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Org aP nl ei ac s &e ꢀ dB oi oꢀ n mo to ꢀ al ed cj uu sl at ꢀrm Ca hr ge imn si ꢀs try
JournalꢀNameꢀ
ꢀARTICLEꢀ
ꢀ
Theꢀmoreꢀelectronꢀwithdrawingꢀgroupꢀtheꢀsubstituentꢀwas,ꢀtheꢀ mixtureꢀwasꢀfilteredꢀthroughꢀaꢀpadꢀofꢀCelit eD ÒO .I :ꢀ T1 0h .e1 0ꢀ a3 q9 u/ Ce 7o Ou Bs 0ꢀ p0 h5 a3 2s eF ꢀ
higherꢀrelativeꢀamountꢀofꢀlactoneꢀ12ꢀwouldꢀbe.ꢀIndeed,ꢀstartingꢀ wasꢀextractedꢀwithꢀethylꢀacetateꢀandꢀtheꢀcombinedꢀorganicꢀlayersꢀ
fromꢀCH
2 2 4
OMeꢀorꢀphenylꢀb-substituted-(Z)-3-iodoacrylicꢀacidsꢀ1,ꢀ wereꢀwashedꢀwithꢀbrine,ꢀdriedꢀoverꢀNa SO ꢀandꢀconcentratedꢀunderꢀ
theꢀamountꢀofꢀtheꢀ6-memberedꢀlactonesꢀ12fꢀandꢀ12gꢀisꢀ35ꢀandꢀ reducedꢀ pressure.ꢀ Theꢀ crudeꢀ productꢀ wasꢀ thenꢀ purifiedꢀ byꢀ flashꢀ
1
8%ꢀrespectively. ꢀ
2
6
chromatographyꢀonꢀsilicaꢀgelꢀusingꢀpetroleumꢀether:ꢀethylꢀacetateꢀasꢀ
eluent.ꢀ
ꢀ
Conclusionsꢀ
Generalꢀ Procedureꢀ forꢀ theꢀ Synthesisꢀ ofꢀ 7:ꢀ (Z)-3-Substituted-3-
iodoprop-2-enoicꢀacidꢀderivativeꢀ1ꢀ(1.0ꢀmmol,ꢀ1ꢀequiv.)ꢀwasꢀdissolvedꢀ
Inꢀsummary,ꢀweꢀhaveꢀdescribedꢀaꢀstraightforwardꢀandꢀversatileꢀ
copper-catalyzedꢀmultiꢀbonds-formingꢀtransformationsꢀforꢀtheꢀ
constructionꢀ ofꢀ pharmaceuticallyꢀ interestingꢀ complexꢀ
polyheterocyclicꢀscaffoldsꢀcontainingꢀanꢀindoleꢀmoiety.ꢀTheseꢀ
processesꢀ featureꢀ readilyꢀ availableꢀ startingꢀ materials,ꢀ mildꢀ
reactionꢀconditions,ꢀandꢀtoleranceꢀofꢀaꢀwideꢀrangeꢀofꢀfunctionalꢀ
groups.ꢀTheꢀgenerationꢀofꢀmolecularꢀcomplexityꢀinꢀaꢀ“one-pot”ꢀ
processꢀshouldꢀrenderꢀthisꢀmethodꢀaꢀusefulꢀorganicꢀsyntheticꢀ
tool.ꢀꢀ
2 3
inꢀi-PrOHꢀ(3.5ꢀmL)ꢀinꢀoven-dried-Schlenkꢀtube.ꢀK CO ꢀ(277ꢀmg,ꢀ2.0ꢀ
mmol,ꢀ2ꢀequiv.)ꢀwasꢀthenꢀaddedꢀtoꢀtheꢀsolutionꢀandꢀtheꢀsuspensionꢀ
wasꢀstirredꢀforꢀ10ꢀminꢀunderꢀArgon.ꢀTheꢀmixtureꢀwasꢀthenꢀdegassedꢀ
atꢀ-78ꢀ°Cꢀforꢀ2x10ꢀminꢀandꢀtheꢀvesselꢀwasꢀbackfilledꢀwithꢀargon.ꢀAfterꢀ
