Stereochemistry and Mechanistic Insight in the [2k+2i+2i] Annulations of Ketenes and Imines

Article abstract of DOI:10.1021/acs.joc.6b00279

The stereochemistry and mechanistic insight in the annulations of one ketene molecule with two imine molecules ([2^k+2ⁱ+2ⁱ] annulation) are studied by using six-membered 3,4-dihydroisoquinoline as an imine probe. A concerted hetero-Diels-Alder cycloaddition mechanism is proposed to explain the stereochemical outcomes. In most cases, the zwitterionic 2-aza-1,3-butadiene-type intermediates, generated from ketenes and imines, undergo endo hetero-Diels-Alder cycloaddition with the second imine molecule. For ketenes with electron-donating substituents, (2,4)-cis-(4,5)-cis-[2^k+2ⁱ+2ⁱ] annuladducts formed stereospecifically, while, for ketenes with electron-accepting substituents, (2,4)-cis-(4,5)-trans-[2^k+2ⁱ+2ⁱ] annuladducts are generated stereospecifically. The [2^k+2ⁱ+2ⁱ] annulations of aryloxyketenes and 3,4-dihydroisoquinoline give stereodivergent products due to the occurrence of the stepwise nucleophilic annulation. However, in the [2^k+2ⁱ+2ⁱ] annulations of seven-membered cyclic imine dibenzo[b,f][1,4]oxazepine, the zwitterionic aza-butadiene-type intermediates exclusively undergo exo hetero-Diels-Alder cycloadditions with another molecule of imine to yield (2,4)-trans-(4,5)-trans-[2^k+2ⁱ+2ⁱ] annuladducts stereospecifically, regardless of the ketene substituents. The mechanistic model not only discloses the nature of the [2^k+2ⁱ+2ⁱ] annulations, but also can be used to explain and predict the stereochemistry of the [2^k+2ⁱ+2ⁱ] annuladducts from different ketenes and imines.

Full text of DOI:10.1021/acs.joc.6b00279

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Article
Stereochemistry and mechanistic insight in the
2k+2i+2i] annulations of ketenes and imines
[
Zhanhui Yang, Wei He, Baoxiang Cheng, and Jiaxi Xu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00279 • Publication Date (Web): 11 May 2016
Downloaded from http://pubs.acs.org on May 12, 2016
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Stereochemistryꢀandꢀmechanisticꢀinsightꢀinꢀtheꢀ[2 +2 +2 ]ꢀ
annulationsꢀofꢀketenesꢀandꢀiminesꢀ
ZhanhuiꢀYang,ꢀWeiꢀHe,ꢀBaoxiangꢀChengꢀandꢀJiaxiꢀXu*ꢀ
StateꢀKeyꢀLaboratoryꢀofꢀChemicalꢀResourceꢀEngineering,ꢀDepartmentꢀofꢀOrganicꢀChemistry,ꢀ
FacultyꢀofꢀScience,ꢀBeijingꢀUniversityꢀofꢀChemicalꢀTechnology,ꢀBeijingꢀ100029,ꢀPeople’sꢀRepublicꢀ
ofꢀChinaꢀ
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Tel/Fax:ꢀ+8610-64435565ꢀ
Email:ꢀjxxu@mail.buct.edu.cnꢀ
ꢀ
Theꢀstereochemistryꢀandꢀmechanisticꢀinsightꢀinꢀtheꢀannulationsꢀofꢀoneꢀketeneꢀmoleculeꢀwithꢀtwoꢀ
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imineꢀ moleculesꢀ ([2 +2 +2 ]ꢀ annulation)ꢀ areꢀ studiedꢀ byꢀ usingꢀ six-memberedꢀ
,4-dihydroisoquinolineꢀ asꢀ anꢀ imineꢀ probe.ꢀ Aꢀ concertedꢀ hetero-Diels-Alderꢀ cycloadditionꢀ
mechanismꢀisꢀproposedꢀtoꢀexplainꢀtheꢀstereochemicalꢀoutcomes.ꢀInꢀmostꢀcases,ꢀtheꢀzwitterionicꢀ
-aza-1,3-butadiene-typeꢀ intermediates,ꢀ generatedꢀ fromꢀ ketenesꢀ andꢀ imines,ꢀ undergoꢀ endoꢀ
hetero-Diels-Alderꢀ cycloadditionꢀ withꢀ theꢀ secondꢀ imineꢀ molecule.ꢀ Forꢀ ketenesꢀ withꢀ
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2
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electron-donating-substituents,ꢀ
stereospecifically,ꢀ while,ꢀ
2,4)-cis-(4,5)-trans-[2 +2 +2 ]ꢀ annuladductsꢀ areꢀ generatedꢀ stereospecifically.ꢀ Theꢀ [2 +2 +2 ]ꢀ
annulationsꢀofꢀaryloxyketenesꢀandꢀ3,4-dihydroisoquinolineꢀgiveꢀstereodivergentꢀproductsꢀdueꢀtoꢀ
(2,4)-cis-(4,5)-cis-[2 +2 +2 ]ꢀ
annuladductsꢀ
formedꢀ
forꢀ
ketenesꢀ withꢀ
electron-accepting-substituents,ꢀ
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(
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theꢀoccurrenceꢀofꢀtheꢀstepwiseꢀnucleophilicꢀannulation.ꢀHowever,ꢀinꢀtheꢀ[2 +2 +2 ]ꢀannulationsꢀofꢀ
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seven-memberedꢀ cyclicꢀ imineꢀ dibenzo[b,f][1,4]oxazepine,ꢀ theꢀ zwitterionicꢀ aza-butadiene-typeꢀ
intermediatesꢀexclusivelyꢀundergoꢀexoꢀhetero-ꢀDiels-Alderꢀcycloadditionsꢀwithꢀanotherꢀmoleculeꢀ
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ofꢀ imineꢀ toꢀ yieldꢀ (2,4)-trans-(4,5)-trans-[2 +2 +2 ]ꢀ annuladductsꢀ stereospecifically,ꢀ regardlessꢀ ofꢀ
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theꢀketeneꢀsubstituents.ꢀTheꢀmechanisticꢀmodelꢀnotꢀonlyꢀdisclosesꢀtheꢀnatureꢀofꢀtheꢀ[2 +2 +2 ]ꢀ
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annulations,ꢀbutꢀalsoꢀcanꢀbeꢀusedꢀtoꢀexplainꢀandꢀpredictꢀtheꢀstereochemistryꢀofꢀtheꢀ[2 +2 +2 ]ꢀ
annuladductsꢀfromꢀdifferentꢀketenesꢀandꢀimines.ꢀ
ꢀ
Introductionꢀ
TheꢀStaudingerꢀcycloadditionsꢀbetweenꢀketenesꢀandꢀiminesꢀhaveꢀprovenꢀtoꢀbeꢀaꢀpowerfulꢀtoolꢀ
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forꢀtheꢀconstructionꢀofꢀβ-lactamsꢀbackbones, ꢀ whichꢀserveꢀasꢀkeyꢀstructuralꢀfeaturesꢀinꢀaꢀseriesꢀ
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ofꢀ antibiotics. ꢀ However,ꢀ experimentalꢀ resultsꢀ fromꢀ severalꢀ groupsꢀ haveꢀ demonstratedꢀ thatꢀ
thereꢀexistꢀfourꢀannuloselectiveꢀreactionꢀpathwaysꢀinꢀtheꢀStaudingerꢀcycloadditionsꢀdependingꢀ
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uponꢀtheꢀsubstituentꢀeffectꢀofꢀketenesꢀandꢀimines,ꢀnamely,ꢀ(1)ꢀ[2 +2 ]ꢀannulationsꢀbetweenꢀoneꢀ
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keteneꢀmoleculesꢀandꢀoneꢀimineꢀmolecules; ꢀ(2)ꢀ[2 +2 +2 ]ꢀannulationsꢀbetweenꢀtwoꢀmoleculesꢀ
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ofꢀdisubstitutedꢀketenesꢀ(R ꢀ≠ꢀH)ꢀandꢀoneꢀimineꢀmolecules; ꢀ (3)ꢀ[2 +2 +2 ]ꢀannulationsꢀbetweenꢀ
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twoꢀ moleculesꢀ ofꢀ monosubstitutedꢀ ketenesꢀ (R ꢀ =ꢀ H)ꢀ andꢀ oneꢀ imineꢀ molecules; ꢀ (4)ꢀ [2 +2 +2 ]ꢀ
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annulationsꢀbetweenꢀoneꢀketeneꢀmoleculesꢀandꢀtwoꢀimineꢀmoleculesꢀ(Schemeꢀ1). ꢀ Theꢀ[2 +2 ]ꢀ
annulationsꢀgenerateꢀtwoꢀstereocentersꢀatꢀtheꢀC3ꢀandꢀC4ꢀpositionsꢀofꢀtheꢀβ-lactamꢀrings,ꢀandꢀtheꢀ
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stereoselectivityꢀ hasꢀ beenꢀ studiedꢀ systematicallyꢀ byꢀ others ꢀ andꢀ ourꢀ group, ꢀ andꢀ aꢀ
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comprehensivelyꢀ stereoselectiveꢀ ruleꢀ wasꢀ proposedꢀ byꢀ us.
ꢀ Theꢀ [2 +2 +2 ]ꢀ andꢀ [2 +2 +2 ]ꢀ
annulationsꢀ yieldꢀ 2-(alkan-2-ylidene)-1,3-oxazinan-6-onesꢀ andꢀ 2,3-dihydro-1,3-oxazin-4-ones,ꢀ
respectively,ꢀbearingꢀonlyꢀoneꢀstereocenterꢀinꢀeachꢀkindꢀofꢀproducts,ꢀandꢀtheꢀstereochemistryꢀisꢀ
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quiteꢀ simple.ꢀ However,ꢀ theꢀ [2 +2 +2 ]ꢀ annulationsꢀ giveꢀ riseꢀ toꢀ substitutedꢀ
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tetrahydropyrimidin-4(1H)-onesꢀwithꢀthreeꢀstereocentersꢀ(R ꢀ≠ꢀR )ꢀatꢀtheꢀC2,ꢀC4,ꢀandꢀC5ꢀpositionsꢀ
(
Schemeꢀ1).ꢀTheꢀstereochemistryꢀinꢀthisꢀcaseꢀseemsꢀtoꢀbeꢀmoreꢀcomplex,ꢀandꢀtoꢀdateꢀveryꢀfewꢀ
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studiesꢀonꢀtheꢀstereochemistryꢀhaveꢀbeenꢀreported.
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Schemeꢀ1ꢀAnnuloselectivitiesꢀandꢀstereochemistryꢀofꢀeachꢀkindꢀofꢀproductsꢀinꢀtheꢀketene-imineꢀ
reactions.ꢀ
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Inꢀviewꢀofꢀtheꢀsignificantꢀimportanceꢀofꢀtetrahydropyrimidin-4(1H)-oneꢀderivativesꢀinꢀsyntheticꢀ
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andꢀ medicinalꢀ chemistryꢀ (Figureꢀ 1), ꢀ theꢀ stereochemistryꢀ inꢀ theꢀ productsꢀ ofꢀ theꢀ [2 +2 +2 ]ꢀ
annulationsꢀisꢀoneꢀofꢀtheꢀmajorꢀissuesꢀinꢀthisꢀfield.ꢀTheꢀdetailedꢀstereostructuresꢀatꢀC2,ꢀC4,ꢀandꢀ
C5ꢀ stereocenters,ꢀ asꢀ wellꢀ asꢀ theꢀ mechanismꢀ forꢀ theꢀ generationꢀ ofꢀ theꢀ stereochemistry,ꢀ stillꢀ
remainsꢀaꢀmystery.ꢀHerein,ꢀusingꢀ3,4-dihydroisoquinolineꢀasꢀanꢀimineꢀprobeꢀtoꢀreactꢀwithꢀvariousꢀ
ketenesꢀ substitutedꢀ byꢀ stericallyꢀ andꢀ electronicallyꢀ differentꢀ groups,ꢀ weꢀ shedꢀ lightꢀ onꢀ theꢀ
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stereochemistryꢀinꢀtheꢀ[2 +2 +2 ]ꢀannulations,ꢀandꢀproposeꢀaꢀplausibleꢀmechanismꢀtoꢀexplainꢀandꢀ
toꢀfurtherꢀpredictꢀtheꢀstereochemicalꢀoutcomes.ꢀ
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Figureꢀ 1ꢀ Representativeꢀ tetrahydropyrimidin-4(1H)-onesꢀ inꢀ medicinalꢀ chemistryꢀ andꢀ therapicꢀ
clinicsꢀ
ꢀ
ResultsꢀandꢀDiscussionꢀ
Experimentalꢀstudiesꢀonꢀtheꢀstereochemistryꢀ
Theꢀstereochemistryꢀstudiesꢀcommencedꢀwithꢀpursuingꢀaꢀsuitableꢀimineꢀprobeꢀtoꢀreactꢀwithꢀaꢀ
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seriesꢀ ofꢀ ketenesꢀ toꢀ giveꢀ predominantlyꢀ orꢀ exclusivelyꢀ [2 +2 +2 ]ꢀ annulationꢀ productsꢀ
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(annuladducts)ꢀinꢀhighꢀyields.ꢀInꢀourꢀpreviousꢀwork, ꢀweꢀreportedꢀthatꢀtheꢀStaudingerꢀreactionsꢀ
ofꢀ cyclicꢀ iminesꢀ 3,4-dihydroisoquinolineꢀ (1a)ꢀ andꢀ dibenzo[b,f][1,4]oxazepineꢀ (1b)ꢀ withꢀ ketenesꢀ
