Nucleophilic substitution of azide acting as a pseudo leaving group: One-step synthesis of various aza heterocycles

Article abstract of DOI:10.1021/jo401738f

The reaction of 3-azidopropanoic acid with the carbodiimide-based coupling reagent DIC leads to a six-membered-ring intermediate acting as a versatile precursor to a diverse set of aza heterocycles, including mono-, bi-, and tricyclic compounds.

Full text of DOI:10.1021/jo401738f

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Article
Nucleophilic substitution of azide acting as a pseudo leaving
group: one step synthesis of various azaheterocycles
Christelle Doebelin, Martine Schmitt, Cyril Antheaume, Jean-Jacques Bourguignon, and Frédéric Bihel
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo401738f • Publication Date (Web): 03 Oct 2013
Downloaded from http://pubs.acs.org on October 6, 2013
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Nucleophilic substitution of azide acting as a pseudo leaving
group: one-step synthesis of various azaheterocycles
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ChristelleꢀDoebelin,ꢀMartineꢀSchmitt,ꢀCyrilꢀAntheaume,ꢀJeanꢁJacquesꢀBourguignon,ꢀFrédéricꢀBihel*ꢀ
Laboratoireꢀd’InnovationꢀThérapeutique,ꢀUMR7200,ꢀCNRS,ꢀUniversitéꢀdeꢀStrasbourg,ꢀFacultéꢀdeꢀ
pharmacie,ꢀ74,ꢀrouteꢀduꢀrhin,ꢀ67400ꢀIllkirch,ꢀFrance.ꢀ
Eꢁmail:ꢀfbihel@unistra.frꢀ
ꢀ
ABSTRACTꢀGRAPHICꢀ
ꢀ
ꢀ
ABSTRACTꢀ
Theꢀreactionꢀofꢀ3ꢁazidopropanoicꢀacidꢀwithꢀtheꢀcarbodiimideꢁbasedꢀcouplingꢀreagentꢀDICꢀleadsꢀtoꢀaꢀ
sixꢁmemberedꢀringꢀintermediateꢀactingꢀasꢀaꢀversatileꢀprecursorꢀtoꢀaꢀdiverseꢀsetꢀofꢀazaheterocycles,ꢀ
includingꢀmonoꢁ,ꢀbiꢁꢀandꢀtricyclicꢀcompounds.ꢀ
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INTRODUCTIONꢀ
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Sinceꢀ theꢀ firstꢀ descriptionꢀ ofꢀ phenylꢀ azidesꢀ byꢀ Grießꢀ inꢀ 1864,1ꢀ organicꢀ chemistryꢀ involvingꢀ organicꢀ
azidesꢀhasꢀbeenꢀextensivelyꢀdeveloped,ꢀleadingꢀtoꢀtheꢀsynthesisꢀofꢀaminoꢀacidsꢀasꢀwellꢀasꢀaꢀdiverseꢀ
rangeꢀofꢀazaheterocycles.2ꢀOverꢀtheꢀlastꢀdecades,ꢀorganicꢀazidesꢀhaveꢀbeenꢀreportedꢀtoꢀexhibitꢀaꢀwideꢀ
rangeꢀ ofꢀ chemicalꢀ reactivities.ꢀ Becauseꢀ ofꢀ theirꢀ 1,3ꢁdipolarꢀ character,ꢀ azidesꢀ reactꢀ withꢀ electronꢁ
deficientꢀ compoundsꢀ atꢀ N1ꢀ andꢀ withꢀ electronꢁrichꢀ compoundsꢀ atꢀ N3,ꢀ providingꢀ accessꢀ toꢀ [3+2]ꢀ
cycloadditionꢀ reactionsꢀ withꢀ unsaturatedꢀ substrates.3ꢀ Organicꢀ azidesꢀ canꢀ alsoꢀ behaveꢀ asꢀ pseudoꢁ
nitrenesꢀandꢀallowꢀforꢀtheꢀformationꢀofꢀaꢀnewꢀbondꢀtoꢀnitrogenꢀN1,ꢀwithꢀlossꢀofꢀmolecularꢀnitrogen.4ꢀ
Inꢀ contrast,ꢀ theꢀ pseudohalogenicꢀ characterꢀ ofꢀ aliphaticꢀ azidesꢀ isꢀ lessꢀ wellꢀ known.ꢀ Althoughꢀ azidesꢀ
haveꢀ beenꢀ reportedꢀ toꢀ undergoꢀ eliminationꢀ toꢀ formꢀ alkenes,5ꢀ toꢀ ourꢀ knowledgeꢀ noꢀ nucleophilicꢀ
substitutionꢀhasꢀeverꢀbeenꢀreportedꢀofꢀanꢀazidoꢀgroupꢀinꢀanꢀaliphaticꢀchain.ꢀHerein,ꢀweꢀdescribeꢀtheꢀ
unexpectedꢀ reactivityꢀ ofꢀ 3ꢁazidopropionicꢀ acidꢀ withꢀ standardꢀ couplingꢀ reagentsꢀ suchꢀ asꢀ
carbodiimides,ꢀopeningꢀaccessꢀtoꢀaꢀvarietyꢀofꢀazaheterocyclicꢀsystemsꢀunderꢀmildꢀconditions.ꢀ
RESULTSꢀandꢀDISCUSSIONꢀ
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DuringꢀourꢀworkꢀonꢀchemicalꢀprobeꢀsynthesisꢀusingꢀClickꢀchemistry,ꢀweꢀplannedꢀtoꢀcoupleꢀtheꢀshortꢀ
spacerꢀ3ꢁazidopropanoicꢀacidꢀ1ꢀ(Schemeꢀ1)ꢀwithꢀaꢀphenylhydrazineꢀderivative,ꢀusingꢀclassicalꢀreactionꢀ
conditionsꢀ(COMU,ꢀTEA,ꢀDMF,ꢀrt,ꢀ5h).ꢀSurprisingly,ꢀtheꢀexpectedꢀhydrazideꢀwasꢀnotꢀformed,ꢀandꢀonlyꢀ
pyrazolidinꢁ3ꢁoneꢀ 2aꢀ wasꢀ isolatedꢀ inꢀ moderateꢀ yieldꢀ (Tableꢀ 1,ꢀ entryꢀ 1).ꢀ Otherꢀ classicalꢀ couplingꢀ
reagentsꢀ wereꢀ alsoꢀ screenedꢀ (Tableꢀ 1);ꢀ whileꢀ theꢀ phosphoniumꢀ saltꢀ PyBOPꢀ andꢀ theꢀ uroniumꢀ saltꢀ
HATUꢀaffordedꢀ2aꢀinꢀlowꢀyields,ꢀtheꢀcarbodiimidesꢀDICꢀandꢀDCCꢀledꢀtoꢀexcellentꢀyieldsꢀ(entriesꢀ4ꢀandꢀ
5).ꢀHowever,ꢀtheꢀwaterꢁsolubleꢀEDCIꢀaffordedꢀ2aꢀinꢀonlyꢀ38%ꢀyield.ꢀSeveralꢀbasesꢀwereꢀscreened,ꢀwithꢀ
DIEAꢀgivingꢀaꢀsimilarꢀresultꢀasꢀthatꢀwithꢀTEAꢀ(Tableꢀ1,ꢀentriesꢀ4ꢀ&ꢀ7).ꢀInꢀcontrast,ꢀtheꢀweaklyꢀbasicꢀNꢁ
methylmorpholineꢀ(NMM)ꢀwasꢀfoundꢀtoꢀbeꢀlessꢀefficientꢀ(entryꢀ8),ꢀandꢀnoꢀreactionꢀoccurredꢀwithꢀtheꢀ
stronglyꢀbasicꢀDBUꢀ(entryꢀ9).ꢀTheꢀmineralꢀbaseꢀK2CO3ꢀ(entryꢀ10)ꢀwasꢀentirelyꢀineffective.ꢀBesidesꢀDMF,ꢀ
otherꢀsolventsꢀsuchꢀasꢀDMSOꢀorꢀMeCNꢀgaveꢀ2aꢀinꢀmoderateꢀyieldsꢀ(entriesꢀ11ꢀ&ꢀ12),ꢀwhileꢀdioxaneꢀorꢀ
DCMꢀledꢀtoꢀlowerꢀyieldsꢀ(entriesꢀ13ꢀ&ꢀꢀ14).ꢀꢀ
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Schemeꢀ1.ꢀOneꢁstepꢀsynthesisꢀofꢀ3ꢁazidopropionicꢀacidꢀ1ꢀasꢀdescribedꢀbyꢀKuangꢀatꢀal.6ꢀ
