Compr. Heterocyclic Chem. III Vol. 4 Five-membered Rings with Two Heteroatoms

1293 Pages·2008·20.279 MB·English

by  Katritzky A.R., et al. (eds.)

4.01
Pyrazoles
L.Yet
AlbanyMolecularResearch,Inc.,Albany,NY,USA
ª2008ElsevierLtd.Allrightsreserved.
4.01.1 Introduction 3
4.01.1.1 SurveyofPossibleStructures 5
4.01.2 TheoreticalMethods 5
4.01.2.1 StructureandReactivityofPyrazoles 5
4.01.2.2 StructureandReactivityofIndazoles 7
4.01.3 ExperimentalStructuralMethods 8
4.01.3.1 X-RayDiffraction 8
4.01.3.2 MicrowaveandPhotoelectronSpectroscopy 9
4.01.3.3 lHand13CNMRSpectroscopy 10
4.01.3.3.1 Aromaticsystems 10
4.01.3.3.2 Nonaromaticsystems 12
4.01.3.4 I9FNMRSpectroscopy 13
4.01.3.5 15NNMRSpectroscopy 13
4.01.3.6 13Cand15NCP/MASNMRSpectroscopy 14
4.01.3.7 UVandIRSpectroscopy 15
4.01.3.8 MassSpectrometryandIonCyclotronResonanceStudies 16
4.01.4 ThermodynamicAspects 17
4.01.4.1 StabilityandStabilization 17
4.01.4.1.1 Thermochemistry 17
4.01.4.2 Tautomerism 17
4.01.4.2.1 Annular(ring)tautomerism 17
4.01.4.2.2 Substituent(chain)tautomerism 19
4.01.5 ReactivityofFullyConjugatedRings 21
4.01.5.1 ThermalandPhotochemicalReactions 21
4.01.5.2 ElectrophilicAttackatNitrogen 22
4.01.5.2.1 Protonacidsonneutralcompounds 22
4.01.5.2.2 Metalions 23
4.01.5.2.3 Azacrownethersandporphyrinogens 28
4.01.5.2.4 Alkylhalidesandrelatedcompounds:CompoundswithafreeNHgroup 28
4.01.5.2.5 Arylhalidesandrelatedcompounds 30
4.01.5.2.6 Acylhalidesandrelatedcompounds 31
4.01.5.2.7 Michaeladditiontodoubleandtriplebonds 32
4.01.5.2.8 Aminatingandnitratingagents 33
4.01.5.2.9 Alkenylation 33
4.01.5.3 ElectrophilicAttackatCarbon 34
4.01.5.3.1 Nitration 34
4.01.5.3.2 Sulfonation 34
4.01.5.3.3 Halogenation 35
4.01.5.3.4 Acylation 36
4.01.5.3.5 Amination 36
4.01.5.3.6 Diazocoupling 37
1
2 Pyrazoles
4.01.5.3.7 Reactionwithaldehydesandketones 37
4.01.5.3.8 Miscellaneous 37
4.01.5.4 NucleophilicAttackatCarbon 38
4.01.5.5 NucleophilicAttackatHydrogen 39
4.01.5.5.1 Metallationataringcarbonatom 39
4.01.5.5.2 Hydrogenexchangeatringcarboninneutralpyrazoles 40
4.01.5.6 ReactionwithRadicalsandElectron-DeficientSpecies 40
4.01.5.6.1 Carbenesandnitrenes 40
4.01.5.6.2 Freeradicalattackattheringcarbonatoms 40
4.01.5.6.3 Electrochemicalreactionsandreactionswithfreeelectrons 41
4.01.5.7 ReactionswithCyclicTransitionStates 41
4.01.6 ReactionsofNonaromaticCompounds 42
4.01.6.1 DihydroDerivatives 42
4.01.6.1.1 Aromatization 42
4.01.6.1.2 Reduction 43
4.01.6.1.3 Thermolysis,photolysis,andpyrolysis 44
4.01.6.1.4 Acylationreactions 46
4.01.6.1.5 Otherreactions 46
4.01.6.2 TetrahydroCompounds 47
4.01.7 ReactionsofSubstituentsAttachedtoRingCarbonAtoms 47
4.01.7.1 Indazoles 47
4.01.7.2 OtherC-LinkedSubstituents 48
4.01.7.2.1 Alkylgroups 48
4.01.7.2.2 Alkenylgroups 50
4.01.7.2.3 Carbonylgroupsandderivatives 50
4.01.7.3 N-LinkedSubstituents 53
4.01.7.3.1 Aminopyrazolesand-indazoles 53
4.01.7.3.2 Imines 55
4.01.7.3.3 Nitroandnitrosogroups 56
4.01.7.3.4 Azo-,diazo-,andazidopyrazoles 56
4.01.7.4 O-LinkedSubstituents 57
4.01.7.4.1 3-Hydroxypyrazoles 57
4.01.7.4.2 4-Hydroxypyrazoles 57
4.01.7.4.3 5-Hydroxypyrazoles 57
