At Long Last: Olefin Metathesis Macrocyclization at High Concentration

Article abstract of DOI:10.1021/jacs.8b04820

Macrocyclic lactones, ketones, and ethers can be obtained in the High-Concentration Ring-Closing Metathesis (HC-RCM) reaction in high yield and selectivity at concentrations 40 to 380 times higher than those typically used by organic chemists for similar macrocyclizations. The new method consists of using tailored ruthenium catalysts together with applying vacuum to distill off the macrocyclic product as it is formed by the metathetical backbiting of oligomers. Unlike classical RCM, no large quantities of organic solvents are used, but rather inexpensive nonvolatile diluents, such as natural or synthetic paraffin oils. Moreover, use of a protecting atmosphere or a glovebox is not needed, as the new catalysts are perfectly moisture and air stable. In addition, some other cyclic compounds previously reported as unobtainable by RCM in neat conditions, or in high dilutions even, can be formed with the help of the HC-RCM method.

Full text of DOI:10.1021/jacs.8b04820

Subscriber access provided by - Access paid by the | UCSB Libraries
Article
At Long Last: Olefin Metathesis Macrocyclization at High Concentration
Adrian Sytniczuk, Micha# D#browski, Łukasz Banach, Mateusz Urban, Sylwia
Czarnocka-#niada#a, Mariusz Milewski, Anna Kajetanowicz, and Karol Grela
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 26 Jun 2018
Downloaded from http://pubs.acs.org on June 26, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 8
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
At Long Last: Olefin Metathesis Macrocyclization at
High Concentration
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
AdrianSytniczuk,†MichałDąbrowski,†ŁukaszBanach,†MateuszUrban,SylwiaCzarnocka-Śniadała,Mariusz
Milewski,AnnaKajetanowicz,KarolGrela*
FacultyofChemistry,BiologicalandChemicalResearchCentre,UniversityofWarsaw,ŻwirkiiWigury101,02-089Warsaw,Poland.
KEYWORDS:olefinmetathesis;ringclosingmetathesis,ruthenium;carbenes;macrocyclisation;musk;highconcentration
ABSTRCT:Macrocycliclactones,ketonesandetherscanbeobtainedintheHigh-ConcentrationRing-ClosingMetathesis(HC-RCM)reaction
inhighyieldandselectivityatconcentrations40to380timeshigherthanthosetypicallyusedbyorganicchemistsforsimilarmacrocyclizations.
Newmethodconsistofusingtailoredrutheniumcatalyststogetherwithapplyingvacuumtodistilloffthemacrocyclicproductasitisformedbythe
metatheticalbackbitingofoligomers.UnlikeclassicalRCM,nolargequantitiesoforganicsolventsareused,butratherinexpensivenon-volatile
diluents,suchasnaturalorsyntheticparaffinoils.Moreover,useofprotectingatmosphereoragloveboxisnotneededasthenewcatalystsareper-
fectlymoistureandairstable.InadditionsomeothercycliccompoundspreviouslyreportedasunobtainablebyRCMinneat,orinhighdilutions
even,canbeformedwithhelpofHC-RCMmethod.
3-5
◼ INTRODUCTION
ofvaluableproducts. isisaresultofverymildconditionsusedin
metathesis,perfectcompatibilityofmodernrutheniumcatalystswith
polarorreactivefunctionalgroupsandtheirstabilitytowardsairand
moisture.
InhisNobellectureLavoslav(Leopold)Ružičkastated“Iwashin-
dered(...)bythegeneralprejudice,sharedbymyself,againsttheprob-
abilityofexistenceof15-and17-memberedring”. Butdespitethis
1
prejudice,heistodayfamousforprovingthatvaluableperfumeingre-
dients,muskoneandcivetoneareinfactmacrocycliccompounds,and
forhisgroundbreaking,althoughlowyielding,synthesisofsuch
macrocyclesbythermolysisofceriumorthoriumdicarboxylicacids
salts.Overtheyears,severalmethodsforpreparingofmacrocycles,
suchasuseofthehighdilutionconditions(Ziegler,aferRuggali),
acyloincondensation(Prelog,Stoll),transestrification-depolymeriza-
tion(Carothers),McMurryreaction(McMurry),Yamaguchimacro-
lactonization(Yamaguchi),ring-closingalkeneandalkynemetathesis
(Grubbs,Schrock,Fürstner),tolistonlyafew,havebeenintroduced.
Despiteenormousprogressthathasbeenmadesincethetimeof
Ružička,macrocyclisationsarestillconsideredaschallengingtransfor-
Scheme2.Substrate-CatalystPrecoordinationasaKeytoMacro-
cycleRCMFormationatHighDilution
a
2
mationsinorganicsyntheticchemistry.