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Tableꢀ1.ꢀOptimizationꢀofꢀtheꢀpyrazolidinꢁ3ꢁoneꢀ2aꢀsynthesis[a]ꢀ
Coupling
Entry
Base
Solvent
Yield[b]
Reagent
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2
COMU
PyBOP
HATU
DIC
TEA
TEA
TEA
TEA
TEA
TEA
DIEA
NMM
DBU
K2CO3
TEA
TEA
TEA
TEA
DMF
DMF
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16
3
DMF
11
4
DMF
91 (82)[c]
89
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DCC
EDCI
DIC
DMF
6
DMF
38
7
DMF
78
8
DIC
DMF
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9
DIC
DMF
0
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12
13
14
DIC
DMF
23
DIC
DMSO
MeCN
Dioxane
DCM
71
DIC
60
DIC
43
DIC
24
[a]ꢀ Reactionsꢀ wereꢀ carriedꢀ outꢀ onꢀ aꢀ scaleꢀ ofꢀ 0.26ꢀ mmolꢀ ofꢀ arylhydrazineꢀ hydrochlorideꢀ ꢀ andꢀ 0.47ꢀ
mmolꢀofꢀ1ꢀinꢀtheꢀpresenceꢀofꢀcouplingꢀreagentꢀ(0.51ꢀmmol)ꢀandꢀbaseꢀ(0.78ꢀmmol)ꢀinꢀ3ꢀmLꢀofꢀsolventꢀ
underꢀargonꢀatmosphere.ꢀ[b]ꢀYieldꢀdeterminedꢀbyꢀHPLC/UVꢀusingꢀcaffeineꢀasꢀinternalꢀstandard.ꢀ[c]ꢀ
Isolatedꢀyieldꢀ
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Whenꢀtheꢀreactionꢀwasꢀconductedꢀonꢀsmallꢀorꢀlargeꢀscaleꢀ(0.2ꢀmmolꢀorꢀ2ꢀmmolꢀofꢀphenylhydrazine,ꢀ
respectively),ꢀ 2bꢀ wasꢀ recoveredꢀ inꢀ excellentꢀ yieldꢀ (Tableꢀ 2).ꢀ Aꢀ setꢀ ofꢀ experimentsꢀ employingꢀ
substitutedꢀ phenylhydrazinesꢀ illustratedꢀ theꢀ transformation’sꢀ generalꢀ substituentꢀ tolerance.ꢀ Theꢀ
stericallyꢀ hinderedꢀ oꢁtolylhydrazineꢀ affordedꢀ 2cꢀ inꢀ 80%ꢀ yield.ꢀ Withꢀ theꢀ electronꢁwithdrawingꢀ 4ꢁ
nitrophenylꢀ group,ꢀ theꢀ reactionꢀ mixtureꢀ hadꢀ toꢀ beꢀ heatedꢀ atꢀ 50°Cꢀ toꢀ affordꢀ 2fꢀ inꢀ 44%ꢀ yield.ꢀ Inꢀ
contrast,ꢀtheꢀelectronꢁdonatingꢀgroupꢀ4ꢁmethoxyphenylꢀledꢀtoꢀanꢀincreaseꢀinꢀtheꢀnucleophilicityꢀofꢀ
theꢀ nitrogenꢀ bearingꢀ theꢀ aromaticꢀ ring,ꢀ affordingꢀ 2eꢀ inꢀ onlyꢀ 18%ꢀ yieldꢀ andꢀ itsꢀ regioisomerꢀ 1ꢁ(4ꢁ
methoxyphenyl)pyrazolidinꢁ3ꢁoneꢀ3ꢀinꢀ39%ꢀyield.ꢀꢀ
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Table 2. DIC-mediated cyclization using various amines
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Entry
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Amine
Product (isolated yield)[a]
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[a]ꢀReactionsꢀwereꢀcarriedꢀoutꢀonꢀaꢀscaleꢀofꢀ0.26ꢀmmolꢀofꢀamineꢀhydrochlorideꢀandꢀ0.47ꢀmmolꢀofꢀ1ꢀinꢀ
theꢀpresenceꢀofꢀcouplingꢀreagentꢀ(0.51ꢀmmol)ꢀandꢀbaseꢀ(0.78ꢀmmol)ꢀinꢀ3ꢀmLꢀofꢀsolventꢀunderꢀargonꢀ
atmosphere.ꢀ[b]ꢀReactionsꢀwereꢀcarriedꢀoutꢀonꢀaꢀscaleꢀofꢀ2ꢀmmolꢀofꢀarylhydrazine.ꢀ[c]ꢀReactionꢀwasꢀ
heatedꢀatꢀ50°C.ꢀ
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Schemeꢀ2.ꢀReportedꢀsynthesisꢀofꢀ2ꢁarylpyrazolidinꢁ3ꢁoneꢀ2b7ꢀ
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Asꢀaꢀcomparison,ꢀ2ꢁarylpyrazolidinꢁ3ꢁonesꢀ2bꢀwasꢀpreviouslyꢀdescribedꢀsynthesisꢀstartingꢀwithꢀBocꢁ
protectionꢀofꢀtheꢀhydrazineꢀNH2ꢀgroup,ꢀfollowedꢀbyꢀcyclizationꢀwithꢀ3ꢁchloropropanoylꢀchlorideꢀandꢀ
finally,ꢀNꢁBocꢀdeprotection.ꢀThisꢀthreeꢁstepꢀstrategyꢀaffordedꢀ2ꢁphenylpyrazolidinꢁ3ꢁoneꢀ2bꢀinꢀ52%ꢀ
globalꢀyieldꢀ(Schemeꢀ2).7ꢀꢀ
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Weꢀ nextꢀ extendedꢀ theꢀ reactionꢀ toꢀ otherꢀ nucleophilesꢀ bearingꢀ twoꢀ aminoꢀ groups.ꢀ Thus,ꢀ 2ꢁ
aminobenzimidazoleꢀandꢀ1,2ꢁdiaminobenzeneꢀaffordedꢀ[6+5+6]ꢀtricyclicꢀguanidineꢀ4,8ꢀandꢀtheꢀ[6+7]ꢀ
bicyclicꢀ compoundꢀ 5,ꢀ respectively,ꢀ inꢀ excellentꢀ yields.ꢀ Inꢀ contrastꢀ toꢀ theꢀ arylhydrazinesꢀ andꢀ
aryldiaminesꢀstudied,ꢀaliphaticꢀaminesꢀorꢀhydrazinesꢀareꢀtooꢀreactiveꢀandꢀleadꢀtoꢀcomplexꢀmixtures.ꢀ
However,ꢀ theꢀ monoamineꢀ 4ꢁchloroanilineꢀ affordedꢀ theꢀ targetꢀ compoundꢀ 6ꢀ inꢀ poorꢀ yield,ꢀ andꢀ aꢀ
numberꢀofꢀbyꢁproductsꢀwereꢀalsoꢀformed.ꢀAmongꢀtheꢀbyꢁproducts,ꢀweꢀwereꢀableꢀtoꢀidentifyꢀtheꢀcyclicꢀ
ureaꢀ1ꢁ(4ꢁchlorophenyl)imidazolidinꢁ2ꢁoneꢀ7cꢀasꢀaꢀcomponentꢀofꢀtheꢀproductꢀmixtureꢀꢀ(Tableꢀ2,ꢀentryꢀ
8).ꢀ Nevertheless,ꢀ theꢀ recoveryꢀ ofꢀ cyclicꢀ ureaꢀ 7cꢀ suggestedꢀ aꢀ mechanismꢀ involvingꢀ aꢀ Curtiusꢀ
rearrangement.ꢀIndeed,ꢀbyꢀjustꢀheatingꢀtheꢀreactionꢀmixtureꢀatꢀ50°C,ꢀimidazolidinꢁ2ꢁoneꢀ7aꢀcouldꢀbeꢀ
obtainedꢀinꢀ86%ꢀyieldꢀ(Tableꢀ3,ꢀentryꢀ3).ꢀHigherꢀtemperaturesꢀdidꢀnotꢀimproveꢀtheꢀyieldꢀofꢀ7a.ꢀAꢀsetꢀofꢀ
substitutedꢀanilinesꢀwereꢀscreened,ꢀandꢀimidazolidinonesꢀ7a–fꢀwereꢀobtainedꢀinꢀyieldsꢀrangingꢀfromꢀ
52%ꢀ toꢀ 86%ꢀ (tableꢀ 3,ꢀ entriesꢀ 6ꢀ –ꢀ 10).ꢀ Noꢀ reactionꢀ occurredꢀ withꢀ theꢀ electronꢁwithdrawingꢀ 4ꢁ
nitroanilineꢀ(Tableꢀ3,ꢀentryꢀ11).ꢀSimilarly,ꢀbenzamideꢀappearedꢀtoꢀbeꢀnotꢀenoughꢀnucleophilicꢀtoꢀreactꢀ
(Tableꢀ3,ꢀentryꢀ12).ꢀ
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Tableꢀ3.ꢀOptimizationꢀofꢀtheꢀimidazolidinonesꢀ7ꢀsynthesis[a]ꢀ