4.01.7.5 S-LinkedSubstituents 59
4.01.7.6 HalogenAtoms 60
4.01.7.6.1 Nucleophilicsubstitutionreactions:Neutralpyrazolesandindazoles 60
4.01.7.6.2 Metal–halogenexchangesubstitutionreactions 61
4.01.7.6.3 Metal-catalyzedcross-couplingreactions 62
4.01.7.6.4 Metalandmetalloid-linkedsubstituents 64
4.01.8 ReactivityofSubstituentsAttachedtoRingNitrogenAtoms 65
4.01.8.1 ArylGroups 65
4.01.8.2 AlkylGroups 66
4.01.8.3 N-AcylandCarbonylDerivatives 67
4.01.8.4 N-Oxides 68
4.01.8.5 N-AminoGroups 68
4.01.8.6 N-NitroGroups 68
4.01.9 SynthesesClassifiedbyNumberofRingAtomsinEachCompound 68
Pyrazoles 3
4.01.9.1 RingSynthesisfromNonheterocycles 68
4.01.9.1.1 Formationofonebond 68
4.01.9.1.2 Formationoftwobonds 74
4.01.10 RingSynthesisbyTransformationofAnotherRing 102
4.01.10.1 RingTransformations 102
4.01.10.1.1 Benzimidazoleandimidazolesystems 102
4.01.10.1.2 Cyclopropanes 103
4.01.10.1.3 Furandiones 103
4.01.10.1.4 Oxazolesandoxadiazoles 103
4.01.10.1.5 Oxazoliumolates 104
4.01.10.1.6 Pyranones 104
4.01.10.1.7 Pyridinesandpyridones 106
4.01.10.1.8 Sydnones 106
4.01.10.1.9 Tetrazoles 106
4.01.10.1.10 Triazines 107
4.01.10.1.11 Otherfive-memberedheterocycles 107
4.01.10.1.12 Othersix-memberedheterocycles 108
4.01.11 SynthesisofaParticularClassofCompoundsandaCriticalComparisonofthe
VariousRoutesAvailable:Pyrazoles,Indazoles,andTheirDerivativesasStarting
MaterialsfortheSynthesesofFusedRingSystems 109
4.01.11.1 SynthesisofFusedRingSystems 109
4.01.11.2 NucleosidesandAminoAcids 110
4.01.11.3 LabeledCompounds 111
4.01.12 ImportantCompoundsandApplications 112
4.01.12.1 PyrazolesinSupramolecularChemistry 112
4.01.12.2 PharmaceuticalsandAgrochemicals 113
4.01.12.2.1 Anti-inflammatoryagents 113
4.01.12.2.2 Cardiovascularagents 114
4.01.12.2.3 CNSapplications 115
4.01.12.2.4 Infectiousdiseases 115
4.01.12.2.5 Metabolicdiseases 116
4.01.12.2.6 Oncologyticagents 117
4.01.12.2.7 Estrogenreceptor 118
4.01.12.2.8 Agriculturaluses 118
4.01.12.3 OtherApplications 119
4.01.12.3.1 Pyrazoleligandapplications 119
4.01.12.3.2 Pyrazolesascatalysts 119
4.01.12.3.3 Pyrazolesasreagents 120
4.01.12.3.4 Metalpyrazolecomplexes 121
4.01.12.3.5 Pyrazoleindustrialapplications 121
4.01.12.4 NaturalProducts 121
4.01.13 FurtherDevelopments 121
References 122
4.01.1 Introduction
Five-memberedringsystemscontainingtwodoublebondsandtwonitrogenatomsadjacenttoeachotherarecalled
pyrazoles. Previous chapters on pyrazoles have been presented in CHEC(1984), covering the literature up to 1981
<1984CHEC(5)167>, and CHEC-II(1996), covering the literature from 1982 to 1995 <1996CHECII(3)1>. This
chapter covers the literature on pyrazoles during the 10-year period, 1996–2006. The previous two chapters of this
seriesonpyrazolesdealtmorewiththeoretical,experimentalstructural,andthermodynamicmethods,andlesswiththe
4 Pyrazoles
reactivity,synthesis,andapplicationsofpyrazoles.Duringthelast10years,morereportshaveappearedonthesynthesis
andreactivityofpyrazoleringsystems.Furthermore,themedicinalchemistryapplicationsofpyrazolesandfused-ring
systemshavefoundnumerousapplicationsindrugdiscovery.Thischapterfocusesonthesecurrentdevelopments.
