Abstract - Worcester Polytechnic Institute (WPI) Abstract When developing potentially medicinally...
34
Project Number: MQP‐ JPD‐0001 Synthesis of a Novel Multicyclic Organic Scaffold via a Photoinitiated Intramolecular Ylide‐Alkene Cycloaddition Reaction A Major Qualifying Project Report Submitted to the Faculty Of the WORCESTER POLYTECHNIC INSTITUE In partial fulfillment of the requirements for the Degree of Bachelor of Science By ______________________________________________ Annie E. Vikart Submitted: April 30, 2009 Approved: ______________________________________________ Professor James P. Dittami Adviser Department of Chemistry
Transcript of Abstract - Worcester Polytechnic Institute (WPI) Abstract When developing potentially medicinally...
ProjectNumber:MQP‐JPD‐0001
SynthesisofaNovelMulticyclicOrganicScaffoldviaaPhotoinitiatedIntramolecularYlide‐AlkeneCycloadditionReaction
AMajorQualifyingProjectReport
SubmittedtotheFaculty
Ofthe
WORCESTERPOLYTECHNICINSTITUE
Inpartialfulfillmentoftherequirementsforthe
DegreeofBachelorofScience
By
______________________________________________
AnnieE.Vikart
Submitted:April30,2009
Approved:
______________________________________________
ProfessorJamesP.Dittami
Adviser
DepartmentofChemistry
ii
AbstractWhendevelopingpotentiallymedicinallyrelevantcompoundsitisimportantto
utilizeefficientsyntheticmethods,controlstereochemistry,liphophilicity,acidity,
andtheincorporationofbioisosteres.Thesynthesisofabioisostericanalogof
morphinewasstudiedutilizinganintramolecularylide‐alkenecycloadditionasthe
finalsteptoestablishthesixstereocentersandthreeoftheringsofthemolecule.
Thismulticyclicscaffoldisexpectedtoproducebiologicallyactivecompoundsfrom
abrief,modifiablesynthesisandsimplestartingmaterials.
iii
AcknowledgementsIwouldliketothankProfessorJamesP.Dittamifortheuseofhislaboratory,
extensiveguidance,thoughtfuladvice,andhelpthroughouttheyear.Iwouldalso
liketothankIlieFishtikandVictorKiryakfortheircounselandassistance
throughouttheresearchprocess.FinallyIwouldliketothankmymotherforher
continuingsupportandencouragement.
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TableofContents
Abstract ...................................................................................................................................... ii
Acknowledgements ...............................................................................................................iiiTableofFigures ........................................................................................................................v
Background ............................................................................................................................... 7ResultsandDiscussion:.......................................................................................................12
Methodology: ..........................................................................................................................153ethoxy3cyclohexenone(AEVI002)..................................................................................163(3Butenyl)2cyclohexenone(AEVI012) ........................................................................176(3butenyl)7oxabicyclo[4.1.0]heptan2one(AEVI026) .........................................18(E)1(2,4dihydroxyphenyl)ethanoneoxime(AEVI019a)............................................192methylbenzo[d]oxazol6ol(AEVI021).............................................................................203(but3enyl)2(2methylbenzo[d]oxazol6yloxy)cyclohex2enone(AEVI023flash)............................................................................................................................................21
References ...............................................................................................................................22Spectra ......................................................................................................................................23
v
TableofFiguresFigure1:Dihydrofuranproductresultingfromhydrogenshiftsdiscoveredby
Schultz .................................................................................................................................................. 7
