An efficient synthesis of 1-arylindazole-3-carboxamides using nitrile imines, isocyanides and 2-hydroxymethylbenzoic acid, followed by a chemoselective Buchwald-Hartwig intramolecular cyclization

Article abstract of DOI:10.1039/c6ra01442a

A convergent and efficient two-step synthesis of pharmaceutically relevant 1-arylindazole-3-carboxamides is reported. These molecules have been obtained in good to excellent yields (up to 98%) starting from a strategic reaction between isocyanides, 2-iodo

Full text of DOI:10.1039/c6ra01442a

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ꢀ
RSCꢀAdvancesꢀ
ꢀ
ARTICLEꢀ
Anꢀefficientꢀsynthesisꢀofꢀ1-arylindazole-3-carboxamidesꢀusingꢀ
nitrileꢀimines,ꢀisocyanidesꢀandꢀ2-hydroxymethylbenzoicꢀacid,ꢀ
followedꢀbyꢀaꢀchemoselectiveꢀBuchwald-Hartwigꢀintramolecularꢀ
cyclization.ꢀ
Receivedꢀ00thꢀJanuaryꢀ20xx,ꢀ
Acceptedꢀ00thꢀJanuaryꢀ20xxꢀ
DOI:ꢀ10.1039/x0xx00000xꢀ
a
b
a
b
M.ꢀGiustiniano, *ꢀV.ꢀMercalli, ꢀE.ꢀNovellino, ꢀandꢀG.ꢀC.ꢀTron *ꢀ
www.rsc.org/ꢀ
Aꢀ convergentꢀ andꢀ efficientꢀ two-stepꢀ synthesisꢀ ofꢀ pharmaceuticallyꢀ relevantꢀ 1-arylindazole-3-carboxamidesꢀ isꢀ reported.ꢀ
Theseꢀmoleculesꢀhaveꢀbeenꢀobtainedꢀinꢀgoodꢀtoꢀexcellentꢀyieldsꢀ(upꢀtoꢀ98ꢀ%)ꢀstartingꢀfromꢀaꢀstrategicꢀreactionꢀbetweenꢀ
isocyanides,ꢀ 2-iodo-N-arylbenzohydrazonoylꢀ chloridesꢀ andꢀ 2-hydroxymethylbenzoicꢀ acidꢀ followedꢀ byꢀ aꢀ chemoselectiveꢀ
Buchwald-Hartwigꢀintramolecularꢀcyclization.ꢀThisꢀnovelꢀstrategyꢀprovidesꢀanꢀadditionalꢀindazoleꢀsynthesisꢀtoꢀthoseꢀalreadyꢀ
reportedꢀ inꢀ literatureꢀ bothꢀ inꢀ theꢀ typeꢀ ofꢀ substrateꢀ asꢀ wellꢀ asꢀ theꢀ substitutionꢀ patternꢀ obtainableꢀ inꢀ theꢀ products.ꢀ
Furthermoreꢀbenzylisocyanideꢀisꢀhereinꢀreportedꢀforꢀtheꢀfirstꢀtimeꢀasꢀaꢀconvertibleꢀisocyanideꢀprovidingꢀanꢀexpeditiousꢀ
accessꢀ
toꢀ
N-arylindazole-3-carbonitriles.ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ
Introductionꢀ
Severalꢀ naturallyꢀ occurringꢀ alkaloidsꢀ andꢀ manyꢀ bioactiveꢀ
syntheticꢀcompoundsꢀshareꢀasꢀaꢀcommonꢀelementꢀtheꢀindazoleꢀ
nucleus. ꢀAccordingꢀtoꢀtheirꢀpatternꢀofꢀsubstitution,ꢀmoleculesꢀ
1
containingꢀtheꢀindazoleꢀringꢀhaveꢀshownꢀtoꢀpossessꢀdifferentꢀ
biologicalꢀ profilesꢀ spanningꢀ fromꢀ anti-cancerꢀ compoundsꢀ toꢀ
serotoninꢀ 5-HT3ꢀ receptorꢀ antagonists. ꢀ Inꢀ particular,ꢀ
2
substitutedꢀ indazole-3-carboxamidesꢀ haveꢀ beenꢀ disclosedꢀ asꢀ
inhibitorsꢀ ofꢀ humanꢀ neutrophilꢀ elastase, ꢀ DNAꢀ intercalatingꢀ
3
4
agents, ꢀkinaseꢀinhibitors, ꢀselectiveꢀsodiumꢀchannelꢀblockers, ꢀ
5
6
7
DGATꢀinhibitors, ꢀandꢀNAMPTꢀinhibitors. ꢀ(Figureꢀ1)ꢀ
8
Dueꢀ toꢀ theꢀ pharmaceuticalꢀ relevanceꢀ ofꢀ indazolesꢀ severalꢀ
methodsꢀ ofꢀ preparationsꢀ haveꢀ beenꢀ reportedꢀ inꢀ literatureꢀ
whichꢀ dependꢀ onꢀ theꢀ patternꢀ ofꢀ substitutionꢀ ofꢀ theꢀ indazoleꢀ
ꢀ
9
Figureꢀ 1ꢀ Pharmaceuticallyꢀ relevantꢀ N-arylindazoles-3-
carboxamides.ꢀ(Numbersꢀcorrespondꢀtoꢀthoseꢀreportedꢀinꢀtheꢀ
patents)ꢀ
ring. ꢀ Inꢀ particularꢀ 1-arylindazole-3-carboxamidesꢀ 3ꢀ areꢀ
preparedꢀ startingꢀ fromꢀ theꢀ correspondingꢀ 1H-indazole-
carboxylicꢀ acidsꢀ 1ꢀ whichꢀ areꢀ coupledꢀ withꢀ aminesꢀ andꢀ thenꢀ
subjectedꢀtoꢀaꢀPdꢀorꢀCuꢀN-arylation.ꢀOneꢀdisadvantageꢀofꢀthisꢀ
syntheticꢀ planꢀ isꢀ thatꢀ arylꢀ substitutedꢀ 1H-indazole-carboxylicꢀ
acidsꢀ requireꢀ aꢀ multistepꢀ synthesisꢀ withꢀ poorꢀ overallꢀ
R2
R
2
O
HO OH
B
O
O
OH
SOCl
R NH
NH
NH
R
1
10
R
1
R
1
2
efficiency. ꢀ(Schemeꢀ1)ꢀ
R3
N
2
2
N
N
N
TEA, Cu(OAc)2
DCM
N
N
H
1
H
2
3
i) NaOH, H
ii) NaNO , H
0°C, 15 minutes;
2
O, 50°C;
SO , H O
4
2
a.
2
2
R
3
DipartimentoꢀdiꢀFarmacia,ꢀUniversitàꢀdegliꢀStudiꢀdiꢀNapoliꢀ“FedericoꢀII”,ꢀviaꢀD.ꢀ
b. Montesanoꢀ49,ꢀ80131ꢀNapoli,ꢀItaly.ꢀ
iii) SnCl
2
, HCl, 0°C, 1h.
DipartimentoꢀdiꢀScienzeꢀdelꢀFarmaco,ꢀUniversitàꢀdegliꢀStudiꢀdelꢀPiemonteꢀ
Orientaleꢀ“A.ꢀAvogadro”,ꢀLargoꢀDoneganiꢀ2,ꢀ28100ꢀNovara,ꢀItaly.ꢀ
O
ꢀ
ꢀ
O
N
H
†
ꢀFootnotesꢀrelatingꢀtoꢀtheꢀtitleꢀand/orꢀauthorsꢀshouldꢀappearꢀhere.ꢀꢀ
1
a
ꢀ
Electronicꢀ Supplementaryꢀ Informationꢀ (ESI)ꢀ available:ꢀ [detailsꢀ ofꢀ anyꢀ
supplementaryꢀ informationꢀ availableꢀ shouldꢀ beꢀ includedꢀ here].ꢀ Seeꢀ
DOI:ꢀ10.1039/x0xx00000xꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
J.ꢀName.,ꢀ2013,ꢀ00,ꢀ1-3ꢀ|ꢀ1ꢀꢀ
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ARTICLEꢀ
JournalꢀNameꢀ
Schemeꢀ 1ꢀ Conventionalꢀ synthesisꢀ ofꢀ N-arylindazoles-3- weꢀwereꢀableꢀtoꢀobtainꢀindazoleꢀ12ꢀinꢀ97%ꢀyields,ꢀwVhieiwchAꢀrtmicleeaOnnsliꢀnaeꢀ
carboxamides.ꢀꢀ
highlyꢀ regioselectiveꢀ formationꢀ ofꢀ inda Dz oO l Ie: ꢀ10 d. 1 e0 r3i v9 a/ Ct i6v Re As 0ꢀ 1 4o 4v 2e Ar ꢀ
indoloneꢀone,ꢀwhenꢀintermediateꢀ11ꢀwasꢀrefluxedꢀinꢀ1,4-dioxanꢀinꢀ
theꢀpresenceꢀofꢀtri-o-tolylphosphineꢀ(0.1ꢀequiv.),ꢀcesiumꢀcarbonateꢀ
(1ꢀequiv.)ꢀandꢀbis(triphenylphosphine)ꢀpalladium(II)ꢀdichlorideꢀ(0.07ꢀ
equiv.).ꢀ
ꢀ
Forꢀ thisꢀ reasonꢀ anꢀ efficientꢀ syntheticꢀ strategyꢀ basedꢀ onꢀ theꢀ
preparationꢀ ofꢀ substitutedꢀ indazolesꢀ withoutꢀ usingꢀ 1H-indazole-
carboxylicꢀacidsꢀisꢀwelcomed.ꢀꢀ
14
Despiteꢀ theꢀ reportedꢀ examplesꢀ ofꢀ bothꢀ intermolecular ꢀ andꢀ
9b
intramolecular ꢀ hydrazoneꢀ N-arylationꢀ (Schemeꢀ 4),ꢀ toꢀ ourꢀ
knowledgeꢀ thisꢀ isꢀ theꢀ firstꢀ exampleꢀ ofꢀ aꢀ regioselectiveꢀ hydrazoneꢀ
palladiumꢀcatalyzedꢀcyclizationꢀinꢀtheꢀpresenceꢀofꢀanꢀamideꢀbond.ꢀ
ꢀ
Recently,ꢀinꢀourꢀon-goingꢀstudiesꢀaimedꢀatꢀtheꢀdiscoveryꢀofꢀnovelꢀ
multicomponentꢀ reactions,ꢀ weꢀ reportedꢀ theꢀ useꢀ ofꢀ hydrazonoylꢀ
chloridesꢀ asꢀ imineꢀ aza-analogueꢀ inꢀ isocyanide-mediatedꢀ
multicomponentꢀ reactions. ꢀ Continuingꢀ ourꢀ interestꢀ inꢀ thisꢀ
chemistry,ꢀ weꢀ recognizedꢀ thatꢀ α-aminocarbonylꢀ hydrazonesꢀ 7,ꢀ
obtainableꢀusingꢀtheꢀsyntheticꢀapproachꢀdevelopedꢀbyꢀus,ꢀ ꢀthanksꢀ
toꢀ theirꢀ atomꢀ connectivityꢀ andꢀ theꢀ presenceꢀ ofꢀ theꢀ hydrazoneꢀ
functionalꢀ groupꢀ canꢀ beꢀ exploitedꢀ inꢀ aꢀ post-condensationꢀ
modificationꢀ usingꢀ aꢀ Buchwald-Hartwingꢀ intramolecularꢀ aminationꢀ
toꢀ generateꢀ theꢀ substitutedꢀ indazoleꢀ ringꢀ 8ꢀ inꢀ twoꢀ operationallyꢀ
simpleꢀreactionꢀsteps.ꢀ(Schemeꢀ2)ꢀ
ꢀ
NC
Ph
11
Ph
NH
N
NH
N
11a
TEA, DCM,
rt, 20h
Cl
0 O
1
O
I
OH
OH
HN
9
I
11, 65%
6
i) EDC, DMAP,
TEA, THF, rt, 20h;
ii) PPh , CCl ,
Pd(OAc) , Xantphos,
2
Cs CO , toluene,
2
3
3
4
reflux, overnight
ꢀ
MeCN, rt, 20h.
