Rearrangements of Allylic Sulfones

8/7/2019 Rearrangements of Allylic Sulfones

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RearrangementsofAllylicSulfones:AMechanisticStudyIntroduction

Allylicsulfonesarepotentiallyusefulsyntheticintermediates,withsignificantsyntheticpotential

intheirabilitytoformcarbon-carbonbondsviasulfonylcarbanions1

.TheyhaverecentlybeeninvestigatedfortheirpossibleapplicationinthetreatmentofAlzheimer’sdiseaseviainhibitionof

gamma-secretase,anenzymebelievedtoplayakeyroleincausingAlzheimer’s2.Theyhavealsobeen

investigatedfortheirpotentialoncologicalapplication3.Whileseveralapproachestoallylicsulfone

synthesisexist4,wechosetoexaminetherearrangementofallylicsulfinatestoallylicsulfonesvia

competingionicandsigmatropicpathways.Inadditiontotherearrangementfromsulfinatetosulfone

occurringundermildconditions,varyingthestructureofthecorrespondingallylicsulfinatesseemsto

allowforcontrolofthepreferredreactionpathway,andthereforetheproducts.Manytypesofallylic

sulfinatesaresynthesizedbythereactionofbenzylicandallylicalcoholswithsulfinylchlorides5,making

thisfacilerearrangementprocessapotentiallyinexpensiveandversatilesynthetictool.

SCHEME1.FormationofAllylicAlcoholsfromKetones,andReactionofAllylicAlcoholswithSulfinylChloridestoform

AllylicSulfinates.

Results

Experimentaldatasuggestsadistincttrendinpathwayselectivityforrearrangementin

sulfinates3c-i,withtheionicpathwaybeingutilized100%bysulfinates 3e-gatroomtemperature(~20°

C).Thisdroppedto50%and30%respectivelyforsulfinates 3hand3i;wherebothrequiredfurther

reactionswithprolongedheatingtoproducethecorrespondingsulfones.Sulfinates 3cand3d

rearrangedtotheirallylicmixtureviatheionicpathwayatroughly50%.Anotableexceptionwas

sulfinate3b,whichrearrangedtosulfone 5bviathe[2,3]sigmatropicpathwayat100%.

(1)Simpkins,N.1993.SulfonesinOrganicSynthesis.NewYork:PregamonPress.

(2)Recentexamplesinclude:(a)Jelley,R.A.,etal.,Bioorganic&MedicinalChemistryLetters,2006.16(14):p.3839-3842.(b)Churcher,I.;D.

B.-G.-S.2006.Bioorganic&MedicinalChemistryLetters ,16(2),280-4.

(3)Recentexamplesinclude:(a)Ji,M.,etal.,HelveticaChimicaActa,2003.86(7):p.2620-2628.(b)Powers,J.C.A.,GA,US),Gotz,Marion

Gabriele(Elmhurst,IL,US),Peptidylallylsulfones.2009,GeorgiaTechResearchCorporation(Atlanta,GA,US):UnitedStates.(c)Neamati,N.;

Kabalka,G.W.;Venkataiah,B.;&Dayam,R.2007.PatentNo.PCT/US2007/000560.US.

(4)Recentexamplesinclude:(a)Cheng,W.C.;Halm,C.;Evarts,J.B.;Olmstead,M.M.;Kurth,M.J.;TheJournalofOrganicChemistry.1999.64

(23),8557-8562(b)TrostB.M.;OrganM.G.;O'Doherty,G.A.; J.Am.Chem.Soc.,1995.117(38),pp.9662–9670(c)Jung,S.;Min,J.;Oh,J.T.;

Koo,S.TheJournalofOrganicChemistry.2006.71(13),4823-4828

(5)Li,H.;Dong,D.;Jin,Y.;Tian,S. J.Org.Chem.2009.74,9501-9504

R (E)

RI

R (E) OH

RI

LAH

X

1 2: X = H, D

RI = H, alkyl

S

O

Cl

Et2O, 0° C DCM, -10 to -15° C

R (E) O

S

ORI X

3: X = H, D

RI = H, alkyl





3

Thisproductdistributionoccursastheresultofseveralfactors,includingfunctionalgrouptypeand

proximitytovinylbond,stericlimitations,andthestabilityofcarbocationresonancestructures AandB,

whichformastheintermediatephaseoftheSn1ionicrearrangement.Forexample,allylicsulfinate 3c

displayscarbocationstabilizationduetotheelectronwithdrawingeffectsof3c’sphenylR-group.Based

solelyonthis,onewouldexpecttoseethesulfoneproduct 4cbefavored.However,thesterichindrance

ofthephenylgrouptowardthenucleophilicattackofsulfanionCoffsetssomewhatthestabilizing

effectsofthephenylsubstituent,asispartiallyreflectedinthe1.33:1ratioofsulfones 4cand5c.