Manyreviewshavebeenwrittenonthesynthesisandreactivityofpyrazoles(Table1)aswellasreviewswhere
pyrazolesarepresentedinthecontextofothertopics(Table2).
Table1 Reviewsonpyrazolesandrelatedtopics
Mainauthor Title Reference
A.P.Sadimenko OrganometalliccomplexesofheterocyclesII.Complexesofpyrazoles 1996CCR247
K.Makino Synthesisofpyrazoles 1998JHC489
S.A.Shevelev Advancesinnitropyrazolechemistry 1998RJO1071
K.Makino Synthesisofpyrazolesandcondensedpyrazoles 1999JHC321
K.N.Zelenin 5-Hydroxy-4,5-dihydropyrazoles 1998THS(2)207
C.Pettinari Organotin(IV)derivativesofimidazoles,pyrazolesandrelated 1999MGM661
pyrazolylandimidazolylligands
R.Mukherjee Coordinationchemistrywithpyrazole-basedchelatingligands: 2000CCR151
Molecularstructuralaspects
A.M.Pinchuk C-Phosphorylatedazoles 2001PJC1137
S.F.Vasilevsky Synthesisandpropertiesofacetylenicderivativesofpyrazoles 2002AHC1
B.Stanovnik Productclass1:Pyrazoles 2002SOS(12)15
C.Kashima SyntheticutilityofN-acylpyrazoles 2003H(60)437
J.W.Pavlik Photochemicalisomerizationsofsomefive-memberedheteroaromatic 2003PHC(15)37
azoles
G.Varvounis Pyrazol-3-ones 2004AHC141
G.I.Yranzo Flashvacuumpyrolysisofisoxazoles,pyrazolesandrelatedcompound 2004COR1071
D.Kumar Structuralrevisioninpyrazolechemistry 2004H(63)145
Table2 Reviewsonpyrazolesdiscussedinthecontextofothertopics
Mainauthor Title Reference
S.A.Lang Fivememberedringsystems:WithmorethanoneNatom 1996PHC(8)146
M.A.Walters Fivememberedringsystems:WithmorethanoneNatom 1997PHC(9)148
K.Turnbull Fivememberedringsystems:WithmorethanoneNatom 1998PHC(10)153
K.Turnbull Fivememberedringsystems:WithmorethanoneNatom 1999PHC(11)163
E.S.ElAshry Carbohydratehydrazonesandosazonesasorganicrawmaterials 2000COR609
fornucleosidesandheterocycles
L.Yet Fivememberedringsystems:WithmorethanoneNatom 2000PHC(12)161
L.Yet Fivememberedringsystems:WithmorethanoneNatom 2001PHC(13)167
L.Yet Fivememberedringsystems:WithmorethanoneNatom 2002PHC(14)180
G.Stajer TheretroDiels–Alderreactionasavaluabletoolforthe 2003COR1423
synthesisofheterocycles
L.Yet Fivememberedringsystems:WithmorethanoneNatom 2003PHC(15)206
A.Rybar Annulatedheterocyclo-purines.1.Fusedfive-membered 2004AHC85
heterocyclo-purinediones,–purinones,and–purineimines
M.A.P.Martins 4-Alkoxy-1,1,1-trichloro-3-alken-2-ones:Preparationand 2004CSY391
applicationsinheterocyclicsynthesis
B.C.Sekhar Cyclic1,3-dionesandtheirderivativesasversatilereactive 2004JHC807
intermediatesinthesynthesisofcondensedfusedring
heterocycles
L.Yet Fivememberedringsystems:WithmorethanoneNatom 2004PHC(16)198
L.Yet Fivememberedringsystems:WithmorethanoneNatom 2005PHC(17)172
G.Molteni Stereoselectivecycloadditionsofnitriliminesasasourceof 2005H(65)2513
enantiopureheterocycles
