Enabling and accelerating C-H functionalization throughcontinuous-flow chemistryGemoets, H.P.L.
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EnablingandAcceleratingC−HFunctionalizationThroughContinuous‐FlowChemistry
PROEFSCHRIFT
terverkrijgingvandegraadvandoctoraandeTechnische
UniversiteitEindhoven,opgezagvanderectormagnificus
prof.dr.ir.F.P.T.Baaijens,vooreencommissieaangewezen
doorhetCollegevoorPromoties,inhetopenbaarte
verdedigenopmaandag10januari2018om16:00uur
door
HannesPaulLucGemoets
geborenteGent,België
II
Ditproefschriftisgoedgekeurddoordepromotorenendesamenstellingvande
promotiecommissieisalsvolgt:
voorzitter: Prof.Dr.Ir.E.J.M.Hensen
promotor: Prof.Dr.V.Hessel
copromotor(en): Dr.T.Noël
leden: Prof.Dr.T.Skrydstrup(AarhusUniversity,Denmark)
Prof.Dr.B.Maes(UAntwerp,Belgium)
Prof.Dr.F.P.J.T.Rutjes(RU,Nijmegen)
Prof.Dr.J.vanMaarseveen(UvA,Amsterdam)
Prof.Dr.A.P.H.J.Schenning
Hetonderzoekofontwerpdatinditproefschriftwordtbeschrevenisuitgevoerdin
overeenstemmingmetdeTU/eGedragscodeWetenschapsbeoefening.
III
Toyou,Ceci.
“Scienceisorganizedknowledge.
Wisdomisorganizedlife.”
‐I.Kant
IV
HannesP.L.Gemoets
EnablingandAcceleratingC−HFunctionalizationThroughContinuous‐Flow
Chemistry
A catalogue record is available from the Eindhoven University of
TechnologyLibrary.
Theworkdescribed in this thesis has been carried outwithin theMicro
Flow Chemistry and Process Technology group, Eindhoven University of
Technology,TheNetherlands.The researchwas financially supportedby
theNetherlandsOrganization forScientificResearch(NWO)viaanECHO
grant(713.013.001).
(FSCLogo)
ISBN:978‐94‐028‐0866‐7
Copyright©2017byHannesP.L.Gemoets
CoverdesignbyEvelienJagtman,http://evelienjagtman.com/
V
TableofContents
Chapter1 IntroductiontoC−HFunctionalizationandFlowChemistry
Chapter2 Aerobic C−H Ole ination of Indoles via a Cross‐
DehydrogenativeCouplinginContinuousFlow
Chapter3 Merger of Visible‐Light Photoredox Catalysis and C−H
Activation for the Room‐Temperature C‐2 Acylation of
IndolesinBatchandFlow
Chapter4 MildandSelectiveBase‐FreeC−HArylationofHeteroarenes:
Optimization,scopeandApplication
Chapter5 MildandSelectiveBase‐FreeC−HArylationofHeteroarenes:
MechanisticInvestigation
Chapter6 AModularFlowDesignforthemeta‐SelectiveC−HArylation
ofAnilines
Chapter7 FlowSynthesisofDiaryliodoniumTriflates
Chapter8 A Critical Assessment of C−H Functionalization for API
Synthesis:ACaseStudy
Summary
ListofAbbreviations
Acknowledgements
ListofPublications
CHAPTER1
Introduction to C−H Functionalization and
FlowChemistry
Thischapterisbasedon:
Gemoets,H.P.L.;Su,Y.;Shang,M.;Hessel,V.;Luque,R.;Noël,T.Chem.Soc.
Rev.2016,45,83‐117
Gemoets,H.P.L.;Hessel,V.;Noel,T.ReactorConceptsforAerobicLiquid‐
phaseOxidation:Microreactorsandtubereactors.InLiquidPhaseAerobic
OxidationAnalysis:IndustrialApplicationsandAcademicPerspectives;Stahl,
S.,Alsters,P.L.,Eds.;Wiley‐VCH:Weinheim,2016;pp397‐419.
Chapter1
2
ABRIEFHISTORYOFC−HACTIVATION
Alkanes, or saturated hydrocarbons, are the principal components of oil
and natural gas feedstocks. Despite their abundance, only few practical
processes to directly convert these hydrocarbons into valuable products
exist.*Thepoor reactivityof alkanes is also exemplifiedby theiroriginal
name “paraffins”, derived from Latin parum and affinis, meaning “poor
affinity”.TheinertnessofalkanesliesinthestrongcovalentC−CandC−H
bonds that keep the molecule together: the bond dissociation energies
(BDE) for such bonds are typically around 90‐100 kcal/mol and the
carbon‐hydrogen bonds are regarded as non‐acidic (pKa = 45‐60) (see
Figure1.1).1
Figure1.1.BDEsandpKaforselectedhydrocarbonC−Hbonds.
Consequently, alkanes are often labeled as ‘the noble gases of organic
chemistry’.1c Nevertheless, atmospheric oxygen is capable of activating
alkanesathightemperatures.Thereactionbetweenoxygenandalkanesis
highly exothermic and results in the formation of thermodynamically
stablewater and carbondioxide. It isworthnoting that, up to date, this
rudimentarychemistrypracticestillrepresentsthemostcommonwayto
provide energy world‐wide. Albeit essential to our current society, the
reactionbetweenoxygenandalkanesisnotsyntheticallyusefulintheeyes
of an organic chemist. Alkanes constitute a significant fraction of the
*Whilemost common practices, such as cracking and thermal dehydrogenation,candelivervaluableolefinsasprimarybuildingblocks,theseindirectapproachesareenormouslyenergyintensiveandofferlittlecontroloverselectivity.
Introduction
3
carbon pool present on our planet, and the possibility to selectively
activate them for the synthesis of valuable organic compounds would
representamajoradvanceinthefieldoforganicchemistry.
For over a century, chemists have pursued the development of novel
strategies to manipulate inexpensive and abundant hydrocarbon
fragments in a controlled manner. The direct activation of C−H bonds
would indeedrepresenta trueexpansionof theorganicchemist toolbox,
allowing to overcome traditional strategies based on the reactivity of
nucleophilestowardselectrophiles.Thefirstevidenceoftheso‐calledC−H
bondactivationdatesback to the endof thenineteenth century,whena
metal promoted C−H activation was reported by Volhard and Dimroth.2
Theirreportfocusedonthedirectmercurationofaromaticmoieties,thus
breakingtheC−Hbondanddisplacingthehydrogenwiththemetalcenter
(see Figure 1.2). Despite this early discovery, another 60 years passed
before the use of transition metal chemistry for C−H activation became
relevant.