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gaveꢀ theꢀ correspondingꢀ [2 +2 +2 ]ꢀ annuladductsꢀ inꢀ satisfactoryꢀ (76%)ꢀ andꢀ lowꢀ (7−12%)ꢀ yields,ꢀ
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respectively.ꢀTheseꢀfactsꢀrevealꢀthatꢀcyclicꢀimineꢀ1aꢀisꢀmoreꢀinclinedꢀtoꢀundergoꢀtheꢀ[2 +2 +2 ]ꢀ
annulationsꢀthanꢀcyclicꢀimineꢀ1b.ꢀTherefore,ꢀherein,ꢀweꢀchoseꢀ3,4-dihydroisoquinolineꢀ(1a)ꢀasꢀtheꢀ
imineꢀ probe,ꢀ andꢀ reactedꢀ itꢀ withꢀ aꢀ varietyꢀ ofꢀ ketenesꢀ generatedꢀ byꢀ photo-inducedꢀ Wolffꢀ
rearrangementsꢀ ofꢀ α-aminomethylꢀ diazomethylꢀ ketonesꢀ 2a,b,ꢀ diazoacetatesꢀ 2c-g,ꢀ
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diazoacetophenoneꢀ (2h),ꢀ 3-diazo-2-oxo-propanoateꢀ 2iꢀ andꢀ propanamidesꢀ 2j,kꢀ (Figureꢀ 2), ꢀ toꢀ
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probeꢀ theꢀ [2 +2 +2 ]ꢀ annulations.ꢀ Theꢀ reactionsꢀ wereꢀ performedꢀ followingꢀ ourꢀ previousꢀ
ꢀ
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experimentalꢀprocedures. ꢀTheꢀstereostructuresꢀofꢀtheꢀ[2 +2 +2 ]ꢀannuladductsꢀwereꢀassignedꢀ
accordingꢀtoꢀtheꢀcouplingꢀconstantsꢀbetweenꢀtheꢀprotonsꢀatꢀC4ꢀandꢀC5ꢀpositionsꢀ(Jꢀ=ꢀ9−11ꢀHzꢀforꢀ
trans-isomers,ꢀ Jꢀ =ꢀ 5−6ꢀ Hzꢀ forꢀ cis-isomers,ꢀ generally)ꢀ togetherꢀ withꢀ theꢀ observedꢀ NOEꢀ valuesꢀ
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betweenꢀtheꢀprotonsꢀatꢀC2ꢀandꢀC4ꢀpositionsꢀ(SeeꢀTableꢀ1).ꢀAssigningꢀtheꢀstereostructuresꢀbyꢀthisꢀ
methodꢀisꢀviable,ꢀasꢀdemonstratedꢀbyꢀtheꢀXRDꢀanalysisꢀofꢀcompoundꢀ4mꢀ(videꢀpost,ꢀSchemeꢀ6).ꢀ ꢀ
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ꢀ
Figureꢀ 2.ꢀSelectedꢀketeneꢀprecursorsꢀandꢀimineꢀprobesꢀinꢀtheꢀstereochemicalꢀinvestigationsꢀonꢀ
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[
ꢀ
2 +2 +2 ]ꢀannulations.ꢀ
Asꢀ summarizedꢀ inꢀ Tableꢀ 1,ꢀ weꢀ giveꢀ ourꢀ observations.ꢀ Toꢀ moreꢀ directly,ꢀ simply,ꢀ andꢀ clearlyꢀ
describeꢀ theꢀ stereochemistry,ꢀ weꢀ usedꢀ theꢀ cis-ꢀ andꢀ trans-terminologyꢀ ratherꢀ thanꢀ theꢀ rel(R,S)ꢀ
terminology,ꢀforꢀexample,ꢀuseꢀ(2,4)-cis-(4,5)-cis-4aꢀratherꢀthanꢀrel(4bR,5S,13bR)-4a.ꢀTheꢀreactionꢀ
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betweenꢀ keteneꢀ 3aꢀ andꢀ 1aꢀ annulospecificallyꢀ formsꢀ theꢀ [2 +2 +2 ]ꢀ annuladductꢀ
(
2,4)-cis-(4,5)-cis-4aꢀinꢀ17%ꢀyieldꢀ(Tableꢀ1,ꢀentryꢀ1).ꢀAnalogously,ꢀtheꢀannulospecificꢀadductꢀ4bꢀ
exhibitsꢀ theꢀ sameꢀ stereochemistryꢀ asꢀ 4aꢀ (Tableꢀ 1,ꢀ entryꢀ 2).ꢀ Forꢀ ketenesꢀ withꢀ strongꢀ
electron-donatingꢀalkoxyꢀgroupsꢀsuchꢀasꢀethoxyꢀ(3c),ꢀisopropoxyꢀ(3d),ꢀandꢀbenzyloxyꢀ(3e),ꢀtheꢀ
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reactionsꢀproceedꢀinꢀtheꢀfollowingꢀtwoꢀdirectionsꢀ(Tableꢀ1,ꢀentriesꢀ3−5):ꢀ(i)ꢀ[2 +2 +2 ]ꢀannulationsꢀ
affordingꢀstereospecificꢀ(2,4)-cis-(4,5)-cis--tetrahydropyrimidin-4(1H)-onesꢀ4c,ꢀ4d,ꢀandꢀ4eꢀinꢀ7%,ꢀ
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trace,ꢀ andꢀ 36%ꢀ yields,ꢀ respectively;ꢀ (ii)ꢀ [2 +2 ]ꢀ annulationsꢀ deliveringꢀ stereospecificꢀ
trans-β-lactamsꢀ5c,ꢀ5d,ꢀandꢀ5eꢀinꢀ26%,ꢀ14%,ꢀandꢀ7%ꢀyields,ꢀrespectively.ꢀHowever,ꢀtheꢀketeneꢀ3fꢀ
substitutedꢀ byꢀ weaklyꢀ electron-donatingꢀ phenoxyꢀ groupꢀ favorablyꢀ underwentꢀ stereodivergentꢀ
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[2 +2 +2 ]ꢀannulationsꢀ(Tableꢀ1,ꢀentryꢀ6),ꢀandꢀtwoꢀdiastereomericꢀtetrahydropyrimidin-4(1H)-onesꢀ
(
2,4)-cis-(4,5)-cis-4faꢀ andꢀ (2,4)-cis-(4,5)-trans-4fbꢀ wereꢀ obtainedꢀ inꢀ 30%ꢀ andꢀ 55%ꢀ yields,ꢀ
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respectively,ꢀ asꢀ wellꢀ asꢀ theꢀ [2 +2 ]ꢀ cycloadductꢀ 5fꢀ inꢀ 12%ꢀ yield.ꢀ Theꢀ reactionꢀ ofꢀ
4-nitrophenoxyketeneꢀ(3g),ꢀhowever,ꢀgaveꢀriseꢀtoꢀnotꢀonlyꢀtheꢀexpectedꢀ(2,4)-cis-(4,5)-trans-4gbꢀ
10
inꢀ 36%ꢀ yield,ꢀ butꢀ alsoꢀ aꢀ surprisingꢀ (2,4)-trans-(4,5)-trans-4gcꢀ inꢀ 19%ꢀ yieldꢀ (Tableꢀ 1,ꢀ entryꢀ 7). ꢀ
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Subsequently,ꢀ weꢀ investigatedꢀ theꢀ stereochemistryꢀ ofꢀ theꢀ [2 +2 +2 ]ꢀ annuladductsꢀ generatedꢀ
fromꢀ aꢀ varietyꢀ ofꢀ electron-withdrawingꢀ groupꢀ (EWG)-substitutedꢀ ketenesꢀ 3h-kꢀ andꢀ imineꢀ 1aꢀ
k
i
i
(
Tableꢀ1,ꢀentriesꢀ8−11).ꢀTheꢀ[2 +2 +2 ]ꢀannulationsꢀofꢀtheseꢀketenesꢀoccurredꢀsmoothly,ꢀandꢀallꢀ
gaveꢀ riseꢀ toꢀ theꢀ correspondingꢀ (2,4)-cis-(4,5)-trans-tetrahydropyrimidin-4(1H)-onesꢀ 4h-kꢀ inꢀ
31−67%ꢀtotalꢀyieldsꢀstereospecificallyꢀ(Tableꢀ1,ꢀentriesꢀ8−11).ꢀTheꢀreactionꢀofꢀtheꢀstericallyꢀbulkyꢀ
k
i
keteneꢀ 3kꢀ furnishedꢀ threeꢀ rotamersꢀ 4ka,ꢀ 4kb,ꢀ andꢀ 4kcꢀ (Tableꢀ 1,ꢀ entryꢀ 11).ꢀ Notably,ꢀ [2 +2 ]ꢀ
cycloadductꢀβ-lactamꢀ(5h,ꢀonlyꢀtraceꢀamount,ꢀTableꢀ1,ꢀentryꢀ8)ꢀwasꢀobservedꢀinꢀtheꢀreactionꢀofꢀ
phenylketeneꢀ(3h),ꢀbutꢀnotꢀinꢀtheꢀotherꢀreactionsꢀofꢀEWG-substitutedꢀketenesꢀ3g,i-kꢀ(Tableꢀ1,ꢀ
entriesꢀ9−11).ꢀ
ꢀ
k
i
i
Tableꢀ 1ꢀ [2 +2 +2 ]ꢀAnnuladductsꢀandꢀtheirꢀstereochemistryꢀinꢀtheꢀannulationsꢀofꢀimineꢀ1aꢀwithꢀ
a
differentꢀketenesꢀ3ꢀ ꢀ
ꢀ
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ꢀ
ꢀ
a
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i
ꢀTheꢀstereostructuresꢀofꢀtheꢀ[2 +2 ]ꢀcycloadductsꢀβ-lactamsꢀwereꢀassignedꢀbasedꢀonꢀtheꢀcouplingꢀ
constantsꢀbetweenꢀtheꢀprotonsꢀatꢀC3ꢀandꢀC4ꢀpositionsꢀ(Jꢀ=ꢀ4−6ꢀHzꢀforꢀcis-isomers,ꢀJꢀ=ꢀ0−3ꢀHzꢀforꢀ
trans-isomers,ꢀgenerally).ꢀTheꢀpercentagesꢀafterꢀtheꢀcompoundꢀnumbersꢀareꢀtheꢀisolatedꢀyields,ꢀ
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b
whileꢀthoseꢀbesideꢀtheꢀdouble-headedꢀarrowsꢀareꢀtheꢀNOEꢀvaluesꢀbetweenꢀtheꢀtwoꢀprotons.ꢀ ꢀ
Theseꢀcompoundsꢀwereꢀisolatedꢀinꢀaꢀtraceꢀamountꢀtogetherꢀwithꢀvariousꢀimpurities,ꢀasꢀindicatedꢀ
1
c
byꢀtheꢀ HꢀNMRꢀspectrum.ꢀFurtherꢀpurificationꢀofꢀthemꢀfailed.ꢀ ꢀRatiosꢀwereꢀdeterminedꢀbyꢀtheꢀ
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correspondingꢀ HꢀNMRꢀspectra.ꢀ ꢀTheꢀlessꢀcongestedꢀstructureꢀ4kbꢀwasꢀassignedꢀasꢀtheꢀmajorꢀ
product.ꢀ
ꢀ
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i
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Natureꢀofꢀtheꢀ[2 +2 +2 ]ꢀannulationsꢀandꢀkeyꢀintermediatesꢀ
k
i
i
k
i
i
Theꢀstereochemicalꢀanalysesꢀofꢀtheꢀ[2 +2 +2 ]ꢀannulationsꢀinꢀTableꢀ1ꢀdiscloseꢀthatꢀtheꢀ[2 +2 +2 ]ꢀ
annulationsꢀofꢀmostꢀketenesꢀwithꢀiminesꢀgiveꢀstereospecificꢀoutcomes.ꢀToꢀexplainꢀtheꢀobservedꢀ
k
i
i
stereospecificity,ꢀandꢀtoꢀbetterꢀunderstandꢀtheꢀnatureꢀofꢀtheꢀselectiveꢀ[2 +2 +2 ]ꢀannulations,ꢀweꢀ
needꢀaꢀfullꢀunderstandingꢀofꢀtheꢀinvolvedꢀkeyꢀintermediates.ꢀAsꢀdelineatedꢀinꢀSchemeꢀ2,ꢀunderꢀ
photoirradiation,ꢀ theꢀ keteneꢀ precursorꢀ diazoꢀ compoundsꢀ 2a-kꢀ firstꢀ undergoꢀ Wolffꢀ
rearrangementsꢀ toꢀ formꢀ theꢀ correspondingꢀ ketenesꢀ 3a-k,ꢀ whichꢀ wereꢀ exoꢀ attackedꢀ byꢀ theꢀ
nucleophilicꢀ imineꢀ 1aꢀ toꢀ generateꢀ zwitterionicꢀ aza-butadiene-typeꢀ intermediatesꢀ 6.ꢀ Probablyꢀ
becauseꢀ ofꢀ theꢀ geometryꢀ andꢀ ringꢀ strainꢀ ofꢀ theꢀ cyclicꢀ iminiumꢀ moiety,ꢀ theꢀ conrotatoryꢀ ringꢀ
closureꢀ ofꢀ intermediatesꢀ 6ꢀ isꢀ decreased.ꢀ Onlyꢀ inꢀ theꢀ reactionsꢀ ofꢀ ketenesꢀ 3c-fꢀ bearingꢀ strongꢀ
electron-donatingꢀgroupsꢀ(EDGs),ꢀtheꢀconrotatoryꢀringꢀclosureꢀoccurs,ꢀgivingꢀtrans-β-lactamsꢀ5c-fꢀ
inꢀ considerableꢀ yields,ꢀ becauseꢀ theꢀ electron-donatingꢀ keteneꢀ substituentsꢀ accelerateꢀ theꢀ ringꢀ
7a
closure, ꢀtoꢀsomeꢀextentꢀcounteractingꢀtheꢀadverseꢀeffectꢀimposedꢀbyꢀtheꢀcyclicꢀiminium.ꢀInꢀallꢀ
casesꢀinꢀTableꢀ1,ꢀasꢀaꢀresultꢀofꢀtheꢀdecreasedꢀdirectꢀconrotatoryꢀringꢀclosureꢀbyꢀtheꢀcyclicꢀiminumꢀ
moiety,ꢀ theꢀ intermediatesꢀ 6ꢀ haveꢀ theꢀ opportunityꢀ toꢀ undergoꢀ [4+2]ꢀ annulationsꢀ withꢀ anotherꢀ
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i
i
11
moleculeꢀ ofꢀ imineꢀ 1a,ꢀ givingꢀ [2 +2 +2 ]ꢀ annuladductsꢀ tetrahydropyrimidin-4(1H)-onesꢀ 4. ꢀ Theꢀ
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[
4+2]ꢀ annulationsꢀ proceedꢀ inꢀ eitherꢀ aꢀ concertedꢀ fashion,ꢀ orꢀ aꢀ stepwiseꢀ nucleophilicꢀ addition.ꢀ
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i
i
Withinꢀthisꢀcontext,ꢀtheꢀstereochemicalꢀoutcomesꢀofꢀtheꢀ[2 +2 +2 ]ꢀannulationsꢀwillꢀbeꢀdiscussedꢀ
inꢀtheꢀfollowing.ꢀ
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ꢀ
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i
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Schemeꢀ2ꢀKeyꢀintermediatesꢀinꢀtheꢀ[2 +2 +2 ]ꢀannulationsꢀofꢀketenesꢀandꢀimines.ꢀ
ꢀ
1
2
Inꢀourꢀopinion,ꢀtheꢀstabilityꢀofꢀtheꢀzwitterionicꢀintermediatesꢀ6, ꢀ whichꢀactꢀasꢀ4πꢀdonorsꢀinꢀ
theꢀsubsequentꢀhetero-Diels-Alderꢀcycloadditions,ꢀshouldꢀbeꢀfurtherꢀclarified:ꢀwhetherꢀtheyꢀcanꢀ
isomerizeꢀoverꢀtheꢀC=Cꢀbondꢀinꢀtheꢀenolateꢀmoietyꢀtoꢀformꢀintermediatesꢀ7.ꢀIfꢀtheꢀisomerizationꢀ
occurs,ꢀtheꢀcis-β-lactamsꢀ5ꢀwouldꢀbeꢀgeneratedꢀviaꢀtheꢀconrotatoryꢀringꢀclosureꢀofꢀ7.ꢀHowever,ꢀinꢀ
allꢀ reactionsꢀ listedꢀ inꢀ Tableꢀ 1,ꢀ cis-β-lactamsꢀ 5ꢀ wereꢀ notꢀ detectedꢀ atꢀ all,ꢀ rulingꢀ outꢀ theꢀ
intermediacyꢀ ofꢀ intermediatesꢀ 7.ꢀ Thisꢀ conclusionꢀ isꢀ furtherꢀ supportedꢀ byꢀ theꢀ accumulatedꢀ
5
f-h,7
evidenceꢀ inꢀ ourꢀ previousꢀ workꢀ onꢀ theꢀ reactionsꢀ ofꢀ ketenesꢀ andꢀ numerousꢀ cyclicꢀ imines.