G.Molteni 1,3-Dipolarcycloadditionsinaqueousmedia 2006H(68)2177
P.Stannety Cross-couplingreactionsonazoleswithtwoandmore 2006EJO3283
heteroatoms
L.Yet Fivememberedringsystems:WithmorethanoneNatom 2006PHC(18)218
Pyrazoles 5
4.01.1.1 Survey of Possible Structures
Pyrazole1isanaromaticmoleculeand,likeitsstructuralisomerimidazole,containsapyrrole-likeandapyridine-like
Natom,butinthe1-and2-positions(1,2-diazole).Thissurveyofpossiblestructuresfollowstheconventionadopted
inCHEC(1984)<1984CHEC(5)167>.Aromaticcompoundswithtwodoublebondsincludethecorestructuressuch
as pyrazole 1, indazole 2, and isoindazole 3 along with their nonaromatic isomers, pyrazolenine or 3H-pyrazole 4,
isopyrazole or 4H-pyrazole 5, and 1H-pyrazol-2-ium salts 6. Other pyrazole structures containing carbonyl groups
include1H-pyrazol-5(4H)-one7,1H-pyrazol-3(2H)-one8,3H-pyrazol-3-one9,and4,5-dihydro-3H-pyrazol-3-one10.
Pyrazolinessuchas4,5-dihydro-3H-pyrazoleor(cid:2)1-pyrazoline11,4,5-dihydro-1H-pyrazoleor(cid:2)2-pyrazoline12,and
2,3-dihydro-1H-pyrazole or (cid:2)3-pyrazoline 13 are also represented. Pyrazolidine 14 and pyrazolidin-3-one 15 are
representativestructureswithnoringdoublebonds.Allofthesestructurescanhavesubstitutiononanyofthecarbon
atoms.Manyotherstructuressuchasthosewithfusedpyrazoleringsarealsopossible,butthosementionedaboveare
themostcommoncoretypesdiscussedinthischapter.
4.01.2 Theoretical Methods
4.01.2.1 Structure and Reactivity of Pyrazoles
N-UnsubstitutedpyrazolescanhaveN–H(cid:2)(cid:2)(cid:2)Nhydrogenbondspresentintheircrystals,whichcanleadtoatleastsix
motifs such as monomers, dimers, trimers, tetramers, hexamers, and catemers. Hydrogen-bonding motifs for pyra-
zoleshavebeenexaminedintheCambridgeStructuralDatabase(CSD)<2004STC173>.Theaccessiblesurfaceof
theN-atomshasbeenfoundtobeusefulasadiscriminatortodividestructuresintodimerandcatemermotifs.Low
accessibilityfavorsdimersandtetramersandhighvaluesfavorcatemersandtrimers.Empiricalrulesweresuccess-
fullyappliedtopredictthemotifsofeightnewstructuresinthesubsequentreleaseoftheCSD.AsearchintheCSD
forNH-pyrazoleslackingotherhydrogen-bonddonorandacceptorsitesidentified49compoundsthatcrystallizedin
47 structures forming dimers (16), tetramers (13), trimers (8), a hexamer (1), and catemers (10) using N–H(cid:2)(cid:2)(cid:2)N
hydrogen bonds <2006ARK15>.These structures weredivided intotwo classes (dimers and tetramers vs.trimers
and catemers) using the accessible surface to an atom with good results. The method has been extended to new
pyrazolesbymeansoftheoreticalcalculations(B3LYP/6-31G*)ofthegeometryofthemonomers.Aspectslikethe
conformation of phenyl substituents, the additivity of substituent effects, and buttressing effects have been
approachedtheoretically.