Scheme1.GeneralEntropicFactorsthatInfluencetheConcen-
tration-DependenceofRCMYields
a
a
SeeRef.(6).CatalystI=(PCy)(Cl)Ru=CHPh
3 2
2
Unfortunately,despiteso-calledcatalyst-substratetemplatingeffect,
6
veryelegantlyprovedexperimentallybyFürstner (Scheme2),for
medium(8-13membered)andmacrocyclicrings(14+membered)
stillthehighdilutionconditionsmustbeused.ismakes,especially
fromtheindustrialperspective,largescaleaccesstosuchcompounds
problematic,duetotheenvironmentalandeconomiccostsofpur-
chasing,storing,transferring,andthenattheendseparatinganddis-
posinglargevolumesofsolvents.Asasolutiontothisproblemwasnot
7a,b
known,sincethefirstreports onconformationallyunbiasedRCM
7c
lactonemacrocyclization,tillthemostrecentexamples preparation
a
Cyclicoligomersnotshown.SeeRef.(3)
ofmediumandlargeringsbyRCMwasalwaysrecommendedtobe
conductedunderhighdilutionconditions.Forexample,inthecaseof
carbocyclesandlactones,Foggrecapitulatedthefollowingrecom-
mendedconcentrationsofadieneinRCM:5-6memberedrings—
100mM;7-membered—5mM;8-13membered—0.5mMand
Transition metal catalyzed ring-closing metathesis (RCM)
(Scheme1)hasrevolutionizedretrosyntheticthinkingaboutthecon-
structionofmacrocycliccompoundsandallowedtoobtainthousands
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 8
1
2
3
4
5
6
7
8
7d
14+macrocycles—5mM. Atconcentrationshigherthanrecom- reducestheyieldandcancontributetoside-reactionslikeC-Cdou-
mended,alargeamountofpolymericproductsisisolatedaferthere- blebondshifs(“alkeneisomerisation”).erefore,inthefirstsetof
action.esepolymersarecomingdirectlyfromadieneinapro- experimentsweusedfastinitiatingbutatthesametimereasonably
9
cessescalledacyclicdienemetathesispolymerization(ADMET)but stablecatalystIIdevelopedinourlaboratories.
canbealsoproducedattheexpenseofthealreadyformedmacro-
cyclicproduct,inring-openingmetathesispolymerization(ROMP)
process(Scheme1).Increasingdilutionsfavorthemacrocycle,how-
ever,conductingRCMinveryhighdilutionisnotonlyunreasonable
fromtheeconomicpointofview,butalsosimplylowyieldingbe-
causeRCMbelowconcentrationsofabout0.5mMisthentooslow
Scheme3.ADMET–then–BB-RCMApproachandtheGCTrace
a
oftheObtainedProduct
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
tocompetewithcatalystdeactivation. Inafundamentalwork,Fogg
showedthatADMETwaskineticallyfavoredevenathighdilution,
butimportantly,oligomers,onceformedcanbelaterconvertedinto
expectedmacrocycleinaprocesscalledbackbiting(BB-RCM,
Scheme1),astheequilibriumbetweenamacrocycleandhigher
8
molecularmassproductsiscontrolledbytheconcentration.
◼ RESULTSANDDISCUSSION
Ourgoalwastoutilizetheinherentreversibilityofolefinmetathe-
sistoproducemacrocylicproductsrelevanttoflavorandfragrance
9
(F+F)industryatconcentrationsmuchhigherthatnormallyusedfor
RCMmacrocyclizations(5mM).Weanticipatedthatundercarefully
selectedconditionsADMEToligomerscanbeeffectivelybackbited
toyieldtheexpectedRCMmacrocyclicproduct.Oncethemacrocy-
cleisformed,weplanedto“remove”itfromtheabovediscussedequi-
10
librium(andfromthereactionmixture)undervacuum.
Chart1.OlefinMetathesisCatalystsDiscussedinisWork
N
N
N
N
PCy3
Cl
Ru
Ph
PCy3
Cl
Ru
Cl
O
Ru
O
MeO
Cl
Cl
Cl
N
Z
I
II (Z = NO2)
III (Z = H)
IV
a
RVP=rotaryvaneoilpump
N
N
N
N
N
N
Cl
Toconfrontourexpectationswiththereality,diene1wasreacted
withoutsolventwithII(1mol%)atconditionsshowedinScheme3
toformADMETpolymer.ereactionwasconductedaccordingthe
Cl
Cl
Ru
O
O
Ru
Ru
Cl
Ph
Cl
Cl
PCy3
O
12
V
VI
VII
literatureprotocol, leadingaviscousmaterial.epolymerwasthen
subjectedtothesecondstageofprocess:BB-RCMdepolymerization.