SCHEME2.ProposedIonicPathwayforRearrangementofAllylicSulfinate3toAllylicSulfones4and5.

However,onemuststillconsiderthe[2,3]-sigmatropicrearrangementpathway,whichyieldsonly

sulfone5,andaccountsfor43%ofsulfinate3c’srearrangedsulfone5c.Sigmatropicrearrangement

SCHEME3.Proposed[2,3]SigmatropicPathwayforRearrangementofAllylicSulfinate3toAllylicSulfone5.

wasobservedinvaryingdegreesintherearrangementpathwaysofsulfinates3a-d,3i,and3h.In

examiningthe[2,3]-sigmatropicpathway, 3bstandsout,asityielded100%rearrangedsulfone 5

exclusivelyvia[2,3]-sigmatropicrearrangement.Howeverin 3a,averysimilarstructure,thereisgreater

than50%ionicpathwayrearrangement.Both 3aand3bareabletoform3°carbocations.Theansweris

oneofkinetics.Sulfinate3aismuchlesskineticallypredisposedtothe[2,3]-sigmatropicrearrangement

becauseofthepresenceoftwomethylgroupsattheR-position,whichincurlargestericdemand.TheE a

forthekineticrearrangementismuchhigherthanthatoftheionicpathway,andthemajorityofthe

reactionproceedsviaSn1atthemorestable3°carbocation B.Conversely,3bisalreadyinanexcellent

configurationtoundergoa[2,3]-sigmatropicrearrangement.Theobserved100%formationof 5bviathe

sigmatropicpathwaymeanstheEaforthekineticpathwayismuchlowerthanthatoftheionic,butthat

spatialorientationisofgreatimportanceforthereactiontoproceedthus.Oftheallylicsulfinates

studied,3a-ddisplayedthegreatestaffinityforthesigmatropicrearrangement,meaningthese

R (E) OS

ORI X

3: X = H, D

RI = H, alkyl

R

(E)

RI R

(Z)

RI

A B

S

O

O

C

R

(E)

S

RI

O

O

R

(E)

RI

SO

O

4: X = H, D

RI = H, alkyl

5: X = H, D

RI = H, alkyl

O

RI

X

3: X = H, D

RI = H, alkyl

SO

(E)R

R

(E)

RI

X

S

O

O 4: X = H, DRI = H, alkyl



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structuresweremorepredisposedspatially,withfreerotationofthechiralcarbon-carbonbond,and

unhinderedvinylgroups.

Sulfinates3e-gallrearrangedexclusivelyviatheionicpathway.Theshapeofthesecyclic

structuresmakesitnearlyimpossibleforthesigmatropicrearrangementtooccur.Theylackthecorrect

spatialorientation,becausethechiralcarbon-carbonbondislockedinplacebythecyclicstructure.

Additionally,in3gthevinylcarbonishindered,makingitmoredifficultforthekineticpathwayto

proceed.Becauseofthesefactors,theE aforthesigmatropicrearrangementbecomesmuchgreater

thanthatoftheionic,andthereactionsproceedexclusivelyviaS n1carbocationintermediates.

Withsulfinates3hand3i,evengreaterchallengeisencountered,asthestabilityoftheπ-bondis

loweredsignificantlybyringstrain.Both3hand3irequiredreactionwithhydroquinoneandformamide

at100°Cfor24htogivesulfones 4h4i,5hand5i.AstheEafortheionicrearrangementwentup

dramaticallyastheresultofincreasingπ-bondinstability,itmadethereactionincreasinglyendothermic.

Eventually,EafortheionicpathwaysurpassedtheEaofthekinetic[2,3]-sigmatropicpathway,givingan

increasein5h(3:1)and5i(5.7:1)products.

Conclusion Therelativelycleandata,andpredictablemannerinwhichtheseallylicsulfinatesrearrange

undermildconditionsmakesthempotentiallyusefulassyntheticintermediates.Thepotentialuseof

thesesulfoneswithcontroloverrearrangementviafunctionalgroupscouldpossiblyyieldapowerful

carbon-carbonbondformingsynthetictool,providedonecouldcontroltheracemizationofthese

rearrangements.Anotheraspectofinterestisregioselectivityofthesecompounds,whichisof

importancetothebiochemicalandmedicalfields.

