1

TheChemistryofYnolandThioynolEthers

VincentJamesGray*andJonathanD.Wilden*,DepartmentofChemistry,UniversityCollegeLondon,20GordonStreet,London,WC1H0AJ,UK

Abstract

Alkynylethersandalkynylthioethers('ynolethers'and'thioynolethers')areappealingbuilding-blocks

in synthetic chemistry due to their ease ofmanipulation and predictable reactivity. Until recently

however,theirpotentialhasremainedunderexploitedduetodifficultiesinpreparationandisolation.

Althoughrecentadvancesinsyntheticchemistryhavehighlightedvariousapplicationsforynolethers,

theequivalentthioynolexampleshavebeenrather lessexploiteddespiteauniqueandfascinating

reactivityprofile.Althoughsuperficiallythechemistryofalkynylethersandtheirsulfidecounterparts

aresimilar,closeexaminationoftheirchemistryrevealsimportantdifferenceswhichcanbeexploited

bythesyntheticchemist.

Thisreviewwillexaminethepreparationofbothclassesofcompoundandexaminetheirreactivityto

highlighttheirpowerfulsyntheticapplications.Particularfocuswillbemadeofthiynoletherswhose

chemistry exhibits some fascinating differences compared to their oxygen counterparts and have

immenseuntappedpotentialforsyntheticchemistry.

AuthorBiographies

VincentGrayobtainedhisMChemfromtheUniversityofBristolin2009,undertakingafourthyear

researchproject inasymmetricepoxidationsupervisedbyDr.EoghanMcGarrigle.Heconsequently

movedtoUniversityCollegeLondonwhereheobtainedhisPh.D.in2014supervisedbyDr.Jonathan

Wilden.HisPh.D.focussedontheuseofsulfur-basedleavinggroupsinsynthesisaswellasdeveloping

newmechanisticrationaleindescribingnovelchemicalreactions.Henextundertookapostdoctoral

positionwith Prof. ErikÅrstad atUCL, directed towards the synthesis of novel sulfonium salts for18F-labellingwhilstworkingparttimeasamassspectroscopytechnicianwithinthedepartment. In

2015hereturnedtotheWildengroupasaresearchassociate,developingandpatentinganewroute

towardsnovela-aminosulfonamides.HewastherecipientofthePeerPrizeattheRoyalSocietyof

Chemistryorganicsectionpostercompetitionin2012aswellastheRamsayMedalin2013.

JonathanWilden iscurrentlysenior lecturer inorganicchemistryatUniversityCollegeLondonand

from 2005was lecturer at the same institution. Previously heworked as a postdoctoral research

associatewithProfessorS.CaddickbothattheUniversityofSussexandatUCL.Heobtainedadouble

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honours degree in chemistry and biochemistry at the University of Southampton where he also

obtainedaPhD,focusedonthesynthesisofthemarinenaturalproductpseudopterosin,underthe

supervisionofProfessorDavidHarrowven.ResearchintheWildengroupiscurrentlydirectedtowards

thedevelopmentofnewsyntheticmethodsandelucidatingtheirmechanisms.

1.0 Introduction

Ynolethersandalkynylthioethersserveasversatilebuildingblocksinorganicsynthesis,allowingfor

a rangeofusefulmoleculararchitectures tobegenerated. Theelectron-richnatureof thealkyne

motifinbothclassesofmoleculeallowsfortheuniquereactivityfeaturestobeexploitedinarange

ofC-Cbond-formingreactions.1Ynolethersinparticularhavebeenshowntopossessabroadrange

ofreactivitythatcanbeexploitedinthesynthesisofcomplexmolecules inordertogainaccessto

otherwise difficult compounds whose preparation would be difficult or cumbersome via classical

methods.2Bothynolethersandalkynylthioetherspossesssimilaritiesinreactivity,giventhepolarised

natureoftheelectronrichdoublebond.Forexample,thisreactivitywasrecentlyexploitedbyTan

andZhu3etal.inaregioselectiveoxyarylationreactiontoformarangeofusefula-arylatedproducts

fromboththeynoletherandalkynylthioether(Scheme1.0).

Scheme1.0

2.0Ynolethersynthesis-Earlymethods

Thepastthirtyyearshaveshownaslowbutsteadyincreasereportsofnewsyntheticmethodstowards

ynolethers.Greeneetal.4showedthatarangeofynoletherscouldbepreparedingoodyieldviathe

dehalogenationof trichloroethylene.Thisclassicmethodhasbeenabenchmarksynthesis towards

ynolethersandismostcommonlyusedtopreparesuchcompoundsonalargescale(Scheme2.0).

