Synthesis

AnIntroductiontoSynthesis
Thestudyoforganicchemistryexposesastudenttoawiderangeofinterrelatedreactions.Alkenes,forexample,maybeconvertedto
structurallysimilaralkanes,alcohols,alkylhalides,epoxides,glycolsandboranescleavedtosmalleraldehydes,ketonesandcarboxylic
acidsandenlargedbycarbocationandradicaladditionsaswellascycloadditions.Alloftheseproductsmaybetransformedsubsequently
toahostofnewcompoundsincorporatingawidevarietyoffunctionalgroups,andtherebyopentoevenfurtherelaboration.Consequently,
thelogicalconceptionofamultistepsynthesisfortheconstructionofadesignatedcompoundfromaspecifiedstartingmaterialbecomes
oneofthemostchallengingproblemsthatmaybeposed.
Aoneortwostepsequenceofsimplereactionsisnotthatdifficulttodeduce.If,forexample,oneisaskedtopreparemeso3,4hexanediol
from3hexyne,moststudentsrealizeitwillbenecessarytoreducethealkynetocisortrans3hexenebeforeundertakingglycolformation.
Permanaganateorosmiumtetroxidehydroxylationofcis3hexenewouldformthedesiredmesoisomer.Fromtrans3hexeneitwouldbe
necessarytofirstepoxidizethealkenewithaperacid,followedbyringopeningwithhydroxideion.Thisexampleillustratesacommon
featureinsynthesis:oftenthereismorethanoneeffectiveprocedurethatleadstothedesiredproduct.
Longermultistepsynthesesrequirecarefulanalysisandthought,sincemanyoptionsneedtobeconsidered.Likeanexpertchessplayer
evaluatingthelongrangeprosandconsofpotentialmoves,thechemistmustappraisethepotentialsuccessofvariouspossiblereaction
paths,focussingonthescopeandlimitationsconstrainingeachoftheindividualreactionsbeingemployed.Thiscanbeadauntingtask,
theskillforwhichisacquiredbyexperience,andoftentrialanderror.
Thethreeexamplesshownbelowareillustrative.Thefirstisasimplefunctionalgroupconversionproblem,thatmayinitiallyseemdifficult.
Itisoftenhelpfultoworksuchproblemsbackwards,startingfromtheproduct.Inthiscaseitshouldbeapparentthatcyclohexanolmaybe
substitutedforcyclohexanone,sincethelattercouldthenbemadebyasimpleoxidation.Also,sincecyclohexane(andalkanesingeneral)
isrelativelyunreactive,bromination(orchlorination)wouldseemtobeanobviousfirststep.Atthispointoneistemptedtoconvert
bromocyclohexanetocyclohexanolbyanSN2reactionwithhydroxideion.ThisreactionwouldundoubtedlybeaccompaniedbyE2
elimination,soitwouldbecleaner,althoughonesteplonger,tofirstmakecyclohexeneandthenhydrateitbyanyofseveralmethods(e.g.
oxymercurationandhydroboration)includingtheoneshownbyclickingonthediagram

Plausiblesolutionsforthesecondandthirdproblemwillalsoappearaboveatthispoint.Inproblem2thedesiredproducthasseven
carbonatomsandthestartingmaterialhasfour.Clearly,twointermediatesderivedfromthestartingcompoundmustbejoinedtogether,
andonecarbonmustbelost,eitherbeforeorafterthisbondingtakesplace.The3alcoholfunctionintheproductsuggestsformationbya
Grignardadditiontoaketone,andisobuteneappearstobeagoodprecursortoeachofthesereactants,asshown.Thereactantand
productcompoundsinthethirdproblemareisomers,butsomekindofbondbreakingandbondmakingsequenceisclearlynecessaryfor
thisstructuralchangetooccur.Onepossibleprocedureisshownabove.Acidcatalyzedrearrangementofcyclohexeneoxide,followedby
reductionmightalsoserve.
Theusefulapproachofworkingoutsynthesesstartingfromthetargetmoleculeandworkingbackwardtowardsimplerstartingmaterials
hasbeenformalizedbyProf.E.J.Corey(Harvard)andtermedretrosyntheticanalysis.Inthisprocedurethetargetmoleculeis
transformedprogressivelyintosimplerstructuresbydisconnectingselectedcarboncarbonbonds.Thesedisconnectionsreston
transforms,whicharethereverseofplausiblesyntheticconstructions.Eachsimplerstructure,sogenerated,becomesthestartingpoint
forfurtherdisconnections,leadingtoabranchedsetofinterrelatedintermediates.Aretrosynthetictransformisdepictedbythe=>symbol,
asshownbelowforpreviousexamples2&3.Onceacompleteanalysishasbeenconducted,thedesiredsynthesismaybecarriedoutby
applicationofthereactionsunderlyingthetransforms.

