Compr. Heterocyclic Chem. III Vol. 8 Six-membered Rings with Two Heteroatoms

899 Pages·2008·13.801 MB·English

by  Katritzky A.R., et al. (eds.)

8.01
Pyridazines and their Benzo Derivatives
B.U.W.MaesandG.L.F.Lemie`re
UniversityofAntwerp,Antwerp,Belgium
ª2008ElsevierLtd.Allrightsreserved.
8.01.1 Introduction 3
8.01.2 TheoreticalMethods 4
8.01.3 ExperimentalStructuralMethods 5
8.01.3.1 X-Ray,NeutronandElectronDiffraction,andMicrowaveSpectroscopy 5
8.01.3.2 NMRSpectroscopy 6
8.01.3.2.1 1HNMR 6
8.01.3.2.2 13CNMR 6
8.01.3.2.3 15NNMR 6
8.01.3.3 MassSpectrometry 8
8.01.3.4 UV,IR,andRaman 9
8.01.4 ThermodynamicAspects 10
8.01.4.1 GeneralPhysicalProperties 10
8.01.4.2 Ionization 12
8.01.4.3 Aromaticity 12
8.01.4.4 ConformationofNonconjugatedCompounds 12
8.01.4.5 Tautomerism 13
8.01.4.5.1 Keto–enoltautomerism 13
8.01.4.5.2 Amino–iminotautomerism 13
8.01.4.5.3 Doublebondtautomersinnonconjugatedsystems 13
8.01.4.5.4 Methyl–methylenetautomerism 13
8.01.5 ReactivityofFullyConjugatedRings 14
8.01.5.1 IntramolecularThermalandPhotochemicalReactions 14
8.01.5.1.1 Intramolecularthermalreactions 14
8.01.5.1.2 Intramolecularphotochemicalreactions 15
8.01.5.2 ElectrophilicAttackatNitrogen 16
8.01.5.2.1 Introduction 16
8.01.5.2.2 Metals 16
8.01.5.2.3 Alkylhalides 18
8.01.5.2.4 Acylhalidesandrelatedcompounds 18
8.01.5.2.5 Peracids 19
8.01.5.2.6 Aminatingagents 19
8.01.5.3 ElectrophilicAttackatCarbon 19
8.01.5.4 NucleophilicAttackatCarbon 21
8.01.5.4.1 Introduction 21
8.01.5.4.2 Amines 21
8.01.5.4.3 Hydrazine 22
8.01.5.4.4 Carbonnucleophiles 22
8.01.5.4.5 Chemicalreduction 25
8.01.5.5 NucleophilicAttackatHydrogenAttachedtoRingCarbonorNitrogen 25
8.01.5.5.1 Metallationatcarbon 25
8.01.5.5.2 Alkylationofanionsformedbydeprotonationofazinones 26
8.01.5.5.3 Acylationofanionsformedbydeprotonationofazinones 27
1
2 PyridazinesandtheirBenzoDerivatives
8.01.5.5.4 Sulfonylationofanionsformedbydeprotonationofazinones 27
8.01.5.5.5 Otherreactions 27
8.01.5.6 ReactionswithRadicals 27
8.01.5.7 CycloadditionReactions 28
8.01.5.7.1 [2þ4]Cycloadditionreactions 28
8.01.5.7.2 1,3-Dipolarcycloadditionreactions 30
8.01.6 ReactivityofNonconjugatedRings 34
8.01.6.1 Introduction 34
8.01.6.2 DihydroDerivativesContainingaCarbonylGroupintheRing 34
8.01.6.3 DihydroDerivativeswithoutaCarbonylGroupintheRing 36
8.01.6.4 TetrahydroDerivatives 36
8.01.6.5 Hexahydroderivatives 37
8.01.7 ReactivityofSubstituentsAttachedtoRingCarbons 39
8.01.7.1 AlkylGroups 39
8.01.7.2 CarboxylicAcidsandEsters 40
8.01.7.3 CarboxylicAmides 41
8.01.7.4 Nitriles 41
8.01.7.5 AldehydesandKetones 42
8.01.7.6 OtherSubstitutedAlkylGroups 43
8.01.7.7 AlkenylGroups 43
8.01.7.8 AlkynylGroups 43
8.01.7.9 ArylGroups 44
8.01.7.10 AminoandIminoGroups 44
8.01.7.10.1 Reactionofelectrophilesattheaminogroup 44
8.01.7.10.2 Reactionofaminoandiminogroupswithnucleophiles 45
8.01.7.10.3 t-Aminoeffect 45
8.01.7.11 OtherN-LinkedSubstituents 46
8.01.7.11.1 Nitrogroups 46
8.01.7.11.2 Hydrazinogroups 46
8.01.7.11.3 Carbodiimidogroups 47
8.01.7.11.4 Azidogroups 47
8.01.7.12 HydroxyandOxoGroups 47
8.01.7.12.1 Reactionswithelectrophiles 47
8.01.7.12.2 Reactionswithnucleophiles 48
8.01.7.13 OtherO-LinkedSubstituents 49
8.01.7.13.1 Alkoxyandaryloxygroups 49
8.01.7.13.2 Triflateandtosylateesters 50
8.01.7.14 S-LinkedSubstituents 51
8.01.7.14.1 Thiolandthionegroups 51
8.01.7.14.2 Alkylthio,alkylsulfinyl,andalkylsulfonylgroups 52
8.01.7.15 HalogenAtoms 52
8.01.7.15.1 Replacementofahalogenbyametal 52