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Entry
Aniline
Temp. (°C) Time (h)
7
Yield
1
2
rt
rt
5
8[b]
32[b]
86[b]
(79)[c]
82[b]
73[b]
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50
5
7a
4
5
70
90
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7b
7c
7d
7e
7f
61[c]
66[c]
70[c]
73[c]
52[c]
8
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10
11
12
50
50
5
5
7g
7h
0
0
[a]ꢀ Reactionsꢀ wereꢀ carriedꢀ outꢀ onꢀ aꢀ scaleꢀ ofꢀ 0.39ꢀ mmolꢀ ofꢀ arylamineꢀ andꢀ 0.70ꢀ mmolꢀ ofꢀ 1ꢀ inꢀ theꢀ
presenceꢀofꢀcouplingꢀreagentꢀ(0.78ꢀmmol)ꢀandꢀbaseꢀ(0.78ꢀmmol)ꢀinꢀ4.5ꢀmLꢀofꢀsolventꢀunderꢀargonꢀ
atmosphere.ꢀ[b]ꢀYieldꢀdeterminedꢀbyꢀHPLC/UVꢀusingꢀinternalꢀstandard.ꢀ[c]ꢀIsolatedꢀyieldꢀ
ꢀ
Weꢀnextꢀfocusedꢀonꢀhomologsꢀofꢀ3ꢁazidopropanoicꢀacidꢀ1ꢀ(Schemeꢀ3).ꢀWhenꢀusingꢀ2ꢁazidoaceticꢀacid9ꢀ
8ꢀorꢀ4ꢁazidobutanoicꢀacid10ꢀ9ꢀwithꢀ3ꢁchlorophenylhydrazine,ꢀtheꢀexpectedꢀcyclicꢀproductsꢀwereꢀnotꢀ
obtained.ꢀInstead,ꢀtheꢀcorrespondingꢀ2ꢁazidoacetohydrazideꢀ10ꢀandꢀ4ꢁazidobutanehydrazideꢀ11ꢀwereꢀ
obtainedꢀ inꢀ goodꢀ yields,ꢀ highlightingꢀ theꢀ importanceꢀ ofꢀ theꢀ βꢁpositionꢀ ofꢀ theꢀ azidoꢀ groupꢀ inꢀ theꢀ
transformation.ꢀ
Additionalꢀinsightsꢀwereꢀgainedꢀwhenꢀtheꢀchiralꢀserineꢀazidoꢀderivativeꢀ12ꢀ(describedꢀbyꢀPandaꢀetꢀal)11ꢀ
wasꢀ subjectedꢀ toꢀ theꢀ transformation.ꢀ Reactionꢀ ofꢀ (L)ꢁ12ꢀ withꢀ 3ꢁchlorophenylhydrazineꢀ inꢀ theꢀ
presenceꢀofꢀDICꢀandꢀTEAꢀatꢀ50°Cꢀledꢀtoꢀcompletelyꢀracemizedꢀpyrazolidinꢁ3ꢁoneꢀ(RS)ꢁ13ꢀinꢀ77%ꢀyield.ꢀ
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Theꢀ analogousꢀ reactionꢀ ofꢀ (L)ꢁ12ꢀ withꢀ 3ꢁchloroꢁ4ꢁmethoxyanilineꢀ affordedꢀ theꢀ racemicꢀ cyclicꢀ ureaꢀ
(RS)ꢁ14ꢀinꢀ44%ꢀyieldꢀ(Schemeꢀ3).ꢀLossꢀofꢀchiralityꢀinꢀ13ꢀwasꢀverifiedꢀbyꢀtheꢀintroductionꢀofꢀaꢀsecondꢀ
chiralꢀ groupꢀ (Schemeꢀ 3).ꢀ Briefly,ꢀ theꢀ Bocꢀ groupꢀ wasꢀ cleavedꢀ withꢀ trifluoroaceticꢀ acid,ꢀ andꢀ theꢀ
resultingꢀaminoꢀfunctionꢀwasꢀcoupledꢀwithꢀFmocꢁLꢁPheꢁOHꢀtoꢀformꢀ15ꢀinꢀ72%ꢀglobalꢀyield.ꢀ1Hꢀandꢀ13Cꢀ
NMRꢀanalysisꢀestablishedꢀthatꢀ15ꢀwasꢀrecoveredꢀasꢀaꢀmixtureꢀofꢀtwoꢀdiastereoisomersꢀinꢀaꢀ[1:1]ꢀratio,ꢀ
highlightingꢀtheꢀracemicꢀformꢀofꢀtheꢀprecursorꢀ13.ꢀTheꢀracemizationꢀwasꢀconfirmedꢀbyꢀstartingꢀwithꢀ
theꢀenantiomerꢀ(D)ꢁ12ꢀ(dataꢀnotꢀshow).ꢀ
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Schemeꢀ3.ꢀDICꢁmediatedꢀcyclizationꢀusingꢀvariousꢀazidoꢀderivativesꢀ
ꢀ
Thisꢀ setꢀ ofꢀ experimentsꢀ allowedꢀ usꢀ toꢀ gainꢀ anꢀ insightꢀ intoꢀ theꢀ possibleꢀ mechanismꢀ byꢀ whichꢀ thisꢀ
reactionꢀmayꢀbeꢀoperating.ꢀInꢀtheꢀreactionꢀleadingꢀtoꢀ2ꢁarylpyrazolidinꢁ3ꢁonesꢀ2,ꢀtheꢀpresenceꢀofꢀtheꢀ
arylꢀgroupꢀatꢀtheꢀ2ꢁpositionꢀledꢀusꢀtoꢀhypothesizeꢀthatꢀtheꢀinitialꢀnucleophilicꢀattackꢀbyꢀtheꢀhydrazineꢀ
displacesꢀ theꢀ azidoꢀ group.ꢀ However,ꢀ anꢀ unmodifiedꢀ azidoꢀ groupꢀ isꢀ notꢀ consideredꢀ toꢀ beꢀ aꢀ goodꢀ
leavingꢀgroup.ꢀConsequently,ꢀweꢀpostulateꢀtheꢀformationꢀofꢀanꢀintermediateꢀshowingꢀelectrophilicꢀ
natureꢀatꢀtheꢀpositionꢀbearingꢀtheꢀazide.ꢀInꢀtheꢀabsenceꢀofꢀaꢀcouplingꢀreagent,ꢀnoꢀreactionꢀoccurred,ꢀ
andꢀhence,ꢀweꢀproposedꢀAꢀasꢀtheꢀfirstꢀintermediateꢀofꢀaꢀpossibleꢀmechanismꢀ(Figureꢀ1).ꢀꢀ
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Figureꢀ1.ꢀPossibleꢀmechanismꢀ
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ꢀFigureꢀ2.ꢀConcomitantꢀformationꢀofꢀ2aꢀandꢀ17ꢀ
100ꢀ
17ꢀ 2aꢀ
75ꢀ
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0ꢀ
0ꢀ
2ꢀ
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Reac�onꢀ�meꢀ(h)ꢀ
ꢀ
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Figureꢀ 3.ꢀ Kineticsꢀ ofꢀ formationꢀ ofꢀ theꢀ ureaꢀ 7eꢀ throughꢀ theꢀ intermediateꢀ F.ꢀ Theꢀ reactionꢀ wasꢀ
quenchedꢀwithꢀmethanolꢀatꢀdifferentꢀtimes.ꢀ7eꢀandꢀ18ꢀwereꢀquantifiedꢀbyꢀHPLC/UV.ꢀByꢀmeasuringꢀ
theꢀdisappearanceꢀofꢀ18ꢀresultingꢀfromꢀtheꢀreactionꢀofꢀintermediateꢀFꢀwithꢀmethanol,ꢀweꢀwereꢀableꢀ
toꢀobserveꢀtheꢀconcomitantꢀformationꢀofꢀ7eꢀwithꢀtheꢀdisappearanceꢀofꢀFꢀduringꢀtheꢀcourseꢀofꢀtheꢀ
reaction.ꢀ
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ꢀ100ꢀꢀꢀꢀ
7eꢀ 18ꢀ
ꢀ75ꢀꢀꢀꢀ
ꢀ50ꢀꢀꢀꢀ
ꢀ25ꢀꢀꢀꢀ
ꢀꢁꢀꢀꢀꢀꢀꢀ
0ꢀ
2ꢀ
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Reac�onꢀ�meꢀ(h)ꢀ
ꢀ
Then,ꢀtakingꢀintoꢀaccountꢀthatꢀtheꢀknownꢀabilityꢀofꢀtheꢀnitrogenꢀN1ꢀofꢀtheꢀazidoꢀgroupꢀtoꢀreactꢀwithꢀ
electrophilicꢀcentersꢀsuchꢀasꢀketonesꢀandꢀaldehydes,12ꢀandꢀthatꢀtheꢀreactionꢀdidꢀnotꢀproceedꢀwithꢀ
homologousꢀ azidoalkanoicꢀ acidsꢀ 8ꢀ andꢀ 9,ꢀ weꢀ proposedꢀ theꢀ formationꢀ ofꢀ theꢀ sixꢁmemberedꢀ ringꢀ
intermediateꢀ B,ꢀ resultingꢀ fromꢀ theꢀ intramolecularꢀ nucleophilicꢀ attackꢀ ofꢀ theꢀ azidoꢀ N1ꢀ atꢀ oxygenꢀ
bearingꢀcarbonꢀofꢀtheꢀureidoꢀetherꢀmoietyꢀofꢀintermediateꢀA.ꢀMoreover,ꢀweꢀhaveꢀseenꢀwithꢀtheꢀchiralꢀ