Todoso,aferadditionofaneutraldiluent(siliconeoil)andafresh
portionofcatalystthereactionflaskwasmountedintoaglassdistilla-
tionapparatusandthereactionwascontinuedundervacuum,usinga
rotaryvaneoilpump(RVP).eGC-MSanalysisofthesamesample
showedthatproductsbetweengroupsdifferfromtheexpected
macrocycliclactone2by±(n×14)massunits.Peaksinsideeach
grouphavesimilarmolecularmassthatsuggest,inadditiontousual
(E)and(Z)isomerism,alsoC-Cdoublebondmigrationsinsidea
macrocyclering(forahydrogenationexperimentsupportingthis,see
SI).Apparently,theseproductsaretheresultofaseriesofisomeriza-
tionsthatoccurredduringtheprocess,whichleadtoaverycomplex
chromatogram.Unluckily,amongthewiderangeofnon-metathesis
pathwayspromotedbytheRumetathesiscatalysts,olefinisomeriza-
Et
Et
Ph
Ph
N
N
N
N
N
N
Cl
Cl
Cl
Et
Et
Ph
Ph
Ru
Ru
O
Ru
O
Cl
Cl
Cl
O
VIII
IX
X
N
+
N
S
N
N
N
N
N
N
Cl
Cl
CCll
Ru
O
Ru
O
RRuu
Cl
Cl
CCll
–
Cl
O
XI
XII
XIII@MOF
(immobilized in MOF)
13
tionisparticularlycommon. Unfortunately,varyingtemperature
Weassumedthatthekeytosuccessliesintherightchoiceofacata-
lyst(Chart1).Metathesisofinternal,mostly(E)-configuredC-C
doublebondsintheADMETproductisconsiderablyslowerthanthe
terminalones.Suchunhurriedbackbitingisaproblembecauseitin-
creasestheopportunityforcompetingcatalystdecomposition,which
(120to150°C),adiluent(siliconoil,liquidandsolidparaffin,etc.)
wasnotofhelp,asinallcasesmixturesoffullyisomerized(E/Z)-
macrocyclesof11to21-memberswereobtained,withmaximalyield
of24%(Scheme3).Obviously,suchcomplicatedmixtureofproducts
2
ACS Paragon Plus Environment

Page 3 of 8
Journal of the American Chemical Society
1
2
Chart2.High-ConcentrationRCM(HC-RCM)
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
b
c
Selectivity=(Int.ofE+Z)/(Int.ofallproducts),determinedbyGC.ODP=oildiffusionpump.GCtracesofproductsfromEntry3and10. TLC
analysesofreactionmixturefromexperimentceasedafer20minutes.Startingfromthelef are:S–standardofthesubstrate6,R–sampleofreactionmix-
ture,P–standardoftheproduct7,CS–co-spot(allthreetogether).Exampleofareaction/distillationHickmanglassapparatususedinourstudy.
d
isnotatractiveforF&Findustry.However,havingthisproofofprin- anoildiffusionpump(ODP).iswayeachhigh-concentration
ciplewedecidedtocombinetheseparatestepsofADMETandBB- RCMexperiment(HC-RCM)wasconductedonlyfor8h,andat
RCMintooneoperation.isshouldmakemoreefficientuseofa lowertemperature(110°C),butatthesametimewecouldexpect
catalystandreducechancesforsidereactionsleadingtoisomerized thatanymoleculeofthemacrocyleproducedbyBB-RCMcanbedis-
–6
products.Moreover,asasubstratewechoosecompound5insteadof tilledoffundersuchhighvacuum(thepumpnominalpressureis10
terminaldiene1.WehypothesizedthatinternalcharacterofC-C mBaratthepumpinlet,unfortunately,duetosensormountinglimita-
doublebondsin5willslowdowntheADMETprocess,andthus tions,wedonotknowtheactualpressureinthereaction/distillation
makeBB-RCMmorecompetitiveallowingtoavoidquickcatalystde- flask).ediluentwasaparaffinoil,anddieneconcentrationwas
compositionandunwantedsidereactions.Inaddition,wedecidedto 9wt.%(0.25mol/kg,ca.200mM).UndersuchconditionselevenRu
increasetheamountoftheparaffindiluentanduse2,3,5,6-tetra- metathesiscatalystswerescreened(Chart2a).Inthecaseofpopular
fluorobenzoquinone,anadditiveknowntoceasetheC-Cdouble general-purposecatalysts,suchasII,III,V-VII,mixturesofheavily
bondisomerization(Scheme3,botom). Regretably,alltheseat- isomerisedproductswereformedmakingtheproductGCtracelooks
temptswereunsuccessful.IntheactofdesperationwereplacedII liketheGaussiandistributionagain(Chart2b).Notdisheartened,we
withthenewlyintroducedcatalystIV, whichisknowntobestable decidedtocontinueexperimentswiththein-housedesignedcata-
upto150°C,buttonoavail.Wewereabletodistilloffabigger lysts.erewardwasnotfaraway,asforcomplexesXI, XII, andre-
14
15
17
18
19
amountofmaterial,upto61%,buttheGCchromatogramtracewas centlypublishedheterogeneousXIII@MOF, weobservedalmost
againshowingaGaussiandistributionofpeaks,likeintheprevious idealselectivityandsurprisinglyveryhighyields(Chart2a).Forthe
cases,witnessingseverealkeneisomerizationduringtheprocess.e firsttimewewereabletoenjoyreallycleanGCtraces,composed
failureoftheaboveexperimentsexplainswhy,despiteallneededcon- practicallyofonlytwopeaks:the(Z)and(E)-geometricalisomersof
ceptualelementshavebeenalreadyknownintheliterature(i.e.anal- theexpectedmacrocycle7(Chart2b).