Scheme2.0

3

Himbertetal.5havealsoharnessedthepropertiesoftrichloroethyleneasausefulsubstrateinthe

synthesisofdichloro(alkoxy)ethenes(ynoletherprecursors).Treatingtrichloroethylenewithsodium

alkoxide followed by nBuLi promoted elimination and lithiation of the acetylide, allows for Pd-

mediatedcross-couplingtoyieldaromaticalkynylethers. This reactionbroadensthescopeof the

Greeneapproachandisaconvenientmethodofmanipulatingthereactivityofthelithiatedacetylide

(Scheme2.1).

Scheme2.1

Intermsofdehalogenation-basedapproaches,Nakaietal.6haveutilisedtrifluoroethanolasacheap

buildingblockinordertogeneratearangeofynolethersingoodyield(Scheme2.2).Thissynthesis

canbecarriedout inasingleoperationstarting fromroutinelypreparedethersoftrifluoroethanol

followedbysuccessiveeliminationsofHFandLiF.

Scheme2.2

Ynolethersynthesis-Modernmethods

MorerecentadvancestowardsynolethershavebeendevelopedbyMinehanetal.In2008hisgroup

describedamild synthesis towardsa rangeof these compounds.7Primary, secondaryand tertiary

alcoholscanbesuccessfullyemployedinthissynthesistoyieldarangeofynolethersstartingwitha-

diazoketones(Scheme2.3)formingthea-ketoether.Enolateformation,triflationandbasepromoted

eliminationthenyieldstheynolether.Althoughemployingadiazoketoneasthestartingmaterialis

lessthanideal,thisthree-stepprotocolprovidestheproductsingoodyieldwithbotharomaticand

aliphaticgroupstolerated.

Cl

Cl Cl NaOR, Δ 1-4 h

RO

Cl

34-54%

nBuLi (2.0 eq.)THF, -78 oC

OR

Li

1) ZnCl2, THF, -30 oC to rt 5 min

2) Cl2Pd(PPh3)2, PPh3 ArI, rt, 4 h

OR

Ar

R = Et, Ar = Ph 65%R = Et, Ar = 4-Cl-Ph 65%

R= iPr, Ar = Ph 73%R = iPr, Ar = 4-Cl-Ph 58%Cl

4

Scheme2.3

Syntheticroutestoterminalynolethersarelimitedduetotheirvolatilityandreactivity. However,

one synthesis that affords a high yield of tert-butoxyethyne was developed by Pericàs et al.8 as

outlinedinScheme2.4.Althoughalengthyprocesstoreachthevinylbromideetherprecursor,this

synthesisoftert-butoxyethynecanbeachievedonapproximately30gscale,allowingforarangeof

furthertransformationstobeaccomplished(Scheme2.4).

Scheme2.4 Figure1

Incommonwithotherunsaturatedtert-butylethers,thisynoletherispronetorearrangement.Inthis

caseanintramolecularene-reactionoccursevenatroomtemperature,generatingketene(Figure1).

Assuch,thisspeciesmustbepreparedandstoredat-20oC.Nevertheless,thisreactive,potentially

usefulcompoundmayallowforanarrayoffurthermodificationsviadeprotonationandnucleophilic

attack,or,metal-mediatedcouplingreactions.

Evanoetal.adoptedacopper-catalysedcouplingbetweenanalcoholandagem-dibromoalkeneto

accessbromo-enolethers.Thesecompoundscouldbecleanlytransformedtothecorrespondingynol

etherinthepresenceofpotassiumtert-butoxide(Scheme2.5).9Onlyaromaticalcoholsaretolerated

in this reactionand theauthorscomment thatdimerisationof thegem-dibromolefinoccurswhen

aliphaticalcoholsareemployed.Overall,thissynthesisfurnishesarangeofynolethersingoodyield

andwithreasonablygoodscope.

R1

O

N2

R2OH, In(OTf)3tol, rt R1 OR2

O 1) LiHMDS, THF, -78 oC2) PhNTf2, DMPU

-78 oC to rt R1 OR2OTf KOtBu

THF, -78 oCR1

OR2

Ph O Ph OtBu

Ph OPh O

75% 68% 70% 68%

Selected Examples:

O

H

O

H

H +H

5

Scheme2.5

In2012,Wildenetal.10publishedanewmethodtowardsynolethersthatavoidstheuseoftransition

metalsoranyexpensivereagents.Thisreactionreliedontheuseofanelectron-withdrawingalkynyl

sulfonamide, which, upon treatment with a potassium alkoxide in DMF, would rapidly allow for

conversiontothecorrespondingynolether(Scheme2.6).

Scheme2.6

By generated potassium alkoxides in situ, the group also showed that a range of primary and

secondaryalcoholscouldbeusedtosynthesiseynoletherswithgreaterscope(Scheme2.7).11Inthis

instanceitwasfoundthatemployingdimethylamineinTHFwasofgreatbenefitasthereactionwas

completeinamatterofminutes.