Figure1.2.EarlyexamplesofC−HActivation.
1
Chapter1
4
During the mid‐60’s, Chatt et al. reported the C−H metalation of
naphthalenethroughtheinsertionofaruthenium(0)complex(seeFigure
1.2).3Afewyearslater,ShilovdiscoveredthefirstinnateC−Hactivationof
saturated hydrocarbons (alkanes) by reporting the platinum‐catalyzed
H−Dexchangeandhalogenationofmethanegasandanalogues.4Notably,
theauthorsobservedthattheproductsobtainedinbothreactionsshowed
different ratios compared to the products obtained through a radical
pathway.Suchadifferenceintheratiosoftheproductswasexplainedby
postulatingthatboththeH−Dexchangeandthehalogenationofmethane
proceedthroughtheformationofanalkylplatinumintermediate.
Around the same period, Fujiwara and Moritani reported the first
carbon‐carbon bond formation through cleavage of aromatic, as well as
aliphatic,C−Hbonds(Figure1.3).5Notably,theintroductionofanoxidant
in their protocol allowed to reduce the amount of transition metal (i.e.,
palladium)tocatalyticamounts.6Forthesereasons,theFujiwara‐Moritani
coupling† reaction is often considered the first practical C−H activation
methodology reported, and can be regarded as the fundamental
transformation that initiated the field of metal‐catalyzed C−H
functionalizationchemistry.
Figure1.3.TheFujiwara‐Moritanicouplingreaction.
†Oftencalledtheoxidative/dehydrogenativeHeckreaction,theFujiwara‐Moritanireaction(1967‐1969)wasactuallyreportedprior to theMizoroki‐Heckreaction(1971‐1972).
Introduction
5
FROMCROSS‐COUPLINGTOC−HFUNCTIONALIZATION
Since its introduction in the 70’s, cross‐coupling chemistry completely
revolutionizedthewayorganicchemistsconceivethesynthesisoforganic
molecules.7 Cross‐coupling strategies allow the efficient formation of
carbon‐carbonandcarbon‐heteroatombondsbymatchingorganometallic
(or organoboron) nucleophiles with organohalide electrophiles in the
presence of a transition metal catalyst (mostly palladium) and a ligand
(see Figure 1.4 a). Following their discovery, cross‐coupling methods
became the most reliable methodologies for the preparation of
(hetero)biaryl structures, which represent important motifs both in
natural products and pharmaceuticals. Nowadays, a plethora of named
reactions, such as Mizoroki‐Heck, Negishi, Suzuki‐Miyaura, Sonogashira
andBuchwaldHartwig coupling, are routinely applied inpharmaceutical
industry andmaterials science.8 Cross‐coupling chemistry owes its great
success to the possibility to control the regioselectivity of the products
obtained.‡ The newly formed C‐C bonds are selectively constructed
between the carbon‐halide position of one moiety and the carbon‐
organometallic position of the other moiety. However, the presence of
leaving groups selectively activate the carbon bonds results in the
concomitant production of stoichiometric amounts of chemical waste.
Therefore, in terms of economical cost and sustainability, cross coupling
methods cannot fully satisfy the 12principles of green chemistry,which
arecurrentlyrecognizedasimportantguidelinesinthechemicalindustry.9
‡AlthoughintheseyearstherewereanumberofinitialreportsonthedirectC−Hbond functionalization (e.g., Fujiwara‐Moritani reaction), it appears that forreasonofselectivity,theattentionofresearcherswasdrawntopre‐functionalizedsubstrates.
1
Chapter1
6
Figure1.4.Traditionalcross‐couplingchemistryandC−Hfunctionalization forcouplingchemistry.
In this context, cross‐coupling chemistry has experienced an extensive
innovationaimedatadaptingoldmethodologiestotherecentneedsofthe
chemicalindustry.Asaconsequence,couplingreactionsproceedingunder
milderconditions,withlowercatalystloadingandfacilitatedbyaplethora
of tailor made ligands have been reported.10 However, despite these
efforts,manycross‐couplingreactionsstillsufferfromlowatomefficiency
and high costs. A solution to improve the atom efficiency would be to
circumvent entirely the need for pre‐functionalization substrates, and
utilize instead C−H bonds as ‘functional handles’ (see Figure 1.4 b). As
stated above, direct C−H functionalization§ was long considered as the
‘holygrail’inmodernorganicchemistry,andonlyfewsuccessfulattempts
were reported (vide supra).11 The reason is that the implementation of
§C−Hfunctionalizationsforcarbon‐heteroatomcouplingandalternativeactivationpathways, such as photoredox or electrochemistry are not included in thisdiscussion.12
Introduction
7
directC−Hbondactivationnotonlyleadstogreenersynthesis,butitalso
provides a true paradigm shift in organic chemistry, affording novel
regioselective functionalizations beyond conventional synthetic
capabilities(seeFigure1.5).
Figure1.5.AdvantagesanddisadvantagesofC−Hfunctionalization.
However,thankstoitsappealforapplicationinmedicinalchemistry,C−H
functionalizationrecentlybecameapowerfulenablingtooltoexplorenew
chemical spaces. Moreover, C−H functionalization represents an ideal
methodology for the so‐called “late stage functionalizations (LSF)”, as it
allowsmedicinalchemiststoselectivelyactivateC−Hbondsinalaterstage
inthesynthesisofdrugcandidates,thusaffordingapointofdiversification
oftheleadcandidatetogenerateclosehomologueswithouttheneedfora
denovosynthesis.13
It is worth noting that coupling reactions by means of C−H
functionalization can proceed via different pathways. Therefore, a useful
classificationofthesetransformationscanbedoneaccordingtothe“redox
concept” (see Figure 1.4), as opposed to traditional cross‐coupling
reactions that are considered to be redox‐neutral (isohypsic) processes.
Fortraditionalcross‐couplingmethods,thegeneralacceptedmechanismis
describedwithacatalyticcyclestartingwiththeoxidativeadditionofthe
1
Chapter1
8
organohalide substrate to themetal catalyst (e.g.,Pd0) (seeFigure1.6).7a
Next, the catalytic cycle proceeds with a transmetalation step with the
organometalliccouplingpartner,generatingametalcomplexbearingboth
couplingfragments.Subsequently,reductiveeliminationresultsintheC−C
bondformationwiththeregenerationoftheactivecatalyst.Contrariwise,
C−H functionalization is initiated through a C−H activation step. Then,
dependingonthecouplingpartner,severaldifferentstepscantakeplace
(see Figure 1.6, a, b and c).1a, 14 In case a, an oxidative addition of the
electrophiletakesplace,renderingahighlyoxidizedmetalcomplex(PdIV)
andfollowedbyareductiveeliminationthatclosesthecatalyticcycle(the
arrowdirectly from [R1‐PdIV‐R2] to PdII is not shownbelow).Notably, in
sucha case the catalytic cycle is regardedan isohypsicprocess, sinceno
external oxidant is needed.On the other hand, in both caseb andc, the
secondstepof thecycle is representedeitherby transmetalationorC−H
activationrespectivelyandaffordsacomplexsimilar to theoneobtained
in traditional cross‐coupling processes. However, after the reductive
eliminationstep,thecatalystisobtainedinitsreducedform(Pd0).