ogytoCarothers’acid-catalyzeddepolymerization,generalmetathe-
sismechanism,Fogg’sBB-RCMconcept)thereisnosingleexampleof
ereasonwhythesecomplexesdonotgivetheGaussian-likedis-
tributionofproducts,althoughnotcompletelyclearforus,canbeas-
sociatedwiththerelativecatalystsstability.eunsymmetricalN-het-
successfulmetathesis-basedsynthesisofmacrocyclesatveryhigh
concentrationcombinedwithdistillation(unsuccessfulexampleswere
erocyclicligand(uNHC)bearingXIandXIIareextremelystableand
16
alsoscarce).
havebeendesignedtoreachhighselectivityinindustriallyimportant
13
emissingelementisapparentlythecatalyst.Stillbelievingthat self-metathesisofα-olefins andinethenolysisofnaturalprod-
weareabletofindacatalystofenoughactivityandstabilitytomake ucts. erefore,wethinkthattheirhighimmunitytoformRu-H
thering-chainequilibriumconvertoligomersselectivelyintoex- species(andprobablyalsootherisomerization-activespecies,suchas
pectedproduct,andthatitispossibletoremovethisproductinvacuo dimetalliccomplexesorevennanoparticles) wasthekeytosuccess.
assoonasisformed,oureffortswerecontinued.Profitingfromour Ofnote,otheruNHCcomplexes(VIII-X)alsoprovidedselectivities
collectionofcatalysts(Chart1)weconductedanumberofoptimiza- higherthen60%,whilecatalystsII,IIIandV-VIIwithstandard
tionsusingthistimeabis-internaldiene6leadingtoindustriallyvalu- SIMesandSIPrNHCligands withnoexceptiongaveselectivitybe-
able16-memberedmacrocycle7(unsaturatedanalogueofExal- low50%.ItisnotacoincidencethatalsocatalystXIII isknownfor
tolide).Tomakethisresearchphasesmoothandtosavetime,weused itssuperiorselectivityinself-metathesisofα-olefins,butonlyifpro-
17,18
20,
21
19
3
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 8
1
2
3
Scheme4.FurtherOptimizationandAssessingtheScopeofHC-RCM
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
Investigationofdifferentdiluents.PE=polyethylene.Ionicliquid=1-butyl-2,3-dimethylimidazoliumhexafluorophosphate.PAO=poly-α-olefinsyn-
b
theticoil.Variousmacrocyclesproducedusingthismethod.Allexperimentsconducedatmolalityb=0.25mol/kg
22
tectedinsideametal-organicframework(MOF). erefore,we catalyst(formoredetailsseetheSI).Fromvariousdiluents,suchas
werenotsurprisedthatthissystemgavegoodresultsinthepresent liquidandwhite(wax)paraffin,low-MWPEand1-butyl-2,3-di-
study,too(Chart2a,entry11).
methylimidazoliumhexafluorophosphateionicliquid,clearlyparaf-
finsbehavethebest(Scheme4).Weexpectedgoodresultsfromlow
MWPE,asitiscompletelynotvolatile,andshallbeliquidatthereac-
tiontemperature(mp.90°C).Unfortunately,thehighviscosityofthe
liquidPEmakethestirringalmostimpossibleandthisprobablywas
reflectedinratherlowyieldoftheproduct(althoughformedinhigh
selectivity).Inthecaseofanionicliquid,erosionofbothyieldandse-
lectivitywasobserved.Averyinterestinganaloguesofnaturalparaffin
arePAOs—branchedhydrocarbonoligomersmadebypolymeriza-
tionofα-olefins—usedwidelyassyntheticmotoroils.InourHC-
RCMbothPAO4(fromExxonMobil)andPAO6(fromChevron
Phillips)workedverywell.Stillusingtheoildiffusionpump,asitwas
moreefficientinthisexploratorystageofinvestigation,eightdienes
weretestedinHC-RCMwithpracticalcatalystsXIandXIIandat
molalityof0.25mol/kg(toreportsuchhighconcentrationsweprefer
InordertoprovethatthestudiedHC-RCMprocessgoesviaback-
bitingofADMETpolymer,oneexperimentwasceasedbeforefirst
dropsofdistillatehavebeencollected(Chart2c).TLCanalysisofthe
reactionmixtureshowsthepresenceofADMETproductsandonly
tracesofsubstrate6(foralmostidenticalTLCpicture,seeFigure3.88
inRef.3).issuggestthatintheveryfirstminutesofthereactionthe
substrateisconvertedmainlyintooligomericandpolymericspecies
(notealargespotatR=0inTLC,forNMRanalysisofthepolymer,
seeSI).Notably,thesameTLCprovesthatmacrocycle7already
startedtoform.
