Palladium-Catalyzed C3-Arylations of 1H- and 2H-Pyrazolo[4,3- b]pyridines on Water

Article abstract of DOI:10.1021/acs.joc.8b01728

Direct C3-arylation of 1H-pyrazolo[4,3-b]pyridines and direct C3-arylation of 2H-pyrazolo[4,3-b]pyridines in water has been developed. A new protocol for a sequential C3-arylation procedure on a mixture of 1H- and 2H-pyrazolo[4,3-b]pyridines followed by in situ PMB cleavage has also been achieved. This procedure led to unprotected (NH) C3-arylated 1H-pyrazolo[4,3-b]pyridines in good yields.

Full text of DOI:10.1021/acs.joc.8b01728

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Note
Palladium-Catalyzed C3 Arylations of 1H
and 2H Pyrazolo[4,3-b]pyridines on Water
Soukaina Faarasse, Saïd El Kazzouli, Franck Suzenet, and Gérald Guillaumet
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01728 • Publication Date (Web): 21 Sep 2018
Downloaded from http://pubs.acs.org on September 22, 2018
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Page 1 of 11
The Journal of Organic Chemistry
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Palladium-Catalyzed C3 Arylations of 1H and 2H Pyrazo-
lo[4,3-b]pyridines on Water
‡
,†
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SoukainaꢀFaarasse ,ꢀSaïdꢀElꢀKazzouli* ,ꢀFranckꢀSuzenet* ꢀandꢀGéraldꢀGuillaumet* ꢀ
‡ꢀ
EuromedꢀFacultyꢀofꢀEngineering,ꢀEuromedꢀUniversityꢀofꢀFesꢀ(UEMF),ꢀRouteꢀdeꢀMeknès,ꢀ30000ꢀFès,ꢀMorocco.ꢀ
†ꢀInstitutꢀdeꢀChimieꢀOrganiqueꢀetꢀAnalytiqueꢀ(ICOA),ꢀUniversitéꢀd'Orléans,ꢀUMRꢀCNRSꢀ7311,ꢀBPꢀ6759,ꢀ45067ꢀOrléansꢀ
Cedexꢀ2,ꢀFrance.ꢀ
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SupportingꢀInformationꢀPlaceholderꢀ
ABSTRACT:ꢀDirectꢀC3-arylationꢀofꢀ1H-pyrazolo[4,3-b]pyridinesꢀandꢀdirectꢀC3-arylationꢀofꢀ2H-pyrazolo[4,3-b]pyridinesꢀinꢀ
waterꢀhaveꢀbeenꢀdeveloped.ꢀNewꢀprotocolꢀforꢀsequentialꢀC3-arylationꢀprocedureꢀonꢀaꢀmixtureꢀofꢀ1H-ꢀandꢀ2H-pyrazolo[4,3-
b]pyridinesꢀfollowedꢀbyꢀinꢀsituꢀPMBꢀcleavageꢀhasꢀalsoꢀbeenꢀachieved.ꢀThisꢀprocedureꢀledꢀtoꢀunprotectedꢀ(NH)ꢀC3-arylatedꢀ
1H-pyrazolo[4,3-b]pyridinesꢀinꢀgoodꢀyields.ꢀꢀ
Directꢀarylationꢀisꢀnowadaysꢀaꢀveryꢀgoodꢀalternativeꢀtoꢀ
directꢀ C3-arylationꢀ onꢀ bothꢀ 1H-pyrazolo[4,3-b]pyridinesꢀ
andꢀ 2H-pyrazolo[4,3-b]pyridinesꢀ (1Hꢀ andꢀ 2Hꢀ 4-
azaindazoles).ꢀInꢀtheꢀcaseꢀofꢀ1H-pyrazolo[4,3-b]pyridines,ꢀ
theꢀprocedureꢀwasꢀdevelopedꢀunderꢀmildꢀconditionsꢀusingꢀ
traditionalꢀ cross-couplingꢀ reactionsꢀ suchꢀ asꢀ Suzuki-
1
2
3
Miyaura ,ꢀStille ꢀandꢀNegeshi .ꢀThisꢀC-Hꢀactivationꢀmethodꢀ
doesn’tꢀrequireꢀtheꢀuseꢀofꢀpre-functionalizedꢀstartingꢀma-
terialsꢀ andꢀ allowsꢀ theꢀ rapidꢀ andꢀ atom-economicalꢀ for-
3
waterꢀasꢀtheꢀsoleꢀsolventꢀandꢀ5ꢀmol%ꢀofꢀPd(PPh )4ꢀ catalystꢀ
4
mationꢀofꢀinterꢀorꢀintraꢀcarbone-carboneꢀbond .ꢀAlthoughꢀ
andꢀ10ꢀmol%ꢀofꢀ1,10-phenanthrolineꢀasꢀligand.ꢀInꢀtheꢀcaseꢀ
ofꢀ2H-pyrazolo[4,3-b]pyridines,ꢀtheꢀreactionꢀwasꢀconduct-
edꢀinꢀwaterꢀandꢀwithꢀaꢀlowꢀcatalystꢀloadingꢀ(2.5ꢀmolꢀ%).ꢀ
theꢀeffortꢀmadeꢀforꢀtheꢀdevelopmentꢀofꢀthisꢀfiled,ꢀtheꢀneedꢀ
ofꢀ specificꢀ conditionsꢀ toꢀ functionalizeꢀ eachꢀ heterocyclicꢀ
systemꢀ isꢀ stillꢀ required.ꢀ Itꢀ isꢀ evenꢀ necessaryꢀ toꢀ developꢀ
specificꢀconditionsꢀforꢀeachꢀpositionalꢀisomer.ꢀForꢀexample,ꢀ
inꢀtheꢀcaseꢀofꢀindazolesꢀandꢀazaindazoles,ꢀtheꢀarylationꢀofꢀ
2Hꢀisomerꢀdoesn’tꢀrequiredꢀtheꢀuseꢀofꢀligandꢀinꢀcontrastꢀtoꢀ
1Hꢀisomerꢀbecauseꢀofꢀtheꢀlackꢀofꢀtheꢀreactivityꢀofꢀ1Hꢀseriesꢀ
comparedꢀtoꢀ2Hꢀseries5-7.ꢀ
Graneyꢀetꢀal.ꢀreportedꢀtheꢀfirstꢀexampleꢀofꢀintermolecularꢀ
directꢀ arylationꢀ ofꢀ 2Hꢀ indazoleꢀ seriesꢀ inꢀ waterꢀ usingꢀ
Pd(dppf)Cl
Twoꢀ yearsꢀ later,ꢀ ourꢀ group ꢀ inꢀ alongꢀ withꢀ Itamiꢀ group ꢀ
developedꢀconditionsꢀtoꢀachieveꢀdirectꢀarylationꢀofꢀ1Hꢀin-
dazoleꢀseries.ꢀTheꢀkeyꢀofꢀthisꢀsuccessꢀwasꢀtheꢀuseꢀofꢀbiden-
tateꢀligandꢀ(1,10-phenanthrolineꢀinꢀbothꢀcases).ꢀLater,ꢀtheꢀ
reactionꢀ conditionsꢀ haveꢀ beenꢀ optimizedꢀ byꢀ Yuꢀ groupꢀ byꢀ
reducingꢀcatalystꢀandꢀligandꢀloading .ꢀRecently,ꢀweꢀreport-
edꢀC3-directꢀarylationꢀofꢀ2Hꢀ7-azaindazolesꢀinꢀwaterꢀusingꢀ
Pd(PPh
Later,ꢀDoucetꢀandꢀhisꢀgroupꢀreportedꢀaꢀphosphineꢀfreeꢀC3-
arylationꢀ ofꢀ 2H-indazolesꢀ inꢀ DMAꢀ usingꢀ 5ꢀ mol%ꢀ ofꢀ
Pd(OAc) ꢀ asꢀ catalyst .ꢀ Veryꢀ recently,ꢀ Popowyczꢀ andꢀ Lav-
rardꢀ reportedꢀ C3-arylationꢀ ofꢀ 1Hꢀ 7-azaindazolesꢀ underꢀ
5
2
ꢀ (5ꢀ molꢀ %)ꢀ andꢀ 10ꢀ molꢀ %ꢀ ofꢀ Ph
3
Pꢀ asꢀ ligand .ꢀ
7
a
8
9
10
3
)
2
Cl
2
ꢀasꢀcatalystꢀandꢀPPh ꢀasꢀligand ꢀ(Schemeꢀ1).ꢀ
3
11
2
9
similarꢀconditionsꢀpreviouslyꢀdevelopedꢀbyꢀYuꢀgroup ꢀus-
ingꢀPd(phen)
tolueneꢀatꢀ160°Cꢀforꢀ72h .ꢀꢀ
2
(PF
6
)
2
ꢀasꢀcatalystꢀinꢀtheꢀpresenceꢀofꢀCs
2
CO
3
ꢀinꢀ
ꢀ
Schemeꢀ1.ꢀReportedꢀmethodsꢀforꢀdirectꢀarylationꢀofꢀinda-
zolesꢀandꢀazaindazolesꢀcomparedꢀtoꢀthisꢀwork.ꢀ
12
Inꢀ continuationꢀ ofꢀ ourꢀ researchꢀ programꢀ onꢀ indazolesꢀ
andꢀazaindazolesꢀfunctionalizationꢀbyꢀCHꢀandꢀCH/CHꢀacti-
vation,
7
,10,13
ꢀweꢀwishꢀtoꢀreportꢀhereinꢀtheꢀfirstꢀexamplesꢀofꢀ
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 11
Weꢀ developedꢀ alsoꢀ anꢀ originalꢀ sequentialꢀ directꢀ C3-
Reactionꢀconditions:ꢀiodobenzeneꢀ(1ꢀequiv.),ꢀPd,ꢀLigand,ꢀBase,ꢀ
1
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arylationsꢀdirectlyꢀonꢀ1Hꢀandꢀ2Hꢀpyrazolo[4,3-b]pyridinesꢀ
inꢀmixtureꢀ(obtainedꢀbyꢀalkylationꢀofꢀstartingꢀmaterialꢀpy-
razolo[4,3-b]pyridineꢀ byꢀ PMBCl).ꢀ Then,ꢀ withoutꢀ purifica-
tionꢀofꢀC3-arylatedꢀintermediates,ꢀtheꢀcleavageꢀofꢀPMBꢀpro-
tectingꢀgroupꢀallowedꢀtheꢀsynthesisꢀofꢀNHꢀC3-arylatedꢀpy-
razolo[4,3-b]pyridinesꢀinꢀgoodꢀyieldsꢀ(Schemeꢀ1).ꢀꢀ
2
H O,ꢀ70ꢀ°C,ꢀ24h. ꢀisolatedꢀyieldꢀofꢀ2a,ꢀ conversionꢀbasedꢀon Hꢀ
ꢀa
bꢀ
ꢀ1
cꢀ
NMR,ꢀ yieldꢀofꢀisolatedꢀstartingꢀmaterialꢀ1.ꢀNIꢀ:ꢀnoteꢀisolated.ꢀ
Withꢀtheꢀoptimizedꢀreactionꢀconditionsꢀinꢀhand,ꢀweꢀdecid-
edꢀtoꢀstudyꢀtheꢀscopeꢀandꢀlimitationsꢀbyꢀusingꢀvariousꢀio-
do-arylsꢀ andꢀ iodo-heteroarylsꢀ asꢀ couplingꢀ partners.ꢀ ꢀ Theꢀ
resultsꢀ setꢀ outꢀ inꢀ Tableꢀ 2ꢀ showꢀ thatꢀ allꢀ theꢀ expectedꢀ C3-
arylatedꢀ productsꢀ wereꢀ regioselectivelyꢀ obtainedꢀ inꢀ goodꢀ
toꢀ excellentꢀ yieldsꢀ (55ꢀ toꢀ 88%).ꢀ Thisꢀ studyꢀ revealedꢀ alsoꢀ
thatꢀunderꢀtheꢀreactionꢀconditionsꢀvariousꢀfunctionalitiesꢀ
10
Inspiredꢀ byꢀ ourꢀ previousꢀ report ,ꢀ weꢀ selectedꢀ pyrazo-
14,15
lo[4,3-b]pyridineꢀ 1
startingꢀmaterialꢀandꢀ1-iodo-benzeneꢀasꢀcouplingꢀpartnerꢀ