Figure2:Intramolecularylide‐alkene[3+2]cycloadditionreaction................................... 8
Figure3:Arylvinylethersprovidethe[3+2]cycloaddtionproduct .................................. 9
Figure4:Variousbenzoxazolesandabenzothazolethatcouldbeutilizedinthecycloadditionreaction ................................................................................................................... 9
Figure5:Pharmaceuticaldrugswithsimilarstructurestothatofthescaffoldcreatedbythe[3+2]cycloadditionreaction.......................................................................................10
Figure6:Syntheticschemefollowedanddiscussedinthispaper.....................................11
Figure7:Syntheticroutefortheproductionof6‐(3‐butenyl)‐7‐oxabicyclo[4.1.0]heptan‐2‐one................................................................................................12
Figure8:Proposedproductsof[3+2]cycloadditionreactionutilizingvariousbenzoxazolesandabenzothiazole .........................................................................................12
Figure9:Syntheticroutefortheproductionof3‐(but‐3‐enyl)‐2‐(2‐methylbenzo[d]oxazol‐6‐yloxy)cyclohex‐2‐enone .........................................................14
Figure10:1HNMR3‐ethoxy‐3‐cyclohexenone(BCC‐i‐001c) ..............................................23
Figure11:1HNMR3‐(3‐Butenyl)‐2‐cyclohexenone(BCC‐I‐011b) ...................................24
Figure12:1HNMR6‐(3‐butenyl)‐7‐oxabicyclo[4.1.0]heptan‐2‐one(BCC‐I‐016) .....25
Figure13:1HNMR(E)‐1‐(2,4‐dihydroxyphenyl)ethanoneoxime(AEV‐I‐019)..........26
Figure14:1HNMR2‐methylbenzo[d]oxazol‐6‐ol(AEV‐I‐021) ..........................................27
Figure15:1HNMR3‐(but‐3‐enyl)‐2‐(2‐methylbenzo[d]oxazol‐6‐yloxy)cyclohex‐2‐enone(AEV‐I‐023flash) ..............................................................................................................28
Figure16:1HNMR3‐(but‐3‐enyl)‐2‐(2‐methylbenzo[d]oxazol‐6‐yloxy)cyclohex‐2‐enonefrommicrowavereaction(AEV‐1‐027a) ...............................................................29
Figure17:Dept90NMRof3‐(but‐3‐enyl)‐2‐(naphthalen‐2‐yloxy)cyclohex‐2‐enone(AEV‐I‐027b) ...................................................................................................................................30
Figure18:Dept135of3‐(but‐3‐enyl)‐2‐(naphthalen‐2‐yloxy)cyclohex‐2‐enone(AEV‐I‐027b) ...................................................................................................................................31
Figure19:COSEYNMRof3‐(but‐3‐enyl)‐2‐(naphthalen‐2‐yloxy)cyclohex‐2‐enone(AEV‐I‐027b) ...................................................................................................................................32
vi
Figure20:IRspectraof3‐(but‐3‐enyl)‐2‐(naphthalen‐2‐yloxy)cyclohex‐2‐enone....33
Figure21:LCMSofof3‐(but‐3‐enyl)‐2‐(naphthalen‐2‐yloxy)cyclohex‐2‐enone........34
7
BackgroundTheheterocyclizationreactionofarylvinylsulfides,arylvinylethers,andarylvinyl
amineswasreportedtoproceedviaylideintermediates.1‐4
Figure1:DihydrofuranproductresultingfromhydrogenshiftsdiscoveredbySchultz
Thiswasconsideredapotentiallyusefulreactiontocreateacarbon‐carbonbondon
anaromaticring.Theylideintermediaterearrangmentproceedsviaaseriesof
hydrogenshiftstoprovidedihydrofuran,dihydrothiopheneanddihydroindole
products.Usualmethodsforthegenerationofthecarbonylylidespecieshave
involvedthermolysisandphotolysisofoxiranerings,5carbineadditiontocarbonyl
groups,6andextrusionreactionssuchasthethermolysisofoxadiazolines.7Theuse
ofarylvinylsulfidesandarylvinyletherstogenerateaylideintermediatewas
consideredanovelandpotentiallyveryreaction.
Ourgroupwasinterestedinbeta‐naphtholringformingreactionsproceedingvia
intermediateylideswithapendantdipolaophile.Thissettheprecedencefortheuse
ofarylvinylethersforphotocyclizationandintramolecularylide‐alkene[3+2]1‐4Schultz,A.G.;Detar,M.B.,J.Am.Chem.Soc.1976,98,3574.,Schults,A.G.Acc.Chem.Res.1983,16,210.,Wolff,T.J.J.Org.Chem.1981,46,978‐983.,Herkstroeter,W.G.;Shultz,A.G.J.Am.Chem.Soc.1984,106,5563.5Eberbach,W.;Brokatzky,J.;Fritz,H.Angew.Chem.,Int.Ed.Engl.1980,19,47.6Padwa,A.;Fryxell,G.E.;Zhi,L.J.Am.Chem.Soc.1990,112,3100.7Shimizu,N.;Bartlett,P.D.J.Am.Chem.Soc.1978,100,4260.