8.01.7.15.2 Replacementofahalogenbytransitionmetalmediatedcoupling 52
8.01.7.15.3 NucleophilicdisplacementbyclassicalS mechanism 63
AE
8.01.7.16 MetalsandMetalloidDerivatives 68
8.01.8 ReactivityofSubstituentsAttachedtoRingNitrogens 69
8.01.8.1 N-AlkylGroups 69
8.01.8.2 N-Chloro 71
PyridazinesandtheirBenzoDerivatives 3
8.01.8.3 N-Nitro 71
8.01.8.4 N-Acyl 71
8.01.8.5 N-Sulfonyl 71
8.01.8.6 N-Amino 71
8.01.8.7 N-Oxide 71
8.01.9 RingSynthesis 72
8.01.9.1 FormationofOneBond 72
8.01.9.1.1 Betweentwoheteroatoms 72
8.01.9.1.2 Adjacenttoaheteroatom 73
8.01.9.1.3 (cid:2)toaheteroatom 75
8.01.9.1.4 Formationofbenzorings 77
8.01.9.2 FormationofTwoBonds 77
8.01.9.2.1 From[5þ1]fragments 77
8.01.9.2.2 From[4þ2]fragments 79
8.01.9.2.3 From[3þ3]fragments 85
8.01.10 RingSynthesisbyTransformationofAnotherRing 85
8.01.10.1 ByRingExpansion 85
8.01.10.2 ByRingContraction 87
8.01.10.3 ByCycloaddition 88
8.01.10.4 ByReactionofHydrazineswithCyclicEquivalentsof1,4-DiketoandRelated
Compounds 90
8.01.10.5 ByCleavageofaSecondfusedRing 90
8.01.10.6 OtherMethods 90
8.01.11 SynthesisofParticularClassesofCompounds 92
8.01.11.1 ParentCompoundsandSyntheticallyImportantDerivatives 92
8.01.11.2 SynthesisofPyridazinoFusedRingSystems 93
8.01.12 ImportantCompoundsandApplications 93
8.01.12.1 Introduction 93
8.01.12.2 CompoundsthatOccurinNature 94
8.01.12.3 Pharmaceuticals 96
8.01.12.4 Agrochemicals 99
8.01.12.5 MaterialSciences 101
8.01.13 FurtherDevelopments 103
References 104
8.01.1 Introduction
Twocomprehensivereviewsonthesyntheticaspectsofpyridazinesandtheirbenzoderivativesappearedsince1995
<2000AHC(75)167, 2000HC(57)1>. The most recent comprehensive work published on pyridazines
<2004SOS(16)125>, phthalazines <2004SOS(16)315>, and cinnolines <2004SOS(16)251> was written by Haider
and Holzer for the Science of Synthesis series.The majority ofthe review material thatappeareddeals with specific
synthetic topics in the field and are often accounts of the authors own scientific work <2001T4059, 2001T4489,
B-2002MI369, 2004COR1463, 2004SL1123, 2006COR277, 2006COR377, B-2006MI541, 2006SL3185>. Some
reviewsonlydealpartlywith1,2-diazines<2004CRV2433,2006S2625>.Itisnotourintentiontociteallavailable
reviewsofthelastdecade,butmerelytogivethereaderanideaofthetypesofpublishedrelatedreviewmaterialas
wellasafirstinsightintothisliterature.
Around the subject area of this chapter also biannual international conferences are organized which started in
Strasbourg(1988)andwereheldinSopron(1996),ClearwaterBeach(1998),SantiagodeCompostela(2000),Ferrara
4 PyridazinesandtheirBenzoDerivatives
(2002),Antwerp(2004),andStrasbourg(2006)inthecoveredperiodofthischapter.Certainlytherehasbeenalotof
activity in the pyridazine and benzo derivative field in the 1996–2006 period. A search on the ‘Web of Science’
revealed1756articlesforthetopic‘pyridazin*’,574for‘phthalazin*’and168for‘cinnolin*’.Thesamesearchonthe
‘Scifinder’ database revealed 5203, 1943 and 462 hits for the concepts ‘pyridazin’, ‘phthalazin’, and ‘cinnolin’,
respectively. Patentshaveonlybeentaken intoaccountin Section8.01.12.Inthischapteremphasishas beenput
on new and adapted older methods, as well as new interesting examples of well established methods. Selections
necessarilyhadtobemadeduetothelargeamountofmaterialpublishedwithintheconsideredtimeframe.Fully
conjugated pyridazines, phthalazines and cinnolines as well as (partly) reduced and oxo forms (both only in the
1,2-diazinering)arecoveredinthiswork.