Experimental

(E)-4-phenylbut-3-en-2-ol

ToadryAr-flushedroundbottomflaskequippedwithastirbarandaseptumwasadded(E)-4-

phenylbut-3-en-2-one(1.75g,12.0mmol)6and30mLofanhydrousdiethylether.Theresultingstirred

solutionwascooledto0°Cinanice-waterbath.TothissolutionwasaddeddropwiseLAHindiethyl

ether(3.33mL,0.40mmol).After1h,asaturatedaqueoussolutionofNH 4Clwasadded,carefully

quenchingtheexcessreducingagent.Theicebathwasremovedandthemixturewasstirreduntilthe

aluminumsaltscoagulated.Theetherealsolutionwaspouredoffthesalts,andthesaltswerewashed

severaltimeswithether.ThecombinedetherealsolutionwaswashedwithbrineanddriedoverMgSO 4.

Theetherwasremovedundervacuum,giving1.56g(89%)ofcrudealcohol.Productwaspurifiedvia

chromatographyonsilicagel,elutingwith5:1hexanes/ethylacetate,giving1.29g(73%)ofdesired

alcoholofadequatepurityforuseinnextreaction.TLC(5:1hexanes/ethylacetate):R f =0.22.

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HNMR(300MHz,CDCl3):δ7.42-7.22(s,5H);6.79-6.56(doublet,J=16.12Hz,1H);6.32-6.23(doubletof

doublets,J=6.45Hz,1H);4.57-4.45(seriesofmultiplets,J=5.27,2.93,1.17Hz,1H);1.58(s,3H);1.40-1.37

(doublet,J=6.44Hz,3H).13CNMR(75MHz,CDCl3):δ136.9,133.7,[129.6,128.7,127.8,126.6],69.2,

23.7.

(6)AcrosBrand:trans-phenyl-3-buten-2-one,C10H10O,Lot#A011527501



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(E,Z )-4-phenylbut-3-en-2-yl4-methylbenzenesulfinate

Toadry,Ar-flushedroundbottomflaskequippedwithastirbarandseptumwasadded(E)-4-

phenylbut-3-en-2-ol(0.76g,5.97mmol),triethylamine(0.86mL,6.24mmol),anddichloromethane(50

mL).Thisstirredsolutionwascooledto-10to-15°Cusingasalt/icebath.Toanotherdry,Arflushed

flaskwasaddedp-toluenesulfinylchloride(1.0g,5.72mmol)anddichloromethane(12mL).Thissolution

wasaddeddropwisetotheoriginalsolutionviasyringe.Theresultingstirredsolutionwasmaintainedat

approximately-15°Cfor1.5h.Thesolutionwastransferredtoaseparatoryfunnelwiththeaidof20mL

ofdichloromethane.Thesolutionwaswashedwith3MHCl(1x10mL),saturatedaqueousNaHCO 3(1x10

mL),andbrine(1x10mL).ThesolutionwasdriedoverMgSO 4,andthesolventremovedundervacuum,

giving1.47g(84%)ofcrudesulfinates.Thecrudematerialwaspurifiedbychromatographyonsilicagel,

elutingwith10/1:hexanes/ethylacetate,giving0.21g(12%)diastereomericsulfinates(1.33:1byNMR).

TLC(5:1hexanes/ethylacetate):R f =0.12,0.25(twospots).1HNMP(300MHz,CDCl3):δ7.8-7.7

(doublet,J=8.1Hz,1H);7.50-7.13(seriesofmultiplets,2H);6.38-6.31(doublet,J=16.11Hz,1H),6.14-

6.04(doubletofdoublets,J=8.2Hz,1H);6.00-5.88(seriesofmultiplets,1H);5.78-5.68(doubletof

doublets,J=5.86Hz,1H);4.64-4.59(doublet,J=9.38Hz,1H);4.17-4.09(quadruplet,J=7.04Hz,1H);3.89-

3.79(quintuplet,J=7.03Hz,1H);2.435(s,1H);2.41(s,1H);2.39(s,1H);1.78-1.74(overlappingdoublets,

J=1.77and6.32Hz,5Hperdiastereomer);1.73-1.70(doublet,J=6.34Hz,1H);1.40-1.36(doublet,J=6.44

Hz,1H).GCMS:13.175-13.205min(peaks:302,278,155,139,123,91m/z;17%);13.329-13.64min

(peaks:285,131,91m/z,34%);14.627-14.684min(peaks:285,131,91m/z,49%).C 17H18O2Scalcdat

285.4g/mol.13CNMR(75MHz,CDCl3):overlycomplicated,1.33:1diastereomerratio 4c/5c.