Scheme2.7

Giventhecuriousnatureofthisreaction,furtherinvestigationledWildenetal.tohypothesisethat

thisreactioninvolvesasingleelectrontransferprocesstoformavinylradicalion,followedbyradical

recombinationandfinallyeliminationtoyieldtheynolether(Scheme2.8).

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Scheme2.8

Inasimilarfashion,GarcíaRuanoetal.latershowed12thattheanalogousalkynylsulfoneswerealso

goodsubstratesfortheformationofynolethersupontreatmentwithpotassiumtert-butoxide.Inthis

report,GarcíaRuanoetal.suggestthatthepotassiumcationcoordinatesanoxygenontheSO2group

ofthealkynylsulfone,allowingthetert-butoxideaniontoattacktheacarbonviaanAnti-Michael

additionprocess.Theintermediatevinylanioncantheneliminatethe–SO2Tolgrouptofurnishthe

productingoodyield(Scheme2.9).

Scheme2.9

3.0ApplicationsofYnolEthers

Thepastthirtyyearshasshownamarkedincreaseintheuseofynolethersasviablereactantsinthe

synthesisofusefulmolecules.Pericàsetal.reported13thattert-butylynolethersareausefulsource

ofketenewhichcanbeusedinanumberofothercycloadditionreactions.Forexample,whentert-

butoxyethyne is gentlywarmed, a retro-ene reactionwill occur, allowing for ketene to reactwith

anothermoleculeoftert-butoxyethynetoaffordacyclobutenoneviaa[2+2]cycloadditionprocess.

FurthertreatmentwithTFAcanthenleadtousefulsymmetricaldi-ketones(Scheme3.0).

Scheme3.0

Ready et al.14 were able to utilise tert-butoxyethyne as a ketene surrogate in a highly efficient

Sonogashiracross-couplingreactiontoformarangeofaromaticynoletherswhichcouldbetrapped

insituwithalargerageofnucleophilesaswellasundergoingcycloadditionsinasingleoperation.This

newdevelopmentalsoallowedfortheformationofquinolinesingoodyield(Scheme3.1).

SO2NEt2

Ar KORAr

Et2NO2S OREt2NO2SSET

ArAr

OROR

OR

7

Scheme3.1

AlsoharnessingtheversatilepropertiesofterminalynoletherswereDaviesetal.15whodevelopeda

three-component reaction for the a-aminoacylation of electron-rich indoles and pyrroles, which

resultedintheregioselectiveintroductionoffournewbondsintotheynolalkynebackboneingood

yield(Scheme3.2).

Scheme3.2

Terminalynolethersalsoreadilyundergometalation insituwhichcanactasveryusefulreactants,

especiallyindiastereoselectivereactions.Poissonetal.havestudiedthereactivityofmetallated(both

lithium16anddimethylaluminium17)ethynyletheranionswithchiralN-sulfinylimines,resultinginthe

synthesis of functionalized alkoxypropargyl sulfinamides in good yield and diastereoselectivity

(Scheme3.3).

8

Scheme3.3

In all instances, the alkynyl ether aluminium species (pathway A of Scheme 3.3) gave superior

diastereomericratios.Acomparisonofbothreactionscomparingyieldsanddiastereomericratiois

giveninTable1.0.

Entry R2 Yield(routeA) Yield(routeB) d.r.(routeA) d.r.(routeB)

1 Ph 92% 95% >98:2 88:12

2 p-OMe-C6H4 77% 91% >98:2 92:8

3 p-NO2-C6H4 90% 56% 97:3 54:46

4 nBu 83% 84% 97:3 85:15

Table1.0

Poisson et al. hypothesise that the aluminium gives greater d.r. values due to a six membered

transitionstateforminginthepresenceoftrimethylaluminium.Twoequivalentsofthealuminium

acetylideallowsfortheactivationoftheimine(thenitrogenatomandanoxygenofthesulfoxide).

Thealkynyletherunitcanthenbedeliveredthroughachairtransitionstatetogivetheproductsin

excellentyieldanddiastereoselectivity.

Althoughtheirreactivityisattimesdifficulttocontrolandharness,thesynthesisofketenesallows

accesstoarangeofheterocycles.Withtheknowledgethattert-butylynoletherscanundergosmooth

retro-ene decomposition, Minehan et al. have shown that ketenes can be either trapped

intramolecularlyviacycloaddition18or,attackedbynucleophiles19togeneratestructuresthatwould

beotherwisedifficulttoaccess(Scheme3.4).

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Scheme3.4

Minehanetal.20hasshownthatynolether-tethereddialkylacetalsparticipateinLewisacid-catalysed

rearrangementstoaffordalkoxycycloalkenecarboxylates(Scheme3.5).Thisreactionshowcasesthe

potentialofexploitingtheynolethermoietyingeneratingnovelringsystems,inamildandexpedient

manner.