ꢀ
5
i
AccordingꢀtoꢀourꢀpreviousꢀDFTꢀcalculationꢀandꢀtheꢀcurrentꢀstereochemicalꢀoutcomes, ꢀitꢀcanꢀbeꢀ
putꢀthatꢀtheꢀ[4+2]ꢀannulationsꢀbetweenꢀintermediatesꢀ6ꢀandꢀcyclicꢀimineꢀ1aꢀprobablyꢀtakeꢀplaceꢀ
throughꢀaꢀconcertedꢀhetero-Diels-Alderꢀcycloaddition.ꢀ
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ꢀ
Schemeꢀ 3ꢀ Proposedꢀ concertedꢀ hetero-Diels-Alderꢀ cycloadditionꢀ toꢀ explainꢀ theꢀ stereochemicalꢀ
k
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outcomesꢀinꢀtheꢀ[2 +2 +2 ]ꢀannulations.ꢀ
ꢀ
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i
i
Explanationꢀonꢀtheꢀmechanismꢀandꢀstereochemistryꢀofꢀtheꢀ[2 +2 +2 ]ꢀannulationsꢀ
FromꢀaꢀDiels-Alderꢀcycloadditionꢀperspective,ꢀtheꢀmodelsꢀtoꢀexplainꢀtheꢀstereochemistryꢀofꢀtheꢀ
k
i
i
formalꢀ[2 +2 +2 ]ꢀcycloadditionsꢀlistedꢀinꢀTableꢀ1ꢀareꢀproposedꢀandꢀpresentedꢀinꢀSchemeꢀ3.ꢀSinceꢀ
theꢀ[4+2]ꢀcycloadditionsꢀbetweenꢀintermediatesꢀ6ꢀandꢀiminesꢀ1ꢀhaveꢀbeenꢀproposedꢀtoꢀfollowꢀaꢀ
concertedꢀprocess,ꢀtheꢀtwoꢀplausibleꢀtransitionꢀstatesꢀTS-1ꢀandꢀTS-2ꢀareꢀputꢀforward.ꢀTheꢀendoꢀ
cycloadditionsꢀ throughꢀ TS-1ꢀ affordꢀ endoꢀ productsꢀ (2,4)-cis-(4,5)-cis-4,ꢀ whileꢀ theꢀ exoꢀ
cycloadditionsꢀ throughꢀ TS-2ꢀ affordꢀ exoꢀ productsꢀ (2,4)-trans-(4,5)-trans-4.ꢀ Weꢀ envisionꢀ thatꢀ
(
2,4)-cis-(4,5)-cis-4ꢀcouldꢀepimerizeꢀintoꢀtheꢀepi-endoꢀproductsꢀ(2,4)-cis-(4,5)-trans-4ꢀbecauseꢀtheꢀ
acidityꢀofꢀtheꢀprotonsꢀadjacentꢀtoꢀtheꢀcarbonylꢀgroupꢀisꢀstrong,ꢀespeciallyꢀwhenꢀRꢀisꢀaꢀstrongꢀEWG.ꢀ
ThisꢀhasꢀbeenꢀverifiedꢀbyꢀaꢀpreliminaryꢀDFTꢀcalculationꢀatꢀtheꢀM06-2XꢀandꢀB3LYPꢀlevelsꢀofꢀtheoryꢀ
byꢀtakingꢀendoꢀproductꢀ(2,4)-cis-(4,5)-cis-4hꢀandꢀepi-endoꢀproductꢀ(2,4)-cis-(4,5)-trans-4hꢀasꢀtheꢀ
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examples,ꢀwithꢀsubstituentꢀRꢀasꢀaꢀweaklyꢀelectron-withdrawingꢀphenylꢀgroup.ꢀTheꢀfreeꢀenergyꢀ
(ΔG)ꢀ ofꢀ theꢀ formerꢀ endoꢀ productꢀ isꢀ 3.19ꢀ kcal/molꢀ higherꢀ thanꢀ theꢀ latterꢀ epi-endoꢀ product,ꢀ
indicatingꢀ thatꢀ theꢀ epimerizationꢀ shouldꢀ occurꢀ smoothly.ꢀ Soꢀ aꢀ plausibleꢀ explanationꢀ toꢀ theꢀ
stereochemistryꢀ isꢀ givenꢀ asꢀ following.ꢀ Theꢀ hetero-Diels-Alderꢀ cycloadditionsꢀ ofꢀ intermediatesꢀ
6a-kꢀ generatedꢀ fromꢀ ketenesꢀ 3a-kꢀ andꢀ imineꢀ 1a,ꢀ allꢀ undergoꢀ endoꢀ cycloadditionsꢀ toꢀ affordꢀ
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(
2,4)-cis-(4,5)-cis-4,ꢀ followingꢀ theꢀ endoꢀ rule;ꢀ however,ꢀ forꢀ (2,4)-cis-(4,5)-cis-4a-e,ꢀ noꢀ
epimerizationꢀ occurs,ꢀ mainlyꢀ becauseꢀ ofꢀ theꢀ electron-donatingꢀ Cbz-aminomethyl,ꢀ
phthalimidomethyl,ꢀ ethoxy,ꢀ isopropoxy,ꢀ andꢀ benzyloxyꢀ substituents,ꢀ andꢀ thusꢀ theseꢀ endoꢀ
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cycloadductsꢀ surviveꢀ andꢀ stayꢀ asꢀ theꢀ stereospecificꢀ formalꢀ [2 +2 +2 ]ꢀ cycloadductsꢀ (Tableꢀ 1,ꢀ
entriesꢀ1−5).ꢀHowever,ꢀwhenꢀstrongꢀEWGsꢀappearꢀatꢀtheꢀα-positionsꢀofꢀtheꢀendoꢀcycloadducts,ꢀ
forꢀ exampleꢀ (2,4)-cis-(4,5)-cis-4h-k,ꢀ theyꢀ wereꢀ completelyꢀ convertedꢀ intoꢀ theꢀ correspondingꢀ
(
2,4)-cis-(4,5)-trans-4h-kꢀviaꢀepimerization,ꢀshowingꢀanotherꢀformꢀofꢀstereospecificityꢀ(Tableꢀ1,ꢀ
entriesꢀ8−11).ꢀ
However,ꢀ exceptionsꢀ existꢀ inꢀ theꢀ formalꢀ [2 +2 +2 ]ꢀ cycloadditionꢀ ofꢀ ketenesꢀ 3fꢀ andꢀ 3gꢀ withꢀ
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i
i
k
i
i
EDGsꢀratherꢀthanꢀEWGs,ꢀwithꢀtwoꢀ[2 +2 +2 ]ꢀannuladductsꢀinꢀeachꢀcaseꢀformedꢀstereodivergentlyꢀ
(
Tableꢀ1,ꢀentriesꢀ6ꢀandꢀ7).ꢀTheꢀaboveꢀconcertedꢀhetero-Diels-Alderꢀcycloadditionꢀmodelꢀcannotꢀ
explainꢀ theꢀ presenceꢀ ofꢀ (2,4)-cis-(4,5)-trans-4fbꢀ andꢀ 4gb.ꢀ Asꢀ depictedꢀ inꢀ Schemeꢀ 4,ꢀ atꢀ roomꢀ
temperature,ꢀtheꢀpurifiedꢀ(2,4)-cis-(4,5)-cis-4faꢀwithꢀtwoꢀequivalentsꢀofꢀimineꢀ1aꢀwasꢀstirredꢀforꢀ
2
4ꢀh,ꢀorꢀphotoirradiatedꢀforꢀ3ꢀh;ꢀhowever,ꢀnoꢀepimerizedꢀ(2,4)-cis-(4,5)-trans-4fbꢀwasꢀdetectedꢀ
1
byꢀ theꢀ Hꢀ NMRꢀ spectralꢀ analysisꢀ ofꢀ theꢀ reactionꢀ mixtures,ꢀ implyingꢀ thatꢀ theꢀ productꢀ 4fbꢀ isꢀ
generatedꢀthroughꢀanotherꢀpathwayꢀratherꢀthanꢀthroughꢀhetero-Diels-Alderꢀcycloadditionꢀandꢀ
subsequentꢀ epimerization.ꢀ Aꢀ similarꢀ problemꢀ alsoꢀ existsꢀ inꢀ explainingꢀ theꢀ stereochemistryꢀ ofꢀ
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(
2,4)-cis-(4,5)-trans-4gb,ꢀ
(2,4)-trans-(4,5)-trans-4gc,ꢀunderꢀtheꢀconditionsꢀlistedꢀinꢀSchemeꢀ3.ꢀTherefore,ꢀweꢀbelieveꢀthatꢀ
2,4)-cis-(4,5)-trans-4fbꢀandꢀ4gbꢀareꢀgeneratedꢀbyꢀaꢀstepwiseꢀ[4+2]ꢀannulationsꢀbetweenꢀ6f,gꢀandꢀ
a.ꢀ
whichꢀ
cannotꢀ
undergoꢀ
epimerizationꢀ
betweenꢀ
(
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ꢀ
Schemeꢀ4ꢀEpimerizationꢀexperimentsꢀofꢀ(2,4,5)-cis-4faꢀtoꢀ(2,4)-cis-(4,5)-trans-4fb.ꢀ
ꢀ
ꢀ
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Schemeꢀ5ꢀProposedꢀexplanationꢀonꢀtheꢀstereochemicalꢀoutcomesꢀinꢀtheꢀ[2 +2 +2 ]ꢀannulations.ꢀ
ꢀ
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Fromꢀ nucleophilicꢀ stepwiseꢀ [4+2]ꢀ annulations,ꢀ theꢀ stereochemistryꢀ ofꢀ theꢀ [2 +2 +2 ]ꢀ
annuladductsꢀ4fbꢀandꢀ4gbꢀisꢀreasonablyꢀrationalizedꢀinꢀSchemeꢀ5.ꢀTheꢀ[4+2]ꢀannulationsꢀwereꢀ
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initiatedꢀbyꢀtheꢀMannich-typeꢀadditionꢀofꢀimineꢀ1aꢀtoꢀintermediatesꢀ6f,gꢀtoꢀaffordꢀzwitterionicꢀ
2,4-diaza-1,5-hexadiene-typeꢀ intermediatesꢀ A.ꢀ Differentꢀ fromꢀ theꢀ 4πꢀ intermediatesꢀ 6,ꢀ Aꢀ mayꢀ
isomerizeꢀ toꢀ theꢀ stericallyꢀ lessꢀ congestedꢀ andꢀ thermodynamicallyꢀ moreꢀ stableꢀ enolateꢀ
intermediatesꢀ Bꢀ underꢀ photoꢀ conditionsꢀ becauseꢀ theyꢀ areꢀ notꢀ conjugatedꢀ systems,ꢀ unlikeꢀ
conjugatedꢀ4πꢀintermediatesꢀ6.ꢀSubsequently,ꢀBꢀundergoꢀanꢀintramolecularꢀnucleophilicꢀaddition,ꢀ
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leadingꢀ toꢀ (2,4)-cis-(4,5)-trans-4fb,4gbꢀ asꢀ theꢀ [2 +2 +2 ]ꢀ annuladducts.ꢀ However,ꢀ theꢀ concertedꢀ
hetero-Diels-Alderꢀcycloadditionꢀisꢀinꢀcompetitionꢀwithꢀtheꢀstepwiseꢀnucleophilicꢀaddition.ꢀTheꢀ
reactionꢀofꢀ6fꢀ(Rꢀ=ꢀPhO)ꢀwithꢀ1aꢀalternativelyꢀundergoesꢀanꢀendoꢀconcertedꢀ[4+2]ꢀcycloadditionꢀtoꢀ
2 6 4
affordꢀ (2,4)-cis-(4,5)-cis-4fa,ꢀ whileꢀ theꢀ reactionꢀ ofꢀ 6gꢀ (Rꢀ =ꢀ 4-O NC H O)ꢀ withꢀ 1aꢀ alternativelyꢀ
undergoesꢀanꢀexoꢀconcertedꢀ[4+2]ꢀcycloadditionꢀtoꢀaffordꢀ(2,4)-trans-(4,5)-trans-4gc.ꢀSurprisingly,ꢀ
inꢀ theꢀ studiesꢀ inꢀ Tableꢀ 1,ꢀ onlyꢀ theꢀ reactionꢀ ofꢀ 4-nitrophenoxyketeneꢀ (3g)ꢀ gaveꢀ theꢀ exoꢀ
cycloadductꢀ4gc.ꢀTheꢀnitroꢀgroupꢀplaysꢀanꢀimportantꢀroleꢀinꢀeffectingꢀtheꢀexoꢀselectivityꢀinꢀtheꢀ
hetero-Diels-Alderꢀ cycloaddition.ꢀ Theꢀ energyꢀ profilesꢀ forꢀ theꢀ [4ꢀ +ꢀ 2]ꢀ cycloadditionsꢀ ofꢀ
intermediatesꢀ6f,gꢀwithꢀimineꢀ1aꢀatꢀtheꢀM06-2XꢀandꢀB3LYPꢀlevelsꢀofꢀtheoryꢀwereꢀcalculated,ꢀandꢀ
theꢀresultsꢀareꢀsummarizedꢀinꢀFigureꢀ3.ꢀForꢀtheꢀcycloadditionꢀbetweenꢀ6fꢀ(Rꢀ=ꢀPhO)ꢀandꢀ1a,ꢀtheꢀ
possibleꢀ endoꢀ andꢀ exoꢀ transitionꢀ statesꢀ endo-TS1-fꢀ andꢀ exo-TS2-fꢀ areꢀ formedꢀ withꢀ 13.34ꢀ andꢀ
20.97ꢀ kcal/molꢀ activationꢀ freeꢀ energy,ꢀ respectively,ꢀ indicatingꢀ thatꢀ theꢀ endoꢀ cycloadditionꢀ isꢀ
2 6 4
favored.ꢀHowever,ꢀtheꢀpresenceꢀofꢀtheꢀnitroꢀgroupꢀinꢀ6gꢀ(Rꢀ=ꢀ4-O NC H O)ꢀrendersꢀ19.85ꢀandꢀ
1
7.36ꢀkcal/molꢀactivationꢀfreeꢀenergyꢀforꢀendo-TS1-gꢀandꢀexo-TS2-g,ꢀrespectively,ꢀindicatingꢀthatꢀ
exoꢀ cycloadditionꢀ isꢀ favored.ꢀ Theꢀ calculationsꢀ alsoꢀ revealedꢀ thatꢀ bothꢀ endoꢀ andꢀ exoꢀ
cycloadditionsꢀ occurꢀ inꢀ aꢀ concertedꢀ butꢀ asynchronousꢀ fashionꢀ (forꢀ details,ꢀ seeꢀ Supportingꢀ
Information).ꢀHowever,ꢀtheꢀattemptsꢀinꢀcalculatingꢀtheꢀstepwiseꢀpathwaysꢀfailed,ꢀandꢀweꢀdidꢀnotꢀ
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succeedꢀinꢀgettingꢀtheꢀTSsꢀinꢀthisꢀpathwayꢀpossiblyꢀbecauseꢀofꢀfavorableꢀconcertedꢀpathway.ꢀ
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ꢀ
Figureꢀ3.ꢀCalculatedꢀenergyꢀprofilesꢀforꢀtheꢀ[4ꢀ+ꢀ2]ꢀcycloadditionsꢀofꢀintermediatesꢀ6f,gꢀwithꢀimineꢀ
1
aꢀatꢀtheꢀM06-2XꢀandꢀB3LYPꢀlevelsꢀofꢀtheory.ꢀ
Theꢀ zwitterionicꢀ intermediatesꢀ 6ꢀ areꢀ syntheticallyꢀ analogousꢀ toꢀ theꢀ neutralꢀ andꢀ isolableꢀ
1
3
3
-trialkylsilyloxy-2-aza-1,3-dienes. ꢀ Onꢀ oneꢀ hand,ꢀ bothꢀ ofꢀ themꢀ canꢀ undergoꢀ conrotatoryꢀ ringꢀ
closureꢀtoꢀformꢀfour-memberedꢀβ-lactams.ꢀOnꢀtheꢀotherꢀhand,ꢀ6ꢀcanꢀundergoꢀ[4+2]ꢀannulationsꢀ
withꢀ anotherꢀ imineꢀ molecule,ꢀ inꢀ mostꢀ casesꢀ followingꢀ aꢀ concertedꢀ hetero-Diels-Alderꢀ
cycloadditionꢀpathway,ꢀevenꢀthoughꢀsometimesꢀaꢀstepwiseꢀmechanismꢀinvolvingꢀintermolecularꢀ
Mannich-typeꢀ additionꢀ andꢀ intramolecularꢀ nucleophilicꢀ additionꢀ isꢀ moreꢀ likely.ꢀ Similarly,ꢀ theꢀ
3-trialkylsilyloxy-2-aza-1,3-dienesꢀ canꢀ alsoꢀ undergoꢀ [4+2]ꢀ annulationsꢀ withꢀ ketenes,ꢀ followingꢀ
eitherꢀ aꢀ concertedꢀ hetero-Diels-Alderꢀ cycloadditionꢀ processꢀ orꢀ aꢀ two-stepꢀ Mukaiyama-typeꢀ
process.ꢀ
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ꢀ
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Roleꢀofꢀphotoirradiationꢀinꢀtheꢀ[2 +2 +2 ]ꢀannulationsꢀ
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Theꢀ precedentedꢀ [2 +2 +2 ]ꢀ annulationsꢀ occurredꢀ mainlyꢀ underꢀ photoirradiationꢀ conditions. ꢀ
Thus,ꢀoneꢀmayꢀthinkꢀtheꢀphotoirraditionꢀpossiblyꢀplaysꢀanꢀimportantꢀroleꢀinꢀtheꢀreactions,ꢀforꢀ
example,ꢀ excitingꢀ theꢀ groundꢀ stateꢀ ofꢀ theꢀ 4πꢀ intermediatesꢀ orꢀ imines,ꢀ orꢀ somethingꢀ else.ꢀ
However,ꢀ theꢀ aboveꢀ mechanisticꢀ studiesꢀ revealꢀ thatꢀ photoirradiationꢀ doesꢀ playꢀ aꢀ roleꢀ inꢀ theꢀ
keteneꢀgenerationꢀstep,ꢀbutꢀnotꢀinꢀtheꢀsubsequentꢀevolutionꢀofꢀketenes.ꢀToꢀdemonstrateꢀthisꢀ
assumption,ꢀ weꢀ performedꢀ theꢀ reactionsꢀ underꢀ thermalꢀ conditionsꢀ atꢀ roomꢀ temperatureꢀ byꢀ