toꢀoptimizeꢀreactionꢀconditions.ꢀWithꢀ5ꢀmol%ꢀPd(PPh
asꢀcatalyst, 10ꢀmol%ꢀPPh ꢀasꢀligandꢀandꢀ1ꢀequiv.ꢀofꢀAg
asꢀbase,ꢀtheꢀreactionꢀproceededꢀinꢀH Oꢀatꢀ70ꢀ°Cꢀforꢀ24hꢀandꢀ
ꢀ (seeꢀ supportingꢀ information)ꢀ asꢀ
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wereꢀ toleratedꢀ (ester,ꢀ CN,ꢀ NO ).ꢀ Pyridine,ꢀ pyridazineꢀ andꢀ
2
3
) Cl2ꢀ
2
thiopheneꢀ wereꢀ efficientlyꢀ coupledꢀ inꢀ 60,ꢀ 70ꢀ andꢀ 55%ꢀ
yield,ꢀrespectivelyꢀ(compoundsꢀ2k,ꢀ2lꢀandꢀ2m,ꢀTableꢀ2).ꢀꢀ
ꢀ
3
2
CO ꢀ
3
2
led,ꢀregioselectively,ꢀtoꢀtheꢀdesiredꢀC3-arylatedꢀproductꢀ2ꢀ
inꢀ90%ꢀisolatedꢀyieldꢀ(entryꢀ1,ꢀTableꢀ1).ꢀTheꢀreactionꢀyieldꢀ
Tableꢀ2.ꢀScopeꢀandꢀlimitationsꢀofꢀC3-arylationꢀofꢀ2Hꢀpyra-
zolo[4,3-b]pyridineꢀ1.ꢀ
3
wasꢀslightlyꢀimprovedꢀwhenꢀPd(PPh )4ꢀwasꢀusedꢀinsteadꢀofꢀ
Pd(PPh Cl ,ꢀ(entryꢀ2,ꢀTableꢀ1).ꢀ1,10-Phenanthrolineꢀusedꢀ
3
)
2
2
CF3
OCH3
3
H CO
asꢀ ligandꢀ insteadꢀ ofꢀ PPh3ꢀ wasꢀ muchꢀ lessꢀ effectiveꢀ (40%,ꢀ
entryꢀ 3,ꢀ Tableꢀ 1).ꢀ Veryꢀ interestingly,ꢀ withoutꢀ additionalꢀ
N
PPh
goodꢀ yieldꢀ (80%).ꢀ Additionalꢀ optimizationsꢀ usingꢀ ofꢀ
Pd(PPh 4ꢀasꢀcatalyst ledꢀtoꢀimprovedꢀyieldꢀ(85%,ꢀentryꢀ5,ꢀ
Tableꢀ 1).ꢀ Lastly,ꢀ theꢀ reductionꢀ ofꢀ bothꢀ Pd(PPh
3
ꢀ(entryꢀ4,ꢀTableꢀ1)ꢀtheꢀdesiredꢀproductꢀwasꢀisolatedꢀinꢀ
N
N
N
N
PMB
N
PMB
N
PMB
N PMB
N
N
N
N
3
)
ꢀ
2
b, 88%
2c, 85%
2d, 80%
2e, 70%
3
)4ꢀ (2.5ꢀ
O
Cl
OCH
2
CH
3
mol%)ꢀandꢀPPh3ꢀ (5ꢀmol%)ꢀloadingꢀdidꢀnotꢀaffectꢀreactionꢀ
yieldꢀandꢀledꢀtoꢀcompoundꢀ2ꢀinꢀ82%ꢀyieldꢀ(entryꢀ6,ꢀTableꢀ
NO
2
3
H CO
1
).ꢀAgain,ꢀunderꢀPd(PPh
3
)
4ꢀ asꢀcatalyst conditionsꢀ(entryꢀ7,ꢀ
ꢀ
N
N
N
Tableꢀ 1),ꢀ theꢀ expectedꢀ productꢀ 2ꢀ wasꢀ obtainedꢀ inꢀ 80%ꢀ
yield.ꢀ Almostꢀ similarꢀ resultsꢀ wereꢀ obtainedꢀ whenꢀ
N
N
PMB
N
N
2g, 70%
PMB
N PMB
N
PMB
N
N
N
2
f, 68%
Pd(PPh
conditionsꢀwithꢀorꢀwithoutꢀligandꢀ(entriesꢀ8ꢀandꢀ9,ꢀTableꢀ
).ꢀWhenꢀPd(PPh 4ꢀloadingꢀwasꢀreducedꢀtoꢀ1.5ꢀmol%,ꢀtheꢀ
3
)
2
Cl2ꢀ ꢀwasꢀusedꢀinsteadꢀofꢀPd(PPh
3
)4ꢀ underꢀeitherꢀ
2h, 80%
2i, 77%
CN
1
3
)
N
N
reactionꢀ requiredꢀ addingꢀ PPh3ꢀ toꢀ achieveꢀ totalꢀ reactionꢀ
conversionꢀ(entries,ꢀ10ꢀandꢀ11,ꢀTableꢀ1).ꢀLowꢀconversionꢀ
N
S
N
N
N
N
N
PMB
N
PMB
N
N
PMB
N
N
PMB
wasꢀ alsoꢀ obtainedꢀ whenꢀ 1.5ꢀ mol%ꢀ ofꢀ Pd(PPh
employedꢀ underꢀ conditionsꢀ usingꢀ Pd(PPh 4ꢀ asꢀ catalyst
38%,ꢀ entryꢀ 12,ꢀ Tableꢀ 1).ꢀ Afterꢀ theꢀ screeningꢀ ofꢀ variousꢀ
3
2
) Cl2ꢀ ꢀ wasꢀ
N
N
3
)
ꢀ
2j, 85%
2k, 60%
2l, 70%
2m, 55%
(
reactionꢀconditionsꢀweꢀdecidedꢀtoꢀuseꢀtheꢀfollowingꢀonesꢀ
toꢀ studyꢀ theꢀ scopeꢀ andꢀ limitationsꢀ ofꢀ thisꢀ methodꢀ
Reactionꢀconditions:ꢀiodobenzeneꢀ(1ꢀequiv.),ꢀPd(PPh
3
2
) Cl2ꢀ
(
2.5ꢀmol%),ꢀAg CO ꢀ(1ꢀequiv.),ꢀH O,ꢀ70ꢀ°C,ꢀ24h.ꢀ
2
3
2
[
Pd(PPh
3
)
2
Cl2ꢀ(2.5),ꢀAg
2
CO
3
ꢀ(1ꢀequiv.),ꢀH O,ꢀ70°C,ꢀ24hꢀ(en-
2
tryꢀ9,ꢀtableꢀ1)].ꢀ
Then,ꢀweꢀturnedꢀourꢀattentionꢀtoꢀstudyꢀC3-directꢀarylationꢀ
ofꢀ 1H-pyrazolo[4,3-b]pyridineꢀ isomers.ꢀ Forꢀ thisꢀ aim,ꢀ weꢀ
14,15
selectedꢀtheꢀstartingꢀmaterialꢀ3
ꢀ(seeꢀsupportingꢀinfor-
Tableꢀ1.ꢀOptimizationꢀofꢀC3ꢀarylationꢀofꢀ2Hꢀpyrazolo[4,3-
b]pyridineꢀ1.ꢀ
mation)ꢀandꢀiodobenzeneꢀasꢀcouplingꢀpartnersꢀforꢀtheꢀop-
timizationꢀstudy.ꢀUsingꢀtheꢀbestꢀreactionꢀconditionsꢀinꢀ1Hꢀ
10
seriesꢀ andꢀ inꢀ 2Hꢀ seriesꢀ ofꢀ 7-azaindazoles ꢀ [5ꢀ mol%ꢀ ofꢀ
Pd(PPh Cl ꢀ asꢀ metal,ꢀ 10ꢀ mol%ꢀ ofꢀ PPh ꢀ asꢀ ligandꢀ andꢀ 1ꢀ
equiv.ꢀofꢀAg CO ꢀasꢀbaseꢀinꢀH Oꢀatꢀ70ꢀ°Cꢀforꢀ24h,],ꢀtheꢀex-
3
)
2
2
3
2
3
2
pectedꢀ C3-arylatedꢀ productꢀ 4ꢀ wasꢀ isolatedꢀ inꢀ lowꢀ yieldꢀ
(30%)ꢀ(entryꢀ1,ꢀTableꢀ3).ꢀTheꢀuseꢀofꢀ1,10-phenanthrolineꢀ
ꢀ
b
a
insteadꢀofꢀPPh
3
ꢀdidꢀnotꢀimprovedꢀtheꢀreactionꢀyieldꢀ(entryꢀ
Entry
Pd (mol%)
Pd(PPh Cl (5)
Ligand (%)
Con. %
100
100
53
Yield %
90
92
40 (45)
80
2
,ꢀTableꢀ3).ꢀTheꢀsameꢀresultꢀwasꢀobservedꢀusingꢀPd(PPh
3
4
) ꢀ
1
2
3
4
5
6
7
8
9
3
)
2
2
PPh
PPh
3
(10)
(10)
Pd(PPh
Pd(PPh
3
)
)
4
(5)
(5)
3
withꢀeitherꢀ1ꢀorꢀ2ꢀequiv.ꢀofꢀAg
2
CO ꢀ(entriesꢀ3ꢀandꢀ4,ꢀTableꢀ
3
c
3
4
Phen(10)
none
none
3).ꢀꢀ
Pd(PPh
3
)
2
Cl
2
(5)
100
100
100
100
100
100
100
62
Pd(PPh
3
)
4
(5)
85
82
80
80
80
80
NI
NI
TheꢀscreeningꢀofꢀotherꢀbasesꢀsuchꢀasꢀK
2
CO
3
,ꢀCs
2
CO ,ꢀK
3 3
PO ,ꢀ
4
Pd(PPh
Pd(PPh
3
3
)
)
4
(2.5)
(2.5)
PPh
3
(5)
resultedꢀ inꢀ aꢀ completeꢀ lossꢀ ofꢀ theꢀ reactivityꢀ (entriesꢀ 5-7,ꢀ
Tableꢀ 3).ꢀImprovedꢀyieldsꢀwereꢀobservedꢀ whenꢀ theꢀ reac-
tionꢀtimeꢀwasꢀprolongedꢀtoꢀ36hꢀatꢀ70°Cꢀ(entryꢀ8ꢀcomparedꢀ
toꢀ 4,ꢀ Tableꢀ 3).ꢀ Whenꢀ theꢀ reactionꢀ mixtureꢀ wasꢀ heatedꢀ toꢀ
90°C,ꢀ theꢀ expectedꢀ productꢀ wasꢀ obtainedꢀ inꢀ aꢀ veryꢀ goodꢀ
80%ꢀyieldꢀinꢀ24hꢀ(entryꢀ9).ꢀꢀ
4
none
Pd(PPh
Pd(PPh
3
)
)
2
2
Cl
Cl
2
(2.5)
(2.5)
PPh
3
(5)
3
2
none
1
0
Pd(PPh
Pd(PPh
3
)
)
4
(1.5)
(1.5)
PPh
3
(5)
11
12
3
4
none
none
Pd(PPh
3
)
2
Cl
2
(1.5)
38
ACS Paragon Plus Environment

Page 3 of 11
The Journal of Organic Chemistry
Allꢀtheꢀotherꢀattemptsꢀtoꢀimproveꢀtheꢀreactionꢀconditionsꢀ
andꢀ yieldꢀ byꢀ usingꢀ 1ꢀ equiv.ꢀ ofꢀ Ag CO3ꢀ insteadꢀ ofꢀ 2ꢀ equiv.ꢀ
(entryꢀ10),ꢀPh Pꢀinsteadꢀofꢀ1,10-phenanthrolineꢀ(entryꢀ11),ꢀ
withoutꢀadditionalꢀPPh ꢀconditionsꢀ(entryꢀ12)ꢀorꢀtheꢀuseꢀofꢀ
5ꢀmol%ꢀofꢀ1,10-phenanthrolineꢀinsteadꢀofꢀ10ꢀmol%ꢀ(entryꢀ
3),ꢀ offeredꢀ lowerꢀ yields.ꢀ Finally,ꢀ theꢀ flowingꢀ conditionsꢀ
Pd(PPh 4ꢀ (5),ꢀ Phenꢀ 10ꢀ mol%,ꢀ Ag CO ꢀ (1.3ꢀ equiv.),ꢀ H O,ꢀ
0°C,ꢀ 24h,ꢀ entryꢀ 14]ꢀ wereꢀ foundꢀ toꢀ beꢀ theꢀ optimumꢀ andꢀ
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
3
3
Table 4. ScopeꢀandꢀlimitationsꢀofꢀC3-arylationꢀofꢀpyrazolo[4,3-
b]pyridineꢀ3.ꢀ
1
[
9
3
)
2
3
2
wereꢀusedꢀtoꢀstudyꢀtheꢀscopeꢀandꢀlimitationsꢀofꢀC3ꢀdirectꢀ
arylationꢀofꢀ1H-4ꢀazaindazoles.ꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Tableꢀ3. OptimizationꢀofꢀC3ꢀarylationꢀofꢀ1H-pyrazolo[4,3-
b]pyridineꢀ3.ꢀ
b
a
entry
Pd
L
base
equiv.)
T
°C
70
Con.%
40
yields%
(
d
1
2
3
4
5
6
7
8
9
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
3
3
3
3
3
3
3
3
3
3
3
3
3
3
)
)
)
)
)
)
)
)
)
)
)
)
)
)
2
2
4
4
4
4
4
4
4
4
4
4
4
4
Cl
Cl
2
2
PPh
3
Ag
1)
Ag
1)
2
2
2
2
CO
CO
CO
CO
3
30(60)
(
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
3
70
70
70
70
70
70
70
90
90
90
90
90
90
40
40
49
0
NI
NI
NI
0
(
Ag
(1)
3
Ag
3
(
2)
K
2
CO
3
(2)
Reactionꢀ conditions:ꢀ iodoarylꢀ (2ꢀ equiv.),ꢀ Pd(PPh
mol%),ꢀ Phenꢀ (10ꢀ mol%),ꢀ Ag CO (1.3 equiv.),ꢀ H O,ꢀ 90°C,ꢀ
4h.ꢀ
3
) ꢀ (5ꢀ
4
Cs
(2)
PO
2
CO
3
0
0
2
3
2
2
K
3
4
(2)
0
0
Then,ꢀweꢀdecidedꢀtoꢀdevelopꢀaꢀsequentialꢀC3ꢀdirectꢀaryla-