Figure 1.6. Comparison of Cross‐coupling and C−H functionalization for couplingchemistry.
Introduction
9
Therefore, in order to render the reaction catalytic, the presence of an
appropriateoxidantisrequiredtocapturetheredundantelectronsandto
re‐oxidizethecatalysttoitsoriginalstate(PdII).Thus,bothcasesbandc
are considered tobeoxidativeprocesses. In termsof atomeconomy, the
ideal case is represented by the direct coupling of two C−H bonds. This
type of reaction is called a cross‐dehydrogenative coupling (CDC), and
affords the C‐C bond formation via the net elimination of two hydrogen
atoms.15
C−H bond functionalization reactions are limited by several
fundamentalchallenges:Firstly,the‘inert’natureofC−Hbondsentailsthe
necessity for high activation energies (i.e., high temperatures). Secondly,
theubiquitousnatureofC−Hbondsposesachallengeforthechemo‐and
regioselectivemodificationofasinglesite.Lastly,asexemplifiedincasesb
orc,thenecessityforanexternaloxidantoftenresultsintheuseofover‐
stoichiometric amounts of hazardous or metal‐containing oxidants. In
order to overcome these inherent hurdles, some successful strategies
emerged. As examples, the installment of a directing group, or the
presenceofaninternaloxidantarevalidapproachesthatcanfacilitatethe
C−Hactivationandreoxidationsteprespectively,thusprovidingimproved
regioselectivities and milder reaction conditions.16 As of today, many
dedicated researchers, such as Du Bois, Fagnou, Ackermann, Gaunt,
Hartwig, Glorius, Sanford, Yu andDavies, among others, are pushing the
boundariesofC−Hfunctionalizationfromtheimprobabletothepossible.
1
Chapter1
10
FLOWCHEMISTRYASANENABLINGTOOL
Ever since Williamson’s first reported synthesis of ethers,17 organic
chemists have been rather conservative towards their laboratory
equipment.Thetraditionalround‐bottomflaskhasnotchangedinshapein
the last centuries and is still regarded as themost fundamental piece of
glasswareinanychemicallab.Althoughveryappropriateforlabpractices
and small scale chemical synthesis, round bottom flasks are highly
inefficientvesselsforlargescalesynthesis,duetothelackofcontrolover
heating and mixing. Therefore, in the industrial sector, such as the
petrochemicalandpolymerindustries,traditionalglasswarehaslongbeen
replaced by tubes and pipes as vessels for production scale. Moreover,
tubing and pipes afford a continuous mode of operation which in turn
provideshighperforming,cost‐effective,safeandatom‐efficientchemical
operations.18
On the other hand, the pharmaceutical and fine‐chemicals industries
still conduct a large part of their production in large scale stirred tank
batch reactors. This is largely due to the relatively smaller scale of
productionofthepharmaceuticalindustry,comparedtothepetrochemical
sector, and to the long time‐frame (1 to 2 decades) required from the
identification of a lead candidate and its ton scale production. In other
words,inordertoavoidtime‐consumingandexpensiveredesigningofthe
active pharmaceutical ingredient (API) synthesis, scale‐up in the
pharmaceutical sectormainly consists in the use of progressively larger
reactors.However, sucha scale‐upstrategy isoftencumbersomeand far
from optimal. The typical limitations observed during the scaling up of
APIs synthesis are connectedwith the poor degree of control in stirred
tankreactorsoverkeyreactionparameters(suchastemperature,stirring
efficiency and pressure). Moreover, the inefficient control of these
Introduction
11
parametersmightposepotentialsafetyissue(e.g.,hotspotformationand
runawayreactions)whenscalingupproductiontothetonscale.19
A technology that can greatly improve the issues associated with
reactor scale‐up as well as reducing safety concerns is continuous‐flow
chemistry.20,**This isduetothefact that flowreactorsofferuniqueheat‐
andmass‐transport capabilities. Because of their high surface‐to‐volume
ratios a finecontroloverall reactionparameterscanbeeasilyachieved,
andtheaccumulationofhighquantitiesofhazardousmaterialsorreaction
intermediates can be avoided. Moreover, the implementation of flow
chemistryintheearlystagesofdrugdiscoveriesprogramswouldallowa
smoothtransitionfromacontinuousgramscaleproductionofleadstothe
kgscaleforclinicaltrials,totonscalerequiredforproductionphase.21This
can be explained by considering that scaling‐up of continuous‐flow
reactors is often a straightforward procedure, requiring a minimal
redesign of the reaction conditions and mainly based on increasing the
throughput of flow reactors by prolonging their operation time (time
equalsquantity), increasing their tubing length (whilekeeping residence
timeconstant)orbynumbering‐uptheflowdevicesinparallel.
The importance and the potential of flow chemistry for the
pharmaceuticalsectorwasofficiallyrecognizedbytheAmericanChemical
SocietyGreenChemistryInstitute(ACSGCI)when,in2005,theyfounded
the so‐called Pharmaceutical Roundtable.22 The Pharmaceutical
Roundtable is a think tank involving allmajor leading companies in the
pharmaceutical sector, andaimedatdefiningkeyaspects to improve the
sustainability and environmental impact of the drug discovery and
**Despitecontinuousflowbeingageneraldefinitionforreactorsofallscales,itisimportant to state that the examples and the research discussed in this thesisfocusoncontinuousreactorsinthemicro(i.d.<1mm)ormilli(1mm<i.d.<fewmm)scale.
1
Chapter1
12
production processes. Notably, in their 2011 report on “key green
engineeringresearchareas”,continuous‐flowmanufacturingwasselected
asthenumberonefieldwiththehighestpotentialtopositivelyimpactthe
overall sustainability of the pharmaceutical sector.23 According to the
Pharmaceutical Roundtable, the main aspects that would benefit by an
extensive implementation of continuous manufacturing would be
improved and reliable quality of products, process safety and
environmental impact. Moreover, an improvement of all these elements
wouldresultinanimprovedtime‐to‐marketandlowercostofproduction,
thusmakingcontinuousmanufacturingappealingalso fromaneconomic
pointofview.