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employingꢀ theꢀ correspondingꢀ acylꢀ chloridesꢀ 2lꢀ andꢀ 2mꢀ asꢀ keteneꢀ precursors.ꢀ Theꢀ [2 +2 +2 ]ꢀ
annulationsꢀ ofꢀ ketenesꢀ 3iꢀ andꢀ 3mꢀ tookꢀ placeꢀ smoothly,ꢀ stereospecificallyꢀ producingꢀ theꢀ
annuladductsꢀ(2,4)-cis-(4,5)-trans-4lꢀandꢀ4mꢀinꢀ46%ꢀandꢀ24%ꢀyields,ꢀrespectivelyꢀ(Schemeꢀ6).ꢀ ꢀ
ꢀ
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Schemeꢀ6ꢀ[2 +2 +2 ]ꢀannulationsꢀwithꢀacylꢀchloridesꢀasꢀketeneꢀprecursors.ꢀ
ꢀ
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Actually,ꢀtheꢀ[2 +2 +2 ]ꢀannulationsꢀinꢀourꢀpreviousꢀworkꢀwereꢀaffectedꢀbyꢀtemperature,ꢀbutꢀ
5
f
notꢀ photoirradiation. ꢀ Studiesꢀ fromꢀ ourꢀ groupsꢀ haveꢀ disclosedꢀ thatꢀ theꢀ conrotationꢀ ofꢀ theꢀ
zwitterionicꢀintermediatesꢀinꢀtheꢀStaudingerꢀketene-imineꢀcycloadditionsꢀareꢀcloselyꢀassociatedꢀ
7
withꢀtemperature:ꢀtheꢀhigherꢀtheꢀtemperature,ꢀtheꢀfasterꢀtheꢀconrotation. ꢀAsꢀshownꢀinꢀSchemeꢀ
o
7
,ꢀ atꢀ highꢀ temperatureꢀ (180ꢀ C)ꢀ withoutꢀ photoirradiation,ꢀ theꢀ zwitterionicꢀ intermediatesꢀ 10,ꢀ
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whichꢀ wereꢀ generatedꢀ fromꢀ ketenesꢀ andꢀ iminesꢀ 1b,c,ꢀ underwentꢀ aꢀ rapidꢀ intramolecularꢀ
conrotationꢀ toꢀ formꢀ β-lactamsꢀ 8b,c,ꢀ outcompetingꢀ theꢀ intermolecularlyꢀ stepwiseꢀ nucleophilicꢀ
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[
4+2]ꢀannulationsꢀbetweenꢀ10ꢀandꢀ1b,c,ꢀandꢀnoꢀ[2 +2 +2 ]ꢀannulationsꢀoccurred.ꢀHowever,ꢀunderꢀ
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photoirradiationꢀ atꢀ lowꢀ temperatureꢀ (-20ꢀ C),ꢀ theꢀ conrotationꢀ wasꢀ significantlyꢀ decreased,ꢀ
leadingꢀtoꢀtheꢀoccurrenceꢀofꢀtheꢀcompetentꢀintermolecularꢀ[4+2]ꢀannulations,ꢀandꢀconsequentlyꢀ
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bothꢀ[2 +2 ]ꢀandꢀ[2 +2 +2 ]ꢀannuladductsꢀ(8b,cꢀandꢀ9b,c)ꢀwereꢀisolated.ꢀBasedꢀonꢀourꢀpreviouslyꢀ
1
reportedꢀcouplingꢀconstantsꢀofꢀtheꢀprotonsꢀinꢀC4ꢀandꢀC5ꢀpositionsꢀinꢀtheꢀ HꢀNMRꢀspectraꢀ(Jꢀ=ꢀ11.4ꢀ
5
f,g
5i
Hz)ꢀ ꢀ andꢀ X-rayꢀ crystallography, ꢀ andꢀ theꢀ currentꢀ NOEꢀ analysisꢀ ofꢀ theꢀ protonsꢀ atꢀ C2ꢀ andꢀ C4ꢀ
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positions,ꢀ theꢀ stereochemistryꢀ ofꢀ theꢀ [2 +2 +2 ]ꢀ annuladductsꢀ wereꢀ assignedꢀ asꢀ
(
2,4)-trans-(4,5)-trans.ꢀSimilarly,ꢀtheꢀreactionsꢀofꢀketenesꢀ3jꢀandꢀ3kꢀwithꢀseven-memberedꢀcyclicꢀ
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iminesꢀ 1bꢀ orꢀ 1cꢀ alsoꢀ gaveꢀ theꢀ [2 +2 +2 ]ꢀ annuladductsꢀ withꢀ theꢀ sameꢀ (2,4)-trans-(4,5)-transꢀ
5
g,i
stereochemistry.
ꢀ
ꢀ
Schemeꢀ7ꢀAnnuloselectivitiesꢀinꢀtheꢀthermalꢀandꢀphotoꢀStaudingerꢀketene-imineꢀcycloadditions.ꢀ
Applicationꢀofꢀourꢀmodelꢀ
Inꢀ 1977,ꢀ Joullie’sꢀ groupꢀ reportedꢀ threeꢀ differentꢀ annuladductsꢀ inꢀ theꢀ reactionꢀ betweenꢀ
5
b
tert-butylcyanoketeneꢀ (11)ꢀ andꢀ linearꢀ imineꢀ N-benzylideneꢀ methylamineꢀ (12)ꢀ (Schemeꢀ 8). ꢀ Atꢀ
o
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-
78ꢀ C,ꢀtheꢀreactionꢀgaveꢀcis-β-lactamꢀ13ꢀinꢀ15.7%ꢀyieldꢀandꢀtwoꢀ[2 +2 +2 ]ꢀannuladductsꢀ14ꢀinꢀ
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2.5%ꢀ yieldꢀ andꢀ 15ꢀ inꢀ 13%ꢀ yield.ꢀ Theꢀ stereochemicalꢀ structuresꢀ ofꢀ 13,ꢀ 14,ꢀ andꢀ 15ꢀ wereꢀ wellꢀ
assignedꢀbyꢀtheꢀNOEꢀstudies.ꢀHowever,ꢀJoullieꢀandꢀcoworkersꢀdidꢀnotꢀproposeꢀaꢀmechanismꢀtoꢀ
explainꢀ andꢀ toꢀ furtherꢀ predictꢀ theꢀ stereochemicalꢀ outcomes.ꢀ Nowꢀ ourꢀ mechanisticꢀ modelꢀ canꢀ
successfullyꢀbeꢀappliedꢀtoꢀexplainꢀtheirꢀresultsꢀ(Schemeꢀ9).ꢀTheꢀabsenceꢀofꢀtrans-β-lactamꢀ18ꢀandꢀ
theꢀpresenceꢀofꢀcis-β-lactamꢀ13ꢀindicateꢀthatꢀtheꢀkeyꢀandꢀlong-livedꢀintermediateꢀisꢀnotꢀ16,ꢀbutꢀ
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7,ꢀwhichꢀisꢀformedꢀbyꢀisomerizationꢀofꢀtheꢀiminiumꢀmoietyꢀofꢀ16.ꢀOnꢀoneꢀhand,ꢀconrotationꢀofꢀ
7ꢀ givesꢀ cis-β-lactamꢀ 13.ꢀ Onꢀ theꢀ otherꢀ hand,ꢀ 17ꢀ undergoesꢀ exoꢀ andꢀ endoꢀ hetero-Diels-Alderꢀ
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cycloadditionsꢀthroughꢀtransitionꢀstatesꢀTS3ꢀandꢀTS4,ꢀproducingꢀ[2 +2 +2 ]ꢀannuladductsꢀ15ꢀandꢀ
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4ꢀ inꢀ theirꢀ ownꢀ configurations,ꢀ respectively.ꢀ Theꢀ configurationꢀ ofꢀ theꢀ [2 +2 +2 ]ꢀ annuladductsꢀ
predictedꢀ byꢀ ourꢀ modelꢀ matchesꢀ veryꢀ wellꢀ withꢀ thoseꢀ experimentallyꢀ observedꢀ byꢀ Joullieꢀ andꢀ
coworkers.ꢀ
ꢀ
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Schemeꢀ 8ꢀ Jullieꢀ andꢀ coworkers’ꢀ experimentalꢀ studiesꢀ onꢀ theꢀ [2 +2 +2 ]ꢀ annuladductsꢀ fromꢀ
tert-butylcyanoketeneꢀandꢀlinearꢀimines.ꢀ
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Schemeꢀ9ꢀExplanationꢀonꢀtheꢀsterereochemistryꢀofꢀ[2 +2 +2 ]ꢀannuladductsꢀwithꢀourꢀmechanisticꢀ
model.ꢀ
ꢀ
Conclusionsꢀ
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Theꢀ stereochemistryꢀ inꢀ theꢀ [2 +2 +2 ]ꢀ annulationsꢀ involvingꢀ oneꢀ keteneꢀ moleculeꢀ andꢀ twoꢀ
imineꢀ moleculesꢀ wereꢀ studiedꢀ experimentallyꢀ andꢀ analyzedꢀ mechanistically.ꢀ Theꢀ zwitterionicꢀ
aza-butadiene-typeꢀintermediates,ꢀgeneratedꢀfromꢀketenesꢀandꢀimines,ꢀinꢀmostꢀcasesꢀunderwentꢀ
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hetero-Diels-Alderꢀcycloadditionꢀwithꢀaꢀsecondꢀimineꢀmolecule,ꢀformingꢀ[2 +2 +2 ]ꢀannuladductsꢀ
tetrahydropyrimidin-4(1H)-oneꢀderivatives.ꢀDependentꢀonꢀtheꢀring-sizeꢀofꢀtheꢀcyclicꢀiminesꢀandꢀ
theꢀsubstituentsꢀofꢀketenes,ꢀtheꢀstereochemistryꢀandꢀmechanismꢀfollowꢀtheꢀempiricalꢀrulesꢀasꢀ
following.ꢀ
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Forꢀ theꢀ [2 +2 +2 ]ꢀ annulationsꢀ ofꢀ six-memberedꢀ cyclicꢀ iminesꢀ asꢀ exemplifiedꢀ byꢀ
3
,4-dihydroisoquinoline,ꢀtheꢀgeneratedꢀzwitterionicꢀaza-butadiene-typeꢀintermediatesꢀ6ꢀmainlyꢀ
undergoꢀ endoꢀ hetero-Diels-Alderꢀ cycloadditionsꢀ withꢀ anotherꢀ moleculeꢀ ofꢀ imines.ꢀ Forꢀ theꢀ
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ketenesꢀ withꢀ electron-donatingꢀ substituents,ꢀ (2,4)-cis-(4,5)-cis-[2 +2 +2 ]ꢀ annuladductsꢀ areꢀ
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formedꢀ stereospecifically.ꢀ Forꢀ theꢀ ketenesꢀ withꢀ electron-acceptingꢀ substituents,ꢀ
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(2,4)-cis-(4,5)-trans-[2 +2 +2 ]ꢀ annuladductsꢀ areꢀ finallyꢀ generatedꢀ stereospecificallyꢀ byꢀ theꢀ
completeꢀepimerizationꢀofꢀtheꢀ(2,4)-cis-(4,5)-cis-products.ꢀForꢀketenesꢀwithꢀaryloxyꢀsubstituents,ꢀ
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theꢀ[2 +2 +2 ]ꢀannuladductsꢀareꢀgeneratedꢀstereodivergently,ꢀandꢀtheꢀstereochemistryꢀisꢀdifficultꢀ
toꢀ predict.ꢀ Inꢀ thisꢀ case,ꢀ theꢀ [4+2]ꢀ annulationꢀ ofꢀ theꢀ correspondingꢀ zwitterionicꢀ
aza-butadiene-typeꢀ intermediatesꢀ withꢀ theꢀ six-memberedꢀ iminesꢀ couldꢀ followꢀ endoꢀ orꢀ exoꢀ
hetereo-Diels-Alderꢀcycloadditionꢀprocessꢀandꢀaꢀtwo-stepꢀnucleophilicꢀadditionꢀprocess.ꢀ
k
i
i
Forꢀ theꢀ [2 +2 +2 ]ꢀ annulationsꢀ ofꢀ seven-memberedꢀ cyclicꢀ iminesꢀ asꢀ exemplifiedꢀ byꢀ
dibenzo[b,f][1,4]oxazepine,ꢀ theꢀ zwitterionicꢀ aza-butadiene-typeꢀ intermediatesꢀ 10ꢀ exclusivelyꢀ
undergoꢀexoꢀhetero-Diels-Alderꢀcycloadditionsꢀwithꢀanotherꢀmoleculeꢀofꢀimines.ꢀConsequently,ꢀ
k
i
i
regardlessꢀofꢀtheꢀketeneꢀsubstituents,ꢀ(2,4)-trans-(4,5)-trans-[2 +2 +2 ]ꢀannuladductsꢀareꢀformedꢀ
stereospecifically.ꢀ
k
i
i
Theꢀ[2 +2 +2 ]ꢀannulationsꢀofꢀN-methylꢀlinearꢀiminesꢀwithꢀtert-butylcyanoketeneꢀdeliverꢀbothꢀ
k
i
i
(2,4)-trans-(4,5)-trans-ꢀ andꢀ (2,4)-cis-(4,5)-cis-[2 +2 +2 ]ꢀ annuladducts,ꢀ asꢀ theꢀ exoꢀ andꢀ endoꢀ
Diels-Alderꢀcycloadducts,ꢀrespectively,ꢀofꢀintermediatesꢀ17ꢀwithꢀanotherꢀmoleculeꢀofꢀN-methylꢀ
imines.ꢀ
k
i
i
Theꢀcurrentꢀmechanisticꢀmodelꢀnotꢀonlyꢀexplainꢀtheꢀnatureꢀofꢀtheꢀ[2 +2 +2 ]ꢀannulations,ꢀbutꢀ
k
i
i
alsoꢀ provideꢀ aꢀ usefulꢀ toolꢀ toꢀ predictꢀ theꢀ stereochemistryꢀ ofꢀ theꢀ [2 +2 +2 ]ꢀ annuladductsꢀ fromꢀ
differentꢀ ketenesꢀ andꢀ imines,ꢀ evenꢀ toꢀ designꢀ theꢀ efficientꢀ synthesisꢀ ofꢀ theꢀ desiredꢀ
tetrahydropyrimidinoneꢀderivatives.ꢀ
ExperimentalꢀSectionꢀ
GeneralꢀInformation:ꢀ ꢀ
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DichloromethaneꢀwasꢀrefluxedꢀoverꢀCaH
2
ꢀandꢀfreshlyꢀdistilledꢀpriorꢀtoꢀuse,ꢀwhileꢀtetrahydrofuranꢀ
wasꢀrefluxedꢀoverꢀsodiumꢀwithꢀdiphenylꢀketoneꢀasꢀanꢀindicatorꢀandꢀfreshlyꢀdistilledꢀpriorꢀtoꢀuse.ꢀ
1
13
Meltingꢀpointsꢀwereꢀobtainedꢀonꢀaꢀmeltingꢀpointꢀapparatusꢀandꢀareꢀuncorrected.ꢀ Hꢀandꢀ CꢀNMRꢀ
0
1
2
3
4
5
6
7
8
9
0
1
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4
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spectraꢀ wereꢀ recordedꢀ onꢀ aꢀ 400ꢀ MHzꢀ spectrometer,ꢀ whileꢀ theꢀ NOEꢀ spectraꢀ onꢀ aꢀ 600ꢀ MHzꢀ
3
spectrometer,ꢀinꢀCDCl ꢀwithꢀTMSꢀasꢀanꢀinternalꢀstandardꢀandꢀtheꢀchemicalꢀshiftsꢀ(δ)ꢀareꢀreportedꢀ
−
1
inꢀ partsꢀ perꢀ millionꢀ (ppm).ꢀ Theꢀ IRꢀ spectraꢀ (KBrꢀ pellets,ꢀ vꢀ [cm ])ꢀ wereꢀ takenꢀ onꢀ aꢀ FTIRꢀ
spectrometer.ꢀ HRMSꢀ measurementsꢀ wereꢀ carriedꢀ outꢀ onꢀ anꢀ LC/MSDꢀ TOFꢀ massꢀ spectrometer.ꢀ
TLCꢀseparationsꢀwereꢀperformedꢀonꢀsilicaꢀgelꢀGF254ꢀplates,ꢀandꢀtheꢀplatesꢀwereꢀvisualizedꢀwithꢀ
1
4
UVꢀ light.ꢀ Allꢀ optimizedꢀ geometriesꢀ wereꢀ calculatedꢀ atꢀ theꢀ DFTꢀ B3LYPꢀ level ꢀ withꢀ theꢀ
1
5
6
-311+G(d,p)ꢀbasisꢀsetꢀforꢀallꢀtheꢀatomsꢀwithꢀtheꢀGaussianꢀ09ꢀsuiteꢀofꢀprograms. ꢀ
Theꢀdiazoacetatesꢀ2c−eꢀwereꢀpreparedꢀbyꢀtheꢀdiazotizationꢀofꢀtheꢀcorrespondingꢀglycineꢀesterꢀ
1
6
hydrochloridesꢀwithꢀNaNO
2
ꢀfollowingꢀMcKenzie’sꢀprocedures. ꢀ Theꢀotherꢀdiazoꢀcompoundsꢀ2a,b,ꢀ
5f-h
2
f−k,ꢀasꢀwellꢀasꢀtheꢀacylꢀchloridesꢀ2l,mꢀwereꢀpreparedꢀaccordingꢀtoꢀourꢀpreviousꢀprecedures.