IUPACnomenclaturehasbeenusedinthemajorityofthenames.Onlywhenthereadabilityofthemanuscriptwas
hampered,wedecidedtousealternativenames.Trivialnameshaveonlybeenincludedwhentheyarereallywell
established.
8.01.2 Theoretical Methods
AsurveyofninecomputationalmethodswasundertakentocalculateC–Hbond-dissociationenergiesofmonocyclic
aromaticmoleculesincludingpyridazine.Comparisonofthecalculatedbond-dissociationenergieswiththeavailable
experimentalvaluesforthesemoleculesrevealedthattheB3LYPmethodprovidesthebestagreement(3kcalmol(cid:2)1)of
calculatedwithexperimentalvalues<1999JA491>.Therelativestabilityandenergybarrierstowardtautomerismofthe
conventionalradical-cationandits(cid:3)-distonictautomerofpyridazineandotherheterocycleshavebeendeterminedby
computationalmethods.Bothradicalcationsarestablespecieswhichexistindiscreteenergywells,withasignificant
barriertowardstheirinterconversion.Theconventionalradicalcationisthemorestableone<2004IJM1>.
Abinitiocalculationshavebeenusedtointerprettheobservedbasicitiesofmonocyclicandbicyclicazines.Intwo
separateseries,A(pyridineandthemonocyclicdiazines)andB(thebenzodiazines),agoodlinearrelationshipexists
between the experimental pK values and the highest occupied molecular orbital (HOMO) energy. Therefore,
a
basicitiesofazinesmaydirectlybeinterpretedintermsofHOMOenergies<1995JMT(339)255>.Similarlyinseries
AagoodlinearrelationshipisobservedbetweenexperimentalpK valuesandthecontractionsofthepolarizabilityby
a
theeffectofsingleprotonation<2004CPL(396)117>.
Hydrogen-bonding interaction received considerable interest because of its important role in chemical and
biological processes. Absorption and fluorescence solvatochromic shifts of dilute pyridazine in water as a result of
solvent–soluteinteractionsarecalculated.Supportisprovidedtothehypothesisthattwolinearhydrogenbondstothe
pyridazineN-atomsareformedindiluteaqueoussolutions<1996JPC9561>.AsurveyoftheCambridgeStructural
DatabaseandintermolecularperturbationtheorycalculationsonN(cid:3)(cid:3)(cid:3)HOCH interactionssuggeststhatthehydrogen
3
bondsareformedprimarilyinthedirectiontraditionallyassignedtothenitrogenlonepair<1997JCC2060>.Inertia
momentsderivedfrommillimeterspectraofthe1:1complexbetweenpyridazineandwatersuggestaplanarstructure
in which one hydrogen of the water molecule is bound to the nitrogen of the aromatic ring, and the ‘free’ water
hydrogenisentgegentothering(Figure1)<1998JPC8097>.
Figure1 Pyridazine–watercomplex.
ThisbenthydrogenbondisconfirmedbyabinitiocalculationsusingtheB3LYPdensityfunctionalmethodanda
6-31þG(d,p) basis set, performed in a more general study on pyridazine–(water) clusters <2002CPH(276)277>.
n
Thermodynamic parameters for the hydrogen-bonding interaction of azabenzenes with thioacetamide in carbon
tetrachloride solution were determined using near-IR absorption spectroscopy (IR – infrared), and the association
energy of these complexes has been calculated at the B3LYP/6-311G** and B3LYP/6-31þG** levels, showing
excellent agreement with the relative hydrogen-bonding strength. Also the association energy of 1:1 complexes
with acetamide and water was calculated at the B3LYP/6-31þG** level. Bifurcated hydrogen bonding of the two
adjacentnitrogenatomsofpyridazinemayenhancethestabilityofthecomplexes<2004JPC921>.
PyridazinesandtheirBenzoDerivatives 5
Infrared spectra for 2-substituted 4,5-dimethoxypyridazin-3(2H)-ones were measured in hexane–CHCl and
3
CH CN–D O mixtures. Free, linearly, and angularly hydrogen-bonded pyridazinones were distinguished by a
3 2
correlationstudyof(cid:4)˜ (CTO)valueswithmolefractionsofthelesspolarcomponentsofthebinarysolventmixtures
<2002CCC1790>.Geometricaloptimizationsofninetautomersandrotamersof4-methyl-1,2-dihydropyridazine-3,6-
dione werecarried out at the B3LYP/6-31G(d), B3LYP/6-31þG(d,p),and MP2/6-31G(d) levels.Energies, thermo-
dynamic quantities, rate constants, and equilibrium constants of ten tautomeric and rotational transformations
betweenthenineformsinthegasphaseandaqueousphasewereobtained<2005CPL(415)176>.