OUTLINEOFTHISTHESIS:C−HACTIVATIONINCONTINUOUSFLOW
Interestingly,thePharmaceuticalRoundtablealsopublishedbackin2007
a report on “key green chemistry research areas” with the purpose to
identify and encourage those methodologies or reactions that would
significantly ameliorate the atom economy, the sustainability and the
waste generation in the synthesis ofAPIs.24According to themajority of
the pharmaceutical companies involved in the think tank, the C−H
activationofaromatics(meaningcross‐couplingtypereactionsthatdonot
require haloaromatics) is the most promising field of research in green
chemistry. Inotherwords, theguidelines supportedbyallworld leading
pharmaceutical companies suggest that both C−H activation and
continuous‐flowprocessesareoffundamentalimportancetoimprovethe
overall sustainability of the pharmaceutical sector. It is therefore
reasonabletopostulatethatthecombinationofthesetwoaspects(thatis
toperformanddiscoverC−Hactivationmethodologiesincontinuous low)
wouldgiveapowerful tool toenable thediscoveryofnovel synthetically
useful strategies,while promoting advances in the two fields deemed as
Introduction
13
most interesting for the pharmaceutical sector. In particular, thanks to
some intrinsic characteristics of continuous processes, C−H activation
methodologies performed in flow reactors would most likely exhibit an
accelerationofthereactionkineticsaswellasanimprovementinreaction
yield and scalability. Specifically, as presented in this thesis, several
inherent advantages of continuous‐flow processing can substantially
improveC−Hactivationstrategies:
1.Flowchemistryforefficientuseofmolecularoxygen
One important reasoning behind the implementation of C−H
functionalizationistodevelopnovelgreenandsustainablealternativesto
traditional chemistries.15, 22 However, the vastmajority of reported C−H
functionalizationreactionsinvolvesanoxidationstep(videsupra),which
requires stoichiometric amounts of transition metal based salts or
hazardous organic oxidants to ensure an efficient catalytic system.
Molecularoxygenorairwouldbeidealreplacementsassustainable,atom
efficientandinexpensiveterminaloxidants.However,onthelargerscale,
aerobic oxidative protocols are often discouraged in pharmaceutical
synthesis due to safety concerns (oxygen headspace) and process
constraints (gas‐liquid mass transfer limitations). Continuous‐flow
processes would represent a viable alternative to overcome these
limitations by providing simple scale‐up procedures, while maintaining
lowhold‐upvolumesandexcellentinterfacialmixingbehaviors(interfacial
areasbetweengasand liquidupto3ordersofmagnitudehigherthan in
batch) (see Table 1.1).25 Furthermore, upon formation of a Taylor flow
regime,(seeFigure1.7)anintenserecirculationwithintheliquidslugsis
obtained,whichallowsforafastrenewaloftheoxygenboundarylayerat
the gas‐liquid interface. Additionally, through the use of mass flow
controllers, the stoichiometry of the gaseous reactant can be easily
1
Chapter1
14
controlled.Moreover,thepossibilitytoapplypressure,thusincreasingthe
solubility of gaseous reactants, is straightforward in microfluidic
devices.20a In Chapter 2, the synergistic use of microreactor technology
andmolecularoxygenassoleoxidantforthecross‐dehydrogenativeHeck
reactionofindolesisdemonstrated.
Table1.1.InterfacialSurfaceArea(a)forOxygenandLiquidphasea
Reactorvessel Innerdiameter(i.d.) aoxygen:liquid(m2.m‐3)
250mLround‐bottomflask 8.6 cm 34
50mLround‐bottomflask 5.0 cm 60
5mLround‐bottomflask 2.8 cm 107
milliflowchannel 1.6 mm<i.d.<1.0 cm 566 ‐ 3536
microflowchannel 0.25 mm<i.d.<1.00 mm 5657 – 22627
aCalculatedforahalf‐filledround‐bottomflaskwhenliquidisstatic . .. Incaseof
milli‐ or microflow channels, calculated for annular flow regime with equal volumes
. .
.
Figure1.7.Taylorflowregimeinamicrocapillarytubing.
2.Flowchemistryforaccessibleandscalablephotochemistry
Inordertomeetthe12principlesofgreenchemistry,newsyntheticroutes
with an improved environmental footprint are required.9 In the last
decade, visible light photoredox catalysis has emerged as a mild
alternativetoactivatesmallmolecules.Inthisfield,chromophores,suchas
transition metal complexes or organic dyes, are used to harvest and
transformvisiblelightenergyintoanelectrochemicalpotentialtoinitiate
Introduction
15
single electron transfers with substrates of interest.20b More recently, it
was demonstrated that photoredox chemistry could be successfully
combined with transition‐metal catalysis to create a dual catalysis
platformforC−Cbondformation.26Thevalueofthisstrategylieswithinits
ability to generate radicals in a mild catalytic manner, and in the
subsequent addition of the generated radicals to a transition‐metal
complex (i.e., single‐electron transmetalation) at room temperature
(Figure1.8).However, scalabilityof suchbatch reactions is cumbersome
duetotheattenuationeffectofphotontransport(Bourgier‐Lambert‐Beer
law), which prevents dual catalysis from being a suitable C−C coupling
protocolon thepreparative scale.However, these limitations can readily
beovercomewiththeuseofcontinuous‐flowmicroreactors.27Dueto the
miniaturized size of the reactor channels, a uniform irradiation of the
reaction mixture can be easily achieved. As part of our interests to
overcome some of the inherent limitations encountered in C−H
functionalization methodologies (such as high energy transition states),
while maintaining an optimal atom economy, we reasoned that dual
catalysis couldbeapowerful strategy forourpurposes.28Asexample, in
Chapter 3, a mild and direct C−H acylation of indoles was developed
employing a dual photoredox/palladium catalysis mode. The room
temperatureprotocoldisplayedexcellentfunctionalgroupstoleranceand
allowedforthecouplingofvariousaromaticandaliphaticaldehydes(both
primaryandsecondary).Moreover,theimplementationofflowchemistry
resulted in a remarkable acceleration of the reaction times, improved
yieldsandstraightforwardscalability.
1
Chapter1
16
Figure1.7.Dualphotoredox/palladiumcatalysistoenablemildC−Hfunctionalizations.
3.Flowchemistryforsolidphase‐assistedsynthesis
The high surface‐to‐volume ratio characteristic of microreactors can
provideseveralbenefitsotherthantheenhancedheat‐andmass‐transfer.