serineꢀ azidoꢀ derivativeꢀ (L)ꢁ12ꢀ thatꢀ theꢀ reactionꢀ ledꢀ toꢀ compoundꢀ (RS)ꢁ13ꢀ throughꢀ aꢀ completeꢀ
racemizationꢀ ofꢀ theꢀ chiralꢀ centerꢀ originallyꢀ present.ꢀ Oneꢀ wayꢀ toꢀ explainꢀ thisꢀ racemizationꢀ isꢀ toꢀ
considerꢀ anꢀ equilibriumꢀ betweenꢀ Bꢀ andꢀ theꢀ correspondingꢀ acrylateꢀ derivativeꢀ C.ꢀ Toꢀ validateꢀ thisꢀ
hypothesis,ꢀ theꢀ reactionꢀ wasꢀ followedꢀ byꢀ NMRꢀ analysisꢀ inꢀ theꢀ absenceꢀ ofꢀ hydrazine,ꢀ inꢀ orderꢀ toꢀ
identifyꢀ theꢀ reactionꢀ intermediates.ꢀ Afterꢀ aꢀ fewꢀ minutesꢀ inꢀDMFꢀd7,ꢀ quantitativeꢀ 13Cꢀ andꢀ 1Hꢀ NMRꢀ
analysisꢀindicatedꢀtheꢀcompleteꢀdisappearanceꢀofꢀtheꢀstartingꢀcarboxylicꢀacidꢀ1,ꢀwhichꢀwasꢀreplacedꢀ
byꢀaꢀmixtureꢀofꢀtwoꢀnewꢀcompoundsꢀinꢀaꢀ[9:1]ꢀratio.13ꢀTheꢀminorꢀcompoundꢀCꢀgaveꢀtheꢀcharacteristicꢀ
peaksꢀ ofꢀ anꢀ acrylateꢀ derivative,ꢀ whileꢀ theꢀ majorꢀ compoundꢀ Bꢀ stillꢀ showedꢀ bothꢀ CH2ꢀ groups.ꢀ Thisꢀ
mixtureꢀappearedꢀstableꢀforꢀmoreꢀthanꢀ1ꢀhꢀinꢀDMFꢀd7ꢀatꢀ25°C.ꢀAdditionꢀofꢀhydrazineꢀledꢀtoꢀtheꢀrapidꢀ
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disappearanceꢀ ofꢀ bothꢀ compoundsꢀ Bꢀ andꢀ C.ꢀ Inꢀ modelꢀ studiesꢀ carriedꢀ outꢀ underꢀ theꢀ experimentalꢀ
conditionsꢀdescribedꢀinꢀTableꢀ2,ꢀnoꢀ1,4ꢁazaMichaelꢀadditionꢀwasꢀobservedꢀbetweenꢀethylꢀacrylateꢀandꢀ
phenylhydrazineꢀorꢀanilineꢀ(Schemeꢀ4).ꢀꢀ
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Schemeꢀ4.ꢀReactionꢀbetweenꢀethylꢀacrylateꢀandꢀphenylhydrazineꢀorꢀanilineꢀ
ꢀ
ꢀ
Thisꢀ resultꢀ suggestsꢀ Bꢀ asꢀ theꢀ likelyꢀ keyꢀ intermediate.ꢀ Moreover,ꢀ equilibriumꢀ betweenꢀ Bꢀ andꢀ Cꢀ isꢀ
probablyꢀachievedꢀveryꢀfast,ꢀasꢀonlyꢀtracesꢀofꢀacrylhydrazideꢀderivativesꢀwereꢀdetectedꢀbyꢀLCMSꢀatꢀ
theꢀ endꢀ ofꢀ theꢀ reaction.ꢀ Intermediateꢀ Bꢀ couldꢀ thenꢀ reactꢀ quicklyꢀ withꢀ theꢀ NH2ꢀ groupꢀ ofꢀ theꢀ
arylhydrazine,ꢀ openingꢀ theꢀ ringꢀ toꢀ formꢀ intermediateꢀ D.ꢀ Aꢀ finalꢀ intramolecularꢀ ringꢀ closureꢀ thenꢀ
occurs,ꢀleadingꢀtoꢀ2a,ꢀalongꢀwithꢀbyꢁproductsꢀsuchꢀasꢀtheꢀexpectedꢀureaꢀ16ꢀandꢀtheꢀ5ꢁaminotetrazoleꢀ
17.ꢀ ꢀ Byꢀ HPLC,ꢀ weꢀ wereꢀ ableꢀ toꢀ observeꢀ theꢀ concomitantꢀ formationꢀ ofꢀ 2aꢀ andꢀ 17ꢀ (Figureꢀ 2).ꢀ Theꢀ
tetrazoleꢀringꢀresultsꢀfromꢀtheꢀelectrocyclizationꢀofꢀintermediateꢀE,ꢀasꢀproposedꢀbyꢀBateyꢀetꢀal.14ꢀAnꢀ
earlierꢀelectrocyclizationꢀhasꢀbeenꢀalsoꢀconsidered,ꢀbutꢀinꢀthisꢀcase,ꢀtheꢀazideꢀgroupꢀwouldꢀnotꢀhaveꢀ
beenꢀavailableꢀforꢀtheꢀCurtiusꢀrearrangement.ꢀIntermediateꢀBꢀcanꢀalsoꢀreactꢀwithꢀaniline,ꢀleadingꢀtoꢀFꢀ
afterꢀringꢀopening.ꢀNucleophilicꢀattackꢀofꢀtheꢀaminoꢀgroupꢀtoꢀformꢀaꢀfourꢁmemberedꢀringꢀwasꢀnotꢀ
observed,ꢀandꢀwithꢀheatingꢀ(50°C),ꢀCurtiusꢀrearrangementꢀoccurredꢀviaꢀintermediateꢀG,ꢀleadingꢀtoꢀ
ureaꢀ7e.ꢀKineticꢀexperimentsꢀwereꢀperformedꢀusingꢀHPLC/UVꢀafterꢀquenchingꢀofꢀtheꢀreactionꢀwithꢀ
methanolꢀ(Figureꢀ3).ꢀDuringꢀtheꢀfirstꢀ20ꢀminꢀfollowingꢀtheꢀanilineꢀaddition,ꢀtheꢀmajorꢀcompoundꢀwasꢀ
foundꢀtoꢀbeꢀtheꢀesterꢀ18,ꢀitsꢀproportionꢀgraduallyꢀdecreasedꢀalongꢀwithꢀtheꢀappearanceꢀofꢀ7e.ꢀTheꢀ
reactionꢀrateꢀappearedꢀtoꢀbeꢀdeterminedꢀbyꢀtheꢀCurtiusꢀrearrangement.ꢀ
CONCLUSIONꢀ
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Weꢀhaveꢀshownꢀforꢀtheꢀfirstꢀtimeꢀthatꢀanꢀaliphaticꢀazidoꢀgroupꢀcanꢀactꢀformallyꢀasꢀaꢀpseudoꢀleavingꢀ
groupꢀinꢀaꢀnucleophilicꢀsubstitutionꢀunderꢀmildꢀconditions.ꢀThisꢀreactionꢀproceedsꢀthroughꢀanꢀoriginalꢀ
mechanism,ꢀopeningꢀaꢀhighlyꢁefficientꢀaccessꢀtoꢀaꢀvarietyꢀofꢀazaheterocycles,ꢀincludingꢀmonoꢁ,ꢀdiꢁꢀandꢀ
tricycles.ꢀꢀ
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EXPERIMENTALꢀSECTIONꢀ
GeneralꢀExperimentalꢀmethods.ꢀChemicalsꢀandꢀsolventsꢀwereꢀpurchasedꢀfromꢀcommercialꢀsuppliers.ꢀ
Abbreviationsꢀ :ꢀ COMUꢀ :ꢀ (1ꢁCyanoꢁ2ꢁethoxyꢁ2ꢁoxoethylidenaminooxy)dimethylaminoꢁmorpholinoꢁ
carbeniumꢀ hexafluorophosphate;ꢀ DCCꢀ :ꢀ N,NꢂꢁDicyclohexylcarbodiimide;ꢀ DICꢀ :ꢀ N,Nꢂꢁ
Diisopropylcarbodiimide;ꢀ EDCIꢀ :ꢀ Nꢁ(3ꢁDimethylaminopropyl)ꢁNꢂꢁethylcarbodiimideꢀ hydrochloride;ꢀ
HATU:ꢀ
1ꢁ[Bis(dimethylamino)methylene]ꢁ1Hꢁ1,2,3ꢁtriazolo[4,5ꢁb]pyridiniumꢀ
3ꢁoxidꢀ
hexafluorophosphate;ꢀ
PyBOPꢀ :ꢀ (Benzotriazolꢁ1ꢁyloxy)tripyrrolidinophosphoniumꢀ
hexafluorophosphate.ꢀ ꢀ Analyticalꢀ thinꢁlayerꢀ chromatographyꢀ wasꢀ performedꢀ usingꢀ silicaꢀ gelꢀ platesꢀ
andꢀ platesꢀ wereꢀ visualizedꢀ byꢀ exposureꢀ toꢀ ultravioletꢀ light.ꢀ Compoundsꢀ wereꢀ purifiedꢀ usingꢀ flashꢀ
chromatographyꢀonꢀsilicaꢀgelꢀ(particleꢀsizeꢀ0.040ꢁ0.063mm),ꢀorꢀonꢀreverseꢀphaseꢀcolumn.ꢀYieldsꢀreferꢀ
toꢀisolatedꢀcompounds,ꢀestimatedꢀtoꢀbeꢀ>97%ꢀpureꢀasꢀdeterminedꢀ1HꢀNMRꢀorꢀHPLC.ꢀ1Hꢀandꢀ13CꢀNMRꢀ
spectraꢀwereꢀrecordedꢀonꢀ 300,ꢀ 400ꢀ orꢀ500MHzꢀspectrometersꢀforꢀprotonꢀandꢀ100ꢀorꢀ125MHzꢀforꢀ