ꢀ
Preparationꢀofꢀ3,4-dihydroisoquilineꢀ(1a):ꢀ
1
7
3
3
,4-Dihydroisoquilineꢀ(1a)ꢀwasꢀpreparedꢀfollowingꢀCava’sꢀprocedure. ꢀ Tetrahydroisoquilineꢀ(5ꢀg,ꢀ
7.6ꢀmmol)ꢀwasꢀtreatedꢀwithꢀN-bromosuccinimideꢀ(7.3ꢀg,ꢀ41.4ꢀmmol)ꢀinꢀ50ꢀmLꢀofꢀCH Cl ꢀatꢀroomꢀ
2
2
temperatureꢀforꢀ2ꢀh.ꢀThenꢀ25ꢀmLꢀofꢀ30%ꢀNaOHꢀsolutionꢀwasꢀadded,ꢀandꢀtheꢀmixtureꢀwasꢀstirredꢀ
2 4
forꢀanotherꢀ3ꢀh.ꢀTheꢀorganicꢀphaseꢀwasꢀwashedꢀwithꢀbrineꢀ(20ꢀmLꢀxꢀ3),ꢀdriedꢀoverꢀNa SO ,ꢀandꢀ
concentratedꢀ atꢀ reducedꢀ pressureꢀ (ca.ꢀ 25ꢀ mmHg).ꢀ Theꢀ obtainedꢀ residueꢀ oilꢀ wasꢀ purifiedꢀ byꢀ
o
distillationꢀ atꢀ vaccumꢀ toꢀ giveꢀ theꢀ desiredꢀ productꢀ (b.p.ꢀ 98−100ꢀ C/2ꢀ mmHg)ꢀ asꢀ aꢀ colorlessꢀ oilꢀ
(
2.30ꢀg,ꢀ45%).ꢀ
Generalꢀprocedureꢀforꢀtheꢀphotoirradiationꢀreactions:ꢀ
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Diazoacetateꢀorꢀdiazomethylꢀketoneꢀ2ꢀ(2ꢀmmol)ꢀandꢀimineꢀ1aꢀ(1ꢀmmol,ꢀ131ꢀmg)ꢀwereꢀplacedꢀintoꢀ
2 2
aꢀ quarzꢀ tube,ꢀ andꢀ dissolvedꢀ inꢀ dryꢀ CH Cl ꢀ (5ꢀ mL)ꢀ underꢀ aꢀ nitrogenꢀ atmosphere.ꢀ Theꢀ resultantꢀ
yellowꢀ solutionꢀ wasꢀ thenꢀ irradiatedꢀ atꢀ roomꢀ temperatureꢀ (cooledꢀ byꢀ tapꢀ water)ꢀ withꢀ aꢀ
high-pressureꢀ mercuryꢀ lampꢀ forꢀ 3ꢀ h.ꢀ Concentrationꢀ ofꢀ theꢀ resultingꢀ brownꢀ solutionꢀ underꢀ
reducedꢀ pressureꢀ (ca.ꢀ 25ꢀ mmHg),ꢀ andꢀ subsequentꢀ purificationꢀ ofꢀ theꢀ residuesꢀ byꢀ columnꢀ
10
11
12
13
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15
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35
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37
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41
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
chromatographyꢀ onꢀ silicaꢀ gelꢀ withꢀ petroleumꢀ etherꢀ (60−90ꢀ C)ꢀ andꢀ ethylꢀ acetateꢀ asꢀ eluentꢀ
affordedꢀtheꢀdesiredꢀproductsꢀ4ꢀandꢀ5.ꢀ
Generalꢀprocedureꢀforꢀtheꢀreactionsꢀofꢀacylꢀchloridesꢀ2l,mꢀandꢀimineꢀ1a:ꢀ
Toꢀanꢀoven-driedꢀbottleꢀchargedꢀwithꢀaꢀsolutionꢀofꢀimineꢀ1aꢀ(2ꢀmmol,ꢀ262ꢀmg)ꢀandꢀtriethylamineꢀ
(
101ꢀmg,ꢀ1ꢀmmol)ꢀinꢀdryꢀTHFꢀ(4ꢀmL)ꢀwasꢀdropwiseꢀaddedꢀaꢀsolutionꢀofꢀacylꢀchlorideꢀ2lꢀorꢀ2mꢀ(1ꢀ
mmol)ꢀinꢀdryꢀTHFꢀ(1ꢀmL)ꢀduringꢀ1ꢀmin.ꢀUponꢀaddition,ꢀtheꢀresultantꢀmixtureꢀwasꢀstirredꢀatꢀroomꢀ
temperatureꢀforꢀ12ꢀh,ꢀfollowedꢀbyꢀadditionꢀofꢀetherꢀ(15ꢀmL),ꢀwashingꢀwithꢀbrineꢀ(15ꢀmL),ꢀandꢀ
dryingꢀoverꢀNa
2
SO
4
.ꢀConcentrationꢀunderꢀreducedꢀpressureꢀ(ca.ꢀ25ꢀmmHg)ꢀandꢀpurificationꢀofꢀtheꢀ
o
residueꢀ byꢀ columnꢀ chromatographyꢀ onꢀ silicaꢀ gelꢀ withꢀ petroleumꢀ etherꢀ (60−90ꢀ C)ꢀ andꢀ ethylꢀ
acetateꢀasꢀeluentꢀaffordedꢀtheꢀdesiredꢀproductꢀ4iꢀorꢀ4m.ꢀ
ꢀ
Benzylꢀ
[[rel(4bS,5S,13bR)-4b,5,9,13b,15,16-hexahydro-6-oxo-6H,8H-pyrimido[2,1-a:4,3-a']ꢀ
diisoquinolin-5-yl]methyl]carbamateꢀ(4a)ꢀ
1
Yellowꢀoil.ꢀYieldꢀ40ꢀmg,ꢀ17%.ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
3
)ꢀδ:ꢀ7.32ꢀ–ꢀ7.26ꢀ(m,ꢀ6H),ꢀ7.24ꢀ–ꢀ7.12ꢀ(m,ꢀ7H),ꢀ
6.09ꢀ(d,ꢀJꢀ=ꢀ7.6ꢀHz,ꢀ1H),ꢀ5.38ꢀ(s,ꢀ1H),ꢀ5.07ꢀ(d,ꢀJꢀ=ꢀ2.5ꢀHz,ꢀ1H),ꢀ4.99ꢀ(d,ꢀJꢀ=ꢀ12.4ꢀHz,ꢀ1H),ꢀ4.94ꢀ(d,ꢀJꢀ=ꢀ
1
3
2.4ꢀHz,ꢀ1H),ꢀ4.64ꢀ(d,ꢀJꢀ=ꢀ5.1ꢀHz,ꢀ1H),ꢀ3.53ꢀ(dd,ꢀJꢀ=ꢀ11.5,ꢀ5.9ꢀHz,ꢀ1H),ꢀ3.47ꢀ–ꢀ3.36ꢀ(m,ꢀ1H),ꢀ3.36ꢀ–ꢀ
13
.26ꢀ(m,ꢀ1H),ꢀ2.96ꢀ–ꢀ2.90ꢀ(m,ꢀ3H),ꢀ2.88ꢀ–ꢀ2.78ꢀ(m,ꢀ2H),ꢀ2.64ꢀ–ꢀ2.59ꢀ(m,ꢀ1H),ꢀ2.59ꢀ–ꢀ2.52ꢀ(m,ꢀ1H).ꢀ Cꢀ
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6
NMRꢀ(100ꢀMHz,ꢀCDCl
3
)ꢀδ:ꢀ170.7,ꢀ155.9,ꢀ136.7,ꢀ134.6,ꢀ133.5,ꢀ129.2,ꢀ128.4,ꢀ128.3,ꢀ128.0,ꢀ127.98,ꢀ
127.95,ꢀ127.91,ꢀ127.84,ꢀ127.77,ꢀ127.2,ꢀ127.1,ꢀ126.6,ꢀ126.3,ꢀ125.2,ꢀ73.9,ꢀ66.2,ꢀ58.9,ꢀ47.0,ꢀ45.0,ꢀ
-1
4
1
0.1,ꢀ36.7,ꢀ28.6,ꢀ27.7.ꢀIRꢀ(film,ꢀKBr)ꢀvꢀ(cm )ꢀ1693,ꢀ1651,ꢀ1600,ꢀ1501,ꢀ1450,ꢀ1434,ꢀ1382,ꢀ1350,ꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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4
5
6
7
8
9
0
+
290,ꢀ1261,ꢀ1196,ꢀ1092,ꢀ1037.ꢀHRMSꢀ(ESI)ꢀcalcdꢀforꢀC29
H
30
N
3
O
3
ꢀ[Mꢀ+ꢀH ]ꢀm/z:ꢀ468.2287,ꢀfoundꢀ
468.2280.ꢀ
ꢀ
2
-[[rel(4bS,5S,13bR)-4b,5,9,13b,15,16-Hexahydro-6-oxo-6H,8H-pyrimido[2,1-a:4,3-a']diisoquin
olin-5-yl]methyl]isoindoline-1,3-dioneꢀ(4b)ꢀ
1
Yellowꢀoil.ꢀYieldꢀ46ꢀmg,ꢀ20%.ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
3
)ꢀδ:ꢀ7.73ꢀ–ꢀ7.56ꢀ(m,ꢀ6H),ꢀ7.37ꢀ–ꢀ7.30ꢀ(m,ꢀ3H),ꢀ
7
.14ꢀ–ꢀ7.05ꢀ(m,ꢀ2H),ꢀ6.99ꢀ(m,ꢀ7.01ꢀ–ꢀ6.97,ꢀ1H),ꢀ5.17ꢀ(s,ꢀ1H),ꢀ4.53ꢀ(d,ꢀJꢀ=ꢀ3.2ꢀHz,ꢀ1H),ꢀ3.90ꢀ–ꢀ3.82ꢀ ꢀ
(m,ꢀ2H),ꢀ3.73ꢀ–ꢀ3.60ꢀ(m,ꢀ2H),ꢀ3.52ꢀ–ꢀ3.42ꢀ(m,ꢀ1H),ꢀ3.36ꢀ–ꢀ3.24ꢀ(m,ꢀ2H),ꢀ3.03ꢀ–ꢀ2.96ꢀ(m,ꢀ2H),ꢀ2.84ꢀ–ꢀ
1
3
2
1
.76ꢀ(m,ꢀ1H),ꢀ2.70ꢀ–ꢀ2.60ꢀ(m,ꢀ1H).ꢀ CꢀNMRꢀ(100ꢀMHz,ꢀCDCl
3
)ꢀδ:ꢀ168.8,ꢀ167.8,ꢀ136.8,ꢀ135.9,ꢀ134.9,ꢀ
33.6,ꢀ133.4,ꢀ132.1,ꢀ129.0,ꢀ128.0,ꢀ127.7,ꢀ126.9,ꢀ126.6,ꢀ126.4,ꢀ125.7,ꢀ124.2,ꢀ122.9,ꢀ73.8,ꢀ58.2,ꢀ46.3,ꢀ
-
1
43.2,ꢀ40.9,ꢀ37.0,ꢀ28.8,ꢀ27.3.ꢀIRꢀ(film,ꢀKBr)ꢀvꢀ(cm )ꢀ2930,ꢀ1774,ꢀ1754,ꢀ1653,ꢀ1498,ꢀ1459,ꢀ1430,ꢀ1384,ꢀ
+
1
356,ꢀ1320,ꢀ1289,ꢀ1268,ꢀ1244,ꢀ1166,ꢀ1105,ꢀ1090,ꢀ1075.ꢀHRMSꢀ(ESI)ꢀcalcdꢀforꢀC29
H
26
N
3
O
3
ꢀ[Mꢀ+ꢀH ]ꢀ
m/z:ꢀ464.1974,ꢀfoundꢀ464.1970.ꢀ
ꢀ
rel(4bR,5S,13bR)-5-Ethoxy-4b,5,9,13b,15,16-hexahydro-6H,8H-pyrimido[2,1-a:4,3-a']diisoquino
lin-6-oneꢀ(4c)ꢀ
1
Colorlessꢀoil.ꢀYield:ꢀ12ꢀmg,ꢀ7%.ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
3
)ꢀδ:ꢀ7.55ꢀ–ꢀ7.49ꢀ(m,ꢀ1H),ꢀ7.30ꢀ–ꢀ7.26ꢀ(m,ꢀ
3
H),ꢀ7.22ꢀ–ꢀ7.17ꢀ(m,ꢀ4H),ꢀ5.80ꢀ(s,ꢀ1H),ꢀ4.95ꢀ–ꢀ4.88ꢀ(m,ꢀ1H),ꢀ4.54ꢀ(d,ꢀJꢀ=ꢀ5.0ꢀHz,ꢀ1H),ꢀ3.96ꢀ(d,ꢀJꢀ=ꢀ5.0ꢀ