tionꢀonꢀ1Hꢀandꢀ2Hꢀseries.ꢀForꢀthisꢀreason,ꢀweꢀ decidedꢀ toꢀ
findꢀreactionꢀconditionsꢀadaptedꢀforꢀtheꢀarylationꢀofꢀbothꢀ
theꢀ isomers.ꢀ Afterꢀ screeningꢀ ofꢀ reactionꢀ conditions,ꢀ weꢀ
finallyꢀfoundꢀthatꢀtheꢀmixtureꢀofꢀcompoundsꢀ1/3ꢀ(obtainedꢀ
asꢀ aꢀ mixtureꢀ (ratioꢀ ofꢀ1/3,ꢀ56/44)ꢀbyꢀ N-alkylationꢀ ofꢀtheꢀ
pyrazolo[4,3-b]pyridineꢀ byꢀ PMBCl)ꢀ reactꢀ smoothlyꢀ withꢀ
c,d
Ag
2)
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
87
100
82
53
54
70(13)
(
Ag
(2)
80
d
d
1
1
1
1
1
0
1
2
3
4
Ag
75 (10)
40 (38)
(
1)
Ag
2)
PPh
3
(
iodobenzeneꢀ (2ꢀ equiv.)ꢀ inꢀ theꢀ presenceꢀ ofꢀ Pd(PPh
mol%), 1,10-phenanthroline (10 mol%) and Ag CO
equiv.) in H O at 90°C for 24h. Under these reaction condi-
3
)
4
(5
d
none
Phen
Phen
Ag
(2)
Ag
45(30)
2
3
(1.3
2
e
48
NI
80
tions, C3ꢀarylatedꢀproductsꢀ2aꢀandꢀ4aꢀwereꢀisolatedꢀasꢀpureꢀ
compoundsꢀ inꢀ 42ꢀ andꢀ 38ꢀ %ꢀ yields,ꢀ respectivelyꢀ (80ꢀ %ꢀ
globalꢀyield)ꢀ(Schemeꢀ2).ꢀꢀ
(
1.3)
Ag CO
1.3)
2
100
(
Reactionꢀ conditions:ꢀ iodobenzeneꢀ (2ꢀ equiv.),ꢀ Pdꢀ (5ꢀ mol%),ꢀ
ꢀa
2
Ligandꢀ(10ꢀmol%),ꢀBase,ꢀH O,ꢀ70ꢀtoꢀ90°C,ꢀ24h. ꢀisolatedꢀyields,ꢀ
bꢀ
ꢀ1
c
d
e
conversionꢀbasedꢀon HꢀNMR,ꢀ ꢀtꢀ=ꢀ36h,ꢀ ꢀisolatedꢀyieldsꢀofꢀ3.ꢀ ꢀ
inꢀthisꢀcaseꢀ5ꢀmol%ꢀinsteadꢀofꢀ10ꢀmol%ꢀofꢀPhenꢀwasꢀused.ꢀNIꢀ:ꢀ
noteꢀisolated.ꢀ
ꢀ
Then,ꢀweꢀsurveyedꢀsubstrateꢀscopeꢀwithꢀvariousꢀiodo-arylsꢀ
andꢀiodo-heteroarylsꢀasꢀcouplingꢀpartnersꢀ(Tableꢀ4).ꢀTheseꢀ
reactionsꢀaffordedꢀtheꢀcorrespondingꢀC3-arylatedꢀproductsꢀ
Schemeꢀ2. SequentialꢀC3-arylationꢀonꢀ3ꢀandꢀ1ꢀmixture.ꢀ
Theꢀscopeꢀwasꢀthenꢀextendedꢀtoꢀiodobenzene,ꢀiodotoluene,ꢀ
4a-lꢀ inꢀ moderateꢀ toꢀ excellentꢀ yieldsꢀ (50ꢀ toꢀ 91%).ꢀ Again,ꢀ
1-chloro-4-iodobenzene,ꢀ ethylꢀ 4-iodobenzoateꢀ orꢀ 2-
pyridineꢀandꢀpyridazineꢀ wereꢀ efficientlyꢀcoupledꢀwithꢀ50ꢀ
andꢀ60%ꢀyield,ꢀrespectivelyꢀ(compoundsꢀ4kꢀandꢀ4l,ꢀTableꢀ
4).ꢀ Surprisingly,ꢀ theꢀ reactionꢀ usingꢀ 2-iodothiopheneꢀ asꢀ
couplingꢀpartnerꢀdidꢀnotꢀleadꢀtoꢀexpectedꢀproductꢀ2m.ꢀInꢀ
thisꢀcaseꢀonlyꢀstartingꢀmaterialꢀwasꢀrecovered.ꢀ
iodopyrazineꢀ asꢀ couplingꢀ partners.ꢀ Asꢀ expected,ꢀ C3-
arylatedꢀproductsꢀ2a/4a,ꢀ2b/4b,ꢀ2g/4g,ꢀ2h/4hꢀandꢀ3l/4lꢀ
asꢀ1Hꢀandꢀ2Hꢀisomerꢀmixturesꢀwereꢀobtainedꢀinꢀ80,ꢀ78,ꢀ85,ꢀ
80ꢀandꢀ60%ꢀglobalꢀyields,ꢀrespectivelyꢀ(Schemeꢀ3).ꢀ
ꢀ
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 11
Inꢀsummary,ꢀweꢀhaveꢀreportedꢀtheꢀfirstꢀpalladiumꢀ catalyzedꢀ
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
directꢀC3ꢀarylationꢀofꢀbothꢀ1Hꢀandꢀ2Hꢀpyrazolo[4,3-b]pyridineꢀ
seriesꢀ underꢀ mildꢀ reactionꢀ conditions.ꢀ Lowꢀ catalystꢀ loadingꢀ
andꢀ waterꢀ conditionsꢀ haveꢀ beenꢀ appliedꢀ inꢀ theꢀ casesꢀ ofꢀ 1Hꢀ
pyrazolo[4,3-b]pyridinesꢀ andꢀ 2Hꢀ pyrazolo[4,3-b]pyridines.ꢀ
Weꢀ developedꢀ alsoꢀ conditionsꢀ toꢀ achieveꢀ unprotectedꢀ C3-
arylatedꢀ 1Hꢀpyrazolo[4,3-b]pyridinesꢀusingꢀ aꢀ threeꢀstepsꢀ se-
quenceꢀ includingꢀ anꢀ originalꢀ sequentialꢀ C3-arylationꢀ onꢀ 1Hꢀ
andꢀ2Hꢀpyrazolo[4,3-b]pyridineꢀmixturesꢀfollowedꢀbyꢀinꢀsituꢀ
cleavageꢀ ofꢀ theꢀ PMBꢀ protectingꢀ group.ꢀ Theꢀ developmentꢀ ofꢀ
newꢀcross-couplingꢀreactionsꢀandꢀtheirꢀmechanisticꢀinvestiga-
tionsꢀareꢀongoingꢀinꢀourꢀlaboratories.ꢀ
ꢀ
Schemeꢀ 3.ꢀ Sequentialꢀ C3-arylationꢀ onꢀ 3ꢀ andꢀ 1ꢀ mixtureꢀ
usingꢀvariousꢀiodoaryls.ꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
DeprotectionꢀofꢀtheꢀPMBꢀprotectingꢀgroupꢀtoꢀgenerateꢀNHꢀ
unprotectedꢀ C3-arylatedꢀ productsꢀ wasꢀ investigated.ꢀ Forꢀ
thisꢀpurpose,ꢀweꢀfound,ꢀthatꢀtheꢀtreatmentꢀofꢀisolatedꢀiso-
mersꢀ2bꢀandꢀ4bꢀwithꢀTFAꢀatꢀ70°Cꢀforꢀ1h ꢀledꢀtoꢀtheꢀonlyꢀ
expectedꢀ NHꢀ unprotectedꢀ C3-arylatedꢀ productꢀ 5bꢀ inꢀ 97ꢀ
15
Experimentꢀsectionꢀ
Generalꢀinformationꢀ
andꢀ95%ꢀyields,ꢀrespectivelyꢀ(Schemeꢀ4).ꢀꢀ
Theꢀreactionsꢀwereꢀmonitoredꢀbyꢀthin-layerꢀchromatographyꢀ
(TLC)ꢀusingꢀaluminumꢀsheetsꢀcoatedꢀwithꢀsilicaꢀgelꢀ60ꢀF254.ꢀ
Flashꢀcolumnꢀchromatographyꢀwasꢀcarriedꢀoutꢀusingꢀsilicaꢀgelꢀ
1
13
60ꢀA
ꢁꢀ(0.04−0.06ꢀmm).ꢀ Hꢀandꢀ CꢀNMRꢀspectraꢀwereꢀrecordedꢀ
1
13
1
withꢀaꢀ250ꢀMHzꢀ( H:ꢀ250ꢀandꢀ C:ꢀ63ꢀMHz)ꢀorꢀ400ꢀMHzꢀ( H:ꢀ
400ꢀ andꢀ 13C:ꢀ 101ꢀ MHz)ꢀ Brukerꢀ spectrometer.ꢀ Usingꢀ CDCl
,ꢀ
3
1
MeOH,ꢀ Acetoneꢀ andꢀ DMSOꢀ asꢀ solvent.ꢀ Chemicalꢀ shiftsꢀ ofꢀ Hꢀ
13
NMRꢀandꢀ CꢀNMRꢀwereꢀrecordedꢀinꢀpartsꢀperꢀmillionꢀ(ppm,ꢀδ)ꢀ
relativeꢀtoꢀtetramethylsilaneꢀ(δꢀ=ꢀ0.00ꢀppm)ꢀcalibratedꢀtoꢀtheꢀ
residualꢀ solventꢀ peakꢀ asꢀ anꢀ internalꢀ standardꢀ [(CDCl
7.26ꢀppmꢀandꢀδ ꢀ=ꢀ77.0ꢀppm)ꢀ(CD OD:ꢀδ ꢀ=ꢀ3.31ꢀandꢀ4.84ꢀppmꢀ
andꢀδ ꢀ=ꢀ49.0ꢀppm);ꢀ(DMSO-d6:ꢀδ ꢀ=ꢀ2.50ꢀppmꢀandꢀδ ꢀ=ꢀ39.4ꢀ
3 H
:ꢀ δ ꢀ =ꢀ
C
3
H
ꢀ
C
H
C
ppm)].ꢀDataꢀareꢀreportedꢀasꢀfollow:ꢀchemicalꢀshiftꢀinꢀppmꢀ(δ),ꢀ
multiplicityꢀ(sꢀ=ꢀsinglet,ꢀdꢀ=ꢀdoublet,ꢀtꢀ=ꢀtriplet,ꢀqꢀ=ꢀquartet,ꢀmꢀ
=ꢀ multiplet),ꢀ couplingꢀ constantꢀ (Hz).ꢀ High-resolutionꢀ massꢀ
spectraꢀ (HRMS)ꢀ wereꢀ recordedꢀ withꢀ aꢀ Maxisꢀ Brukerꢀ 4Gꢀ in-
strumentꢀandꢀwereꢀperformedꢀinꢀpositiveꢀmodeꢀwithꢀ anꢀ ESIꢀ
sourceꢀonꢀaꢀQ-TOFꢀmassꢀspectrometerꢀwithꢀanꢀaccuracyꢀtoler-
anceꢀofꢀ2ꢀppm.ꢀ
Schemeꢀ4.ꢀCleavageꢀofꢀPMBꢀprotectingꢀgroup.ꢀ
Encouragedꢀbyꢀtheseꢀresultsꢀ(Schemesꢀ3ꢀandꢀ4),ꢀweꢀdecid-
edꢀtoꢀdirectlyꢀrunꢀtheꢀreactionꢀonꢀtheꢀmixtureꢀofꢀcompoundꢀ
ꢀandꢀ3ꢀwithꢀvariousꢀiodoarylsꢀinꢀtheꢀpresenceꢀofꢀPd(PPh
5 mol%), 1,10-phenanthroline (10 mol%) and Ag CO (1.3
equiv.) in H O at 90°C for 24h. ꢀTheꢀexpectedꢀC3-arylatedꢀ
productsꢀ wereꢀ obtainedꢀ asꢀ 1Hꢀ andꢀ 2Hꢀ isomerꢀ mixtures.ꢀ
Afterꢀ aꢀ simpleꢀ filtration,ꢀ withoutꢀ anyꢀ columnꢀ chromatog-
raphyꢀseparation,ꢀtheꢀcrudeꢀ(1Hꢀandꢀ2Hꢀisomerꢀmixtures)ꢀ
wasꢀ treatedꢀ withꢀ TFAꢀ atꢀ 70°Cꢀ forꢀ 1hꢀ andꢀ ledꢀ toꢀ theꢀ ex-
pectedꢀ C3-arylatedꢀ unprotectedꢀ NHꢀ pyrazolo[4,3-
b]pyridinesꢀ 5a-eꢀ inꢀ goodꢀ toꢀ excellentꢀ globalꢀ yieldsꢀ (overꢀ
threeꢀ stepsꢀ startingꢀ fromꢀ 1H-pyrazolo[4,3-b]pyridine)ꢀ
1
(
3
)
4
2
3
2
Materials:ꢀ Unlessꢀ otherwiseꢀ noted,ꢀ allꢀ reagent-gradeꢀ chemi-
calsꢀ andꢀ solventsꢀ commerciallyꢀ availableꢀ wereꢀ usedꢀ withoutꢀ
furtherꢀ purification.ꢀ Allꢀ arylꢀ iodides,ꢀ silverꢀ carbonate,ꢀ 1,10-
phenanthrolineꢀ andꢀ triphenylphosphineꢀ wereꢀ storedꢀ inꢀ
sealed,ꢀcoolꢀandꢀdryꢀconditions.ꢀ
(Schemeꢀ5).ꢀꢀ
Syntheticꢀprocedures:ꢀ
Synthesisꢀofꢀ1H-pyrazolo[4,3-b]ꢀpyridine:ꢀ
Hydrazineꢀhydrateꢀ(10ꢀmL)ꢀwasꢀaddedꢀtoꢀaꢀmixtureꢀofꢀ3-
fluoro-2-formylpyridineꢀ1ꢀ(3.00ꢀ g,ꢀ 24ꢀ mmol)ꢀ andꢀ p-TsOHꢀ
(2.06ꢀg,ꢀ12ꢀmmol).ꢀTheꢀreactionꢀmixtureꢀwasꢀstirredꢀforꢀ3ꢀhꢀ