(E,Z )-1-methyl-4-(4-phenylbut-3-en-2-yl)sulfonyl-benzene&(E,Z )-1-methyl-4-(1-phenylbut-

2-en-1-yl)sulfonyl-benzene

Thepreviouslypurifiedmaterialwasagainelutedonsilicagelbychromatographywith5:1:

hexanes/ethylacetatetoinducefurtherrearrangement8

.Uponsolventremovalviavacuum,0.17g(81%)ofpurifiedsulfones4cand5cwereobtained.TLC(5:1hexanes/ethylacetate):R f =0.16,0.25(two

spots).1HNMP(300MHz,CDCl3):δ7.75-7.7(overlappingtriplets,J=8.49,1.76Hz,1H);7.52-7.13(series

ofmultiplets,3H);6.40-6.30(doublet,J=16.12Hz,1H);6.287(s,1H);6.264-6.6238(doublet,J=6.16Hz,

1H);6.14-6.04(overlappingdoublets,J=8.2Hz,1H);5.99-5.88(overlappingquadruplets,J=7.33,1.26Hz,

1H);5.80-5.66(overlappingquadruplets,J=7.03,6.45Hz,1H);4.64-4.59(doublet,J=9.38Hz,1H);3.91-

3.79(overlappingquintuplet,J=7.03Hz 4c&5c,1H);2.435(s,1H);2.41(s,1H);2.39(s,1H);1.78-1.74

(overlappingdoublets,J=1.77and6.32Hz,1Hperdiastereomer);1.58-1.37(seriesofmultiplets,2H)

GCMS:13.188-13.193min(peaks:285,278,155,139,123,91m/z;12%);13.348-13.359min(peaks:

285,131,91m/z,34%);14.679-14.685min(peaks:285,131,91m/z,54%).C 17H18O2Scalcdat285.4

g/mol.13CNMR(75MHz,CDCl3):overlycomplicated,1.33:1diastereomerratio 4c/5c.

(8)Padwa,A.,W.H.Bullock,andA.D.Dyszlewski.TetrahedronLetters,1987.28(28):p.3193-3196.



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WorksCited:

Cheng,W.-C.,etal., AllylicSulfonesinSolid-PhaseSynthesis:PreparationofCyclobutylidenes.The

JournalofOrganicChemistry,1999. 64(23):p.8557-8562.

IanChurcher,D.B.-G.-S.(2006).4-substitutedcyclohexylsulfonesaspotent,orallyactivegamma-

secretaseinhibitors.Bioorganic&MedicinalChemistryLetters ,16(2),280-4

Jelley,R.A.,etal.,3-Substitutedgem-cyclohexanesulfonebased[gamma]-secretaseinhibitorsfor

Alzheimer'sdisease:Conformationalanalysisandbiologicalactivity.Bioorganic&MedicinalChemistry

Letters,2006.16(14):p.3839-3842.

Ji,M.,etal., AllylicSulfonesContainingTrieneMoietiesasKeySynthonsforCarotenoidSynthesis.

HelveticaChimicaActa,2003. 86(7):p.2620-2628.

Jung,S.-Y.,etal.,StereoselectiveSynthesisofAllylicSulfonesviatheOxonia-CopeRearrangementof

HomoallylicAlcoholsContainingaHomoallylicSulfoneMoiety.TheJournalofOrganicChemistry,2006.

71(13):p.4823-4828.

Neamati,N.,Kabalka,G.W.,Venkataiah,B.,&Dayam,R.(2007). PatentNo.PCT/US2007/000560. US.

Padwa,A.,W.H.Bullock,andA.D.Dyszlewski, Allylic1,3-rearrangementofthiophenylsubstituted

sulfones.TetrahedronLetters,1987.28(28):p.3193-3196.

Powers,J.C.A.,GA,US),Gotz,MarionGabriele(Elmhurst,IL,US), Peptidylallylsulfones.2009,Georgia

TechResearchCorporation(Atlanta,GA,US):UnitedStates.

Simpkins,N.S.,SulphonesinOrganicSynthesis.Vol.10.1993,Oxford,England:PergamonPress.

Trost,B.M.,M.G.Organ,andG.A.O'Doherty, Asymmetricsynthesisofallylicsulfonesusefulasasymmetricbuildingblocks.JournaloftheAmericanChemicalSociety,1995. 117(38):p.9662-9670.

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Rearrangements of Allylic Sulfones