Hz,ꢀ1H),ꢀ3.81ꢀ(dq,ꢀJꢀ=ꢀ9.2,ꢀ7.0ꢀHz,ꢀ1H),ꢀ3.26ꢀ(ddd,ꢀJꢀ=ꢀ11.2,ꢀ4.4,ꢀ4.4ꢀHz,ꢀ1H),ꢀ3.14ꢀ(dq,ꢀJꢀ=ꢀ9.2,ꢀ7.0ꢀHz,ꢀ
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1
H),ꢀ3.05ꢀ–ꢀ2.96ꢀ(m,ꢀ2H),ꢀ2.94ꢀ–ꢀ2.86ꢀ(m,ꢀ1H),ꢀ2.82ꢀ–ꢀ2.73ꢀ(m,ꢀ1H),ꢀ2.68ꢀ(dd,ꢀJꢀ=ꢀ16.4,ꢀ4.2ꢀHz,ꢀ1H),ꢀ
1
3
3
2.48ꢀ(dd,ꢀJꢀ=ꢀ11.1,ꢀ7.2ꢀHz,ꢀ1H),ꢀ0.70ꢀ(t,ꢀJꢀ=ꢀ7.0ꢀHz,ꢀ3H).ꢀ CꢀNMRꢀ(100ꢀMHz,ꢀCDCl )ꢀδ:ꢀ169.1,ꢀ136.6,ꢀ
1
3
36.1,ꢀ133.6,ꢀ132.7,ꢀ128.8,ꢀ128.6,ꢀ127.6,ꢀ127.5,ꢀ127.0,ꢀ126.7,ꢀ125.8,ꢀ125.2,ꢀ77.6,ꢀ75.1,ꢀ70.1,ꢀ61.6,ꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
-
1
8.0,ꢀ37.1,ꢀ28.5,ꢀ28.4,ꢀ15.0.ꢀIRꢀ(film,ꢀKBr)ꢀvꢀ(cm )ꢀ2925,ꢀ1651,ꢀ1604,ꢀ1494,ꢀ1454,ꢀ1432,ꢀ1385,ꢀ1354,ꢀ
+
1287,ꢀ1258,ꢀ1198,ꢀ1090,ꢀ1034,ꢀ747,ꢀ701.ꢀHRMSꢀ(ESI)ꢀcalcdꢀforꢀC22
H
25
N
2
O
2
ꢀ[Mꢀ+ꢀH ]ꢀm/z:ꢀ349.1916,ꢀ
foundꢀ349.1913.ꢀ
ꢀ
rel(4bR,5S,13bR)-5-Benzyloxy-4b,5,9,13b,15,16-hexahydro-6H,8H-pyrimido[2,1-a:4,3-a']diisoqu
inolin-6-oneꢀ(4d)ꢀ
o
1
3
Colorlessꢀcrystals.ꢀM.p.ꢀ163ꢀ–ꢀ164ꢀ C.ꢀYield:ꢀ74ꢀmg,ꢀ36%.ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl )ꢀδ:ꢀ7.53ꢀ–ꢀ7.45ꢀ
(m,ꢀ1H),ꢀ7.25ꢀ–ꢀ7.21ꢀ(m,ꢀ3H),ꢀ7.20ꢀ–ꢀ7.14ꢀ(m,ꢀ3H),ꢀ7.13ꢀ–ꢀ7.05ꢀ(m,ꢀ4H),ꢀ6.64ꢀ(d,ꢀJꢀ=ꢀ6.4ꢀHz,ꢀ2H),ꢀ5.81ꢀ
s,ꢀ1H),ꢀ4.93ꢀ–ꢀ4.89ꢀ(m,ꢀ1H),ꢀ4.87ꢀ(d,ꢀJꢀ=ꢀ11.5ꢀHz,ꢀ1H),ꢀ4.57ꢀ(d,ꢀJꢀ=ꢀ5.0ꢀHz,ꢀ1H),ꢀ4.35ꢀ(d,ꢀJꢀ=ꢀ11.5ꢀHz,ꢀ
H),ꢀ4.08ꢀ(d,ꢀJꢀ=ꢀ5.0ꢀHz,ꢀ1H),ꢀ3.25ꢀ(td,ꢀJꢀ=ꢀ11.3,ꢀ4.4ꢀHz,ꢀ1H),ꢀ2.97ꢀ(d,ꢀJꢀ=ꢀ10.3ꢀHz,ꢀ2H),ꢀ2.94ꢀ–ꢀ2.85ꢀ(m,ꢀ
(
1
1
3
1H),ꢀ2.81ꢀ–ꢀ2.71ꢀ(m,ꢀ1H),ꢀ2.64ꢀ(dd,ꢀJꢀ=ꢀ16.4,ꢀ4.0ꢀHz,ꢀ1H),ꢀ2.46ꢀ(dd,ꢀJꢀ=ꢀ11.2,ꢀ7.1ꢀHz,ꢀ1H).ꢀ CꢀNMRꢀ
(
3
100ꢀMHz,ꢀCDCl )ꢀδ:ꢀ168.7,ꢀ138.1,ꢀ136.6,ꢀ136.2,ꢀ133.7,ꢀ132.7,ꢀ128.9,ꢀ128.6,ꢀ127.8,ꢀ127.63,ꢀ127.55,ꢀ
1
27.4,ꢀ127.1,ꢀ127.0,ꢀ126.8,ꢀ125.9,ꢀ125.6,ꢀ76.8,ꢀ75.6,ꢀ75.1,ꢀ61.5,ꢀ37.9,ꢀ37.2,ꢀ28.5,ꢀ28.4.ꢀIRꢀ(film,ꢀKBr)ꢀ
-
1
vꢀ(cm )ꢀ2923,ꢀ1651,ꢀ1496,ꢀ1454,ꢀ1429,ꢀ1386,ꢀ1354,ꢀ1321,ꢀ1286,ꢀ1264,ꢀ1243,ꢀ1166,ꢀ1133,ꢀ1105,ꢀ
+
1
4
ꢀ
090,ꢀ1075,ꢀ1051,ꢀ1034,ꢀ906,ꢀ814,ꢀ774,ꢀ745,ꢀ698.ꢀHRMSꢀ(ESI)ꢀcalcdꢀforꢀC27
11.2073,ꢀfoundꢀ411.2076.ꢀ
H
27
N
2
O
2
ꢀ[Mꢀ+ꢀH ]ꢀm/z:ꢀ
rel(4bR,5S,13bR)-5-Phenoxy-4b,5,9,13b,15,16-hexahydro-6H,8H-pyrimido[2,1-a:4,3-a']diisoqui
nolin-6-oneꢀ(4fa)ꢀ
2
3
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The Journal of Organic Chemistry
Page 24 of 34
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2
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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
o
1
3
Colorlessꢀcrystals.ꢀM.p.ꢀ172ꢀ–ꢀ174ꢀ CꢀYield:ꢀ60ꢀmg,ꢀ30%.ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl )ꢀδ:ꢀ7.58ꢀ–ꢀ7.46ꢀ
(m,ꢀ1H),ꢀ7.33ꢀ–ꢀ7.26ꢀ(m,ꢀ2H),ꢀ7.22ꢀ–ꢀ7.14ꢀ(m,ꢀ3H),ꢀ7.08ꢀ–ꢀ7.02ꢀ(m,ꢀ2H),ꢀ6.97ꢀ(t,ꢀJꢀ=ꢀ7.1ꢀHz,ꢀ1H),ꢀ6.90ꢀ
d,ꢀJꢀ=ꢀ7.5ꢀHz,ꢀ1H),ꢀ6.84ꢀ(t,ꢀJꢀ=ꢀ7.3ꢀHz,ꢀ1H),ꢀ6.68ꢀ(d,ꢀJꢀ=ꢀ7.6ꢀHz,ꢀ2H),ꢀ5.87ꢀ(s,ꢀ1H),ꢀ4.99ꢀ–ꢀ4.91ꢀ(m,ꢀ1H),ꢀ
.80ꢀ(d,ꢀJꢀ=ꢀ5.2ꢀHz,ꢀ1H),ꢀ4.67ꢀ(d,ꢀJꢀ=ꢀ5.2ꢀHz,ꢀ1H),ꢀ3.36ꢀ(ddd,ꢀJꢀ=ꢀ11.4,ꢀ4.4,ꢀ4.4ꢀHz,ꢀ1H),ꢀ3.08ꢀ–ꢀ2.92ꢀ(m,ꢀ
(
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
4
1
3
3
3H),ꢀ2.83ꢀ–ꢀ2.74ꢀ(m,ꢀ2H),ꢀ2.56ꢀ(dd,ꢀJꢀ=ꢀ11.3,ꢀ7.1ꢀHz,ꢀ1H).ꢀ CꢀNMRꢀ(100ꢀMHz,ꢀCDCl )ꢀδ:ꢀ167.4,ꢀ160.4,ꢀ
1
1
36.6,ꢀ135.8,ꢀ132.8,ꢀ132.5,ꢀ128.84,ꢀ128.83,ꢀ128.6,ꢀ127.8,ꢀ127.5,ꢀ127.1,ꢀ127.0,ꢀ126.3,ꢀ125.5,ꢀ121.9,ꢀ
-
1
17.5,ꢀ78.0,ꢀ75.0,ꢀ61.8,ꢀ38.3,ꢀ37.0,ꢀ28.6,ꢀ28.4.ꢀIRꢀ(film,ꢀKBr)ꢀvꢀ(cm )ꢀ3024,ꢀ2927,ꢀ1655,ꢀ1595,ꢀ1491,ꢀ
1455,ꢀ1431,ꢀ1390,ꢀ1354,ꢀ1322,ꢀ1287,ꢀ1227,ꢀ1165,ꢀ1132,ꢀ1099,ꢀ1070,ꢀ1033,ꢀ978,ꢀ880,ꢀ745,ꢀ693.ꢀ
+
HRMSꢀ(ESI)ꢀcalcdꢀforꢀC26
ꢀ
H
25
N
2
O
2
ꢀ[Mꢀ+ꢀH ]ꢀm/z:ꢀ397.1916,ꢀfoundꢀ397.1915.ꢀ
rel(4bR,5R,13bR)-5-Phenoxy-4b,5,9,13b,15,16-hexahydro-6H,8H-pyrimido[2,1-a:4,3-a']diisoqui
nolin-6-oneꢀ(4fb)ꢀ
1
Yellowꢀoil.ꢀYield:ꢀ109ꢀmg,ꢀ55%.ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
3
)ꢀδ:ꢀ7.59ꢀ–ꢀ6.87ꢀ(m,ꢀ13H),ꢀ6.03ꢀ(s,ꢀ1H),ꢀ
4.97ꢀ(d,ꢀJꢀ=ꢀ9.4ꢀHz,ꢀ1H),ꢀ4.76ꢀ(ddd,ꢀJꢀ=ꢀ12.7,ꢀ4.4,ꢀ2.8ꢀHz,ꢀ1H),ꢀ4.69ꢀ(d,ꢀJꢀ=ꢀ9.4ꢀHz,ꢀ1H),ꢀ3.11ꢀ–ꢀ2.90ꢀ(m,ꢀ
1
3
3
1
H),ꢀ2.84ꢀ–ꢀ2.77ꢀ(m,ꢀ2H),ꢀ2.70ꢀ–ꢀ2.66ꢀ(m,ꢀ2H).ꢀ CꢀNMRꢀ(100ꢀMHz,ꢀCDCl
3
)ꢀδ:ꢀ167.9,ꢀ159.5,ꢀ136.5,ꢀ
35.4,ꢀ133.5,ꢀ132.3,ꢀ129.2,ꢀ129.1,ꢀ128.8,ꢀ128.2,ꢀ127.8,ꢀ127.4,ꢀ127.3,ꢀ127.2,ꢀ125.9,ꢀ121.6,ꢀ116.6,ꢀ
-
1
76.2,ꢀ74.4,ꢀ61.3,ꢀ38.3,ꢀ37.3,ꢀ28.9,ꢀ28.6.ꢀIRꢀ(film,ꢀKBr)ꢀvꢀ(cm )ꢀ3026,ꢀ2925,ꢀ1664,ꢀ1596,ꢀ1493,ꢀ1455,ꢀ
1
C
ꢀ
427,ꢀ1384,ꢀ1353,ꢀ1320,ꢀ1287,ꢀ1233,ꢀ1163,ꢀ1133,ꢀ1096,ꢀ1038,ꢀ911,ꢀ751,ꢀ690.ꢀHRMSꢀ(ESI)ꢀcalcdꢀforꢀ
+
26
H
25
N
2
O
2
ꢀ[Mꢀ+ꢀH ]ꢀm/z:ꢀ397.1916,ꢀfoundꢀ397.1913.ꢀ
rel(4bR,5R,13bR)-5-(4-Nitrophenoxy)-4b,5,9,13b,15,16-hexahydro-6H,8H-pyrimido[2,1-a:4,3-a']
diisoquinolin-6-oneꢀ(4gb)ꢀ
2
4
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The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
o
1
3
Colorlessꢀcrystals.ꢀM.p.ꢀ245ꢀ–ꢀ246ꢀ C.ꢀYield:ꢀ77ꢀmg,ꢀ36%.ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl )ꢀδ:ꢀ8.23ꢀ(d,ꢀJꢀ=ꢀ
8.7ꢀHz,ꢀ2H),ꢀ7.55ꢀ(dd,ꢀJꢀ=ꢀ5.1,ꢀ4.0ꢀHz,ꢀ1H),ꢀ7.36ꢀ–ꢀ7.27ꢀ(m,ꢀ4H),ꢀ7.24ꢀ–ꢀ7.19ꢀ(m,ꢀ1H),ꢀ7.19ꢀ–ꢀ7.12ꢀ(m,ꢀ
2
4
H),ꢀ6.91ꢀ–ꢀ6.83ꢀ(m,ꢀ1H),ꢀ6.19ꢀ(s,ꢀ1H),ꢀ6.00ꢀ(d,ꢀJꢀ=ꢀ7.7ꢀHz,ꢀ1H),ꢀ4.86ꢀ(ddd,ꢀJꢀ=ꢀ12.8,ꢀ4.3,ꢀ3.0ꢀHz,ꢀ1H),ꢀ
.67ꢀ(d,ꢀJꢀ=ꢀ10.5ꢀHz,ꢀ1H),ꢀ4.03ꢀ(d,ꢀJꢀ=ꢀ10.5ꢀHz,ꢀ1H),ꢀ3.14ꢀ(ddd,ꢀJꢀ=ꢀ12.4,ꢀ3.2,ꢀ3.2ꢀHz,ꢀ1H),ꢀ3.02ꢀ–ꢀ2.85ꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
3
(m,ꢀ3H),ꢀ2.81ꢀ(ddd,ꢀJꢀ=ꢀ15.9,ꢀ2.8,ꢀ2.8ꢀHz,ꢀ1H),ꢀ2.77ꢀ–ꢀ2.70ꢀ(m,ꢀ1H),ꢀ2.68ꢀ–ꢀ2.61ꢀ(m,ꢀ1H).ꢀ CꢀNMRꢀ
(
3