carbon.ꢀ 500MHzꢀ spectrometerꢀ wasꢀ equippedꢀ withꢀ cryoprobeꢀ toꢀ provideꢀ quantitativeꢀ andꢀ highꢀ
sensitivityꢀcarbonꢀspectra.ꢀ.ꢀAllꢀchemicalꢀshiftꢀvaluesꢀandꢀcouplingꢀconstantsꢀJꢀareꢀquotedꢀinꢀppmꢀandꢀ
inꢀ Hz,ꢀ respectively.ꢀ InfraꢁRedꢀ analysisꢀ wereꢀ performedꢀ byꢀ FTꢁIR.ꢀ Analyticalꢀ RPꢁHPLCꢁMSꢀ wasꢀ
performedꢀusingꢀaꢀC18ꢀcolumnꢀ(30ꢀmmꢀ×ꢀ1ꢀmm;ꢀ1.9ꢀμm)ꢀusingꢀtheꢀfollowingꢀparametersꢀ:ꢀ1)ꢀTheꢀ
solventꢀsystemꢀ:ꢀꢀAꢀ(acetonitrile)ꢀandꢀBꢀ(0.05%ꢀTFAꢀinꢀH2O);ꢀ2)ꢀAꢀlinearꢀgradientꢀ:ꢀtꢀ=ꢀ0ꢀmin,ꢀ98%B;ꢀtꢀ=ꢀ5ꢀ
min,ꢀ5%ꢀB;ꢀtꢀ=ꢀ6ꢀmin,ꢀ5%B;ꢀtꢀ=ꢀ7ꢀmin,ꢀ98%B;ꢀtꢀ=ꢀ9ꢀmin,ꢀ98%B;ꢀ3)ꢀFlowꢀrateꢀofꢀ0.3ꢀmL/min;ꢀ4)ꢀColumnꢀ
temperatureꢀ:ꢀ50°C;ꢀ5)ꢀTheꢀratioꢀofꢀproductsꢀwasꢀdeterminedꢀbyꢀintegrationꢀofꢀspectraꢀrecordedꢀatꢀ
210ꢀnmꢀorꢀ254ꢀnm;ꢀ6)ꢀIonizationꢀmodeꢀ:ꢀMMꢁES+APCI.ꢀHighꢁresolutionꢀspectraꢀ(HRMS)ꢀwereꢀrecordedꢀ
onꢀaꢀQTOFꢀmassꢀanalyzerꢀwithꢀelectrosprayꢀionizationꢀ(ESI)ꢀ
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WARNING!ꢁLowꢁmolecularꢁweightꢁcarbonꢁazidesꢁusedꢁinꢁthisꢁstudyꢁareꢁpotentiallyꢁexplosive.ꢁAsꢁfreeꢁ
azideꢁionꢁisꢁformedꢁduringꢁtheꢁreaction,ꢁthereꢁisꢁalsoꢁaꢁpotentialꢁforꢁtheꢁformationꢁofꢁhydrazoicꢁacidꢁasꢁ
well.ꢁAppropriateꢁprotectionꢁmeasuresꢁshouldꢁalwaysꢁbeꢁtakenꢁwhenꢁhandlingꢁtheseꢁcompounds.ꢁ
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Generalꢀmethods:ꢀ
MethodꢀAꢀ:ꢀPreparationꢀofꢀtheꢀcompoundsꢀ2aꢁf,ꢀ3,ꢀ4,ꢀ5,ꢀ6,ꢀ10,ꢀ11,ꢀ13ꢀ
ꢀDiisopropylcarbodiimideꢀDICꢀ(2eq,ꢀ81µL,ꢀ0.51mmol)ꢀandꢀEt3Nꢀ(3eq,ꢀ109µL,ꢀ0.78mmol)ꢀwereꢀmixedꢀ
together,ꢀthenꢀ3ꢁazidopropanoicꢀacidꢀ1ꢀ(1.8eq.,ꢀ0.47mmol)ꢀinꢀDMFꢀ(5mmol/mL)ꢀwasꢀaddedꢀdropwiseꢀ
andꢀtheꢀreactionꢀmixtureꢀwasꢀstirredꢀatꢀ25°Cꢀforꢀ5min.ꢀThen,ꢀaꢀsolutionꢀofꢀamineꢀhydrochlorideꢀ(1eq,ꢀ
0.26mmol)ꢀinꢀDMFꢀ(0.09mmol/mL)ꢀwasꢀargonꢀflushedꢀforꢀ10minꢀandꢀaddedꢀdropwiseꢀtoꢀtheꢀreaction.ꢀ
Theꢀreactionꢀvialꢀwasꢀwrappedꢀwithꢀanꢀaluminumꢀfoilꢀtoꢀprotectꢀfromꢀlightꢀandꢀtheꢀreactionꢀmixtureꢀ
wasꢀ stirredꢀ atꢀ 25°Cꢀ forꢀ 5hꢀ underꢀ argon.ꢀ Solventꢀ wasꢀ concentratedꢀ underꢀ vacuumꢀ andꢀ theꢀ crudeꢀ
productꢀwasꢀpurifiedꢀbyꢀflashꢀchromatographyꢀonꢀreverseꢀphaseꢀusingꢀH2O(0.05%TFA)/MeOHꢀtoꢀgiveꢀ
theꢀexpectedꢀproducts:ꢀ2aꢁf,ꢀ3,ꢀ4,ꢀ5,ꢀ6,ꢀ10,ꢀ11,ꢀ13.ꢀ
MethodꢀBꢀ:ꢀPreparationꢀofꢀtheꢀcompoundsꢀ7aꢁf,ꢀ14ꢀ
DICꢀ (2eq,ꢀ 120µL,ꢀ 0.78mmol)ꢀ andꢀ Et3Nꢀ (2eq,ꢀ 109µL,ꢀ 0.78mmol)ꢀ wereꢀ mixedꢀ together,ꢀ thenꢀ 3ꢁ
azidopropanoicꢀacidꢀ1ꢀ(1.8eq,ꢀ0.70mmol)ꢀinꢀDMFꢀ(5mmol/mL)ꢀwasꢀaddedꢀdropwiseꢀandꢀtheꢀreactionꢀ
mixtureꢀ wasꢀ stirredꢀ atꢀ 25°Cꢀ forꢀ 5min.ꢀ Then,ꢀ aꢀ solutionꢀ ofꢀ anilineꢀ (1eq,ꢀ 0.39mmol)ꢀ inꢀ DMFꢀ
(0.09mmol/mL)ꢀwasꢀargonꢀflushedꢀforꢀ10minꢀandꢀaddedꢀdropwiseꢀtoꢀtheꢀreaction.ꢀTheꢀreactionꢀvialꢀ
wasꢀwrappedꢀwithꢀanꢀaluminumꢀfoilꢀtoꢀprotectꢀfromꢀlightꢀandꢀtheꢀreactionꢀmixtureꢀwasꢀstirredꢀatꢀ50°Cꢀ
forꢀ5hꢀunderꢀargon.ꢀSolventꢀwasꢀconcentratedꢀunderꢀvacuumꢀandꢀtheꢀcrudeꢀproductꢀwasꢀpurifiedꢀbyꢀ
flashꢀchromatographyꢀonꢀsilicaꢀgelꢀusingꢀEtOAc/heptaneꢀtoꢀgiveꢀtheꢀexpectedꢀproducts:ꢀ7aꢁf,ꢀ14.ꢀ
2ꢀ(3ꢀChlorophenyl)pyrazolidinꢀ3ꢀone,ꢁ2a.15ꢀFollowingꢀtheꢀgeneralꢀmethodꢀA,ꢀ2aꢀwasꢀobtainedꢀasꢀanꢀoilꢀ
(42mg,ꢀ0.21mmol,ꢀ82%).ꢀ1HꢀNMRꢀ(CDCl3,ꢀ300MHz):ꢀδꢀ7.91ꢀ(s,ꢀ1H),ꢀ7.76ꢀ(d,ꢀJꢁ=ꢀ8.1Hz,ꢀ1H),ꢀ7.32ꢀ(m,ꢀ1H),ꢀ
7.11ꢀ(d,ꢀJꢁ=ꢀ7.8Hz,ꢀ1H),ꢀ3.43ꢀ(t,ꢀJꢁ=ꢀ7.6Hz,ꢀ2H),ꢀ2.76ꢀ(t,ꢀJꢁ=ꢀ7.6Hz,ꢀ2H);ꢀ13CꢀNMRꢀ(CDCl3,ꢀ100MHz):ꢀδꢀ
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172.0,ꢀ139.9,ꢀ134.5,ꢀ129.8,ꢀ124.1,ꢀ118.1,ꢀ116.0,ꢀꢀ43.7,ꢀ35.6;ꢀIRꢀ(cmꢁ1):ꢀ1688,ꢀ1591,ꢀ1481,ꢀ777;ꢀHPLCꢀtRꢀ=ꢀ
2.69ꢀmin;ꢀESIꢁMS:ꢀm/zꢀ197.0,ꢀ[M+H]+.ꢀ
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2ꢀPhenylpyrazolidinꢀ3ꢀone,ꢁ2b.16ꢀFollowingꢀtheꢀgeneralꢀmethodꢀA,ꢀ2bꢀwasꢀobtainedꢀasꢀanꢀoilꢀ(38mg,ꢀ
0.24mmol,ꢀ92%).ꢀ1HꢀNMRꢀ(CD3OD,ꢀ400MHz):ꢀδꢀ7.78ꢀ(d,ꢀJꢁ=ꢀ7.8Hz,ꢀ2H),ꢀ7.34ꢀ(t,ꢀJꢁ=ꢀ7.9Hz,ꢀ2H),ꢀ7.10ꢀꢁꢀ
7.22ꢀ(m,ꢀ1H),ꢀ3.43ꢀ(t,ꢀJꢁ=ꢀ7.7Hz,ꢀ2H),ꢀ2.74ꢀ(t,ꢀJꢁ=ꢀ7.7Hz,ꢀ2H);ꢀ13CꢀNMRꢀ(CD3OD,ꢀ100MHz):ꢀδꢀ174.5,ꢀ140.2,ꢀ
129.7,ꢀ 125.7,ꢀ 120.2,ꢀ 44.4,ꢀ 36.4;ꢀ IR(cmꢁ1):ꢀ 1682,ꢀ 1595,ꢀ 1495,ꢀ 755;ꢀ HPLCꢀ tRꢀ =ꢀ 1.30ꢀ min;ꢀ ESIꢁMS:ꢀ m/zꢀ
161.3,ꢀ[M+H]+.ꢀ
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2ꢀ(2ꢀMethylphenyl)pyrazolidinꢀ3ꢀone,ꢁ2c.ꢀFollowingꢀtheꢀgeneralꢀmethodꢀA,ꢀ2cꢀwasꢀobtainedꢀasꢀanꢀoilꢀ
(37mg,ꢀ0.20mmol,ꢀ80%).ꢀ1HꢀNMRꢀ(CD3OD,ꢀ400MHz):ꢀδꢀ7.19ꢀꢁꢀ7.34ꢀ(m,ꢀ4H),ꢀ3.54ꢀ(t,ꢀJꢁ=ꢀ7.7Hz,ꢀ2H),ꢀ2.75ꢀ
(t,ꢀJꢁ=ꢀ7.7Hz,ꢀ2H),ꢀ2.28ꢀ(s,ꢀ3H);ꢀ13CꢀNMRꢀ(CD3OD,ꢀ100MHz):ꢀδꢀ174.3,ꢀ137.4,ꢀ137.2,ꢀ132.1,ꢀ129.8,ꢀ128.1,ꢀ
127.7,ꢀ45.2,ꢀ34.3,ꢀ18.1;ꢀIR(cmꢁ1):ꢀ1681,ꢀ1495,ꢀ762;ꢀHPLCꢀtRꢀ=ꢀ1.16ꢀmin;ꢀHRMSꢀ(ESIꢁTOF)ꢀm/z:ꢀ[Mꢀ+ꢀH]+ꢀ
CalcdꢀforꢀC10H12N2O 177.1022; found 177.1018.ꢀ
2ꢀ(4ꢀBromophenyl)pyrazolidinꢀ3ꢀone,ꢁ2d.ꢀFollowingꢀtheꢀgeneralꢀmethodꢀA,ꢀ2dꢀwasꢀobtainedꢀasꢀaꢀwhiteꢀ