R
2
O
H
N
Ph
NH
NH
N
I
O
R
2
N
R
1
O
H
N
NH
+
Cl
O
intramolecular
hydrazone
N
N
I
OH
H
R
1
R3
R
1
H
N
N
O
N
N-arylation
+ H2N
R3
N
I
Ph
N
4
Ph
9
b
13
N
9a
O
Ph
12
R
3
OH
OH
12.5%
R
2
CN
66%
ꢀ
8
7
5
Schemeꢀ 3ꢀ 3-CRꢀ affordingꢀ α-aminocarbonylꢀ hydrazonesꢀ andꢀ testꢀ
reactionꢀforꢀtheꢀformationꢀofꢀindazoleꢀderivatives.ꢀꢀ
6
ꢀ
Schemeꢀ 2ꢀ Generalꢀ structureꢀ ofꢀ α-aminocarbonylꢀ hydrazonesꢀ andꢀ
ꢀ
cyclicꢀindazoleꢀderivatives.ꢀ
ꢀ
Intermolecular hydrazone N-arylation
Resultsꢀandꢀdiscussionꢀꢀ
ꢀ
Pd(OAc)2, BINAP, NaOtBu
NH2
Inꢀ orderꢀ toꢀ testꢀ ourꢀ hypothesis,ꢀ weꢀ reactedꢀ 2-iodo-N'-
phenylbenzohydrazonoylꢀchlorideꢀ9,ꢀcyclohexylisocyanideꢀ10ꢀandꢀ2-
hydroxymethylbenzoicꢀ acidꢀ (sacrificialꢀ acid)ꢀ 6ꢀ inꢀ DCMꢀ atꢀ roomꢀ
temperatureꢀovernightꢀtoꢀobtainꢀα-aminocarbonylꢀhydrazoneꢀ11ꢀinꢀ
toluene, 80°C, 12h
N
NH
Ph
+
N
8
2%
Ph
Ph
Br
Ph
6
5%.ꢀ Theꢀ reactionꢀ isꢀ triggeredꢀ byꢀ theꢀ inꢀ situꢀ generationꢀ ofꢀ nitrileꢀ
Intramolecular hydrazone N-arylation
imineꢀ byꢀ aꢀ base-inducedꢀ dehydrochlorinationꢀ ofꢀ hydrazonoylꢀ
chloride.ꢀ Theꢀ 2-hydroxymethylbenzoicꢀ acidꢀ behavesꢀ likeꢀ aꢀ pseudoꢀ
waterꢀmoleculeꢀinꢀorderꢀtoꢀoverpassꢀtheꢀpoorꢀreactivityꢀofꢀwaterꢀonꢀ
N
H
N
Pd(dba) , DPEphos, K PO
2
3
4
N
12
N
toluene, 110°C, 12h
R1
R2
theꢀnitriliumꢀion. ꢀSubsequently,ꢀthisꢀlinearꢀintermediateꢀwasꢀthenꢀ
reactedꢀ inꢀ classicꢀ Buchwald-Hartwingꢀ conditionsꢀ toꢀ evaluateꢀ
indazoleꢀ12ꢀformation.ꢀ(Schemeꢀ3)ꢀItꢀisꢀimportantꢀtoꢀhighlightꢀthatꢀaꢀ
prioriꢀbothꢀtheꢀhydrazoneꢀandꢀtheꢀamideꢀfunctionꢀcouldꢀcyclizeꢀtoꢀ
R1
R2
2
0-98%
4 examples
13
2
giveꢀeitherꢀtheꢀindazoleꢀorꢀtheꢀindoloneꢀderivatives, ꢀbothꢀbeingꢀatꢀ
aꢀ suitableꢀ distanceꢀ (5ꢀ centers)ꢀ fromꢀ theꢀ aromaticꢀ iodineꢀ atomꢀ ofꢀ
ꢀ
Schemeꢀ 4ꢀ Examplesꢀ ofꢀ inter-ꢀ andꢀ intra-molecularꢀ hydrazineꢀ N-
intermediateꢀ 11.ꢀ Refluxingꢀ 11ꢀ inꢀ toluene,ꢀ andꢀ inꢀ theꢀ presenceꢀ ofꢀ arylationꢀreportedꢀinꢀliterature.ꢀꢀ
palladiumꢀacetate,ꢀXantphosꢀandꢀcesiumꢀcarbonateꢀgaveꢀindeedꢀtheꢀ
desiredꢀindazoleꢀ12ꢀinꢀ66%ꢀyieldꢀ(entryꢀ1,ꢀTableꢀ1),ꢀandꢀ12.5ꢀ%ꢀofꢀ
ꢀ
Toꢀ evaluateꢀ theꢀ scopeꢀ ofꢀ thisꢀ cyclization,ꢀ weꢀ synthesizedꢀ fiveꢀ
differentꢀ hydrazonoylꢀ chlorides ꢀ (9,ꢀ 14-17)ꢀ andꢀ weꢀ selectedꢀ sixꢀ
isocyanidesꢀ(10,ꢀ18-22)ꢀasꢀstartingꢀinputsꢀ(Fig.ꢀ2),ꢀtoꢀformꢀaꢀlibraryꢀofꢀ
indoloneꢀderivativeꢀ13ꢀcomingꢀfromꢀintramolecularꢀamidation.ꢀꢀ
11a
ꢀ
Inꢀ orderꢀ toꢀ optimizeꢀ indazoleꢀ formationꢀ weꢀ screenedꢀ differentꢀ α-aminocarbonylꢀ hydrazonesꢀ (31-74%ꢀ yields)ꢀ (Fig.ꢀ 3).ꢀ Aliphaticꢀ
palladiumꢀsourcesꢀ(entriesꢀ2,ꢀ4-6),ꢀligandsꢀ(entriesꢀ3-6),ꢀandꢀsolventsꢀ hydrazonoylꢀchloridesꢀareꢀmuchꢀlessꢀstableꢀthanꢀaromaticꢀonesꢀandꢀ
(
(
entryꢀ 6),ꢀ andꢀ weꢀ alsoꢀ triedꢀ copperꢀ catalystꢀ inꢀ placeꢀ ofꢀ palladiumꢀ didꢀnotꢀreactꢀsuccessfullyꢀinꢀthisꢀreactionꢀ(poorꢀyield,ꢀby-productsꢀ
entryꢀ3).ꢀWithꢀpalladiumꢀcatalystsꢀ(entriesꢀ1,2ꢀandꢀ4-6)ꢀ1ꢀequivalentꢀ formationꢀandꢀdifficultꢀpurificationꢀprocedure).ꢀ
ofꢀCesiumꢀcarbonateꢀhasꢀbeenꢀusedꢀasꢀbase.ꢀWithꢀourꢀsatisfaction,ꢀ
2
ꢀ|ꢀJ.ꢀName.,ꢀ2012,ꢀ00,ꢀ1-3ꢀ
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ꢀARTICLEꢀ
ꢀ
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Yieldꢀofꢀ
12ꢀ
Catalystꢀ
0%ꢀmolꢀ
Ligandꢀ
Entryꢀ
Solventꢀ
1
7%ꢀmolꢀ
(yieldꢀofꢀ
1
3)ꢀ
6%ꢀ
12.5%)ꢀ
8%ꢀ
4%)ꢀ
6
1
2
ꢀ
ꢀ
Tolueneꢀ
Tolueneꢀ
Pd(OAc)
2
ꢀ
Xantphosꢀ
Xantphosꢀ
(
4
Pd(dppf)Cl
CuIꢀ
2
ꢀ
(
N,N’-
dimehtylethyleneꢀ
2
2%ꢀ
3
ꢀ
Tolueneꢀ
(
(
10%)ꢀ
diamineꢀ
XPhosꢀ
3
8%ꢀ
4
5
6
ꢀ
ꢀ
ꢀ
Tolueneꢀ
Tolueneꢀ
2
Pd(dppf)Cl ꢀ
20%)ꢀ
78%ꢀ
Tri-o-tolyl-ꢀ
phosphineꢀ
Tri-o-tolyl-ꢀ
Phosphineꢀ
Pd(PPh
Pd(PPh
3
3
)
)
2
2
Cl
2
ꢀ
ꢀ
(traces)ꢀ
97%ꢀ
Figureꢀ3ꢀSynthesizedꢀlibraryꢀofꢀlinearꢀα-aminocarbonylꢀhydrazones.ꢀ
1
,4-
Cl
2
ꢀ
dioxanꢀ
(traces)ꢀ
Theꢀreactionꢀprovedꢀtoꢀbeꢀquiteꢀgeneralꢀinꢀscopeꢀasꢀtheꢀpresenceꢀofꢀ
bothꢀ aliphaticꢀ (34-37,ꢀ 39-41,ꢀ 43ꢀ andꢀ 44)ꢀ andꢀ aromaticꢀ (38,ꢀ 42)ꢀ
carboxamidesꢀ gaveꢀ goodꢀ yields.ꢀ Onlyꢀ electron-withdrawingꢀ nitrileꢀ
groupꢀonꢀtheꢀhydrazoneꢀaromaticꢀringꢀinꢀderivativesꢀ40,ꢀ41ꢀandꢀ42ꢀ
showedꢀtoꢀdecreaseꢀyieldsꢀtoꢀ65,ꢀ64ꢀandꢀ48%,ꢀrespectively.
Tableꢀ1ꢀOptimizationꢀofꢀindazoleꢀcyclizationꢀconditions.ꢀ
ꢀ
ꢀ
ꢀ
Figureꢀ 2ꢀ Startingꢀ materialsꢀ forꢀ theꢀ synthesisꢀ ofꢀ α-aminocarbonylꢀ
hydrazones.
ꢀ
Weꢀthenꢀreactedꢀtheꢀintermediateꢀhydrazonesꢀusingꢀtheꢀoptimizedꢀ
conditionsꢀ toꢀ getꢀ elevenꢀ differentꢀ substitutedꢀ 1-arylindazole-3-
carboxamidesꢀinꢀgoodꢀtoꢀexcellentꢀyieldsꢀ(48-98%)ꢀ(Figureꢀ4).
ꢀ
ꢀ
Figureꢀ4ꢀSynthesizedꢀlibraryꢀofꢀindazoleꢀcyclicꢀderivatives.
ꢀ
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ARTICLEꢀ
JournalꢀNameꢀ
Aꢀworkingꢀhypothesisꢀforꢀtheꢀformationꢀofꢀhydrazoneꢀderivativesꢀisꢀ Toꢀ ourꢀ knowledge,ꢀ thisꢀ transformationꢀ accountsꢀVfieowrꢀArttihcleeꢀOfnilrinsetꢀ
depictedꢀinꢀSchemeꢀ5.ꢀTheꢀhydrazonoylꢀchloridesꢀ4ꢀreadilyꢀformꢀtheꢀ applicationꢀofꢀbenzylisocyanideꢀasꢀaꢀconverti Db lOe Iꢀ :i s1 o0 c. 1 y0 a3 n9 i/dC e6 . Rꢀ ꢀA01442A
nitrilimine,ꢀwhichꢀisꢀtheꢀactiveꢀ1,3-dipolarꢀspeciesꢀandꢀisꢀattackedꢀbyꢀ
theꢀ isocyanideꢀ carbonꢀ atomꢀ toꢀ formꢀ aꢀ nitriliumꢀ ion.ꢀ Theꢀ latterꢀ isꢀ
ꢀ
thenꢀattackedꢀbyꢀtheꢀcarboxylateꢀfunctionꢀofꢀsacrificialꢀacidꢀ6ꢀtoꢀgiveꢀ
anꢀ unstableꢀ imidate:ꢀ theꢀ hydroxy-functionꢀ cyclizeꢀ intoꢀ theꢀ C=Oꢀ
carbonylꢀtoꢀgiveꢀtheꢀN-arylhydrazono-acetamidesꢀ7ꢀandꢀphtalide.ꢀInꢀ
thisꢀ reactionꢀ sacrificialꢀ acidꢀ 6ꢀ enablesꢀ toꢀ overcomeꢀ theꢀ poorꢀ
nucleophilicityꢀofꢀwaterꢀtowardsꢀtheꢀnitriliumꢀion.ꢀ6ꢀbehavesꢀindeedꢀ
likeꢀaꢀpseudoꢀwaterꢀmolecule,ꢀasꢀitꢀtrapsꢀtheꢀnitriliumꢀionꢀandꢀthenꢀ
undergoesꢀanꢀintramolecularꢀcyclizationꢀtoꢀdeliverꢀoneꢀoxygenꢀatomꢀ
toꢀtheꢀproduct,ꢀasꢀwaterꢀwould,ꢀandꢀtheꢀaromaticꢀlactoneꢀphthalide.ꢀ
ꢀ
ꢀ
R2
R2
R2
Schemeꢀ 6ꢀ Conversionꢀ ofꢀ N-arylindazole-3-carboxamidesꢀ toꢀ N-
R2
arylindazole-3-carbonitriles.ꢀ
N-
NH
Cl
N+
NH
O
NH
TEA
N
N
N
NR3
Conclusionsꢀ
R3NC
N+
5
O
R3
4
R1
O- HO
R1
OH
R1
R1
O
Inꢀconclusionꢀweꢀdevelopedꢀaꢀnovel,ꢀconciseꢀtwo-stepꢀsynthesisꢀforꢀ
