01Science by n-FAC

REACTIONSOF SUBSTITUTEDCYCLOHEXADIE NES

by

SUNNY M. OGBOMO B.Sc.{Honou rs),BendelState University,

Ekpoma,Nigel ia.

A thesis submitted to the Schoolof Graduate Studiesin partial lulfilmentof the

requirementsfor the degreeof Master01Science

Departmen t of Chemistry MemorialUniversity of New foundl and

July1995

St. John's Newfoundland

.+.

^ofCanadaAcquiSitionsand DirectiOndesacquisilionsEll BobhOl1rapticseveeeBranctl dessevcesbibiograpt\iQl.m :J'6~9reeI :J95,rue~

:l:':;~.f"·l0 ~~)

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ISBN0-612-13933-6

Canada

TheDiels-Alde rrea ction or cis-cyclohexa -3,5-diene-1.2-ciolderivative s 50,51,40a.41aand428withdiethylazodlcamcxytate (D EAD)gavevery predo minantlypro ducts56,58,59,60and62,whicharosebyaddition10 the oxygenfuncncna.

Similarly,cs-cvcichexa-a.s-oiene.t.z-oorderivatives50,51, 40a,413 , 42a,and benzeneoxide- oxepln48reactedwith4·p henyl·',2,4·triazoline-3,5·

diane{PTADl109toaffordantiadducts70,68,70,71and69excluslv e'y,and theantiadducl66was the predominantproductIn the case ofdiene50.

Moreove r, therewasareversalof selectivity whenthecis· di o149 reacted with PTAD,the predom inantproduct64aroseby additionsyntothe oxyg en

wncncn

Thestructures of theadductsweredeterminedbynmr,andX-ray cry stallographyin the case s 0172,67,and64.Whitetheantiselectivi ty was rationafiz edinterms of elect roniceffects.hydrogenbondingexplained thesyn selectivityobtainedwithdiene49_

The acetonide40aanditsDiels-Alderreac tion withdlenopblle s are de scribed.TheexperimentsIndica tedtha t theace tcnldedimerizedin aDtels- Alder manneraffordingtwo productsIna ratio016:1.Themajordimer wasthat inwhich additionoccurred10the aoUlaceof both reactingpartner s.

Theresults 01Diets-Alderre actions ofacetonlde408withPTAD,DEAD, dime thylacethylen eotcarb oxylate (oMAo),tetracy anoelhy lene(TeNE)andethyl

respectively.Whenbutenone,benzoquinone,meretmtne andN- methylmaleimidewereused, the predominantproductswereantiadduets,but selectivity was infavorofsynwith vinylenecarbonate andtherewasno selectivity whendimethylmaleatewasused.lone pair-lone pairl.e.electronic factorisInvoked toexplain these selectivities, ananemauverationalizationis in terms of electro n-dona tingand electron-withdrawingettects .

A stud yoftheInfluence ofsolventonfacial selectivitywas carriedout usingtheacetonide40awith mejelmlde.Thekineticre sultsindicated that there v-assignificantfacialselectivity whenwaterora polarsolvent wasused but selcclivitywaslessin anon-po larsolvent. A1M solution of UClln100mLwater gay,=, higher se'ecnvity than aSM solutionofUCK).inether,However,selectivity waswith UCiO,in water.Solubilityand concentrationphenomenaareused to ration afeeth ese selectivities.

I would like 10extendmy sincerestappreciationto my supervisor,Dr.D.

JeanBurnell,forhishelpfulinstructionand encouragementduring the courseof myresearch project.

Many thanksaregivento every mem...eroftheBurnellgroup, in particular Messrs.JimA.GlIIard andDean Stricklandfortheir support.

Iam InceptedtoDr. C.A.Jablonski andMs. NatalieBrunet for300 NMR spectra,toDr.B.Gregoryand Ms.M.Baggsfor mass spectra, and toOr.J.N.

Bridson forX-ray structures.

I thank my wife. Joan,and alsoElizabethKamar for typing the manuscript.

Financial support frombothMemorialUniversityandDr.D.Jean Burnell isgratefully acknowledged.

page Title .. ..•.

Abstract. Acknowledge ments Tat/eof Contents•.. listof Figures,,..

Lis tof Schemes .

List of Tables ... Glossaryof Abbr"vlat/o ns.. . . Dedication..... . •..

...ii .iv

..vii . ...ix xii ...• •...• ••. ..•. .xiii .. .. xv

(1.0)INTROOUCTION 1

(2.0)Dlels-Alderreact/on. . . . •. . 1

(2.1)Cis-transconformstlon.

(2.2)Stereospecifi cityofthe Diets-AIderreacrton.. ... . •. . ....6

(2.2.1)CIs prin cipl e .....•.. •.• ... . . . 6

(2.2.2)Endo-exostereoselectl vlty. ... .8

(2.3)Subsrftuenteffec ts.. 10

(2.4)Regloselectlvlly. .12

(2.5)Rsl..... . .... 13

(2.5.1)Pressure.• •. ... . 13

(2.5.2)Temperature .•.. .... .•..•.•. . . ... . .•.. . .. ..15

(3.0) n·Facfai SelectIvity. ..17

(3.1)Carbocyclicflve.membered rIng systems...•. . ..20

(3.2)Heterosubstltutedcyclopentsd lenesystems. . . ... 21

(3.3)Substituted 1.3.cy clohe xsdi ene systems 24

(3.4)Multlcycllcsyst ems. . •29

(3.5)Theories... .. ... . . ..32

(4.0)Water and Selectivity .38

(5.0)RESULTS ...42

(6.0)DISCUSSION.. 75

(7.0)EXPERIMENTAL. . . 88

(8.0)REFERENCES.. . . . 131

(9.0)Appendices. ... . .... ...•.... ... . 138

page 1. Frontier molecular orbitaldiagrams ofbothendo andexotransitionstates of the Diels·Alderreactionofcyclopentadiene withmaleicanhydride..•3 2. Frontier orbitalenergydiagram fo rnormal,neutralandinverse-electron

demandDiels-Alder reactions

A

=

electron-donatinggroup and X

=

electron'withdrawinggroup 11 3. Orbital Interactio nsIna z-subsrttuted otenecase 13 4. Frontlermolecular orbitalcontrolin regiochemlstry. " 14 5. Secondary orbitalinteraction asstabilizingfactorinreqlocontrot of

Dtels-Atd erreactton 15

6. Syn-anli sterecserecuvnyinthe Die's-Alderreaction of 1,2,3.4,5- pentamelh y!cyclopentadiene withcrerc cnues... ... . . ,19 7. Transitionstate andpropellanestructures. ..•. .. • .. ..31 8. Fukui'spostulateofHOMOelectrondensily distributionsof s-.chloro·

and S-methylcyclopentadiene... ... .• .• .•. .• ,.. .33 9. Kahn and Hehre'spostulateofelectrostaticinteraction .. 34 10. Anh'spostulate .... .. . ...•.,... ... 34 11. Cleplak'spostu late ofthe favored axial attack01anucleop hile 35 12. Rationalization01the syn-adductobtainedIn reaction011,2,3,4,5-

pentachlorocyclopentadiene ,.. . . .. ..36 13. An extension of Cleplak'shyperconjugativeo-bondassletance by

Macaulay andFallis. . ,.., , 37

14. An extension01Cieplak'shyperconjugativea-bond by le Noble ., . ,.38 15. Four possibleadducts in dimerization01the acetonideand benzylidene

dienes.•... • •... ..•.•...•.•.. .... •.. . ... ...•. ,.. . .70

16. Perspectiveview0167.. 17. Perspective viewof64.

... .. 57 ..58

18. Perspective view of 72. .62

19. Perspective viewof87. .... 73

20. Perspective view of88. .73

21. Possibleorientationofnitrogendtenophtreswithdial49and its derivatives. .. ... ... ... ... .. ., ,76 22. Highest occupiedasymmetric molecularorbital'sfor thesynandanti

additionsto theeponoe, ...78

23. Hydrogenbondphenomenon asa stabilisingfactor forsynaddition

of dial. ...79

24. Possibleaddilio ns01acetytenlc otenophtleswiththe acetonide .. .80 25. Possible additionsof ethylenlcdienophlles withthe acetonlce , ..81 26. Possible additions of the acetonlde duringdimerization ..•82 27. Electron-donating andeleclron-wJthdrawingphenomenonin5-

acetoxycyclopentadleneeanddial49and its derivatives 84

28. Conformationsof cyclic dlenes .85

page 1. Diels-Alder reaction of1,3-butadiene withethylene 1 2. Dimerization ofz-memyr.t.a-cotacrene (isoprene) 2 3. Dlmertzation of tenachlorocycropent adlenone. . 3 4. Reaction of cyclopentadienewith para-benzoquinor:e toafford 4 4 5. Diels-Alderreaction ofcyclopentacie ne anddiethyl azodlcarbcxytate..4 6. 1,3·Butadieneconformations.