solidꢀ(35mg,ꢀ0.15mmol,ꢀ56%).ꢀmp:ꢀ126ꢀ–ꢀ128°C;ꢀ1HꢀNMRꢀ(CD3OD,ꢀ400MHz):ꢀδꢀ7.71ꢀꢁꢀ7.80ꢀ(d,ꢀJꢁ=ꢀ9.0Hz,ꢀ
2H),ꢀ7.43ꢀꢁꢀ7.53ꢀ(d,ꢀJꢁ=ꢀ9.0Hz,ꢀ2H),ꢀ3.42ꢀ(t,ꢀJꢁ=ꢀ7.7Hz,ꢀ2H),ꢀ2.74ꢀ(t,ꢀJꢁ=ꢀ7.7Hz,ꢀ2H);ꢀ13CꢀNMRꢀ(100MHz,ꢀ
CD3OD)ꢀδꢀ174.7,ꢀ139.6,ꢀ132.7,ꢀ121.5,ꢀ118.0,ꢀ44.4,ꢀ36.4;ꢀIRꢀ(cmꢁ1):ꢀ1672,ꢀ1588,ꢀ1485,ꢀ1075;ꢀHPLCꢀtRꢀ=ꢀ
2.81ꢀmin;ꢀHRMSꢀ(ESIꢁTOF)ꢀm/z:ꢀ[Mꢀ+ꢀH]+ꢀCalcdꢀforꢀC9H9BrN2O 240.9971; found 240.9968.ꢀ
2ꢀ(4ꢀMethoxyphenyl)pyrazolidinꢀ3ꢀone,ꢁ 2e.ꢀ Followingꢀ theꢀ generalꢀ methodꢀ A,ꢀ 2eꢀ wasꢀ obtainedꢀ asꢀ
whiteꢀsolidꢀ(9mg,ꢀ0.047mmol,ꢀ18%).ꢀmp:ꢀ114ꢀ–ꢀ115°C;ꢀ1HꢀNMRꢀ(CD3OD,ꢀ400MHz):ꢀδꢀ7.65ꢀ(d,ꢀJꢁ=ꢀ9.0Hz,ꢀ
2H),ꢀ 6.91ꢀ (d,ꢀ Jꢁ =ꢀ 9.0Hz,ꢀ 2H),ꢀ 3.78ꢀ (s,ꢀ 3H),ꢀ 3.42ꢀ (t,ꢀ Jꢁ =ꢀ 7.7Hz,ꢀ 2H),ꢀ 2.73ꢀ (t,ꢀ Jꢁ =ꢀ 7.7Hz,ꢀ 2H);ꢀ 13Cꢀ NMRꢀ
(CD3OD,ꢀ100MHz):ꢀδꢀ173.7,ꢀ158.4,ꢀ133.2,ꢀ122.3,ꢀ114.8,ꢀ55.9,ꢀ44.3,ꢀ36.0;ꢀIRꢀ(cmꢁ1):ꢀ1681,ꢀ1508,ꢀ1245,ꢀ
1032,ꢀ830;ꢀHPLCꢀtRꢀ=ꢀ1.74ꢀmin;ꢀHRMSꢀ(ESIꢁTOF)ꢀm/z:ꢀ[Mꢀ+ꢀH]+ꢀCalcdꢀforꢀC10H12N2O2 193.0972; found
193.0968.ꢀ
2ꢀ(4ꢀNitrophenyl)pyrazolidinꢀ3ꢀone,ꢁ 2f.ꢀ Followingꢀ theꢀ generalꢀ methodꢀ Aꢀ (theꢀ reactionꢀ mixtureꢀ wasꢀ
heatedꢀatꢀ50°C),ꢀ2fꢀwasꢀobtainedꢀasꢀaꢀyellowꢀsolidꢀ(28mg,ꢀ0.11mol,ꢀ44%).ꢀmp:ꢀ186ꢀ–ꢀ187°C;ꢀ1HꢀNMRꢀ
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(DMSOꢁd6,ꢀ400MHz):ꢀδꢀ8.27ꢀ(d,ꢀJꢁ=ꢀ9.3Hz,ꢀ2H),ꢀ8.03ꢀ(d,ꢀJꢁ=ꢀ9.3Hz,ꢀ2H),ꢀ6.47ꢀ(t,ꢀJꢁ=ꢀ8.4Hz,ꢀ1H),ꢀ3.38ꢀ(m,ꢀ
2H),ꢀ2.73ꢀ(t,ꢀJꢁ=ꢀ7.4Hz,ꢀ2H);ꢀ13CꢀNMRꢀ(DMSOꢁd6ꢀ,100MHz):ꢀδꢀ173.9,ꢀ144.6,ꢀ142.1,ꢀ124.9,ꢀ117.2,ꢀ43.0,ꢀ
35.2.ꢀIRꢀ(cmꢁ1):ꢀ1693,ꢀ1593,ꢀ1510,ꢀ1496,ꢀ1312,ꢀ847.ꢀ;ꢀHPLCꢀtRꢀ=ꢀ2.31ꢀmin;ꢀHRMSꢀ(ESIꢁTOF)ꢀm/z:ꢀ[Mꢀ+ꢀ
H]+ꢀCalcdꢀforꢀC9H9N3O3 208.0717; found 208.0710.ꢀ
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1ꢀ(4ꢀMethoxyphenyl)pyrazolidinꢀ3ꢀone,ꢁ3.ꢀFollowingꢀtheꢀgeneralꢀmethodꢀA,ꢀ3ꢀwasꢀobtainedꢀasꢀaꢀwhiteꢀ
solidꢀ(19mg,ꢀ0.10mmol,ꢀ39%).ꢀmp:ꢀ145ꢀ–ꢀ147°Cꢀ(lit.17ꢀmp:ꢀ144ꢀ–ꢀ146°C);ꢀ1HꢀNMRꢀ(CD3OD,ꢀ400MHz):ꢀδꢀ
7.01ꢀ(d,ꢀJꢁ=ꢀ9.0Hz,ꢀ2H),ꢀ6.88ꢀ(d,ꢀJꢁ=ꢁ9.0Hz,ꢀ2H),ꢀ3.81ꢀ(t,ꢀJꢁ=ꢀ7.9Hz,ꢀ2H),ꢀ3.75ꢀ(s,ꢀ3H),ꢀ2.50ꢀ(t,ꢀJꢁ=ꢀ7.9Hz,ꢀ
2H);ꢀ13CꢀNMRꢀ(CD3ODꢀ,100MHz):ꢀδꢀ177.2,ꢀ157.5,ꢀ146.5,ꢀ119.6,ꢀ115.5,ꢀ57.0,ꢀ56.0,ꢀ30.7;ꢀIRꢀ(cmꢁ1):ꢀ1673,ꢀ
1508,ꢀ1247,ꢀ1034,ꢀ833;ꢀHPLCꢀtRꢀ=ꢀ2.10ꢀmin;ꢀESIꢁMS:ꢀm/zꢀ193.0,ꢀ[M+H]+.ꢀ
2,10ꢀDihydropyrimido[1,2ꢀa]benzimidazolꢀ4(3H)ꢀone,ꢁ 4.ꢀ Followingꢀ theꢀ generalꢀ methodꢀ A,ꢀ 4ꢀ wasꢀ
obtainedꢀasꢀaꢀwhiteꢀsolidꢀ(41mg,ꢀ0.22mmol,ꢀ85%).ꢀmp:ꢀ264ꢀ–ꢀ165°Cꢀ(lit.18ꢀmp:ꢀ260ꢀ–ꢀ262°C);ꢀ1HꢀNMRꢀ
(DMSOꢁd6,ꢀ400MHz):ꢀδꢀ11.43ꢀ(s,ꢀ1H),ꢀ7.40ꢀ(m,ꢀ2H),ꢀ7.03ꢀꢁꢀ7.19ꢀ(m,ꢀ2H),ꢀ4.24ꢀ(t,ꢀJꢁ=ꢀ7.0Hz,ꢀ2H),ꢀ2.88ꢀ(t,ꢀJꢁ
=ꢀ7.0Hz,ꢀ2H);ꢀ13CꢀNMRꢀ(DMSOꢁd6,ꢀ100MHz):ꢀδꢀ168.1,ꢀ148.1,ꢀ141.8,ꢀ132.9,ꢀ121.2,ꢀ120.6,ꢀ117.2,ꢀ108.8,ꢀ
40.1,ꢀ36.9,ꢀ30.0;ꢀIRꢀ(cmꢁ1):ꢀ1681,ꢀ1516,ꢀ1453,ꢀ746;ꢀHPLCꢀtRꢀ=ꢀ0.98ꢀmin;ꢀESIꢁMS:ꢀm/zꢀ188.2,ꢀ[M+H]+.ꢀ
1,3,4,5ꢀTetrahydroꢀ2Hꢀ1,5ꢀbenzodiazepinꢀ2ꢀone,ꢁ5.ꢀFollowingꢀtheꢀgeneralꢀmethodꢀA,ꢀ5ꢀwasꢀobtainedꢀ
asꢀaꢀwhiteꢀsolidꢀ(37mg,ꢀ0.23mmol,ꢀ87%).ꢀmp:ꢀ138ꢀ–ꢀ140°Cꢀ(lit.19ꢀmp:ꢀ140ꢀ–ꢀ141°C);ꢀ1HꢀNMRꢀ(CD3ODꢀ
,400MHz):ꢀδꢀ6.88ꢀꢁꢀ6.99ꢀ(m,ꢀ2H),ꢀ6.74ꢀꢁꢀ6.87ꢀ(m,ꢀ2H),ꢀ3.56ꢀꢁꢀ3.64ꢀ(m,ꢀ2H),ꢀ2.54ꢀꢁꢀ2.65ꢀ(m,ꢀ2H).ꢀ13CꢀNMRꢀ
(CD3OD,ꢀ100MHz):ꢀδꢀ176.5,ꢀ141.2,ꢀ128.2,ꢀ126.6,ꢀ123.3,ꢀ121.2,ꢀ121.2,ꢀ47.6,ꢀ36.6;ꢀIRꢀ(cmꢁ1):ꢀ1662,ꢀ1175,ꢀ
1131;ꢀHPLCꢀtRꢀ=ꢀ0.86ꢀmin;ꢀESIꢁMS:ꢀm/zꢀ163.0,ꢀ[M+H]+.ꢀ
Nꢀ(4ꢀChlorophenyl)ꢀ3ꢀ[(4ꢀchlorophenyl)amino]propanamide,ꢁ6.ꢀFollowingꢀtheꢀgeneralꢀmethodꢀAꢀ(3.6ꢀ
eq.ꢀ ofꢀ 4ꢁchloroanilineꢀ wereꢀ usedꢀ (120mg,ꢀ 0.94ꢀ mmol),ꢀ 6ꢀ wasꢀ obtainedꢀ asꢀ aꢀ whiteꢀ solidꢀ (20mg,ꢀ
0.065mmol,ꢀ25%).ꢀmp:ꢀ138ꢀꢁꢀ140°Cꢀ(lit.20ꢀmp:ꢀ141°C);ꢀ1HꢀNMRꢀ(CD3OD,ꢀ400MHz):ꢀδꢀ7.56ꢀ(d,ꢀJꢁ=ꢀ8.8Hz,ꢀ
2H),ꢀ7.29ꢀ(d,ꢀJꢁ=ꢀ8.8Hz,ꢀ2H),ꢀ7.08ꢀ(d,ꢀJꢁ=ꢀ8.8Hz,ꢀ2H),ꢀ6.64ꢀ(d,ꢀJꢁ=ꢀ8.8Hz,ꢀ2H),ꢀ3.46ꢀ(dd,ꢀJꢁ=ꢀ6.7Hz,ꢀ2H),ꢀ2.65ꢀ
(dd,ꢀ Jꢁ =ꢀ 6.7Hz,ꢀ 2H);ꢀ 13Cꢀ NMRꢀ (CD3OD,ꢀ 100MHz):ꢀ δꢀ 172.8,ꢀ 148.7,ꢀ 138.8,ꢀ 130.1,ꢀ 130.0,ꢀ 129.8,ꢀ 122.7,ꢀ
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122.6,ꢀ115.3,ꢀ41.2,ꢀ37.6;ꢀIRꢀ(cmꢁ1):ꢀ3306,ꢀ2924,ꢀ1657,ꢀ1492,1090;ꢀHPLCꢀtRꢀ=ꢀ4.48ꢀmin;ꢀESIꢁMS:ꢀm/zꢀ
309.0,ꢀ[M+H]+.ꢀ
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1ꢀPhenylimidazolidinꢀ2ꢀone,ꢁ7a.ꢀFollowingꢀtheꢀgeneralꢀmethodꢀB,ꢀ7aꢀwasꢀobtainedꢀasꢀaꢀwhiteꢀsolidꢀ
(50mg,ꢀ0.31mmol,ꢀ79%).ꢀmp:ꢀ163ꢀꢁꢀ164°Cꢀ(lit.21ꢀmp:ꢀ162ꢀꢁꢀ163°C);ꢀ1HꢀNMRꢀ(CDCl3,ꢀ400MHz):ꢀδꢀ7.54ꢀ(d,ꢀ
Jꢁ=ꢀ7.8Hz,ꢀ2H),ꢀ7.32ꢀꢁꢀ7.42ꢀ(m,ꢀ2H),ꢀ7.03ꢀꢁꢀ7.15ꢀ(m,ꢀ1H),ꢀ3.91ꢀꢁꢀ4.03ꢀ(m,ꢀ2H),ꢀ3.55ꢀꢁꢀ3.66ꢀ(m,ꢀ2H).ꢀ13Cꢀ
NMRꢀ(CDCl3,ꢀ100MHz):ꢀδꢀ159.8,ꢀ140.0,ꢀ128.9,ꢀ122.8,ꢀ118.0,ꢀ45.4,ꢀ37.5;ꢀIR(cmꢁ1):ꢀ3264,ꢀ1682;ꢀHPLCꢀtRꢀ=ꢀ
2.22ꢀmin;ꢀESIꢁMS:ꢀm/zꢀ163.0,ꢀ[M+H]+.ꢀ
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1ꢀ(3ꢀBromophenyl)imidazolidinꢀ2ꢀone,ꢁ7b.ꢀFollowingꢀtheꢀgeneralꢀmethodꢀB,ꢀ7bꢀwasꢀobtainedꢀasꢀaꢀlightꢀ