AtheoreticalstudyofthestructureandtautomerismofthefourpossiblehydroxypyridazineN-oxides,aswellas
pyridazine1,2-dioxideispresented.Gas-phasepropertiesaremodeledwithhigh-levelabinitiocalculationsemploy-
ing large basis sets (6-311þþG(3df,3pd)) and quadratic configuration interaction treatment of electron correlation
(QCISD(T)).Sincetheseacidicheterocyclesareofinterestascarboxylatebio-isosteres,theiranionicconjugatebases
are also examined. Aqueous solution-phase properties are investigated using the isodensity polarized continuum
model (IPCM), and the semi-empirical AM1–SM2 and PM3–SM3 models, and relative acidities compared. The
calculated properties are generally in good agreement with existing experimental data, indicating that the oxo-
1-hydroxytautomerpredominatesbothinthegasphaseandinsolutioninthecaseofthe6-substitutedsystem,and
that the hydroxy-1-oxide tautomers predominate in the 3- and 5-substituted systems. The behavior of the
4-substitutedisomerislessclear,withnonplanar1-hydroxyandplanar4-hydroxytautomersbeingsimilarinstability
<1997JMT(419)97>.
The lipophilicity of 4- and 5-aminopyridazin-3(2H)-ones has been calculated by KOWWIN-EVA and 3DNET
computationalmethods.ThecalculatedlogPvaluesareingoodagreementwiththeexperimentalvalues.Generally,
the4-aminoderivativeshavebeenfoundtopossesshigherlogPvalues.Itseemsthathydrogen-bondingcapacityand/or
aromaticityarethemostrelevantparametersdeterminingthelogPvaluesofthisclassofcompounds<2003JFA5262>.
Semi-empiricalAM1andPM3calculations,anddensityfunctionaltheory(DFT)calculationshavebeenexecuted
to support proposed reaction mechanisms of the 1,3-dipolar cycloaddition reaction of 5-substituted pyridazinones
with nitrile imines <2000JMT(528)13>, the ring-closure reaction of 5-morpholino-4-vinylpyridazin-3(2H)-ones by
tert-amino effect <2003JMT(666/7)667> and the reaction of chloropyridazin-3(2H)-ones with 57% HI or sodium
iodideindimethylformamide(DMF)<2005JMT(713)235>.Theselectivityoffree-radicalbrominationsofmethyl-
3-methoxypyridazinederivativeswithN-bromosuccinimide(NBS)isconfirmedtoberelatedtothestabilityofthe
freeradicalsformedintherate-limitingstep.Semi-empiricalcalculationsusingthePM3Hamiltoniangenerallygive
relative energies which qualitatively reproduce the selectivities observed experimentally <1996JMT(368)235>.
Atopologicalanalysisoftheelectronlocalizationfunctionhasbeenappliedtoexplorethenatureofbondinginthe
thermalcyclization of(2-ethynylphenyl)triazene tocinnoline.The analysisshows thatthiscyclization isapseudo-
pericyclicprocessincontrasttothecyclizationof2-ethynylstyrenetonaphthalenewhichisamorepericyclicprocess
<2005JPC4352>.
Thestructuralpropertiesofpyridazineandphthalazinederivedfrommicrowavespectroscopy,electronandX-ray
diffractionhavebeencomparedwiththeoreticaldataobtainedfromtransitionalabinitiocalculations,includingboth
restrictedHartree–Fockandsecond-orderMoller–Plessetperturbationtheory,andDFTcalculations<1996JPC6973,
1998JMT(423)225, 2005JMT(717)171>. In addition, theoretical data were obtained from infrared and/or Raman
spectroscopyinthevapor,theliquid,orthecrystallinephases,whichwereusedtointerpretthevibrationalspectraof
pyridazine <1995JMT(349)409, 1996JPC6973, 1998JMT(423)225, 2001JPC9354>, chlorinated pyridazines
<2000PCA2599, 2001JPC9354>, and phthalazine <2005JMT(717)171>. These studies not only include results
obtainedbyusingstandard (scaled)harmonicforcefieldcalculations,butalsoincorporate resultsderivedbyusing
newermethodologiesemployedforthepredictionofanharmonicforcefields<2004JPC3085,2004JPC4146>andby
usingcorrectionsforanharmonicresonances<2005PJP425>.Finally,differentmethodologiesusedfortheprediction
of electronic spectra <2000CPH(257)1, 1998JRS547> and resonance-enhanced multiphoton ionization (REMPI)
spectra<1998JPC8084>havebeenevaluated.
8.01.3 Experimental Structural Methods
8.01.3.1 X-Ray, Neutron and Electron Diffraction, and Microwave Spectroscopy
InCHEC(1984) <1984CHEC(2)1> electron diffraction, microwavespectroscopy, and X-rayanalysis ofpyridazine
andsimplederivativeswereincluded.AlldataareconsistentwithaplanarstructureandsignificantN–Nsinglebond
character.CHEC-II(1996)<1996CHEC-II(6)1>containedsomeadditionalstructuralparametersderivedfromX-ray
6 PyridazinesandtheirBenzoDerivatives
analysis of 1,2-diazines such as pyridazine-3,6-dicarboxylic acid. Phthalazine derivatives were also discussed.