7. Sequenceof reactivityof dienes. B. Cisprinciple.

. 5

...6 ... ... . .... ... .... . ... ...7

9. Retention of stereochemicalintegrityin dlenes. . ..7

10. Endo-exostereoselectivtty.. . 6

11. Diels-Alder reactionof furan withmaleicanhydride. ... ..10 12. Thereqtoselectivtty of unsymmetrically substituteddienesand

orencornes , ... . 12

13 . Isomerization of dicyclopentadiene.. . 16 14. Diels-Alderreaction of 5-acetoxycyclohexadienewith ethylene .20 15. Diels-Alderreaction 01s-rretrwtcyclccentectene awilh

maleic anhydride.... ... ... ... .21 16. Diels-Alderreaction of1,2,3,4,S-pentamethyl-cyclopentadiene10with

maleicanhydride.... 21

17. Diels-Alder reactionof heterosubsfltutedcyclopenteolenesystemwilh

mejetcanhydride.. . 22

18. Diels-Alderreaction of14withdienophiles ... . .23

benzoquinone ...23 20. Diels-Alder reaction ofs-naiccvcrcceruecreneswith some dianophilas.25 21. Diels-Alderreaction of 5-flourocyclopentadlene 20 with ethylene... ..26 22. DieIs-Alderreaction 011.z.a.e.s-pemacmorccvccpentarnene21with

somedienophiles. . .27

23. Diels-Alderreaction 01dial derivative22with NPM ..28 24. Dials-Alder reaction of diene diacetata23withchiral

heterodienophile 24.. . 28

25. Dlels-Alderreaction ofsomesubstituteddialderivatives withdimethyl

acetytenedrcarboxylate(DMAD) .. ..29

26. Dials-Alder reactionsofpropellanes. .. 30

27. Dtels-Ad erreaction of31with benzoquinone 28. Endolexostereoeerecwny.

..31 ..40 29. Dibromodiol35from benzene

30. Derivattzancns 01dibromodial 35 .

..42 ..42 31. Further derivatizationsof dlbromodiol35

32. Dienesfrom differentderivativesof dibromodiol..., 33. Method lorthe preparationofbenzeneoxide-oxeptn 34. Derivatizatian ofce-cyctcnexe-a.s-crene- t ,2-diol ...

35. DIets-Alderreectcnaf derivatives ofdial with DEAD. 36. Diels-AlOerreaction40a,50 and 51with DEAD 37. Dials-Alder reactionot 41a and 428with DEAD

..44 .45 ..46

.. .... ...47 ..46 ...50 ...52 38. Dials-Alderreactionofdial 49anditsderivatives with PTAD59 ... .. 55

40. Dials-Alderreaction0140a.41aand51withPlAO

.... ..56 ...59 41. Diels-Alderreactionof benzylidenediene42aar.dbenzene oxide48

withPTAD .. .•.. •. . .•... • . . .. • . .. ... ....61 42. Diels-Alderreaction40awithOMAO andbutenone.. •.•. ....67 43. Diels-Alderreaction of40awithbenzoquinone andvinylene carbonate68 44. Diels-Alderreacucn of40awithleNE, styreneand mejetmioe 69 45. Diels·Alderreaction of40awithcis-stilbene,DMMand EP. ...70 46. Diels-AlderreactionofN-methylmalei mideand acetonlde dlmerlzatio n 71 47. Diels-Alder reactionof maleimidewith acetonlde40a... .. . ...73

Listof Tables

1. Hete-catc m directedn-recieuyselectedadductrati os. 2. Summluyof the reactionof 21with

«erccnnes

Page .22 ... ... .27 3. Relative amountsof adductsin % involvedin reactionabove.•.... ..28 4. Rates atdifferentreaction conditions .

5. Relativeamountsofadductsofsubstituteddiol49

.. .39 48 6. Relative amountsof adducts forthereaction of dial49andits deriva tives

withPTAD...•... .... .. ... . .. .. .. .... ..•.. ...•54 7. Results ofcycloadd ilionof the acetonide40awithdifferent dienophiles 65 B. Diets-Alderreaction ofthe aceronide408with malenniceindifferent

solvents . . , 74

Glossary of Abbreviations

Ac acetyl

APT attacneoproton test COSY correlationspectrum

DBU 1,B·diazabicyclo[5.4.Ojundec-7-ene DEAD diethyl azodicarboxylate DMAD dimethyl acetylenedicarboxylate DMF N,N-dimelhylformamide DMSO dimethylsulfoxide EDG electrcn-donatinqgroup EP ethylpropiolate Et ",thyl

EWG electron-withdrawing group

GCIMS gaschrcmatcqraohy-masaspectrometry HOMO highestoccupied molecularorbital IR infrared[spectroscopy}

LU MO lowest unoccupiedmolecular orbital

MA maleicanhydride MP melting point MS massspectrometry mCPBA meta-chloroperoxybenzoicacid

NMA nuclearmagneticresonance[spectroscopy]

n.O.e. nuclearOverhausereffect NPM N-phenylmaleimide PTAD 4·phenyl-1,2,4-triazoline·3,5-dione pTsOH para-toluenesuJfonicacid TeNE tetracyanoethylene THF tetrahydrofuran TLC thin layerchromatography TM S trimethy lsilyl UV ultravio let[spectroscopy)

To my wife,Joan,andmy children,Efosa antiIziegb e.

The Diets·AlderReaction

Cycloadditionsareamongthemostwidely-used reactionsIn organic synthesis,and theirapplicationto synthesis formsthe basts ofmuch research.U.3Cycloaddilionsprovide useful routesforthe creationof a wide varietyof rings.Importantclasses of cyc'oeocmcnsinclude[2+2] photo- chemicalreactionsof alkanes andalkynes, Ihe1,3·dipolar additio nandthe(4+21 thermaladdition.l.3··

The latterclassofcycloadditions,knownoriginallyasIh~"diene synlhesis~,5hasbecomeunivers a llyreco g nized as theDiels·Arl.i~rreaction (Scheme 1),althoughthisreactionmayhavebeen knowntorquite alongtime

~ ...J

~ + 1'1 1

41ts 21ts

- (~\ I- O

Scheme 1. Dials·Alder reectlo nof1,3- butadie newith ethylen e

beforethe work ofDielsand Alder.Its originmay betracedbackto1667 when BertheiotGreportedly claimedareaction01benzenewithdienophiles.The lirsl experimentaldimerization of dienesutilizing2·methyl·1,3·buladiene(isoprene)

Limonene

Scheme2:Dlmerization of2·me~1,3-butadiere~soprene)

couple ofyearslater, Ipatleff!synthesizedisopreneand proposeda scheme whichthenbecamea usefulguide10formotherdimers.Worthy of note was howZinckeand his colleagues¹isolatedperc hloroindenone 3 by pyrolysisof 2,2,3,4,5,5-hexachloro,'·hydroxycyclopent·3-ene+carboxylicacid2 with the elimination of carbonmonoxideanda chlorinemoleculefromthe tetrachlorocyclopentadienoneelmer(Scheme3).

Dimerizalion reactions provedto beof limitedimportance,and theywere replacedby mixedreactions.The firstreactionofthis typewas reportedby Albrecht!in1906,and ItInvolved reactionof cyclopentadlene withpara- benzoquinone(Scheme 4) for whichhe erroneouslyassigned structures5 and 6

~

^{I I}

H I

HO:!

I I

- + -CO -{!HCI

1

dtrrerlzatlon

C~CI

C~CI

CI 0 3

Scheme3:Oimerizationol letrachlorocyclopentadierone

estabJJshedthecorrect structure4.Theyalsopresentedstructure7forthe reaction01cyclopentadieneand diethylazcdicarboxylate '"(Scheme5).The work of DielsandAlder opened a new,verypromising pagein the annalsof organic chemistry,' and theyjointlyreceivedaNobelPrize in1950for their work.1.B

The Diefs-Alder reactionhas becomeone ofthe mostimportant toolsfor the constructionof six-memberedcarbo-andheterocyclicring systems.The Diels-Alder reaclionis a [4

n,

+2nJcycloaddition(Scheme1)in whicha

o.¢

o

C .Ho ~

w;c

H

_LH _

1000,.{, -sso

o

~ ^{H o}

^HH~"

Scheme4:Reactionof cyclopentadiena withpara-oenzoquirone 10afford4.