atꢀ130ꢀC°.ꢀUponꢀcoolingꢀwithꢀcoldꢀwater,ꢀtheꢀmixtureꢀwasꢀ
extractedꢀ threeꢀ timesꢀ withꢀ EtOAc.ꢀ Theꢀ combinedꢀ organicꢀ
extractsꢀwereꢀdriedꢀoverꢀanhydrousꢀMgSO .ꢀAfterꢀfiltration,ꢀ
4
theꢀsolventꢀwasꢀremovedꢀinꢀvacuum.ꢀTheꢀresidueꢀwasꢀpuri-
fiedꢀbyꢀflashꢀchromatographyꢀtoꢀgiveꢀcompoundꢀ2gꢀinꢀ70%ꢀ
yieldꢀasꢀaꢀwhiteꢀsolid.ꢀ
Schemeꢀ5.ꢀSequentialꢀC3-arylationꢀofꢀ1Hꢀandꢀ2Hꢀseriesꢀofꢀ
pyrazolo[4,3-b]pyridinesꢀandꢀcleavageꢀofꢀtheꢀPMBꢀprotect-
ingꢀgroup.ꢀ
ꢀ
Conclusionꢀ
N-Alkylationꢀofꢀ1H-pyrazolo[4,3-b]ꢀpyridine:ꢀ
ACS Paragon Plus Environment

Page 5 of 11
The Journal of Organic Chemistry
edꢀinꢀvacuo.ꢀTheꢀresidueꢀwasꢀpurifiedꢀbyꢀflashꢀchromatog-
Potassiumꢀhydroxideꢀ(1.4ꢀg,ꢀ25.21ꢀmmol)ꢀwasꢀaddedꢀtoꢀaꢀ
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
solutionꢀofꢀ1H-pyrazoloꢀ[4,3-b]ꢀpyridineꢀ(1ꢀg,ꢀ8.40ꢀmmol)ꢀꢀ
inꢀacetoneꢀ(30ꢀmL),ꢀandꢀtheꢀmixtureꢀwasꢀmaintainedꢀforꢀ60ꢀ
minꢀ atꢀ 0ꢀ °C.ꢀ Then,ꢀ 4-methoxybenzylꢀ chlorideꢀ (1.9ꢀ g,ꢀ 12.6ꢀ
mmol,ꢀ 1.5ꢀ equiv)ꢀ wasꢀ added.ꢀ Theꢀ reactionꢀ mixtureꢀ wasꢀ
warmedꢀtoꢀroomꢀtemperatureꢀandꢀmaintainedꢀforꢀ4ꢀh.ꢀTheꢀ
reactionꢀmixtureꢀwasꢀquenchedꢀwithꢀwaterꢀandꢀextractedꢀ
withꢀ EtOAc.ꢀ Theꢀ combinedꢀ organicꢀ extractsꢀ wereꢀ driedꢀ
raphyꢀ(silica;ꢀpetroleumꢀether/ꢀethylꢀacetate,ꢀ1:1,ꢀtheꢀsameꢀ
systemꢀ wasꢀ usedꢀ toꢀ purifyꢀ allꢀ synthesizedꢀ products)ꢀ toꢀ
provideꢀtheꢀtitleꢀcompoundꢀasꢀaꢀwhiteꢀsolidꢀinꢀ80%ꢀyieldꢀ
SequentialꢀC3-arylationꢀꢀ
100ꢀmgꢀofꢀtheꢀmixtureꢀ[1+3/56%+44%],ꢀ1equiv)ꢀwasꢀputꢀ
inꢀ aꢀ tube,ꢀ iodobenzeneꢀ (2ꢀ equiv),ꢀ Pd(PPh
3
) ꢀ (ꢀ 5ꢀ mol%),ꢀ
4
overꢀ anhydrousꢀ MgSO
4
.ꢀ Afterꢀ filtration,ꢀ theꢀ solventꢀ wasꢀ
Ag CO ꢀ(1,3ꢀequiv)ꢀandꢀphenanthrolineꢀ(10ꢀmol%).ꢀAꢀmag-
2
3
removedꢀ inꢀ vacuum.ꢀ Theꢀ desiredꢀ productsꢀ wereꢀ purifiedꢀ
byꢀ columnꢀ chromatographyꢀ (petroleumꢀ ether/ꢀ ethylꢀ ace-
tate,ꢀ 6:4)ꢀ whichꢀ ledꢀ toꢀ para-methoxybenzylatedꢀ productsꢀ
1-3ꢀ(50%-43%ꢀyield).ꢀ
neticꢀstirrerꢀbarꢀwasꢀaddedꢀandꢀtheꢀmixtureꢀofꢀsolidsꢀwasꢀ
gentlyꢀshakenꢀforꢀaꢀfewꢀsecondsꢀtoꢀensureꢀallꢀsolidsꢀwereꢀ
wellꢀmixed.ꢀDistilledꢀwaterꢀ(3ꢀml)ꢀwasꢀaddedꢀandꢀtheꢀtubeꢀ
wasꢀ coveredꢀ withꢀ aꢀ cap.ꢀ Theꢀ tubeꢀ andꢀ itsꢀ contentsꢀ wereꢀ
thenꢀheatedꢀandꢀstirredꢀatꢀ90ꢀ°Cꢀforꢀ24ꢀh.ꢀAfterꢀthisꢀtimeꢀ
theꢀreactionꢀmixtureꢀwasꢀcooledꢀdownꢀtoꢀroomꢀtempera-
ture.ꢀ CH Cl ꢀ (10ꢀ ml)ꢀ wasꢀ addedꢀ andꢀ theꢀ contentsꢀ ofꢀ theꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Generalꢀ procedureꢀ forꢀ directꢀ arylationꢀ ofꢀ iodoarenesꢀ
withꢀ 1-para-methoxybenzy-pyrazolo[4,3-b]pyridineꢀ
onꢀwater:ꢀ
2
2
tubeꢀwereꢀfilteredꢀthroughꢀaꢀshortꢀpadꢀofꢀcelite.ꢀTheꢀtubeꢀ
wasꢀrinsedꢀonceꢀwithꢀanꢀadditionalꢀ5ꢀmlꢀofꢀCH Cl .ꢀTheꢀor-
ganicꢀlayerꢀwasꢀseparated,ꢀandꢀtheꢀaqueousꢀphaseꢀextract-
edꢀ onceꢀ withꢀ CH Cl .ꢀ Theꢀ organicꢀ layersꢀ wereꢀ combinedꢀ
2
2
Aꢀ sealedꢀ tubeꢀ wasꢀ chargedꢀ withꢀ 1-para-methoxybenzy-
pyrazolo[4,3-b]pyridineꢀ (100ꢀ mg,ꢀ 0,41ꢀ mmol,ꢀ 1ꢀ equiv),ꢀ
2
2
3
iodobenzeneꢀ (0,83ꢀ mmol,ꢀ 2ꢀ equiv),ꢀ Pd(PPh )4ꢀ (24,17ꢀ mg,ꢀ
andꢀ concentratedꢀ inꢀ vacuoꢀ Theꢀ residueꢀ wasꢀ purifiedꢀ byꢀ
flashꢀchromatographyꢀ(silica;ꢀpetroleumꢀether/ꢀethylꢀace-
tate,ꢀ 1:1,ꢀ theꢀ sameꢀ systemꢀ wasꢀ usedꢀ toꢀ purifyꢀ allꢀ synthe-
sizedꢀproducts)ꢀtoꢀprovideꢀtheꢀC3ꢀarylatedꢀproductsꢀ2aꢀandꢀ
0
,020mmol,ꢀ 5ꢀ mol%),ꢀ Ag CO ꢀ (150ꢀ mg,ꢀ 0,54ꢀ mmol,ꢀ 1,3ꢀ
2
3
equiv)ꢀ andꢀ phenanthrolineꢀ (7,5ꢀ mg,ꢀ 0,041ꢀ mmol,ꢀ 10ꢀ
mol%).ꢀAꢀmagneticꢀstirrerꢀbarꢀwasꢀaddedꢀandꢀtheꢀmixtureꢀ
ofꢀsolidsꢀwasꢀgentlyꢀshakenꢀforꢀaꢀfewꢀsecondsꢀtoꢀensureꢀallꢀ
solidsꢀwereꢀwellꢀmixed.ꢀDistilledꢀwaterꢀ(3ꢀml)ꢀwasꢀaddedꢀ
andꢀtheꢀtubeꢀwasꢀcoveredꢀwithꢀaꢀcap.ꢀTheꢀtubeꢀandꢀitsꢀcon-
tentsꢀ wereꢀ thenꢀ heatedꢀ andꢀ stirredꢀ 90ꢀ °Cꢀ forꢀ 24ꢀ h.ꢀ Afterꢀ
thisꢀ timeꢀ theꢀ reactionꢀ mixtureꢀ wasꢀ cooledꢀ downꢀ toꢀ rt.ꢀ
4aꢀ wereꢀ isolatedꢀ asꢀ pureꢀ compoundsꢀ inꢀ 42ꢀ andꢀ 38ꢀ %ꢀ
yields,ꢀrespectivelyꢀ(80ꢀ%ꢀglobalꢀyield).ꢀ
Generalꢀprotocolꢀforꢀdeprotectionꢀsequence:ꢀ
Toꢀaꢀ50ꢀmgꢀofꢀ2bꢀorꢀ(4b)ꢀwasꢀaddedꢀTFAꢀ(3ꢀml).ꢀTheꢀreac-
tionꢀmixtureꢀwasꢀstirredꢀatꢀ70ꢀ°Cꢀforꢀ2ꢀh,ꢀafterꢀconcentra-
tion,ꢀ theꢀ residueꢀ wasꢀ dissolvedꢀ inꢀ EtOAcꢀ (10ꢀ ml)ꢀ andꢀ
CH
filteredꢀthroughꢀaꢀshortꢀpadꢀofꢀcelite.ꢀTheꢀtubeꢀwasꢀrinsedꢀ
onceꢀwithꢀanꢀadditionalꢀ2ꢀmlꢀofꢀCH Cl .ꢀTheꢀorganicꢀlayerꢀ
wasꢀseparated,ꢀandꢀtheꢀaqueousꢀphaseꢀextractedꢀonceꢀwithꢀ
CH Cl .ꢀTheꢀorganicꢀlayersꢀwereꢀcombinedꢀandꢀconcentrat-
2
Cl
2
ꢀ(5ꢀml)ꢀwasꢀaddedꢀandꢀtheꢀcontentsꢀofꢀtheꢀtubeꢀwereꢀ
2
2
washedꢀwithꢀNaHCO ꢀ(10ꢀml),ꢀbrineꢀ(10ꢀml),ꢀdriedꢀ(MgSO )ꢀ
3
4
andꢀconcentratedꢀinꢀvacuo.ꢀResidueꢀwasꢀpurifiedꢀbyꢀflashꢀ
chromatographyꢀ (silica;ꢀ ethylꢀ acetate)ꢀ toꢀ provideꢀ theꢀ
productꢀ5bꢀinꢀ97%ꢀyield.ꢀ
2
2
edꢀinꢀvacuo.ꢀTheꢀresidueꢀwasꢀpurifiedꢀbyꢀflashꢀchromatog-
raphyꢀ(silica;ꢀpetroleumꢀether/ꢀethylꢀacetate,ꢀ4:1,ꢀtheꢀsameꢀ
systemꢀ wasꢀ usedꢀ toꢀ purifyꢀ allꢀ synthesizedꢀ products)ꢀ toꢀ
provideꢀtheꢀtitleꢀcompoundꢀasꢀaꢀwhiteꢀsolidꢀinꢀ80%ꢀyield.ꢀ
Generalꢀ protocolꢀ forꢀ arylation/deprotectionꢀ sequenc-
es:ꢀ
1H-Pyrazoloꢀ [4,3-b]ꢀ pyridineꢀ (100ꢀ mg,ꢀ 0.84ꢀ mmol)ꢀ wasꢀ dis-
solvedꢀinꢀ3ꢀmlꢀacetoneꢀandꢀcooledꢀtoꢀ0ꢀ°Cꢀthen,ꢀKOHꢀ(141ꢀmg,ꢀ
2.52ꢀmmol,ꢀ3ꢀequiv)ꢀwasꢀaddedꢀatꢀ0ꢀ°Cꢀandꢀtheꢀresultingꢀmix-
tureꢀ wasꢀ allowedꢀ toꢀ stirꢀ forꢀ 60ꢀ minutes.ꢀ 4-Methoxybenzylꢀ
chlorideꢀ(197ꢀmg,ꢀ1.26ꢀmmol,ꢀ1.5ꢀequiv)ꢀwasꢀaddedꢀandꢀtheꢀ
reactionꢀallowedꢀtoꢀwarmꢀtoꢀroomꢀtemperatureꢀandꢀstirredꢀforꢀ
anꢀ additionalꢀ 4ꢀ hours.ꢀ Theꢀ reactionꢀ mixtureꢀ wasꢀ quenchedꢀ
withꢀwaterꢀandꢀextractedꢀwithꢀEtOAc.ꢀTheꢀcombinedꢀorganicꢀ
Generalꢀ procedureꢀ forꢀ directꢀ arylationꢀ ofꢀ iodoarenesꢀ
withꢀ 2-para-methoxybenzy-pyrazolo[4,3-b]pyridineꢀ
onꢀwater:ꢀ
Aꢀ sealedꢀ tubeꢀ wasꢀ chargedꢀ withꢀ 2-para-methoxybenzy-
pyrazoloꢀ [4,3-b]pyridineꢀ (100ꢀ mg,ꢀ 0,41ꢀ mmol,ꢀ 1ꢀ equiv),ꢀ
iodobenzeneꢀ(0,41ꢀmmol,ꢀ1ꢀequiv),ꢀPd(PPh
3
2
) Cl2ꢀ(7,34ꢀmg,ꢀ
0
.010mmol,ꢀ2,5ꢀmol%),ꢀandꢀAg CO ꢀ(115ꢀmg,ꢀ0,41ꢀmmol,ꢀ1ꢀ
2
3
extractsꢀ wereꢀ driedꢀ overꢀ anhydrousꢀ MgSO
theꢀ solventꢀ wasꢀ removedꢀ inꢀ vacuum.ꢀ Theꢀ desiredꢀ productsꢀ
1+3)ꢀwereꢀfilteredꢀbyꢀsimpleꢀfiltration.ꢀThen,ꢀtheꢀmixtureꢀwasꢀ
putꢀ inꢀ aꢀ tubeꢀ [1+3/56%+44%],ꢀ 1ꢀ equiv),ꢀ iodoꢀ heteroarylꢀ (2ꢀ
equiv),ꢀPd(PPh ꢀ(5ꢀmol%),ꢀAg CO ꢀ(1,3ꢀequiv)ꢀandꢀphenan-
4
.ꢀ Afterꢀ filtration,ꢀ
equiv).ꢀAꢀmagneticꢀstirrerꢀbarꢀwasꢀaddedꢀandꢀtheꢀmixtureꢀ