Scheme3.5

Alkoxyalkyneshavealsoseenuseasmaskedacylatingagentsinamidebondformation.Danheiseret

al.haveemployedethoxyacetyleneasaketenesurrogateinordertosynthesisebothmacrocycleand

linearamides.21 Commonacylatingagents includeacidchloridesandmixedanhydrides,whichare

less atom-economical than ethoxyacetylene (the only leaving group being ethene in this case)

(Scheme3.6).

10

Scheme3.6

Morerecently,Whitbyetal.wereabletotrapketeneswithaminesandalcoholsviaflowchemistry.

Thisproducedthecorrespondingamidesandestersingoodyield.ByusinginlineIRspectroscopythey

wereabletomonitorandoptimisereactionsmorerapidlyandsafelythanconventionalmeans.22

Zhuetal.23havealsoshownthatynoletherscanundergohaloallylationinthepresenceofapalladium

catalyst to yield useful a-chloro- and a-bromoenol ethers. Consequently, these compounds can

undergoSuzuki-MiyauraandSonogashirareactionstoaffordsubstitutedenolethers ingoodyield.

Hydrolysisofsuchcompoundstogivetheketonecanalsobeachievedinexcellentyield(Scheme3.7).

Scheme3.7

Complementarytothisapproach,Zhuetal.24havereportedapalladium-catalysedadditionofboronic

acidstoynoletherswhichallowsforaregioselectiveadditionofarangeofgroupstotheacarbonon

theynolether.Thisreactionresultsinthesynthesisofarangeoftrisubstitutedvinylethersingood

yieldandtoleratesbotharylandalkenylgroups(Scheme3.8).

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Scheme3.8

Zhuetal.25havealsosuccessfullymanagedtoswitchtheregioselectivityofadditiontoaynoletherby

employing a two-stage hydroboration/Suzuki−Miyaura coupling in order to gain access to β,β-

disubstituted vinyl ethers, after studying work by Suzuki from the late 1980’s.26 Again, this

methodologypresentsgoodyieldsandgoodsubstratescope(Scheme3.9)

Scheme3.9

Reddyetal27havereportedaPd-catalysedregio-andstereoselectivesynthesisofvaluable1,4-enyn-

3-onesviareactionofterminalalkyneswithynolethers.Thishighlyefficientreactionworkswellat

room temperature and provides a range of useful compounds in high yield. Advantageously, the

relatively cheap palladium complex – [Pd(PPh3)2Cl2] proved to be highly efficient in catalysing the

reactionwithouttheneedofaligand(Scheme3.10).

12

.

Scheme3.10

Besidesphenylacetylene,manyotherterminalalkyneswerealsoreportedtobecompatibleunder

the same reaction conditions giving it greater scope and promise for future applications in

constructingsuchmolecules.

Due to theirunique chemical andbiological properties, fluorinated compoundsareofwidespread

interestinthechemicalcommunity. Withthisinmind,Zhuetal.28haverecentlydisclosedanovel

fluorohalogenativereactionofynoletherstoyieldpotentiallyusefula,a-fluorohaloesters.Thisuseful

reactionallowsfortheadditionofthreedifferentgroups(F,BrandI)aswellasOHacrossthealkynyl

ethertriplebondinaregiocontrolledmanner.Thisallowsaccesstoarangeofusefuldi-halogenated

compoundsthatwouldotherwisebemoredifficulttoproduce(Scheme3.11).

Scheme3.11

Themildtemperatures,relativelyshortreactiontimesandgoodyieldsmakesthissynthesistowards

a,a-fluorohalo esters extremely useful. a,a-Difluoro esters are also successfully prepared when

Selectfluor®isemployedasthesolereagentinthereaction.

Thereactionof1,3-dipolarcompoundswithunsaturatedsystemsiswellknowntobeoneofthemost

powerfulmethods of preparing five-membered rings. It is perhaps surprising therefore that [3+2]

cycloadditions have not beenmorewidely reportedwith ynol ethers since the additional oxygen

functionality lends an additional handle in the product for further manipulation (although, one

example is given in Scheme 3.2). Nevertheless, Ready et al.29 reported the formation of highly

substitutedcyclopentanonesvia reactionof ynoletherswith functionalisedcyclopropanes. In the

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presenceofaLewisAcid,thecyclopropaneringopenstoformaZwitterionwhichcanthenundergoa

cycloadditionwithaynolether(Scheme3.12).

Scheme3.12

Utilisingtheoxygenonanalkynylynoletherasadirectinggroup,MinamiandHiyamaetal30were

able to access substituted benzopyran frameworks via a C-H activation/cycloaddition reaction.

Consequentlytheseproductscouldbeemployedinfurthercycloadditionreactionstoyieldcondensed

polycycles(Scheme3.13).