Scheme5:Diels-Alderreactionof c:yI:lopentadiene 800 diethylazodicarboxylate

The product.which is a cyclohexenederivative,iscalledan adductwhereasthe reactantsareknownasadoencs."

TheDiets-AiderreactionIs a thermallyallowed,stereospecific,suprafaclal processwithaconcerted,one-stepsynchronousor nearlysynchronous:

mechanism.'This is consistent withthe low solventand polarityeffectson the reactionrate,which rules outzwittertonlcintermediates,B.9·,oIn supportof the concertedmechanism³,' .,\!>isthe czs-stereospecuclty andbythe principleof microscopicreversibility,secondary deuteriumkinetic isotope measurements alsoledtothe same mechanistic conclusion Interms ofa concerted reaction.

Cls·t ransconform al/on

t.a-aueerenescan existIn three typesofconformations:sods,s·trans andskewedas shownIn Scheme6,Inthis caseskewedrefers10all non-

H H

H ) j H

_H~ ~H

^{H:x;::CH,H CH}

^,

H H

&Cis s-tmns skev.ed

Scheme6:1,3·buladiene conformations

pla nar forms,as opposedto the othertwo,whichare planar.Molecularorbital calculationshave shownthat thes·transconformerofl,3-butadleneis 2-5

stablethan theplanar

e-as.

butthe energydifferenceis very small."

Onlydienes inthe

s-ee

confo rmationcanundergoaDiels-Alde rreaction.

Thisgeomet ryisnecessary to permiteffectiveorbitaloverlap,electron delocalizationandalsoformationofadoublebondin a six-memberedring.s Dienes which areheld inthes-etsconformationareconsequently morereactive than those whichare not.The reactivityofsomedienesisas showninScheme 7.Cyclopentadieneis morereactive thancyclcbexacnenebecauseit is

Scheme7:Sequenceofreaeti~tyof dlenes

flat whereasthelatter Is puckered.

Stereospecificityof the Dlels-Alderresctlon

The synthetic utilityof theDial s-Alder reactiondepends not only on the factthat Itprovidesaneasy accesstoa widevariety01cycliccompoundsbut also onitsremarkable stereosetectivity.

The cIs-principle:Therelative stereochemistryofa Diels-Alderreact ionadduct can bepredictedbasedonempirical rules.The firstwasformulated by Alder andSteinin1937_This isnow knownastheMas-principle".Therelative stereochemistryofaddends isretainedIntheprodUCt.,

·3.5.13Forexamples,trans

andcisdienophlles givestransandcisadduct(scheme 8).Furthermor e,acis-

O

+" 'C, Co,CH,If -

~ ~

H+

~ C.... H COCH

H"

CO,CH,

CO

CH CO

tHo

a

Co,CR,' H

H

a cis-dienophiIe bothcis SchemeB:Cis principle

Scheme 9:Retention ofstereochemicallntegrlty indlenes trans-l,4·disubslituteddienegives an adduct withtranssubstltuents,and a trans·trans-l,4·disubslituteddtene givesanadductwithcissubstltuents (Scheme9).

statesthat addition proceedspreferentially via theorientation of the addends in whichthere is themaximum"accurmlancn ofdoublebends"."Woodwardand Hottma n'tandsubsequentlyHouk,16Salem"and Alston¹⁸explainedenao selectivitybyinvokingfrontiermolecular orbitaltheory,Le.,byconsiderationof the highestoccupiedmolecular orbitals(HOMO) andlowest unoccupied molecularorbitals(LUMOjofthe addends."Considerthereaction of cyclopentadieneandmaleic anhydridein Scheme10.InFigure1,theprimary

Scheme10:Endo-exostereoseJecti'oity

interaction(incipienta-bonds)areindicatedby solidlines(betweenHOMO and LUMOforbot horientations)inthetransition states,Intheendotransitionstate, thereIs anotherstabilizingeffect,shownbythebroken lines,knownas a symmetry-co ntrolledsecondaryorbitalinteraction,'S.20Thepresenceof the

transitio nstate.Clearly,thisinteractionisnotpresent intheexoorientation

(a)Endo (b).xo

Flgu rel :Frontiermolecularcrbltal diagramsofbothendoand ex o transition slatesof the Oiels--Alderreactionof

~apentadienewithmaleicarYlydride

becaus e thepolar groupis directedawayfrom thediane'sn-system.Dip ole dipole,:!1charg etransferInteractionsbe tweon polargroupsinthe dienop hileand aneas ilypolari zedctene,"electrostatic,^21lnductive,22 sterie,'andgeome trical ccneide rancne'"havebeen suggesled by ethersasresp onsible for theendo selectivity.

The reactionof cyclcpentaoieneand maleicanhydridegives a99 :1ratio oftheendoto exo add ucts;however,the predominanceof oneIsomerbya 99: 1ratiocorresp ondstoa differe nceofless than3 kcaVm olinthe aclivation energy.'Theendorule isviola ted bythe reactionaffuranwilh maleicanhydride (Sche me11).3,11Thereason is thatIhe initiallyformedendaadduct easily dissoc iatesat moderate temperatures, allowing conversionofthekineticproduct

intothethermodynamicallymore stableexoisomer.· Indeed, in someother

Scheme11 ;Diels-Akjerreactionoffinnwi#!maleicantl'tdride Diels-Alder reactions, prolongedreaction timesmay lead to theformationof someexoisomerattheexpense 01theendo.w

SubsUwenfeffects

The successoftheDiels-Alder reactiondependslargelyonstructural featuresofthereaclingcorrccnents."TheDiels-AlderreactionIsmorerapid if thedienebears oneormoreelectron-donatinggroups suchasC6H5,OCH3 ,CHJ,

OAe,N{CH_3l2,etc"andthedienophilebearselectron-withdrawingsubstiluents suchasCOR,eN,N~,C02CH"CHOy ,5Intermsof frontiermolecularorbital theory,theceneHOMOdonates electrondensitytotiledienophile LUMO. erectron-donatingsubstltuenaonthe dieneraise thediane HOMO while electron-withdrawinggroups tower thedienophileLUMO,resultingina smaller energydifference,whichin turn resultsinan increaseinrate. Thiscaseis knownasthe normalDiels-Aklerreaction(Figure2).However,whenthectene anddienophilehavenosubstiluentsthe differenceIntheorbital energies (HOMOandLUMO)ofthedieneanddienophilearesimilar,sobothmodes of additioncantakeplace,albeitslowly.Thistypeofreaction Isknownasthe

Case1 Normal

Case2 Neulral (tm\b stiluted)

Case3 nwrseelectron demand

LUMO

(

LUMO

HOM HOMO

+- 2

HOM

(

/ /LUM

••, LUMO··. ,/

I~_ . ---- - - --- - -- --- --.~ ._••:;.f..,.: ---•••---

-. _{.. ..}

Figure2:Frontierorbital energydiagramfornormal,neutralandinverse- electron-demandDiels-A1derreactions

R=eleetron-donatinggroup andX...electron-withdrawinggroup

an electron-donatingsubslituent. Thistype of cycicaodincnis referredto as an inverse-electron-demandDials-Alder reaction." In thiscase,thedienophile HOMO donateselectrondensity tothe dieneLUMO.

RegJoselectlv lty

The regioselectivilyof reactions of unsymm etricall ysubstituteddienes and dienophiles,such ast-sub stlnrted dlenesand z-substltuteddieneswith methylacrylate'"in Scheme12.canbe ratlonauzecin terms ofresonance

OC2H

60C2HS

^{OC 2Hs}

(

5 CO Me ..CO,Me

6

+ (

~ I

+

I ,

'co

Me

ortho meta 2

H5C'O'(

⁺

Scheme 12:Theregioselectivityof unsymmetricallysubstituteddienesand dienophiles

contributo rsand perturbationmolecular orbitaltnecry"(see Figures 3 and 4).

Secondarymolecularorbita linteractionshavebeen consideredas additional

o ^H,c,oD

.! - ^I · · ..·r

^OMe

')-OMe 0

o

mainlypara

Figure3-:OrbitaliJieractionsIn a 2·sLCstinied diane case

modifyingfactors favoringtheMhoandparaisomers"(Figure 5).This regioseleetivity phenomenon is alsoreferredto asthe ertha/pararule.