ofꢀsolidsꢀwasꢀgentlyꢀshakenꢀforꢀaꢀfewꢀsecondsꢀtoꢀensureꢀallꢀ
solidsꢀwereꢀwellꢀmixed.ꢀDistilledꢀwaterꢀ(3ꢀml)ꢀwasꢀaddedꢀ
andꢀtheꢀtubeꢀwasꢀcoveredꢀwithꢀaꢀcap.ꢀTheꢀtubeꢀandꢀitsꢀcon-
tentsꢀwereꢀthenꢀheatedꢀandꢀstirredꢀatꢀ70ꢀ°Cꢀforꢀ24ꢀh.ꢀAfterꢀ
thisꢀ timeꢀ theꢀ reactionꢀ mixtureꢀ wasꢀ cooledꢀ downꢀ toꢀ rt.ꢀ
(
)
3 4
2
3
throlineꢀ(10ꢀmol%).ꢀAꢀmagneticꢀstirrerꢀbarꢀwasꢀaddedꢀandꢀtheꢀ
mixtureꢀofꢀsolidsꢀwasꢀgentlyꢀshakenꢀforꢀaꢀfewꢀsecondsꢀtoꢀen-
sureꢀ allꢀ solidsꢀ wereꢀ wellꢀ mixed.ꢀ Distilledꢀ waterꢀ (3ꢀ ml)ꢀ wasꢀ
addedꢀandꢀtheꢀtubeꢀwasꢀcoveredꢀwithꢀaꢀcap.ꢀTheꢀtubeꢀandꢀitsꢀ
contentsꢀwereꢀthenꢀheatedꢀandꢀstirredꢀatꢀ90ꢀ°Cꢀforꢀ24ꢀh.ꢀAfterꢀ
thisꢀtimeꢀtheꢀreactionꢀmixtureꢀwasꢀcooledꢀdownꢀtoꢀroomꢀtem-
CH
filteredꢀthroughꢀaꢀshortꢀpadꢀofꢀcelite.ꢀTheꢀtubeꢀwasꢀrinsedꢀ
onceꢀwithꢀanꢀadditionalꢀ2ꢀmlꢀofꢀCH Cl .ꢀTheꢀorganicꢀlayerꢀ
wasꢀseparated,ꢀandꢀtheꢀaqueousꢀphaseꢀextractedꢀonceꢀwithꢀ
CH Cl .ꢀTheꢀorganicꢀlayersꢀwereꢀcombinedꢀandꢀconcentrat-
2
Cl
2
ꢀ(5ꢀml)ꢀwasꢀaddedꢀandꢀtheꢀcontentsꢀofꢀtheꢀtubeꢀwereꢀ
2
2
2
2
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 11
perature.ꢀ CH
tubeꢀwereꢀfilteredꢀthroughꢀaꢀshortꢀpadꢀofꢀcelite.ꢀTheꢀtubeꢀwasꢀ
rinsedꢀ onceꢀ withꢀ anꢀ additionalꢀ 5ꢀ mlꢀ ofꢀ CH Cl .ꢀ Theꢀ organicꢀ
layerꢀ wasꢀ separatedꢀ andꢀ theꢀ aqueousꢀ phaseꢀ extractedꢀ onceꢀ
withꢀCH Cl .ꢀTheꢀorganicꢀlayersꢀwereꢀcombinedꢀandꢀconcen-
2
Cl
2
ꢀ(10ꢀ ml)ꢀ wasꢀ addedꢀ andꢀ theꢀ contentsꢀofꢀtheꢀ
2-(4-Methoxybenzyl)-3-p-tolyl-2H-pyrazolo[4,3-
b]pyridineꢀ2b:ꢀꢀ
Yellowꢀsolidꢀ(118ꢀmg,ꢀ0.35ꢀmmol,ꢀ88%),ꢀmpꢀ=ꢀ85-87ꢀ°C. Hꢀ
NMRꢀ (250ꢀ MHz,ꢀ CDCl )ꢀ δ ꢀ 8.58ꢀ (dd,ꢀ Jꢀ =ꢀ 4.0,ꢀ 2.6ꢀ Hz,ꢀ 1H),ꢀ
.07ꢀ(dd,ꢀJꢀ=ꢀ8.7,ꢀ2.6ꢀHz,ꢀ1H),ꢀ7.48ꢀ(d,ꢀJꢀ=ꢀ8.0ꢀHz,ꢀ2H),ꢀ7.34ꢀ
d,ꢀJꢀ=ꢀ8ꢀHz,ꢀ2H),ꢀ7.2ꢀ(dd,ꢀJꢀ=ꢀ8.7,ꢀ4.0ꢀHz,ꢀ1H),ꢀ7.08ꢀ(d,ꢀJꢀ=ꢀ8.5ꢀ
Hz,ꢀ2H),ꢀ6.82ꢀ(d,ꢀJꢀ=ꢀ8.5ꢀHz,ꢀ2H),ꢀ5.63ꢀ(s,ꢀ2H),ꢀ3.77ꢀ(s,ꢀ3H),ꢀ
2.44ꢀ (s,ꢀ 3H).ꢀ 13Cꢀ NMRꢀ (101ꢀ MHz,ꢀ CDCl
)ꢀ δ ꢀ 159.4,ꢀ 148.2,ꢀ
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
2
ꢀ
1
3
H
2
2
8
tratedꢀ inꢀ vacuo,ꢀ thenꢀ afterꢀ aꢀ simpleꢀ filtrationꢀ ofꢀ theꢀ crudeꢀ
product,ꢀTFAꢀ(3ꢀml)ꢀwasꢀaddedꢀandꢀtheꢀmixtureꢀwasꢀstirredꢀatꢀ
(
7
0ꢀ°ꢀCꢀforꢀ2ꢀhours.ꢀAfterꢀconcentration,ꢀtheꢀresidueꢀwasꢀdis-
solvedꢀ inꢀ EtOAcꢀ (10ꢀ ml)ꢀ andꢀ washedꢀ withꢀ NaHCO ꢀ (10ꢀ ml),ꢀ
brineꢀ(10ꢀml),ꢀdriedꢀ(MgSO )ꢀandꢀconcentratedꢀinꢀvacuo.ꢀResi-
3
C
3
141.4,ꢀ 139.3,ꢀ 137.4,ꢀ 137.0,ꢀ 130.0,ꢀ 129.8,ꢀ 128.7,ꢀ 128.7,ꢀ
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
125.6,ꢀ125.5,ꢀ121.6,ꢀ114.3,ꢀ55.4,ꢀ54.6,ꢀ21.5;ꢀHRMSꢀcalcdꢀforꢀ
dueꢀwasꢀpurifiedꢀbyꢀflashꢀchromatographyꢀ(silica;ꢀpetroleumꢀ
ether/ꢀethylꢀacetate,ꢀ1:1)ꢀtoꢀprovideꢀtheꢀdesiredꢀproduct.ꢀ
+
C
21
H
20
N Oꢀ([M+H] ):ꢀ330.1599;ꢀFound:ꢀ330.1600.ꢀIRꢀ(neat)ꢀ
3
ν˜=ꢀ3031,ꢀ1609.1337ꢀcm-1.ꢀ
Characterization dataꢀꢀ
2-(4-Methoxybenzyl)-3-(4-(trifluoromethyl)phenyl)-
1
H-Pyrazolo[4,3-b]pyridine:ꢀ
Whiteꢀ solidꢀ (2g,ꢀ 16.80ꢀ mmol,ꢀ 70%),ꢀ mpꢀ =ꢀ 95-97ꢀ °C. Hꢀ
NMRꢀ(400ꢀMHz,ꢀCDCl )ꢀδ ꢀ13.00ꢀ(s,ꢀ1H),ꢀ8.61ꢀ(d,ꢀJꢀ=ꢀ4.1ꢀHz,ꢀ
H),ꢀ8.38ꢀ(s,ꢀ1H),ꢀ7.88ꢀ(d,ꢀJꢀ=ꢀ8.5ꢀHz,ꢀ1H),ꢀ7.29ꢀ(s,ꢀ1H).ꢀꢀ Cꢀ
2H-pyrazolo[4,3-b]pyridineꢀ2c:ꢀꢀ
ꢀ
1
Yellowꢀsolidꢀ(133ꢀmg,ꢀ0.34ꢀmmol,ꢀ85%),ꢀmpꢀ=ꢀ113-115°C.ꢀ
1HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
)ꢀδ ꢀ8.60ꢀ(dd,ꢀJꢀ=ꢀ4.1,ꢀ1.5ꢀHz,ꢀ1H),ꢀ
3
H
3
H
13
8.10ꢀ(dd,ꢀJꢀ=ꢀ8.8,ꢀ1.5ꢀHz,ꢀ1H),ꢀ7.77(q,ꢀJꢀ=ꢀ8.6ꢀHz,ꢀ4H),ꢀ7.27ꢀ
1
NMRꢀ(101ꢀMHz,ꢀCDCl
3
)ꢀδ ꢀ145.5,ꢀ140.8,ꢀ134.6,ꢀ133.1,ꢀ121.1,ꢀ
C
(dd,ꢀJꢀ=ꢀ8.8,ꢀ4.1ꢀHz,ꢀ1H),ꢀ7.06ꢀ(d,ꢀJꢀ=ꢀ8.6ꢀHz,ꢀ2H),ꢀ6.83ꢀ(d,ꢀJꢀ=ꢀ
+
13
1
18.6;ꢀHRMSꢀ(calcdꢀforꢀC
6
H
6
N
3ꢀ([M+H] ):ꢀ120.0555;ꢀFound:ꢀ
8.6ꢀHz,ꢀ2H),ꢀ5.65ꢀ(s,ꢀ2H),ꢀ3.76ꢀ(s,ꢀ3H).ꢀ CꢀNMRꢀ(101ꢀMHz,ꢀ
CDCl )ꢀδ ꢀ159.5,ꢀ148.9,ꢀ141.4,ꢀ137.5,ꢀ135.0,ꢀ132.1,ꢀ131.0ꢀ(q,ꢀ
20.0556.ꢀIRꢀ(neat)ꢀν˜=ꢀ3440,ꢀ3089,ꢀ1430ꢀcm-1.ꢀ
1
3
C
Jꢀ =ꢀ 32.9ꢀ Hz),ꢀ 130.3,ꢀ 128.4,ꢀ 128.1,ꢀ 126.0ꢀ (q,ꢀ Jꢀ =ꢀ 3.7ꢀ Hz),ꢀꢀ
25.9,ꢀ 124.0ꢀ (q,ꢀ Jꢀ =ꢀ 272.3ꢀ Hz),ꢀ 121.9,ꢀ 114.3,ꢀ 55.3,ꢀ 55.0;ꢀ
HRMSꢀ calcdꢀ forꢀ C H F N Oꢀ ([M+H] ):ꢀ 384.1317;ꢀ Found:ꢀ
1-(4-Methoxybenzyl)-1H-pyrazolo[4,3-b]pyridineꢀ3:ꢀ
1
ꢀ
1
+
Redꢀ oilꢀ (860ꢀ mg,ꢀ 3.59ꢀ mmol,ꢀ 43%). Hꢀ NMRꢀ (400ꢀ MHz,ꢀ
CDCl )ꢀδ ꢀ8.55ꢀ(dd,ꢀJꢀ=ꢀ4.4,ꢀ0.9ꢀHz,ꢀ1H),ꢀ8.26ꢀ(s,ꢀ1H),ꢀ7.63ꢀ(d,ꢀ
21 17
3
3
-1
3
H
384.1318.ꢀIRꢀ(neat)ꢀν˜=ꢀ3030,ꢀ1600,ꢀ1400,ꢀ1330ꢀcm .ꢀ
Jꢀ=ꢀ8.6ꢀHz,ꢀ1H),ꢀ7.21ꢀ(dd,ꢀJꢀ=ꢀ8.6,ꢀ4.4ꢀHz,ꢀ1H),ꢀ7.16ꢀ(d,ꢀJꢀ=ꢀ8.6ꢀ
Hz,ꢀ2H),ꢀ6.84ꢀ(d,ꢀJꢀ=ꢀ8.6ꢀHz,ꢀ2H),ꢀ5.53ꢀ(s,ꢀ2H),ꢀ3.76ꢀ(s,ꢀ3H).ꢀ
2-(4-Methoxybenzyl)-3-(4-methoxyphenyl)-2H-
13Cꢀ NMRꢀ(101ꢀ MHz,ꢀ CDCl
pyrazolo[4,3-b]pyridineꢀ2d:ꢀꢀ
3
)ꢀ δ ꢀ159.5,ꢀ 145.6,ꢀ 142.4,ꢀ 134.2,ꢀ
C
Yellowꢀsolidꢀ(113ꢀmg,ꢀ0.32ꢀmmol,ꢀ80%),ꢀmpꢀ=ꢀ106-108ꢀ°C.ꢀ
132.3,ꢀ128.8,ꢀ128.2,ꢀ120.6,ꢀ117.4,ꢀ114.3,ꢀ55.4,ꢀ53.4;ꢀHRMSꢀ
+
1HꢀNMRꢀ(250ꢀMHz,ꢀCDCl
(calcdꢀ forꢀ C14
H
14
N
3
Oꢀ ([M+H] ):ꢀ 240.1332;ꢀ Found:ꢀ
3
)
ꢀ
H
δ ꢀ8.57ꢀ(dd,ꢀJꢀ=ꢀ4.1,ꢀ1.5ꢀHz,ꢀ1H),ꢀ
240.1331.ꢀIRꢀ(neat)ꢀν˜=ꢀ3417,ꢀ2964,ꢀ2840,ꢀ1601,ꢀ1175ꢀcm-1ꢀ
8.06ꢀ(dd,ꢀJꢀ=ꢀ8.8,ꢀ1.5ꢀHz,ꢀ1H),ꢀ7.52ꢀ(d,ꢀJꢀ=ꢀ8.8ꢀHz,ꢀ2H),ꢀ7.22ꢀ
(dd,ꢀJꢀ=ꢀ8.8,ꢀ4.1ꢀHz,ꢀ1H),ꢀ7.13ꢀ–ꢀ7.01ꢀ(m,ꢀ4H),ꢀ6.82ꢀ(d,ꢀJꢀ=ꢀ8.8ꢀ
2-(4-Methoxybenzyl)-2H-pyrazolo[4,3-b]pyridineꢀ1:ꢀ
13
Hz,ꢀ 2H),ꢀ 5.62ꢀ (s,ꢀ 2H),ꢀ 3.87ꢀ (s,ꢀ 3H),ꢀ 3.76ꢀ (s,ꢀ 3H).ꢀ Cꢀ NMRꢀ
1
(101ꢀ MHz,ꢀ CDCl )ꢀ δ ꢀ 160.3,ꢀ 159.3,ꢀ 148.1,ꢀ 141.3,ꢀ 137.4,ꢀ
Redꢀoilꢀ(1ꢀg,ꢀ4.1ꢀmmol,ꢀ50%).ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
3
)ꢀδ
.52ꢀ(d,ꢀJꢀ=ꢀ4.1ꢀHz,ꢀ1H),ꢀ8.20ꢀ(s,ꢀ1H),ꢀ8.00ꢀ(d,ꢀJꢀ=ꢀ8.7ꢀHz,ꢀ1H),ꢀ
.21ꢀ(d,ꢀJꢀ=ꢀ8.7ꢀHz,ꢀ2H),ꢀ7.10ꢀ(dd,ꢀJꢀ=ꢀ8.7,ꢀ4.1ꢀHz,ꢀ1H),ꢀ6.82ꢀ
H
ꢀ
3
C
8
7
136.7,ꢀ 131.4,ꢀ 128.7,ꢀ 128.5,ꢀ 125.6,ꢀ 121.6,ꢀ 120.7,ꢀ 114.6,ꢀ
114.2,ꢀ 55.5,ꢀ 55.3,ꢀ 54.5;ꢀ HRMSꢀ calcdꢀ forꢀ C21
([M+H] ):ꢀ346.1547;ꢀFound:ꢀ346.1550.ꢀIRꢀ(neat)ꢀν˜=ꢀ3007,ꢀ
H
20
N
3
2
O ꢀ
1
3
+
(
d,ꢀJꢀ=ꢀ8.7ꢀHz,ꢀ2H),ꢀ5.46ꢀ(s,ꢀ2H),ꢀ3.67ꢀ(s,ꢀ3H).ꢀ CꢀNMRꢀ(101ꢀ
MHz,ꢀ CDCl )ꢀ δ ꢀ 159.2,ꢀ 147.4,ꢀ 141.1,ꢀ 138.6,ꢀ 129.1,ꢀ 126.8,ꢀ
25.0,ꢀ 123.2,ꢀ 120.5,ꢀ 113.7,ꢀ 57.0,ꢀ 54.6;ꢀ HRMSꢀ calcdꢀ forꢀ
2961,ꢀ1606,ꢀ1250ꢀcm-1ꢀ
3
C
1
C
+
2-(4-Methoxybenzyl)-3-(3-methoxyphenyl)-2H-
14
H
14
N Oꢀ[M+H] ):ꢀ240.1131;ꢀFound:ꢀ240.1131.ꢀIRꢀ(neat)ꢀ
3
ν˜=ꢀ3410,ꢀ2836,ꢀ1511,ꢀ1246ꢀcm-1ꢀ
pyrazolo[4,3-b]pyridineꢀ2e:ꢀꢀ
ꢀ
1
Orangeꢀoilꢀ(99ꢀmg,ꢀ0.28ꢀmmol,ꢀ70%). HꢀNMRꢀ(400ꢀMHz,ꢀ
CDCl )ꢀδ ꢀ8.58ꢀ(dd,ꢀJꢀ=ꢀ4.3,ꢀ1.5ꢀHz,ꢀ1H),ꢀ8.07ꢀ(dd,ꢀJꢀ=ꢀ8.8,ꢀ1.5ꢀ
Hz,ꢀ1H),ꢀ7.43ꢀ(t,ꢀJꢀ=ꢀ7.6ꢀHz,ꢀ1H),ꢀ7.22ꢀ(dd,ꢀJꢀ=ꢀ8.8,ꢀ4.3ꢀHz,ꢀ
2
-(4-Methoxybenzyl)-3-phenyl-2H-pyrazolo[4,3-
b]pyridineꢀ2a:ꢀꢀ
Yellowꢀsolidꢀ(104ꢀmg,ꢀ0.33ꢀmmol,ꢀ80%),ꢀmpꢀ=ꢀ90-92ꢀ°C. Hꢀ