Scheme3.13

O-Silyatedynolethershavealsoprovedvaluableinmediumringsynthesis.Liandsunetal.31recently

reportedacatalyticringexpansionofcyclichemiaminalstoformarangeof7and8-memberedcyclic

lactams. Keyto this reactionwastheuseofa tosylprotectinggrouponthenitrogenatom.Upon

formationoftheimine,thetosylgroupincreasesitselectrophilicity,allowingthesilyatedynolether

toattackthroughtheb-carbonatom(Scheme3.14).

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Scheme3.14

SynthesisandApplicationsofMetalYnolates

Havingconsideredthereactionsofynolethers,aninterestingquestionarisesastothepreparation

and reactivity of ynolates. These species are the alkyne equivalent of enolates and, given the

prevalenceandsignificanceofenolatechemistrytoorganicchemistry,aconsiderationoftheynolates

is certainly warranted. As expected, ynolates are significantly more reactive than their ether

counterpartsbutareneverthelessexcellentsubstratesforarangeoforganictransformations.Given

their reactivity, they are usually prepared in situ and consequently reacted with an appropriate

substrate.AnearlyexampleofynolatesynthesiswasreportedbyKowalskietal.32whodesigneda

single-steponecarbonhomologationofestersthatproceededviaanynolateintermediate(Scheme

3.15).

Scheme3.15

ThisreactioncanberegardedasthecarbonanalogueoftheHoffmanrearrangement33andisamuch

milderalternativetotheArndt-Eisterthomologation34whichrequireshazardousdiazomethane.

Juliaetal.35havealsoreportedarapidroutetowardslithiumynolatesinsitu,viaoxygentransferto

anacetyleniccarbanion.Thisrouteallowsforthesynthesisofarangeoflithiatedynolateswhichcan

beisolatedastheO-silylatedderivative.Comparedtootherynolatesyntheses,thisrouteisfasterand

muchmoreatomeconomical(Scheme3.16).

15

Scheme3.16

Shindo et al.36 have also exploited the high reactivity of ynolates by developing a tandem [2+2]

cycloaddition-Dieckmann condensation to afford 2,3-disubstituted-2-cyclohexanones and

pentanonesregioselectivelyandinexcellentyield(Scheme3.17).

Scheme3.17

Havingoutlinedthechemistryofynolethersandynolatesinorganicsynthesis, it isworthyofnote

thattheapplicationsforwhichthesespeciesarewideandvariedandyetthisareaofresearchisstill

relatively neglected. It is also striking that although these species are clearly reactive towards

electrophiles,thereactionsareonlyoccasionallyreminiscentofthetypicalreactionsoftheirclosest

relatives;enolethersandenolates.Althoughperhapssurprising,thisleadsustosuspectthatthere

willbemanymorenoveltransformationsemployingthesecompoundsintheyearstocome.

4.0ThioynolEtherSynthesis

In recentyears thenumberof reports in thechemical literatureof thepreparationofynolethers,

ynolates,alkynylphosphoruscompoundsandynamides/ynamineshasincreaseddramatically.Itis

surprising therefore that despite alkynyl thioethers serving as useful, reactive building blocks in

organic synthesis, convenientmethods towards their preparation are still somewhat lacking. The

mostgeneralpathfortheirpreparationinvolvesthedeprotonationofaterminalalkyne,followedby

reactionwith an electrophilic sulfur unit. For example,MaGee et al.37 developed a high-yielding

synthesisofarangeofalkynylthioethersviareactionofdeprotonatedalkyneswithdiphenyldisulfide

(Scheme4.0).

16

Scheme4.0

TheuseofmethyliodideisimportantinthiscaseasitisthoughttoS-alkylatethediphenyldisulfide,

renderingitasuperiorelectrophileinthereaction.TheuseofmethyliodidealsoensurestheMeSPh

sideproductdoesnotreactwiththedesiredproductasthephenylthiolateanionismorenucleophilic.

Theuseofathiolatetrapiscriticalinthesereactionstoensurehighyields.Tametal.38haveshown

thatemployingp-nitrobenzylbromideisagoodwaytosuppressfurtherreactionofthedesiredalkynyl

thioether (Scheme 4.1). Although an elegant solution to the problem, employing p-

nitrobenzylbromideisclearlyundesirablebothintermsoftoxicityandatomefficiency.

Scheme4.1

Shibasakietal.39havealsoshownthatacombinationofCuOTfandPhSSPhformsanexcellentsource

of‘PhS+’whichwasusedtoformalkynylthioethersingoodyield(Scheme4.2).

Scheme4.2

Asoundmechanisticrationale isalsoprovidedforthisreaction. Theauthorshypothesisethatthe

CuOTfallowsfortransientformationofPhS+whichcanaddtothetrimethylsilyl-protectedalkyne.The

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highlyreactivevinylcationcanthenundergoeliminationtoformthetargetalkynylthioetheringood

yield(Scheme4.3).