Pertubation molecularorbitalcalculationson reqloselectivlrywere carried out by Herndon and coworkers."suennann"utilizedthe frontier orbital approachto accountfor reactivityphenomena. anda similarapproachhasbeen usedby Houk"and Anh²⁸¹⁰revealthe origin of reqioselectlvtty.Hehre"

suggestedthat electrostaticpotentialsinherer:!to the reactants couldexplainthe regioseleclivityof disubslitutedcompounds,

Rates

Generally,rates havebeenknown10be influencedby a numberof factors.Some of the factorsresponsiblelor accelerationof the Dlels-Alder reactionsare:

Pressure:Pressureaffectsreactionsthatare sensitiveto volumechanges,' Somereactionsthat are sloweror do not occur underat normalconditionsare

)C,H, (co, _ Me

~

⁺

.e a ( OM •

••

I I

oc,H, t ^{O C,H0}

.,e _l../ --- --- --- _- ^{O M .} 6 _{I . , ,,} ^~( _{O Me}

0-·-··-·_---- -

mairiyortilo Flgc.n4:FronliermoleetJarortJitalccnlTOlilregioc:hemistry

LUMO

accelerated by highor ultrahigh pressureconditions.Anenormouslyhigh

HSlP C2-~ ^{H OMO H SC2}

⁰

D... ^{( OMe}

secondary _

orbital ~ ~

tnteractio..~ para

Me§ ,

~

Figure5:SecondaryorbitalInteractionas a stabilisingfactor in regiocontrol ofa Diels-A1der reaction

pressure,e.g.10 -20kbar, is alwaysassociatedwith a decreaseof 26·40 cm³/molinthevolume of activation}Anexampleof a reaction whichhasbeen influencedbypressureis the additionofmaleicanhydride10 naphthalene 10 afford anadductin a yieldof 76%ar

tu

^kbar,whereasayield of lessthan 1%

was achievedatatmosphericpressure.'Some reactionswhich occur at about 100°Catatmosphericpressure canbe realized atroom temperature with a pressureof9·10kbar.z

Temperature:Thermochemicalmeasurementsconfirmthat Diels-Alder reactionsare exothermic,in the order of .6.H;::30 •40kcaVmol,butmany reactionsdorequiredrasticccncmcns."Itshouldbe notedthairaising the

While some addends react at roomtemperature orbelow,others require very high temperatures beforethey can undergoany transformation.

A changein reactiontemperature affectsthe isomericratio 01someDiels- Alderreactions. Forexample.lscmertaats-,' of endata exoforms of dlcyclcpentadiene have beenreponeo.v" AI a temperature 01 160·lBO'C, endodicyclopentadienedissociates into the monomer cyclopentadiene,which can yield the thermodynamicallymore stable exotscmer (Schem e 13). Also,

endo

Scheme 13:Isomerizationof dicyclopentadlene exo

thes-transconformer of1,3-butadiene is between 2·5kcarmotlower in energy thanthes-cisccnrormer."Th erefore, thes-transconformation requires this energyin order to be isomerized lnto the s-eis conformation suitable for Dlels- Alder fuaction.w Finally,prolongedexposure of adducts to heat or high temperatures usually leads to dissociat ionor decomposition (relro-Diels-Alder reacucnj."

Cstalysls:Until Yates and seton"in 1960 recognized that some Dials-Alder reactions proceed much more rapidly in the presence of Alel₃it was thought that the Dlels-Alder reaction could beInfluenced only slightly by catalysis."Itwas

subsequentlydiscov ered that thereacti onis also catalyzedby other Lewisacid s suchas(BF,. SnCI••TiCI. ).'Lewis acids not only acceleratetherate but also alterthe isomerdistribu tion (regiochemist ry)when both addends are unsymmetrical.' Whilecis stereospecificityis retainedIncatalysedreactions,the enaostereoselectivity increases,e.g.Ihe proportion of theendoadduct rises from80%withoutcatalysisin the reactionofcyclopentadiene and methyl acrylate10 95% in IheAICI,-catalysed reacucn."

Theexplanation for thesephenom ena Is conta ined infrontie r molecular orbitalchanges.to The Lewisacidcatalystlo wersIhedienophileLUMO energy.

Thisthen allows lor a stronger interacUon betweenthe addends andlowers the activationenergy.'OComplexationbetween the Lewisacidand thepolar groups ofthe dlenophilepolarizesthe dlenophileLUMO(leadingto a furtherreductionof theelectron densityatthe double bond and increased dienophilecharacter), whichthenincreasesthe regioseleclivityand theenaopreference respectlvely.3.13An earlier transitionstateforthe catalyzedreactionisknown to increase dlastereoselectivltyaswell asendo-exorencs."

"-Facial Selectivity

The stereochemistryof the Dlels-Alder reactionhas three controlling factors.Theyare the cis-principle,theencc-prtnclpleandthe rt-tacial stereoselecttvlly.Itis thislast facetthat decides the syrranti isomerism.3

Theissue offacial stereoselectlvlty hasattracted considerableattentionin

fascinatingthat a singleallylicheteroatomsubstituent on thediencphife."or the utene," can controldiastereofac ialselectivity in Diels-Aloer reactions .Studies of facial selectivityin dienes may be groupedintotwo mainclasses. " The firstone involves allylical1ysubstituted cyclic and multlcycllc compounds. andthe second is concernedwithchlratacyclicctenes. This thesis will attempt to cover experimentallyareasrelatedtothelormer.In the latter.conformational ambiguitiesconstitutea majorareaof dispute.

An example01rt-faclalselectivity is demonstratedinthe reactionof l,2,3,4,S-pentamethylcyclopentad ienewith substitutedetnylenlcdienoptntes (Figure 6).37There are two possiblemodesof endo dienophileattackon the dtene. Thetwo possibilitiesdependon the approachof the dienophile with respect to the diene face,givingrise tosyn-antistereoeelectlvity.Synis defined as orenccbne additionto the same side asthe plane-nonsymmetrlcallylic substituentand anti ifit adds to the oppositeside.Oftenboth diastereomersare obtained.

The alternativeapproachto facialstereoselecnon Is 10incorporate a stereogeniccenterwithin the dieneor dlencphlte.usuallyat an allylicposition.

The productsofthe cyclcadditlonare diastereomers becausethe stereogenic centeris buill intothe product." There is no simplerule for predictingthe effects of substlnrents on the facial selectivityof the Dtels-Alder reaction,Considerable controversyexists in this area and there havebeenmanyattempts to rationalize

H

H R1~H

R- L!H M~---c7'.

! l

syn-e~

: :

: ! : !

syn-fece

, ,

~ ^{Me it i "-}

^Me

Me :

, H

i Me

Me r anti-face

!: ~o

R

~H

H Me

R anJjadduct major

FigU'96:Syn-Ai';';stereoselectivityintheOiels-Alder reaction of1,2~,q,5~entame~pentadiene withethylerW:dierophiles

facialeeecevny."Someofthe factorsconsideredhavebeensterlc effects.van derWaals-London attraction, various orbitalinteractions,dipole-dipole, dipole- induceddipole,torsionaleffects (andsec ondary orbitalinteractio nslor conjugated dlencphtles).electronicand electrostatic attractions,rt-orbttal

distortionor tilting,hyperc onjugati veettects.polarizability ,productstabilityanda host of others."

Carbocyclic Five-Membered Ring Systems

In 1955 Woodwardand cow orkers " reported an exclusivesyn-addition product9 from the reactionof5·acetoxycyclopentadiene8with ethylene (Scheme 14).However,noreasonwhatsoeverwasadvancedfor this

26

^0CH3

syn-adduct

•

Scheme14: Dlels-Aderreactionof 5-acetoxycyclopentadiene withethylene

selectivity.Sincethen therehasbeen tremendousprogressin boththeoretical andexperimental work intothe possiblefactorsresponsiblefor facial selectivity.

Thesyn-antistereoselectloninthecyclcaodtions of 5-

methylcyclopenladiene10 wasinteresting. Minorov(lhad reportedhigh facial selectivitywhen10 reactedwith maleicanhydrideto give as a predominant

product11,whichresultedbyadditionantito the C·Smethylgroup(Scheme15).