NMRꢀ(250ꢀMHz,ꢀCDCl )ꢀδ ꢀ8.62ꢀ(d,ꢀJꢀ=ꢀ4.3ꢀHz,ꢀ1H),ꢀ8.10ꢀ(d,ꢀJꢀ
=ꢀ9.0ꢀHz,ꢀ1H),ꢀ7.71ꢀ–ꢀ7.43ꢀ(m,ꢀ5H),ꢀ7.26ꢀ(dd,ꢀJꢀ=ꢀ9.0,ꢀ4.3ꢀHz,ꢀ
3
H
1
H),ꢀ7.18ꢀ(d,ꢀJꢀ=ꢀ7.6ꢀHz,ꢀ1H),ꢀ7.11ꢀ–ꢀ7.05ꢀ(m,ꢀ3H),ꢀ7.01ꢀ(dd,ꢀJꢀ
ꢀ8.8,ꢀ2.6ꢀHz,ꢀ1H),ꢀ6.81ꢀ(d,ꢀJꢀ=ꢀ8.8ꢀHz,ꢀ2H),ꢀ5.63ꢀ(s,ꢀ2H),ꢀ3.76ꢀ
ꢀ
1
=
3
H
1
3
(
s,ꢀ3H),ꢀ3.74ꢀ(s,ꢀ3H).ꢀ CꢀNMRꢀ(101ꢀMHz,ꢀCDCl
3
)ꢀδ ꢀ159.8,ꢀ
C
159.3,ꢀ 148.2,ꢀ 141.2,ꢀ 137.3,ꢀ 136.5,ꢀ 130.0,ꢀ 129.5,ꢀ 128.5,ꢀ
1H),ꢀ7.09ꢀ(d,ꢀJꢀ=ꢀ8.7ꢀHz,ꢀ2H),ꢀ6.84ꢀ(d,ꢀJꢀ=ꢀ8.7ꢀHz,ꢀ2H),ꢀ5.66ꢀ(s,ꢀ
13
ꢀ13CꢀNMRꢀ
128.5,ꢀ125.5,ꢀ122.3,ꢀ121.5,ꢀ115.3,ꢀ115.1,ꢀ114.1,ꢀ55.2,ꢀ55.2,ꢀ
2
H),ꢀ3.79ꢀ(s,ꢀ3H).ꢀ CꢀNMRꢀ(101ꢀMHz,ꢀCDCl
)ꢀδ
3 C
+
54.6;ꢀ HRMSꢀ calcdꢀ forꢀ C21
H
20
N
3
O
2
ꢀ ([M+H] ):ꢀ 346.1548;ꢀ
(
101ꢀ MHz,ꢀ CDCl
3
)ꢀ δ ꢀ 159.4,ꢀ 148.4,ꢀ 141.4,ꢀ 137.4,ꢀ 136.8,ꢀ
C
Found:ꢀ346.1550.ꢀIRꢀ(neat)ꢀν˜=ꢀ3059,ꢀ2938,ꢀ1604,ꢀ1283ꢀcm-
1ꢀ
1
1
3
1
30.1,ꢀ 129.2,ꢀ 129.1,ꢀ 128.6,ꢀ 128.6,ꢀ 128.5,ꢀ 125.7,ꢀ 121.72,ꢀ
+
14.3,ꢀ 55.4,ꢀ 54.7;ꢀ HRMSꢀ calcdꢀ forꢀ C20
H
18
N
3
Oꢀ ([M+H] ):ꢀ
16.1444;ꢀ Found:ꢀ 316.1444.ꢀ IRꢀ (neat)ꢀ ν˜=ꢀ 3410,ꢀ 2928,ꢀ
-
1
173ꢀcm ꢀ
ACS Paragon Plus Environment

Page 7 of 11
The Journal of Organic Chemistry
2
-(4-Methoxybenzyl)-3-(2-methoxyphenyl)-2H-
4-(2-(4-Methoxybenzyl)-2H-pyrazolo[4,3-b]pyridin-3-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
pyrazolo[4,3-b]pyridineꢀ2f:ꢀꢀ
yl)benzonitrileꢀ2j:ꢀꢀ
Yellowꢀsolidꢀ(96ꢀmg,ꢀ0.27ꢀmmol,ꢀ68%),ꢀmpꢀ=ꢀ106-108ꢀ°C.ꢀ
1HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
Whiteꢀsolidꢀ(118ꢀmg,ꢀ0.34ꢀmmol,ꢀ85%),ꢀmpꢀ=ꢀ190-192ꢀ°C.ꢀ
)ꢀδ
H
ꢀ8.54ꢀ(dd,ꢀJꢀ=ꢀ4.1,ꢀ1.5ꢀHz,ꢀ1H),ꢀ
1HꢀNMRꢀ(250ꢀMHz,ꢀCDCl3)ꢀδ
ꢀ8.62ꢀ(dd,ꢀJꢀ=ꢀ4.1,ꢀ1.4ꢀHz,ꢀ1H),ꢀ
H
3
8.06ꢀ(dd,ꢀJꢀ=ꢀ8.8,ꢀ1.5ꢀHz,ꢀ1H),ꢀ7.49ꢀ(t,ꢀJꢀ=ꢀ8.7ꢀHz,ꢀ1H),ꢀ7.37ꢀ
8.12ꢀ(dd,ꢀJꢀ=ꢀ8.8,ꢀ1.4ꢀHz,ꢀ1H),ꢀ7.78ꢀ(q,ꢀJꢀ=ꢀ8.8ꢀHz,ꢀ4H),ꢀ7.29ꢀ
(dd,ꢀJꢀ=ꢀ8.8,ꢀ4.1ꢀHz,ꢀ1H),ꢀ7.05ꢀ(d,ꢀJꢀ=ꢀ8.6ꢀHz,ꢀ2H),ꢀ6.83ꢀ(d,ꢀJꢀ=ꢀ
8.6ꢀHz,ꢀ2H),ꢀ5.67ꢀ(s,ꢀ2H),ꢀ3.77ꢀ(s,ꢀ3H).ꢀ13CꢀNMRꢀ(101ꢀMHz,ꢀ
(
dd,ꢀJꢀ=ꢀ7.5,ꢀ1.5ꢀHz,ꢀ2H),ꢀ7.20ꢀ(dd,ꢀJꢀ=ꢀ8.8,ꢀ4.1ꢀHz,ꢀ1H),ꢀ7.12ꢀ
t,ꢀJꢀ=ꢀ7.5ꢀHz,ꢀ1H),ꢀ7.05ꢀ(d,ꢀJꢀ=ꢀ8.7ꢀHz,ꢀ1H),ꢀ7.00ꢀ(d,ꢀJꢀ=ꢀ8.7ꢀHz,ꢀ
(
2H),ꢀ6.75ꢀ(d,ꢀJꢀ=ꢀ8.7ꢀHz,ꢀ2H),ꢀ5.46ꢀ(s,ꢀ2H),ꢀ3.74ꢀ(s,ꢀ3H),ꢀ3.72ꢀ
CDCl
3
)ꢀ δ ꢀ 159.6,ꢀ 149.2,ꢀ 141.4,ꢀ 137.5,ꢀ 134.4,ꢀ 133.1,ꢀ 132.7,ꢀ
C
1
3
(s,ꢀ3H).ꢀ CꢀNMRꢀ(101ꢀMHz,ꢀCDCl
3
)ꢀδ
C
ꢀ159.3,ꢀ157.3,ꢀ148.0,ꢀ
130.5,ꢀ128.4,ꢀ127.9,ꢀ126.1,ꢀ122.0,ꢀ118.5,ꢀ114.4,ꢀ112.6,ꢀ55.4,ꢀ
+
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
141.4,ꢀ 138.0,ꢀ 133.8,ꢀ 132.9,ꢀ 131.3,ꢀ 129.3,ꢀ 128.5,ꢀ 125.7,ꢀ
55.3;ꢀ HRMSꢀ calcdꢀ forꢀ C21
H
17
N
4
Oꢀ ([M+H] ):ꢀ 341.1395;ꢀ
Found:ꢀ341.1396.ꢀIRꢀ(neat)ꢀν˜=ꢀ3350,ꢀ3187,ꢀ2221,ꢀ1608ꢀcm-
1ꢀ
121.3,ꢀ 121.3,ꢀ 117.4,ꢀ 113.9,ꢀ 111.5,ꢀ 55.6,ꢀ 55.3,ꢀ 55.3;ꢀ HRMSꢀ
+
calcdꢀforꢀC21
IRꢀ(neat)ꢀν˜=ꢀ3058,ꢀ2960,ꢀ1615,ꢀ1495ꢀcm-1ꢀ
H
20
N
3
O ꢀ([M+H] ):ꢀ346.1550;ꢀFound:ꢀ346.1550.ꢀ
2
2-(4-Methoxybenzyl)-3-(pyridin-4-yl)-2H-
pyrazolo[4,3-b]pyridineꢀ2k:ꢀꢀ
2-(4-Methoxybenzyl)-3-(4-chlorophenyl)-2H-
pyrazolo[4,3-b]pyridineꢀ2g:ꢀꢀ
Whiteꢀsolidꢀ(100ꢀmg,ꢀ0.28ꢀmmol,ꢀ70%),ꢀmpꢀ=ꢀ119-121ꢀ°C.ꢀ
1HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
ꢀ1
Yellowꢀsolidꢀ(77ꢀmg,ꢀ0.24ꢀmmol,ꢀ60%),ꢀmpꢀ=ꢀ97-99ꢀ°C. Hꢀ
3
)ꢀδ ꢀ8.58ꢀ(dd,ꢀJꢀ=ꢀ4.1,ꢀ1.4ꢀHz,ꢀ1H),ꢀ
H
NMRꢀ(400ꢀMHz,ꢀCDCl3)ꢀδ ꢀ8.77ꢀ(d,ꢀJꢀ=ꢀ5.9ꢀHz,ꢀ2H),ꢀ8.64ꢀ(dd,ꢀ
H
8.08ꢀ(dd,ꢀJꢀ=ꢀ8.8,ꢀ1.4ꢀHz,ꢀ1H),ꢀ7.51ꢀ(q,ꢀJꢀ=ꢀ8.7ꢀHz,ꢀ4H),ꢀ7.24ꢀ
Jꢀ=ꢀ4.1,ꢀ1.4ꢀHz,ꢀ1H),ꢀ8.12ꢀ(dd,ꢀJꢀ=ꢀ8.8,ꢀ1.4ꢀHz,ꢀ1H),ꢀ7.58ꢀ(d,ꢀJꢀ=ꢀ
8.8ꢀHz,ꢀ2H),ꢀ7.29ꢀ(dd,ꢀJꢀ=ꢀ8.8,ꢀ4.1ꢀHz,ꢀ1H),ꢀ7.06ꢀ(d,ꢀJꢀ=ꢀ8.8ꢀHz,ꢀ
(dd,ꢀJꢀ=ꢀ8.8,ꢀ4.1ꢀHz,ꢀ1H),ꢀ7.06ꢀ(d,ꢀJꢀ=ꢀ8.7ꢀHz,ꢀ2H),ꢀ6.82ꢀ(d,ꢀJꢀ=ꢀ
13
13
8
.7ꢀHz,ꢀ2H),ꢀ5.62ꢀ(s,ꢀ2H),ꢀ3.76ꢀ(s,ꢀ3H).ꢀ CꢀNMRꢀ(101ꢀMHz,ꢀ
)ꢀ δ ꢀ 159.5,ꢀ 148.6,ꢀ 141.4,ꢀ 137.4,ꢀ 135.4,ꢀ 135.4,ꢀ 131.3,ꢀ
2H),ꢀ6.83ꢀ(d,ꢀJꢀ=ꢀ8.8ꢀHz,ꢀ2H),ꢀ5.70ꢀ(s,ꢀ2H),ꢀ3.77ꢀ(s,ꢀ3H).ꢀ Cꢀ
CDCl
3
C
NMRꢀ (101ꢀ MHz,ꢀ CDCl3)ꢀ δ ꢀ 159.6,ꢀ 150.6,ꢀ 149.3,ꢀ 141.5,ꢀ
C
129.4,ꢀ128.5,ꢀ128.3,ꢀ126.9,ꢀ125.8,ꢀ121.8,ꢀ114.3,ꢀ55.3,ꢀ54.8;ꢀ
137.6,ꢀ 136.2,ꢀ 133.5,ꢀ 128.4,ꢀ 128.0,ꢀ 126.1,ꢀ 124.0,ꢀ 122.0,ꢀ
+
+
HRMSꢀ calcdꢀ forꢀ C20
H17ClN
3
Oꢀ ([M+H] ):ꢀ 350.1052;ꢀ Found:ꢀ
114.5,ꢀ 55.4,ꢀ 55.4;ꢀ HRMSꢀ calcdꢀ forꢀ C H N Oꢀ ([M+H] ):ꢀ
1
9
17
4
-1
350.1054.ꢀIRꢀ(neat)ꢀν˜=ꢀ3059,ꢀ1500,ꢀ706ꢀcm .ꢀ
317.1395;ꢀ Found:ꢀ 317.1396.ꢀ IRꢀ (neat)ꢀ ν˜=ꢀ 3369,ꢀ 2849,ꢀ
-1
1
398,ꢀ1275ꢀcm ꢀ
Ethylꢀ
4-(2-(4-methoxybenzyl)-2H-pyrazolo[4,3-
b]pyridin-3-yl)benzoateꢀ2h:ꢀꢀ
2-(4-Methoxybenzyl)-3-(pyrazin-2-yl)-2H-
Whiteꢀsolidꢀ(126ꢀmg,ꢀ0.32ꢀmmol,ꢀ80%),ꢀmpꢀ=ꢀ117-119ꢀ°C.ꢀ
1HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
pyrazolo[4,3-b]pyridineꢀ2l:ꢀꢀ
)ꢀδ ꢀ8.61ꢀ(dd,ꢀJꢀ=ꢀ4.1,ꢀ1.4ꢀHz,ꢀ1H),ꢀ
H
Yellowꢀsolidꢀ(90ꢀmg,ꢀ0.28ꢀmmol,ꢀ70%),ꢀmpꢀ=ꢀ128-130ꢀ°C.ꢀ
3
8.20ꢀ(d,ꢀJꢀ=ꢀ8.3ꢀHz,ꢀ2H),ꢀ8.10ꢀ(dd,ꢀJꢀ=ꢀ8.8,ꢀ1.4ꢀHz,ꢀ1H),ꢀ7.71ꢀ
(d,ꢀJꢀ=ꢀ8.3ꢀHz,ꢀ2H),ꢀ7.27ꢀ(dd,ꢀJꢀ=ꢀ8.8,ꢀ4.1ꢀHz,ꢀ1H),ꢀ7.07ꢀ(d,ꢀJꢀ=ꢀ
8.7ꢀHz,ꢀ2H),ꢀ6.82ꢀ(d,ꢀJꢀ=ꢀ8.7ꢀHz,ꢀ2H),ꢀ5.66ꢀ(s,ꢀ2H),ꢀ4.42ꢀ(q,ꢀJꢀ=ꢀ
1
HꢀNMRꢀ(400ꢀMHz,ꢀCDCl )ꢀδ ꢀ9.98ꢀ(d,ꢀJꢀ=ꢀ1.6ꢀHz,ꢀ1H),ꢀ8.67ꢀ
3
H
(m,ꢀ2H),ꢀ8.54ꢀ(d,ꢀJꢀ=ꢀ2.5ꢀHz,ꢀ1H),ꢀ8.12ꢀ(dd,ꢀJꢀ=ꢀ8.7,ꢀ1.6ꢀHz,ꢀ
1H),ꢀ7.28ꢀ(dd,ꢀJꢀ=ꢀ8.7,ꢀ4.1ꢀHz,ꢀ1H),ꢀ7.23ꢀ(d,ꢀJꢀ=ꢀ8.6ꢀHz,ꢀ2H),ꢀ
13
13
7.1ꢀHz,ꢀ2H),ꢀ3.76ꢀ(s,ꢀ3H),ꢀ1.42ꢀ(t,ꢀJꢀ=ꢀ7.1ꢀHz,ꢀ3H).ꢀ CꢀNMRꢀ
6.77ꢀ(d,ꢀJꢀ=ꢀ8.6ꢀHz,ꢀ2H),ꢀ6.26ꢀ(s,ꢀ2H),ꢀ3.72ꢀ(s,ꢀ3H).ꢀ CꢀNMRꢀ
(101ꢀ MHz,ꢀ CDCl )ꢀ δ ꢀ 166.1,ꢀ 159.4,ꢀ 148.7,ꢀ 141.4,ꢀ 137.5,ꢀ
3
C
(101ꢀ MHz,ꢀ CDCl )ꢀ δ ꢀ 159.3,ꢀ 149.1,ꢀ 146.1,ꢀ 144.8,ꢀ 143.3,ꢀ
3
C
1
1
C
35.5,ꢀ 132.8,ꢀ 130.8,ꢀ 130.1,ꢀ 129.9,ꢀ 128.5,ꢀ 128.2,ꢀ 125.8,ꢀ
143.0,ꢀ 141.1,ꢀ 138.1,ꢀ 129.7,ꢀ 129.3,ꢀ 128.7,ꢀ 126.2,ꢀ 121.7,ꢀ
114.0,ꢀ 56.5,ꢀ 55.2;ꢀ HRMSꢀ calcdꢀ forꢀ C H N Oꢀ ([M+H] ):ꢀ
21.8,ꢀ 114.3,ꢀ 61.3,ꢀ 55.3,ꢀ 55.0,ꢀ 14.4;ꢀ HRMSꢀ calcdꢀ forꢀ
+
18
16
5
+
23
H
22
N O
3 3
ꢀ ([M+H] ):ꢀ 388.1658;ꢀ Found:ꢀ 388.1655.ꢀ IRꢀ
318.1349;ꢀ Found:ꢀ 318.1349.ꢀ IRꢀ (neat)ꢀ ν˜=ꢀ 3057,ꢀ 2919,ꢀ
1603,ꢀ1395,ꢀ1187ꢀcm-1.ꢀ
-1
(neat)ꢀν˜=ꢀ2977,ꢀ1712,ꢀ1606,ꢀ1162ꢀcm ꢀ
2-(4-Methoxybenzyl)-3-(4-nitrophenyl)-2H-
2-(4-Methoxybenzyl)-3-(thiophen-2-yl)-2H-
pyrazolo[4,3-b]pyridineꢀ2i:ꢀꢀ
pyrazolo[4,3-b]pyridineꢀ2m:ꢀꢀ
Yellowꢀsolidꢀ(113ꢀmg,ꢀ0.31ꢀmmol,ꢀ77%),ꢀmpꢀ=ꢀ130-132ꢀ°C.ꢀ
1HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
1
Orangeꢀoilꢀ(72ꢀmg,ꢀ0.22ꢀmmol,ꢀ55%).ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀ
3
H
)ꢀδ ꢀ8.64ꢀ(dd,ꢀJꢀ=ꢀ4.1,ꢀ1.4ꢀHz,ꢀ1H),ꢀ
CDCl
3
)ꢀδ ꢀ8.64ꢀ(dd,ꢀJꢀ=ꢀ4.1,ꢀ1.4ꢀHz,ꢀ1H),ꢀ8.07ꢀ(dd,ꢀJꢀ=ꢀ8.7,ꢀ1.4ꢀ
H
8.38ꢀ(d,ꢀJꢀ=ꢀ8.8ꢀHz,ꢀ2H),ꢀ8.13ꢀ(dd,ꢀJꢀ=ꢀ8.8,ꢀ1.4ꢀHz,ꢀ1H),ꢀ7.83ꢀ
(d,ꢀJꢀ=ꢀ8.8ꢀHz,ꢀ2H),ꢀ7.31ꢀ(dd,ꢀJꢀ=ꢀ8.8,ꢀ4.1ꢀHz,ꢀ1H),ꢀ7.06ꢀ(d,ꢀJꢀ=ꢀ