New work includes X-ray data on the 1:1 salt of pyridazine and 4-chloro-3-nitrobenzoic acid <2002AXE1081>,
3,4,6-tris(pyrazol-1-yl)pyridazine <2002AXE1408>, and 2-bromobenzo[c]cinnoline 6-oxide <2001AXE645>. The
tricyclicskeletonofthelastmentionedcompoundconsistsofalmostplanarrings.TheN–Obondseemstobeshorter
thaninthecorrespondingbondinpyridineN-oxidewhichisprobablyaresultoftheelectronresonancebetweenthe
oxygenatomandthearomaticnucleus.Alsoseveralpyridazin-3(2H)-onederivativeshavebeenanalyzedviaX-ray
<1996JST(374)251, 2004T12177, 2005T4785, 2006AXE446>. Interesting to mention is the further study of the
polymorphism of maleic hydrazide <2001AXB697>. There seems to be a third polymorph which is monoclinic.
X-Raydatauptomid-1998havebeensummarizedbyTisˇler<2000AHC(75)167>.
8.01.3.2 NMR Spectroscopy
8.01.3.2.1 1HNMR
InCHEC(1984)<1984CHEC(2)1>,1HNMRspectraofsimplepyridazines,pyridazin-3(2H)-ones,andpyridazine
N-oxidesweretabulated.Cinnolinederivativeswerealsocoveredinthisway.Areferencetothe1HNMRspectrum
ofphthalazinewasgiven.Besidestheshiftvaluesalsocouplingconstantswerenicelysummarizedforallthese1,2-
diazines. In CHEC-II(1996) <1996CHEC-II(6)1>, phthalazin-1(2H)-ones were mentioned. Moreover, useful gen-
eralshiftandcouplingconstanttrendsfor1HNMRspectraof1,2-diazineswereprovided.1HNMRisnowaroutine
techniqueandamajorityofthefullpaperarticlescontaininterpreteddata.Takingintoaccounttheimportanceof
pyridazin-3(2H)-ones(Figure2)andthelimitednumberprovidedintheCHEC(1984)table,weincludedhereanew
table(Table1).Additionally,wehavetabulateddataforsomebicyclicderivatives:[1,2,4]triazolo[4,3-b]pyridazines
andtetrazolo[1,5-b]pyridazines(Table2andFigure3).
Figure2 Structureandnumberingofpyridazin-3(2H)-ones.
8.01.3.2.2 13CNMR
Since the publication ofCHEC(1984) <1984CHEC(2)1>, the use of 13C NMRseriously expanded. The majority
of the full papers now published contain 13C NMR spectroscopic data. Unfortunately, this is usually only for
characterization of the synthesized compounds and no interpretation of the data is provided. In CHEC-II(1996)
<1996CHEC-II(6)1>, a representative and very useful table with assigned 13C shifts of simple pyridazines and
pyridazin-3(2H)-ones was published. Phthalazin-1(2H)-ones were also briefly mentioned. As an extension we here
summarize some assigned 13C NMR data of bicyclic derivatives: [1,2,4]triazolo[4,3-b]pyridazines and tetrazolo[1,5-b]-
pyridazines(Table2andFigure3),andisoxazolo[3,4-d]pyridazin-7(6H)-ones(Table3andFigure4).
8.01.3.2.3 15NNMR
InCHEC-II(1996)<1996CHEC-II(6)1>15Nshiftsofpyridazine,phthalazine,cinnoline,aswellassomederivatives
werementioned.15NNMRdataofsomesimple[1,2,4]triazolo[4,3-b]-andtetrazolo[1,5-b]pyridazinesaresummarized
in Table2. The 15NNMRis especially useful for structureanalysis ofsuch compoundsas they consistof a large
number of nitrogen atoms consequently leading to limited information resulting from classical 1H and 13C NMR
spectra. After all, the 15N shift gives an immediate correlation with the electronic environment of the chemically
different nitrogen atoms present in the molecule. For the [1,2,4]triazolo[4,3-b]pyridazines 15N NMR in dimethyl
sulfoxide (DMSO) supported a triazolo rather than an open azido form <1999MRC493>. More derivatives were
studiedinalaterpaper<2002MRC507>.HolzerandDalPiazprovided15Nshiftsofthesynthetically(seeSection
8.01.10.5)andbiologicallyimportantisoxazolo[3,4-d]pyridazin-7(6H)-ones(Table3).