Scheme4.3

Thiscombinationofreagentsappearstonothavebeenstudiedfurthersincethis1990publication

whichleavesagreatdealofscopetobeinvestigated.

Bragaetal.40havealsodevelopedanapproachtoalkynylthioethersusingacopper(I)salt.Inthiscase

thestartingmaterialisanalkynylbromideandHMPAisusedasthesolvent(Scheme4.4).

Scheme4.4

ComparedtothereactionreportedbyShibasakietal.39,thesetworequirementsarenotdesirableas

thestartingmaterialwillusuallyneedtobepreparedbybrominationoftheterminalalkyneandHMPA

isarathertoxicsolvent.Ontheotherhand,thereactionproceedsatroomtemperatureintwohours

infairyieldwhereasShibasaki’sreportrequireslongrefluxconditions.

Alsointhearenaofcopper(I)catalysis,Riouxetal.41havedevelopedafacileroutetowardsalkynyl

thioethers using terminal alkynes and thiols. Advantageously, the relatively cheap, commercially-

availablestartingmaterialsallowsfortherapidsynthesisofawiderangeofalkynylthioethersinhigh

yield(Scheme4.5).

Scheme4.5

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Awiderangeoffunctionalgroups,aswellasbotharomaticandaliphaticgroupsaretoleratedinthis

reactionmakingitaverydesirablemethodforthesynthesisofalkynylthioethers.

Similarly,Wildenetal.42 haveutilisedalkynyl chlorides in the synthesisof alkynyl sulfides. In this

synthesis,itispostulatedthatthereactionproceedsviaaradicalanionintermediate.Iftheamine

additiveisremoved,thereactiontakesmuchlongertocomplete,suggestingthattheamineaidsan

electrontransferprocessbetweenthethiolateanionandthealkyne(Scheme4.6).

Scheme4.6

In general, compared to other alkynyl thioether synthesis, this reaction is noteworthy as low

temperatures are allowed for the reaction to proceed smoothly and in high yields without any

transitionmetalcatalyst.

Wildenetal.havealsoshown43thatalkynylsulfonamidesserveasexcellentreactantsinthesynthesis

ofalkynylthioethers.Similartothealkynylchloridesstudiedwithinthegroup,theseelectrondeficient

alkynesarehypothesisedtobegoodelectronacceptorsthusstabilisingradicalanionintermediates

whichcanthenundergoradicalrecombinationwithathiylradical(Scheme4.7).Thedrawbackofthis

synthesis exists in the synthesis of the alkynyl sulfonamide which is cumbersome and relatively

inefficient,sincenosatisfactoryprotocolforthegenerationofalkynylsulfonamidescurrentlyexists.

Scheme4.7

Inthefieldofcompositematerials,Matsudaetal.44wereabletogenerateself-assembledmonolayers

of alkynyl thioethers on a gold surface. In the course of their work, they describe a synthesis of

19

intermediatetrimethylsilylethylalkynylthioethersasdescribedinScheme4.8.Thesecanbefurther

manipulated to yield various other alkynyl thioethers by treatment with TBAF and subsequent

trappingofthealkynylthiolateanioninsitu.

Scheme4.8

ArelativelyinexpensivemethodforthesynthesisofalkynylthioetherswasdevisedbyHuetal.45who

demonstratedthatelementalsulfurcouldbereactedwithdeprotonatedalkynesandtheconsequent

alkynylthiolatestrappedwitharangeofelectrophilies(Scheme4.9).

Scheme4.9

Thereactionishighyieldingandcanbeachievedinasingleoperation,avoidingtheuseofodorous

thiols.

Morerecently,Qingetal.46haveshownthattrifluoromethylthiolationcanbeeasilyachievedbyusing

elemental sulfurand theRuppert−Prakash reagent47,CF3SiMe3.This reaction is successfulat room

temperatureandshowsexcellentsubstratescope(Scheme4.10).

Scheme4.10

20

Basedontheirfindings,itissuggestedthatS8isbehavingasanoxidantinthereaction,generatingthe

reactive –SCF3anionwhich then reactswithphenylacetylene. A rangeofmedicinally relevantand

usefulcompoundscanthereforebysynthesisedinasingleoperation.

Similar compounds can be generatedwith a slightlymore complicated trifluoromethanesulfenate

shownin(Scheme4.11).StudiesbyShenetal.48haveshownthatterminalalkynescanreactsmoothly

andingoodyieldinthepresenceofacopper(I)catalyst.Althoughtheyieldsarelowercomparedto

Qing,thissynthesisavoidstheuseoftheexpensiveRuppert-Prakashreagent.