theꢀ constructionꢀ ofꢀ 1-aryl-indazoles-3-carboxamidesꢀ performingꢀ aꢀ
reactionꢀ betweenꢀ isocyanides,ꢀ 2-iodo-N-arylbenzohydrazonoylꢀ
chloridesꢀandꢀ2-hydroxymethylbenzoicꢀfollowedꢀbyꢀaꢀregioselectiveꢀ
intramolecularꢀ hydrazoneꢀ palladiumꢀ catalyzedꢀ cyclization.ꢀ
Furthermoreꢀbenzyl-isocyanideꢀwasꢀunconventionallyꢀemployedꢀasꢀ
aꢀconvertibleꢀisocyanideꢀforꢀtheꢀsynthesisꢀofꢀbiologicallyꢀinterestingꢀ
N-arylindazole-3-carbonitriles.ꢀ Theꢀ presentꢀ workꢀ stepꢀ forwardꢀ theꢀ
considerationꢀ ofꢀ post-condensationꢀ modificationsꢀ ofꢀ isocyanide-
basedꢀreactionsꢀasꢀaꢀpass-holderꢀtoꢀgainꢀaꢀdirectꢀaccessꢀnotꢀonlyꢀtoꢀ
medicinallyꢀrelevantꢀcompounds,ꢀbutꢀstillꢀtoꢀtheꢀexploitationꢀofꢀtheꢀ
R2
OH HO
TEA
O
NH
O
N
R3
+
NH
6
O
O
R1
7
ꢀ
Schemeꢀ 5ꢀ Proposedꢀ reactionꢀ mechanismꢀ forꢀ theꢀ synthesisꢀ ofꢀ fullꢀpotentialꢀofꢀlandmarkꢀtransformationsꢀasꢀtheꢀBuchwald-Hartwigꢀ
hydrazono-acetamideꢀderivativeꢀ7.ꢀ
reactions.ꢀ
ꢀ
Experimentalꢀsectionꢀꢀ
Inꢀ orderꢀ toꢀ furtherꢀ expandꢀ theꢀ scopeꢀ ofꢀ theꢀ reactionꢀ weꢀ triedꢀ aꢀ
directꢀ conversionꢀ ofꢀ N-arylindazole-3-carboxamidesꢀ toꢀ N-
arylindazole-3-carbonitriles.ꢀ Theꢀ synthesisꢀ ofꢀ suchꢀ derivativesꢀ isꢀ
usuallyꢀaccomplishedꢀinꢀtwoꢀorꢀmoreꢀsteps,ꢀwithꢀoverallꢀyieldsꢀofꢀ26ꢀ
toꢀ 44%ꢀ andꢀ theꢀ useꢀ ofꢀ harshꢀ reactionꢀ conditions,ꢀ withꢀ Zn-ꢀ orꢀ Cu-
Generalꢀ
Commerciallyꢀ availableꢀ reagentsꢀ andꢀ solventsꢀ wereꢀ usedꢀ withoutꢀ
furtherꢀpurification.ꢀDichloromethaneꢀwasꢀdriedꢀbyꢀdistillationꢀfromꢀ
P O ꢀ andꢀ storedꢀ overꢀ activatedꢀ molecularꢀ sievesꢀ (4ꢀ Å).ꢀ Whenꢀ
2 5
15
containingꢀ waste ꢀ orꢀ promotedꢀ byꢀ tri-n-butyltinꢀ chlorideꢀ andꢀ
16
palladium. ꢀ Anꢀ alternativeꢀ two-stepꢀ route,ꢀ basedꢀ onꢀ aꢀ primaryꢀ
amideꢀ formationꢀ andꢀ subsequentꢀ dehydrationꢀ toꢀ nitrileꢀ (overallꢀ
yieldꢀ 63%)ꢀ hasꢀ beenꢀ reportedꢀ forꢀ theꢀ synthesisꢀ ofꢀ p38ꢀ kinaseꢀ
necessaryꢀ theꢀ reactionsꢀ wereꢀ performedꢀ inꢀ oven-driedꢀ glasswareꢀ
underꢀ aꢀ positiveꢀ pressureꢀ ofꢀ dryꢀ nitrogen.ꢀ Meltingꢀ pointsꢀ wereꢀ
determinedꢀ inꢀ openꢀ glassꢀ capillariesꢀ andꢀ areꢀ uncorrected.ꢀ Allꢀ theꢀ
compoundsꢀ wereꢀ characterizedꢀ byꢀ IR.ꢀ Hꢀ andꢀ Cꢀ APTꢀ NMRꢀ wereꢀ
recordedꢀ onꢀ aꢀ 400ꢀ MHz.ꢀ High-resolutionꢀ ESI-MSꢀ spectraꢀ wereꢀ
performedꢀonꢀaꢀThermoꢀLTQꢀOrbitrapꢀXLꢀmassꢀꢀspectrometer.ꢀTheꢀ
spectraꢀwereꢀrecordedꢀbyꢀinfusionꢀintoꢀtheꢀESIꢀꢀsourceꢀusingꢀMeOHꢀ
asꢀtheꢀsolvent.ꢀChemicalꢀshiftsꢀ(δ)ꢀareꢀreportedꢀinꢀpartꢀperꢀmillionꢀ
5
1
13
inhibitors. ꢀDealingꢀwithꢀtheirꢀbiologicalꢀactivities,ꢀN-arylindazole-3-
carbonitrileꢀ derivativesꢀ haveꢀ beenꢀ describedꢀ alsoꢀ asꢀ xanthineꢀ
15
oxidaseꢀ inhibitors ꢀ andꢀ asꢀ lowꢀ nanomolarꢀ bradykininꢀ receptorꢀ
16
antagonists. ꢀWeꢀspeculatedꢀindeedꢀthatꢀaꢀone-stepꢀconversionꢀofꢀ
theꢀ reportedꢀ N-arylindazole-3-carboxamidesꢀ toꢀ N-arylindazole-3-
carbonitrileꢀ couldꢀ beꢀ usefulꢀ toꢀ furtherꢀ enlargeꢀ theꢀ sizeꢀ andꢀ theꢀ
variabilityꢀ ofꢀ theꢀ synthesizableꢀ libraries.ꢀ So,ꢀ byꢀ reactingꢀ ꢀ N-
(
ppm)ꢀ relativeꢀ toꢀ theꢀ residualꢀ solventꢀ peak.ꢀ Columnꢀ
chromatographyꢀwasꢀperformedꢀonꢀsilicaꢀgelꢀ(70–230ꢀmeshꢀASTM)ꢀ
usingꢀ theꢀ reportedꢀ eluents.ꢀ Thinꢀ layerꢀ chromatographyꢀ (TLC)ꢀ wasꢀ
carriedꢀoutꢀonꢀ5ꢀxꢀ20ꢀcmꢀplatesꢀwithꢀaꢀlayerꢀthicknessꢀofꢀ0.25ꢀmmꢀ
arylindazole-3-carboxamideꢀ 37ꢀ inꢀ POCl
3
ꢀ atꢀ 150°Cꢀ inꢀ aꢀ sealedꢀ tubeꢀ
forꢀ4hꢀweꢀwereꢀableꢀtoꢀgetꢀN-arylindazole-3-carbonitrileꢀ45ꢀinꢀ96%ꢀ
17
yieldꢀ(Schemeꢀ6). ꢀ
(
Silicaꢀ gelꢀ 60ꢀ F254).ꢀ Whenꢀ necessaryꢀ theyꢀ wereꢀ developedꢀ withꢀ
KMnO .ꢀ
4
4
ꢀ|ꢀJ.ꢀName.,ꢀ2012,ꢀ00,ꢀ1-3ꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
Pleaseꢀdoꢀnotꢀadjustꢀmarginsꢀ

Pleaseꢀdoꢀnotꢀadjustꢀmarginsꢀ
RSC Advances
Page 5 of 9
JournalꢀNameꢀ
ꢀARTICLEꢀ
11a
Generalꢀ preparationꢀ ofꢀ hydrazonoylꢀ chloridesꢀ (9,ꢀ 14-17). ꢀ Theꢀ (Z)-N-cyclohexyl-2-(2-iodophenyl)-2-(2-phenylhydrazono)acet-
View Article Online
hydrazonoylꢀ chloridesꢀ wereꢀ readilyꢀ synthesizedꢀ inꢀ twoꢀ steps:ꢀ amideꢀ (11).ꢀ Theꢀ crudeꢀ materialꢀ wasꢀD Op Iu: r1 i 0f i. e1 0d 3ꢀ 9 /bC y6 ꢀR Ac 0o 1l 4u 4m2 nA ꢀ
Preparationꢀ ofꢀ acylhydrazines.ꢀ Toꢀ aꢀ stirredꢀ solutionꢀ ofꢀ 2- chromatographyꢀ (n-hexane/ꢀ EtOAcꢀ 30:1)ꢀ toꢀ giveꢀ theꢀ productꢀ asꢀ
1
iodobenzoicꢀacidsꢀonꢀaꢀ5ꢀmmolꢀscaleꢀinꢀTHFꢀꢀ(0.2ꢀM,ꢀ10ꢀmL)ꢀwereꢀ yellowꢀsolidꢀ(0.15ꢀg,ꢀ66%ꢀyield).ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
3
)ꢀδꢀ13.25ꢀ
addedꢀEDCꢀHClꢀ(1.05ꢀg,ꢀ5.50ꢀmmol,ꢀ1.1ꢀeq.),ꢀDMAPꢀ(0.12ꢀg,ꢀ1ꢀmmol,ꢀ (brꢀs,ꢀNH),ꢀ7.93ꢀ(brꢀd,ꢀ1ꢀH),ꢀ7.46-7.45ꢀ(m,ꢀ2ꢀH),ꢀ7.29-7.10ꢀ(m,ꢀ5ꢀH),ꢀ
.2ꢀeq.),ꢀtriethylamineꢀ(1.40ꢀmL,ꢀ10ꢀmmol,ꢀ2ꢀeq.)ꢀandꢀhydrazineꢀ(5ꢀ 6.93ꢀ(brꢀt,ꢀ1ꢀH),ꢀ5.17ꢀ(brꢀd,ꢀNH),ꢀ3.89-3.82ꢀ(m,ꢀ1ꢀH),ꢀ1.94-1.92ꢀ(m,ꢀ2ꢀ
0
13
mmol,ꢀ1ꢀeq.)ꢀatꢀ0ꢀ°C.ꢀTheꢀresultingꢀmixtureꢀwasꢀallowedꢀtoꢀwarmꢀtoꢀ H),ꢀ1.68-1.58ꢀ(m,ꢀ3ꢀH),ꢀ1.42-1.33ꢀ(m,ꢀ2ꢀH),ꢀ1.16-1.04ꢀ(m,ꢀ3ꢀH).ꢀ Cꢀ
roomꢀ temperatureꢀ overꢀ 24ꢀ h.ꢀ Theꢀ crudeꢀ reactionꢀ mixtureꢀ wasꢀ NMRꢀ(100ꢀMHz,ꢀCDCl )ꢀδꢀ162.6,ꢀ143.5,ꢀ140.7,ꢀ140.0,ꢀ132.8,ꢀ131.8,ꢀ
washedꢀ withꢀ HClꢀ 1Mꢀ sol.ꢀ (x2),ꢀ sat.ꢀ NaHCO ꢀ (x2)ꢀ andꢀ brineꢀ (x1),ꢀ 130.4,ꢀ129.2,ꢀ128.9,ꢀ121.7,ꢀ113.8,ꢀ100.6,ꢀ48.2,ꢀ32.7,ꢀ25.4,ꢀ24.8.ꢀIRꢀ
evaporatedꢀ toꢀ drynessꢀ andꢀ usedꢀ inꢀ theꢀ nextꢀ stepꢀ withoutꢀ furtherꢀ (KBr)ꢀ3390,ꢀ2923,ꢀ2846,ꢀ1632,ꢀ1497,ꢀ1171,ꢀ760ꢀνmax/cm ; Mpꢀ121.1-
3
3
-
1 ꢀ
+
ꢀ
purification.ꢀꢀPreparationꢀofꢀhydrazonoylꢀchloridesꢀ(9,ꢀ14-17).ꢀTheꢀ 122.3°C;ꢀ MSꢀ (ESI)ꢀ m/zꢀ ꢀ (M+H) Calcdꢀ forꢀ C20
correspondingꢀ acylhydrazineꢀ (2.50ꢀ mmol)ꢀ wasꢀ dissolvedꢀ inꢀ CH CNꢀ Found:ꢀ 448.0895ꢀ (100%)ꢀ
0.5ꢀM,ꢀ5ꢀmL)ꢀandꢀtriphenylphosphineꢀ(0.79ꢀg,ꢀ3ꢀmmol,ꢀ1.2ꢀeq.)ꢀandꢀ (Z)-N-(tert-butyl)-2-(2-iodophenyl)-2-(2-(4-methoxyphenyl)-
3
H23IN O:ꢀ 448.0886;ꢀ
+
3
[M+H] .ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ
(
carbonꢀ tetrachlorideꢀ (0.29ꢀ mL,ꢀ 3ꢀ mmol,ꢀ 1.2ꢀ eq.)ꢀ wereꢀ added.ꢀ Theꢀ hydrazono)acetamideꢀ (23).ꢀ Theꢀ crudeꢀ materialꢀ wasꢀ purifiedꢀ byꢀ