6 Pyrazoles
Thesupramolecularstructureof1H-pyrazolesinthesolidstatewasinvestigatedbycrystallographicandabinitio
studies <2000AXB1018>. Harmonic force fields were calculated at the corresponding optimized geometry for
pyrazole at the Hartree–Fock (HF), B3LYP, MP2, CCSD (coupled-cluster singles and doubles), and CCSD(T)
(coupledclusterwithperturbativetriples)levelsusingthe6-31G* basissetandattheHFandB3LYPlevelsusing
the ccpVTZ basis set <2003SAA2009>. Ab initio coupled gauge-independent atomic orbital (GIAO) calculations
werecarriedouton211-substitutedpyrazolesusingfourdifferentabinitiomethodswhichledtothefinalselectionof
thehybridB3LYP/6-311þG(2d,p)//B3LYP/6-31þG(d)basisset<1998JMT(453)255>.Comparisonwithexperimen-
talchemicalshiftsinsolution(takingintoaccountthecalculatedshieldingsofthecorrespondingreferences)showed
anexcellentagreementbetweenbothsets,allowingforafactorofproportionalityofabout0.96.Theinfrared(IR)
spectra and quantum-mechanical calculations ofvibrational spectra and structure of pyrazole and 3,5-dimethylpyr-
azole in solution, gas phase, and solid state have been investigated over a wide range of concentrations and
temperatures <2003JMT(660)25>. It was found that in the gas phase, both pyrazole and 3,5-dimethylpyrazole
exist in an equilibrium between monomers, dimers, and trimers. In solution, the equilibrium between monomers
and trimers dominated and no bands which could be attributed to dimers were detected. 3,5-Dimethylpyrazole
retainedthetrimerstructureinthesolidstate,whileinthecaseofpyrazole,formationofthecrystalprovidedanother
typeofassociation.Geometricalandspectralcharacteristicsofdimersandtrimers,obtainedbyabinitiocalculations,
werepresentedandcomparedwithexperimentaldata.Moleculardynamicsoftheself-organizingstronghydrogen-
bonded3,5-dimethylpyrazolewasstudiedbyquasi-elasticneutronscattering(QENS)<2006NJC425>.
Hindered pyramidal inversion and restricted rotation in N-propyl-N-(4-pyridyl)-1-amino-1H-pyrazoles 16 were
studied by dynamic nuclear magnetic resonance (NMR) spectroscopy and molecular modeling methods
<2000T1739>.Acoupled-clusterstudyofthestructureandvibrationalspectraofpyrazolehasbeenreported.The
structure of 5-tert-butyl-4-nitro-1H-pyrazol-3-ol 17 consisted of molecules that pack in a linear hydrogen-bonded
ribbon motif <2005AXEo2347>. This hydrogen-bonding arrangement was constructed through two dimer forma-
tions,onethatisatypicalofpyrazoles(N–H(cid:2)(cid:2)(cid:2)N)andtheotherviaaninteractionfromthehydroxygrouptooneof
thenitrooxygenatoms.Themolecularstructureofanovelmonohydrated3-p-nitrophenylpyrazolewasfoundtoexist
as the 3-tautomer 18 rather than the corresponding 5-tautomer 19 using NMR spectroscopy, single crystal X-ray
diffraction,andabinitiocalculations(Equation1)<2003JMT(650)223>.
Pyrazoles 7
ð1Þ
C–HandN–Hbond-dissociationenergies(BDEs)ofpyrazolewerecalculatedusingcompositeabinitioCBS-Q,
G3,andG3B3methods(Table3)<2003JPO883>.ItwasfoundthatallthesemethodsprovidedverysimilarBDEs,
despitethefactthatdifferentgeometriesanddifferentproceduresintheextrapolationtocompleteincorporationof
electroncorrelationandcompletebasissetlimitwereused.