XO
R
C- XO
R
XO
R
hν H shift
24 25 26X = N, O, S, R'
8
cycloadditionreactions.ItwasreportedbyDittamiet.al.thatarylvinylethers
bearingapendantalkenesidechainundergo[3+2]photocycilizationand
subsequentintramolecularylide‐alkeneaddition.8
Figure2:Intramolecularylidealkene[3+2]cycloadditionreaction
Thiswasviewedasapotentiallyrapidandpowerfulwaytoconstructcomplex
multicyclicscaffoldsforminguptosix‐chiralcentersandthreeringswithexcellent
stereocontrol.TheDittamigrouputilizedthisreactiontotestwhethertheycould
createcomplexanduseful[3+2]cycloadditionproducts.Earlyworkwitharylvinyl
sulfidesdidnotprovidetheexpected[3+2]cycloadditionproduct.However,work
witharylvinylethersyieldedthedesired[3+2]product.9
8Dittami,J.P.;Nie,X,‐Y.;Nie,H.;Ramanathan,H.;Breining,S.;Bordner,J.;Decosta,D.;Kiplinger,J.;Rieche,P.;Ware,R.J.Org.Chem.1991,56,5572.9Dittami,J.P.;Nie,X,‐Y.;Nie,H.;Ramanathan,H.;Buntel,C.;Rigatti,S.J.Org.Chem.1992,57,1151‐1158.
X
On
X
O
n
O
X
O
X
4a 4bn= 1, 2
or
n=1 n=2
4 5 6 7
9
Figure3:Arylvinylethersprovidethe[3+2]cycloaddtionproduct
Itwasfoundthatmanyfactorssuchasheat,heteroatom(i.e.Ovs.S),andaromatic
ring(naphthylversusphenyl)greatlyaffectedthekindsofintramolecularaddition
productsobserved.Itwasfoundthatcarbonylylidescanundergointramolecular
cycloadditionreactionswithaloweractivationbarrierandhigherpuritywhenan
electronwithdrawinggroupisaddedtothependantalkene.5Throughstudiesitwas
determinedthatnaphthylvinyletherswithelectrondeficientalkenesprovidethe
highestyieldof[3+2]cycloadditionproducts.8
Theseresultsleadtoaninterestinincorporatingbiologicallyactivearomatic
systemsotherthanthenaphtholgroup.
Figure4:Variousbenzoxazolesandabenzothazolethatcouldbeutilizedinthecycloadditionreaction
Byincorporatingbenzoxazoles(8and9)andbenzothiazoles10intothemulticyclic
scaffolditmaybepossibletocreatenewcompoundsthatexhibitusefulbiological
utilityfromverysimplestartingmaterials.Thispaperwillfocusonthe
photoprecursorcreatedutilizing2‐methylbenzo[d]oxazol‐6‐ol9.
O
O
O
O O
H Oh!
110°C
[3+2] cycloaddition
27 28 29
N
O
O
N
S
N
CH3 CH3 NH2
8 9 10
10
Figure5:Pharmaceuticaldrugswithsimilarstructurestothatofthescaffoldcreatedbythe[3+2]cycloadditionreaction.
Manypharmaceuticaldrugsrelyonaspecificmotiftoimbuebiologicalactivity.
Differentcompoundsincorporatingthesamemotifwilloftenexhibitsimilar
biologicalactivity.Thusthesamemulticyclicscaffoldisfoundinthestructuresof
morphine11,dextromethorphan12,andlevomethorphan13.Thegoalofthis
projectwastopreparemulticyclicscaffoldssimilartothatfoundintheopiods
whichalsoincorporateabioisostericreplacementforthecatecholgrouputilizedby
morphineanditsanalogs.
