.;Kryshtal’,G.V.;Kul’ganek,V.V.Usp.Khim.,1984,53,1280.
15. Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry. Part A: Structure and
Mechanisms,Springer:NewYork,2007.
16. Yanovskaya,L.A.;Umirzakov,B.;Kucherov,V.F.;Yakovlev,I.P.;Zolotarev,B.M.;
Chizhov,O.S.;Vorontsova,L.G.;Fundyler,I.N.;Grunfest,M.G.;Kolodyazhny,Y.V.;
Osipov,O.A.Terahedron,1973,29,4321.
17. Kryshtal’,G.V.;Burshtein,K.Y.;Kul’ganek,V.V.;Yanovskaya,L.A.Izv.Akad.Nauk
Ser.Khim.,1984,2541.
18. Yang,L.;Xu,L.-W.;Zhou,W.;Li,L.;Xia,C.-G.TetrahedronLett.,2006,47,7723.
19. Shankar,R.;Jha,A.K.;Singh,U.S.;Hajela,K.TetrahedronLett.,2006,47,3077.
20. Lesma,G.;Danieli,B.;Sacchetti,A.;Silvani,A.J.Org.Chem.,2006,71,3317.
21. Gandelman,M.;Jacobsen,E.N.Angew.Chem.Int.Ed.,2005,44,2393.
4 Introduction
22. Zahouily,M.;Bahlaouan,B.;Rayadh,A.;Sebti,S.TetrahedronLett.,2004,45,4135.
23. Cimarelli,C.;Palmieri,G.;Volpini,E.Tetrahedron,2001,57,6808.
24. Monleon,L.M.;Grande,M.;Anaya,J.Tetrahedron,2007,63,3017.
25. Dalpozzo,R.;Nino,A.D.;Nardi,M.;Russo,B.;Procopio,A.Synthesis,2006,1127.
26. Man,C.L.;Tin,W.C.;Wong,K.-Y.;Tak,H.C.J.Org.Chem.,2007,72,923.
27. Moonen,K.;Stevens,C.V.Synthesis,2005,20,3603.
28. Joffe,A.L.;Thomas,T.M.;Adrian,J.C.TetrahedronLett.,2004,45,5087.
29. Chatani,N.;Kamitani,A.;Murai,S.J.Org.Chem.,2002,67,7014.
30. Eisch,J.J.;Dluzniewski,T.J.Org.Chem.,1989,54,1269.
31. Weissberger,A.TheChemistryofHeterocyclicCompounds,Wiley,NewYork,1967.
32. Barton D., Ollis W. D. (Eds.). Comprehensive Organic Chemistry: The Synthesis and
Reactions of Organic Compounds, vol. 4. Heterocyclic Compounds, Pergamon Press:
Oxford,1979.
33. Lavrushin,V.F.;Bezugly,V.D.;Belous,G.G.;Tishchenko,V.G.Zh.Obshch.Khim.,
1964,34,7.
34. vonAuwers,K.;Muller,K.Chem.Ber.,1921,54,1000.
35. Suchchar,S.P.;Singh,A.K.J.IndianChem.Soc.,1985,62,142.
36. Ferres,H.;Hamdam,M.S.;Jackson,W.R.J.Chem.Soc.B,1971,1892.
37. Bezuglyi,V.D.;Kotok,L.A.;Shimanskaya,N.P.;Bondarenko,V.E.Zh.Obsch.Khim.,
1969,39,2167.
38. Raiford,L.C.;Manley,R.H.J.Org.Chem.,1940,5,345.
39. Bayer,H.;Dieterle,H.Chem.Ber.,1911,44,2697.
40. Tsukerman,S.V.;Danil’chenko,E.V.;Lavrushin,V.F.Ukr.Khim.Zh.,1976,42,383.
41. Grekov,A.P.;Veselov,V.Y.Russ.Chem.Rev.,1978,47,631.
42. Fina,N.J.;Edwards,J.O.;Int.J.Chem.Kinet.,1973,5,1.
43. Smith,M.B.;March,J.March’sAdvancedOrganicChemistry:Reactions,Mechanisms
andStructure,Wiley-Interscience:Hoboken,2007,p.495.
44. Pozharskii,A.F.;Kuz’menko,V.V.;Bumber,A.A.;Petrov,E´.S.Terekhova,M.I.;
Chikina,N.L.;Nanavyan,I.M.Khim.Geterotsikl.Soedin.,1989,221.
45. Al-Farkh,Y.A.;Al-Hajjar,F.H.;Al-Shamali,F.S.;Hamoud,H.S.Chem.Pharm.Bull.
1979,27,257.
46. Orlov,V.D.;Papiashvili,I.Z.Khim.Geterotsikl.Soedin.,1985,241.
47. Menger,F.M.;Smith,J.H.J.Am.Chem.Soc.,1969,91,4211.
48. Kinatowski, S.; Grabarkiewitz-Szczesna, J. Bull. Acad. Pol. Sci. Ser. Sci. Chim.,
1979,27,1.