Theabovediagramdoesnotprovideacompletesetoftransformsforthesetargetcompounds.Whenastartingmaterialisspecified,asin
theaboveproblems,theproposedpathwaysmustreflectthatconstraint.Thusthe4methyl2pentanoneand3methylbutyrateester
optionsinexample2,whileentirelyreasonable,donotfitwellwithatertbutanolstart.Likewise,acyclopentylintermediatemightprovide
anexcellentroutetotheproductinexample3,butdoesnotmeetthespecifiedconditionsoftheproblem.
Retrosyntheticanalysisisespeciallyusefulwhenconsideringrelativelycomplexmoleculeswithoutstartingmaterialconstraints.Ifitis
conductedwithoutbias,unusualandintriguingpossibilitiessometimesappear.Unfortunately,molecularcomplexity(composedofsize,
functionality,heteroatomincorporation,cyclicconnectivityandstereoisomerism)generallyleadstoverylargeandextensivelybranched
transformtrees.Computerassistedanalysishasprovenhelpful,butintheendtheinstinctsandexperienceofthechemistplayacritical
roleinarrivingatasuccessfulsyntheticplan.Somerelativelysimpleexamples,mosthavingstartingmaterialrestrictions,areprovided
below.

Problem1
AsynthesisofNethyl2aminomethylspiro[3.3]heptanefromstartingcompoundshavingnomorethanthreecontiguouscarbonatomsis
required.Thisprovidesagoodexampleoftheimportanceofsymmetryinplanningasynthesis.First,itshouldberecognizedthatthe
aminegroupisbestintroducedattheendofthesynthesis,byreactingethylaminewithanester(oracylchloridederivative)of
spiro[3.3]heptane2carboxylicacid,followedbyLiAlH4reduction.Thisapproachavoidsthenecessityofprotectinganucleophilicnitrogen
fromundesiredparticipationinotherreactions.Second,thesymmetryoftheremainingcarbonskeletonsuggestsitsdisconnectioninto1,3
difunctionalizedpropaneunits,asshownbelow.Allofthesehaveacommonoriginindiethylmalonate,whichcanbereducedtoa1,3
glycolandthenconvertedinto1,3dibromopropane.

Problem2
Asynthesisof2,7dimethyl4octanonefromstartingcompoundshavingnomorethanfourcontiguouscarbonatomsisrequired.The
structuralformulaandafirststageretroanalysisofthisketonearedisplayedinthefollowingdiagram.Threestraightforwarddisconnections
areshown,asdrawnbythedashedlines.Thefirst(magentaarrow)isundoubtedlythesimplest,sinceaGrignardreagentadditiontoa
suitablenitrilegivestheproductdirectly.However,oneormoreofthereactantsislargerthanC4andmustthereforebeprepared
independentlybeforeuse.AtwostepprocedureinvolvingGrignardadditiontoanaldehyde,followedbyoxidationofthe2alcohol
product,alsosuffersthesamerequirement,asdotheepoxideopeningroutespresentedinthesecondrow(cyanarrow).Secondary
preparationsoftheseintermediatesareeasilyconceivedbywayofcyanidesubstitutionofa1halide,couplingofaGilmanreagentwith
allylbromide,orGrignardadditiontoethyleneoxide.
Thelastdisconnection(greenarrow)createsthedesiredcarbonskeletonbysequentialalkylationsofterminalalkynes(firstacetyleneand
then4methyl1pentyne).Mercurycatalyzedhydrationofthesymmetricaloctyneproductgeneratesthedesiredketone.Allthenecessary
reactantsareC4orless,sothesynthesisisaccomplishedinthreesteps(notcountingtheformationofalkynesalts).