warmingꢀ toꢀ roomꢀ temperature,ꢀ terminalꢀ alkyneꢀ 2ꢀ (2.0ꢀ mmol,ꢀ 2ꢀ
equiv.),ꢀtryptamineꢀ9ꢀ(320ꢀmg,ꢀ2.0ꢀmmol,ꢀ2ꢀequiv.)ꢀandꢀCuIꢀ(38ꢀmg,ꢀ
0
.2ꢀmmol,ꢀ0.2ꢀequiv.)ꢀwereꢀrespectivelyꢀaddedꢀintoꢀtheꢀmixture.ꢀTheꢀ
mixtureꢀwasꢀthenꢀrapidlyꢀdegassedꢀandꢀtheꢀvesselꢀwasꢀbackfilledꢀwithꢀ
argon.ꢀTheꢀsealedꢀSchlenkꢀtubeꢀwasꢀplacedꢀinꢀtheꢀpreheatedꢀoilꢀbathꢀ
(
50ꢀ°C)ꢀandꢀwasꢀstirredꢀovernight.ꢀTheꢀreactionꢀmixtureꢀwasꢀcooledꢀ
ExperimentalꢀSectionꢀ
toꢀ0ꢀ°C,ꢀthenꢀaꢀsolutionꢀofꢀhydrochloricꢀacidꢀ(3.4ꢀmL,ꢀ6ꢀM,ꢀ20ꢀequiv.)ꢀ
wasꢀaddedꢀdropwise.ꢀTheꢀreactionꢀwasꢀthenꢀheatedꢀatꢀ50ꢀ°Cꢀuntilꢀtheꢀ
disappearanceꢀ ofꢀ theꢀ γ-hydroxybutyrolactamꢀcheckedꢀbyꢀTLC.ꢀTheꢀ
reactionꢀmixtureꢀwasꢀcooledꢀtoꢀ0ꢀ°Cꢀthenꢀfilteredꢀthroughꢀaꢀpadꢀofꢀ
CeliteÒ.ꢀTheꢀaqueousꢀphaseꢀwasꢀextractedꢀwithꢀethylꢀacetateꢀandꢀtheꢀ
Generalꢀ Procedureꢀ forꢀ theꢀ Synthesisꢀ ofꢀ 5:ꢀ (Z)-3-Substituted-3-
iodoprop-2-enoicꢀacidꢀderivativeꢀ1ꢀ(2.0ꢀmmol,ꢀ1ꢀequiv.)ꢀwasꢀdissolvedꢀ
2 3
inꢀ i-PrOHꢀ (7ꢀ mL)ꢀ inꢀ oven-dried-Schlenkꢀ tube.ꢀ K CO ꢀ (553ꢀ mg,ꢀ 4.0ꢀ
mmol,ꢀ2ꢀequiv.)ꢀwasꢀthenꢀaddedꢀtoꢀtheꢀsolutionꢀandꢀtheꢀsuspensionꢀ
wasꢀstirredꢀforꢀ10ꢀminꢀunderꢀArgon.ꢀTheꢀmixtureꢀwasꢀthenꢀdegassedꢀ
atꢀ-78ꢀ°Cꢀforꢀ2x10ꢀminꢀandꢀtheꢀvesselꢀwasꢀbackfilledꢀwithꢀargon.ꢀAfterꢀ
warmingꢀ toꢀ roomꢀ temperature,ꢀ terminalꢀ alkyneꢀ 2ꢀ (4.0ꢀ mmol,ꢀ 2ꢀ
equiv.),ꢀtryptamineꢀ9ꢀ(641ꢀmg,ꢀ4.0ꢀmmol,ꢀ2ꢀequiv.)ꢀandꢀCuIꢀ(76ꢀmg,ꢀ
2 4
combinedꢀorganicꢀlayersꢀwereꢀwashedꢀwithꢀbrine,ꢀdriedꢀoverꢀNa SO ꢀ
andꢀconcentratedꢀunderꢀreducedꢀpressure.ꢀTheꢀcrudeꢀproductꢀwasꢀ
thenꢀpurifiedꢀbyꢀflashꢀchromatographyꢀonꢀsilicaꢀgelꢀusingꢀpetroleumꢀ
ether:ꢀethylꢀacetateꢀasꢀeluent.ꢀ
ꢀ
0
.4ꢀmmol,ꢀ0.2ꢀequiv)ꢀwereꢀrespectivelyꢀaddedꢀintoꢀtheꢀmixture.ꢀTheꢀ
Orꢀ (Z)-3-Substituted-3-iodoprop-2-enoicꢀ acidꢀ derivativeꢀ 1ꢀ (0.5.ꢀ