reactionꢀwasꢀstirredꢀatꢀroomꢀtemperatureꢀuntilꢀallꢀtheꢀacylhydrazineꢀ columnꢀ chromatographyꢀ (n-hexane/ꢀ EtOAcꢀ ꢀ 30:1)ꢀ toꢀ giveꢀ theꢀ
1
wasꢀconsumedꢀasꢀjudgedꢀbyꢀTLCꢀ(typicallyꢀ8-12ꢀhours).ꢀTheꢀreactionꢀ productꢀ asꢀ stickyꢀ reddishꢀ solidꢀ (0.10ꢀ g,ꢀ 44%ꢀ yield).ꢀ Hꢀ NMRꢀ (400ꢀ
wasꢀconcentratedꢀunderꢀreducedꢀpressureꢀandꢀpurifiedꢀbyꢀcolumnꢀ MHz,ꢀCDCl
3
)ꢀδꢀ13.20ꢀ(bs,ꢀNH),ꢀ7.92ꢀ(d,ꢀJꢀ=ꢀ7.96ꢀHz,ꢀ1ꢀH),ꢀ7.45-7.44ꢀ
chromatographyꢀ (n-hexane/EtOAc)ꢀ andꢀ storedꢀ belowꢀ 0°C.ꢀꢀꢀꢀꢀꢀ (ꢀ mꢀ ꢀꢀ ꢀ,ꢀ ꢀꢀ 2ꢀH),ꢀ7.14ꢀ(brꢀd,ꢀAA’XX’,ꢀ2ꢀH),ꢀ7.12-7.07ꢀ(m,ꢀ1ꢀH),ꢀ6.83ꢀ(d,ꢀJꢀ=ꢀ8.92ꢀ
1
3
(
Z)-2-iodo-N'-phenylbenzohydrazonoylꢀ chlorideꢀ (9).ꢀ Theꢀ crudeꢀ Hz,ꢀ2ꢀH),ꢀ5.05ꢀ(brꢀs,ꢀNH),ꢀ3.76ꢀ(s,ꢀ3ꢀH),ꢀ1.35ꢀ(s,ꢀ9ꢀH);ꢀ CꢀNMRꢀ(100ꢀ
materialꢀwasꢀpurifiedꢀbyꢀcolumnꢀchromatographyꢀ(n-hexane/ꢀEtOAcꢀ MHz,ꢀCDCl )ꢀδꢀ163.5,ꢀ154.9,ꢀ141.2,ꢀ139.6,ꢀ137.6,ꢀ132.3,ꢀ131.8,ꢀ130.1,ꢀ
0:1)ꢀ toꢀ giveꢀ theꢀ productꢀ asꢀ aꢀ whiteꢀ solidꢀ (0.41ꢀ g,ꢀ 46%ꢀ yield).ꢀ Hꢀ 128.9,ꢀ 115.0,ꢀ 114.6,ꢀ 100.7,ꢀ 55.6,ꢀ 51.6,ꢀ 28.6.ꢀ IRꢀ (KBr)ꢀ 3406,ꢀ 2956,ꢀ
3
1
3
-
1 ꢀ
+ꢀꢀ
3
NMRꢀ(400ꢀMHz,ꢀCDCl )ꢀδꢀ8.16ꢀ(brꢀs,ꢀNH),ꢀ8.05ꢀ(d,ꢀJꢀ=ꢀ7.88ꢀHz,ꢀ1ꢀH),ꢀ 1635,ꢀ1530,ꢀ1500,ꢀ1229,ꢀ1157ꢀνmax/cm ; MSꢀ(ESI)ꢀm/zꢀꢀ(M+H) Calcdꢀ
+
7
2
1
.64ꢀ(brꢀd,ꢀ1ꢀH),ꢀ7.48-7.41ꢀ(m,ꢀ3ꢀH),ꢀ7.35-7.33ꢀ(m,ꢀ2ꢀH),ꢀ7.14-7.07ꢀ(m,ꢀ forꢀ ꢀ C19
ꢀH).ꢀ CꢀNMRꢀ(100ꢀMHz,ꢀCDCl
29.6,ꢀ 128.3,ꢀ
H
23IN
3
O
2
:ꢀ 452.0835;ꢀ Found:ꢀ 452.0774ꢀ (100%)ꢀ [M+H] .ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ
)ꢀδꢀ143.3,ꢀ140.5,ꢀ139.9,ꢀ130.9,ꢀ130.7,ꢀ (Z)-2-(2-iodophenyl)-2-(2-(4-methoxyphenyl)hydrazono)-N-
123.0,ꢀ 121.6,ꢀ 113.7,ꢀ 96.8.ꢀꢀꢀꢀꢀꢀ pꢀ ꢀ eꢀ ꢀ ꢀnꢀ ꢀ tꢀ ꢀyꢀ ꢀl ꢀaꢀ ꢀcꢀ ꢀeꢀ ꢀ tꢀ ꢀaꢀ ꢀmꢀ ꢀꢀ iꢀ dꢀ ꢀ ꢀeꢀ ꢀ ꢀꢀ ꢀ( ꢀ 2ꢀ ꢀ 4ꢀ ꢀ )ꢀ ꢀ. ꢀꢀTheꢀcrudeꢀmaterialꢀwasꢀpurifiedꢀbyꢀcolumnꢀ
13
3
(
Z)-2-iodo-N'-(4-methoxyphenyl)benzohydrazonoylꢀ chlorideꢀ (14).ꢀ chromatographyꢀ (n-hexane/ꢀ EtOAcꢀ 95:5)ꢀ toꢀ giveꢀ theꢀ productꢀ asꢀ
1
Theꢀ crudeꢀ materialꢀ wasꢀ purifiedꢀ byꢀ columnꢀ chromatographyꢀ (n- reddishꢀoilꢀ(0.11ꢀg,ꢀ46%ꢀyield).ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
3
)ꢀδꢀ13.19ꢀ(brꢀ
hexane/ꢀEtOAcꢀ30:1)ꢀtoꢀgiveꢀtheꢀproductꢀasꢀaꢀyellowishꢀsolidꢀ(0.43ꢀg,ꢀ s,ꢀ NH),ꢀ 7.94ꢀ (d,ꢀ Jꢀ =ꢀ 7.96ꢀ Hz,ꢀ 1ꢀ H),ꢀ 7.47-7.42ꢀ (m,ꢀ 2ꢀ H),ꢀ 7.13ꢀ (brꢀ d,ꢀ
1
4
7
7
4%ꢀyield).ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
3
)ꢀδꢀ7.96ꢀ(d,ꢀJꢀ=ꢀ7.96ꢀHz,ꢀ1ꢀH),ꢀ AA’XX’,ꢀ2ꢀH),ꢀ7.11-7.08ꢀ(m,ꢀ1ꢀH),ꢀ6.83ꢀ(d,ꢀJꢀ=ꢀ8.88ꢀHz,ꢀ2ꢀH),ꢀ5.27ꢀ(brꢀt,ꢀ
.90ꢀ(brꢀs,ꢀNH),ꢀ7.54ꢀ(d,ꢀJꢀ=ꢀ7.72ꢀHz,ꢀ1ꢀH),ꢀ7.40ꢀ(t,ꢀJꢀ=ꢀ7.52ꢀHz,ꢀ1ꢀH),ꢀ NH),ꢀ3.76ꢀ(s,ꢀ3ꢀH),ꢀ3.26ꢀ(q,ꢀJꢀ=ꢀ6.56ꢀHz,ꢀ2ꢀH),ꢀꢀ1.53-1.46ꢀ(m,ꢀ2ꢀH),ꢀ1.33-
13
.15ꢀ(d,ꢀJꢀ=ꢀ8.88ꢀHz,ꢀ2ꢀH),ꢀ7.06ꢀ(t,ꢀJꢀ=ꢀ7.52ꢀHz,ꢀ1ꢀH),ꢀ6.87ꢀ(d,ꢀJꢀ=ꢀ8.92ꢀ 1.25ꢀ(m,ꢀ4ꢀH),ꢀ0.89-0.86ꢀ(m,ꢀ3ꢀH);ꢀ CꢀNMRꢀ(100ꢀMHz,ꢀCDCl
3
)ꢀδꢀ163.7,ꢀ
)ꢀδꢀ154.7,ꢀ140.5,ꢀ 155.0,ꢀ140.9,ꢀ140.0,ꢀ139.7,ꢀ137.5,ꢀ131.7,ꢀ130.2,ꢀ128.8,ꢀ115.0ꢀ(2ꢀC),ꢀ
39.9,ꢀ 137.2,ꢀ 130.8,ꢀ 130.5,ꢀ 128.2,ꢀ 122.0,ꢀ 114.8ꢀ (4C),ꢀ 96.6,ꢀ 55.7.ꢀꢀꢀꢀꢀꢀ 1ꢀ ꢀ 1ꢀ ꢀ ꢀ4ꢀ ꢀ. ꢀ6ꢀ ꢀꢀ ꢀ( ꢀ2ꢀ ꢀC),ꢀ101.0,ꢀ55.6,ꢀ39.2,ꢀ29.1,ꢀ29.0,ꢀ22.3,ꢀ14.0.ꢀIRꢀ(KBr)ꢀ3417,ꢀ
13
Hz,ꢀ1ꢀH),ꢀ3.79ꢀ(s,ꢀ3ꢀH);ꢀ CꢀNMRꢀ(100ꢀMHz,ꢀCDCl
3
1
(
-
1 ꢀ
Z)-4-chloro-2-iodo-N'-phenylbenzohydrazonoylꢀ chlorideꢀ (15).ꢀ Theꢀ 2950,ꢀ 2923,ꢀ 1635,ꢀ 1506,ꢀ 1220,ꢀ 1168,ꢀ 823ꢀ νmax/cm ; MSꢀ (ESI)ꢀ m/zꢀꢀ
crudeꢀmaterialꢀwasꢀpurifiedꢀbyꢀcolumnꢀchromatographyꢀ(n-hexane/ꢀ (M+H) Calcdꢀ forꢀ C20
EtOAcꢀ30:1)ꢀtoꢀgiveꢀtheꢀproductꢀasꢀaꢀlightꢀyellowꢀsolidꢀ(0.69ꢀg,ꢀ71%ꢀ [M+H] .ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ
yield).ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
+
ꢀ
H
25IN
3
O
2
:ꢀ 466.0991;ꢀ Found:ꢀ 466.0956ꢀ (100%)ꢀ
+
1
3
)ꢀδꢀ8.04ꢀ(s,ꢀNH),ꢀ7.97ꢀ(s,ꢀ1ꢀH),ꢀ7.47ꢀ (Z)-2-(4-chloro-2-iodophenyl)-N-cyclohexyl-2-(2-phenylhydrazono)ꢀ
(
2
1
brꢀd,ꢀ1ꢀH),ꢀ7.39ꢀ(brꢀd,ꢀAA’XX’,ꢀ1ꢀH),ꢀ7.33-7.29ꢀ(m,ꢀ2ꢀH),ꢀ7.22-7.20ꢀ(m,ꢀ acetamideꢀ (25).ꢀ Theꢀ crudeꢀ materialꢀ wasꢀ purifiedꢀ byꢀ columnꢀ
13
ꢀH),ꢀ6.96ꢀ(t,ꢀJꢀ=ꢀ7.24ꢀHz,ꢀ1ꢀH).ꢀ CꢀNMRꢀ(100ꢀMHz,ꢀCDCl
39.8,ꢀ138.2,ꢀ135.5,ꢀ131.2,ꢀ129.4,ꢀ128.4,ꢀ121.6,ꢀ121.5,ꢀ113.5,ꢀ96.3.ꢀꢀꢀꢀꢀꢀ yꢀ ꢀ eꢀ ꢀ lꢀ lꢀ oꢀ ꢀ ꢀwꢀ ꢀꢀsolidꢀ(0.18ꢀg,ꢀ74%ꢀyield).ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
3
)ꢀδꢀ142.9,ꢀ chromatographyꢀ (n-hexane/ꢀ EtOAcꢀ 30:1)ꢀ toꢀ giveꢀ theꢀ productꢀ asꢀ
1
3
)ꢀδꢀ13.20ꢀ
(
Z)-N'-(4-chlorophenyl)-2-iodobenzohydrazonoylꢀchlorideꢀ(16).ꢀTheꢀ (brꢀs,ꢀNH),ꢀ7.45ꢀ(brꢀd,ꢀAA’XX’,ꢀ1ꢀH),ꢀ7.37ꢀ(brꢀd,ꢀAA’XX’,ꢀ1ꢀH),ꢀ7.28-7.24ꢀ
crudeꢀmaterialꢀwasꢀpurifiedꢀbyꢀcolumnꢀchromatographyꢀ(n-hexane/ꢀ (m,ꢀ2ꢀH),ꢀ7.17ꢀ(brꢀd,ꢀAA’XX’,ꢀ2ꢀH),ꢀ6.94ꢀ(brꢀt,ꢀ1ꢀH),ꢀ5.07ꢀ(brꢀd,ꢀNH),ꢀ
EtOAcꢀ30:1)ꢀtoꢀgiveꢀtheꢀproductꢀasꢀaꢀlightꢀyellowꢀsolidꢀ(0.33ꢀg,ꢀ34%ꢀ 3.88-3.80ꢀ(m,ꢀ1ꢀH),ꢀ1.95-1.92ꢀ(m,ꢀ2ꢀH),ꢀ1.69-1.59ꢀ(m,ꢀ3ꢀH),ꢀ1.42-1.32ꢀ
1
13
yield).ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
3 3
)ꢀδꢀ8.03ꢀ(brꢀs,ꢀNH),ꢀ7.ꢀ(brꢀd,ꢀAA’XX’,ꢀ2ꢀ (m,ꢀ 2ꢀ H),ꢀ 1.17-1.06ꢀ (m,ꢀ 3ꢀ H);ꢀ Cꢀ NMRꢀ (100ꢀ MHz,ꢀ CDCl )ꢀ δꢀ 162.3,ꢀ
H),ꢀ7.41(brꢀt,ꢀ1ꢀH),ꢀ7.26ꢀ(brꢀd,ꢀAA’XX’,ꢀ2ꢀH),ꢀ7.15ꢀ(brꢀd,ꢀAA’XX’,ꢀ2ꢀH),ꢀ 143.3,ꢀ139.4,ꢀ139.0,ꢀ135.2,ꢀ132.3,ꢀ131.5,ꢀ129.2,ꢀ129.1,ꢀ122.0,ꢀ113.9,ꢀ
1
3
7
1
(
.08ꢀ(brꢀt,ꢀ1ꢀH);ꢀ CꢀNMRꢀ(100ꢀMHz,ꢀCDCl
3
)ꢀδꢀ141.8,ꢀ140.4,ꢀ139.6,ꢀ 100.6,ꢀ48.2,ꢀ32.8,ꢀ25.4,ꢀ24.8.ꢀIRꢀ(KBr)ꢀ3395,ꢀ2928,ꢀ2851,ꢀ1635,ꢀ1495,ꢀ
-
1 ꢀ
30.8,ꢀ 130.7,ꢀ 129.3,ꢀ 128.2,ꢀ 126.1,ꢀ 123.7,ꢀ 114.8,ꢀ 96.5.ꢀꢀꢀꢀꢀꢀ 1ꢀ ꢀ 2ꢀ ꢀ ꢀ4ꢀ ꢀ5ꢀ ꢀ ,ꢀ ꢀꢀ 1ꢀ ꢀ 1ꢀ ꢀ ꢀ6 8,ꢀ 990,ꢀ 740ꢀ νmax/cm ; Mpꢀ 132.6-133.2°C;ꢀ MSꢀ (ESI)ꢀ m/zꢀꢀ
Z)-N'-(4-cyanophenyl)-2-iodobenzohydrazonoylꢀchlorideꢀ(17).ꢀTheꢀ (M+H) CalcdꢀforꢀC20H22ClIN O:ꢀ482.0496;ꢀFound:ꢀ482.0482ꢀ(100%)ꢀ
3
crudeꢀmaterialꢀwasꢀpurifiedꢀbyꢀcolumnꢀchromatographyꢀ(n-hexane/ꢀ [M+H] .ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ
+ꢀ
+
EtOAcꢀ9:1)ꢀtoꢀgiveꢀtheꢀproductꢀasꢀaꢀlightꢀorangeꢀsolidꢀ(0.84ꢀg,ꢀ88%ꢀ ꢀꢀꢀꢀꢀ(Z)-N-benzyl-2-(2-(4-chlorophenyl)hydrazono)-2-(2-iodophenyl)-
1
yield).ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
3
)ꢀδꢀ10.44ꢀ(brꢀs,ꢀNH),ꢀ7.98ꢀ(brꢀd,ꢀ1ꢀH),ꢀ acetamideꢀ (26).ꢀ Theꢀ crudeꢀ materialꢀ wasꢀ purifiedꢀ byꢀ columnꢀ
7