8.8ꢀHz,ꢀ2H),ꢀ6.83ꢀ(d,ꢀJꢀ=ꢀ8.8ꢀHz,ꢀ2H),ꢀ5.69ꢀ(s,ꢀ2H),ꢀ3.78ꢀ(s,ꢀ
Hz,ꢀ1H),ꢀ7.55ꢀ(dd,ꢀJꢀ=ꢀ5.1,ꢀ1.1ꢀHz,ꢀ1H),ꢀ7.47ꢀ(dd,ꢀJꢀ=ꢀ3.6,ꢀ1.1ꢀ
Hz,ꢀ1H),ꢀ7.27ꢀ(dd,ꢀJꢀ=ꢀ8.7,ꢀ4.1ꢀHz,ꢀ1H),ꢀ7.20ꢀ(dd,ꢀJꢀ=ꢀ5.1,ꢀ3.6ꢀ
Hz,ꢀ1H),ꢀ7.10ꢀ(d,ꢀJꢀ=ꢀ8.7ꢀHz,ꢀ2H),ꢀ6.83ꢀ(d,ꢀJꢀ=ꢀ8.7ꢀHz,ꢀ2H),ꢀ
5.78ꢀ (s,ꢀ 2H),ꢀ 3.77ꢀ (s,ꢀ 3H).ꢀ 13Cꢀ NMRꢀ (101ꢀ MHz,ꢀ CDCl3)ꢀ δCꢀ
159.5,ꢀ 148.5,ꢀ 141.4,ꢀ 137.6,ꢀ 130.4,ꢀ 129.0,ꢀ 128.4,ꢀ 128.4,ꢀ
128.3,ꢀ128.2,ꢀ127.9,ꢀ125.9,ꢀ121.9,ꢀ114.3,ꢀ55.4,ꢀ55.2;ꢀHRMSꢀ
3
1
1
H).ꢀ 13Cꢀ NMRꢀ (101ꢀ MHz,ꢀ CDCl
41.5,ꢀ 137.7,ꢀ 134.9,ꢀ 134.0,ꢀ 130.7,ꢀ 128.4,ꢀ 127.9,ꢀ 126.1,ꢀ
3
)ꢀ δ ꢀ 159.6,ꢀ 149.3,ꢀ 147.8,ꢀ
C
24.2,ꢀ122.1,ꢀ114.5,ꢀ55.4,ꢀ55.4;ꢀHRMSꢀcalcdꢀforꢀC20
H
17
N
4
3
O ꢀ
+
+
([M+H] ):ꢀ361.1292;ꢀFound:ꢀ361.1295.ꢀIRꢀ(neat)ꢀν˜=ꢀ3059,ꢀ
calcdꢀ forꢀ C H N OSꢀ ([M+H] ):ꢀ 322.1008;ꢀ Found:ꢀ
1
8
16
3
1
576,ꢀ1541,ꢀ1328ꢀcm-1ꢀ
322.1008.ꢀIRꢀ(neat)ꢀν˜=ꢀ3057,ꢀ2600,ꢀ1350,ꢀ1080ꢀcm-1ꢀ
1-(4-Methoxybenzyl)-3-phenyl-1H-pyrazolo[4,3-
b]pyridineꢀ4a:ꢀꢀ
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 11
ꢀ
1
Whiteꢀsolidꢀ(104ꢀmg,ꢀ0.33ꢀmmol,ꢀ80%),ꢀmpꢀ=ꢀ80-82ꢀ°C. Hꢀ
NMRꢀ(400ꢀMHz,ꢀCDCl )ꢀδ ꢀ8.64ꢀ(d,ꢀJꢀ=ꢀ4.3ꢀHz,ꢀ1H),ꢀ8.52ꢀ(d,ꢀJꢀ
ꢀ7.7ꢀHz,ꢀ2H),ꢀ7.61ꢀ(d,ꢀJꢀ=ꢀ8.5ꢀHz,ꢀ1H),ꢀ7.51ꢀ(t,ꢀJꢀ=ꢀ7.7ꢀHz,ꢀ
H),ꢀ7.39ꢀ(t,ꢀJꢀ=ꢀ7.7ꢀHz,ꢀ1H),ꢀ7.28ꢀ–ꢀ7.17ꢀ(m,ꢀ3H),ꢀ6.84ꢀ(d,ꢀJꢀ=ꢀ
159.4,ꢀ 145.4,ꢀ 142.7,ꢀ 140.1,ꢀ 133.8,ꢀ 133.6,ꢀ 129.7,ꢀ 128.75,ꢀ
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
H
128.2,ꢀ120.5,ꢀ119.9,ꢀ117.4,ꢀ114.3,ꢀ114.2,ꢀ112.1,ꢀ55.4,ꢀ55.3,ꢀ
+
=
2
8
53.3;ꢀ HRMSꢀ calcdꢀ forꢀ C21
H
20
N
3
O
2
ꢀ ([M+H] ):ꢀ 346.1549;ꢀ
Found:,346.1550.ꢀIRꢀ(neat)ꢀν˜=ꢀ3050,ꢀ2934,ꢀ1601,ꢀ1280cm-
1.ꢀ
1
3
.5ꢀHz,ꢀ2H),ꢀ5.59ꢀ(s,ꢀ2H),ꢀ3.77ꢀ(s,ꢀ3H).ꢀ CꢀNMRꢀ(101ꢀMHz,ꢀ
)ꢀ δ ꢀ 159.5,ꢀ 145.5,ꢀ 143.1,ꢀ 140.2,ꢀ 133.8,ꢀ 132.5,ꢀ 128.8,ꢀ
CDCl
3
C
1
-(4-Methoxybenzyl)-3-(2-methoxyphenyl)-1H-
pyrazolo[4,3-b]pyridineꢀ4f:ꢀꢀ
ꢀOrangeꢀoilꢀ(90ꢀmg,ꢀ0.260ꢀmmol,ꢀ63%).ꢀ HꢀNMRꢀ(250ꢀMHz,ꢀ
CDCl )ꢀδ ꢀ8.58ꢀ(d,ꢀJꢀ=ꢀ4.3ꢀHz,ꢀ1H),ꢀ7.80ꢀ(dd,ꢀJꢀ=ꢀ7.5,ꢀ1.8ꢀHz,ꢀ
128.7,ꢀ128.3,ꢀ128.2,ꢀ127.3,ꢀ120.6,ꢀ117.5,ꢀ114.3,ꢀ55.4,ꢀ53.5;ꢀ
+
HRMSꢀ calcdꢀ forꢀ C20
H
18
N
3
Oꢀ ([M+H] ꢀ ):ꢀ 316.1441;ꢀ Found:ꢀ
3
16.1444.ꢀIRꢀ(neat)ꢀν˜=ꢀ3410,ꢀ2930,ꢀ1170ꢀcm-1ꢀ
1
3
H
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1-(4-Methoxybenzyl)-3-p-tolyl-1H-pyrazolo[4,3-
1H),ꢀ7.60ꢀ(dd,ꢀJꢀ=ꢀ8.5,ꢀ1.8ꢀHz,ꢀ1H),ꢀ7.45ꢀ–ꢀ7.33ꢀ(m,ꢀ1H),ꢀ7.24ꢀ
(d,ꢀJꢀ=ꢀ9.2ꢀHz,ꢀ2H),ꢀ7.24ꢀ–ꢀ7.02ꢀ(m,ꢀ3H),ꢀ6.84ꢀ(d,ꢀJꢀ=ꢀ9.2ꢀHz,ꢀ
b]pyridineꢀ4b:ꢀꢀ
Yellowꢀsolidꢀ(94ꢀmg,ꢀ0.28ꢀmmol,ꢀ70%),ꢀmpꢀ=ꢀ60-62ꢀ°C. Hꢀ
NMRꢀ (400ꢀ MHz,ꢀ CDCl )ꢀ δ ꢀ 8.62ꢀ (dd,ꢀ Jꢀ =ꢀ 4.3,ꢀ 1.4ꢀ Hz,ꢀ 1H),ꢀ
.44ꢀ(d,ꢀJꢀ=ꢀ8.2ꢀHz,ꢀ2H),ꢀ7.57ꢀ(dd,ꢀJꢀ=ꢀ8.2,ꢀ1.4ꢀHz,ꢀ1H),ꢀ7.33ꢀ
ꢀ
1
13
2H),ꢀ5.61ꢀ(s,ꢀ2H),ꢀ3.86ꢀ(s,ꢀ3H),ꢀ3.77ꢀ(s,ꢀ3H).ꢀ CꢀNMRꢀ(101ꢀ
3
H
MHz,ꢀ CDCl
3
)ꢀ δ ꢀ 159.4,ꢀ 157.8,ꢀ 145.4,ꢀ 142.6,ꢀ 141.0,ꢀ 133.0,ꢀ
C
8
132.0,ꢀ 130.0,ꢀ 128.9,ꢀ 128.5,ꢀ 120.9,ꢀ 120.9,ꢀ 120.5,ꢀ 117.4,ꢀ
(d,ꢀJꢀ=ꢀ7.9ꢀHz,ꢀ2H),ꢀ7.21ꢀ–ꢀ7.16ꢀ(m,ꢀ3H),ꢀ6.83ꢀ(d,ꢀJꢀ=ꢀ8.2ꢀHz,ꢀ
114.2,ꢀ112.0,ꢀ56.2,ꢀ55.4,ꢀ53.5;ꢀHRMSꢀcalcdꢀforꢀC21
H
20
N
3
2
O ꢀ
13
+
2
H),ꢀ5.55ꢀ(s,ꢀ2H),ꢀ3.75ꢀ(s,ꢀ3H),ꢀ2.42ꢀ(s,ꢀ3H).ꢀ CꢀNMRꢀ(101ꢀ
([M+H] ):ꢀ346.1549;ꢀFound:ꢀ346.1550.ꢀIRꢀ(neat)ꢀν˜=ꢀ3055,ꢀ
-1
MHz,ꢀ CDCl )ꢀ δ
3 C
ꢀ 159.4,ꢀ 145.2,ꢀ 143.1,ꢀ 140.1,ꢀ 138.0,ꢀ 133.6,ꢀ
2962,ꢀ1610,ꢀ1490ꢀcm .ꢀꢀꢀ
1
5
29.6,ꢀ129.4,ꢀ128.7,ꢀ128.4,ꢀ127.1,ꢀ120.4,ꢀ117.4,ꢀ114.2,ꢀ55.3,ꢀ
+
1-(4-Methoxybenzyl)-3-(4-chlorophenyl)-1H-
3.3,ꢀ 21.5;ꢀ HRMSꢀ forꢀ C21
H
20
N Oꢀ ([M+H] ):ꢀ 330.1601;ꢀ
3
-1
pyrazolo[4,3-b]pyridineꢀ4g:ꢀꢀ
Found:ꢀ330.1600.ꢀIRꢀ(neat)ꢀν˜=ꢀ3030,ꢀ1605,ꢀ1340ꢀcm .ꢀꢀꢀ
Whiteꢀsolidꢀ(124ꢀmg,ꢀ0.35ꢀmmol,ꢀ87%),ꢀmpꢀ=ꢀ104-106ꢀ°C.ꢀ
1-(4-Methoxybenzyl)-3-(4-(trifluoromethyl)phenyl)-
1HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
3
)ꢀδ ꢀ8.59ꢀ(dd,ꢀJꢀ=ꢀ4.3,ꢀ1.4ꢀHz,ꢀ1H),ꢀ
H
1H-pyrazolo[4,3-b]pyridineꢀ4c:ꢀꢀ
8
.49ꢀ(d,ꢀJꢀ=ꢀ8.5ꢀHz,ꢀ2H),ꢀ7.57ꢀ(d,ꢀJꢀ=ꢀ8.5ꢀHz,ꢀ1H),ꢀ7.45ꢀ(d,ꢀJꢀ=ꢀ
8.5ꢀHz,ꢀ2H),ꢀ7.17ꢀ(m,ꢀ3H),ꢀ6.81ꢀ(d,ꢀJꢀ=ꢀ8.5ꢀHz,ꢀ2H),ꢀ5.52ꢀ(s,ꢀ
2H),ꢀ 3.73ꢀ (s,ꢀ 3H).ꢀ 13Cꢀ NMRꢀ (101ꢀ MHz,ꢀ CDCl
)ꢀ δ ꢀ 159.5,ꢀ
Whiteꢀ solidꢀ (117ꢀ mg,ꢀ 0.30ꢀ mmol,ꢀ 75%),ꢀ mpꢀ =ꢀ 100-102ꢀ
1
°C. HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
3
)ꢀδ
H
ꢀ8.72ꢀ–ꢀ8.61ꢀ(m,ꢀ3H),ꢀ7.74ꢀ
3
C
(d,ꢀJꢀ=ꢀ7.8ꢀHz,ꢀ2H),ꢀ7.63ꢀ(d,ꢀJꢀ=ꢀ8.5ꢀHz,ꢀ1H),ꢀ7.27ꢀ–ꢀ7.17ꢀ(m,ꢀ
145.5,ꢀ 141.8,ꢀ 139.9,ꢀ 133.8,ꢀ 133.7,ꢀ 131.0,ꢀ 128.8,ꢀ 128.7,ꢀ
1
3
3H),ꢀ6.84ꢀ(d,ꢀJꢀ=ꢀ7.8ꢀHz,ꢀ2H),ꢀ5.58ꢀ(s,ꢀ2H),ꢀ3.76ꢀ(s,ꢀ3H).ꢀ Cꢀ
NMRꢀ (101ꢀ MHz,ꢀ CDCl3)ꢀ δCꢀ 159.5,ꢀ 145.7,ꢀ 141.4,ꢀ 140.1,ꢀ
128.4,ꢀ 128.1,ꢀ 120.6,ꢀ 117.5,ꢀ 114.3,ꢀ 55.3,ꢀ 53.4;ꢀHRMSꢀcalcdꢀ
+
forꢀC20
H
17ClN Oꢀ([M+H] ):ꢀ350.1051;ꢀFound:ꢀ350.1054.ꢀIRꢀ
3
-1
1
1
1
3
1
35.9,ꢀ 133.7,ꢀ 129.6ꢀ (q,ꢀ Jꢀ =ꢀ 32.3ꢀ Hz),ꢀ 128.7,ꢀ 128.4,ꢀ 127.8,ꢀ
(neat)ꢀν˜=ꢀ3060,ꢀ1501,ꢀ701ꢀcm .ꢀꢀꢀ
27.1,ꢀ125.4ꢀ(q,ꢀJꢀ=ꢀ3.8ꢀHz),ꢀ124.4ꢀ(q,ꢀJꢀ=ꢀ270ꢀHz),ꢀ120.7,ꢀ
+
Ethylꢀ
4-(1-(4-methoxybenzyl)-1H-pyrazolo[4,3-
17.6,ꢀ 55.2,ꢀ 53.5;ꢀ HRMSꢀ calcdꢀ forꢀ C21
H
17
F
3
N
3
Oꢀ ([M+H] ):ꢀ
b]pyridin-3-yl)benzoateꢀ4h:ꢀꢀ
84.1315;ꢀ Found:ꢀ 384.1318.ꢀ IRꢀ (neat)ꢀ ν˜=ꢀ 3030,ꢀ 1500,ꢀ
-1
Whiteꢀsolidꢀ(126ꢀmg,ꢀ0.32ꢀmmol,ꢀ80%),ꢀmpꢀ=ꢀ111-113ꢀ°C.ꢀ
300,ꢀ1330ꢀcm .ꢀ
1HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
Hz,ꢀ2H),ꢀ7.61ꢀ(d,ꢀJꢀ=ꢀ8.3ꢀHz,ꢀ1H),ꢀ7.22ꢀ(m,ꢀ3H),ꢀ6.83ꢀ(d,ꢀJꢀ=ꢀ
.3ꢀHz,ꢀ1H),ꢀ5.57ꢀ(s,ꢀ2H),ꢀ4.41ꢀ(q,ꢀJꢀ=ꢀ7.1ꢀHz,ꢀ2H),ꢀ3.75ꢀ(s,ꢀ
)ꢀδ ꢀ8.65ꢀ(m,ꢀ3H),ꢀ8.17ꢀ(d,ꢀJꢀ=ꢀ8.3ꢀ
3
H
1-(4-Methoxybenzyl)-3-(4-methoxyphenyl)-1H-
pyrazolo[4,3-b]pyridineꢀ4d:ꢀꢀ
8
1
3
Whiteꢀsolidꢀ(91ꢀmg,ꢀ0.263ꢀmmol,ꢀ65%),ꢀmpꢀ=ꢀ113-115ꢀ°C.ꢀ
3H),ꢀ1.42ꢀ(t,ꢀJꢀ=ꢀ7.1ꢀHz,ꢀ3H).ꢀ CꢀNMRꢀ(101ꢀMHz,ꢀCDCl
3
)ꢀδ ꢀ
C
1HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
)ꢀδ
ꢀ8.61ꢀ(dd,ꢀJꢀ=ꢀ4.4,ꢀ1.4ꢀHz,ꢀ1H),ꢀ
166.7,ꢀ 159.5,ꢀ 145.8,ꢀ 141.8,ꢀ 140.3,ꢀ 136.8,ꢀ 133.8,ꢀ 129.9,ꢀ
3
H
8.47ꢀ(d,ꢀJꢀ=ꢀ8.8ꢀHz,ꢀ2H),ꢀ7.58ꢀ(dd,ꢀJꢀ=ꢀ8.8,ꢀ1.4ꢀHz,ꢀ1H),ꢀ7.20ꢀ
(m,ꢀ3H),ꢀ7.05ꢀ(d,ꢀJꢀ=ꢀ8.8ꢀHz,ꢀ2H),ꢀ6.83ꢀ(d,ꢀJꢀ=ꢀ8.8ꢀHz,ꢀ2H),ꢀ
129.7,ꢀ128.8,ꢀ128.0,ꢀ126.8,ꢀ120.7,ꢀ117.7,ꢀ114.3,ꢀ61.0,ꢀ55.3,ꢀ
+
53.6,ꢀ14.4;ꢀHRMSꢀcalcdꢀforꢀC23
H
22
N O
3 3
ꢀ([M+H] ):ꢀ388.1656;ꢀ
1
3
Found:ꢀ388.1655.ꢀIRꢀ(neat)ꢀν˜=ꢀ2975,ꢀ1710,ꢀ1606,ꢀ1161ꢀcm-
1.ꢀꢀꢀ
5.55ꢀ(s,ꢀ2H),ꢀ3.87ꢀ(s,ꢀ3H),ꢀ3.76ꢀ(s,ꢀ3H).ꢀ CꢀNMRꢀ(101ꢀMHz,ꢀ
CDCl )ꢀ δ ꢀ 159.7,ꢀ 159.4,ꢀ 145.1,ꢀ 143.0,ꢀ 140.0,ꢀ 133.7,ꢀ 128.7,ꢀ
28.6,ꢀ128.4,ꢀ125.3,ꢀ120.5,ꢀ117.3,ꢀ114.3,ꢀ114.2,ꢀ55.4,ꢀ55.3,ꢀ
3
C
1
5
+
1-(4-Methoxybenzyl)-3-(4-nitrophenyl)-1H-
3.3;ꢀ HRMSꢀ calcdꢀ forꢀ C21
H
20
N
3
O ꢀ ([M+H] ):ꢀ 346.1546;ꢀ
2
Found:ꢀ346.1550.ꢀIRꢀ(neat)ꢀν˜=ꢀ3000,ꢀ2955,ꢀ1606,ꢀ1250ꢀcm-
pyrazolo[4,3-b]pyridineꢀ4i:ꢀꢀ
1.