For example, in the field of heterogeneous catalysis, great progresswas
madethankstotheimplementationofso‐calledpackedbedorwall‐coated
continuous‐flow reactors.29 In such devices, the catalytic active species
(mostlytransitionmetalcomplexes)areimmobilizedontoasolid‐support
system (typically silica or alumina). Throughout the duration of the
reaction, the catalyst remains static, while reagents flow through the
reactor. Notably, this immobilization strategy leads to very high local
concentration ratios between the active catalyst and the reagents, thus
resulting in increased reaction rates and higher turnover numbers. In
addition, time‐consuming separation steps can be circumvented. More
recently, continuous flow reactors with a supported catalyst have been
appliedinthefieldofhomogeneouscatalysisaswell.30Inthesecases,the
supportedmetalactsasareservoirof thecatalyst’sprecursorcapableof
Introduction
17
releasing the catalytically active species into the reaction stream.
Remarkably, after participating in the catalytic cycle, the active catalyst
canre‐adsorbonthesolidsupport(i.e.,leaching/re‐adsorptionsystem).In
Chapter 6, a copper tube flow reactor (CTFR) was constructed out of
inexpensiveandcommerciallyavailablecoppertubing,inordertoperform
themeta‐selectiveC−Harylationofelectron‐richanilines inacontinuous
process.Inthiscase,theimplementationofacoppercoilcomprisingboth
thereactorbodyandthereservoirfortheactivecatalyticspecies(i.e.,CuI),
resulted in a significant breakthrough in terms of operational simplicity
forC−Hactivationchemistry.
4.Flowchemistryforin‐linepurificationsanddown‐streamprocessing
The vastmajority ofwork‐up procedures employed in the fine chemical
industry relies on conventional ‘off‐line’ methods. These down‐stream
procedures often employ large quantities of solvents, and frequently
requiremoretimethanthesynthesisitself.Inthefieldofdrugdiscovery,
time is of the utmost importance: in order to accelerate the complex
processof identification,validationandapprovalonthemarketofadrug
candidate, it is of vital importance to design time efficient processes.
Unlike batch processing, flow chemistry opens the possibility to
implement in‐line workup procedures.31 The most commonly employed
workup devices for continuous reactors are membrane‐based
separators.32 Such devices can be operated in a telescoped fashion to
achievestraightforwardcontinuous liquid‐liquidorgas‐liquidextractions
(see Figure 1.9). In Chapter 6, a commercially available liquid‐liquid
membrane separator (Zaiput) was used in‐line in order to separate the
transition‐metalcatalystusedfortheC−Harylationstepfromthedesired
product.Specifically,theintroductionoftheextractionmoduleresultedin
adramaticaccelerationoftheentireprotocol(consistingoffourdifferent
1
Chapter1
18
modules, including workup procedures), thus affording the desired
productwithinatotalresidencetimeof1hour.Moreover,owingtothein‐
lineextractionprocedure,theneedforfurtherpurificationstepscouldbe
obviated.
Figure 1.9. Continuous purification of a reaction stream using a membrane‐basedseparator.
5.Flowchemistrytotamehazardousreactionconditions
Performing highly exothermic reactions in a stirred tank reactor might
leadtohotspotformationortothermalrunaway.Inordertocircumvent
these matters, chemists generally reduce heat generation either by
workingunderdilutedconditions,byslowlyaddingreagentsovertimeor
by intense cooling of the reactor (in most cases, more than one of this
strategies might be required). Despite being practical for small scale
laboratorysynthesis,thesemeasuresarefarfromidealduetothefactthat
they require an intensive consumption of solvent, time and energy.
Moreover, it is important to consider that in order to ensure isothermal
conditionsthroughoutthereaction,thenetheatdissipatingfromareactor
needs to be higher than the heat generated by an exothermic reaction.
Because of the fact that the heat transfer in the reactor is directly
proportional to the area of the reactors wall (~m2), while the heat
generated from an exothermic reaction is proportionate to its volume
(~m3), it becomes clear thatwithin classical batch reactors scale‐up can
become increasingly difficult.33 For this reason, in the pharmaceutical
industrytheassessmentofareactionthermalprofileisavitalpartofany
Introduction
19
scale‐up process. During the scale‐up process, reactions whose thermal
profilecan’tcomplywiththesafetystandardsmightcausetheneedtore‐
developacompoundsynthesis, thussubstantially increasing the time‐to‐
market of a drug candidate.Becauseof their excellent surface‐to‐volume
ratios(upto50000m2.m‐3),microreactorsrepresentanidealtoolforthe
safemanufacturingofAPIsfromsmalltoproductionscale.34InChapter7,
aflowmodulewasdesignedforthe“one‐pot”synthesisofdiaryliodonium
triflates.Recently,thesecompoundshaveattractedmuchattentionasaryl
electrophilic sources, and employed in mild arylation methodologies.
However, despite being shelf stable and non‐toxic, diaryliodonium salts
havealimitedcommercialavailabilityandarethereforeexpensive.Thisis
mainly due to their cumbersome synthesis, characterized by a highly
exothermic profile (up to 180 kcal/mol). To demonstrate the benefits
associated with the implementation of microflow technology for highly
exothermic reactions, we successfully developed a continuous reactor
enabling a fast, scalable and safe synthesis of diaryliodonium salts.
Notably,withasingle100µLmicrochannel,weachievedaproductivityof
upto3.8g/hofdesiredproductandobtainedabroadsubstratescope.
Moreover,reactionsthatwereconsidered“forbidden”whenperformed
in batch due to their safety profile, can be safely managed by using
microreactors. Thanks to improved transport phenomena attainable in
microflowreactors,unstableorotherwisehazardousintermediate,suchas
organolithium,Grignardreagentsordiazocompounds,canbegeneratedin
situ and readily converted to the desired product in a highly controlled
manner. Furthermore, gaining access to such highly reactive reagents
wouldallowscientiststoperformmanyreactionsinmilderconditions(i.e.,
lower temperature). In the context of C−H functionalization, Chapter 4
describes the development of a mild and selective strategy for the C−H
1
Chapter1
20
arylation of heteroarenes, using highly electrophilic aryldiazonium
tetrafluoroborates. A deep understanding of the arylation reaction
mechanism was achieved through DFT calculations and in depth
mechanistic studies, as described in Chapter 5. In Chapter 8, a critical
assessment on the environmental impact of the samemethodology was
conducted, based on experimental results, cost analysis and green
chemistry metrics. The evaluation revealed that the developed C−H
activationmethodologyexhibitedamuchlowerenvironmentalimpactand
required lower cost than a patented procedure for the synthesis of
saprisartan. Moreover, we reasoned that the safety profile of our C‐H
arylationmethodologywould significantly improvebyperforming the in
situ generation of the diazo compounds in continuous flow. Preliminary
results using a microreactor showed increased operational safety., and
good scalability of the procedure. Further optimization towards the
development of a continuous‐flow process appropriate for multi‐gram
scaleproductioniscurrentlyunderwayinourlaboratory.