Threemorefirststageanalyseswillbedisplayedabovebyclickingonthediagram.Thefirstofthese(redarrow)isatwostepsequence
initiatedbyisobutylmagnesiumbromideadditiontoacetonitrile,followedbyisobutylbromidealkylationoftheresulting4methyl2
pentanone.Regioselectivecontrolmightbeaprobleminthelaststep.Theseconddisconnection(orangearrow)suggestsan,'
dialkylationofacetone.Sinceacetoneitselfispronetobasecatalyzedcondensation,thismightbedifficulttoaccomplishdirectly.However,
theuseofethylacetoacetateavoidsthisproblemforthefirststep,andthesecondalkylationisthesameoneproposedaspartofthefirst
disconnectionsynthesis.Bothofthesesequenceswouldprovideefficientroutestothetargetketone.
Finally,thelastdisconnectionisafourcomponentassemblyconsistingoftwoconjugateadditionsandaGrignardaddition.Thiswould
mostlikelyresultinalongerandloweryieldprocedurethantheprevioustwo.

Problem3
Asynthesisof1,4,6trimethylnaphthalenefromparaxyleneandotherstartingcompoundshavingnomorethanfourcontiguouscarbon
atomsisrequired.PlausibletransformsfortheattachmentofthesecondringcarbonstoparaxyleneareFriedelCraftalkylationor
acylation(acylationisusuallybetter),nucleophilicattackofanarylmetalreagentderivedfrom2bromoparaxyleneoncarbonylorepoxide
electrophiles,orpossiblybycycloadditiontoaaryneintermediate.Apalladiumcatalyzedcouplingreactionmightalsoproveuseful.
Becauseoftheirsimplicityandbroadscope,weshallconsideronlythefirsttwotransforms.
ThefollowingdiagramshowsretrosyntheticanalysesbasedontheFriedelCrafttransformforbothbondformationstothearomaticring.
Ofthese,thefirstseemstoofferthemostefficientsynthesisroute,consistingofFriedelCraftacylation,WolffKischnerreduction,asecond
FriedelCraftacylationandmethylationofaketoneenolate.Inallcasesthesubstitutedtetraloneprecursorofthedesirednaphthalene
mustbereducedtoanalcoholanddehydrated.TheresultingdihydronaphthaleneisthenaromatizedbyPtcatalyzeddehydrogenation,or
mildoxidationbyheatingwithsulfurorselenium.

Byclickingonthediagram,anewsetofdisconnections,startingfrom2bromoparaxylene,willbedisplayed.AderivedGilmanorlithium
reagentisusedforconjugateadditiontoanunsaturatedcarbonylcompoundorringopeningofanepoxide.Furtherlengtheningoftheside
chainiseffectedbycyanohydrinformation(topexample),malonicesteralkylation(middleexample),andArndtEisterthomologation
(bottomexample).Thefinalstepsmustthenparallelthoseusedforthefirstexamples.

Problem4

Asynthesisof2acetyl2methylbicyclo[2.2.2]octanefromcyclohexeneandotherstartingcompoundshavingnomorethanfourcontiguous
carbonatomsisrequired.Thetargetmoleculehastwobridgedsixmemberedcarbonrings,andcyclohexeneisoneofthestarting
materials.Wheneverasixmemberedcarbonringmustbeformed,possibleDielsAldertransformsshouldalwaysbeconsidered.Forsuch
aconstructiononeneedsaconjugateddieneandadienophile.Cyclohexenemightbeconsideredadienophile,butactingassuchwould
leadtoafusedringproduct,notabridgedringstructure.Also,commonlyusedelectronrichdienesarenotexpectedtoreactwellwithan
unstrained,electronrichalkene.
Iftheroleofcyclohexeneischangedtothatofadiene,theseobjectionsareovercome.Thisalterationiseasilymanagedbyadditionof
brominetocyclohexene,followedbyadoubleelimination,yielding1,3cyclohexadiene.