ꢀꢀꢀ
1
Yellowꢀoilꢀ(135ꢀmg,ꢀ0.37ꢀmmol,ꢀ91%),ꢀmpꢀ=ꢀ160-162ꢀ°C.ꢀ Hꢀ
NMRꢀ(250ꢀMHz,ꢀCDCl
Jꢀ=ꢀ4.3,ꢀ1.2ꢀHz,ꢀ1H),ꢀ8.33ꢀ(d,ꢀJꢀ=ꢀ9.0ꢀHz,ꢀ2H),ꢀ7.68ꢀ(dd,ꢀJꢀ=ꢀ8.6,ꢀ
.2ꢀHz,ꢀ1H),ꢀ7.34ꢀ–ꢀ7.17ꢀ(m,ꢀ3H),ꢀ6.86ꢀ(d,ꢀJꢀ=ꢀ8.6ꢀHz,ꢀ2H),ꢀ
5.61ꢀ (s,ꢀ 2H),ꢀ 3.77ꢀ (s,ꢀ 3H).ꢀ 13Cꢀ NMRꢀ (101ꢀ MHz,ꢀ CDCl
)ꢀ δ
3
H
)ꢀδ ꢀ8.77ꢀ(d,ꢀJꢀ=ꢀ9.0ꢀHz,ꢀ2H),ꢀ8.68ꢀ(dd,ꢀ
1
-(4-Methoxybenzyl)-3-(3-methoxyphenyl)-1H-
pyrazolo[4,3-b]pyridineꢀ4e:ꢀꢀ
Yellowꢀsolidꢀ(101ꢀmg,ꢀ0.29ꢀmmol,ꢀ72%),ꢀmpꢀ=ꢀ90-92ꢀ°C. Hꢀ
NMRꢀ (400ꢀ MHz,ꢀ CDCl )ꢀ δ ꢀ 8.61ꢀ (dd,ꢀ Jꢀ =ꢀ 4.3,ꢀ 1.4ꢀ Hz,ꢀ 1H),ꢀ
.19ꢀ(d,ꢀJꢀ=ꢀ7.7ꢀHz,ꢀ1H),ꢀ8.14ꢀ(s,ꢀ1H),ꢀ7.57ꢀ(dd,ꢀJꢀ=ꢀ8.7,ꢀ1.4ꢀHz,ꢀ
H),ꢀ7.43ꢀ(t,ꢀJꢀ=ꢀ8.0ꢀHz,ꢀ1H),ꢀ7.18ꢀ(m,ꢀ3H),ꢀ6.95ꢀ(dd,ꢀJꢀ=ꢀ7.7,ꢀ
1
ꢀ
1
3
C
ꢀ
3
H
159.7,ꢀ 147.2,ꢀ 146.3,ꢀ 140.6,ꢀ 140.3,ꢀ 139.0,ꢀ 133.9,ꢀ 128.9,ꢀ
8
1
127.7,ꢀ127.5,ꢀ124.0,ꢀ121.0,ꢀ118.0,ꢀ114.4,ꢀ55.4,ꢀ53.9;ꢀHRMSꢀ
+
calcdꢀforꢀC20
H
17
N
4
O
3
ꢀ([M+H] ):ꢀ361.1295;ꢀFound:ꢀ361.1295.ꢀ
-1
3.0ꢀHz,ꢀ1H),ꢀ6.82ꢀ(d,ꢀJꢀ=ꢀ8.7ꢀHz,ꢀ2H),ꢀ5.54ꢀ(s,ꢀ2H),ꢀ3.92ꢀ(s,ꢀ
3H),ꢀ 3.74ꢀ (s,ꢀ 3H).ꢀ 13Cꢀ NMRꢀ (101ꢀ MHz,ꢀ CDCl
)ꢀ δ ꢀ 159.9,ꢀ
ACS Paragon Plus Environment
IRꢀ(neat)ꢀν˜=ꢀ3050,ꢀ1573,ꢀ1540,ꢀ1320ꢀcm .ꢀꢀꢀ
3
C

Page 9 of 11
The Journal of Organic Chemistry
-(1-(4-Methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-
Found:ꢀ210.1025.ꢀIRꢀ(neat)ꢀν˜=ꢀ3057,ꢀ2919,ꢀ1603,ꢀ1395ꢀcm-
4
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1.ꢀ
yl)benzonitrileꢀ4j:ꢀꢀ
Whiteꢀsolidꢀ(118ꢀmg,ꢀ0.34ꢀmmol,ꢀ85%),ꢀmpꢀ=ꢀ178-180ꢀ°C.ꢀ
1HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
Hz,ꢀ2H),ꢀ7.64ꢀ(dd,ꢀJꢀ=ꢀ8.8,ꢀ1.2ꢀHz,ꢀ1H),ꢀ7.25ꢀ(m,ꢀ3H),ꢀ6.85ꢀ(d,ꢀ
3-(4-Chlorophenyl)-1H-pyrazolo[4,3-b]pyridineꢀ5c:ꢀꢀ
3
)ꢀδ ꢀ8.65ꢀ(m,ꢀ3H),ꢀ7.95ꢀ(d,ꢀJꢀ=ꢀ8.8ꢀ
H
Yellowꢀsolidꢀ(147ꢀmg,ꢀ0.39ꢀmmol,ꢀ76%),ꢀmpꢀ=ꢀ230-232ꢀ°C.ꢀꢀ
1HꢀNMRꢀ(400ꢀMHz,ꢀDMSO)ꢀδ
.3,ꢀ1.4ꢀHz,ꢀ1H),ꢀ8.55ꢀ(d,ꢀJꢀ=ꢀ8.7ꢀHz,ꢀ2H),ꢀ8.07ꢀ(dd,ꢀJꢀ=ꢀ8.7,ꢀ1.4ꢀ
Hz,ꢀ1H),ꢀ7.58ꢀ(d,ꢀJꢀ=ꢀ8.7ꢀHz,ꢀ2H),ꢀ7.44ꢀ(dd,ꢀJꢀ=ꢀ8.7,ꢀ4.3ꢀHz,ꢀ
1H).ꢀ 13Cꢀ NMRꢀ (101ꢀ MHz,ꢀ DMSO)ꢀ δ
ꢀ 145.6,ꢀ 140.6,ꢀ 138.1,ꢀ
34.0,ꢀ132.4,ꢀ131.5,ꢀ128.6,ꢀ127.8,ꢀ121.0,ꢀ118.9;ꢀHRMSꢀcalcdꢀ
ꢀ13.52ꢀ(s,ꢀ1H),ꢀ8.63ꢀ(dd,ꢀJꢀ=ꢀ
1
3
H
Jꢀ =ꢀ 8.8ꢀ Hz,ꢀ 2H),ꢀ 5.59ꢀ (s,ꢀ 2H),ꢀ 3.76ꢀ (s,ꢀ 3H).ꢀ Cꢀ NMRꢀ (101ꢀ
MHz,ꢀ CDCl )ꢀ δ ꢀ 169.4,ꢀ 159.6,ꢀ 145.8,ꢀ 141.8,ꢀ 140.3,ꢀ 136.1,ꢀ
4
3
C
133.8,ꢀ 132.5,ꢀ 128.8,ꢀ 128.0,ꢀ 127.8,ꢀ 127.2,ꢀ 120.8,ꢀ 117.7,ꢀ
+
C
114.4,ꢀ 55.4,ꢀ 53.6;ꢀ HRMSꢀ calcdꢀ forꢀ C21
H
17
N
4
Oꢀ ([M+H] ):ꢀ
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
341.1503;ꢀ Found:ꢀ 341.1502.ꢀ IRꢀ (neat)ꢀ ν˜=ꢀ 3350,ꢀ 3180,ꢀ
+
218,ꢀ1605ꢀcm-1ꢀ
forꢀ C12
H
9
ClN ꢀ ([M+H] ):ꢀ 230.0479;ꢀ Found:ꢀ 230.0479.ꢀ IRꢀ
3
2
-1
(neat)ꢀν˜=ꢀ3067,ꢀ2919,ꢀ1603,ꢀ1395,ꢀ706ꢀcm .ꢀ
1-(4-Methoxybenzyl)-3-(pyridin-4-yl)-1H-
pyrazolo[4,3-b]pyridineꢀ4k:ꢀꢀ
Ethylꢀ4-(1H-pyrazolo[4,3-b]pyridin-3-yl)benzoateꢀ5d:ꢀꢀ
Whiteꢀsolidꢀ(167ꢀmg,ꢀ0.40ꢀmmol,ꢀ75%),ꢀmpꢀ=ꢀ184-186ꢀ°C.ꢀ
Yellowꢀsolidꢀ(64ꢀmg,ꢀ0.20ꢀmmol,ꢀ50%),ꢀmpꢀ=ꢀ123-125ꢀ°C.ꢀ
1HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
1HꢀNMRꢀ(250ꢀMHz,ꢀCDCl3)ꢀδ
ꢀ10.55ꢀ(s,ꢀ1H),ꢀ8.73ꢀ(dd,ꢀJꢀ=ꢀ
.3,ꢀ1.1ꢀHz,ꢀ1H),ꢀ8.64ꢀ(d,ꢀJꢀ=ꢀ8.5ꢀHz,ꢀ1H),ꢀ8.19ꢀ(d,ꢀJꢀ=ꢀ8.5ꢀHz,ꢀ
H
3
)ꢀδ ꢀ8.77ꢀ(dd,ꢀJꢀ=ꢀ4.5,ꢀ1.6ꢀHz,ꢀ2H),ꢀ
H
4
2
4
8
7
7
3
1
.64ꢀ(dd,ꢀJꢀ=ꢀ4.5,ꢀ1.4ꢀHz,ꢀ1H),ꢀ8.12ꢀ(dd,ꢀJꢀ=ꢀ8.8,ꢀ1.6ꢀHz,ꢀ1H),ꢀ
H),ꢀ7.84ꢀ(d,ꢀJꢀ=ꢀ8.5ꢀHz,ꢀ1H),ꢀ7.36ꢀ(dd,ꢀJꢀ=ꢀ8.5,ꢀ4.3ꢀHz,ꢀ1H),ꢀ
.42ꢀ(q,ꢀJꢀ=ꢀ7.1ꢀHz,ꢀ2H),ꢀ1.43ꢀ(t,ꢀJꢀ=ꢀ7.1ꢀHz,ꢀ3H).ꢀ 13CꢀNMRꢀ
.59ꢀ(dd,ꢀJꢀ=ꢀ4.5,ꢀ1.6ꢀHz,ꢀ2H),ꢀ7.30ꢀ(dd,ꢀJꢀ=ꢀ8.8,ꢀ4.1ꢀHz,ꢀ1H),ꢀ
.06ꢀ(d,ꢀJꢀ=ꢀ8.8ꢀHz,ꢀ2H),ꢀ6.83ꢀ(d,ꢀJꢀ=ꢀ8.8ꢀHz,ꢀ2H),ꢀ5.70ꢀ(s,ꢀ2H),ꢀ
.77ꢀ (s,ꢀ 3H).ꢀ 13Cꢀ NMRꢀ (101ꢀ MHz,ꢀ CDCl
(101ꢀ MHz,ꢀ MeOD)ꢀ δ
C
ꢀ 167.9,ꢀ 147.0,ꢀ 143.3,ꢀ 139.7,ꢀ 138.4,ꢀ
3
)ꢀ δ ꢀ 159.6,ꢀ 150.6,ꢀ
C
135.9,ꢀ130.8,ꢀ130.6,ꢀ127.9,ꢀ122.4,ꢀ120.1,ꢀ62.1,ꢀ14.6;ꢀHRMSꢀ
49.2,ꢀ 141.5,ꢀ 137.6,ꢀ 136.2,ꢀ 133.5,ꢀ 128.4,ꢀ 127.9,ꢀ 126.1,ꢀ
+
calcdꢀforꢀC15
H
14
N
3
O ꢀ([M+H] ):ꢀ268.1081;ꢀFound:ꢀ268.1080.ꢀ
2
124.0,ꢀ122.0,ꢀ114.4,ꢀ55.4,ꢀ55.3;ꢀHRMSꢀcalcdꢀforꢀC19
H
17
4
N Oꢀ
IRꢀ(neat)ꢀν˜=ꢀ3369,ꢀ3031,ꢀ1710,ꢀ1603,ꢀ1161ꢀcm-1.ꢀ
+
([M+H] ):ꢀ317.1394;ꢀFound:ꢀ317.1396.ꢀIRꢀ(neat)ꢀν˜=ꢀ3369,ꢀ
-
1
2850,ꢀ1395,ꢀ1270ꢀcm .ꢀꢀꢀ
3
-(Pyrazin-2-yl)-1H-pyrazolo[4,3-b]pyridineꢀ5e:ꢀꢀ
Whiteꢀsolidꢀ(87ꢀmg,ꢀ0.38ꢀmmol,ꢀ53%),ꢀmpꢀ=ꢀ180-182ꢀ°C. Hꢀ
NMRꢀ(400ꢀMHz,ꢀMeOD)ꢀδ ꢀ9.76ꢀ(d,ꢀJꢀ=ꢀ1.3ꢀHz,ꢀ1H),ꢀ8.75ꢀ(dd,ꢀ
ꢀ
1
1-(4-Methoxybenzyl)-3-(pyrazin-2-yl)-1H-
pyrazolo[4,3-b]pyridineꢀ4l:ꢀꢀ
H
Jꢀ=ꢀ2.3,ꢀ1.3ꢀHz,ꢀ1H),ꢀ8.69ꢀ(d,ꢀJꢀ=ꢀ3.6ꢀHz,ꢀ1H),ꢀ8.60ꢀ(d,ꢀJꢀ=ꢀ2.3ꢀ
Hz,ꢀ1H),ꢀ8.10ꢀ(dd,ꢀJꢀ=ꢀ8.6,ꢀ1.3ꢀHz,ꢀ1H),ꢀ7.48ꢀ(dd,ꢀJꢀ=ꢀ8.6,ꢀ4.4ꢀ
Hz,ꢀ1H).ꢀ CꢀNMRꢀ(101ꢀMHz,ꢀMeOD)ꢀδ ꢀ147.5,ꢀ146.5,ꢀ144.3,ꢀ
143.4,ꢀ143.1,ꢀ121.3,ꢀ121.0,ꢀ118.1,ꢀ115.2,ꢀ112.3;ꢀHRMSꢀcalcdꢀ
ꢀ1
Yellowꢀsolidꢀ(77ꢀmg,ꢀ0.24ꢀmmol,ꢀ60%),ꢀmpꢀ=ꢀ80-82ꢀ°C. Hꢀ
NMRꢀ(400ꢀMHz,ꢀCDCl )ꢀ9.93ꢀ(d,ꢀJꢀ=ꢀ1.1ꢀHz,ꢀ1H),ꢀ8.78ꢀ(s,ꢀ1H),ꢀ
.73ꢀ(d,ꢀJꢀ=ꢀ2,4Hz,ꢀ1H),ꢀ8.58ꢀ(d,ꢀJꢀ=ꢀ2.4ꢀHz,ꢀ1H),ꢀ7.67ꢀ(dd,ꢀJꢀ=ꢀ
.4,ꢀ1.1ꢀHz,ꢀ1H),ꢀ7.28ꢀ(dd,ꢀJꢀ=ꢀ8.4,ꢀ3.1ꢀHz,ꢀ1H),ꢀ7.24ꢀ(d,ꢀJꢀ=ꢀ8.8ꢀ
3
13
C
8
8
+
forꢀ C10
H
8
N ꢀ ([M+H] ):ꢀ 198.0774;ꢀ Found:ꢀ 198.0774.ꢀ IRꢀ
5
-1
(neat)ꢀν˜=ꢀ3057,ꢀ2850,ꢀ1600,ꢀ1390,ꢀ1187ꢀcm .ꢀ
Hz,ꢀ2H),ꢀ6.85ꢀ(d,ꢀJꢀ=ꢀ8.8ꢀHz,ꢀ2H),ꢀ5.68ꢀ(s,ꢀ2H),ꢀ3.76ꢀ(s,ꢀ3H).ꢀ
13Cꢀ NMRꢀ (101ꢀ MHz,ꢀ CDCl
ꢀ
3
)ꢀ δ
C
159.6,ꢀ 147.5,ꢀ 146.8,ꢀ 144.6,ꢀ
SupportingꢀInformationꢀ
144.6,ꢀ 143.4,ꢀ 140.2,ꢀ 140.1,ꢀ 133.7,ꢀ 128.9,ꢀ 127.6,ꢀ 121.0,ꢀ
118.1,ꢀ 114.3,ꢀ 55.3,ꢀ 54.1;ꢀ HRMSꢀ calcdꢀ forꢀ C18
H
16
5
N Oꢀ
TheꢀSupportingꢀInformationꢀisꢀavailableꢀfreeꢀofꢀchargeꢀonꢀtheꢀ
ACSꢀ Publicationsꢀ websiteꢀ atꢀ DOI:ꢀ
10.1021/acs.orglett.5b02136.ꢀ
CharacterizationꢀdataꢀforꢀallꢀnewꢀCompoundsꢀ(PDF).ꢀ
CorrespondingꢀAuthorꢀ
+
(
[M+H] ):ꢀ318.1346;ꢀFound:ꢀ318.1349.ꢀIRꢀ(neat)ꢀν˜=ꢀ3050,ꢀ
-1
2920,ꢀ1603,ꢀ1392,ꢀ1183ꢀcm .ꢀꢀꢀ
3-Phenyl-1H-pyrazolo[4,3-b]pyridineꢀ5a:ꢀ
Whiteꢀsolidꢀ(116ꢀmg,ꢀ0.32ꢀmmol,ꢀ71%),ꢀmpꢀ=ꢀ168-169°C.ꢀ
1HꢀNMRꢀ(400ꢀMHz,ꢀMeOD)ꢀδHꢀ8.62ꢀ(dd,ꢀJꢀ=ꢀ4.4,ꢀ1.3ꢀHz,ꢀ1H),ꢀ
*E-mail:ꢀs.elkazzouli@ueuromed.org.ꢀ
*E-mail:ꢀgerald.guillaumet@univ-orleans.fr.ꢀ
8.39ꢀ(d,ꢀJꢀ=ꢀ7.5ꢀHz,ꢀ2H),ꢀ8.03ꢀ(dd,ꢀJꢀ=ꢀ8.5,ꢀ1.3ꢀHz,ꢀ1H),ꢀ7.52ꢀ(t,ꢀ
*E-mail:ꢀfranck.suzenet@univ-orleans.fr.ꢀ
1
3
Jꢀ=ꢀ7.5ꢀHz,ꢀ2H),ꢀ7.47ꢀ–ꢀ7.36ꢀ(m,ꢀ2H).ꢀ CꢀNMRꢀ(101ꢀMHz,ꢀ
MeOD)ꢀ δ
C
ꢀ146.6,ꢀ 144.8,ꢀ 139.4,ꢀ 135.9,ꢀ 133.7,ꢀ 129.5,ꢀ129.3,ꢀ
ACKNOWLEDGMENT
+
128.4,ꢀ 122.3,ꢀ 120.0;ꢀ HRMSꢀ calcdꢀ forꢀ C12
H
10
N
3
ꢀ ([M+H] ):ꢀ
ThisꢀworkꢀwasꢀpartiallyꢀsupportedꢀbyꢀtheꢀLabexꢀSynOrgꢀ(ANR-
11-LABX-0029),ꢀ Labexꢀ IRONꢀ (ANR-11-LABX-0018-01)ꢀ Uni-
versityꢀofꢀOrleans,ꢀEuromedꢀUniversityꢀofꢀFes,ꢀandꢀtheꢀregionꢀ
Centre-ValꢀdeꢀLoire.ꢀꢀꢀ
196.0869;ꢀ Found:ꢀ 196.0870.ꢀ IRꢀ (neat)ꢀ ν˜=ꢀ 3209,ꢀ 3146,ꢀ
055,ꢀ1600,ꢀ1292ꢀcm-1.ꢀ
3
3-p-Tolyl-1H-pyrazolo[4,3-b]pyridineꢀ5b:ꢀꢀ
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