PyridazinesandtheirBenzoDerivatives 7
Table1 1H-NMR(cid:5)-valuesofsubstitutedpyridazin-3(2H)-ones
(cid:5)-NH
Substituents (bs) (cid:5)-(H-4) (cid:5)-(H-5) (cid:5)-(H-6) (cid:5)-Substituents
4-Cl,5-MeOb,c 13.26 8.10 4.06s3H
4-Br,5-MeOb,c 13.24 8.10 4.07s3H
4-Cl,5-Nb,c 13.26 8.08
3
4-Br,5-Nb,c 13.32 8.04
3
4-Cl,5-NHEta,c 12.42 7.63 1.32t3H,3.41q2H,5.19bs1H
4-Br,5-NHEta,c 12.42 7.42 1.12t3H,3.21q2H,4.98bs1H
4-Cl,5-OPha,c 7.54 7.26-7.48m5H
4-Br,5-OPhb,c 13.43 7.53 7.23-7.51m5H
6-Phb,d 13.18 6.98d 8.00d 7.84m2H,7.46m3H
J¼9.9Hz J¼9.9Hz
5-Cl,6-Phb,d 13.85 7.44 7.58-7.50m5H
5-Br,6-Phb,d 13.78 7.45 7.51m5H
5-N,6-Phb,d 13.16 6.80 7.58m2H,7.45m3H
3
5-OMe,6-Phb,d 12.86 6.31 7.59m2H,7.14m3H;3.80s3H
5-SMe,6-Phb,d 12.93 6.59 7.48m5H;2.39s3H
5-CN,6-Phb,e 14.03 7.93 7.63m2H,7.50m3H
5-CHOH,6-Phb,e 13.07 6.93 7.46-7.44m5H;5.62s1H,4.26s2H
2
5-CHO,6-Pha,f 13.82 7.46 7.70-7.60m5H;9.87s1H
5-COMe,6-Pha,f 12.64 7.43 7.44m5H;2.14s3H
(cid:5)-NMe
Substituents (s) (cid:5)-(H-4) (cid:5)-(H-5) (cid:5)-(H-6) (cid:5)-Substituents
5-OMeb,g 3.72 6.15d 7.54d 3.80s3H
J¼2.9Hz J¼2.9Hz
5-OPha,g 3.74 5.98d 7.75d 7.09d2H,7.29t1H,7.44t2H
J¼2.8 J¼2.8
5-NHEta,g 3.67 5.68d 7.31d 1.27t3H,3.12m2H,4.54bs1H
J¼2.6 J¼2.6
5-Ia,h 3.72 7.46d 7.90d
J¼2.05 J¼2.05Hz
4-Cl,5-OMeb,i 3.69 8.21 4.07s3H
4-OMe,5-Clb,j 3.64 7.99 4.14s3H
4-Cl,5-OPha,h 3.82 7.45 7.44m2H,7.27tt1H,7.09dd2H
4-OPh,5-Cla,h 7.80 7.32dd2H,7.12tt1H,6.96dd2H
Substituents (cid:5)-NPh (cid:5)-(H-4) (cid:5)-(H-5) (cid:5)-(H-6) (cid:5)-Substituents
4,5-diCla,k 7.59-7.42 7.91
4-Cl,5-OMea,k 7.58-7.39 7.95
4-Cl,5-Na,k 7.58-7.41 7.76
3
4-OMe,5-Clb,j 7.50-7.53 8.16 4.17s3H
Substituents (cid:5)-NCl (cid:5)-(H-4) (cid:5)-(H-5) (cid:5)-(H-6) (cid:5)-Substituents
4,5-diCla,l 7.76
4-Cl,5-OMea,l 8.21 4.07s3H
aCDCl .
3
bDMSO-d .
6
c1999JHC277.
d2002BMC2873.
e1999JHC985.
f2003CPB427.
g1998JHC819.
h2004T2283.
ispectrumrecordedinthelaboftheauthors.
j2001T1323.
k2004TL8781.
l2005S1136.
8 PyridazinesandtheirBenzoDerivatives
Table2 1H,13Cand15NNMRvaluesof6-substituted[1,2,4]triazolo[4,3-b]pyridazinesandtetrazolo[1,5-b]pyridazines
X¼CH X¼N
R1 Cld N((CH) )Od Ha,d Cla,d OMea,d N((CH)) Oa,d N b,e NPPhc,e
222 222 3 3
(cid:5)-(H-3) 9.63 9.20
(cid:5)-(H-7) 7.48 7.36 8.05 7.50 7.71 7.43 7.26
(cid:5)-(H-8) 8.45 8.09 8.95 8.63 8.40 8.62 7.83
(cid:5)-(H-29) 3.50 3.65
(cid:5)-(H-39) 3.74 3.76
(cid:5)-(H-OMe) 4.12
J (Hz) 10.15 9.46 9.46 10.00 9.5 9.5
7-8
(cid:5)-(C-3) 138.8 138.3
(cid:5)-(C-6) 149.1 155.1 148.4 151.4 162.3 156.2 155.8 160.5
(cid:5)-(C-7) 123.0 114.8 125.9 127.3 120.9 117.9 121.8 128.4
(cid:5)-(C-8) 126.6 124.1 125.6 128.2 126.1 123.7 127.7 121.6
(cid:5)-(C-8a) 142.2 141.7 143.2 142.6 141.4 139.7 143.1 140.0
(cid:5)-(C-29) 45.6 45.3
(cid:5)-(C-39) 65.5 65.4
(cid:5)-(C-OMe) 55.8
J (Hz) 221.0 216.7
CH-3
J (Hz) 180.1 171.0 182.4 176.7 172.6
CH-7
J (Hz) 178.3 174.7 181.3 180.4 178.8
CH-8
(cid:5)-(N-1) (cid:2)74.7 (cid:2)77.1 (cid:2)64.2 (cid:2)63.1 (cid:2)64.1 (cid:2)64.0 (cid:2)63.5 (cid:2)68.6
(cid:5)-(N-2) (cid:2)48.8 (cid:2)54.8 þ14.5 þ10.6 þ8.6 þ12.3 þ3.8
(cid:5)-(N-3) (cid:2)25.6 (cid:2)26.1 (cid:2)26.4 (cid:2)27.0 (cid:2)28.6
(cid:5)-(N-4) (cid:2)153.5 (cid:2)161.2 (cid:2)99.9 (cid:2)101.6 (cid:2)109.3 (cid:2)105.4 (cid:2)106.2 (cid:2)103.9
(cid:5)-(N-5) (cid:2)84.8 (cid:2)133.9 (cid:2)68.9 (cid:2)82.5 (cid:2)124.4 (cid:2)131.5 (cid:2)108.8 (cid:2)121.4
(cid:5)-(N-19) (cid:2)302.6 (cid:2)297.7 (cid:2)276.8 (cid:2)284.0
(cid:5)-(N-29) (cid:2)146.0
(cid:5)-(N-39) (cid:2)140.3
aDMSO-d .