H
O
HO
N
HO
H
O
N
N
O
llevomethorphanmorphine dextromethorphan
11 12 13
11
Thefollowingsyntheticschemewillbeused:
Figure6:Syntheticschemefollowedanddiscussedinthispaper
O
OH O
O
Et
O
R
O
R
O
EtOH
p-TsOH 2. H2O
H2O2
NaOH
1. RMgBr
R=
O
HO OH
NHO
O
N
HO
NH2OH!HCl, CH3COONa
H2O, D
1. POCl2, CH3CN-DMF <30°C2. CH3COONa, H2O
O
N
HOO
N O
HO
O
R
KH, DMPU, THF
", #6hrs
O
NO
OH
O
O
NO
OH
O
O
H
O
NO
OH
O
CO2Et
1. O3, CH2CH2, -78°C2. CH3SCH3
NaH/DMSOPh3P=CHCO2Et
O
R
O
O
N
O
OH
H
CO2EtO
NO
OH
O
CO2Et
h$, RT, Pyrex
14 15 16 17
18 19 9
9 17 20
20 21 22
22 23
12
ResultsandDiscussion:InordertopreparephotoprecursorsforthePhotoinitatedIntramolecularYlide‐
AlkeneCycloadditionReaction,thefollowinggeneralsyntheticmethodwas
utilized.9
Figure7:Syntheticroutefortheproductionof6(3butenyl)7oxabicyclo[4.1.0]heptan2one
Compound14wastreatedwithp‐toluenesulfonicacidtoprovide15.This
compoundunderwentaGrignardreactiontoform16.Thisreactionwasinitially
difficultasitwasfoundthatthesolventusedwaswetandquenchedtheGrignard
productassoonasitwasformed.Onceanhydroussolventwasobtainedthis
reactionproceededwithgoodpurityandyield(73%).Facialepoxidationof16
provided17in33%yield.Theepoxide17canbeusedasastartingpointfor
synthesisofavarietyofsubstitutedalkenesystems,whichcanbefurtheremployed
inthephotoinitiatedintramolecularylide‐alkenecycloadditionreaction.
Figure8:Proposedproductsof[3+2]cycloadditionreactionutilizingvariousbenzoxazolesandabenzothiazole
O
OH O
O
Et
O
R
O
R
O
EtOH
p-TsOH 2. H2O
H2O2
NaOH
1. RMgBr
R=14 15 16 17
N
O
O
OH
H
CO2Et
O
N
O
OH
H
CO2Et
N
S
H2N
O
OH
H
CO2Et
24 25 26
13
Inthiscase17wascoupledwith3‐(but‐3‐enyl)‐2‐(2‐methylbenzo[d]oxazol‐6‐
yloxy)cyclohex‐2‐enone9tocreate18.Compound9wasmadethroughatreatment
of2,4‐Dihydroxyacetophenone18withhydroxylaminehydrochlorideandsodium
acetateinwateratroomtemperaturetoproduce(E)‐1‐(2,4‐
dihydroxyphenyl)ethanoneoxime19in91%yield.10
Compound19wasthentreatedfurtherwithN,N‐Dimethylacetamideand
Phosphorusoxychloridetoproduce3‐(but‐3‐enyl)‐2‐(2‐methylbenzo[d]oxazol‐6‐
yloxy)cyclohex‐2‐enone9(67%yield).
Theepoxide17wasthencoupled,viaabasecatalyzedepoxideopening,with9to
giveriseto20whichwillbefurthertreatedtoprovideaphotoprecursorthatcanbe
utilizedtocompletethe[3+2]photoinitiatedylide‐alkenecycloaddtionreaction.
10Fujita,S.;Koyama,K.;Inagaki,Y.Synthesis1982,1,68.
O
HO OH
NHO
NH2OH!HCl, CH3COONa
H2O, D
18 19
NHO
O
N
HO
1. POCl2, CH3CN-DMF <30°C
2. CH3COONa, H2O
19 9
14
Figure9:Syntheticroutefortheproductionof3(but3enyl)2(2methylbenzo[d]oxazol6yloxy)cyclohex2enone
Compound20wasfirstproducedinfairlylowyieldandwithoutverygoodpurity.
After20hasbeenpurifiedthesidechainwillbeconvertedanaldehydewhichin
turnwillundergotheWittigreactiontoprovidephotoprecursor23.
Oncethishasbeendone,and23hasbeenpurified,asamplewillbesentfor
biologicaltestingtodeterminewhetherthisproducthasanymedicallyrelevant
biologicalactivity.