HavingachievedforthefirsttimeasuccessfulRCMmacrocyclisa-
tioninconcentrationof0.25mol/kg(ca.200mM;so40timeshigher
thenrecommended)wewerecurioustocheckifthemethoddevel-
opedbyuscanworkwithothersubstrates,too.However,beforetry-
ingthis,ashortoptimizationwasundertaken,usingXIIasthemodel
f
3
tousemolality[mol/kg]insteadofmolarity[mol/dm],howeverthe
laterisalsoprovidedforconvenience).
4
ACS Paragon Plus Environment

Page 5 of 8
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
Toourdelightalloftesteddienes,bothinternalandterminalones, setupthatcanbeconsideredpractical.AstheHC-RCMprocess
yieldedexpectedmacrocyclicproductswithgoodtoexcellentselec- seemstoworkwellwithinternalolefins,wesimplyutilizedarenew-
tivity(allbutone>90%)andusuallyhighyield(Scheme4).From13- ablebio-basedmaterial—oleicacid—asthesubstrateinsynthesisof
membered(E/Z)-yuzulactone(9)till17-memberedvaluableIsoam- 7and27,withoutaneedtoconvertitfirstbyethenolysisinto9-de-
24
bretolide(17)productswereformedwiththesameeasiness,only cenoicacid. Fortunately,theotherproductsofthisRCMreaction—
19-memeberedring(19)wasobtainedinloweryield(55%).Diene olefinsderivedfromtheC-Cdoublebondendgroups(CH,CH,
2 5 8 17
12,anesterofbio-sourcedoleicacidandcitronellolledtoloweryield fordetailsseeSI)wereeasytoseparatefromthemuskduringdistilla-
too(56%),butitshallbenotedthatinthiscasemetathesisproceeds tion.
betweenonedisubstitutedandonetrisubstitutedC-Cdoublebond TopushthelimitsofourHC-RCMmethod,werepeatedthecy-
—achallengingsituationevenathighdilution.Notonlylactonesbut clizationof6underevenhigherconcentration(33wt.%,1.23
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
alsomacrocyclicether(10)canbeproducedbythismethod.
mol/kg,soca.700mM)andstillenjoyedverygood78%isolated
yieldof16-memberedmacrocycle7in0.5gramscale,and68%of
yieldin3gramscale(Scheme6).Bearinginmindthattherecom-
mendedconcentrationformacrocycliclactonesformationinclassical
RCMinsolutionisca.140timeslower(5mM),ourmethod—al-
thoughstillatthebeginningofdevelopment—seemstohavesome
practicalperspective(Scheme6).Forexample,toproduce3gramsof
7usingclassicalRCMat5mM,assumingthequantitativeyieldof
thisprocess,oneshalluse2.5Loftheorganicsolvent.Inourcase,we
needonly15g(18mL)ofPAO6,adiluentthathaditsoriginina
nearbygasstation.
Encouragedbyaboveresults,weatemptedtoexamineourHC-
RCMprotocolwithanon-macrocyclicsubstrateaswell.Seven-mem-
beredketonescanberelativelyeasilyformedbyRCM,howeverifthis
cyclizationisnotfacilitatedbyorpe–Ingoldeffectthehighdilution
3
(5mM)isrecommended. Forexample,itwasreportedthatketone
23
21cannotbeformedbyRCMinneat. Wewerethereforepleasedto
seethatdiene20waseffectivelycyclizedat200mM,leadingselec-
tivelytotheexpectedproduct21in79%isolatedyield(Scheme5).
Scheme5.ProbingtheLimitsofHC-RCM
Scheme6.PreparationofMacrocycleswithMuskSmellby
a
HC-RCMusingStandardLaboratoryVacuumPump
Finally,16-memberedmacrocycle4,describedbyFürstnerasimpos-
sibletobeobservedinRCM,evenathighdilution,duetolackoftem-
6
platingeffect,inourmethodwasformedat200mMconcentration,
althoughinlimitedyield(22%,Scheme5).Anyway,takinginaccount
thatinthiscasetherearenoconformationalconstraintsthatcanre-
ducetheentropicpenaltyofthecyclization,andthatthisisthevery
firstreportedexampleofpurelyhydrocarbonunbiasedmacrocycle
everobservedinRCM,thisresultsisoftheoreticalimportance.
a
b
c
Greencolordenotesbio-sourcedfragments.At0.5gramscale.At3
gramscale.Reactionwasperformedfor2×6h.