6
bacetone-d .
6
cCDCl .
3
d1999MRC493.
e2002MRC507.
Figure3 Structureandnumberingof6-substituted[1,2,4]triazolo[4,3-b]pyridazinesandtetrazolo[1,5-b]pyridazines.
Figure4 Structureandnumberingof4,6-disubstituted3-methylisoxazolo[3,4-d]pyridazin-7(6H)-ones.
8.01.3.3 Mass Spectrometry
The electron ionization (EI) mass spectral behavior of pyridazine, pyridazin-3(2H)-one, and phthalazine was dis-
cussed in CHEC(1984) <1984CHEC(2)1>. In CHEC-II(1996) <1996CHEC-II(6)1> the comparison of the high-
resolution EI mass spectra of pyridazin-3(2H)-one, phthalazin-1(2H)-one and cinnolin-3(2H)-one was mentioned.
PyridazinesandtheirBenzoDerivatives 9
Table3 13Cand15NNMR(cid:5)-values(DMSO-d )of4,6-disubstituted3-methylisoxazolo[3,4-d]pyridazin-7(6H)-ones
6
<2005MRC240>
R1 2-Thienyl 3-Thienyl Ph Me Me Me Phe 4-Pyridyl
R2 H H H H Me Ph Me Me
13C
C-3 171.0 171.1 171.0 171.3 171.7 171.9 171.3 171.3
C-3a 110.4 111.0 110.9 112.0 112.0 111.9 111.0 110.5
C-4 136.8 138.3 142.5 140.4 140.1 140.9 141.9 139.6
C-7 153.3 153.5 153.5 153.7 152.4 152.4 152.3 152.4
C-7a 151.9 151.9 152.0 151.6 151.3 152.1 151.7 151.7
3-Me 14.3 13.8 13.7 12.8 12.8 12.9 13.7 13.9
R1 135.7(2), 134.7(3), 133.8(1), 18.7 18.7 18.9 133.4(1), 150.1(2,6),
129.0(3), 127.6(4), 129.6(4), 129.8(4), 140.8(4),
128.5(5), 127.0(5), 128.5(3,5), 128.5(3,5), 122.8(3,5)
127.7(4) 126.7(2) 128.4(2,6), 128.4(2,6)
R2 37.5 140.9(1), 38.0 38.1
128.6(3,5),
127.6(4),
126.2(2,6)
15N
N-1 (cid:2)1.2 (cid:2)0.9 (cid:2)0.7 (cid:2)0.1 (cid:2)0.2 1.4 (cid:2)0.8 (cid:2)0.7
N-5 (cid:2)71.5 (cid:2)70.3 (cid:2)69.0 (cid:2)74.6 (cid:2)65.6 (cid:2)66.4 (cid:2)60.5 (cid:2)57.7
N-6 (cid:2)190.5 (cid:2)190.8 (cid:2)190.2 (cid:2)192.0 (cid:2)195.2 (cid:2)180.7 (cid:2)193.5 (cid:2)192.4
EI mass spectral behavior of 1,10-diethylbenzo[c]cinnoline was also discussed. There are not so many scientific
papers that specifically study fragmentation of 1,2-diazines. In most cases the reported work deals with synthetic
aspectsof1,2-diazinesandlow-orhigh-resolutionmassspectraarejustusedasacharacterizationtooltoconfirmthe
molecularmassofthemolecule.Inthelastdecadeonecanclearlyseethatmoreandmoremassspectrometry(MS)
datareporteddonotuseclassicalEIbutelectrosprayionization(ESI)toionizethe1,2-diazinemolecule.ESI(based
onprotonationordeprotonation)(nounpairedelectrons)isasoftermethodthanEI(unpairedelectrons),inherently
leadingtolesseasyfragmentationofthegeneratedion.Newfundamentalmassspectrometrystudiesthatappeared
include the EI ionization and fragmentation of 2-(3-oxo-1,3-dihydro-2-benzofuran-1-yl)phthalazin-1(2H)-one 1
<2000SAA1045> (Scheme 1), 6-phenyl-4-phenylsulfonylpyridazin-3(2H)-one 2 <2001H(54)237> (Scheme 2),
and6-phenyl-2-phenylsulfonylpyridazin-3(2H)-one3<2001H(54)237>(Scheme2).