O
N
HOO
N O
HO
O
R
KH, DMPU, THF
!, "6hrs
O
R
O
9 17 20
O
NO
OH
O
O
NO
OH
O
O
H
O
NO
OH
O
CO2Et
1. O3, CH2CH2, -78°C2. CH3SCH3
NaH/DMSOPh3P=CHCO2Et
O
N
O
OH
H
CO2EtO
NO
OH
O
CO2Et
hν, RT, Pyrex
20 21 22
22 23
15
Methodology:GeneralMethods.Highresolution1HNMRspectrawereobtainedusingaBruker
500MHzNMRspectrometer.Chemicalshiftsarereportedinppm(δ)relativeto
tetramethysilaneat0.00.Thegeneralexperimentalproceduresincludedequipment,
analyticalmethods,andsolventandchemicalpurificationprocessesthathavebeen
reportedelsewhere.8Unlessotherwisenoted,solventremovalwascarriedoutona
rotaryevaporatoratreducedpressure.InfraredspectrawererecordedonaBruker
Vertex70InfraredSpectrometerwitha4cm‐1resolutionscanningfrom4000to
650cm‐1over10scans.Analyticalthin‐layerchromatographyweredoneonpre‐
coatedsilicagelplates(0.25mmthickness)witha254nmfluorescentindicatorand
werevisualizedunderaUVlampand/orbystainingwithp‐anisaldehyde.Flash
chromatographywasruninasilicagelcolumnonanAnaLogixIntelliFlash280.
16
3ethoxy3cyclohexenone(AEVI002)
1,3‐cyclohexanedione14(67.5g,602mol)wasdissolvedin100mLofethanolover
lowheat.Thiswasaddedtop‐toluenesulfonicacidmonohydride(2.76g,14.5
mmol)dissolvedin900mLoftoluene,andheatedinathree‐neckroundbottom
flask(2L)fittedwithadeanstarktrapandcold‐watercondenser.Thereactionwas
heatedatrefluxfor1.5handtheazeotropeoftolueneandethanol(~15mL)was
removedapproximatelyevery10min.Themixturewaswashedfourtimeswith100
mLportionsof10%NaOHinsaturatedNaClwater.Theaqueouslayerwaswashed
with100mLportionsofwateruntilthepHtestedneutral.Theaqueousphasewas
dried(Mg2SO4).Removalofsolventfollowedbydistillationprovidedapaleyellow
oil,3‐ethoxy‐2‐cyclohexenone15(50.4g,60%).1HNMR(CDCl3,600MHz)δ1.36(t,
3H),1.97(t,2H),2.37(dt,4H),3.90(q,2H),5.34(s,1H).
O
OH O
O
Et
EtOH
p-TsOH
14 15
17
3(3Butenyl)2cyclohexenone(AEVI012)
Toavigorouslydried100‐mLround‐bottomflaskfittedwithaClaisenadapterand
water‐cooledrefluxcondenser,undernitrogen,wasaddedfinelychopped
Magnesium(2.52g,104mmol)inanhydrousTHF(18mL).4‐Bromo‐1‐butene(6.95
mL,68.4mmol)wasaddeddropwiseviasyringe.Avigorousexothermicreaction
wasobserved,afterwhichanadditionalportionofanhydrousTHF(18mL)was
added.Themixturewasstirredunderexothermicheatuntilthereactionsubsided,
andsubsequentlystirredatroomtemperature,foratotalof30min.2‐
cyclohexenone15(7.06mL,47.0mmol)wasaddeddropwise,anduponaddition
theformerlycloudyreactionmixtureclarifiedbecomingolive‐greenincolor,with
theevolutionofheat.Thereactionmixturewasstirredovernightatroom
temperature.Saturatedaqueousammoniumchloridesolution(20mL)wasadded.
TheproductwaspartitionedbetweenDCMandsaturatedaqueousoxalicacid.The
aqueousphasewasfurtherwashedwithwaterandbrineanddried(Mg2SO4).The
productwasdeterminedtobe3‐(3‐Butenyl)‐2‐cyclohexenone16(7.06g,47.0
mmol,73.2%yield).1HNMR(CDCl3,600MHz)δ2.00(m,2H),2.30(m,5H),2.37(t,
2H),5.00(dq,1H),5.06(dq,1H,5.79(m,1H),5.89(t,1H).