Table3 Bonddissociationenergiesofpyrazole(kcalmol(cid:3)1)
Bond CBS-Q G3 G3B3recommended B3LYP Charge Spin Bondangle((cid:4))
N(1)–H 112.0 111.3 109.2 107.6 0.401 113.3
C(3)–H 118.7 118.7 117.8 115.5 0.201 0.967 112.1
C(4)–H 122.6 122.2 121.0 118.9 0.221 0.953 104.5
C(5)–H 121.1 121.1 119.9 117.9 0.210 0.948 106.1
4.01.2.2 Structure and Reactivity of Indazoles
Nuclearquadrupoleresonance(NQR)frequenciesweredeterminedonthe35Clisotopeforseveralchloroindazoles
andfortwochloroindazolenucleosidesatliquidnitrogentemperature<2000JMT(530)217>.Theinfluenceofthe
site of substitution and type of substituent on the resonance frequency was analyzed and the electron density
distribution and electrostatic potential in the molecules were calculated by the B3LYP/6-31G(p) method and the
resultswerecorrelatedwithexperimentaldata.
Theaqueous-phasephysicochemicalpropertiesofsome3-substitutedindazoles(H,Me,Br,Cl)werecomputed
usingsemi-empirical methodsandtheresultsobtainedwereevaluatedbysearchingforapossiblecorrelationwith
the previously obtained experimental properties <2002JMT(588)145>. The aqueous-phase geometries, relative
stabilities, acidity constants, tautomerism, proton affinities (PAs) and dipole moments for the tautomeric forms of
some3-substituted indazolesand theirfixedforms(modelcompoundsinwhichprotonmigration iseliminatedby
replacing the mobile hydrogen atom with a methyl group) were calculated with full geometry optimization using
AM1, PM3, and modified neglect of diatomic overlap (MNDO) methods. The results of aqueous-phase semi-
empirical calculations indicate that 1H-form 20 of the studied molecules is more stable than the 2H-form 21
(Equation2).
8 Pyrazoles
ð2Þ
Ab initio and density functional theory (DFT) methods have been used to study the five tautomeric forms of
indazole in gaseous and aqueous phases <2004JMT(686)83>. The tautomers in the gas phase were optimized at
MP2/6-311G(2d,2p),B3LYP/6-311G(2d,2p),andB3PW91/6-311G(2d,2p)levelsoftheory.Computationalstudieson
the three tautomeric forms of four 1,5,6,7-tetrahydro-4H-indazol-4-ones, 1,5,6,7-tetrahydro-4H-indazol-4-one, 6,6-
dimethyl-1,5,6,7-tetrahydro-4H-indazol-4-one, 3-methyl-1,5,6,7-tetrahydro-4H-indazol-4-one, and 3,6,6-trimethyl-
1,5,6,7-tetrahydro-4H-indazol-4-one,wereperformedatdifferentlevels,rangingfromsemi-empiricalAM1,abinitio
HF/6-31G* and HF/6-31G**, to B3LYP/6-31G** density functional calculations <2006MOL415>. These calcula-
tionswereusedtoestablishthemoststabletautomer,whichinallcaseswasinagreementwiththeexperimentaldata.
4.01.3 Experimental Structural Methods
4.01.3.1 X-Ray Diffraction
Thestructureof3(5)-phenyl-4-bromo-5(3)-methylpyrazoleinthesolidstatewasdeteminedbyX-raycrystallography
andshowedbothtautomerstobepresentinthecrystals,formingcyclictetramers(Equation3)<1999JMT(484)197>.