.65ꢀ(brꢀd,ꢀAA’XX’,ꢀ2ꢀH),ꢀ7.59ꢀ(brꢀd,ꢀ1ꢀH),ꢀ7.49ꢀ(brꢀt,ꢀ1ꢀH),ꢀ7.40ꢀ(brꢀd,ꢀ chromatographyꢀ (n-hexane/ꢀ EtOAcꢀ 99:1)ꢀ toꢀ giveꢀ theꢀ productꢀ asꢀ
13
1
AA’XX’,ꢀ2ꢀH),ꢀ7.19ꢀ(brꢀt,ꢀ1ꢀH);ꢀ CꢀNMRꢀ(100ꢀMHz,ꢀCDCl
3
)ꢀδꢀ148.1,ꢀ yellowishꢀ solidꢀ (0.10ꢀ g,ꢀ 41%ꢀ yield).ꢀ Hꢀ NMRꢀ (400ꢀ MHz,ꢀ CDCl
3
)ꢀ δꢀ
1
9
40.3,ꢀ140.2,ꢀ134.0,ꢀ131.8,ꢀ131.0,ꢀ129.0,ꢀ125.0,ꢀ120.0,ꢀ114.2,ꢀ102.2,ꢀ 13.24ꢀ(brꢀs,ꢀNH),ꢀ7.92ꢀ(brꢀd,ꢀ1ꢀH),ꢀ7.45-7.10ꢀ(m,ꢀ12ꢀH),ꢀ5.63ꢀ(brꢀs,ꢀ
13
7.5.ꢀꢀ
NH),ꢀ4.50ꢀ(d,ꢀJꢀ=ꢀ5.92ꢀHz,ꢀ2ꢀH).ꢀ CꢀNMRꢀ(100ꢀMHz,ꢀCDCl
3
)ꢀδꢀ163.4,ꢀ
42.15,ꢀ 140.4,ꢀ 139.8,ꢀ 137.3,ꢀ 132.9,ꢀ 131.5,ꢀ 130.5,ꢀ 129.2,ꢀ 128.9,ꢀ
28.7,ꢀ126.7,ꢀ115.2,ꢀ100.6,ꢀ43.3.ꢀIRꢀ(KBr)ꢀ3390,ꢀ1629,ꢀ1533,ꢀ1495,ꢀ
1
1
1
Generalꢀ preparationꢀ ofꢀ α-aminocarbonylhydrazonesꢀ (11,ꢀ 23-33).ꢀ
Theꢀ hydrazonoylꢀ chlorideꢀ (0.5ꢀ mmol,ꢀ 1ꢀ eq.),ꢀ theꢀ isocyanideꢀ (0.5ꢀ
mmol,ꢀ1ꢀeq.),ꢀ2-hydroxymethylbenzoicꢀacidꢀ(0.5ꢀmmol,ꢀ1ꢀeq.)ꢀandꢀ
TEAꢀ(1ꢀmmol,ꢀ2ꢀeq.)ꢀwereꢀone-potꢀmixedꢀinꢀDCMꢀ(0.5ꢀM,ꢀ1ꢀmL)ꢀandꢀ
stirredꢀ atꢀ roomꢀ temperatureꢀ underꢀ aꢀ nitrogenꢀ atmosphereꢀ
overnight.ꢀAfterꢀevaporationꢀofꢀtheꢀsolvent,ꢀtheꢀcrudeꢀmaterialꢀwasꢀ
-
1 ꢀ
+ꢀꢀ
160,ꢀ823,ꢀ754ꢀνmax/cm ; Mpꢀ110.4-111.7ꢀ°C;ꢀMSꢀ(ESI)ꢀm/zꢀꢀ(M+H)
+
CalcdꢀforꢀꢀC21
3
H18ClIN O:ꢀ490.0183;ꢀFound:ꢀ490.0152ꢀ(100%)ꢀ[M+H] .ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ
(
Z)-2-(2-iodophenyl)-N-(4-methoxyphenyl)-2-(2-phenylhydrazono)ꢀ
acetamideꢀ (27)ꢀ Theꢀ crudeꢀ materialꢀ wasꢀ purifiedꢀ byꢀ columnꢀ
chromatographyꢀ (n-hexane/ꢀ EtOAcꢀ 95:5)ꢀ toꢀ giveꢀ theꢀ productꢀ asꢀ
purifiedꢀ
byꢀ
columnꢀ
chromatography.ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
J.ꢀName.,ꢀ2013,ꢀ00,ꢀ1-3ꢀ|ꢀ5ꢀ
Pleaseꢀdoꢀnotꢀadjustꢀmarginsꢀ

Pleaseꢀdoꢀnotꢀadjustꢀmarginsꢀ
RSC Advances
Page 6 of 9
ARTICLEꢀ
yellowꢀsolidꢀ(0.07ꢀg,ꢀ31%ꢀyield).ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
JournalꢀNameꢀ
)ꢀδꢀ13.22ꢀ (Z)-2-(2-(4-chlorophenyl)hydrazono)-N-cyclohexyl-2-(2-iodo-
1
3
View Article Online
(
brꢀs,ꢀNH),ꢀ7.99ꢀ(brꢀd,ꢀ1ꢀH),ꢀ7.57-7.50ꢀ(m,ꢀ2ꢀH),ꢀ7.34-7.15ꢀ(m,ꢀ7ꢀH),ꢀ phenyl)acetamideꢀ(33).ꢀTheꢀcrudeꢀmaterialꢀ Dw Oa Is: ꢀ 1p 0u. 1r 0i f 3i e9 d/ Cꢀ b6 yR ꢀAc 0o 1l 4u 4m2 An ꢀ
6
.96ꢀ(brꢀt,ꢀ1ꢀH),ꢀ6.88ꢀ(brꢀd,ꢀAA’XX’,ꢀ2ꢀH),ꢀ6.83ꢀ(brꢀs,ꢀNH),ꢀ3.80ꢀ(s,ꢀ3ꢀH);ꢀ chromatographyꢀ (n-hexane/ꢀ EtOAcꢀ 97:3)ꢀ toꢀ giveꢀ theꢀ productꢀ asꢀ
1
3
1
Cꢀ NMRꢀ (100ꢀ MHz,ꢀ CDCl
3 3
)ꢀ δꢀ 161.1,ꢀ 157.2,ꢀ 143.4,ꢀ 140.5,ꢀ 139.9,ꢀ orangeꢀsolidꢀ(0.08ꢀg,ꢀ34%ꢀyield).ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl )ꢀδꢀ13.25ꢀ
1
5
32.4,ꢀ132.0,ꢀ130.6,ꢀ129.5,ꢀ129.1,ꢀ123.1,ꢀ122.2,ꢀ114.3,ꢀ114.1,ꢀ100.9,ꢀ (brꢀs,ꢀNH),ꢀ7.93ꢀ(brꢀd,ꢀ1ꢀH),ꢀ7.46-7.41ꢀ(m,ꢀ2ꢀH),ꢀ7.20ꢀ(brꢀd,ꢀAA’XX’,ꢀ
-
1 ꢀ
5.5.ꢀIRꢀ(KBr)ꢀ3351,ꢀ1601,ꢀ1506,ꢀ1484,ꢀ1234,ꢀ1146,ꢀ998ꢀνmax/cm ; 2H),ꢀ7.14-7.09ꢀ(m,ꢀ4ꢀH),ꢀ5.16ꢀ(brꢀd,ꢀNH),ꢀ3.87-3.79ꢀ(m,ꢀ1ꢀH),ꢀ1.92-
+ꢀ
Mpꢀ 119.3-120.6ꢀ °C;ꢀ MSꢀ (ESI)ꢀ m/zꢀ ꢀ (M+H) Calcdꢀ forꢀ C21
72.0522;ꢀ Found:ꢀ 472.0556ꢀ (100%)ꢀ
Z)-2-(2-(4-chlorophenyl)hydrazono)-2-(2-iodophenyl)-N-(4-
methoxybenzyl)acetamideꢀ(28).ꢀTheꢀcrudeꢀmaterialꢀwasꢀpurifiedꢀbyꢀ 24.7.ꢀIRꢀ(KBr)ꢀ3390,ꢀ2923,ꢀ2846,ꢀ1635,ꢀ1492,ꢀ1160,ꢀ993ꢀ νmax/cm ;
3 2
H19IN O :ꢀ 1.89ꢀ (m,ꢀ 2H),ꢀ 1.67-1.63ꢀ (m,ꢀ 3H),ꢀ 1.38-1.31ꢀ (m,ꢀ 2H),ꢀ 1.12-1.05ꢀ (m,ꢀ
+
13
4
(
[M+H] .ꢀꢀꢀꢀꢀꢀ 3ꢀ ꢀ Hꢀ ꢀꢀ )ꢀ .ꢀ ꢀꢀꢀꢀ ꢀCꢀ ꢀꢀ Nꢀ ꢀꢀ Mꢀ ꢀꢀꢀ Rꢀ ꢀꢀ ꢀ( ꢀ 1ꢀ ꢀ 0ꢀ ꢀ ꢀ0ꢀ ꢀꢀ Mꢀ ꢀꢀ ꢀHꢀ ꢀ ꢀz ꢀ ,ꢀ ꢀ ꢀCꢀ DCl
3
)ꢀδꢀ162.5,ꢀ142.2,ꢀ140.5,ꢀ139.7,ꢀ133.5,ꢀ
131.7,ꢀ 130.4,ꢀ 129.2,ꢀ 128.9,ꢀ 126.3,ꢀ 114.9,ꢀ 100.4,ꢀ 48.2,ꢀ 32.7,ꢀ 25.4,ꢀ
-
1 ꢀ
+ꢀ ꢀ
3
columnꢀ chromatographyꢀ (n-hexane/ꢀ EtOAcꢀ 99:1)ꢀ toꢀ giveꢀ theꢀ Mpꢀ134.8-135.4ꢀ°C;ꢀMSꢀ(ESI)ꢀm/zꢀꢀ(M+H) CalcdꢀforꢀC20H22ClIN O:ꢀ
productꢀasꢀwhiteꢀsolidꢀ(0.11ꢀg,ꢀ43%ꢀyield).ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
1
+
3
)ꢀ 482,0496;ꢀFound:ꢀ482.0472ꢀ(100%)ꢀ[M+H] .ꢀ
δꢀ13.24ꢀ(brꢀs,ꢀNH),ꢀ7.91ꢀ(brꢀd,ꢀ1ꢀH),ꢀ7.44-7.42ꢀ(m,ꢀ2ꢀH),ꢀ7.23-7.10ꢀ(m,ꢀ GeneralꢀpreparationꢀofꢀN-arylindazole-3-carboxamidesꢀ(12,ꢀ34-44).ꢀ
7
3
1
1
1
ꢀH),ꢀ6.85ꢀ(brꢀd,ꢀAA’XX’,ꢀ2ꢀH),ꢀ5.60-5.57ꢀ(m,ꢀ1ꢀH),ꢀ4.42ꢀ(brꢀd,ꢀ2ꢀH),ꢀ Theꢀα-aminocarbonylhydrazoneꢀ(0.1ꢀmmol,ꢀ1ꢀequiv.)ꢀisꢀdissolvedꢀinꢀ
13
.78ꢀ (s,ꢀ 3ꢀ H).ꢀ Cꢀ NMRꢀ (100ꢀ MHz,ꢀ CDCl
40.3,ꢀ139.8,ꢀ132.9,ꢀ131.6,ꢀ130.5,ꢀ129.3,ꢀ129.2,ꢀ129.1,ꢀ128.9,ꢀ126.6,ꢀ tri-o-tolylphosphineꢀ
15.1,ꢀ 114.1,ꢀ 100.6,ꢀ 55.3,ꢀ 42.8.ꢀ IRꢀ (KBr)ꢀ 3324,ꢀ 3208,ꢀ 1626,ꢀ 1517,ꢀ bis(triphenylphosphine)palladium(II)ꢀ dichlorideꢀ (0.007ꢀ mmol,ꢀ 0.07ꢀ
3
)ꢀ δꢀ 160.3,ꢀ 159.1,ꢀ 142.1,ꢀ dryꢀ1,4-dioxanꢀ(0.3M)ꢀandꢀcesiumꢀcarbonateꢀ(0.1ꢀmmol,ꢀ1ꢀequiv.),ꢀ
(0.01ꢀ mmol,ꢀ 0.1ꢀ equiv.)ꢀ andꢀ
-
1 ꢀ
489,ꢀ1242,ꢀ1160,ꢀ1004,ꢀ825ꢀνmax/cm ; Mpꢀ143.3-144.4ꢀ°C;ꢀMSꢀ(ESI)ꢀ equiv.)ꢀ wereꢀ added.ꢀ Theꢀ reactionꢀ mixtureꢀ wasꢀ stirredꢀ atꢀ refluxꢀ
+ꢀ ꢀ
3 2
m/zꢀꢀ(M+H) CalcdꢀforꢀꢀC22H20ClIN O :ꢀ520.0289;ꢀFound:ꢀ520.0292ꢀ temperatureꢀ overnight,ꢀ evaporatedꢀ andꢀ purifiedꢀ byꢀ
+
(
100%)ꢀ
[M+H] .ꢀꢀꢀꢀꢀꢀ cꢀ ꢀhꢀ ꢀ rꢀ ꢀoꢀ ꢀ mꢀ ꢀꢀ ꢀaꢀ ꢀtꢀ oꢀ ꢀ ꢀgꢀ ꢀrꢀ aꢀ ꢀ pꢀ ꢀ ꢀhꢀ ꢀ iꢀ cꢀ ꢀꢀ ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ cꢀ ꢀ oꢀ ꢀ lꢀ uꢀ ꢀ ꢀmꢀ ꢀꢀ nꢀ ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ ꢀ( ꢀ nꢀ ꢀ -ꢀ ꢀhꢀ ꢀ eꢀ ꢀ xꢀ ꢀ aꢀ ꢀ nꢀ ꢀ ꢀeꢀ ꢀ/ꢀ ꢀeꢀ ꢀt ꢀ hꢀ ꢀ ꢀyꢀ ꢀl ꢀꢀ
acetate).ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ
(
Z)-N-(tert-butyl)-2-(2-(4-cyanophenyl)hydrazono)-2-(2-iodo-
N-cyclohexyl-1-phenyl-1H-indazole-3-carboxamideꢀ(12).ꢀTheꢀcrudeꢀ
phenyl)acetamideꢀ(29).ꢀTheꢀcrudeꢀmaterialꢀwasꢀpurifiedꢀbyꢀcolumnꢀ materialꢀwasꢀpurifiedꢀbyꢀcolumnꢀchromatographyꢀ(n-hexane/ꢀEtOAcꢀ
1
chromatographyꢀ (n-hexane/ꢀ EtOAcꢀ 95:5)ꢀ toꢀ giveꢀ theꢀ productꢀ asꢀ 95:5)ꢀtoꢀgiveꢀtheꢀproductꢀasꢀyellowꢀsolidꢀ(0.03ꢀg,ꢀ97%ꢀyield).ꢀ HꢀNMRꢀ
1
whiteꢀsolidꢀ(0.11ꢀg,ꢀ47%ꢀyield).ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
3
)ꢀδꢀ13.45ꢀ(brꢀ (400ꢀMHz,ꢀCDCl
3
)ꢀδꢀ8.49ꢀ(d,ꢀJꢀ=ꢀ8.12ꢀHz,ꢀ1ꢀH),ꢀ7.73-7.66ꢀ(m,ꢀ3ꢀH),ꢀ
s,ꢀNH),ꢀ7.94ꢀ(brꢀd,ꢀ1ꢀH),ꢀ7.53-7.41ꢀ(m,ꢀ4ꢀH),ꢀ7.21-7.16ꢀ(m,ꢀ3ꢀH),ꢀ5.18ꢀ 7.58-7.54ꢀ(m,ꢀ2ꢀH),ꢀ7.46-7.40ꢀ(m,ꢀ2ꢀH),ꢀ7.35-7.32ꢀ(m,ꢀ1ꢀH),ꢀ7.04ꢀ(brꢀd,ꢀ
1
3
(
3
brꢀs,ꢀNH),ꢀ1.35ꢀ(s,ꢀ9ꢀH).ꢀ CꢀNMRꢀ(100ꢀMHz,ꢀCDCl )ꢀδꢀ162.7,ꢀ147.0,ꢀ NH),ꢀ4.10-4.00ꢀ(m,ꢀ1ꢀH),ꢀ2.08-2.03ꢀ(m,ꢀ2ꢀH),ꢀ1.80-1.64ꢀ(m,ꢀ3ꢀH),ꢀ1.50-