O
O
Et
O
R
2. H2O
1. RMgBr
R=15 16
18
6(3butenyl)7oxabicyclo[4.1.0]heptan2one(AEVI026)
Aqueoushydrogenperoxide(1.567mL,33.3mmol)wasaddedtoasolutionof
enone16(5g,33.3mmol)inmethanol(6.285mL).Themixturewascooledto0°C
withstirring.Aqueoussodiumhydroxide(0.571mL,3.43mmol)wasadded
dropwisetothereactionmixture.Thereactionflaskwasthenwarmedtoroom
temperature,andstirredfor2h.TLCanalysis(onsilicagel)ofthereactionmixture
afteronehouratroomtemperatureshowedtheappearanceofaproductspot
(hexanes‐ethylacetate(6:4)).Theresultingmixturewaspartitionedbetween
methylenechlorideandwater.TheproductwasextractedwithDCM.Thecombined
organicphaseswerethenwashedwithwaterandbrine,andthendried(Mg2SO4).
Productwascharacterizedanddeterminedtobe6‐(3‐butenyl)‐7‐
oxabicyclo[4.1.0]heptan‐2‐one17(0.073g,33.33%).1HNMR(CDCl3,600MHz)δ
1.60‐2.24(m,10H),2.51(dt,1H),3.11(s,1H),5.04(q,2H),5.74‐5.85(m,1H).
O
R
O
R
O
H2O2
NaOH
16 17
19
(E)1(2,4dihydroxyphenyl)ethanoneoxime(AEVI019a)
Toasolutionofhydroxylaminehydrochloride(2.71mL,65.1mmol)andsodium
acetate(9.06g,110mmol)inwater(15mL)wasadded2,4‐
Dihydroxyacetophenone18(3.00g,19.7mmol)andwater(20mL).Thesolution
washeatedatrefluxtemperaturefor75minafterwhichproductwasextractedwith
ethylacetate.Thecombinedorganicphaseswerewashedwithwater,brine,and
dried(Na2SO4).Removalofsolventprovided(E)‐1‐(2,4‐dihydroxyphenyl)ethanone
oxime19(3.00g,91%yield)asalightorangesolid.1HNMR(DMSO‐d6,600MHz)δ
2.19(s,3H),6.24(s,1H),6.32(d,1H),7.29(d,1H),9.70(broads,1H),11.20(broad
s,1H),11.76,(s,1H).
O
HO OH
NHO
NH2OH!HCl, CH3COONa
H2O, D
18 19
20
2methylbenzo[d]oxazol6ol(AEVI021)
Asolutionof(E)‐1‐(2,4‐dihydroxyphenyl)ethanoneoxime19(4g,23.93mmol)in
dryacetonitrile(7mL)anddryN,N‐dimethylacetamide(15mL)wastreatedwith
phosphorusoxychloride(3.67g,23.93mmol)overaperiodof2min.Duringthe
addition,thetemperaturewasmaintainedbelow30°C.Theresultingmixturewas
stirredatroomtemperaturefor75min.AqueousSodiumacetate(1.96g,47.86
mmol)wasaddedandstirringwascontinuedfor5min.Thecrudeproductwas
extractedwithethylacetate.Thecombinedorganicphaseswerewashedwithwater,
brineanddried(Na2SO4).Removalofsolventprovidedabrownsolid.
Recrystallizationfromacetonitrileyielded2‐methylbenzo[d]oxazol‐6‐olasalight
brownsolid.9(2.41g,67.6%)1HNMR(DMSO‐d6,600MHz)δ2.52(s,3H),6.76(d,
1H),6.96(s,1H),7.41(d,1H),9.65(s,1H).
NHO
O
N
HO
1. POCl2, CH3CN-DMF <30°C
2. CH3COONa, H2O
19 9
21
3(but3enyl)2(2methylbenzo[d]oxazol6yloxy)cyclohex2enone(AEVI023flash)
Ina25‐mLroundbottomflaskundernitrogen,2‐methylbenzo[d]oxazol‐6‐ol9
(0.027g,0.180mmol)wasdissolvedindryTHF(3mL).Theflaskwascooledto0°C
onanicebath.Asuspensionofpotassiumhydride(0.023g,0.2mmol)inTHF(2
mL)wasaddedtotheflask.Gasevolutionwasobserved.After5minutes,asolution
of6‐(3‐butenyl)‐7‐oxabicyclo[4.1.0]heptan‐2‐one17(0.03g,0.180mmol)indry
THF(2mL)wasadded.DMPU(0.1mL,0.180mmol)wasaddedandthemixturewas
heatedtorefluxfor4h.TLConsilicagel(hexanes‐ethylacetate(1:2))showedthat
theepoxidehadbeenconsumed.Theresiduewaspartitionedbetweenetherand
water.Theorganicextractswerewashedwithwater,withbrine,anddriedover
anhydrous(Mg2SO4).Removalofsolventgaveayellowsemisolid(0.023g,42%).