Fortheintroductoryresearchandforassessingthescope,theexpen-
sivediffusionvacuumpumpwasusedbyus.However,ourprospec-
tivegoalistoofferthismethodologytoindustrialusers,ofcourse
whenitwillbematureenough.Tobringusclosertothisfuturegoal
wedecidedtotestHC-RCMinmorepracticalconditions,namelyus-
ingthestandardrotary-vanepumppresentinpracticallyallorganic
chemistrylaboratoriesworldwide.epieceofhardwareavailablein
ourlabs,theVacuumbrandtRZ2.5introductory-levelpumpwascer-
Finally,wetriedourluckinmakingmacrocylizationinreallycon-
centratedmixtures.esameHC-RCMprocessconducedat67wt%
diene6inPAO6(concentration4.9mol/kg,ca.1400mM)gaveonly
26%isolatedyieldof7wasobtained,howeverwithsillsatisfactoryse-
lectivityof89%.Whenweriskedalmostneatconditions(90wt.%,25
mol/kg,ca.1900mM,0.95mol%ofXI)still34%ofmuskmacrocy-
cle7wasproducedwith83%selectivity.Bycontinuingthedistillation
foralongertimeandwith1.7mol%ofXIitwaspossibletoincrease
theyieldto65%,althoughatthecostoferodedselectivity(72%,for
details,seeSI).Despitethefactthatthistimetheconcentrationwas
280-380timeshigherthatthoseusedtypicallyforasolution-based
RCM,andnospecialhardware—otherthanstandardlaboratoryvac-
uumpump—isneeded,wearenotfullysatisfiedwiththeseresults.
–3
tifiedtogivemaximumvacuumof10 mBar.Aswecheckedusinga
separateMcLeodvacuumgaugeinstalledattheendoftheglassreac-
tion/distillationapparatus,theHC-RCMofamodeldiene(6)was
–2
operationalatpressure10 mBar.erefore,usingastandardlabora-
torypumpwewereabletoprovethatvaluablemusks—unsaturated
analogueofExaltolide(7)and(E/Z)-civetone(27)canbesuccess-
fullyobtainedin92and69%yield(Scheme6),atconcentrationof
0.25mol/kg(ca.200mM,9-11wt.%)underpracticalvacuum,soina
5
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 8
1
2
3
4
5
6
7
8
3. B.J.vanLierop,J.A.M.Lummiss,D.E.Foggin“Olefin
However,toimproveHC-RCMinclose-to-neatconditions,process
engineersshallbeinvolved,aswethinkthatthefurtheroptimization
ismorerelatedtochemicalengineering(eg.choosingappropriatedis-
tillation/reactorequipment,optimizationofpumpingprotocol,stir-
ring,time,etc.)thentoolefinmetathesischemistryitself.Instead,we
seeourmainachievementinprovingthatproductionofmacrocycles
byRCMispossibleatconcentrationsneverreportedbefore,ifthe
correctconditionsandthecatalystareprovided.
Metathesis:eoryandPractice”(ed.K.Grela.)85−152(Wiley
andSons,2014).
4. R.Hanson,S.Maitra,R.Chegondi,J.L.Markleyin“Handbook
ofMetathesis”Vol.2(ed.R.H.Grubbs,D.J.O’Leary)1−170
(Wiley-VCH,2015).
5. S.Monfete,D.E.Fogg“EquilibriumRing-ClosingMetathesis”
Chem.Rev.109,3783−3816(2009).
6. A.Fürstner,O.R.iel,C.W.Lehmann,“StudyConcerningthe
EffectsofChelationontheStructureandCatalyticActivityof
RutheniumCarbeneComplexes”Organometallics,21,331-335
(2002).
9
Tosumup,weshowedforthefirsttimethatmacrocycliclactones,
ethersandketones(including7-memberedone)canbeobtainedin
highyieldandselectivityatconcentrations40to380timeshigher
thanthosetypicallyusedbyorganicchemistsforsimilarmacrocy-
clizations.UnlikeinclassicalRCM,inourmethodnoregularorganic
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7. a)A.Fürstner,K.Langemann,“ConformationallyUnbiased
MacrocyclizationReactionsbyRingClosingMetathesis”J.Org.
Chem.,61,3942−3943(1996);b)W.J.Wiegers,A.G.Van
Loveren,M.R.Hanna,D.Luccarelli,D.R.Bowen,M.H.Vock,
"Macrocyclic carbonates, processes for preparing same,
organolepticusesthereofandintermediatesusedinsaidprocess"
US4490544(1984);c)Forarecentreportshowingthatwhen
RCMisconducedat35mMconcentration,themacrocyclic
muskyieldisreducedalmostby½(from70to40%),see:T.K.
Olszewski, A. Tracz, A. Gawin, M. Bieniek, K. Skowerski,
“AmmoniumNHC-taggedolefinmetathesiscatalysts—influence
ofcounter-ionsoncatalyticactivity”NewJ.Chem.,42,8609-
8614(2018);d)SeeTable3.2inRef.3.
8. a)J.C.Conrad,M.D.Edelman,J.A.DuarteSilva,S.Monfete,H.