yellowꢀ solidꢀ (57mg,ꢀ 0.24mmol,ꢀ 61%).ꢀ mp:ꢀ 127ꢀ ꢁꢀ 129°Cꢀ (lit.22ꢀ mp:ꢀ 127ꢀ ꢁꢀ 130°C);ꢀ ꢀ 1Hꢀ NMRꢀ (CDCl3,ꢀ
400MHz):ꢀδꢀ7.72ꢀ(s,ꢀ1H),ꢀ7.47ꢀ(dt,ꢀJꢁ=ꢀ6.8,ꢀ2.4Hz,ꢀ1H),ꢀ7.12ꢀꢁꢀ7.23ꢀ(m,ꢀ2H),ꢀ5.65ꢀ(brs,ꢀ1H),ꢀ3.89ꢀ(dd,ꢀJꢁ=ꢀ
8.0Hz,ꢀ2H),ꢀ3.58ꢀ(dd,ꢀJꢁ=ꢀ8.0Hz,ꢀ2H);ꢀ13CꢀNMRꢀ(CDCl3ꢀ,100MHz):ꢀδꢀ159.6,ꢀ141.3,ꢀ130.0,ꢀ125.5,ꢀ122.6,ꢀ
120.5,ꢀ116.1,ꢀ45.1,ꢀ37.3;ꢀIRꢀ(cmꢁ1):ꢀ3257,ꢀ2922,ꢀ1678,ꢀ1479;ꢀHPLCꢀtRꢀ=ꢀ3.18ꢀmin;ꢀESIꢁMS:ꢀm/zꢀ241.0,ꢀ
[M+H]+.ꢀ
1ꢀ(3ꢀChlorophenyl)imidazolidinꢀ2ꢀone,ꢁ 7c.ꢀ Followingꢀ theꢀ generalꢀ methodꢀ B,ꢀ 7cꢀ wasꢀ obtainedꢀ asꢀ aꢀ
whiteꢀsolidꢀ(51mg,ꢀ0.26mmol,ꢀ66%).ꢀmp:ꢀ105ꢀꢁꢀ107°C;ꢀ1HꢀNMRꢀ(CD3OD,ꢀ400MHz):ꢀδꢀ7.52ꢀ(d,ꢀJꢁ=ꢀ9.0Hz,ꢀ
2H),ꢀ 7.29ꢀ (d,ꢀ Jꢁ =ꢀ 9.0Hz,ꢀ 2H),ꢀ 3.92ꢀ (dd,ꢀ Jꢁ =ꢀ 8.0Hz,ꢀ 2H),ꢀ 3.53ꢀ (dd,ꢀ Jꢁ =ꢀ 8.0Hz,ꢀ 2H);ꢀ 13Cꢀ NMRꢀ (CD3OD,ꢀ
100MHz):ꢀδꢀ140.8,ꢀ129.9,ꢀ129.0,ꢀ120.9,ꢀ46.9,ꢀ38.6;ꢀIRꢀ(cmꢁ1):ꢀ3446,ꢀ2923,ꢀ1696,ꢀ1496,ꢀ845;ꢀHPLCꢀtRꢀ=ꢀ
2.97ꢀmin;ꢀHRMSꢀ(ESIꢁTOF)ꢀm/z:ꢀ[Mꢀ+ꢀH]+ꢀCalcdꢀforꢀC9H9ClN2O 197.0476; found 197.0471.ꢀ
1ꢀ(3ꢀMethoxyphenyl)imidazolidinꢀ2ꢀone,ꢁ7d.ꢀFollowingꢀtheꢀgeneralꢀmethodꢀB,ꢀ7dꢀwasꢀobtainedꢀasꢀaꢀ
lightꢀ yellowꢀ solidꢀ (52mg,ꢀ 0.27mmol,ꢀ 70%).ꢀ mp:ꢀ 118ꢀ ꢁꢀ 121°Cꢀ (lit.23ꢀ mp:ꢀ 123°C);ꢀ 1Hꢀ NMRꢀ (CD3OD,ꢀ
400MHz):ꢀδꢀ7.25ꢀ(t,ꢀJꢁ=ꢀ2.4Hz,ꢀ1H),ꢀ7.21ꢀ(t,ꢀJꢁ=ꢀ8.3Hz,ꢀ1H),ꢀ6.99ꢀ(ddd,ꢀJꢁ=ꢀ8.2,ꢀ2.4,ꢀ0.8Hz,ꢀ1H),ꢀ6.62ꢀ(ddd,ꢀ
Jꢁ=ꢀ8.3,ꢀ2.4,ꢀ0.8Hz,ꢀ1H),ꢀ3.93ꢀ(dd,ꢀJꢁ=ꢀ8.0Hz,ꢀ2H),ꢀ3.78ꢀ(s,ꢀ3H),ꢀ3.52ꢀ(dd,ꢀJꢁ=ꢀ8.0Hz,ꢀ2H);ꢀ13CꢀNMRꢀ(CD3OD,ꢀ
100MHz):ꢀδꢀ161.6,ꢀ142.8,ꢀ130.5,ꢀ111.5,ꢀ109.4,ꢀ105.7,ꢀ55.7,ꢀ46.8,ꢀ38.4;ꢀIRꢀ(cmꢁ1):ꢀ3448,ꢀ2928,ꢀ1693,ꢀ
841;ꢀHPLCꢀtRꢀ=ꢀ2.54ꢀmin;ꢀESIꢁMS:ꢀm/zꢀ193.0,ꢀ[M+H]+.ꢀ
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1ꢀ(3ꢀChloroꢀ4ꢀmethoxyphenyl)imidazolidinꢀ2ꢀone,ꢁ 7e.ꢀ Followingꢀ theꢀ generalꢀ methodꢀ B,ꢀ 7eꢀ wasꢀ
obtainedꢀasꢀaꢀwhiteꢀsolidꢀ(65mg,ꢀ0.28mmol,ꢀ73%).ꢀmp:ꢀ160ꢀꢁꢀ162°C;ꢀ1HꢀNMRꢀ(CD3OD,ꢀ400MHz):ꢀδꢀ7.68ꢀ
(d,ꢀJꢁ=ꢀ2.5Hz,ꢀ1H),ꢀ7.30ꢀ(dd,ꢀJꢁ=ꢁ9.0,ꢀ2.5Hz,ꢀ1H),ꢀ7.03ꢀ(d,ꢀJꢁ=ꢀ9.0Hz,ꢀ1H),ꢀ3.90ꢀ(dd,ꢀJꢁ=ꢀ8.3Hz,ꢀ2H),ꢀ3.85ꢀ(s,ꢀ
3H),ꢀ3.52ꢀ(dd,ꢀJꢁ=ꢀ8.3Hz,ꢀ2H);ꢀ13CꢀNMRꢀ(CD3OD,ꢀ100MHz):ꢀδꢀ162.1,ꢀ152.4,ꢀ135.5,ꢀ126.8,ꢀ123.5,ꢀ122.0,ꢀ
119.1,ꢀ113.7,ꢀ101.4,ꢀ78.1,ꢀ75.8,ꢀ56.9,ꢀ46.9,ꢀ38.4;ꢀIRꢀ(cmꢁ1):ꢀ2927,ꢀ1697,ꢀ1504,ꢀ843;ꢀHPLCꢀtRꢀ=ꢀ2.86ꢀmin;ꢀ
HRMSꢀ(ESIꢁTOF)ꢀm/z:ꢀ[Mꢀ+ꢀH]+ꢀCalcdꢀforꢀC10H11ClN2O2 227.0582; found 227.0578.ꢀ
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1ꢀ(5,6,7,8ꢀTetrahydronaphthalenꢀ2ꢀyl)imidazolidinꢀ2ꢀone,ꢁ7f.ꢀFollowingꢀtheꢀgeneralꢀmethodꢀB,ꢀ7fꢀwasꢀ
obtainedꢀasꢀaꢀwhiteꢀsolidꢀ(44mg,ꢀ0.20mmol,ꢀ52%).ꢀmp:ꢀ186ꢀꢁꢀ188°C;ꢀ1HꢀNMRꢀ(CDCl3,ꢀ400MHz):ꢀδꢀ7.17ꢀ
(d,ꢀJꢁ=ꢀ8.3Hz,ꢀ1H),ꢀ7.12ꢀ(s,ꢀ1H),ꢀ6.95ꢀ(d,ꢀJꢁ=ꢀ8.3Hz,ꢀ1H),ꢀ5.43ꢀ(brs,ꢀ1H),ꢀ3.81ꢀ(dd,ꢀJꢁ=ꢀ8.0Hz,ꢀ2H),ꢀ3.47ꢀ(dd,ꢀ
Jꢁ=ꢀ8.0Hz,ꢀ2H),ꢀ2.58ꢀꢁꢀ2.75ꢀ(m,ꢀ4H),ꢀ1.66ꢀꢁꢀ1.79ꢀ(m,ꢀ4H);ꢀ13CꢀNMRꢀ(CDCl3,ꢀ100MHz):ꢀδꢀ159.2,ꢀ136.5,ꢀ
136.5,ꢀ130.9,ꢀ128.4,ꢀ117.8,ꢀ115.0,ꢀ44.7,ꢀ36.6,ꢀ28.7,ꢀ27.8,ꢀ22.3,ꢀ22.2;ꢀIRꢀ(cmꢁ1):ꢀ3236,ꢀ2928,ꢀ1682;ꢀHPLCꢀ
tRꢀ=ꢀ3.16ꢀmin;ꢀHRMSꢀ(ESIꢁTOF)ꢀm/z:ꢀ[Mꢀ+ꢀH]+ꢀCalcdꢀforꢀC13H16N2O 217.1335; found 217.1337.ꢀ
2ꢀAzidoꢀN'ꢀ(3ꢀchlorophenyl)acetohydrazide,ꢁ10.ꢀFollowingꢀtheꢀgeneralꢀmethodꢀA,ꢀ10ꢀwasꢀobtainedꢀasꢀ
aꢀlightꢀyellowꢀoilꢀ(51mg,ꢀ0.23mmol,87%).ꢀ1HꢀNMRꢀ(CD3OD,ꢀ400MHz):ꢀδꢀ7.14ꢀ(t,ꢀJꢁ=ꢀ8.0Hz,ꢀ1H),ꢀ6.75ꢀꢁꢀ
6.81ꢀ(m,ꢀ2H),ꢀ6.72ꢀ(d,ꢀJꢁ=ꢀ8.3ꢀHz,ꢀ1H),ꢀ4.00ꢀ(s,ꢀ2H);ꢀ13CꢀNMRꢀ(CD3OD,ꢀ100MHz):ꢀδꢀ170.3,ꢀ151.3,ꢀ135.9,ꢀ
131.3,ꢀ120.7,ꢀ113.7,ꢀ112.3,ꢀ51.8;ꢀIRꢀ(cmꢁ1):ꢀ3276,ꢀ2107,ꢀ1681,ꢀ1598,ꢀ773;ꢀHPLCꢀtRꢀ=ꢀ2.83ꢀmin;ꢀHRMSꢀ
(ESIꢁTOF)ꢀm/z:ꢀ[Mꢀ+ꢀH]+ꢀCalcdꢀforꢀC8H8ClN5O 226.0490; found 226.0479.ꢀ
4ꢀAzidoꢀN'ꢀ(3ꢀchlorophenyl)butanehydrazide,ꢁ11.ꢀFollowingꢀtheꢀgeneralꢀmethodꢀA,ꢀ11ꢀwasꢀobtainedꢀasꢀ
aꢀlightꢀbrownꢀoilꢀ(55mg,ꢀ0.22mmol,ꢀ83%).ꢀ1HꢀNMRꢀ(CD3OD,ꢀ400MHz):ꢀδꢀ7.12ꢀ(t,ꢀJꢁ=ꢀ8.0Hz,ꢀ1H),ꢀ6.73ꢀꢁꢀ
6.79ꢀ(m,ꢀ2H),ꢀ6.70ꢀ(d,ꢀJꢁ=ꢀ8.3Hz,ꢀ1H),ꢀ3.38ꢀ(t,ꢀJꢁ=ꢀ6.7Hz,ꢀ2H),ꢀ2.37ꢀ(t,ꢀJꢁ=ꢀ7.3Hz,ꢀ2H),ꢀ1.92ꢀ(m,ꢀ2H);ꢀ13Cꢀ
NMRꢀ(CD3OD,ꢀ100MHz):ꢀδꢀ174.9,ꢀ151.6,ꢀ135.9,ꢀ131.3,ꢀ120.5,ꢀ113.6,ꢀ113.1,ꢀ112.2,ꢀ51.9,ꢀ31.8,ꢀ25.9;ꢀIRꢀ
(cmꢁ1):ꢀ3270,ꢀ2094,ꢀ1662,ꢀ1596,ꢀ771;ꢀHPLCꢀtRꢀ=ꢀ3.28ꢀmin;ꢀHRMSꢀ(ESIꢁTOF)ꢀm/z:ꢀ[Mꢀ+ꢀH]+ꢀCalcdꢀforꢀ
C10H12ClN5O 254.0803; found 254.0795.ꢀ
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tButylꢁ[1ꢀ(3ꢀchlorophenyl)ꢀ5ꢀoxopyrazolidinꢀ4ꢀyl]carbamate,ꢁ(RS)ꢀ13.ꢀFollowingꢀtheꢀgeneralꢀmethodꢀAꢀ
(preꢁactivationꢀ ofꢀ theꢀ acidꢀ 12ꢀ withꢀ DICꢀ andꢀ TEAꢀ wasꢀ performedꢀ atꢀ 50°Cꢀ forꢀ 5ꢀ min),ꢀ (RS)ꢁ13ꢀ wasꢀ
obtainedꢀasꢀaꢀwhiteꢀsolidꢀ(62mg,ꢀ0.20mmol,ꢀ77%).ꢀmp:ꢀ148ꢀꢁꢀ150°C;ꢀ1HꢀNMRꢀ(CD3OD,ꢀ400MHz):ꢀδꢀ7.92ꢀ
(s,ꢀ1H),ꢀ7.78ꢀ(d,ꢀJꢁ=ꢀ8.2Hz,ꢀ1H),ꢀ7.32ꢀ(t,ꢀJꢁ=ꢀ8.2Hz,ꢀ1H),ꢀ7.12ꢀ(d,ꢀJꢁ=ꢀ8.2Hz,ꢀ1H),ꢀ4.65ꢀ(t,ꢀJꢁ=ꢀ9.3Hz,ꢀ1H),ꢀ
3.68ꢀ(dd,ꢀJꢁ=ꢀ11.3,ꢀ9.3Hz,ꢀ1H),ꢀ3.17ꢀ(t,ꢀJꢁ=ꢀ11.3Hz,ꢀ1H),ꢀ1.46ꢀ(s,ꢀ9H);ꢀ13CꢀNMRꢀ(CD3OD,ꢀ100MHz):ꢀδꢀ
172.3,ꢀ158.0,ꢀ141.5,ꢀ135.4,ꢀ131.0,ꢀ125.3,ꢀ119.3,ꢀ117.5,ꢀ55.9,ꢀ50.1,ꢀ28.7;ꢀIRꢀ(cmꢁ1):ꢀ1688,ꢀ1592,ꢀ1366,ꢀ