mmol,ꢀ 1ꢀ equiv.)ꢀ wasꢀ dissolvedꢀ inꢀ i-PrOHꢀ (1.75ꢀ mL)ꢀ inꢀ oven-dried-
mixtureꢀwasꢀthenꢀrapidlyꢀdegassedꢀandꢀtheꢀvesselꢀwasꢀbackfilledꢀwithꢀ
argon.ꢀTheꢀsealedꢀSchlenckꢀtubeꢀwasꢀplacedꢀinꢀtheꢀpreheatedꢀoilꢀbathꢀ
2 3
Schlenkꢀtube.ꢀK CO ꢀ(138ꢀmg,ꢀ1.0ꢀmmol,ꢀ2ꢀequiv.)ꢀwasꢀthenꢀaddedꢀtoꢀ
(
50ꢀ°C)ꢀandꢀwasꢀstirredꢀovernight.ꢀTheꢀreactionꢀmixtureꢀwasꢀcooledꢀ
toꢀ 0ꢀ °C,ꢀ thenꢀ quenchedꢀ byꢀ theꢀ additionꢀ ofꢀ anꢀ aqueousꢀ saturatedꢀ
NH Clꢀ solutionꢀ andꢀ stirredꢀ forꢀ furtherꢀ 15ꢀ min.ꢀ Theꢀ mixtureꢀ wasꢀ
theꢀsolutionꢀandꢀtheꢀsuspensionꢀwasꢀstirredꢀforꢀ10ꢀminꢀunderꢀArgon.ꢀ
Theꢀmixtureꢀwasꢀthenꢀdegassedꢀatꢀ-78ꢀ°Cꢀforꢀ2x10ꢀminꢀandꢀtheꢀvesselꢀ
wasꢀ backfilledꢀ withꢀ argon.ꢀ Afterꢀ warmingꢀ toꢀ roomꢀ temperature,ꢀ
terminalꢀalkyneꢀ2ꢀ(1.0ꢀmmol,ꢀ2ꢀequiv.),ꢀtryptamineꢀ9ꢀ(160ꢀmg,ꢀ1.0ꢀ
mmol,ꢀ 2ꢀ equiv.)ꢀ andꢀ CuIꢀ (19ꢀ mg,ꢀ 0.1ꢀ mmol,ꢀ 0.2ꢀ equiv.)ꢀ wereꢀ
respectivelyꢀaddedꢀintoꢀtheꢀmixture.ꢀTheꢀmixtureꢀwasꢀthenꢀrapidlyꢀ
degassedꢀ andꢀ theꢀ vesselꢀ wasꢀ backfilledꢀ withꢀ argon.ꢀ Theꢀ sealedꢀ
Schlenkꢀtubeꢀwasꢀplacedꢀinꢀtheꢀpreheatedꢀoilꢀbathꢀ(50ꢀ°C)ꢀandꢀwasꢀ
stirredꢀovernight.ꢀTheꢀreactionꢀmixtureꢀwasꢀcooledꢀtoꢀ0ꢀ°C,ꢀthenꢀaꢀ
solutionꢀ ofꢀ hydrochloricꢀ acidꢀ (3.5ꢀ mL,ꢀ 1ꢀ M,ꢀ 7ꢀ equiv.)ꢀ wasꢀ addedꢀ
dropwise.ꢀ Theꢀ reactionꢀ wasꢀ thenꢀ heatedꢀ atꢀ 50ꢀ °Cꢀ untilꢀ theꢀ
disappearanceꢀofꢀtheꢀγ-hydroxybutyrolactamꢀcheckedꢀbyꢀTLC.ꢀTheꢀ
reactionꢀmixtureꢀwasꢀcooledꢀtoꢀ0ꢀ°Cꢀthenꢀfilteredꢀthroughꢀaꢀpadꢀofꢀ
CeliteÒ.ꢀTheꢀaqueousꢀphaseꢀwasꢀextractedꢀwithꢀethylꢀacetateꢀandꢀtheꢀ
4
filteredꢀthroughꢀaꢀpadꢀofꢀCeliteÒ.ꢀTheꢀaqueousꢀphaseꢀwasꢀextractedꢀ
withꢀethylꢀacetateꢀandꢀtheꢀcombinedꢀorganicꢀlayersꢀwereꢀwashedꢀ
2 4
withꢀ brine,ꢀ driedꢀ overꢀ Na SO ꢀ andꢀ concentratedꢀ underꢀ reducedꢀ
pressure.ꢀ Theꢀ crudeꢀ productꢀ wasꢀ thenꢀ purifiedꢀ byꢀ flashꢀ