The molecular and crystal structure of 3(5)-nitropyrazole was determined by X-ray analysis <1997JPO637>. The
triclinic unit cell contained 12 molecules which form four hydrogen-bonded (N–H(cid:2)(cid:2)(cid:2)N) trimers. Each trimer
comprised a pseudo-ring in a flattened envelope, distorted towards a chair conformation. The crystal packing
consisted of layers formed by centrosymmetric-related trimers joined through C–H(cid:2)(cid:2)(cid:2)O interactions. The X-ray
molecularstructureof4-methylpyrazole22showedittoexistasahydrogen-bondedtrimerinthesolidstateat100K
<1999NJC237>. The X-ray molecular structure of the important molecule 3,5-bis(trifluoromethyl)pyrazole 23,
determinedat120K,revealedcrystalsbelongingtothetriclinicP1spacegroup<1999NJC1231>.Thecompound
formedtetramersthroughN–H(cid:2)(cid:2)(cid:2)Nhydrogenbonds.Someprotondisorderwasnecessarytoexplainthegeometric
features of the monomers. The X-ray crystal structure of 1H-pyrazole-3-(N-tert-butyl)-carboxamide 24 was deter-
mined<2005MRC89>.Inthesolidstate,the13Cand15Ncross-polarization/magicanglespinning(CP/MAS)NMR
spectra corresponded to this tautomer. In solution, both tautomers were present in a ratio that depended on the
temperature (at 293K, 90% 3-substituted/10% 5-substituted). Some unusual 1H,1H-couplings involving the NH
proton were observed. DFT (GIAO) calculations were carried out. The conformation and distortion of flexible
pyranoidringsin1-(2-hydroxy-iminopyranosyl)pyrazolecarbohydrateswerediscussedinthelightofcrystalstructure
analysisofninecompoundsandtheresultsofsemi-empiricalcalculations of16modelcompoundswerepresented
<1997JMT(436)173>. Conformational similarities of several modified sugars studied by X-ray methods suggested
that the presence of intramolecular C–H(cid:2)(cid:2)(cid:2)N hydrogen bonds between the aglycone (pyrazole ring) and axial
hydrogenatomsatC-3and/orC-5.ResultsfromthePM3methodshowedthatringpuckeringwasalsodependent
onweakinteractionsbetweentheaglyconegroupandthepyranoidring.Conclusionsfrombothmethodsconverge.
The crystal structures of two NH-pyrazole derivatives forming intermolecular N–H(cid:2)(cid:2)(cid:2)N hydrogen bonds were
reported: 5-methyl-4-(3-methylpyrazol-5-yl)pyrazol-3-ol and 3-methyl-5-dihydro-1H-naphtho[1,2-d]pyrazole hemi-
hydrochloride<1999AXB985>.Otherstructuresweresurveyedinordertoobtainadeeperinsightintothewaysin
whichNH-pyrazolesself-assemblebymeansofintermolecularN–H(cid:2)(cid:2)(cid:2)Nhydrogenbondsinmolecularcrystals.The
single crystal X-ray structures of 3(5)-(2,5-dimethoxyphenyl)pyrazole and the hemihydrate of 3(5)-(3,4-dimethoxy-
phenyl)pyrazole have been determined (Equation 4) <1996AXB746>. The first compound exists purely as the 5-
substitutedprototropomerinthecrystal;thepyrazolepyrrolicN–Hprotonisinvolvedinathree-wayhydrogenbond,
involvinganintramolecularcontactwithamethoxyoxygendonorandanintermolecularinteractiontothepyridinic
N-atomofaneighboringmolecule,formingdiscretehydrogen-bondeddimers.Inthesecondmolecule,however,the
Pyrazoles 9
pyrrolic proton is disordered over both N-1 and N-2 via hydrogen bonding to the solvent water molecule. The
structureof3(5)-[(4-diphenylphosphinoyl)phenyl]pyrazolehasbeendeterminedbyX-raycrystallographyasthe1H-
3-substitutedtautomer(monoclinic,spacegroupP21/c)<2003ARK209>.
ð3Þ
ð4Þ
X-Raycrystalstructuresof1-(nitrophenyl)-(cid:2)2-pyrazolines25and26havebeendetermined<2004AJC1103>.The
differencesinconformationbetweenbothmoleculesandbetweenthesolidandgasphaseswereexplainedintermsof
steric effects. The structure of 1-formyl-3-phenyl-(cid:2)2-pyrazoline 27 in the gas phase (DFT calculations), solution
(NMR), and solid state (X-ray crystallography) was evaluated <2004JMT(689)251>. The crystal and molecular
structureof1,1,3-trimethyl-(cid:2)2-pyrazoliniumperchlorate28hasbeendeterminedandcomparedwiththoseofother
pyrazoliniumsalts(both1,1-and1,2-disubstituted)<2004SPE605>.Reported13Cand15Nchemicalshiftsforaseries
ofrelatedpyrazolineshavebeencomparedwithGIAO/DFTcalculations,withexcellentagreement.Thecorrelation
ofthebiologicalpropertiesofpyrazolineswiththoseoftheperchlorateanioninthesamemoleculewasalsodiscussed.