8.01.3.4 UV, IR, and Raman
The IR spectrum of pyridazine was obtained as the pure liquid and in solution, in the gas phase, and as a
polycrystallinefilm.ARamanspectrumoftheliquidwasalsoreported<1998JRS547>.Vibrationalspectraofsimple
derivativessuchas3,6-dichloropyridazineand3,4,5-trichloropyridazineassolidsandinsolutionwerereportedaswell
<2000PCA2599>.Soteloandco-workersstudiedthe(cid:4)˜ CTOaborptionbandinIRspectraofseveral5-substituted
(H, CHO, CN, SO Me, NH ,OEt) 6-phenylpyridazin-3(2H)-ones as solids confirmingthat the lactam form is the
2 2
majortautomer<2002T2389>.The13CNMRshiftsofthecarbonatomoftheCO’swereinagreementwiththeseIR
data.AnIRstudyonpyridazin-3(2H)-oneand4,5-dichloropyridazin-3(2H)-onerevealedtheirexistanceinalactam–
lactim tautomeric equilibrium in dioxane. Upon dilution the equilibrium shifts to the enol form. The compounds
probably appear as intermolecular cyclic dimers similar to the well-known carboxylic acid dimers
<1997JST(408)467>. Konecˇny´ studied IR spectra of 5-disubstituted-amino 4-acetylamino-2-phenylpyridazin-
3(2H)-ones. The spectra displayed two NH bands in the 3240–3400cm(cid:2)1 region assigned to the intramolecular
bondedNHgroups.The(cid:4)˜/CTObandsofthecarbonylgroupsoverlappedwiththe(cid:4)˜/CTNand(cid:4)˜/CTCowingto
the very high absorption coefficients of the bands at 1610cm(cid:2)1. For 5-disubstituted-amino 4-amino-2-phenylpyr-
idazin-3(2H)-ones,thesymmetricandasymmetric(cid:4)˜/NH areobservedinthe3370–3500cm(cid:2)1region.The(cid:4)˜/CTO
2
are shifted to higher wave numbers in comparison with 5-disubstituted-amino 4-acetylamino-2-phenylpyridazin-
3(2H)-ones <1997CCC800>. The (cid:4)˜/ SH in 2-substituted 4-alkoxy-5-mercaptopyridazin-3(2H)-ones and (cid:4)˜/ OH in
2-substituted 5-alkylthio-4-hydroxypyridazin-3(2H)-ones was also investigated <1996CCC437>. Ultraviolet (UV)
spectroscopyhasbeenusedtostudytheself-associationofpyridazineinaqueoussolutionatneutral,acidic,andbasic
10 PyridazinesandtheirBenzoDerivatives
Scheme1
pH<2003SAA1223>.Electronicspectraandsolvatochromicbehaviorofazocinnolines4indifferentsolventswere
alsostudied(Figure5)<2004SAA103>.Forthe above-mentioned5-disubstituted-amino4-acetylamino-2-phenyl-
pyridazin-3(2H)-ones, 5-disubstituted amino 4-amino-2-phenylpyridazin-3(2H)-ones, 2-substituted 4-alkoxy-5-mer-
captopyridazin-3(2H)-ones,and2-substituted5-alkylthio-4-hydroxypyridazin-3(2H)-onesUVdatawerealsoprovided
<1996CCC437,1997CCC800>.
8.01.4 Thermodynamic Aspects
8.01.4.1 General Physical Properties
InCHEC-II(1996)<1996CHEC-II(6)1>,somestandardphysicalpropertiesofpyridazine,phthalazineandcinnoline
weresummarized.Whenonecomparesthemelting(pyridazine(cid:2)8(cid:4)C,phthalazine89–92(cid:4)C,cinnoline40–41(cid:4)C)and
boilingpoints(pyridazine208(cid:4)C,phthalazine315–317(cid:4)C,cinnoline114(cid:4)C/0.35mm)withthecorrespondingdideaza
analogstheeffectoftheintroductionoftwoelectronegativenitrogenatomsbecomesvisible.Thenitrogenatomsare
hydrogenbondacceptorswhichforpyridazine,forinstance,resultsinacompletemiscibilitywithwaterandalcohols.
Melting points of pyridazin-3(2H)-one (104–105(cid:4)C), pyridazin-4(1H)-one (245–246(cid:4)C), phthalazin-1(2H)-one
(183–184(cid:4)C), and cinnolin-3(2H)-one (201–203(cid:4)C) were also incorporated in CHEC-II(1996) <1996CHEC-
II(6)1>. Some melting points of simple substituted pyridazin-3(2H)-ones are summarized in Table 4. A general
trendisthatN-unsubstituted pyridazin-3(2H)-oneshavehigher meltingpointsthanthe corresponding substituted
derivatives. Similarly, hydroxypyridazin-3(2H)-ones melt at a higher temperature than the corresponding ethers
<2000HC(57)1, 2002T5645>. LogP values of substituted pyridazin-3(2H)-ones, which are important indications
for their potential to be ‘drugable’, received attention. Ma´tyus studied the lipophilicity of a set of 4- and