Scheme4.11

Aswithmanyorganicprocesses, eliminating transitionorheavymetals in the synthesisof alkynyl

thioethers would be of benefit as this may make the overall process cheaper and more

environmentally-friendly.Panetal.49recentlyreportedamethodutilisinggem-dibromoalkenesand

substitutedthiophenols(Scheme4.12).

Scheme4.12

Although the conditions are rather forcing, this synthesis shows good scopewith good yields and

avoidstheneedfortransitionmetalscatalysis.

21

Anotherfineexampleoftransitionmetal-freealkynylthioethersynthesiswasreportedbyWaseret

al.50in2014.Inthiscase,awiderangeofthiolscouldbereactedwithanarrayoffunctionalisedEBX

reagentstogainaccesstoarangeofinterestingandhighlyfunctionalisedcompoundsincludingsugars

andaminoacids(Scheme4.13).

Scheme4.13

Thisreactionisrapidandhigh-yielding,withhighfunctionalgrouptolerance,leadingtocompounds

withgreatpotentialindrugdiscovery.

In2014,Reevesetal.51reportedathiol-freesynthesisofsulfides,viareactionofBuntesalts52with

Grignardreagents.Thissynthesisavoidstheuseofmalodorousthiols,withthethiolcomponentbeing

aneasy-to-handle,non-toxiccrystallinesolid.Someinterestingalkynylthioetherscanbegenerated

fromthissynthesisinexcellentyield(Scheme4.14).

Scheme4.14

5.0ApplicationsofAlkynylThioethers

Giventhepaucityofreliablesyntheticroutestowardsalkynylthioethers,itisofnosurprisethattheir

reactivity has not been explored in-depth. In the sameway as ynol ethers, with their degree of

22

unsaturationandfunctionality,thesecompoundshaveenormouspotentialtobeversatilesynthetic

intermediates, and, given the polarised nature of the alkyne fragment, can be employed in

regioselective transformationsyieldinganarrayof interestingcompounds.Abriefoverviewof the

chemistryofthesefascinatingcompoundsisgiveninthesectionsthatfollow.

PdandCu-MediatedReactions

In2001,SroglandLiebskindetal.reported53newmethodologyforthesynthesisofsubstitutedalkynes

fromalkynyl thioethers andboronic acidsvia a copper carboxylate-mediated, palladium-catalysed

thioalkyne−boronicacidcross-coupling.Quiteremarkably,thisreactionrequiresnobaseandworks

well under mild conditions (in particular at relatively low temperatures) and is an umpolung

complement to theSonogashira reaction.Botharylandalkenylboronicacidsareemployed in the

reactiontogiveawiderangeofsubstitutedalkynes(Scheme5.0).

Scheme5.0

Followingupthisworkin2011,Srogletal.reportedaPd2+andCu2+catalysedoxidativecross-coupling

of mercaptoacetylenes and arylboronic acids54, yielding aryl thioethers and an aryl alkyne. This

reactionisadvantageousastwopotentiallyusefulcompoundsareformed,ratherthanoneofthem

beinganunwantedby-product(Scheme5.1).

23

Scheme5.1

Pleasingly,thereactioncanbeexecutedinairatmildtemperatures,allowingforarangeofalkynes

andarylthioetherstobesynthesised.

Inafurtherdevelopmenttothischemistry,Knocheletal.reported55,56thatorganozincreagentscould

beusedinsteadoftheboronicacids.InthissynthesistherelativelycheaperPd(OAc)2isusedrather

thanPd(PPh3)4. Bothsynthesesusethesamemildtemperaturesandtakeapproximatelythesame

time(ca10h)toreachcompletion(Scheme5.2).

Scheme5.2

It is also clear that this reactionpossesses good substrate scope. Both electronwithdrawing and

donatinggroupsaretoleratedoneithersideofthetriplebondaswellasaliphaticgroups.

Hiltetal.57, 58disclosedamild [4+2] cycloaddition reactionwithunactivatedalkynyl thioethersand

alkenesinthepresenceofacobalt(II)catalyst. Giventhefactthatsulfurcancoordinatetransition

metals, a greater concentration of the catalyst was required in order for the reaction to reach

completion.Theintermediatedihydrocompoundscanbeeasilyoxidisedtothearylthioethersingood

yieldwithDDQ.(Scheme5.3)

24

Scheme5.3

Inthelanthanideseries,Yb(OTf)3wasfoundtobeaneffectivecycloadditioncatalystinthesynthesis

ofd-thiolactams59viaanaza-DielsAlderreaction(Scheme5.4).Thereactionproceedsviaan

intriguingbis-thioketeneintermediateasoutlinedinScheme5.4.

Scheme5.4

This reaction produced a range of substituted d-thiolactams in fair yield which could be further

transformedintotheBrazilianalkaloidOnychine(Scheme5.5),highlightingtheabilityofthischemistry

togeneratecomplexmolecularframeworks,includingnaturalproductsinanefficientmanner.