FUTUREPERSPECTIVE
As summarized in the previous paragraphs, the implementation of
continuous‐flowtechnologycanbringmanybenefitsfortheproductionof
pharmaceuticals and fine chemicals. Owing to the enhanced rate of heat
andmass transfer, the safe handling of explosive or hazardous reaction
mixtures, and the potential to efficiently scale up production, the last
decadehaswitnessedaremarkableincreaseintheuseofcontinuous‐flow
technologyinthepharmaceuticalindustry.Moreover,theintroductionon
themarketofcommerciallyavailableplatformssuitedbothforlaboratory
andproductionscales(e.g., theRseriesfromVapourtec,theH‐cubefrom
ThalesNanoandtheAsiafromSyrris,),35largelycontributedtomakingthis
technologybroadlyavailable.
Introduction
21
Despite all these positive aspects, new progresses in the field of flow
chemistry are of pivotal importance and will require interdisciplinary
efforts from the newer generations of chemists, engineers and material
scientists.Asanexample,owingtothe improvedsafetycharacteristicsof
microflow reactors, pure oxygenor carbonmonoxidehave only recently
beenreportedasatomefficientreagentsinorganicsynthesis.Inthesame
way, many different opportunities might develop thanks to other
possibilities granted by flow chemistry. However, to exploit to its full
potential flow devices, studies on the fundamentals of multiphase
transport phenomena are required and need to be further developed in
combinationwithnovelchemistries.36
Moreover, for significant progresses in the continuous‐flow C−H
functionalization chemistry, full support from both academia and
pharmaceutical industryiscrucial.Interestfromthebigpharmaisfueled
by the increased safety, the higher reaction selectivity and the overall
efficiency of the C−H activation protocols. Such collaborative efforts are
notonlyimportantfromafundingperspective,butindustrialapplications
will facilitate the widespread use of this technology, reduce the overall
cost,andstimulateinnovationsinreallifeexamples.
In this thesis, several examples on the beneficial and successful
combinationofC−Hactivationandmicro lowtechnologyarepresented.
1
Chapter1
22
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CHAPTER2
AerobicC−HOle inationofIndolesviaaCross‐
DehydrogenativeCouplinginContinuousFlow
Thischapterisbasedon:
Gemoets,H.P.L.;Hessel,V.;Noël,T.Org.Lett.2014,16,5800‐5803
Chapter2
28
ABSTRACT
Herein, we report the first site‐selective, Pd(II)‐catalyzed, cross‐
dehydrogenative Heck reaction of indoles in micro flow. By use of a
capillary microreactor, we were able to boost the intrinsic kinetics to
accelerate former hour‐scale reaction conditions in batch to the minute
range inflow.Thesynergisticuseofmicroreactortechnologyandoxygen,
as both terminal oxidant and mixing motif, highlights the sustainable
aspectofthisprocess.
AerobicC−HOle inationofIndolesinFlow
29
INTRODUCTION
3‐Vinylindole motifs play a prominent role in APIs as they impart
interesting biological properties, such as anticarcinogenic, antiviral,
antibacterial and antidepressant activities (Figure 2.1).1–8 Consequently,
reliablemethodstopreparesuchcompoundsareofgreatimportance.One
appealingapproachtopreparevinylindolesisviaacross‐dehydrogenative
Heckcoupling.9,10CDCreactionsallowtheconnectionoftwodifferentC−H
bonds under oxidative conditions. In contrast to traditional cross‐
coupling,11 CDC bypasses the need for pre‐functionalized coupling
partners and produces, in theory, only water as a by‐product. Despite
these apparent advantages, challenges still remain with regard to
reactivity,selectivity,practicalityandscope.12–15
In 1967, Moritani and Fujiwara were the first to report a cross‐
dehydrogenative Heck reaction.16 Their pioneering studies involved the
coupling between olefins and benzene in the presence of stoichiometric
amounts of PdCl2. In 1999, Fujiwara described a highly efficient
dehydrogenative Heck reaction of heterocycles, including (NH)‐indole
substrates, with olefins using catalytic amounts of palladium acetate
(Pd(OAc)2) and tert‐butylhydroperoxide (TBHP) as a terminaloxidant.17
InspiredbytheworkofFujiwara,severalotherresearchgroupscontinued
developing selectiveC‐3 cross‐dehydrogenativeHeck reactions for (NH)‐
indoles,utilizingavarietyofoxidants.18–22In2012,Wangreportedtheuse
of gaseous oxygen as a sole terminal oxidant for this transformation.20
Despite being the cleanest and cheapest oxidant, the use of oxygen in
combination with flammable solvents raises significant safety concerns,
especially on a larger scale. In addition, direct oxidation of Pd(0) by
molecular oxygen is kinetically unfavored, allowing for the reduced
palladiumtoagglomerateintoinactivebulkmetal.23–30Withthisinmind,
2
Chapter2
30
Figure 2.1. Examples of 3‐vinylindole compounds displaying interesting biologicalactivities.3,5,7
the development of a safe and reliable CDC procedure to prepare 3‐
vinylindoleswouldbeanattractivegoal.
Duetoitssmalldimensions,continuous‐flowmicroreactorshavereceived
an increasing amount of attention to carry out such hazardous and
challenging reactions.31–46 Moreover, high gas‐liquid mass transfer
coefficientsaretypicallyobtainedinsuchdeviceswhichprovidesuniform
oxygenconcentrationintheliquidphase.Gas‐liquidflowregimesleadsto
a segmented flow which enables an intense contact between the liquid
phase and gaseous reactants, and induces small vortices inside each
segment, allowing for fastmixing.47–53Weanticipated that these features
could prevent possible palladium agglomeration, assure reoxidation of
Pd(0) to Pd(II) and thus, efficiently avoiding catalyst deactivation. The
excellent gas‐liquid mass transfer in combination with high reaction
temperatures can further boost the reactivity of the catalytic system in
flow. Herein, we report aminute‐range protocol for the formation of 3‐
vinylindoles via cross‐dehydrogenativeHeck reaction in continuous flow
usingoxygenbothasgreenoxidantandmixingmotif.