777;ꢀHPLCꢀtRꢀ=ꢀ3.96ꢀmin;ꢀHRMSꢀ(ESIꢁTOF)ꢀm/z:ꢀ[Mꢀ+ꢀNa]+ꢀCalcdꢀforꢀC14H18ClN3O3 334.0934; found
334.0929.ꢀ
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tButylꢁ [1ꢀ(3ꢀchloroꢀ4ꢀmethoxyphenyl)ꢀ2ꢀoxoimidazolidinꢀ4ꢀyl]carbamate,ꢁ (RS)ꢀ14.ꢀ Followingꢀ theꢀ
generalꢀmethodꢀBꢀ(preꢁactivationꢀofꢀtheꢀacidꢀ12ꢀwithꢀDICꢀandꢀTEAꢀwasꢀperformedꢀatꢀ50°Cꢀforꢀ5ꢀmin),ꢀ
(RS)ꢁ14ꢀ wasꢀ obtainedꢀ asꢀ aꢀ whiteꢀ solidꢀ (59mg,ꢀ 0.17mmol,ꢀ 44%).ꢀ mp:ꢀ 280ꢀ ꢁꢀ 282°C;ꢀ 1Hꢀ NMRꢀ (CDCl3,ꢀ
400MHz):ꢀδꢀ7.51ꢀ(d,ꢀJꢁ=ꢀ2.3Hz,ꢀ1H),ꢀ7.38ꢀ(dd,ꢀJꢁ=ꢀ9.0,ꢀ2.3Hz,ꢀ1H),ꢀ6.89ꢀ(d,ꢀJꢁ=ꢀ9.0Hz,ꢀ1H),ꢀ5.40ꢀꢁꢀ5.53ꢀ(m,ꢀ
2H),ꢀ5.28ꢀꢁꢀ5.38ꢀ(m,ꢀ1H),ꢀ4.16ꢀ(dd,ꢀJꢁ=ꢀ8.5Hz,ꢀ1H),ꢀ3.88ꢀ(s,ꢀ3H),ꢀ3.59ꢀ(dd,ꢀJꢁ=ꢀ8.5,ꢀ3.4Hz,ꢀ1H),ꢀ1.47ꢀ(s,ꢀ9H);ꢀ
13CꢀNMRꢀ(CDCl3,ꢀ100MHz):ꢀδꢀ151.2,ꢀ133.0,ꢀ122.7,ꢀ120.4,ꢀ117.7,ꢀ112.5,ꢀ56.4,ꢀ52.1,ꢀ28.3;ꢀIRꢀ(cmꢁ1):ꢀ3257,ꢀ
2975,ꢀ 1689,ꢀ 1507;ꢀ HPLCꢀ tRꢀ =ꢀ 3.77ꢀ min;ꢀ HRMSꢀ (ESIꢁTOF)ꢀ m/z:ꢀ [Mꢀ +ꢀ H]+ꢀ Calcdꢀ forꢀ C15H20ClN3O4
342.1215; found 342.1209.ꢀ
(9Hꢀfluorenꢀ9ꢀyl)methyl((2S)ꢀ1ꢀ((1ꢀ(3ꢀchlorophenyl)ꢀ5ꢀoxopyrazolidinꢀ4ꢀyl)amino)ꢀ1ꢀoxoꢀ3ꢀ
phenylpropanꢀ2ꢀyl)carbamate,ꢀ15.ꢀ(RS)ꢁ13ꢀ(21mg,ꢀ0.067mmol)ꢀwasꢀsolubilizedꢀinꢀ0.5mLꢀofꢀCH2Cl2ꢀandꢀ
0.5mLꢀofꢀTFA.ꢀTheꢀsolutionꢀwasꢀstirredꢀ1hꢀatꢀr.t.ꢀTheꢀreactionꢀwasꢀmonitoredꢀbyꢀHPLC.ꢀSolventsꢀwereꢀ
concentratedꢀunderꢀvacuumꢀtoꢀaffordꢀaꢀlightꢀyellowꢀsolidꢀdirectlyꢀusedꢀinꢀtheꢀnextꢀstep.ꢀFmocꢁPheꢁOHꢀ
(34mg,ꢀ 0.087mmol)ꢀ wasꢀ solubilizedꢀ inꢀ 1mLꢀ ofꢀ CH2Cl2ꢀ followedꢀ byꢀ theꢀ additionꢀ ofꢀ DIEAꢀ (44µL,ꢀ
0.27mmol)ꢀandꢀBOPꢀ(35mg,ꢀ0.080mmol).ꢀTheꢀobtainedꢀsolutionꢀwasꢀaddedꢀtoꢀtheꢀdeprotectedꢀamine.ꢀ
Theꢀreactionꢀsolutionꢀwasꢀstirredꢀovernightꢀatꢀr.t.ꢀSolventꢀwasꢀconcentratedꢀunderꢀvacuumꢀandꢀtheꢀ
obtainedꢀresidueꢀwasꢀdilutedꢀinꢀEtOAc.ꢀTheꢀorganicꢀlayerꢀwasꢀwashedꢀwithꢀNaHCO3ꢀsat.,ꢀHClaq.ꢀ1N,ꢀ
brine,ꢀ driedꢀ overꢀ Na2SO4ꢀ andꢀ concentratedꢀ underꢀ vacuum.ꢀ Theꢀ crudeꢀ productꢀ wasꢀ purifiedꢀ byꢀ
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chromatographyꢀonꢀsilicaꢀgelꢀusingꢀEtOAc/Heptane:ꢀ7/3ꢀtoꢀaffordꢀtheꢀdiastereomericꢀmixtureꢀ15ꢀasꢀaꢀ
whiteꢀsolidꢀ(28mg,ꢀ0.048mmol,ꢀ72%).ꢀ1HꢀNMRꢀ(DMSOꢁd6,ꢀ400MHz):ꢀδꢀ8.57ꢀ(m,ꢀ1H),ꢀ7.82ꢀꢁꢀ7.93ꢀ(m,ꢀ
3H),ꢀ7.75ꢀꢁꢀ7.82ꢀ(m,ꢀ1H),ꢀ7.59ꢀꢁꢀ7.75ꢀ(m,ꢀ3H),ꢀ7.36ꢀꢁꢀ7.47ꢀ(m,ꢀ3H),ꢀ7.21ꢀꢁꢀ7.36ꢀ(m,ꢀ6H),ꢀ7.13ꢀꢁꢀ7.21ꢀ(m,ꢀ
2H),ꢀ6.20ꢀꢁꢀ6.33ꢀ(m,ꢀ1H),ꢀ4.76ꢀꢁꢀ4.96ꢀ(m,ꢀ1H),ꢀ4.23ꢀꢁꢀ4.38ꢀ(m,ꢀ1H),ꢀ4.05ꢀꢁꢀ4.16ꢀ(m,ꢀ2H),ꢀ3.49ꢀꢁꢀ3.69ꢀ(m,ꢀ
1H),ꢀ2.93ꢀꢁꢀ3.16ꢀ(m,ꢀ2H),ꢀ2.77ꢀꢁꢀ2.92ꢀ(m,ꢀ1H);ꢀ13CꢀNMRꢀ(DMSOꢁd6,ꢀ100MHz):ꢀδꢀ172.4,ꢀ172.3,ꢀ170.8,ꢀ
170.7,ꢀ156.3,ꢀ156.3,ꢀ144.2,ꢀ144.2,ꢀ141.1,ꢀ141.1,ꢀ140.8,ꢀ140.8,ꢀ138.5,ꢀ138.4,ꢀ133.6,ꢀ133.6,ꢀ131.0,ꢀ131.0,ꢀ
129.7,ꢀ129.7,ꢀ128.6,ꢀ128.5,ꢀ128.1,ꢀ128.1,ꢀ127.5,ꢀ127.5,ꢀ126.8,ꢀ126.7,ꢀ125.9,ꢀ125.8,ꢀ123.9,ꢀ123.9,ꢀ120.5,ꢀ
120.5,ꢀ117.2,ꢀ117.2,ꢀ116.2,ꢀ116.2,ꢀ66.2,ꢀ66.2,ꢀ56.6,ꢀ56.6,ꢀ53.4,ꢀ53.3,ꢀ48.9,ꢀ48.6,ꢀ47.0;ꢀIRꢀ(cmꢁ1):ꢀ3275,ꢀ
2926,ꢀ1709,ꢀ1686,ꢀ1657,ꢀ1531,ꢀ1262;ꢀHPLCꢀtRꢀ=ꢀ5.18ꢀmin;ꢀHRMSꢀ(ESIꢁTOF)ꢀm/z:ꢀ[Mꢀ+ꢀH]+ꢀCalcdꢀforꢀ
C33H29ClN4O4 581.1950; found 581.1957.ꢀ
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N,N''''ꢀdipropanꢀ2ꢀylcarbamimidicꢁ azide,ꢁ Compoundꢁ 17ꢁ .ꢀ Followingꢀ theꢀ generalꢀ methodꢀ A,ꢀ 17ꢀ wasꢀ
quantifiedꢀbyꢀHPLC.ꢀmp:ꢀ139ꢀꢁꢀ140°C;ꢀꢀ1HꢀNMRꢀ(DMSOꢁd6,ꢀ400MHz):ꢀδꢀ6.57ꢀ(d,ꢀJꢁ=ꢀ7.0Hz,ꢀ1H),ꢀ4.56ꢀ(dt,ꢀ
Jꢁ=ꢀ13.3,ꢀ7.0Hz,ꢀ1H),ꢀ3.80ꢀ(dq,ꢀJꢁ=ꢀ13.3,ꢀ7.0Hz,ꢀ1H),ꢀ1.40ꢀ(s,ꢀ3H),ꢀ1.38ꢀ(s,ꢀ3H),ꢀ1.21ꢀ(s,ꢀ3H),ꢀ1.20ꢀ(s,ꢀ3H);ꢀ
13CꢀNMRꢀ(DMSOꢁd6,100MHz):ꢀδꢀꢀ154.0,ꢀ47.2,ꢀ45.5,ꢀ22.4,ꢀ21.5;ꢀIRꢀ(cmꢁ1):ꢀ3268,ꢀ2978,ꢀ1673,ꢀ1594,ꢀ1139;ꢀ
HPLCꢀtRꢀ=ꢀ2.21ꢀmin;ꢀHRMSꢀ(ESIꢁTOF)ꢀm/z:ꢀ[Mꢀ+ꢀH]+ꢀCalcdꢀforꢀC7H15N5 170.1400; found 170.1395.ꢀ
Methylꢁ 3ꢀ[(3ꢀchloroꢀ4ꢀmethoxyphenyl)amino]propanoate,ꢁ Compoundꢁ 18.ꢀ Followingꢀ theꢀ generalꢀ
methodꢀB,ꢀreactionꢀwasꢀquenchedꢀwithꢀMeOH,ꢀandꢀ18ꢀwasꢀquantifiedꢀbyꢀHPLC.ꢀmp:ꢀ43ꢀꢁꢀ44°C;ꢀ1Hꢀ
NMRꢀ(CD3OD,ꢀ400MHz):ꢀδꢀ6.86ꢀ(d,ꢀJꢁ=ꢀ8.8Hz,ꢀ1H),ꢀ6.70ꢀ(d,ꢀJꢁ=ꢀ3.0Hz,ꢀ1H),ꢀ6.55ꢀ(dd,ꢀJꢁ=ꢀ8.8,ꢀ3.0Hz,ꢀ1H),ꢀ
3.76ꢀ(s,ꢀ3H),ꢀ3.67ꢀ(s,ꢀ4H),ꢀ3.33ꢀ(dd,ꢀJꢁ=ꢀ6.8Hz,ꢀ3H),ꢀ2.57ꢀ(dd,ꢀJꢁ=ꢀ6.8Hz,ꢀ2H);ꢀ13CꢀNMRꢀ(CD3OD,ꢀ100MHz):ꢀ
δꢀ174.3,ꢀ148.6,ꢀ144.6,ꢀ124.4,ꢀ116.1,ꢀ115.8,ꢀ113.5,ꢀ57.5,ꢀ52.1,ꢀ41.2,ꢀ34.6;ꢀIRꢀ(cmꢁ1):ꢀ3390,ꢀ2951,ꢀ1729,ꢀ
1504,ꢀ1230,ꢀ1059,1018;ꢀHPLCꢀtRꢀ=ꢀ3.13ꢀmin;ꢀHRMSꢀ(ESIꢁTOF)ꢀm/z:ꢀ[Mꢀ+ꢀH]+ꢀCalcdꢀforꢀC11H14ClNO3
244.0735; found 244.0734.ꢀ
Acknowledgmentsꢀ
WeꢀthankꢀtheꢀMESRꢀforꢀaꢀdoctoralꢀfellowshipꢀ
Supportingꢀinformationꢀ
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1Hꢀandꢀ13CꢀNMRꢀspectraꢀofꢀintermediatesꢀBꢀandꢀC,ꢀalongꢀwithꢀspectraꢀofꢀtheꢀreportedꢀcompounds.ꢀ
ThisꢀmaterialꢀisꢀavailableꢀfreeꢀofꢀchargeꢀviaꢀtheꢀInternetꢀatꢀhttp://pubs.acs.org/.ꢀ
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