13
1
9
9
C
40.2,ꢀ139.7,ꢀ136.7,ꢀ133.5,ꢀ131.5,ꢀ130.8,ꢀ129.0,ꢀ119.7,ꢀ113.8,ꢀ103.5,ꢀ 1.20ꢀ (m,ꢀ 5ꢀ H);ꢀ Cꢀ NMRꢀ (100ꢀ MHz,ꢀ CDCl
9.6,ꢀ52.1,ꢀ28.4.ꢀIRꢀ(KBr)ꢀ3390,ꢀ3164,ꢀ2961,ꢀ2214,ꢀ1637,ꢀ1508,ꢀ1149,ꢀ 139.5,ꢀ 129.6ꢀ (2ꢀ C),ꢀ 127.6ꢀ (2C),ꢀ 123.9,ꢀ 123.4ꢀ (2ꢀ C),ꢀ 123.3,ꢀ 123.2,ꢀ
90ꢀνmax/cm ; Mpꢀ167.8-168.8ꢀ°C;ꢀMSꢀ(ESI)ꢀm/zꢀꢀ(M+H) Calcdꢀforꢀ 110.4,ꢀ48.0,ꢀ33.3ꢀ(2ꢀC),ꢀ25.6,ꢀ25.0ꢀ(2ꢀC).ꢀIRꢀ(KBr)ꢀ2923,ꢀ2851,ꢀ1662,ꢀ
19 4
H20IN O:ꢀ 447,0682;ꢀ Found:ꢀ 447.0646ꢀ (100%)ꢀ [M+H] .ꢀꢀꢀꢀꢀꢀ 1ꢀ ꢀ 5ꢀ ꢀ ꢀ5ꢀ ꢀ5ꢀ ꢀ ,ꢀ ꢀꢀ 1ꢀ ꢀ 3ꢀ ꢀ ꢀ6ꢀ ꢀ3ꢀ ꢀ ,ꢀ ꢀꢀ 1ꢀ 245,ꢀ 1171,ꢀ 1056ꢀ νmax/cm ; Mpꢀ 104.3-105.5ꢀ °C;ꢀ MSꢀ
Z)-2-(2-(4-cyanophenyl)hydrazono)-2-(2-iodophenyl)-N-pentyl-
acetamideꢀ (30).ꢀ Theꢀ crudeꢀ materialꢀ wasꢀ purifiedꢀ byꢀ columnꢀ (100%)ꢀ[M+H] .ꢀꢀꢀ
chromatographyꢀ (n-hexane/ꢀ EtOAcꢀ 9:1)ꢀ toꢀ giveꢀ theꢀ productꢀ asꢀ N-(tert-butyl)-1-(4-methoxyphenyl)-1H-indazole-3-carboxamideꢀ
3
)ꢀ δꢀ 161.6,ꢀ 140.4,ꢀ 139.7,ꢀ
-
1 ꢀ
+ꢀ ꢀ
+
-1 ꢀ
+ꢀꢀ
(
22 3
(ESI)ꢀm/zꢀꢀ(M+H) CalcdꢀforꢀꢀC20H N O:ꢀ320.1763;ꢀFound:ꢀ320.1730ꢀ
+
1
yellowishꢀ solidꢀ (0.12ꢀ g,ꢀ 52%ꢀ yield).ꢀ Hꢀ NMRꢀ (400ꢀ MHz,ꢀ CDCl
3
)ꢀ δꢀ (34).ꢀ Theꢀ crudeꢀ materialꢀ wasꢀ purifiedꢀ byꢀ columnꢀ chromatographyꢀ
1
3.43ꢀ(brꢀs,ꢀNH),ꢀ7.96ꢀ(brꢀd,ꢀ1ꢀH),ꢀ7.54-7.41ꢀ(m,ꢀ4ꢀH),ꢀ7.22-7.15ꢀ(m,ꢀ3ꢀ (n-hexane/ꢀ EtOAcꢀ 9:1)ꢀ toꢀ giveꢀ theꢀ productꢀ asꢀ reddishꢀ oilꢀ (0.03ꢀ g,ꢀ
1
H),ꢀ5.42ꢀ(brꢀs,ꢀNH),ꢀ3.30-3.25ꢀ(m,ꢀ1ꢀH),ꢀ1.55-1.48ꢀ(m,ꢀ2ꢀH),ꢀ1.33-1.25ꢀ 90%ꢀyield).ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
3
)ꢀδꢀ8.48ꢀ(d,ꢀJꢀ=ꢀ8.08ꢀHz,ꢀ1ꢀH),ꢀ
13
(
m,ꢀ4ꢀH),ꢀ0.88ꢀ(brꢀt,ꢀ3ꢀH).ꢀ CꢀNMRꢀ(100ꢀMHz,ꢀCDCl )ꢀδꢀ163.1,ꢀ146.9,ꢀ 7.60-7.56ꢀ(m,ꢀ3ꢀH),ꢀ7.42ꢀ(brꢀt,ꢀ1ꢀH),ꢀ7.31ꢀ(brꢀt,ꢀ1ꢀH),ꢀ7.08-7.04ꢀ(m,ꢀ3ꢀ
3
13
1
9
1
39.9,ꢀ139.8,ꢀ135.9,ꢀ133.6,ꢀ131.4,ꢀ130.8,ꢀ129.0,ꢀ119.7,ꢀ113.9,ꢀ103.8,ꢀ H),ꢀ3.89ꢀ(s,ꢀ3ꢀH),ꢀ1.53ꢀ(s,ꢀ9ꢀH);ꢀ CꢀNMRꢀ(100ꢀMHz,ꢀCDCl
3
)ꢀδꢀ162.0,ꢀ
9.9,ꢀ39.5,ꢀ29.1,ꢀ28.8,ꢀ22.3,ꢀ13.9.ꢀIRꢀ(KBr)ꢀ3329,ꢀ2923,ꢀ2214,ꢀ1646,ꢀ 159.0,ꢀ140.7,ꢀ139.6,ꢀ132.4,ꢀ127.4,ꢀ125.2ꢀ(2ꢀC),ꢀ123.4,ꢀ123.3,ꢀ123.0,ꢀ
-
1 ꢀ
+ꢀꢀ
508,ꢀ1149,ꢀ828ꢀνmax/cm ; Mpꢀ91.0-92.4ꢀ°C;ꢀMSꢀ(ESI)ꢀm/zꢀꢀ(M+H)
114.7ꢀ(2ꢀC),ꢀ110.3,ꢀ55.7,ꢀ51.3,ꢀ29.1.ꢀIRꢀ(KBr)ꢀ3406,ꢀ2956,ꢀ1668,ꢀ1533,ꢀ
+
-1 ꢀ
+ꢀ
CalcdꢀforꢀꢀC20
4
H22IN O:ꢀ461,0838;ꢀFound:ꢀ461,0852ꢀ(100%)ꢀ[M+H] .ꢀꢀꢀꢀꢀꢀ 1ꢀ ꢀ 5ꢀ ꢀ ꢀ0ꢀ ꢀ8ꢀ ,ꢀ 1196,ꢀ 1028,ꢀ 751ꢀ νmax/cm ; MSꢀ (ESI)ꢀ m/zꢀ ꢀ (M+H) Calcdꢀ forꢀ
+
(
Z)-2-(2-(4-cyanophenyl)hydrazono)-2-(2-iodophenyl)-N-(4-
19 22 3 2
C H N O :ꢀ324.1712;ꢀFound:ꢀ324.1728ꢀ(100%)ꢀ[M+H] .ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ
methoxyphenyl)acetamideꢀ(31).ꢀTheꢀcrudeꢀmaterialꢀwasꢀpurifiedꢀbyꢀ ꢀꢀ1-(4-methoxyphenyl)-N-pentyl-1H-indazole-3-carboxamideꢀ (35).ꢀ
columnꢀchromatographyꢀ(n-hexane/ꢀEtOAcꢀ9:1)ꢀtoꢀgiveꢀtheꢀproductꢀ Theꢀ crudeꢀ materialꢀ wasꢀ purifiedꢀ byꢀ columnꢀ chromatographyꢀ (n-
1
asꢀ reddishꢀ solidꢀ (0.08ꢀ g,ꢀ 34%ꢀ yield).ꢀ Hꢀ NMRꢀ (400ꢀ MHz,ꢀ CDCl
3
)ꢀ δꢀ hexane/ꢀEtOAcꢀ9:1)ꢀtoꢀgiveꢀtheꢀproductꢀasꢀanꢀoff-whiteꢀsolidꢀ(0.03ꢀg,ꢀ
1
1
3.40ꢀ(brꢀs,ꢀNH),ꢀ8.00ꢀ(brꢀd,ꢀ1ꢀH),ꢀ7.56-7.54ꢀ(m,ꢀ5ꢀH),ꢀ7.34-7.21ꢀ(m,ꢀ4ꢀ 92%ꢀyield).ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
3
)ꢀδꢀ8.47ꢀ(d,ꢀJꢀ=ꢀ8.12ꢀHz,ꢀ1ꢀH),ꢀ
H),ꢀ 6.92ꢀ (brꢀ s,ꢀ NH),ꢀ 6.89ꢀ (brꢀ s,ꢀ AA’XX’,ꢀ 2ꢀ H).ꢀ Cꢀ NMRꢀ (100ꢀ MHz,ꢀ 7.59-7.56ꢀ(m,ꢀ3ꢀH),ꢀ7.41ꢀ(brꢀt,ꢀ1ꢀH),ꢀ7.31ꢀ(brꢀt,ꢀ1ꢀH),ꢀ7.14ꢀ(brꢀt,ꢀNH),ꢀ
CDCl )ꢀ δꢀ 161.2,ꢀ 157.6,ꢀ 146.7,ꢀ 140.0,ꢀ 139.7,ꢀ 135.7,ꢀ 133.6,ꢀ 131.8,ꢀ 7.06ꢀ(brꢀd,ꢀAA’XX’,ꢀ2ꢀH),ꢀ3.87ꢀ(s,ꢀ3ꢀH),ꢀ3.52-3.47ꢀ(m,ꢀ2ꢀH),ꢀ1.66-1.61ꢀ
31.1,ꢀ129.2,ꢀ128.9,ꢀ123.1,ꢀ119.6,ꢀ114.3,ꢀ114.1,ꢀ104.2,ꢀ100.0,ꢀ55.5.ꢀ (m,ꢀ2ꢀH),ꢀ1.39-1.35ꢀ(m,ꢀ4ꢀH),ꢀ0.92-0.88ꢀ(m,ꢀ3ꢀH);ꢀ CꢀNMRꢀ(100ꢀMHz,ꢀ
13
3
13
1
-1 ꢀ
IRꢀ (KBr)ꢀ 3395,ꢀ 2208,ꢀ 1607,ꢀ 1506,ꢀ 1229,ꢀ 1141,ꢀ 825ꢀ νmax/cm ; Mpꢀ CDCl
11.2-112.3ꢀ °C;ꢀ MSꢀ (ESI)ꢀ m/zꢀ ꢀ (M+H) Calcdꢀ forꢀ C22
97,0474;ꢀ Found:ꢀ 497.0482ꢀ (100%)ꢀ
Z)-N-(tert-butyl)-2-(2-(4-chlorophenyl)hydrazono)-2-(2-iodo-
phenyl)acetamideꢀ(32).ꢀTheꢀcrudeꢀmaterialꢀwasꢀpurifiedꢀbyꢀcolumnꢀ Found:ꢀ
chromatographyꢀ (n-hexane/ꢀ EtOAcꢀ 97:3)ꢀ toꢀ giveꢀ theꢀ productꢀ asꢀ 6-chloro-N-cyclohexyl-1-phenyl-1H-indazole-3-carboxamideꢀ (36).ꢀ
3
)ꢀδꢀ162.5,ꢀ159.1,ꢀ140.6,ꢀ139.0,ꢀ132.5,ꢀ127.4,ꢀ125.1ꢀ(2ꢀC),ꢀ123.5,ꢀ
+
ꢀ
1
4
H18IN O :ꢀ 123.2,ꢀ123.1,ꢀ114.7ꢀ(2C),ꢀ110.3,ꢀ55.6,ꢀ39.1,ꢀ29.5,ꢀ29.2,ꢀ22.4,ꢀ14.0.ꢀIRꢀ
[M+H] .ꢀꢀꢀꢀꢀꢀ (ꢀ Kꢀ ꢀ ꢀBꢀ ꢀ rꢀ ꢀ) ꢀ ꢀꢀ 3ꢀ ꢀ 2ꢀ ꢀ ꢀ9ꢀ ꢀ1ꢀ ꢀ ,ꢀ ꢀ 2ꢀ ꢀ ꢀ9ꢀ ꢀ5ꢀ ꢀ 6ꢀ ꢀ ,ꢀ ꢀ ꢀ1ꢀ ꢀ6ꢀ ꢀ 4ꢀ ꢀ 0ꢀ ꢀ ꢀ, ꢀ ꢀ1ꢀ ꢀ 5ꢀ 44,ꢀ1245,ꢀ1201,ꢀ1026ꢀνmax/cm ; Mpꢀ58.7-
4 2
+
-1 ꢀ
+
ꢀ
(
59.8ꢀ °C;ꢀ MSꢀ (ESI)ꢀ m/zꢀ ꢀ (M+H) Calcdꢀ forꢀ C20
H
24
N
3
O
2
:ꢀ 338.1869+;ꢀ
338.1843ꢀ (100%)ꢀ
[M+H] .ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ
1
yellowꢀsolidꢀ(0.11ꢀg,ꢀ46%ꢀyield).ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
3
)ꢀδꢀ13.26ꢀ Theꢀ crudeꢀ materialꢀ wasꢀ purifiedꢀ byꢀ columnꢀ chromatographyꢀ (n-
(
brꢀs,ꢀNH),ꢀ7.93ꢀ(brꢀd,ꢀ1ꢀH),ꢀ7.46-7.42ꢀ(m,ꢀ2ꢀH),ꢀ7.22-7.10ꢀ(m,ꢀ5ꢀH),ꢀ hexane/ꢀEtOAcꢀ9:1)ꢀtoꢀgiveꢀtheꢀproductꢀasꢀanꢀoff-whiteꢀsolidꢀ(0.03ꢀ
.11ꢀ(brꢀs,ꢀNH),ꢀ1.35ꢀ(s,ꢀ9ꢀH).ꢀ CꢀNMRꢀ(100ꢀMHz,ꢀCDCl )ꢀδꢀ163.2,ꢀ mg,ꢀ98%ꢀyield).ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl )ꢀδꢀ8.41ꢀ(d,ꢀJꢀ=ꢀ8.60ꢀHz,ꢀ1ꢀ
3 3
42.3,ꢀ140.8,ꢀ139.7,ꢀ134.0,ꢀ131.7,ꢀ130.4,ꢀ129.1,ꢀ128.9,ꢀ126.2,ꢀ114.9,ꢀ H),ꢀ7.69-7.67ꢀ(m,ꢀ3ꢀH),ꢀ7.60-7.57ꢀ(m,ꢀ2ꢀH),ꢀ7.48-7.44ꢀ(m,ꢀ1ꢀH),ꢀ7.30ꢀ
13
1
5
1
1
8
C
00.2,ꢀ51.8,ꢀ28.5.ꢀIRꢀ(KBr)ꢀ3406,ꢀ2956,ꢀ1643,ꢀ1489,ꢀ1231,ꢀ1157,ꢀ987,ꢀ (d,ꢀJꢀ=ꢀ8.64ꢀHz,ꢀ1ꢀH),ꢀ6.99ꢀ(brꢀd,ꢀNH),ꢀ4.08-4.00ꢀ(m,ꢀ1ꢀH),ꢀ2.08-2.05ꢀ
-
1 ꢀ
+ꢀ
13
23ꢀνmax/cm ; Mpꢀ139.4-140.6ꢀ°C;ꢀMSꢀ(ESI)ꢀm/zꢀꢀ(M+H) Calcdꢀforꢀꢀ (m,ꢀ2ꢀH),ꢀ1.80-1.66ꢀ(m,ꢀ4ꢀH),ꢀ1.49-1.17ꢀ(m,ꢀ4ꢀH);ꢀ CꢀNMRꢀ(100ꢀMHz,ꢀ
+
18 3 3
H20ClIN O:ꢀ 456,0340;ꢀ Found:ꢀ 456.0304ꢀ (100%)ꢀ [M+H] .ꢀꢀꢀꢀꢀꢀ Cꢀ ꢀ Dꢀ ꢀꢀ Cꢀ ꢀ ꢀl ꢀꢀ )ꢀ ꢀ ꢀδꢀ ꢀꢀ ꢀ 1ꢀ ꢀ 6ꢀ ꢀ ꢀ1 .1,ꢀ140.7,ꢀ139.8,ꢀ139.0,ꢀ134.2,ꢀ129.7ꢀ(2ꢀC),ꢀ128.0,ꢀ124.4ꢀ
6
ꢀ|ꢀJ.ꢀName.,ꢀ2012,ꢀ00,ꢀ1-3ꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
Pleaseꢀdoꢀnotꢀadjustꢀmarginsꢀ

Pleaseꢀdoꢀnotꢀadjustꢀmarginsꢀ
RSC Advances
Page 7 of 9
JournalꢀNameꢀ