H. Parnas, J. L. Snelgrove, D. E. Fogg, “Oligomers as
IntermediatesinRing-ClosingMetathesis”J.Am.Chem.Soc.,
129,1024–1025(2007);b)ForadiscussionofJacobson-
StockmayertheoryinthecontextofRCM,seeJ.C.Conrad,D.E.
Fogg,“Ruthenium-CatalyzedRing-ClosingMetathesis:Recent
Advances,LimitationsandOpportunities”Curr.Org.Chem.,10,
185−202(2006).
9. Forselectedreviews,see:a)P.Kraf,J.A.Bajgrowicz,C.Denis,G.
Fráter “Odds and Trends: Recent Developments in the
Chemistry of Odorants” Angew. Chem., Int. Engl. Ed., 39,
2980−3010(2000);b)A. S. Williams, "eSynthesis of
MacrocyclicMusks"Synthesis,1707−1723(1999);c)G.Fráter,J.
A.Bajgrowicz,P.Kraf “Fragrancechemistry”Tetrahedron,54,
7633−7703 (1998); d) A. Gradillas J. Pérez-Castells in
“Metathesis in Natural Product Synthesis” (ed. J. Cossy)
149−182(Wiley‐VCH,2010);d)Foroneofearlyindustrial
disclosuresonmacrocyclicmuskproductionbyRCM,see:Ref.
7b.
10. Uptodatestaticvacuumwasusedinolefinmetathesis(including
RCM)toremoveethylene,whichhasbeneficialeffecttothe
reactionoutcome.Forarepresentativereference,see:T.S.
Ahmed,R.H.Grubbs,"AHighlyEfficientSynthesisofZ-
Macrocycles Using Stereoretentive, Ruthenium-Based
MethatesisCatalyst"Angew.Chem.Int.Ed.,129,11365−11368
(2017).
solventssuchasanhydroustolueneorCHClareused,butratherin-
2 2
expensivenon-volatilediluents,suchasparaffinoilorPAO.Alsothe
useofprotectingatmosphere,Schlenktechniquesoragloveboxisno
needed,astheHC-RCMreactionscanbesetupinairandthenew
catalystsdesignedbyusareperfectlymoistureandairstable.
Itisastonishingthatdespiteofitslogicalsimplicity,thereisnodoc-
umentedapplicationofsuchBB-RCM/distillationprotocolinselec-
tiveproductionofmacrocyclesathighconcentrations.Probably,the
missingelementwasapropercatalyst,andmorespecifically,thecata-
lystpossessinglongevitycombinedwithactivitysufficienttoreact
withstericallyhinderedADMETpolymer.elowstabilityofclassi-
calRucatalystspropagatingspeciesundersuchdemandingcondi-
tionstranslatesintosevereisomerizationofdoublebondsbycatalyst
decompositionproducts,thustoformationofcomplicatedmixtures
28
ofproducts.equestforbetercatalystsforRCMiscontinuing
andwewerepleasedtofindthatafewofourcatalysts—originallyde-
signedtoofferhighfidelityinself-metathesisofα-olefins—alsomade
theselectivehigh-concentrationRCMofmacrocyclespossibleforthe
firsttime.
ASSOCIATED CONTENT
Materialsandmethods,synthesisofsubstrates,detailedexperimental
proceduresandcopiesofNMRspectraofproducts.ismaterialisavail-
ablefreeofchargeviatheInternetathtp://pubs.acs.org/.
AUTHOR INFORMATION
Corresponding Author
*Correspondingauthor.Email:karol.grela@gmail.com
Author Contributions
†eseauthorscontributedequally.
11. A. Michrowska, R. Bujok, S. Harutyunyan, V. Sashuk, G.
Dolgonos, K. Grela, “Nitro-Substituted Hoveyda-Grubbs
RutheniumCarbenes:EnhancementofCatalystActivitythrough
Electronic Activation” J. Am. Chem. Soc., 126, 9318–9325
(2004).
12. H.Li,L.C.daSilva,M.D.Schulz,G.Rojas,K.B.Wagener,“A
reviewofhowtodoanacyclicdienemetathesisreaction”Polym.
Int.,66,7-12(2017).
13. For isomerization as unintended side-reaction encountered
duringself-metathesisofα-olefins,see:M.Rouen,P.Queval,E.
Borré,L.Falivene,A.Poater,M.Berthod,F.Hugues,L.Cavallo,
OBaslé,H.Olivier-Bourbigou,MMauduit,“SelectiveMetathesis
ACKNOWLEDGMENT
WearegratefultotheNationalScienceCentre(Poland)fortheNCN
MAESTROGrantNo.DEC-2012/04/A/ST5/00594forfundingthis
work.
REFERENCES
1. htps://www.nobelprize.org/nobel_prizes/chemistry/-
laureates/1939/ruzicka-lecture.pdf.