100ꢀMHz,ꢀCDCl )ꢀδ:ꢀ168.0,ꢀ147.4,ꢀ147.0,ꢀ136.7,ꢀ135.2,ꢀ133.3,ꢀ132.3,ꢀ130.8,ꢀ129.5,ꢀ128.6,ꢀ127.9,ꢀ
1
27.44,ꢀ127.41,ꢀ127.2,ꢀ127.0,ꢀ125.0,ꢀ123.9,ꢀ74.8,ꢀ64.2,ꢀ52.4,ꢀ38.5,ꢀ36.2,ꢀ28.7,ꢀ28.5.ꢀIRꢀ(film,ꢀKBr)ꢀvꢀ
-
1
(cm )ꢀ 2926,ꢀ 1643,ꢀ 1605,ꢀ 1518,ꢀ 1494,ꢀ 1456,ꢀ 1428,ꢀ 1386,ꢀ 1346,ꢀ 1317,ꢀ 1287,ꢀ 1242,ꢀ 1186,ꢀ 1156,ꢀ
+
1
4
ꢀ
110,ꢀ 1095,ꢀ 1047,ꢀ 850,ꢀ 750,ꢀ 729,ꢀ 689,ꢀ 651.ꢀ HRMSꢀ (ESI)ꢀ calcdꢀ forꢀ C26
26.1818,ꢀfoundꢀ426.1812.ꢀ
H
24
N
3
O
3
ꢀ [Mꢀ +ꢀ H ]ꢀ m/z:ꢀ
rel(4bR,5R,13bS)-5-(4-Nitrophenoxy)-4b,5,9,13b,15,16-hexahydro-6H,8H-pyrimido[2,1-a:4,3-a']
diisoquinolin-6-oneꢀ(4gc)ꢀ
o
1
3
Colorlessꢀcrystals.ꢀM.p.ꢀ261ꢀ–ꢀ263ꢀ C.ꢀYield:ꢀ40ꢀmg,ꢀ19%.ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl )ꢀδ:ꢀ8.09ꢀ(d,ꢀJꢀ=ꢀ
8
2
.4ꢀHz,ꢀ2H),ꢀ7.67ꢀ(d,ꢀJꢀ=ꢀ7.7ꢀHz,ꢀ1H),ꢀ7.37ꢀ–ꢀ7.20ꢀ(m,ꢀ5H),ꢀ7.16ꢀ(t,ꢀJꢀ=ꢀ7.4ꢀHz,ꢀ1H),ꢀ6.91ꢀ(d,ꢀJꢀ=ꢀ8.7ꢀHz,ꢀ
H),ꢀ6.73ꢀ(t,ꢀJꢀ=ꢀ7.4ꢀHz,ꢀ1H),ꢀ5.60ꢀ(d,ꢀJꢀ=ꢀ7.8ꢀHz,ꢀ1H),ꢀ5.57ꢀ(s,ꢀ1H),ꢀ5.00ꢀ–ꢀ4.90ꢀ(m,ꢀ1H),ꢀ4.25ꢀ(d,ꢀJꢀ=ꢀ
10.8ꢀHz,ꢀ1H),ꢀ3.96ꢀ(d,ꢀJꢀ=ꢀ10.8ꢀHz,ꢀ1H),ꢀ3.82ꢀ(ddd,ꢀJꢀ=ꢀ11.6,ꢀ4.3,ꢀ4.3ꢀHz,ꢀ1H),ꢀ3.49ꢀ–ꢀ3.39ꢀ(m,ꢀ1H),ꢀ
3
1
.39ꢀ–ꢀ3.28ꢀ(m,ꢀ2H),ꢀ3.27ꢀ–ꢀ3.17ꢀ(m,ꢀ1H),ꢀ3.06ꢀ(dd,ꢀJꢀ=ꢀ16.4,ꢀ4.1ꢀHz,ꢀ1H),ꢀ2.86ꢀ(dd,ꢀJꢀ=ꢀ16.1,ꢀ3.1ꢀHz,ꢀ
13
3
H).ꢀ CꢀNMRꢀ(100ꢀMHz,ꢀCDCl )ꢀδ:ꢀ167.5,ꢀ146.8,ꢀ146.7,ꢀ136.1,ꢀ135.8,ꢀ134.0,ꢀ133.4,ꢀ129.5,ꢀ129.3,ꢀ
128.4,ꢀ127.6,ꢀ127.41ꢀ(2C),ꢀ126.9,ꢀ125.1,ꢀ124.6,ꢀ123.5,ꢀ78.6,ꢀ58.1,ꢀ50.8,ꢀ45.9,ꢀ41.9,ꢀ29.3,ꢀ28.2.ꢀIRꢀ
-
1
(
film,ꢀ KBr)ꢀ vꢀ (cm )ꢀ 2923,ꢀ 1635,ꢀ 1602,ꢀ 1514,ꢀ 1489,ꢀ 1466,ꢀ 1435,ꢀ 1370,ꢀ 1343,ꢀ 1302,ꢀ 1282,ꢀ 1245,ꢀ
+
1
145,ꢀ 1112,ꢀ 846,ꢀ 784,ꢀ 761,ꢀ 752,ꢀ 725,ꢀ 693.ꢀ HRMSꢀ (ESI)ꢀ calcdꢀ forꢀ C26
H
24
N
3
O
3
ꢀ [Mꢀ +ꢀ H ]ꢀ m/z:ꢀ
2
5
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The Journal of Organic Chemistry
Page 26 of 34
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2
3
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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
4
ꢀ
26.1818,ꢀfoundꢀ426.1818.ꢀ
rel(4bS,5R,13bR)-5-Phenyl-4b,5,9,13b,15,16-hexahydro-6H,8H-pyrimido[2,1-a:4,3-a']diisoquino
lin-6-oneꢀ(4h)ꢀ
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
o
1
3
Colorlessꢀcrystals.ꢀM.p.ꢀ175ꢀ–ꢀ176ꢀ C.ꢀYield:ꢀ128ꢀmg,ꢀ67%.ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl )ꢀδ:ꢀ7.60ꢀ–ꢀ7.53ꢀ
(
m,ꢀ1H),ꢀ7.32ꢀ–ꢀ7.27ꢀ(m,ꢀ4H),ꢀ7.22ꢀ–ꢀ7.09ꢀ(m,ꢀ6H),ꢀ6.90ꢀ–ꢀ6.84ꢀ(m,ꢀ1H),ꢀ6.17ꢀ(s,ꢀ1H),ꢀ6.12ꢀ(d,ꢀJꢀ=ꢀ7.7ꢀ
Hz,ꢀ1H),ꢀ4.84ꢀ(ddd,ꢀJꢀ=ꢀ12.9,ꢀ4.2,ꢀ3.5ꢀHz,ꢀ1H),ꢀ4.70ꢀ(d,ꢀJꢀ=ꢀ10.4ꢀHz,ꢀ1H),ꢀ3.86ꢀ(d,ꢀJꢀ=ꢀ10.3ꢀHz,ꢀ1H),ꢀ
3.20ꢀ–ꢀ3.11ꢀ(m,ꢀ1H),ꢀ3.00ꢀ–ꢀ2.86ꢀ(m,ꢀ3H),ꢀ2.82ꢀ–ꢀ2.75ꢀ(m,ꢀ1H),ꢀ2.75ꢀ–ꢀ2.68ꢀ(m,ꢀ1H),ꢀ2.63ꢀ–ꢀ2.56ꢀ(m,ꢀ
1
3
1
1
H).ꢀ CꢀNMRꢀ(100ꢀMHz,ꢀCDCl
3
)ꢀδ:ꢀ169.6,ꢀ139.8,ꢀ137.0,ꢀ136.3,ꢀ133.2,ꢀ132.8,ꢀ129.7,ꢀ129.1,ꢀ128.8,ꢀ
28.5,ꢀ127.8,ꢀ127.6,ꢀ127.4,ꢀ127.15,ꢀ127.07,ꢀ127.00,ꢀ124.9,ꢀ74.7,ꢀ64.5,ꢀ52.5,ꢀ38.6,ꢀ36.3,ꢀ28.9,ꢀ28.7.ꢀ
-
1
IRꢀ(film,ꢀKBr)ꢀvꢀcm ꢀ3027,ꢀ2924,ꢀ1644,ꢀ1494,ꢀ1454,ꢀ1426,ꢀ1384,ꢀ1354,ꢀ1287,ꢀ1242,ꢀ1188,ꢀ1154,ꢀ
+
1
3
ꢀ
094,ꢀ1039,ꢀ922,ꢀ750,ꢀ727,ꢀ699.ꢀHRMSꢀ(ESI)ꢀcalcdꢀforꢀC26
81.1961.ꢀ
H
25
N
2
Oꢀ[Mꢀ+ꢀH ]ꢀm/z:ꢀ381.1967,ꢀfoundꢀ
Ethylꢀ
rel(4bR,5S,13bS)-4b,5,9,13b,15,16-Hexahydro-6-oxo-6H,8H-pyrimido[2,1-a:4,3-a']ꢀ
diisoquinoline-5-carboxylateꢀ(4i)ꢀ
o
1
Colorlessꢀcrystals.ꢀM.p.ꢀ141ꢀ–ꢀ142ꢀ C.ꢀYield:ꢀ64ꢀmg,ꢀ34%ꢀfromꢀ2g,ꢀ87ꢀmg,ꢀ46%ꢀfromꢀ2j.ꢀ HꢀNMRꢀ
(
3
400ꢀMHz,ꢀCDCl )ꢀδ:ꢀ7.55ꢀ–ꢀ7.47ꢀ(m,ꢀ1H),ꢀ7.31ꢀ–ꢀ7.23ꢀ(m,ꢀ3H),ꢀ7.23ꢀ–ꢀ7.16ꢀ(m,ꢀ2H),ꢀ7.17ꢀ–ꢀ7.10ꢀ(m,ꢀ
2
H),ꢀ6.96ꢀ(d,ꢀJꢀ=ꢀ7.4ꢀHz,ꢀ1H),ꢀ6.00ꢀ(s,ꢀ1H),ꢀ4.93ꢀ(d,ꢀJꢀ=ꢀ10.4ꢀHz,ꢀ1H),ꢀ4.79ꢀ(ddd,ꢀJꢀ=ꢀ12.9,ꢀ4.4,ꢀ3.1ꢀHz,ꢀ
1H),ꢀ4.31ꢀ(q,ꢀJꢀ=ꢀ7.1ꢀHz,ꢀ2H),ꢀ3.77ꢀ(d,ꢀJꢀ=ꢀ10.4ꢀHz,ꢀ1H),ꢀ3.08ꢀ(ddd,ꢀJꢀ=ꢀ12.4,ꢀ3.3,ꢀ3.3ꢀHz,ꢀ1H),ꢀ2.99ꢀ–ꢀ
1
3
2
.85ꢀ(m,ꢀ2H),ꢀ2.77ꢀ(dt,ꢀJꢀ=ꢀ15.9,ꢀ2.9ꢀHz,ꢀ1H),ꢀ2.69ꢀ–ꢀ2.53ꢀ(m,ꢀ3H),ꢀ1.32ꢀ(t,ꢀJꢀ=ꢀ7.1ꢀHz,ꢀ3H).ꢀ CꢀNMRꢀ
(
3
100ꢀMHz,ꢀCDCl )ꢀδ:ꢀ170.7,ꢀ164.4,ꢀ136.5,ꢀ136.0,ꢀ133.2,ꢀ132.2,ꢀ129.3,ꢀ128.5,ꢀ127.7,ꢀ127.40,ꢀ127.36,ꢀ
2
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Page 27 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
-
1
1
27.0,ꢀ126.2,ꢀ125.8,ꢀ74.4,ꢀ61.6,ꢀ59.6,ꢀ52.8,ꢀ38.2,ꢀ36.3,ꢀ28.6,ꢀ28.5,ꢀ14.1.ꢀIRꢀ(film,ꢀKBr)ꢀvꢀ(cm )ꢀ2929,ꢀ
1729,ꢀ1652,ꢀ1494,ꢀ1455,ꢀ1428,ꢀ1390,ꢀ1355,ꢀ1333,ꢀ1304,ꢀ1286,ꢀ1241,ꢀ1177,ꢀ1146,ꢀ1094,ꢀ1034,ꢀ940,ꢀ
+
7
ꢀ
47,ꢀ727,ꢀ669.ꢀHRMSꢀ(ESI)ꢀcalcdꢀforꢀC23
H
25
N
2
O
3
ꢀ[Mꢀ+ꢀH ]ꢀm/z:ꢀ377.1865,ꢀfoundꢀ377.1867.ꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
rel(4bR,5R,13bS)-N-Methyl-4b,5,9,13b,15,16-hexahydro-6-oxo-6H,8H-pyrimido[2,1-a:4,3-a']diis
oquinoline-5-carboxamideꢀ(4j)ꢀ
o
1
3
Colorlessꢀcrystals.ꢀM.p.ꢀ170ꢀ–ꢀ172ꢀ C.ꢀYield:ꢀ76ꢀmg,ꢀ42%.ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl )ꢀδ:ꢀ7.56ꢀ–ꢀ7.51ꢀ
(m,ꢀ1H),ꢀ7.31ꢀ–ꢀ7.26ꢀ(m,ꢀ2H),ꢀ7.22ꢀ–ꢀ7.13ꢀ(m,ꢀ4H),ꢀ7.10ꢀ–ꢀ7.08ꢀ(m,ꢀ1H),ꢀ6.51ꢀ(d,ꢀJꢀ=ꢀ3.7ꢀHz,ꢀ1H),ꢀ5.92ꢀ
s,ꢀ1H),ꢀ5.39ꢀ(d,ꢀJꢀ=ꢀ9.1ꢀHz,ꢀ1H),ꢀ4.49ꢀ(ddd,ꢀJꢀ=ꢀ12.9,ꢀ4.4,ꢀ4.4ꢀHz,ꢀ1H),ꢀ3.45ꢀ(d,ꢀJꢀ=ꢀ9.1ꢀHz,ꢀ1H),ꢀ3.32ꢀ–ꢀ
.23ꢀ(m,ꢀ1H),ꢀ2.91ꢀ(d,ꢀJꢀ=ꢀ4.8ꢀHz,ꢀ3H),ꢀ2.97ꢀ–ꢀ2.83ꢀ(m,ꢀ2H),ꢀ2.78ꢀ(dt,ꢀJꢀ=ꢀ15.8,ꢀ3.9ꢀHz,ꢀ1H),ꢀ2.66ꢀ–ꢀ
(
3
1
3
3
2.58ꢀ(m,ꢀ1H),ꢀ2.56ꢀ–ꢀ2.44ꢀ(m,ꢀ2H).ꢀ CꢀNMRꢀ(100ꢀMHz,ꢀCDCl )ꢀδ:ꢀ169.0,ꢀ166.0,ꢀ137.7,ꢀ136.6,ꢀ133.1,ꢀ
1
2
32.4,ꢀ129.0,ꢀ128.2,ꢀ127.79,ꢀ127.75,ꢀ127.2,ꢀ127.0,ꢀ126.7,ꢀ126.2,ꢀ73.8,ꢀ57.7,ꢀ53.8,ꢀ38.9,ꢀ37.0,ꢀ28.8,ꢀ
-
1