In a similarreactioninvolving1,2,3,4,S-penlamethylcyclopentadiene12

c{.(o- X~". X-:

o ~~ ~~

10 11 0 0

antl·sndo major

Scheme15:Dials-Alderreactionol5-methylcyclopentadiene8 wlthmaleic anhydride

Me 0

~eH

^HMe

Me'>==t , a

Q

^{Me MeH}M i t ; M e

~u+1

^{0 _ H H}

Me Me H O M e, Me

rO~e

^Me

r~

o

0 0

cI

12 13

anti-sndo major

Scheme16:Dials-Alderreactionofl,2,3,4,S-pentamethylcyclopenta·

diane10withmaleicanhydride

withdienophiles,selectivityalso lavoredtheantJ-endoproduct13(Scheme 16).37 Hetero5ubstltuted Cyclopentsdlene Systems

Asystematicstudyof hetercatcmdirectedn-taciat selectivity was

performedbyMacaulayandFallis. usingdifferenlsubstituentsatthe5·position

Me^__

Me ^x

^{0 Me}

~Me ~ ~X

^Me

^Me

^Me

+ 0_ H H

Me- 9Me ~ ^Me

^Me

r:

^{Me Me}

_~

00 0

'10 anti

Scheme 17:Dials-Alderreaction ofhelerosubstilutedcYClopernadiene system withmaleicanhydride

%endo-syn %endo-anti

entry. X addUd adduct

1 CI 100· 0

2 OH 100 0

3

OCHJ

100 0

4 NH2 100 0

5 NHAc 100 0

6 SH 55 45

7 SMe 10 90

8 SCH2Ph 3 97

9 SOMe 0 100

10 502Me 0 100

Table1.Heleroatom directedx-faciallyselectedadductratios

as showninScheme 17.Thediastereomeric ratios forthe exc lusive lyendo- additionsatmaleicanhydrideare giveninTable 1.

X:zSeR. TeR anti

Scheme 18:Dials-Alderreactionof 14withdienophilas

15 16

Sct-eme19:Dials·Alderreaction of 2,S-dirrethylthiopheres-onde16 withbenzoqulnore

Orbital mixingrule arguments have been extended 10the neteroatom directedtt- tac faletereoselec rivttyexperienced with s-substlnrted-t,3- cyclopentadienes14shown in Scheme18byinvokingthe mixingof0 orbitals01 the carbo n framework with thatof the s-sub sntuents."

Nap erstkaw andcoworkers"estab lishedthat the 2,S-dimethylthiophene oxide16obtainedin situbyperacid oxidatio nof 2,5-dimeth yllhiophene 15 reacted with a numberofdienophilessynto the sulfoxideoxygenof the diane, (Scheme19).It was postulatedthatsi nce there was acompetitionbetween the lonepair of the sulfurand sulfoxideoxygen,the interactionbetween the lone pair andthe diane HOMO led to the observed seleclivity,· 4Productsofthereactions of the(halo)dienes⁴⁵17with variou s dienophiles(Scheme20) were exclusivel y anti.The bromoderivati ve18 reacted100%antibutDMAD gave bethproducts, whenit reacted with chtcrcderivat ives19.¹⁹.•S

MorerecentlyIMcUnton reporteda completereversal of selecnvlty when S-f1uorocyclopentadiene 20reacted withethylene."The adduct obtained was 100%synas showninScheme 21,Williamsonand others³.4s

haveobserved that 1.z.a.a.s-oemectnorccycocentectene 21reacted withsome dienophilesto givemainly thesvo-enaoadducts(Scheme 22 and Table 2).

Substituted1,3-Cy clohexadleneSystems

Gillardandeum ea" studiedthe cycicaodncneof the ptane-ronsymmerrrc six-membere ddiene system22.They foundthat N-phenylmaleimideadde dto the dianeandmany of itsderivatives preferentiallyto tne facesyn10thecis-

x ~ ~ XH

C\+~~ -~~

17=CI,Br,1

OQ;

18

CI

C><

_H

19 _major moor

SCherre20:Dials-Alder reactionof5-habcyclopertadienas withsomedierophiles

F

C\

20 ^+HH

^X--

^HH

~

syn^HHHH

Scheme21:Diels-Alderreacnonof 5·fluorocyclopenladiene20 withethylene

oxyge n substituents(Sc heme 23 and Table3).Theirresultsdemonstratedthai thesyn-directingeffectofsome neterc alom12 is notrestricted to cyclopentadtene derivatives.Theprobablereasonfor the observedselectivityis electronic,becausethere is no otherreasonto expectthedienophile to attack the dianeat themore stenceuyhinderedsyn face.Their resultsparalleled those obtained from 5-acetoxycyclopentadienebyWoodwardandcoworkers." and they areamongthe casesin whichetectrcntcfactorsoveride stenc hindrance,In a relatedreaction,Werbitzkyandcoworkers"reportedtI•..Jtdiane 23 reacted withthe chlrel dienophile1-chloro-1-nilrosomannose24,to give product 25 (Scheme 24)invery high opticalyield.

Bio-oxiuattcnof benzenederivativessuchas toluene.chlorobenzeneetc., withPseudomonasputidahaveproduceddienesof synthetic importance." For example,compounds 26 and 27 in Scheme25 are opticallyactive,and HUdlickyandPnce"^utilizedtheselorthe preparationof enanliomerical1ypure

21 H X

~ ^H

^CICI i & C IHCI

C H CI H

H

X

y

7

^{C H·CI C H}

Y Y

syn-endo anti-endo

:i&

^{C HCI}

C CI

~/

H anti-sxo Scheme22:Dials-Alderreactionof 1,2,3,4,5-pentachlorocyclopenta-

diene21 with some dieoophiles

enlJy dienopt'ile endo-syn%end~nfjC! exo-anti%

1 maleican~ride 91 9

2 acrylorilrile 72 15 13

3 methyl acrylate 53 37 10

4 vinyl acrylate

47 45 7

5 ~rr,ichloride 46 40 14

6 styrene 38 62

7 propene 31 12 57

Table 2:SUllmaryoflhereactionsof21withdienophiles

Scheme23:Diels-Alderreaction of dielderivatives22withNPM

entry R, R2 syn anti

1 H H 94 6

2 Ac Ac B8 12

3 SI(CH3l3 Si(CH3)3

100 0

4 -Si(CH3)2-

85 35

5 -C(CH312-

40 60

Table3:Relative amounts01adductsin%involvedinreactionabove

23 24 25

Scheme24:Diels·Alder reaetionol dianediacetate 23withchiral

"'t.rodi.nop~1e24

prostaglandinsandsugar derivatives.

Pitteletal,uandMahoneta'.~treat ed thefourcenes27inScheme 25

e«

^RH'HOHOH

26

R.Me,CI CH

l

R O OCH H3Cio H

~O\CHl

⁺

1

²

_{~ ~HR}

~\

^{CH , C}

H 3 CO_CH ~CH

-, l C~Cf/33

27

R", H,F,CF3. 7-rotbomadierr,i anti

Scheme25:Dials·Alderreactionsof somestbstitu:ed dialderivatives w;,hdimethylacetylenedicarlloxylate (OMAO)

withDMAO,andthey propo sed matstencreasonswere responsiblefor the exclusivelyantiadducls observ edinallcases.

MUIll~yCIlCSystems

Gi nsburgand Gfeller!demonsl ated how subtleeffects canexertamajor impacton the courseof the Dlels-Alderreactionbymodulatingthebridgehead substituent01thepropellanes.Theyobserved thatInthereactionof propellanes 28inScheme26 withN-phenyltriazolinedione,selectivitywas in favo rofthe syn- syf).bis adduct29.Anexplanationforthis was advancedbyGleiler⁵who

28

X=O.NH.NCH3 . NC6HS

~ ^o

^{+ PTAD _ Ph..}

~~

⁰

1

^PTAO

Ph'~dr

OJY~~N-Ph

29 SCheme26:Diels-Alderreactionsofpropellanes

invoked a secondaryorbital interaction asshown inFigure 7.He statedthaithe interactionbetween the N"'Nlone pairs and the antisymmetricrt"orbital01the

co -x-co

bridge01thepropellanestabilized

the

syn-transilion state.For prope llanes30withX•SO.501treatedwithN-phenytriazolinedioneattackwas 97%syn(Fig u re7). This sele ct ivitycouldnotbe expla inedbyasecondary orbita linteraction,but ratheritwasexplainedin termsofa polargroupeffectin whichtherewasanattraction betweenthestronglyelectrondeficientSatomin the SOand50₂groups andtheelect ronrich -N=N·groupinthedienophile.with theresultingstabilization 01thesyntransitionstae."We mustconsiderthearea

syn-transitionstale

30 X.S.S O.S02 Figure 7:Transitionstateandprop~~lan estructures

r/J -

31

major minor

SCheme27;Diels-Alderreaetionof31 withbenzoquinone

of electron density aroundtheoxygencentersofthe502groupandthe charge deficientregion on eithersideorthe n-planeof thedie nophile.However, Ma caulay and Fallis"slatedthat th eresults obtainedwerecases ofho w neighbouringcouble-bcnoscouldinfluenceselectivity.