Thepossibleuseofcyclohexadieneinthissynthesisisshownabove.ADielsAldercycloadditiontoadienophilicdoublebondgenerates
thedesiredbicyclooctaneringsystem,andthetaskistoidentifyareasonableintermediateforthispurpose.Amongthemanyreactions
thatformketones,theadditionofaGrignardreagenttoanitrileisparticularlyefficient.Ifwechoosethisasthelaststep,thedienophile
becomes2methylacrylonitrile,andtheretrosyntheticpathiscomplete.Theisolateddoublebondproducedbythecycloadditionisreduced
bycatalytichydrogenation,sodistinctionbetweenexoandendoadditionproductsislost(theendoadductshownpredominated).

Problem5
Asynthesisof2benzyl3,3dimethylcyclohexanonefrombenzenederivativeshavingnomorethansevencarbonsandotherstarting
compoundshavingnomorethanfourcontiguouscarbonatomsisrequired.Sinceconjugateadditionofamethylgroupto2benzyl3
methyl2cyclohexen1oneshouldproceedingoodyield,thisunsaturatedketoneprovidesagoodalternativetarget,asshown.Once
again,thecyclohexaneringsuggestsaDielsAldertransform.Threesuchdisconnectionsaredepictedinthefollowingdiagramalongwith
apossiblealdolcyclization(example4).DielsAlderapproach1isthemostpromising,sinceitfeaturesanelectronrichdienereactingwith
anelectrondeficientdienophile.Chloroacrylonitrileisausefulsurrogatetoketeneasadienophile(ketenenormallyreactsby[2+2}
cycloaddition).Hydrolysisofthechloronitrileunitintheadductconvertsittoacarbonylgroup.Unfortunately,theregioselectivityofthis
cycloadditionislikelytobepoor,with5benzyl4methyl2cyclohexen1one(orangeboxbottomleft)beingformedinsignificantor
possiblymajoramount.Also,thediene,(3E)3methyl5phenyl1,3pentadiene,neededforthisreactionmaybedifficulttoobtainasthe
desiredstereoisomer(theZisomerwillberelativelyunreactivebecauseofsterichindranceinthecisoidconformation).
DielsAldersynthesis2doesnothavearegioselectivityproblem,butthereactionofanelectronrichdienewithanelectronrichdienophile
isoftensluggishandincomplete.Alsotheinitialadducthasamethyletherwhereacarbonylfunctionisneeded.ThethirdDielsAlder
proposalinthegrayshadedareahasevenmoreproblems.Asinreaction2,electronicfactorsmakethecycloadditionpoor,andthe
regioselectivitywilllikelyfavorthewrongadduct(circledinorange).Evenifthedesired3,3dimethylcyclohexanonewereobtained,
benzylationatthedesiredposition(green)willhavetocompetewiththatatthelesshindered'position(magenta).

Byclickingonthediagram,anewsetofdisconnectionswillbedisplayed.Thefirstofthese(topline)isacyclicaldoltransformsimilarto
thelastcasediscussed.Here,however,thesymmetryofthe1,5diketone(afterdecarboxylation)permitsonlyonecyclohexenoneproduct,
3methyl2cyclohexen1one(drawninthelightgraybox).Thiskeysyntheticintermediate,knownasasynthon,mayleadtothetarget
moleculeintwoways,dependingontheorderinwhichconjugateadditionandalkylationareconducted.Anotherusefulconcept,

revealedbythedisconnectionsinthelasttworows,isthatbenzenederivativesmayserveasprecursorstocyclohexanecompounds.
Byclickingonthediagramasecondtime,thereactionswhichmaybeusedtoachievetheproposedconstructionswillbeshownabove.
NotetheuseofaBirchreductioninthesecondline.Allthreeapproachesshouldproducethetargetcompound,themostefficientarguably
beingthethird.