2. V.Martí-Centelles,M.D.Pandey,M.I.Burguete,S.V.Luis
“Macrocyclization Reactions: e Importance of Confor-
mational, Configurational, andTemplate-InducedPreorgani-
zation”Chem.Rev.,115,8736−8834(2015).
6
ACS Paragon Plus Environment

Page 7 of 8
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
ofα-OlefinsfromBio-SourcedFischer–TropschFeeds”ACS
Catal.,6,7970−7976(2016).
14. S.H.Hong,D.P.Sanders,C.W.Lee,R.H.Grubbs,“Prevention
ofUndesirableIsomerizationduringOlefinMetathesis”J.Am.
Chem.Soc.,127,17160−17161(2005).
15. S.J.Czarnocki,I.Czelusniak,T.K.Olszewski,M.Malinska,K.
Wozniak,K.Grela,“RationalandenSerendipitousFormation
ofAzaAnaloguesofHoveyda-TypeCatalystsContaininga
ChelatingEsterGroupLeadingtoaPolymerizationCatalyst
Family”ACSCatal.,7,4115−4121(2017).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
16. S.D.Kamau,P.Hodge,A.J.Hall,S.Dad,A.Ben-Haida,“Cyclo-
depolymerization of olefin-containing polymers to give
macrocyclicoligomersbymetathesisandtheentropically-driven
ROMPoftheolefin-containingmacrocyclicesters”Polymer,48,
6808−6822(2007).
17. K. Grela, M. Smoleń, "Ruthenium complexes, method of
producingthem,andtheiruse",PatentEP3294747(2018).
18. M.Dąbrowski,K.L.Grela,"Anovelrutheniumcomplex,the
methodforitspreparationanduseintheolefinmetathesis
reaction"WO2018100515(2018).
19. A. Chołuj, A. Zielinski, K. Grela, M. J. Chmielewski,
“Metathesis@MOF: Simple and Robust Immobilization of
OlefinMetathesisCatalystsinside(Al)MIL-101-NH”,ACS
2
Catal.,6,6343−6349(2016).
20. a)G.A.Bailey,J.A.Lummiss,M.Foscato,G.Occhipinti,R.
McDonald,V.Jensen,D.E.Fogg,“DecompositionofOlefin
Metathesis Catalysts by Bronsted Base: Metallacyclobutane
DeprotonationasaPrimaryDeactivatingEvent”J.Am.Chem.
Soc.139,16446−16449(2017);b)C.S.Higman,A.E.Lanterna,
M.L.Marin,J.C.Scaiano,D.E.Fogg,“CatalystDecomposition
during Olefin Metathesis Yields Isomerization-Active
Ruthenium Nanoparticles” ChemCatChem., 8, 2446−2449
(2016);c)C.S.Higman,L.Plais,D.E.Fogg,"Isomerization
DuringOlefinMetathesis:AnAssessmentofPotentialCatalyst
Culprits"ChemCatChem,5,3548−3551(2013).
21. C.Samojłowicz,M.Bieniek,K.Grela,“Ruthenium-BasedOlefin
MetathesisCatalystsBearingN-HeterocyclicCarbeneLigands”
Chem.Rev.,109,3708–3742(2009).
22. K.Grela,M.Chmielewski,A.Zieliński,M.Milewski,A.Chołuj,
“Immobilizedcomplexesofruthenium ontheMOFtype
carriers,methodforobtainingthemandapplicationsinthe
metathesisofolefins”PatentPL418051(2018).
23. M.D.E.Forbes,J.T.Paton,T.L.Myers,H.D.Maynard,D.W.
SmithJr.,G.R.Schulz,K.B.Wagener,“Solvent-freecyclizationof
lineardienesusingolefinmetathesisandtheorpe-Ingold
effect”J.Am.Chem.Soc.,114,10978–10980(1992).
24. J.Bidange,C.Fischmeister,C.Bruneau,“Ethenolysis:AGreen
CatalyticTooltoCleaveCarbon–CarbonDoubleBonds”Chem.
Eur.J.,22,12226–12244(2016).
25. Forarecentimpressiveexamplesofextendingthecatalyst
longevityinhigh-dilutionmacrocyclisation,see:C.S.Higman,D.
L.Nascimento,B.J.Ireland,S.Audorsch,G.A.Bailey,R.
McDonald, D. E. Fogg, “Chelate-Assisted Ring-Closing
Metathesis:AStrategyforAcceleratingMacrocyclizationat
AmbientTemperatures”J.Am.Chem.Soc.,140,1604−1607
(2018).
7
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 8
1
2
SYNOPSISTOC
100
80
60
40
20
0
3
4
5
6
7
8
9
HC-RCM at 1.23 mol/kg
(this work)
HC-RCM at 0.25 mol/kg
(this work)
Classical RCM in solution
(state of the art)
[Ru] cat.
R
HC-RCM
c = 0.2-1.2 M
R'
( )n
( )n
☹ Low yield
200 300
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
0
100
400
500
600
700
molar concentration (mM)
8
ACS Paragon Plus Environment