chromatographyꢀonꢀsilicaꢀgelꢀusingꢀpetroleumꢀether:ꢀethylꢀacetateꢀasꢀ
eluent.ꢀ
ꢀ
Generalꢀ Procedureꢀ forꢀ theꢀ Synthesisꢀ ofꢀ 6:ꢀ (Z)-3-Substituted-3-
iodoprop-2-enoicꢀacidꢀderivativeꢀ1ꢀ(1.0ꢀmmol,ꢀ1ꢀequiv.)ꢀwasꢀdissolvedꢀ
2 3
inꢀi-PrOHꢀ(3.5ꢀmL)ꢀinꢀoven-dried-Schlenkꢀtube.ꢀK CO ꢀ(277ꢀmg,ꢀ2.0ꢀ
mmol,ꢀ2ꢀequiv.)ꢀwasꢀthenꢀaddedꢀtoꢀtheꢀsolutionꢀandꢀtheꢀsuspensionꢀ
wasꢀstirredꢀforꢀ10ꢀminꢀunderꢀArgon.ꢀTheꢀmixtureꢀwasꢀthenꢀdegassedꢀ
atꢀ-78ꢀ°Cꢀforꢀ2x10ꢀminꢀandꢀtheꢀvesselꢀwasꢀbackfilledꢀwithꢀargon.ꢀAfterꢀ
warmingꢀtoꢀroomꢀtemperature,ꢀ1-prop-2-yn-1-yl-1H-indoleꢀ10ꢀ(310ꢀ
mg,ꢀ2.0ꢀmmol,ꢀ2ꢀequiv.),ꢀprimaryꢀamineꢀ3ꢀ(3.0ꢀmmol,ꢀ3ꢀequiv.)ꢀandꢀ
CuIꢀ(190ꢀmg,ꢀ1.0ꢀmmol,ꢀ1ꢀequiv)ꢀwereꢀrespectivelyꢀaddedꢀintoꢀtheꢀ
mixture.ꢀTheꢀmixtureꢀwasꢀthenꢀrapidlyꢀdegassedꢀandꢀtheꢀvesselꢀwasꢀ
backfilledꢀ withꢀ argon.ꢀ Theꢀ sealedꢀ Schlenkꢀ tubeꢀ wasꢀ placedꢀ inꢀ theꢀ
preheatedꢀoilꢀbathꢀ(50ꢀ°C)ꢀandꢀwasꢀstirredꢀovernight.ꢀTheꢀreactionꢀ
mixtureꢀwasꢀcooledꢀtoꢀ0ꢀ°C,ꢀthenꢀquenchedꢀbyꢀtheꢀadditionꢀofꢀanꢀ
2 4
combinedꢀorganicꢀlayersꢀwereꢀwashedꢀwithꢀbrine,ꢀdriedꢀoverꢀNa SO ꢀ
andꢀconcentratedꢀunderꢀreducedꢀpressure.ꢀTheꢀcrudeꢀproductꢀwasꢀ
thenꢀpurifiedꢀbyꢀflashꢀchromatographyꢀonꢀsilicaꢀgelꢀusingꢀpetroleumꢀ
ether:ꢀethylꢀacetateꢀ(statedꢀbelow)ꢀasꢀeluent.ꢀ
ꢀ
Generalꢀ Procedureꢀ forꢀ theꢀ Synthesisꢀ ofꢀ 14:ꢀ (Z)-3-Substituted-3-
iodoprop-2-enoicꢀacidꢀderivativeꢀ1ꢀ(0.5ꢀmmol,ꢀ1ꢀequiv.)ꢀwasꢀdissolvedꢀ
2 3
inꢀi-PrOHꢀ(1.75ꢀmL)ꢀinꢀoven-dried-Schlenkꢀtube.ꢀK CO ꢀ(139ꢀmg,ꢀ1.0ꢀ
mmol,ꢀ2ꢀequiv.)ꢀwasꢀthenꢀaddedꢀtoꢀtheꢀsolutionꢀandꢀtheꢀsuspensionꢀ
wasꢀstirredꢀforꢀ10ꢀminꢀunderꢀArgon.ꢀTheꢀmixtureꢀwasꢀthenꢀdegassedꢀ
4
aqueousꢀsaturatedꢀNH Clꢀsolutionꢀandꢀstirredꢀforꢀfurtherꢀ15ꢀmin.ꢀTheꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
J.ꢀName.,ꢀ2013,ꢀ00,ꢀ1-3ꢀ|ꢀ5ꢀ
Pleaseꢀdoꢀnotꢀadjustꢀmarginsꢀ
Mardjan