Burnelletap eassertedthatthe syn-antistereoseleClivityexperiencedin sp ir o(bicyclo[2,2.11·heptan e -2,1'·[2 .4]cyclopentadienej31wa sdueto a stenc Interaction between the incomingdi e nophil e and hyd rogens onthe diene moiety (Scheme 27).The more favorableapproachwastha t inwhic h the dienophile approach ed thediene moietysyntothe C-3 methyleneofdiane31.^{5 9}The other add uctwas theresult ofenaoaddition to thefaceof the dienemoietysyntothe C-1methine.carcuaucns verifiedthisresult."

TheorIes

Attempts to probetheoriginof facialselectivityhaveculminated in several int eresting raflcnaltzations.In earlyworkbyFukui⁶¹(Figure8),he statedthat the HO MOof s-chc rocyciopentadene was biasedtowa rdsthesynsurface.This presentedtwounequal electron surfacestoanincoming dienophile.Inother wor ds,the non-bon ding orbitalof thes-subsmuent perturbed the HOMO of the dieneand allowed lowlying a-orbitalsof thecarbonskeletontomileintothe HO MO.

Fuku i'scalculationsindicatedthattheHOMOof s-cnrorocyccpeotaotene wasbiasedintheregionsyntothe chlorineatom,therebythesynadductwould

X=CI

be obtained.He alsoindicatedthat since a S-methylsubstituentdoesnothav e

e;j

X=C H3

.C _/~H H"r

ⁿ

anti Figur e 8: Fukui'spostulate 01HOMO electrondensity distri butionsofs-cntcrc-

and s-memylcyctcpentadiene

tone-pair electrons,theHOMOelectrondensitydistributionabove andbelowthe orene wouldbethe same.Theimplica tion of this was that the additionwouldbe expected tobe governed by stenccontrol.Experimen tally,whatwas obtained was theantiadduct,whichinferredthat the additionwas indeedgovernedby sterieeffects :the dienophile would avoidthe staricallyhinderedsynface and attack fromtheantiface.The modelfailedto accountfor the antiadducts obtained in5·bromo·ands-tooocycicpentaenenesystems.

Kahn andHehre"concludedfromanelectrostaticpointof vie w that there wasanInh erent preference torthe additionof efectrophtllc dienophiles to the more nucleophilicface of thedienesynto"Ione-pair-eontainingallylic substituent"(Figure9).Thissimplemodel cannot be extended to sulfur systems.

The Anh⁶³model wasbased onthe assumptionthat theremig h t lie an

attractive inte raction between the tone pair orbitals of the allylicheteroatomand Low

EIeCfrophilicity

Low X .. eleetrorKIonatirg group Y=electron-withdrawirg group

Figure 9:Kahn andHehre's postulate of electrostaticinteraction

the LUMO of the Incomi ng dlenophlle (Figure10).Thissecondaryorbital

Figure 10;Anh'spostulate

interaction stabilizedthesyntransitionstateleading tosynadduct.Thus,Anh's model couldbeusedtorationalize the syn adductobtainedin the 5-

acetoxycyclopentadtene reaction,butitfailedto explaintheantiadducts observedInmany reactions,forexample.thereactionofbenzene cxlce/cxepm withoienophites.sa

Ananalysisof rt-tacianyselectivereactionswhich invokes the inte raction 01the incipientbond withthe twononequlvelent faceswas put forwardby O'eplak"(Figure11).Hestated that thehyperconjugationof the annpenplanar

~r

^vacan

~!-omiml

vaca nt /orbital 0 " , 0

~\

_Nu

favored ^aCH>aCC

Figure 11:Claplak's postulateof the favoredaxialattack of a I1Jc1eophite

a-bond givesriseto transitionstate stabilizationby o-electrondonation into the vacanto'orbitalassociatedwiththeincipientbond. MacaulayS'gave Eplotls list of orde rof increasinga-donor abilityas aCS:>aCH:>aCC:>aCCI:>aeN>

aCO.The Cieplakmodel could be used to rationalizesynattackto chlorinein the reaction of 1,2,3,4,S-pentachlorocyclopentadiene(Figure12).Thiswas becauseoCHis a betterdonorthan oCCI.

t:3

^{1 CI}

^:'1

rotpreierrec CI CI

, I CH>CCI

CI -.../

better

Figure 12: Rationalizationoftresyn-adductobtainedinthe reactionof 1,2,3,4.5-pentachlorocyclopentadiene Macaulay and FaUis⁵?supportedand extended the Cieplakmodel. This extension ofthe Cleplak theory correctlyexplainedtheantiselectivityobserved in sulfursystems. Asin the example,in Figure13,Ihebetter a-donoris the CC bondcompared to theCO bond,thereforeadditionshouldoccuran/ito CC bond hencesyntoCO was formed.In the same fashion, the CS bond is a better o- donor thanthe CC bond, therefore addition should occurant/tothe CS bond, hencetheantiadductwas formed.

La Noble and coworkers" studiedthereaction of butadienewith 5- fluoroadamantane-2·thione(Figure 14).Theycouldnotaccountfor the syn attackof its reactionbased on the electrostaticmodel. Howeverby an extension or the Cieplak model to this system,Ie Noble was ableto explainthis selectivity.

The thermal and photochemicalreactions orbond formation were demonstrated to occuronthe face anti to the moreelectron-ncb o-tone.

; c1)C H 3

C~

~

^{} an6toCCbond}

1

^{andsyntoCObord}

additionantito isespecta daoo observed thebettera- be

cc rcrp reterred

~ :

ecc

>oCO

• .-2 }

notexpected

l) •

^andnotobserved

_ j }

anntoC Sbordand

add itIOnantI10 {

o·

synto theCC observed thebettera-bard

preferred

•• o •• ~ ~~

Figure13:AnexiensionofC ieplak'shyperconjugativee-boro asslstarca byMacaulayaooFallis

d~ ^{x x}

X", efectron-donaVrg group X=eJsctrorrwithdrawirggroup Figure 14:AnextenslonofC leplak'shyperconjugative

a -bord or assistancebyIe Noble

Water and Selectivity

Hopffand Bautenstrauch"in 1942 reportedthefirst Diets-Alderreaction condu ctedin water.Sauer"showedth at for awide rangeofsolventsystems.

thera teofrea ction isonly slightly affec tedby achang e inmedium.Although water has beeeconsidered as apossible solventIn Dials-Alderreactionsever since itwas first used byHoptt,"itspoor solvent propertiesforolenes madeit look~nfavourable.Consequently,in numerouspapersonthesubject, water is absent from thelist ofsolvents under investig a tion,a factwhichundoubte dly discouraged its utilization.⁵⁷

However,In 1980Breslow and hiscoworker" reopened theuse ofwater andreportedremarkableaccelerationbothin rateand endolexo stereoselectivi ty.They attributedthis intriguingresult toa hydrophobic effect.

Table 4 shows thedramatictatechangein switchingfrom theuse ofisooct ane 10wateras solvent

additional ccmocn ent rate entry solvent C)'dopentadlene-+- (k2X 105,,,"1,.1)

euercre.zocc

1 isooctaoe 5.94:.0.3

2 MeoH 75.5

3 H2O 4000.±.70

4 H2O LiCI 10800

5 H2O C(NH2l3+C~ 4300

6 H2O ~-<¥Jod e>drin 10900

7 H2O u-cvco dexrin 2610

Table 4.Rate s atdiffer enl reac tionconditions

withanimprovedrate."Bresl ow and hiscowo rker"alsoreportedthatlithium chloridewhe nadded 10 the water enhancedth erate evenmore,andthey contras tedthiswithguanidium chloride, which has a su rface -tension-reduci ng properties anddecrease dtherate. More evidenceforthe hydrophobiceffect came fromthe use ofa-cycrcoextrln.which is knownto havea hydrophobic cavity.Reactions conductedwitha·cyclodextringave dramaticresults, which paralleledrateenhancementbyhydrophobicbinding ofthe molecules.The reasonfor thesmallrate accelerationin c-cyclooextrtnwas ascribedtothe

}nspite ofthe evidenceforthe hydrophObiceffect.Griecoet^BtUin1983 argued thattheincreasedrate was due to micellaraggregation.Further experiments conductedbyBreslow andhiscoworkers "and others?'showed thatthe hydrophobiceffect was indeedthe phenomenon responsible.Ever since,therehasbeen remarkableimprov ementinutility01 aqueous mediainthe formof mtcroemutslonand aqueoussurfactant- based

mecna."