Chromatographyoftheresultingoilonsilicagel(hexanes‐ethylacetate(6:4))
provided20(0.013g,24.3%).IR(film)3102,2927,1681,1619cm‐1.1HNMR
(CDCl3)δ2.10(m,2H),2,26(q,2H),2.46(t,2H),2.56(m,7H),4.90(dd,1H),5.04
(dd,1H),5.75(m,1H),6.88(dd,1H),6.94(d,1H),7.50(d,1H).13CNMR(CDCl3)δ
14.2,14.4,21.0,22.2,29.7,30.9,31.2,38.4,97.1,112.0,115.6,119.3,136.1,137.1,
144.3,151.5,151.7,155.7,163.1,193.0s.LC/MSm/e298.9(M+).
O
N
HOO
N O
HO
O
R
KH, DMPU, THF
!, "6hrs
O
R
O
9 17 20
22
References1. Schultz,A.G.;Detar,M.B.,J.Am.Chem.Soc.1976,98,3574.2. Schultz,A.G.Acc.Chem.Res.1983,16,210.3. Wolff,T.J.J.Org.Chem.1981,46,978‐983.4. Herkstroeter,W.G.;Shultz,A.G.J.Am.Chem.Soc.1984,106,5563.5. Eberbach,W.;Brokatzky,J.;Fritz,H.Angew.Chem.,Int.Ed.Engl.1980,19,47.6. Padwa,A.;Fryxell,G.E.;Zhi,L.J.Am.Chem.Soc.1990,112,3100.7. Shimizu,N.;Bartlett,P.D.J.Am.Chem.Soc.1978,100,4260.8. Dittami,J.P.;Nie,X,‐Y.;Nie,H.;Ramanathan,H.;Breining,S.;Bordner,J.;
Decosta,D.;Kiplinger,J.;Rieche,P.;Ware,R.J.Org.Chem.1991,56,55729. Dittami,J.P.;Nie,X,‐Y.;Nie,H.;Ramanathan,H.;Buntel,C.;Rigatti,S.J.Org.
Chem.1992,57,1151‐11510. Fujita,S.;Koyama,K.;Inagaki,Y.Synthesis1982,1,68.
23
Spectra
Figure10:1HNMR3ethoxy3cyclohexenone(BCCi001c)
24
Figure11:1HNMR3(3Butenyl)2cyclohexenone(BCCI011b)
25
Figure12:1HNMR6(3butenyl)7oxabicyclo[4.1.0]heptan2one(BCCI016)
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Figure13:1HNMR(E)1(2,4dihydroxyphenyl)ethanoneoxime(AEVI019)
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Figure14:1HNMR2methylbenzo[d]oxazol6ol(AEVI021)
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Figure15:1HNMR3(but3enyl)2(2methylbenzo[d]oxazol6yloxy)cyclohex2enone(AEVI023flash)
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Figure16:1HNMR3‐(but‐3‐enyl)‐2‐(2‐methylbenzo[d]oxazol‐6‐yloxy)cyclohex‐2‐enonefrommicrowavereaction(AEV‐1‐027a)
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Figure17:Dept90NMRof3(but3enyl)2(naphthalen2yloxy)cyclohex2enone(AEVI027b)
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Figure18:Dept135of3(but3enyl)2(naphthalen2yloxy)cyclohex2enone(AEVI027b)
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Figure19:COSEYNMRof3(but3enyl)2(naphthalen2yloxy)cyclohex2enone(AEVI027b)
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Figure20:IRspectraof3(but3enyl)2(naphthalen2yloxy)cyclohex2enone
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Figure21:LCMSofof3(but3enyl)2(naphthalen2yloxy)cyclohex2enone