Problem6
Asynthesisofallcis1,2,3,4tetrakis(hydroxymethyl)cyclopentanefromsimplestartingmaterials(sixorfewercontiguouscarbons)is
required.Sincecarboxylicacids,esters,aldehydesand1alcoholsareeasilyinterconverted,thistargetmaybechangedtothe
correspondingtetracarboxylicacid,asshowninthefollowingdiagram.Constructingthecyclopentaneringbecomesaprimarygoal,and
thismaybedonebycondensationreactions(firsttwodisconnections),cycloaddition(thirddisconnection)orbystartingwitha
cyclopentanereagent(lastexample).Althoughthereisprecedentinknownchemistryforalltheseapproaches,someturnouttohave
seriousflaws.

Byclickingonthediagram,chemicalreactionscorrespondingtoeachofthedisconnectionpathswillbeshownabove.Thefirstexample,
whichtakesadvantageofsymmetry,turnsouttosufferfromsubsequentrapidMichaeladditionofasecondacetonedicarboxylicacid
moietytotheintermediatecyclopentadienone.Thisis,infact,ageneralsynthesisofbicyclo[3.3.0]octane3,7diones,knownastheWeiss
reaction.ThesecondapproachconstructsthefivememberedringbyaDieckmanncondensationofatetracarboxylicesterprepared
fromtriethylaconitate.Additionofthefourthcarboxylgroupbywayofacyanohydrinshouldbestraightforward,butamixtureof
stereoisomerswillresult,withtheallciscompoundbeingaminorcomponent.Thecycloadditionproposedforthethirdapproachisallowed
byorbitalsymmetry,butonlyafewexampleshavebeenobserved.Pursingthissynthesiswouldbeunwise,becauseitsuffersfromthe
samelackofstereoselectivityasthesecondcase.Finally,Thelastapproach,involvingsequential[2+2]cycloadditionofketenesto
cyclopentadiene,islongerandhasaninherentproblemassociatedwiththeregioselectivityoftheconventionalBaeyerVilligeroxidation.
Thisproblemmaybeovercomebyusingchiralcatalysts(enzymesortransitionmetalcomplexes)withhydrogenperoxide,buta50%
conversionisthebestthatcanbeachievedandstereoselectivitymaystillbeaproblem.
AcarefulexaminationofthetetracarboxylicacidtargetrevealsapossibleprecursorinwhichtheciscarboxylgroupsatC1andC4are
maskedbyincorporationinadoublebond.Suchabicyclo[2.2.1]heptenestructureisreadilyachievedfrom1,3cyclopentadienebywayof
aDielsAlderreaction,asshowninthefollowingretrosyntheticdisconnection.Withthisasaguide,asimplethreestepsynthesismaybe
proposed(shownbyclickingonthediagram).Theborohydrideworkupoftheozonolysisinthelaststepwillconvertaldehydesto1
alcohols.

PracticeProblems

Thefollowingproblemsexaminemanyaspectsoforganicsynthesis.Theyareroughlyorganizedbyincreasingdifficulty.
ChooseaProblem