Grie coand his coworkers"reporteda dramaticrate accelerationofDiets-Alderreactions using lithiumperchlorate in diethylether(LPDE).They proposedthai a~high"internal solventpressurepresentin water was equallypresent in this reagent.Itwas concluded thatDiela-Aideradductsthat could not be accessibleIhrough conventionalmeanswould nowbe possible.In one of theirstudiesusingLPDE a93%yieldwilh anendo:exoratio018:1wasrealized when ethylacrylate and cyclopentadienewasreacted,whereasasimilarreactioninwaterafforded onlya 73%yieldandanendo:exo ratioof4:1(Scheme28).

C ^~Hcn H.l

-Z^El

~IOJ+

^El20 H⁺

rt+

CO:1Et

CO,E t H

enoo

Scheme 28:EndoJexoslereoselectivity 6XO

As an alternativeexplanation,Forman and hiscoworkers"claimed that the rateenhancementby LPDEwas not due to internalpressure but10Lewis acid catalysiswiththe lithiumion functioningas theLewis acid.It Isimportant to note thatlPDE should behandled withcare because a recent reportbySuva"

indicated thatit has anexplosive character.

From the work of Gillardand Burnell"two thingswere remarkable:(a) that the Diets-Alderreaction ofcs-cvcrcnexe-a.s-ctene-t,2·diol andits derivativeswithN-phenylmaleimideafforded adductswhose additionoccurred fromthe morestencally hinderedfaceof the diane.synto the oxygenfunctions, and (b) thatthe facial selectivitywaslesspronounced with cyclic derivatives of this dial.TheresearchdescribedInthisthesis was gearedtowards examining syn·antistereoselectlvlty ofthe same substratesbut with different dienophiles.

Also,forthe first time, the effect of water on facialselectivityusing the cyclic derivatives hasbeen examined.

RESULTS

Synthesisof the dJenes

The dibromodiol35appearedto be an efficientcommonprecursorto manydlenes.Benzene32wasreduced underBirch conditions¹⁶togive1,4- cyclohexadiene33. Additionof onemolarequivalentof bromine in the cold using the procedureby Wibautand Hauk⁷¹afforded34,which was purifiedby vacuumdistillation.Following anestablishedprocedureby Yang and co- workers."cis-hydroxylation0134by potassiumpermanganate scluuon"gave dibromod iot35 in 40·45%yield (Scheme 29).Treatmentof35 withacetic

o ^{LimH~ 0 ~} :: :0

32 33 34

lKM n0

⁴

~ S'''''''.('f--0H

S " - v - O H

H

35 Scheme29:Dibromodiol35lrombenzer.e

anhydride inpyridine provided compound36(90%). Whencompound35was treated withchlorotrimethylsilanein pyridine,37 was obtainedin72% yieldalong withasmall amountof 38(Scheme30).Aphase-transfer reactionutilizinga

procedure byMerz^towith dimethylsulfateasthemethylatingagentresultedin

I

^AcZ_I:l^{HpyO. 38}

Br,•...~OTMS

B~OAC

H 39 37

36

I:l I:l H

B'"....( " i -0Ac B'"....['i-OTMS+Br"...~TMS

Br~OAC B~OTMS

^Br- v - . -OH

H H

Scheme30;Oerivatizalionofdibromodiol35

44

1

TMSCI.

py

B...",,~M.~

B~OTMS

H 46

~ B'''''' ' ( ' ' i - -0M.

Br~OMe

H 43

45

Scheme31.Furtherderivatizationsof dibromodiol 35

B'....".("i--OM.

~

Br~AC

H Bo..".

~~ ~

^...•

⁽⁶⁾

B~ _H

42

.: :q:x©

~

! ^{6 °}

C

"J )2.

41

pTSA

~ BO"''''( Y0H

B~OH

³⁵

1

(CH,Oj, SO,

Br"' '''( ' ' i - -0 H~

B~OM.

H

obtainedas a yellow oilingood yieldby acetonlzanonof3Swith 2,2- dimelhoxypropaneanda cataly ticamount of pTsO H(Scheme30 ).71The benz ylidin edenvatlves" 41and 42were obtained by aclo-catalysed acetauzauc nof35with a large excess of benzaldehydedlmethylacetalfollowed by chromatography. The dibromomonoTMS 38(S chem e 30)and dibr omo moncmethyl44compounds(Scheme 31)were acetylaled toprovide correspondingacerylatedcompounds 39and 45.In thesamefashion.silylatlon 0144afforded 46(Sche me31).•

Double dehydrobromlnatlon"of40.41, and42with 1,8- diazabicyclo(5.4.0jundec-7-ene (CBU)inboiling benzeneyielded dienes40a, 418,and42&(Scheme32). These dteneawerechromatographedon silicagel

Scheme32: Dienesfromdifferent derivati""'es of dibromodlol

to affordpurecompounds.Dienes 408,418, and 42ahaveatendencyto dlmerize, evenin thecold,sothey were usedimmediately.

(Sc heme 33).Epaxidation of34with meta-Chloroper oxybenzoic acdgave47 anddoubledehyd robromina tion withDBUafforded48as amixture of benzene

B Br"" '~

^{n>CPBAB......}

("1.... :o

~ -+er--V""

DBU

0

^''':0."

34 47

Scheme33.MeUY-'dforthe preparation01 benzene oxide· oxepin

oxideand cxepn,itsvalence tautcmer," The'H nmr spectrum01thisproduct displayed a single set ofsignals.whichaccording10Vogelandcoworkers,"

resultedfromaveragingof the signal sof both tautcmers.

Dienes50,51,52and53we reobtainedingoodyields Iromcomm ercially availablecis-cyclo hexa-3,5-die ne-1-2-dioI49byderivatization in a straightforw ard manner (ch lorot rimelhylsilane/pyridineor aceuc anhydrid e/pyridine or dimethylsulfatejas shownin Scheme34.Diol49has beenproducedbystereospec ificmicrobialoxidation ofbenze nebymutants 01

Pseudomonasputida,a soilbactenu m."

1

Pseudomonas pu#da

~Me

V-OMe 53 H+

~

0: '

^OMe

i OH

A

54

~OTMS

~OH A

52

~SCI

a

~

;

^OTMS

1 OTMS H 51

o: ^~ A

^{, OHOH}

49

A)~2a;

I

a ^A

~^OAeOAe 50

Scheme 34: Derivatiza1ion of cis-cyclohexa·3,5·diene-1.a-oict

DJeJs~Alderreactions

TheDiets-Alderreactions of dienes 50 and51 with diethyl azodlcarboxylate(DEAD)55 wereconducted inchloroform (Scheme 35). The

r-Y0R' /CO,EI

R~~ 'O ~~YO'Et

~ + N N

A

^OR2_EIO,C

,,~

^-

J

_I

55 CO, EI

anti major

syn minor

Scheme35.Dials-Alder reaction of derivatives of dialwithDEAD

addld ratio

enlly diene exclusivelyanti. %yield

1 50 a 73

2 51 tOO 43

3 40. 100 96

4 41. roo 54

5 42. 100 50

-adductratio couldnetbe obtained

Table 5.Relative amountsofadductsof substituted dial49

reaction mixture containing50was stirred tor about72 hours atroom temperaturewhile that for51 was stirredfor 24 hours.Thinlayer

chromatography (TlC)of the reactionwith50 indicated two newspots along with sameunreacl ed startingmaterials .Thesolventwasevaporatedand analysis of the crude sampleby'H nmrspectroscopy revealed considerablebroadening of the signals01the putativeadcuctsinthe regiona5.0·7.0sotheir ratio could not be measured .Flashcclumr.chromatography ofthesampleresultedin the Isolation of 56a and 56b ascolorless oils.Their 'H nmr spectra werestill unclear.

Similarly,the 'H nmrspectrumof the crudesampleafterevaporatingthe solventfrom the reacncnof 51Indicatedthe presenceofanti adducts, Subsequentchromatography was problematicasthematerial provedunstable towardsthe chromatographicsystem,However,alight pinkoil was collected and a small amountofthe startingmaterialswas recovered.Rerunning the spectrumof compound 568atsOGeledto simplificationof thespectrum,butat- 70^G

e

more signalswerediscerned.Nevertheless, there was still ambiguity regardingthenumberof differentadductseachcrudeproductcontained.