ꢀARTICLEꢀ
1
(
(
1
3
2ꢀC),ꢀ123.5ꢀ(2ꢀC),ꢀ122.2,ꢀ110.2,ꢀ48.0,ꢀ33.2ꢀ(2ꢀC),ꢀ25.6,ꢀ25.0ꢀ(2ꢀC).ꢀIRꢀ solidꢀ(0.02ꢀg,ꢀ48%ꢀyield).ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
3
)ꢀδꢀ8.78ꢀ(brꢀs,ꢀNH),ꢀ
View Article Online
-
1 ꢀ
KBr)ꢀ3324,ꢀ2934,ꢀ2851,ꢀ1637,ꢀ1536,ꢀ1495,ꢀ1251,ꢀ751ꢀνmax/cm ; Mpꢀ 8.56ꢀ(brꢀd,ꢀ1ꢀH),ꢀ7.96ꢀ(brꢀd,ꢀAA’XX’,ꢀ2ꢀH),ꢀ7 D. 8O8 I ꢀ: (1b0 r. ꢀ1 d0 3, ꢀ 9A/ AC 6’ XR XA ’ 0, ꢀ1 24 ꢀ4 H2 )A ,ꢀ
+
ꢀ
46.1-147.2ꢀ °C;ꢀ MSꢀ (ESI)ꢀ m/zꢀ ꢀ (M+H) Calcdꢀ forꢀ C20
H
21ClN
3
O:ꢀ 7.78ꢀ(brꢀd,ꢀ1ꢀH),ꢀ7.66ꢀ(brꢀd,ꢀAA’XX’,ꢀ2ꢀH),ꢀ7.56ꢀ(brꢀt,ꢀ1ꢀH),ꢀ7.43ꢀ(brꢀt,ꢀ1ꢀ
+
13
54.1373;ꢀFound:ꢀ354.1349ꢀ(100%)ꢀ[M+H] .ꢀ
3
H),ꢀ6.93ꢀ(brꢀd,ꢀAA’XX’,ꢀ2ꢀH),ꢀ3.82ꢀ(s,ꢀ3ꢀH).ꢀ CꢀNMRꢀ(100ꢀMHz,ꢀCDCl )ꢀ
N-benzyl-1-(4-chlorophenyl)-1H-indazole-3-carboxamideꢀ (37).ꢀ Theꢀ δꢀ 159.5,ꢀ 156.5,ꢀ 142.9,ꢀ 141.0,ꢀ 140.2,ꢀ 133.7,ꢀ 130.6,ꢀ 128.7,ꢀ 124.5,ꢀ
crudeꢀmaterialꢀwasꢀpurifiedꢀbyꢀcolumnꢀchromatographyꢀ(n-hexane/ꢀ 124.3,ꢀ123.8,ꢀ122.9,ꢀ121.6,ꢀ118.1,ꢀ114.3,ꢀ110.7,ꢀ110.4,ꢀ55.5.ꢀIRꢀ(KBr)ꢀ
1
-1 ꢀ
EtOAcꢀ95:5)ꢀtoꢀgiveꢀtheꢀproductꢀasꢀwhiteꢀsolidꢀ(0.03ꢀg,ꢀ92%ꢀyield).ꢀ Hꢀ 3302,ꢀ2225,ꢀ1648,ꢀ1599,ꢀ1506,ꢀ1237,ꢀ1168,ꢀ836ꢀνmax/cm ; Mpꢀ191.5-
+ꢀ
NMRꢀ(400ꢀMHz,ꢀCDCl
H),ꢀ7.53-7.29ꢀ(m,ꢀ10ꢀH),ꢀ4.73ꢀ(brꢀd,ꢀ2ꢀH);ꢀ CꢀNMRꢀ(100ꢀMHz,ꢀCDCl
3
)ꢀδꢀ8.52ꢀ(d,ꢀJꢀ=ꢀ8.12ꢀHz,ꢀ1ꢀH),ꢀ7.68-7.65ꢀ(m,ꢀ3ꢀ 192.4ꢀ °C;ꢀ MSꢀ (ESI)ꢀ m/zꢀ ꢀ (M+H) Calcdꢀ forꢀ C22
H
17
N
4
O
2
:ꢀ 369,1352+;ꢀ
[M+H] .ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ
13
3
)ꢀδꢀ Found:ꢀ
369.1341ꢀ
(100%)ꢀ
1
1
4
62.1,ꢀ 140.2,ꢀ 139.5,ꢀ 138.2,ꢀ 138.0,ꢀ 133.2,ꢀ 129.7ꢀ (2ꢀ C),ꢀ 128.7ꢀ (2ꢀ C),ꢀ N-(tert-butyl)-1-(4-chlorophenyl)-1H-indazole-3-carboxamideꢀ (43).ꢀ
28.0,ꢀ 127.9ꢀ (2ꢀ C),ꢀ 127.5,ꢀ 124.4ꢀ (2ꢀ C),ꢀ 124.0,ꢀ 123.6,ꢀ 123.3,ꢀ 110.3,ꢀ Theꢀ crudeꢀ materialꢀ wasꢀ purifiedꢀ byꢀ columnꢀ chromatographyꢀ (n-
-
1 ꢀ
3.1.ꢀIRꢀ(KBr)ꢀ3302,ꢀ1648,ꢀ1539,ꢀ1492,ꢀ1196,ꢀ1086,ꢀ976ꢀ νmax/cm ; hexane/ꢀEtOAcꢀ98:2)ꢀtoꢀgiveꢀtheꢀproductꢀasꢀyellowꢀsolidꢀ(0.02ꢀg,ꢀ59%ꢀ
+
ꢀ
1
Mpꢀ 101.3-102.6ꢀ °C;ꢀ MSꢀ (ESI)ꢀ m/zꢀ ꢀ (M+H) Calcdꢀ forꢀ C21
62.1060;ꢀ Found:ꢀ 362.1030ꢀ (100%)ꢀ
H
17ClN
3
O:ꢀ yield).ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
3
)ꢀδꢀ8.49ꢀ(brꢀd,ꢀ1ꢀH),ꢀ7.67-7.61ꢀ(m,ꢀ3ꢀ
+
3
[M+H] .ꢀꢀꢀꢀꢀꢀ Hꢀ ꢀ ꢀ)ꢀ ,ꢀ ꢀ 7ꢀ ꢀ ꢀ. ꢀ5ꢀ ꢀ 2ꢀ ꢀꢀ ꢀ( ꢀbꢀ ꢀ rꢀ ꢀ ꢀdꢀ ꢀ ,ꢀ ꢀ ꢀAꢀ ꢀ Aꢀ ꢀ ꢀ’ ꢀXꢀ ꢀ Xꢀ ꢀ ’ꢀ ,ꢀ ꢀ ꢀ2ꢀ ꢀꢀ ꢀ Hꢀ ꢀ ꢀ)ꢀ ,ꢀ ꢀ ꢀ7 .45ꢀ(brꢀt,ꢀ1ꢀH),ꢀ7.33ꢀ(brꢀt,ꢀ1ꢀH),ꢀ7.01ꢀ(brꢀ
13
3
N-(4-methoxyphenyl)-1-phenyl-1H-indazole-3-carboxamideꢀ (38).ꢀ s,ꢀ NH),ꢀ 1.53ꢀ (s,ꢀ 9ꢀ H).ꢀ Cꢀ NMRꢀ (100ꢀ MHz,ꢀ CDCl )ꢀ δꢀ 161.7,ꢀ 140.5,ꢀ
Theꢀ crudeꢀ materialꢀ wasꢀ purifiedꢀ byꢀ columnꢀ chromatographyꢀ (n- 140.3,ꢀ138.0,ꢀ133.1,ꢀ129.7,ꢀ127.9,ꢀ124.5,ꢀ123.8,ꢀ123.6,ꢀ123.4,ꢀ110.1,ꢀ
hexane/ꢀ EtOAcꢀ 9:1)ꢀ toꢀ giveꢀ theꢀ productꢀ asꢀ redꢀ solidꢀ (0.03ꢀ g,ꢀ 75%ꢀ 51.3,ꢀ29.1.ꢀIRꢀ(KBr)ꢀ3401,ꢀ3060,ꢀ2961,ꢀ1662,ꢀ1530,ꢀ1497,ꢀ1193,ꢀ1091ꢀ
1
-1 ꢀ
+ꢀ ꢀ
yield).ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
7
3
)ꢀδꢀ8.88ꢀ(brꢀs,ꢀNH),ꢀ8.53ꢀ(d,ꢀ(d,ꢀJꢀ=ꢀ
νmax/cm ; Mpꢀ 47.1-48.7ꢀ °C;ꢀ MSꢀ (ESI)ꢀ m/zꢀ ꢀ (M+H) Calcdꢀ forꢀꢀ
+
.00ꢀHz,ꢀ1ꢀH),ꢀ7.73-7.66ꢀ(m,ꢀ5ꢀH),ꢀ7.57-7.54ꢀ(m,ꢀ2ꢀH),ꢀ7.46-7.41ꢀ(m,ꢀ2ꢀ
C
18
H
19ClN
3
O:ꢀ 328,1217;ꢀ Found:ꢀ 328.1224ꢀ (100%)ꢀ [M+H] .ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ
H),ꢀ7.34ꢀ(brꢀt,ꢀ1ꢀH),ꢀ6.91ꢀ(d,ꢀJꢀ=ꢀ8.68ꢀHz,ꢀ2ꢀH),ꢀ3.78ꢀ(s,ꢀ3ꢀH);ꢀ CꢀNMRꢀ 1-(4-chlorophenyl)-N-cyclohexyl-1H-indazole-3-carboxamideꢀ (44).ꢀ
100ꢀMHz,ꢀCDCl )ꢀδꢀ160.1,ꢀ156.3,ꢀ140.5,ꢀ139.4,ꢀ139.3,ꢀ131.0,ꢀ129.6,ꢀ Theꢀ crudeꢀ materialꢀ wasꢀ purifiedꢀ byꢀ columnꢀ chromatographyꢀ (n-
27.8ꢀ(2C),ꢀ123.9,ꢀ123.5,ꢀ123.4,ꢀ123.2,ꢀ121.5,ꢀ114.2,ꢀ110.6,ꢀ55.5.ꢀIRꢀ hexane/ꢀEtOAcꢀ98:2)ꢀtoꢀgiveꢀtheꢀproductꢀasꢀyellowꢀsolidꢀ(0.03ꢀg,ꢀ83%ꢀ
13
(
3
1
(
1
-1 ꢀ
1
3
KBr)ꢀ3318,ꢀ2956,ꢀ1668,ꢀ1530,ꢀ1240,ꢀ1020,ꢀ823ꢀνmax/cm ; Mpꢀ116.6- yield).ꢀ Hꢀ NMRꢀ (400ꢀ MHz,ꢀ CDCl )ꢀ δꢀ 8.49ꢀ (brꢀ d,ꢀ 1ꢀ H),ꢀ 7.67ꢀ (brꢀ d,ꢀ
+ꢀ
17.3ꢀ °C;ꢀ MSꢀ (ESI)ꢀ m/zꢀ ꢀ (M+H) Calcdꢀ forꢀ C21
344.1407ꢀ (100%)ꢀ
-(4-chlorophenyl)-N-(4-methoxybenzyl)-1H-indazole-3-
H
18
N
3
O
2
:ꢀ 344.1399;ꢀ AA’XX’,ꢀ2ꢀH),ꢀ7.63ꢀ(brꢀd,ꢀ1ꢀH),ꢀ7.52ꢀ(brꢀd,ꢀAA’XX’,ꢀ2ꢀH),ꢀ7.45ꢀ(brꢀt,ꢀ1ꢀH),ꢀ
+
Found:ꢀ
[M+H] .ꢀꢀꢀꢀꢀꢀ 7ꢀ ꢀ .ꢀ 3ꢀ ꢀ ꢀ4ꢀ ꢀꢀ ꢀ (ꢀ ꢀbꢀ ꢀrꢀ ꢀ ꢀtꢀ ,ꢀ ꢀ ꢀ1ꢀ ꢀꢀ ꢀ Hꢀ ꢀꢀ )ꢀ ,ꢀ ꢀ ꢀ7ꢀ ꢀ .ꢀ 0ꢀ ꢀ 0ꢀ ꢀꢀ ꢀ(ꢀ bꢀ ꢀ ꢀr ꢀꢀ ꢀs ꢀ ,ꢀ ꢀ ꢀNꢀ ꢀ ꢀHꢀ ꢀ )ꢀ ꢀ, ꢀꢀ 4ꢀ ꢀ .ꢀ 1ꢀ ꢀ ꢀ0ꢀ ꢀ-ꢀ 4ꢀ ꢀ.01ꢀ(m,ꢀ1ꢀH),ꢀ2.08-2.03ꢀ(m,ꢀ2ꢀ
13
1
3
H),ꢀ1.83-1.76ꢀ(m,ꢀ3ꢀH),ꢀ1.49-1.20ꢀ(m,ꢀ5ꢀH).ꢀ CꢀNMRꢀ(100ꢀMHz,ꢀCDCl )ꢀ
carboxamideꢀ (39).ꢀ Theꢀ crudeꢀ materialꢀ wasꢀ purifiedꢀ byꢀ columnꢀ δꢀ 161.3,ꢀ 140.2,ꢀ 140.0,ꢀ 138.0,ꢀ 133.1,ꢀ 129.7,ꢀ 127.9,ꢀ 124.4,ꢀ 124.0,ꢀ
chromatographyꢀ (n-hexane/ꢀ EtOAcꢀ 9:1)ꢀ toꢀ giveꢀ theꢀ productꢀ asꢀ 123.5,ꢀ 123.4,ꢀ 110.1,ꢀ 48.0,ꢀ 33.3,ꢀ 25.6,ꢀ 25.0.ꢀ IRꢀ (KBr)ꢀ 3401,ꢀ 2923,ꢀ
1
-1 ꢀ
orangeꢀsolidꢀ(0.03ꢀg,ꢀ85%ꢀyield).ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
3
)ꢀδꢀ8.52ꢀ(brꢀ 2846,ꢀ 1657,ꢀ 1528,ꢀ 1492,ꢀ 1196,ꢀ 1086,ꢀ 831ꢀ νmax/cm ; Mpꢀ 58.9-60.8ꢀ
+ꢀ
d,ꢀ1ꢀH),ꢀ7.64-7.61ꢀ(m,ꢀ3ꢀH),ꢀ7.49-7.46ꢀ(m,ꢀ4ꢀH),ꢀ7.37-7.31ꢀ(m,ꢀ3ꢀH),ꢀ °C;ꢀMSꢀ(ESI)ꢀm/zꢀꢀ(M+H) CalcdꢀforꢀC20
H
3
21ClN O:ꢀ354,1373;ꢀFound:ꢀ
13
+
6
.86ꢀ(brꢀd,ꢀAA’XX’,ꢀ2ꢀH),ꢀ4.64ꢀbrꢀd,ꢀ2ꢀH),ꢀ3.77ꢀ(s,ꢀ3ꢀH).ꢀ CꢀNMRꢀ(100ꢀ 354.1384ꢀ(100%)ꢀ[M+H] .ꢀ
MHz,ꢀCDCl )ꢀδꢀ162.0,ꢀ159.0,ꢀ140.2,ꢀ139.7,ꢀ138.0,ꢀ133.1,ꢀ130.4,ꢀ129.7,ꢀ
29.3,ꢀ128.0,ꢀ124.3,ꢀ124.0,ꢀ123.5,ꢀ123.4,ꢀ114.1,ꢀ110.3,ꢀ55.3,ꢀ42.6.ꢀIRꢀ
KBr)ꢀ3313,ꢀ1646,ꢀ1541,ꢀ1492,ꢀ1086,ꢀ828ꢀνmax/cm ; Mpꢀ135.0-136.1ꢀ
C;ꢀMSꢀ(ESI)ꢀm/zꢀꢀ(M+H) CalcdꢀforꢀC22
92.1133ꢀ (100%)ꢀ
3
1
(
°
3
-
1 ꢀ
Generalꢀ preparationꢀ ofꢀ N-arylindazole-3-carbonitrilesꢀ (45).ꢀ N-
benzyl-1-(4-chlorophenyl)-1H-indazole-3-carboxamideꢀ 37ꢀ (0.07ꢀ
mmol,ꢀ 1ꢀ equiv.)ꢀ isꢀ dissolvedꢀ inꢀ phosphorousꢀ oxychlorideꢀ (0.03M)ꢀ
[M+H] .ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ
+ꢀꢀ
H
19ClN
3
O
2
:ꢀ392.1166;ꢀFound+:ꢀ
stirredꢀatꢀ150°Cꢀforꢀ4ꢀhours.ꢀTheꢀreactionꢀmixtureꢀisꢀcooledꢀatꢀroomꢀ
temperatureꢀ andꢀ pouredꢀ intoꢀ ice/ammoniumꢀ hydroxide.ꢀ Theꢀ
productꢀisꢀthenꢀextractedꢀwithꢀethylꢀacetateꢀ(x3);ꢀtheꢀorganicꢀphaseꢀ