HistoricalBackground
Oneoftheearliest,andperhapsmostsignificantalthoughaccidentalexamplesofsynthesiswasreportedbyFriederichWhlerin1828.In
anexperimentdesignedtoprepareammoniumcyanatefromsilvercyanate,heheatedthelatterwithammoniumchlorideexpectingthe
outcomeshownbelow.
AgOCN+NH4Cl > ?NH4OCN+AgCl
TheproductWhlerobtaineddidnotcorrespondtotheexpectedcyanatesalt,butwasidentifiedasurea,NH2CONH2,anorganic
compoundisolatedfromurinefiftyyearsearlier.Thisresultwasrevolutionaryintworespects.Firstitprovidedanotherexampleof
isomerism,inthatammoniumcyanate,ammoniumfulminate(NH4ON=C)andureaareallisomers,anovelconceptforthetime.Second
itcastdoubtonthewidelyhelddoctrineofvitalism,whichmaintainedthatalllivingorganismswereendowedwithavitalorlifeforcethat
renderedthemandtheircomponentpartsuniquelydifferentfromordinary"inorganic"matter.Thus,stronglyheatingorganicsubstances
suchascarbohydratesandproteinsyieldedwater,ammoniaandcarbonaceoussolids(allinorganic),withlossofthevialessence.
Whler'sexperimentwasacclaimedasthefirstconversionofaninorganicsubstanceintoanorganiccompound.
Lessthantwentyyearslater,theGermanchemistAdolfKolbeprovidedanevenmoreconvincingsynthesisoforganicfrominorganic
substances.Thetwoequationswrittenbelowoutlinehisexperiment.First,carbondisulfide,obtainedbyreactionofcarbonwithsulfur,was
convertedtocarbontetrachloridebyheatingwithchlorine,andthesimultaneouspyrolysisofCCl4yieldedamixtureofproductswhich
includedtetrachloroethene,presumablyformedfromdichlorocarbene(:CCl2).Treatmentoftetrachloroethenewithaqueouschlorine(think
HOCl)gavetrichloroaceticacid,whichKolbereducedelectrolyticallytoaceticacid.Thisendedthereignofvitalismasascientifictheory.
CS2+Cl2+heat

> CCl4+Cl2C=CCl2+manyotherproducts

Cl2C=CCl2+Cl2&H2O > CCl3CO2H>CH3CO2H

Duringthe1850's,theFrenchchemistPierreBerthelotsynthesizedscoresofsimpleorganiccompounds,rangingfromethanolto
acetyleneandbenzene,settingthestageformoreambitiousattempts.Justasthealchemistssoughttotransmutebasemetalsintogold,
earlyorganicchemistsweredrawntotheisolationorpreparationofraredyes,exoticperfumesandunusualspices,oftenworthmorethan
theirweightingold.AnotableexampleofthisinterestisWilliamPerkin'sattempttosynthesizequinine.
Quinine,animportantdrugforthetreatmentofmalaria,wasavailableonlyfromthebarkoftheSouthAmericantreeCinchonaofficinolis,
andinthemid1850'sadeclineinthenativetreepopulationhadcausedalargeriseinthepriceofthedrug.Verylittlewasknownabout
thecompound,otherthanitsmolecularformulaC20H24N2O2.Nevertheless,inthespringof1856,WilliamH.Perkin,astudent(age18)at
theRoyalCollegeofChemistryinLondon,attempteditssynthesisinhishomelaboratory.Perkinreasonedthatoxidationofasuitable10
carbonamine,suchasallyltoluidene,C10H13N,mightgeneratequinine,asshowninthefollowingequation.
2C10H13N+3K2Cr2O7 > ?C20H24N2O2+H2O
Thissimpleapproachfailed,andfromourvantagepointacenturyandahalflateritiseasytoseewhy.Manythousandsofisomershaving
themolecularformulaofquininearepossible,butonlyoneuniqueconfigurationofthese48atomsconstitutesamoleculeofquinine.That
theatomsofallyltoluidineshould,inthecourseofonereaction,selectivelyreorganizeandcombineinthisspecificfashionisbeyondall
reasonableprobability.
Perkin'sexperimentwasafailureonlyintherespectitdidnotyieldquinine,andhissubsequentstudyofaromaticamineoxidations
demonstratesthevalueofpersistence.Fromanimpuresampleofanilineheobtainedapurpledyehecalledanilinepurple(alsocalled
mauve),whichbecamethecornerstoneofthesyntheticdyestuffindustryinEuropeandmadeafortuneforitsdiscoverer.
Atotalsynthesisofquininewasachievedin1944byR.B.WoodwardandW.E.Doering(Harvard),andimprovedsynthesescontinueto
bereported.

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