Scheme5.5

Jia and Sunet al. have shown60 that alkynyl thioethers serve as excellent reactive partners in the

Huisgen1,3-dipolarazide–alkynecycloaddition.Usinganiridiumcatalystalongwitharangeofazides,

a selection of triazoles can be rapidly synthesised in high yield, with excellent regioselectivity.

Incorporationofboththetriazoleandthioetherlinkagehasthepotentialtoleadtosomehighlyactive

antifungalagents(Scheme5.6)

25

Scheme5.6

TheproductscanthenbeoxidisedusingmCPBAtoform5-sulfonyltriazolesinatotallyregioselective

manner.

Tam et al. have reported61 a ruthenium-catalysed [2+2] cycloaddition of alkynyl thioethers and

strainedbicyclicalkenes,givingsolelytheexo-productisgoodyield.Theadductsformedcanbefuther

transformedviadesulfonylationortreatmentwithmCPBAandanorganolithiumreagenttogenerate

quitecomplexchiralhydrocarbonsexpeditiouslyandingoodyield(Scheme5.7).

Scheme5.7

Alkynylthioethershavealsobeenshowntoundergosyn-additionwithtributyltinhydridetoyieldvery

usefulalkenylstannaneswhichcanbeusedinanumberoffurthertransformations.Magriotisetal.

reported a highly regio- and stereoselective hydrostannylation of a range of alkynyl thioethers in

199162. This very useful reaction is rapid and is complete within minutes at room temperature,

yieldingarangeofusefulcompounds(Scheme5.8).

26

Scheme5.8

Basedonthesefindings,Caietal.63reportedaone-pothydrostannylation-Stillecouplingreactionto

generatearangeof(Z)-a-arylthio-a,b-unsaturatedketones.Bothelectrondonatingandwithdrawing

substituentsaretoleratedontheacylchloridealthough,disappointingly,aliphaticacylchloridesdo

notreactunderthegivenconditions(Scheme5.9).

Scheme5.9

Similarly,Zhuetal.recentlyreported64ahydrohalogenationacrossthealkynylthioethertriplebond

to form (E)-α-halo vinyl sulfides and consequentlyexploiting them for accessing stereodefined tri-

substitutedalkenes.TheyreasonedthatgiventhepolarisednatureoftheC-Ctriplebondinanalkynyl

thioetherduetothesulfuratom,controllingtheregioselectivityoftheadditionshouldbemucheasier

asonecarbonatomwillbemorepositivelychargedthantheotherallowingforasyn-additionoverall

(Scheme5.10).

27

Scheme5.10

Performing the hydrohalogenation at room temperature was found to be optimal and a single

regioisomer could be isolated in high yield (Scheme 5.11). Unlike the analogous (E)-α-halo vinyl

ethers,thesecompoundsarestabletocolumnchromatography.

Scheme5.11

With these (E)-α-halovinyl sulfidesathand,a rangeofwell-knowntransitionmetalcross-coupling

reactions could be carried out i.e. Suzuki, Sonogashira and Negishi reactions, allowing for the

otherwisedifficultsynthesisofstereo-defined,trisubstitutedalkenes(Scheme5.12).

Scheme5.12

6.0Concludingremarks

In summary, it has been shown that both ynol ethers and alkynyl thioethers are highly versatile

moleculesinvariousbranchesoforganicchemistry.Whenweembarkedonthisreview,ourintention

wasto‘compareandcontrast’thereactivityofthesemoleculesgiventheirsimilarityinstructure.In

writingthisreviewhowever,itsoonbecamecleartousthatthedifferencesbetweenthetwoclasses

of compounds far outweigh the similarities and we decided therefore that considering them

separatelywouldbemoreuseful.Nevertheless,the importantpointremainsthatbothynolethers

andtheirsulfuranaloguesexhibitfascinatingreactivityprofileswhichallowavarietyC-Cbondforming

28

processestooccurunderrelativelymildconditions,offeringaccesstoarangeofmoleculesthatwould

beotherwisechallengingtoprepare.Althoughstraightforwardsynthesesofbothtypesofmolecule

havehistoricallybeensomewhatlacking,thepasttenyearshaveshownasteadyriseinthenumber

ofroutestowardsbothcompoundclasses.Giventhehighdegreeoffunctionalitywithinthesespecies

and their unique reactivity profiles, we expect that their popularity for effecting otherwise

cumbersometransformationswillcontinuetogrowinyearstocome.

7.0Acknowledgements

TheauthorsgratefullyacknowledgetheEPSRC(grantreferenceEP/M02220X/1),Leverhulme

Trust,GlaxoSmithKlineandUniversityCollegeLondonforgenerousfinancialsupportoftheirwork.

8.0Notesandreferences

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