A benzenesolutionofthe acetonide40awithDEADwasstirredatroom temperature,and subsequentanalysisofthecrude samplerevealed onlyone adduct(Scheme 36).Purificationofthis sampleaffordeda colorless

en sa

in good yield. The completeassignmentofthe'H nmrspectrumof the adductwas done on the basis 01chemicalshiftand nuclearOverhauser effect(nOe)

AcO H

H

AC~

^{yo,El 7(oAC}

et

^"

_H

^{; DACOAe DEAD}

^{"'-N J}

^{1 + H}

^~}o,El

^OAc

CO,El ₁

50 56. 56b C0₂EI

anti ^syn

H

d OTMS^{, OTMS}

-

DEAD ^TMS

TM~H

^HyO,El

H "'-N

61

J

1

Co,Et 57 anfi

~

~CH,^CH,

H 40.

H'C'(C~9%

3 .5%( b~H

~ \~ ;tf'EI

H 1

Co,Et anti 58

Scheme 36,Diels-Alderreaction40a,50and 51withDEAD

experiments.Signalsat 0 6.50and 5.15 were assigne d 10 the olefinicandthe bridg eheadprotons,respectiv ely, whereasthat at04.46 was that forthe acetoxy proton s.Multipl ets at04.26 and 15 1.28arosefrom the methylene andmethyl portionsof themolecule. Saturationof theolefinicsignal at 156.50 enhancedthe intensity of the bridgeheadprotons at(55.15 ppm.Conversely,saturation of the methylsignal gave enhancementoftheolefinic signal. Theseresultsshowed the proximity of the olefinichydrogenstoamethylgroup and clearlyshowedthe adduct was58(Scheme36).

The benzylidenedienes41aor428 reacted with DEAD(Scheme 37).

The 'H nmranal ysisofthe two crudesample sshowedsignalsforadtmerwhich completelymasked the signals forthe DEAD adducts inthe downfield region of the spectrum.Chromatography of eachcrude sampleafforded an oily adcucts 60and 62 anddimers61and 63. Assignmentsof the signals in'Hnmrspectra werecarried out in afashion analogouswiththat previously used for adduct58.

Moreover,correlationspectroscopy(COSY)confirmed theseassignments.

NuclearOverhauserenhancements(nOe)established the stereochemistry of60.

Similar nOe experimentswere performed on62(Scheme37).Saturation of the olefinicsignal gave an enhancementof 0.6% for the phenylsignal. Thisresult confirmedthe stereochemistryInwhich thephenylring was closertotheolefinlo hydrogens l.e., anantiadduct.

There werefour possible modesofdimerizatlonofdienes4Oa, 41a and 42a(Figure 15).Thepredominantproduct in allcasesofdteneewastheonein

¢;g

:~ ^jQ> ~ JdJ

10y-)06% _1o~~>

'R _~H 'o -Z~02E~ I ^(%

H H

~ }:t©

0

0

N '

H I H H

COzEI

60 anti 61 anti H H

d:>P _~

9

H42a

H

_{) 6%} ©l _{/ ~~} l : :r ~ ⁰

0 .6%( ⁰ '""-f'I ^HrOzEl

+

_1%(~,

Ii'

^,

H

^!;fH

H0L),²

^H

. I H ~

~ ^{H 2}

62 antiC~Et 63 anti H H

Scheme37.Dir:rs·A[d~,reaclion of41aan(l 42awithDEAD whichboththediane andthe dienophilepartners wereanti.Inthecaseofthe acetonidediane40a,the selectivitywas 6:1 in favorof thisdimer.Rigorous

~ 4 possibleadducts:

Rl~'

1

0_

H R¹

~

^H

^H

^H

^~R"

^H-HH

~

^H

^{:'~R'~ ir"t}

^{HHH 0H-HHR,}

A

=

anti, S=syn

o

^edlere OP•dienop~1e

So SOP Rl=CH3,R2' CfiJ Rl=H,R2= Ph Rl=Ph,R2= H

Figure15: Fourpossible adductsin dimerizationof the acetonidaand benzylidene dienes

assignmentof the stereochemistryofthe twodimers 61and63 was obtained spectroscopically.Results01nOe experimentswithdimer61 showedthatit resulted fromanti-antiendoadditionof the diane(Scheme37) because saturationof the signalforthe hydrogen atC-12gavean enhancement01C-B (6%), C-3a(5%) andC-G(6%) hydrogenswhereas saturationof the singlet signalatC·Bgave enhancementof0.35%for the phenylgroup.In thecase of dimer63(Scheme 37), enhancements of 0.8%and1%,respectively,of the phenylsignal of c-a and C-3ahydrog en was observed when hydrogens on C-l 1 and C-12weresaturated.Moreover,saturation01hydrogen on C·3aresultedin significantenhancement011% ofolefinichydrogens on C·l1andC-12.

4·Phenyl-1,2,4-triazoline-3,5-dione59is oneof the mostreactive dienophllesknown.Itwaspreparedfrom 4-pheny!urazoleby.he action01t- butylhypochlorite^Uas theoxidizingagent. Sublimation wasused to purifythis dlenophlle,which is intenselyred.

Slowadditionofthe requisiteamountofa solutionof59in acetoneintoa solutionof dianesOled toinstantaneous dischargeof the red colour.The mixturewasnevertheless stirredfor16 hoursafterwhichTLC indicatedtwo spots.The 'H nmrspectrumofthe crudesampleindicatedsignalsfor two adductsin a ratio of9:1.Flashcolumnchromatographyyieldedbothadductsas colorlesssolids.The major one (66)was isolatedin 77% yield andthe minor one(67)In13%yield(Schemes 38 and 39).AnalysisoftheH nmrand COSY spectraofthe two adductsshowedthat the olefinichydrogenwas coupledto the

w - -Z _R,~~H

⁰

_::rc;~~

⁰

II

N-~ JJ..--.j~ • C1--"',t--<

N-,(O

NY~Ph N~-'Ph

59 0 0

anti syn

major minor

Scheme 38:Diets-Alderreaclionof diol 49anditsderivativeswilh,PTAD59

relatiwamol.l"lt ofadduct %~eld

entry R, R2 ^{anti syn}

1 H H ₇₁ : 23 75

2 Ac Ac 90 : 10 90

3 TMS TMS 100 : 0 72

" ' CH, ₁₀₀ : 0 97

4 / C<CH,

H

5

~l'h

^{100 : 0 62}

6 )'h

)c"'H 100 : 0 55

Table 6:Relative amountsof adduetsforthe reactionofdiel 49and its derivativeswithPTAD

a

H

^~

^{i OH}

^OH

49

~-(N-15'

N--( ~ o

60

a 9f~

o

67 syn minor , fdienes49and50withPTAD 39'Dials-Alder reaction0

Scheme .

bridgeheadhydrogen,andthisin tu rn was coupled to theacetcxyprotons.

Irra diation of theolefinichyd rogengave an enhancement of 0.2%of the acetate group.This showedconclusively thatthemajoradduct wasanti66,l.e.,the result 01antiaddition.Theoppositestereochemicalassignmentwasmadefor 61which showedthatthe minoradduct re s ulted fromsynattack ofthe diane10 the dienophile.AnX-raycrystallog raphicstudy ofthe minor adduct67revealed unambig uouslythe stereochemis try10bethat of asyn add uct(Figure 16)

Figur e16:Perspec tiveviewof 67

Following asimilarprocedure asthatusedabove,slowadditionofthe requisiteamountofPTADinto diane49and stirring for16hours followed by subsequent spectroscopic analysisrevealed twoadducls64and65as shownin

Scheme39. An x-ray crystal structure (Figure17)provedthat themajor

64

Figure 17:Perspective viewof64

adduct was64.Also.the assignment ofthe majoradduct 64was confirmedby chemicalcorrelationwiththeadduct67 by a straightforwardtransformation of theadduct64to the correspondingester 67whosestructurehad been elucidatedunambiguoslyboth by nDeexperimentsandx-reycrystallography.

TheDiels-Alderreaction of dene 51was performedbyslow additionof the requisiteamount ofa solutio nor59in acetoneintoa solutionofdlene51, and thiswas stirredatroomtemperaturefor16hours(Scheme40).Analysisof

H

Ct '

^OTMS

i OTMS

H

51

n0~5%

^H

TMS ~ 0

2 o/(H li'1)

H ' (

~

68 anti

anti

anti

d 51 withPTAD ctions of 408,418 an Scheme 40:Dials-Alderrea