AerobicC−HOle inationofIndolesinFlow
31
RESULTSANDDISCUSSION
We commenced our investigations by performing an initial screening of
some reaction parameters in batch (Table 2.1). (NH)‐indole (1a) was
reactedwithcyclohexene(2j)inthepresenceof10mol%ofPd(OAc)2asa
catalyst andmolecular oxygen (O2) as sole oxidant in dimethyl sulfoxide
(DMSO).Fromtheliterature,DMSOwasfoundtobestronglycoordinating,
overridinganyeffectthatacidsmayhaveonselectivity(e.g.,migrationto
theC‐2carbon).18,20Asaresult, thereactionischaracterizedbyexcellent
C‐3 regioselectivity and E stereoselectivity. In addition, the use of such
polar solvents is advantageous since they allow effective dissolution of
organic products, efficiently avoiding microreactor clogging. At first,
different organic acids, such as trifluoroacetic acid (TFA), pivalic acid
(PivOH), benzoic acid (PhCOOH) and p‐toluenesulfonic acid (p‐TsOH)
were testedaspossible ligands toactivate thePd(II)‐complex (Table2.1,
entries1‐5).TFAwasfoundtobethemostsuitableligand(entry2).Dueto
itsstrongelectronwithdrawingproperties,TFAoffers the formationofa
more electrophilic Pd(II)‐complex, which facilitates the C–H activation
step. Next, the amount of TFA was investigated (entries 6‐10)
demonstrating that 1 equivalent of TFA was optimal (entry 7). It was
found that lowering the catalyst loading resulted in sluggish reaction
conditionsandincompleteconversion(entries11‐13).
With optimized batch conditions in hand, a continuous‐flow
microreactor setup was assembled as described in Figure 2.2 (see the
Supporting Information (SI) for a detailed description). Initially, we
investigated the temperature dependence in flow while keeping the
residence/reaction time constant at 10minutes (Table 2.2, entries 1–7).
Microreactortechnologyofferstheopportunitytoacceleratereactions
2
Chapter2
32
Table2.1.OptimizationofReactionConditionsinBatcha,54
EntryAdditive(equiv)
Temp(°C)
Reactiontime(h)
Conversion(%)b
1 ‐ 70 1 trace2 TFA(8) 70 1 433 PivOH(8) 70 1 304 p‐TsOH(8) 70 1 145 PhCOOH(8) 70 1 trace6 ‐ 60 14 117 TFA(1) 60 14 >958 TFA(2) 60 14 >959 TFA(4) 60 14 7810 TFA(8) 60 14 6911c TFA(8) 60 14 NR12d TFA(8) 60 14 trace13e TFA(8) 60 14 21
aReactionconditions:1a(0.5mmol),2j(1.0mmol,2equiv),Pd(OAc)2(0.05mmol,10mol%),internalstandard(0.05mmol)andadditiveinDMSO(2.5mL),O2balloonandatthespecified temperature.Amixtureof3k and3lwasobtained. bConversionof indolewasdeterminedwithGC‐FIDanddecafluorobiphenylasthe internalstandard. cNoPd(OAc)2.dPd(OAc)2(0.005mmol,1mol%).ePd(OAc)2(0.025mmol,5mol%).NR=noreaction.
substantially at elevated temperatures without compromising safety
aspects.32,55,56 Moreover, by keeping the exposure time of the reaction
mixture in the heated zone limited to what is kinetically required,
extensiveproductdegradation canbe avoided.We found that increasing
the temperature had a positive impact on the conversion, with 110 °C
beingtheoptimaltemperature(Table2.2,entry4).
AerobicC−HOle inationofIndolesinFlow
33
Figure2.2.SchematicrepresentationofmicroflowsetupandTaylorflowregime.MFC=massflowcontroller.
Afurtherincreaseofthetemperaturegavelowerconversion,presumably
due to catalyst decomposition (Table 2.2, entries 5‐7). Indeed, we
observed microreactor clogging at 150 °C due to excessive Pd(0)
precipitation inside themicrochannels (entry 7).57 Next,we investigated
two more activated olefins (tert‐butyl acrylate and 2,2,2‐trifluoroethyl
acrylate) (entries 9 and 11). To avoid catalyst degradation and thus
microreactor clogging, we found that 2 equivalents of TFA were
mandatory (entries 8‐9). To achieve complete conversion, the residence
timewasdoubledandthereactorwasmadetwiceas long(entry10and
12).Thelatterensuredthathigherflowratescouldbeobtained,leadingto
a higher degree of mixing in the segmented flow regime. This has a
pronounced effect on the gas‐liquid mass transfer, ensuring efficient
palladium reoxidation. To our delight, this provided the conditions
necessarytoobtainfullconversion(entry12).
2
Chapter2
34
Table2.2.OptimizationofReactionConditionsinContinuousFlowa
Entry OlefinTemp(°C)
Conversion(%)b
1 cyclohexene (2j) 70 182 2j 90 413 2j 100 574 2j 110 67;43g
5 2j 120 676 2j 130 597 2j 150 clogging8c tert‐butylacrylate (2c) 110 clogging9d 2c 110 7310d,e 2c 110 9011d 2,2,2‐trifluoroethylacrylate (2a) 110 7912d,f 2a 110 100;82g;82h
aReaction conditions flow: 1a (4.0 mmol), Pd(OAc)2 (0.4 mmol, 10 mol %), internalstandard (0.4mmol) andTFA (32.0mmol, 8 equiv) inDMSO (10mL) loaded in10mLsyringe. 2 (8.0 mmol, 2 equiv) in DMSO (10 mL) loaded in 10 mL syringe. 2 mLmicroreactor, FEP tubing 750 µm inner diameter, tr (residence time) = 10 min, 5:1gas:liquidflowratioprovidedaTaylorflowregime.bConversionofindolewasdeterminedwithGC‐FIDanddecafluorobiphenylas the internalstandard. cTFA(4.0mmol,1equiv).dTFA (8.0 mmol, 2 equiv). etr = 20 min. f4mL microreactor, FEP tubing 750 µm innerdiameter, tr = 10 min, Taylor flow regime. gIsolated yield. h 19F NMR yield withdecafluorobiphenylastheinternalstandard.