X-Raycrystallographyshowedthat7-nitroindazolecrystallizedasanN(1)–Htautomerdimerandadoptedaplanar
conformationassistedbyintramolecularhydrogenbonding<2000AXC474>.
4.01.3.2 Microwave and Photoelectron Spectroscopy
The electronicstructureand gas-phasethermolysisof4-substituted3,3,5,5-tetramethyl-3,5-dihydro-4H-pyrazoleshas
been studied by photoelectron spectroscopy and the first evidence for an alkylideneselenirane was obtained
<1996T1965>. The 351.1nm photoelectron spectrum of the 1-pyrazolide anion has been measured
<2006PCA8457>.The1-pyrazolideion29isproducedbyhydroxidedeprotonationofpyrazoleinaflowingafterglow
ionsourceandasmallamountofthe5-pyrazolideion30wasalsodetectedandstudiedbyphotoelectronspectroscopy.
10 Pyrazoles
4.01.3.3 lH and 13C NMR Spectroscopy
4.01.3.3.1 Aromaticsystems
The1Hand13CNMRspectraofpyrazolesderivedfromchiralcyclohexanones(3-methylcyclohexanone,menthone,
pulegone, dihydrocarvone, and carvone) were measured and assigned <2002H(57)307>. Thirteen C- and N-tri-
methylsilylpyrazoles werestudiedby1Hand13CNMRspectroscopy<1998MRC110>.Acompletemodelforthe
predictionof1Hand13CNMRchemicalshiftsandtorsionalanglesinphenyl-substitutedpyrazoleshasbeenreported
<2001T4179>. A correlation between torsion angles calculated by molecular mechanics and differences in 13C
chemical shifts of the ortho- and meta-carbon atoms of the phenyl groups in 29 N-phenyl-substituted pyrazole
derivatives and 11 C-phenyl-substituted pyrazoles has been identified. Three N-substituted pyrazoles and three
N-substituted indazoles, 1-(4-nitrophenyl)-3,5-dimethylpyrazole 31, 1-(2,4-dinitrophenyl)-3,5-dimethylpyrazole 32,
1-tosylpyrazole 33, 1-p-chlorobenzoylindazole 34, 1-tosylindazole 35, and 2-(2-hydroxy-2-phenylethyl)indazole 36,
havebeenstudiedbyNMRspectroscopyinsolution(1H,13C,15N)andinthesolidstate(13C,15N)<2006MRC566>.
3-Methyland5-methyltautomersof3(5)-methylpyrazoleinaratioof54:46werefoundinmethanolbytheuseof13C
NMRspectroscopy<1998MRC110>.Thechemicalshiftsandcouplingconstantsof23pyrazolesbearingdifferent
substitutents at position 1 have been studied by 1H, 13C, and 15N NMR spectroscopy in solution (Table 4)
<1998H(47)301>. Variable-temperature 1H NMR studies of a range of 1,3,5-trisubstituted-4-nitrosopyrazoles
(R1,R2,R3¼Me,CF ,Ph,ort-Bu)haveledtotheidentificationofindividualrotationalisomersatlowtemperatures
3
arisingfromtheslowingdownoftherotationofthenitrosofunctionwithrespecttothepyrazolering(Equation5)
<1997J(P2)721>.ThecouplingconstantsofeightN–R-pyrazoles37havebeencalculatedandcomparedwiththeir
experimentalvalues<2005MRC985>.Theagreementwasgoodandcouldbeusedtoestimatenewcouplings;the
wholecollectionwasstatisticallyanalyzed.1-Hydroxymethylindazole38hasbeenstudiedinsolutionby1H,13C,and
15NNMRspectroscopy<2004JHC285>.