N-(tert-butyl)-1-(4-cyanophenyl)-1H-indazole-3-carboxamideꢀ (40).ꢀ
Theꢀ crudeꢀ materialꢀ wasꢀ purifiedꢀ byꢀ columnꢀ chromatographyꢀ (n-
hexane/ꢀEtOAcꢀ95:5)ꢀtoꢀgiveꢀtheꢀproductꢀasꢀyellowishꢀsolidꢀ(0.02ꢀg,ꢀ
1
isꢀ washedꢀ withꢀ brine,ꢀ driedꢀ overꢀ Na
productꢀ isꢀ thenꢀ purifiedꢀ byꢀ chromatographicꢀ columnꢀ (n-
hexane/ethylꢀ acetate).ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ
-(4-chlorophenyl)-1H-indazole-3-carbonitrileꢀ (45).ꢀ Theꢀ crudeꢀ
materialꢀwasꢀpurifiedꢀbyꢀcolumnꢀchromatographyꢀ(n-hexane/ꢀEtOAcꢀ
2 4
SO ꢀ andꢀ evaporated.ꢀ Theꢀ
6
5%ꢀyield).ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
3
)ꢀδꢀ8.50ꢀ(brꢀd,ꢀ1ꢀH),ꢀ6.91ꢀ(brꢀd,ꢀ
AA’XX’,ꢀ2ꢀH),ꢀ7.84ꢀ(brꢀd,ꢀAA’XX’,ꢀ2ꢀH),ꢀ7.73ꢀ(brꢀd,ꢀ1ꢀH),ꢀ7.49ꢀ(brꢀt,ꢀ1ꢀH),ꢀ
1
3
7
.35ꢀ(brꢀt,ꢀ1ꢀH),ꢀ6.99ꢀ(brꢀs,ꢀNH),ꢀ1.53ꢀ(s,ꢀ9ꢀH).ꢀ CꢀNMRꢀ(100ꢀMHz,ꢀ
CDCl )ꢀδꢀ161.3,ꢀ143.0,ꢀ141.7,ꢀ140.0,ꢀ133.6,ꢀ128.5,ꢀ124.4,ꢀ123.9ꢀ(2ꢀC),ꢀ
22.7,ꢀ 118.2,ꢀ 110.3,ꢀ 110.3,ꢀ 51.5,ꢀ 29.0.ꢀ IRꢀ (KBr)ꢀ 3340,ꢀ 2967,ꢀ 2230,ꢀ
1
3
1
1
1
-1 ꢀ
9
8:2)ꢀtoꢀgiveꢀtheꢀproductꢀasꢀyellowishꢀsolidꢀ(0.02ꢀg,ꢀ96%ꢀyield).ꢀ Hꢀ
NMRꢀ(400ꢀMHz,ꢀCDCl )ꢀδꢀ7.93ꢀ(brꢀd,ꢀ1ꢀH),ꢀ7.75ꢀ(brꢀd,ꢀ1ꢀH),ꢀ7.68ꢀ(brꢀd,ꢀ
AA’XX’,ꢀ2ꢀH),ꢀ7.57-7.55ꢀ(m,ꢀ3ꢀH),ꢀ7.44ꢀ(brꢀt,ꢀ1ꢀH).ꢀ CꢀNMRꢀ(100ꢀMHz,ꢀ
CDCl )ꢀ δꢀ 130.0,ꢀ 137.4,ꢀ 134.3,ꢀ 130.0,ꢀ 128.9,ꢀ 126.1,ꢀ 124.6,ꢀ 124.4,ꢀ
20.6,ꢀ120.1,ꢀ113.1,ꢀ111.2.ꢀIRꢀ(KBr)ꢀ2236,ꢀ1495,ꢀ1355,ꢀ1218,ꢀ1089,ꢀ
651,ꢀ1541,ꢀ1363,ꢀ850ꢀνmax/cm ; Mpꢀ131.7-133.0ꢀ°C;ꢀMSꢀ(ESI)ꢀm/zꢀꢀ
+ꢀ
(
[
M+H) Calcdꢀ forꢀ C19
M+H] .ꢀꢀꢀꢀ
H
19
N
4
O:ꢀ 319,1559;ꢀ Found:ꢀ 319.1525ꢀ (100%)ꢀ
3
13
+
1
-(4-cyanophenyl)-N-pentyl-1H-indazole-3-carboxamideꢀ (41).ꢀ Theꢀ
3
1
8
C
crudeꢀmaterialꢀwasꢀpurifiedꢀbyꢀcolumnꢀchromatographyꢀ(n-hexane/ꢀ
-
1 ꢀ
+ꢀ
34ꢀ νmax/cm ; Mpꢀ 164.4-165.6ꢀ °C;ꢀ MSꢀ (ESI)ꢀ m/zꢀ (M+H) Calcdꢀ forꢀꢀꢀ
EtOAcꢀ 95:5)ꢀ toꢀ giveꢀ theꢀ productꢀ asꢀ lightꢀ pinkꢀ solidꢀ (0.02ꢀ g,ꢀ 64%ꢀ
ꢀ+
1
14 9 3
H ClN :ꢀ254,0485;ꢀFound:ꢀ254.0467ꢀ(100%)ꢀ[M+H] .ꢀ
yield).ꢀ Hꢀ NMRꢀ (400ꢀ MHz,ꢀ CDCl
3
)ꢀ δꢀ 8.51ꢀ (brꢀ d,ꢀ 1ꢀ H),ꢀ 7.91ꢀ (brꢀ d,ꢀ
AA’XX’,ꢀ2ꢀH),ꢀ7.84ꢀ(brꢀd,ꢀAA’XX’,ꢀ2ꢀH),ꢀ7.75ꢀ(brꢀd,ꢀ1ꢀH),ꢀ7.51ꢀ(brꢀt,ꢀ1ꢀH),ꢀ
.37ꢀ(brꢀt,ꢀ1ꢀH),ꢀ7.12ꢀ(brꢀt,ꢀNH),ꢀ3.53-3.48ꢀ(m,ꢀ2ꢀH),ꢀ1.76-1.65ꢀ(m,ꢀ2ꢀ
7
13
H),ꢀ1.39-1.38ꢀ(m,ꢀ4ꢀH),ꢀ0.92-0.89ꢀ(m,ꢀ3ꢀH).ꢀ CꢀNMRꢀ(100ꢀMHz,ꢀCDCl
δꢀ 161.8,ꢀ 143.1,ꢀ 141.1,ꢀ 140.0,ꢀ 133.6,ꢀ 128.5,ꢀ 124.5,ꢀ 124.0,ꢀ 123.8,ꢀ
3
)ꢀ Acknowledgementsꢀ
FinancialꢀsupportꢀfromꢀUniversitàꢀdelꢀPiemonteꢀOrientale,ꢀNovara,ꢀ
andꢀUniversitàꢀdegliꢀStudiꢀdiꢀNapoliꢀ“FedericoꢀII”ꢀisꢀacknowledged.ꢀ
Thisꢀ researchꢀ wasꢀ fundedꢀ byꢀ Regioneꢀ Campaniaꢀ underꢀ PORꢀ
1
3
1
22.7,ꢀ 118.2,ꢀ 110.4,ꢀ 110.3,ꢀ 39.2,ꢀ 29.5,ꢀ 29.1,ꢀ 22.4,ꢀ 14.0.ꢀ IRꢀ (KBr)ꢀ
-
1 ꢀ
285,ꢀ2934,ꢀ2225,ꢀ1646,ꢀ1555,ꢀ1421,ꢀ1179,ꢀ842ꢀνmax/cm ; Mpꢀ144.2-
+
ꢀ
45.5ꢀ °C;ꢀ MSꢀ (ESI)ꢀ m/zꢀ ꢀ (M+H) Calcdꢀ forꢀ C20
333.1728ꢀ (100%)ꢀ
-(4-cyanophenyl)-N-(4-methoxyphenyl)-1H-indazole-3-
21 4
H N O:ꢀ 333,1715;ꢀ
+
Campaniaꢀ FESRꢀ 2007-2013-O.O.2.1ꢀ (FarmaBioNet,ꢀ CUPꢀ
B25C13000230007)ꢀꢀ
Found:ꢀ
1
[M+H] .ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ
carboxamideꢀ (42).ꢀ Theꢀ crudeꢀ materialꢀ wasꢀ purifiedꢀ byꢀ columnꢀ
chromatographyꢀ(n-hexane/ꢀEtOAcꢀ9:1)ꢀtoꢀgiveꢀtheꢀproductꢀasꢀpinkꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
J.ꢀName.,ꢀ2013,ꢀ00,ꢀ1-3ꢀ|ꢀ7ꢀ
Pleaseꢀdoꢀnotꢀadjustꢀmarginsꢀ

Pleaseꢀdoꢀnotꢀadjustꢀmarginsꢀ
RSC Advances
Page 8 of 9
ARTICLEꢀ
JournalꢀNameꢀ
ꢀ
Referencesꢀ
ꢀ
View Article Online
DOI: 10.1039/C6RA01442A
However,ꢀ asꢀ theꢀ synthesisꢀ ofꢀ compoundꢀ “a”ꢀ needsꢀ
paramethoxy-benzylisocyanideꢀinꢀplaceꢀofꢀtheꢀcommerciallyꢀ
availableꢀ benzylꢀ isocyanideꢀ usedꢀ forꢀ benzylꢀ amideꢀ 37,ꢀ andꢀ
theꢀyieldsꢀofꢀtheꢀconversionꢀofꢀbothꢀtheꢀbenzylꢀamidesꢀareꢀ
theꢀsameꢀ(96%),ꢀweꢀreasonedꢀthatꢀtheꢀbestꢀwayꢀtoꢀgetꢀsuchꢀaꢀ
carbonitrileꢀwasꢀbyꢀusingꢀtheꢀcommerciallyꢀavailableꢀbenzylꢀ
isocyanide.ꢀꢀ
1
(a)ꢀ D.ꢀ D.ꢀ Gaikwad,ꢀ A.ꢀ D.ꢀ Chapolikar,ꢀ C.ꢀ G.ꢀ Devkate,ꢀ K.ꢀ D.ꢀ
Warad,ꢀA.ꢀP.ꢀTayade,ꢀR.ꢀP.ꢀPawar,ꢀDomb,ꢀA.ꢀJ.ꢀEur.ꢀJ.ꢀMed.ꢀ
Chem.ꢀ 2015,ꢀ 90,ꢀ 707.ꢀ (b)ꢀ H.ꢀ Cerecetto,ꢀ ꢀ A.ꢀ Gerpe,ꢀ M.ꢀ
Gonzalez,ꢀV.ꢀJ.ꢀAran,ꢀC.ꢀO.ꢀdeꢀOcariz,ꢀMini-Rev.ꢀMed.ꢀChem.ꢀ
2
P.ꢀLi,ꢀC.ꢀWu,ꢀJ.ꢀZhao,ꢀD.C.ꢀRogness,ꢀF.ꢀShi,ꢀJ.ꢀOrg.ꢀChem.ꢀ2012,ꢀ
005,ꢀ5,ꢀ869.ꢀꢀ
2
3
ꢀ
7
2
7,ꢀ 3149.ꢀ (b)ꢀ C.ꢀ Spiteri,ꢀ S.ꢀ Keeling,ꢀ J.ꢀ E.ꢀ Moses,ꢀ Org.ꢀ Lett.ꢀ
010,ꢀ12,ꢀ3368.ꢀꢀ
ꢀ
L.ꢀCrocetti,ꢀM.ꢀP.ꢀGiovannoni,ꢀI.ꢀA.ꢀSchepetkin,ꢀM.ꢀT.ꢀQuinn,ꢀA.ꢀ
I.ꢀKhlebnikov,ꢀA.ꢀCilibrizzi,ꢀV.ꢀDalꢀPiaz,ꢀA.ꢀGraziano,ꢀC.ꢀVergelli,ꢀ
Bioorg.ꢀMed.ꢀChem.ꢀ2011,ꢀ19,ꢀ4460.ꢀ
4
5
G.ꢀ A.ꢀ Pinna,ꢀ M.ꢀ A.ꢀ Pirisi,ꢀ J.-M.ꢀ Mussinu,ꢀ G.ꢀ Murineddu,ꢀ G.ꢀ
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R.ꢀ D'Alessio,ꢀ A.ꢀ Bargiotti,ꢀ M.ꢀ G.ꢀ Brasca,ꢀ A.ꢀ Ermoli,ꢀ P.ꢀ
Pevarello,ꢀM.ꢀTibolla,ꢀWOꢀ2003070236.ꢀ
6
7
D.ꢀJ.ꢀKyle,ꢀC.ꢀNi,ꢀL.ꢀTafesse,ꢀJ.ꢀYao,ꢀWOꢀ2011158108.ꢀꢀ
S.ꢀ Kitamura,ꢀ T.ꢀ D.ꢀ Aicher,ꢀ S.ꢀ Gonzales,ꢀ Y.ꢀ Leꢀ Huerou,ꢀ S.ꢀ A.ꢀ
Pratt,ꢀT.ꢀTurner,ꢀY.ꢀNakada,ꢀWOꢀ2008011131.ꢀꢀ
8
9
D.ꢀV.ꢀKumar,ꢀP.ꢀM.ꢀSlattum,ꢀK.ꢀM.ꢀYager,ꢀM.ꢀD.ꢀShenderovich,ꢀ
R.ꢀTangallapally,ꢀS.-H.ꢀKim,ꢀWOꢀ2012ꢀ177782.ꢀꢀ
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Lebedev,ꢀA.ꢀS.ꢀKhartulyari,ꢀA.ꢀZ.ꢀVoskoboynikov,ꢀJ.ꢀOrg.ꢀChem.ꢀ
2
005,ꢀ70,ꢀ596.ꢀ(c)ꢀP.ꢀLi,ꢀJ.ꢀZhao,ꢀC.ꢀWu,ꢀR.ꢀC.ꢀLarock,ꢀF.ꢀShi,ꢀ
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7 Theꢀ conversionꢀ toꢀ carbonitrileꢀ hasꢀ beenꢀ successfullyꢀ
accomplishedꢀ withꢀ highꢀ yieldꢀ alsoꢀ withꢀ theꢀ para-methoxyꢀ
analogꢀofꢀbenzylꢀamideꢀ37:ꢀ
O
H
N
O
CN
POCl3, 150°C
N
sealed tube, 4h
N
N
a
N
Cl
b
Cl
8
ꢀ|ꢀJ.ꢀName.,ꢀ2012,ꢀ00,ꢀ1-3ꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
Pleaseꢀdoꢀnotꢀadjustꢀmarginsꢀ

Page 9 of 9
RSC Advances
View Article Online
DOI: 10.1039/C6RA01442A
A convergent, efficient and regio-selective two-step synthesis of pharmaceutically relevant 1-
arylindazole-3-carboxamides through a Multi-Component Reaction and a Buchwald-Hartwig
cyclization.
R2
NH
N
R2
R1
O
H
NH
O
N
Cl
N
I
R1
R3
MCR
Buchwald-Hartwig
cyclization
R3
R1
H
I
N
N
O
N
R3
OH
OH
R2
CN