8.6,ꢀ26.9.ꢀIRꢀ(film,ꢀKBr)ꢀvꢀ(cm )ꢀ2922,ꢀ1655,ꢀ1638,ꢀ1578,ꢀ1561,ꢀ1544,ꢀ1493,ꢀ1458,ꢀ1431,ꢀ1354,ꢀ
+
1286,ꢀ1242,ꢀ1157,ꢀ1094,ꢀ1037,ꢀ921,ꢀ751.ꢀHRMSꢀ(ESI)ꢀcalcdꢀforꢀC22
H
24
N
3
O
2
ꢀ[Mꢀ+ꢀH ]ꢀm/z:ꢀ362.1869,ꢀ
foundꢀ362.1868.ꢀ
ꢀ
rel(4bR,5R,13bS)-N-Methyl-N-phenyl-4b,5,9,13b,15,16-hexahydro-6-oxo-6H,8H-pyrimido[2,1-a:
4
,3-a']diisoquinoline-5-carboxamideꢀ(4ka)ꢀ
o
1
Colorlessꢀcrystals.ꢀM.p.ꢀ198ꢀ–ꢀ199ꢀ C.ꢀYield:ꢀ39ꢀmg,ꢀ18%.ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
3
)ꢀδ:ꢀ7.52ꢀ–ꢀ7.32ꢀ
(m,ꢀ7H),ꢀ7.23ꢀ–ꢀ7.14ꢀ(m,ꢀ4H),ꢀ7.13ꢀ–ꢀ7.07ꢀ(m,ꢀ1H),ꢀ6.79ꢀ–ꢀ6.74ꢀ(m,ꢀ1H),ꢀ5.69ꢀ(s,ꢀ1H),ꢀ4.77ꢀ(ddd,ꢀJꢀ=ꢀ
2.6,ꢀ3.9,ꢀ3.9ꢀHz,ꢀ1H),ꢀ4.65ꢀ(d,ꢀJꢀ=ꢀ9.3ꢀHz,ꢀ1H),ꢀ4.29ꢀ(d,ꢀJꢀ=ꢀ9.3ꢀHz,ꢀ1H),ꢀ3.69ꢀ(ddd,ꢀJꢀ=ꢀ10.8,ꢀ5.1,ꢀ5.1ꢀ
Hz,ꢀ1H),ꢀ3.11ꢀ(ddd,ꢀJꢀ=ꢀ12.3,ꢀ2.8,ꢀ2.8ꢀHz,ꢀ1H),ꢀ2.97ꢀ(ddd,ꢀJꢀ=ꢀ10.8,ꢀ4.2,ꢀ4.2ꢀHz,ꢀ1H),ꢀ2.87ꢀ(s,ꢀ3H),ꢀ2.81ꢀ
1
2
7
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The Journal of Organic Chemistry
Page 28 of 34
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
3
–
3
ꢀ2.71ꢀ(m,ꢀ3H),ꢀ2.40ꢀ(dd,ꢀJꢀ=ꢀ11.0,ꢀ6.2ꢀHz,ꢀ1H).ꢀ CꢀNMRꢀ(100ꢀMHz,ꢀCDCl )ꢀδ:ꢀ168.3,ꢀ167.0,ꢀ144.7,ꢀ
136.9,ꢀ135.5,ꢀ134.0,ꢀ132.6,ꢀ129.5,ꢀ129.4,ꢀ129.1,ꢀ128.2,ꢀ127.8,ꢀ127.7,ꢀ127.2,ꢀ127.00,ꢀ126.96,ꢀ126.1,ꢀ
-1
1
1
24.3,ꢀ74.1,ꢀ58.9,ꢀ48.5,ꢀ38.4,ꢀ37.5,ꢀ35.6,ꢀ28.6,ꢀ28.2.ꢀIRꢀ(film,ꢀKBr)ꢀvꢀ(cm )ꢀ2926,ꢀ1660,ꢀ1638,ꢀ1595,ꢀ
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
496,ꢀ1455,ꢀ1420,ꢀ1380,ꢀ1358,ꢀ1324,ꢀ1287,ꢀ1269,ꢀ1233,ꢀ1155,ꢀ1116,ꢀ774,ꢀ752,ꢀ702,ꢀ666.ꢀHRMSꢀ
+
(ESI)ꢀcalcdꢀforꢀC28
ꢀ
H
28
N
3
O
2
ꢀ[Mꢀ+ꢀH ]ꢀm/z:ꢀ438.2182,ꢀfoundꢀ438.2185.ꢀ
rel(4bR,5R,13bS)-N-Methyl-6-oxo-N-phenyl-4b,5,9,13b,15,16-hexahydro-6H,8H-pyrimido[2,1-a:
4,3-a']diisoquinoline-5-carboxamideꢀ(Twoꢀinseparableꢀrotamers)ꢀ
Colorlessꢀoil.ꢀTotalꢀyield:ꢀ29ꢀmg,ꢀ13%.ꢀ ꢀ
Minorꢀrotamerꢀ(4kb):ꢀ
1
3
HꢀNMRꢀ(400ꢀMHz,ꢀCDCl )ꢀδ:ꢀ7.59ꢀ–ꢀ7.03ꢀ(m,ꢀ13H),ꢀ6.05ꢀ(s,ꢀ1H),ꢀ5.05ꢀ(d,ꢀJꢀ=ꢀ10.8ꢀHz,ꢀ1H),ꢀ4.86ꢀ(ddd,ꢀ
Jꢀ=ꢀ12.0,ꢀ4.4,ꢀ2.6ꢀHz,ꢀ1H),ꢀ3.77ꢀ(d,ꢀJꢀ=ꢀ10.8ꢀHz,ꢀ1H),ꢀ3.34ꢀ(s,ꢀ3H),ꢀ3.30ꢀ–ꢀ3.23ꢀ(m,ꢀ2H),ꢀ2.99ꢀ–ꢀ2.92ꢀ(m,ꢀ
1
3
2
3
H),ꢀ2.87ꢀ–ꢀ2.76ꢀ(m,ꢀ2H),ꢀ2.27ꢀ(ddd,ꢀJꢀ=ꢀ12.0,ꢀ4.4,ꢀ4.4ꢀHz,ꢀ1H).ꢀ CꢀNMRꢀ(100ꢀMHz,ꢀCDCl )ꢀδ:ꢀ169.6,ꢀ
165.5,ꢀ143.5,ꢀ136.5,ꢀ135.9,ꢀ133.2,ꢀ132.5,ꢀ129.39,ꢀ129.30,ꢀ128.6,ꢀ127.58,ꢀ127.51,ꢀ127.40,ꢀ127.37,ꢀ
-
1
1
2
27.2,ꢀ126.9,ꢀ126.2,ꢀ125.5,ꢀ74.7,ꢀ59.8,ꢀ48.2,ꢀ38.0,ꢀ37.6,ꢀ36.3,ꢀ29.7,ꢀ28.6.ꢀIRꢀ(film,ꢀKBr)ꢀvꢀ(cm )ꢀ
925,ꢀ1655,ꢀ1642,ꢀ1594,ꢀ1495,ꢀ1462,ꢀ1427,ꢀ1388,ꢀ1354,ꢀ1300,ꢀ1283,ꢀ1241,ꢀ1143,ꢀ1115,ꢀ771,ꢀ742,ꢀ
+
700,ꢀ678.ꢀHRMSꢀ(ESI)ꢀcalcdꢀforꢀC28
H
28
N
3
O
2
ꢀ[Mꢀ+ꢀH ]ꢀm/z:ꢀ438.2182,ꢀfoundꢀ438.2179.ꢀ
Majorꢀrotamerꢀ(4kc):ꢀ
1
3
HꢀNMRꢀ(400ꢀMHz,ꢀCDCl )ꢀδ:ꢀ7.59ꢀ–ꢀ7.03ꢀ(m,ꢀ13H),ꢀ5.27ꢀ(s,ꢀ1H),ꢀ4.85ꢀ–ꢀ4.78ꢀ(m,ꢀ1H),ꢀ4.56ꢀ(d,ꢀJꢀ=ꢀ
10.7ꢀHz,ꢀ1H),ꢀ3.66ꢀ(d,ꢀJꢀ=ꢀ10.7ꢀHz,ꢀ1H),ꢀ3.29ꢀ–ꢀ3.14ꢀ(m,ꢀ2H),ꢀ3.20ꢀ(s,ꢀ3H),ꢀ3.10ꢀ–ꢀ3.01ꢀ(m,ꢀ2H),ꢀ2.69ꢀ
1
3
(
3
dd,ꢀJꢀ=ꢀ15.5,ꢀ3.2ꢀHz,ꢀ2H),ꢀ2.42ꢀ(dd,ꢀJꢀ=ꢀ12.5,ꢀ6.2ꢀHz,ꢀ1H).ꢀ CꢀNMRꢀ(100ꢀMHz,ꢀCDCl )ꢀδ:ꢀ168.8,ꢀ164.9,ꢀ
1
43.6,ꢀ136.0,ꢀ135.9,ꢀ135.0,ꢀ133.3,ꢀ129.26,ꢀ129.23,ꢀ129.0,ꢀ128.1,ꢀ127.5,ꢀ127.41,ꢀ127.37,ꢀ127.29,ꢀ
2
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Page 29 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
-
1
1
26.5,ꢀ125.4,ꢀ125.0,ꢀ78.5,ꢀ54.2,ꢀ47.1,ꢀ45.8,ꢀ41.3,ꢀ37.0,ꢀ28.9,ꢀ28.0.ꢀIRꢀ(film,ꢀKBr)ꢀvꢀ(cm )ꢀ2925,ꢀ1655,ꢀ
1642,ꢀ1594,ꢀ1495,ꢀ1462,ꢀ1427,ꢀ1388,ꢀ1354,ꢀ1300,ꢀ1283,ꢀ1241,ꢀ1143,ꢀ1115,ꢀ771,ꢀ742,ꢀ700,ꢀ678.ꢀ
+
HRMSꢀ(ESI)ꢀcalcdꢀforꢀC28
ꢀ
H
28
N
3
O
2
ꢀ[Mꢀ+ꢀH ]ꢀm/z:ꢀ438.2182,ꢀfoundꢀ438.2179.ꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
rel(4bR,5R,13bS)-4b,5,9,13b,15,16-Hexahydro-6-oxo-6H,8H-pyrimido[2,1-a:4,3-a']diisoquinolin
e-5-carbonitrileꢀ(4m)ꢀ
o
1
3
Colorlessꢀcrystals.ꢀM.p.ꢀ196ꢀ–ꢀ197ꢀ C.ꢀYield:ꢀ40ꢀmg,ꢀ24%.ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl )ꢀδ:ꢀ7.58ꢀ–ꢀ7.51ꢀ
(m,ꢀ1H),ꢀ7.51ꢀ–ꢀ7.45ꢀ(m,ꢀ1H),ꢀ7.32ꢀ–ꢀ7.26ꢀ(m,ꢀ4H),ꢀ7.22ꢀ–ꢀ7.18ꢀ(m,ꢀ1H),ꢀ7.17ꢀ–ꢀ7.13ꢀ(m,ꢀ1H),ꢀ5.94ꢀ(s,ꢀ
H),ꢀ4.84ꢀ(ddd,ꢀJꢀ=ꢀ13.2,ꢀ4.5,ꢀ2.8ꢀHz,ꢀ1H),ꢀ4.81ꢀ(d,ꢀJꢀ=ꢀ10.6ꢀHz,ꢀ1H),ꢀ3.85ꢀ(d,ꢀJꢀ=ꢀ10.6ꢀHz,ꢀ1H),ꢀ3.10ꢀ
ddd,ꢀJꢀ=ꢀ12.5,ꢀ3.3,ꢀ3.3ꢀHz,ꢀ1H),ꢀ3.01ꢀ–ꢀ2.87ꢀ(m,ꢀ2H),ꢀ2.84ꢀ–ꢀ2.76ꢀ(m,ꢀ1H),ꢀ2.67ꢀ(d,ꢀJꢀ=ꢀ16.0ꢀHz,ꢀ1H),ꢀ
1
(
1
3
3
2.64ꢀ–ꢀ2.53ꢀ(m,ꢀ2H).ꢀ CꢀNMRꢀ(100ꢀMHz,ꢀCDCl )ꢀδ:ꢀ160.1,ꢀ136.3,ꢀ134.1,ꢀ133.1,ꢀ131.4,ꢀ129.5,ꢀ128.8,ꢀ
1
28.3,ꢀ128.2,ꢀ127.34,ꢀ127.31,ꢀ127.28,ꢀ126.5,ꢀ117.6,ꢀ74.7,ꢀ59.7,ꢀ38.9,ꢀ38.4,ꢀ36.0,ꢀ28.40,ꢀ28.36.ꢀIRꢀ
-
1
(
film,ꢀ KBr)ꢀ vꢀ (cm )ꢀ 2927,ꢀ 1660,ꢀ 1537,ꢀ 1455,ꢀ 1430,ꢀ 1389,ꢀ 1354,ꢀ 1308,ꢀ 1285,ꢀ 1261,ꢀ 1241,ꢀ 1157,ꢀ
+
1131,ꢀ1094,ꢀ1048,ꢀ881,ꢀ795,ꢀ737,ꢀ657.ꢀHRMSꢀ(ESI)ꢀcalcdꢀforꢀC21
H
20
N
3
Oꢀ[Mꢀ+ꢀH ]ꢀm/z:ꢀ330.1606,ꢀ
foundꢀ330.1606.ꢀ
ꢀ
trans-1-Ethoxy-1,4,5,9b-tetrahydro-2H-azeto[2,1-a]isoquinolin-2-oneꢀ(5c)ꢀ
1
Yellowishꢀoil.ꢀYield:ꢀ56ꢀmg,ꢀ26%.ꢀ HꢀNMRꢀ(400ꢀMHz,ꢀCDCl
3
)ꢀδ:ꢀ7.31ꢀ–ꢀ7.09ꢀ(m,ꢀ4H),ꢀ4.58ꢀ(s,ꢀ1H),ꢀ
4
.45ꢀ(d,ꢀJꢀ=ꢀ1.4ꢀHz,ꢀ1H),ꢀ3.98ꢀ(ddd,ꢀJꢀ=ꢀ12.8,ꢀ6.6,ꢀ3.6ꢀHz,ꢀ1H),ꢀ3.81ꢀ(q,ꢀJꢀ=ꢀ7.0ꢀHz,ꢀ2H),ꢀ3.17ꢀ(ddd,ꢀJꢀ=ꢀ
13.0,ꢀ9.5,ꢀ5.2ꢀHz,ꢀ1H),ꢀ3.00ꢀ(ddd,ꢀJꢀ=ꢀ16.0,ꢀ9.5,ꢀ6.6ꢀHz,ꢀ1H),ꢀ2.76ꢀ(ddd,ꢀJꢀ=ꢀ16.0,ꢀ4.2,ꢀ4.2ꢀHz,ꢀ1H),ꢀ
1
3
1
1
.33ꢀ(t,ꢀJꢀ=ꢀ7.0ꢀHz,ꢀ3H).ꢀ CꢀNMRꢀ(100ꢀMHz,ꢀCDCl
3
)ꢀδ:ꢀ167.1,ꢀ134.0,ꢀ133.5,ꢀ129.6,ꢀ127.6,ꢀ127.0,ꢀ
-1
25.8,ꢀ89.1,ꢀ66.0,ꢀ57.3,ꢀ37.2,ꢀ28.2,ꢀ15.2.ꢀIRꢀ(film,ꢀKBr)ꢀvꢀ(cm )ꢀ2975,ꢀ1755,ꢀ1455,ꢀ1370,ꢀ1333,ꢀ1298,ꢀ
2
9
ACS Paragon Plus Environment