Withoptimizedflowconditionsinhand,weexploredthesubstratescope
foroursystembyvaryingtheolefincouplingpartner(Table2.3)andthe
indole moiety (Table 2.4). A reaction between (NH)‐indole and 2,2,2‐
trifluoroethylacrylate(2a)resultedinagoodisolatedyield(82%)inonly
10 minutes reaction time (Table 2.3, entry 1). Remarkably, a control
AerobicC−HOle inationofIndolesinFlow
35
experimentinbatchshowedthatafourhourreactiontimewasrequiredto
achievefullconversion.Inaddition,adropinselectivitywasobserveddue
toprolongedexposureintheheatedzoneleadingtoalowerisolatedyield
of58%(Table2.3, entry1). It is generallyknown that free (NH)‐indoles
areprone todecompositionwhenexposed tohigher temperatures (>60
°C).20 Next, a variety of electron‐deficient olefins (acrylates, fluorinated
acrylates, N,N‐dimethylacrylamide and 1‐octen‐3‐one) and non‐activated
olefins(styreneandcyclohexene)couldbesuccessfullycoupledwithfree
(NH)‐indole inmoderate to excellent yields (27–92%)within a 10 to 20
minutesresidencetime(entries2‐10).C‐3olefinationoccurssmoothlyfor
activated acrylates: (NH)‐indole (1a) reactedwith2a–2e to form3a‐3e
productsinhighyield(72‐92%).Thereactionof6‐fluoroindole(1b)with
methyl acrylate (2f) produced methyl (E)‐3‐(6‐fluoro‐1H‐indol‐3‐
yl)acrylate(3f),apotentialanticanceragent,3withagoodyieldof67%.1‐
octen‐3‐one(2h)showedalowerreactivity(49%)towardC‐3olefination
of indole, as compared to acrylates. Interestingly, within 20 minutes
residencetime,non‐activatedolefins,suchasstyrene(2i)andcyclohexene
(2j), gave the desired compounds (3i and 3j), albeit in more moderate
yield(27‐43%).
Variation of the indole substratewasperformedwith ethyl acrylate as a
benchmarkcouplingpartner.Thereactionproceededsmoothlywitheither
electron‐withdrawing (NO2 and F) or electron‐donating (MeO)
substituents, producing respectively the 3‐vinylindoles 3f, 4c and 4d in
goodyields (66‐78%).Methylsubstituentson theC‐2positionwerewell
tolerated(52‐62%)(Table2.4,entries2and5).TheuseofN‐methylindole
(1c)assubstrateonlyresultedinasmalldropinyield(84%).
2
Chapter2
36
Table 2.3. Olefin Substrate Scope for the Pd(II)‐catalyzed Cross‐
DehydrogenativeHeckReactioninFlowa
Entry Olefin Product tr(min)Yield(%)b
1
10 82;58c
2
20 75
3
15 72
4
10 92
5 10 83
6d
10 67
7
20 70
8
15 49
9
20 27
10
20 43e
aReactionconditions:1a (4.0mmol),Pd(OAc)2 (0.4mmol,10mol%), internalstandard(0.4mmol)andTFA(8.0mmol,2equiv)inDMSO(10mL)loadedin10mLsyringe.2(8.0mmol,2equiv)inDMSO(10mL)loadedin10mLsyringe.4mLmicroreactor,FEPtubing750 µm inner diameter, 5:1 gas:liquid flow ratio provided a Taylor flow regime.ConversionmonitoredwithTLCand/orGC‐MS.bIsolatedyield.cYieldafter4hoursbatch
AerobicC−HOle inationofIndolesinFlow
37
reaction in similar conditions. d6‐fluoroindole (1b) as substrate. eIsolated yield afterhydrogenation.
Table 2.4. Indole Substrate Scope for the Pd(II)‐catalyzed Cross‐
DehydrogenativeHeckReactioninFlowa
Entry Indole Product tr(min)Yield(%)b
1
10 84
2
20 52c
3
20 66
4
20 78
5
20 62c
aReaction conditions: 1c‐1g (4.0 mmol), Pd(OAc)2 (0.4 mmol, 10 mol %), internalstandard (0.4mmol) and TFA (8.0mmol, 2 equiv) in DMSO (10mL) loaded in 10mLsyringe. 2d (8.0 mmol, 2 equiv) in DMSO (10 mL) loaded in 10 mL syringe. 4 mLmicroreactor, FEP tubing 750 µm inner diameter, 5:1 gas:liquid flow ratio provided aTaylor flow regime. ConversionmonitoredwithTLC and/orGC‐MS. bIsolated yield. cNofullconversionwasobserved.
CONCLUSION
In summary, we have developed a fast and straightforward continuous‐
flow protocol for the dehydrogenative C‐3 olefination of indoles, using
molecularoxygenasthesoleoxidant.Becauseoftheenhancedmass‐and
2
Chapter2
38
heat‐transfer characteristics and the high degree of control provided by
microflowprocessing,wewereable toaccelerate the intrinsickineticsof
thecross‐dehydrogenativeHeckcoupling.Furthermore, thehighsurface‐
to‐volume ratio of the oxygen phase with the liquid phase prevents
catalystdegradation.Ourprotocoliseffectivetoprepareawidevarietyof
3‐vinylindoles in good to excellent yields (27–92%), within residence
timesof10to20minutes.Notably,wewereabletopreparemethyl(E)‐3‐
(6‐fluoro‐1H‐indol‐3‐yl)acrylate(3f),apotentialanticanceragent.
EXPERIMENTALSECTION
General procedure for the aerobic C−H ole ination of indoles via a
cross‐dehydrogenative coupling in continuous flow. A 10 ml oven‐
dried volumetric flask was charged with indole (4.0 mmol),
decafluorobiphenyl (0.4mmol) and Pd(OAc)2 (0.4mmol, 0.1 equiv) The
flaskwasfittedwithaseptum.Asecond10mloven‐driedvolumetricflask
was subsequently fitted with a septum. Both flasks were degassed by
alternating vacuum and argon backfill. Both vials were filled with
approximately 5 ml of degassed solvent (DMSO) via a syringe. In
succession,trifluoroaceticacid(8.0mmol,2.0equiv)wasaddedtothefirst
flask via a syringe. Olefin (8.0mmol, 2 equiv) was added to the second
flaskviaasyringe. Inbothflaskssolvent(DMSO)wasaddedtomakethe
solutionupto10ml.Thetwosolutionswereloadedin10mlBDDiscardit
II syringes and fitted to a single syringepump (Fusion200Classic). The
syringe pump andmass flow controllerwere operated at a 1:5 reaction
mixture:oxygen volume flow ratio to obtain a stable segmented flow
regime.Residence timesvariedbetween10 to20minutesdependingon
usedflowrates(liquidflowrate:100–200µl.min‐1,oxygenflowrate:500
– 1000 µl.min‐1). The progress of the reactionwasmonitored using TLC
and/orGC‐MS.Tworesidencetimeswerediscardedtoensuresteady‐state
AerobicC−HOle inationofIndolesinFlow
39
data collection. Next, the reaction mixture was collected until at least 1
mmolofproductwascollected.Theorganicmixturewasdiluted inethyl
acetateand filtered throughaplugofCelite®.Afterconcentrationunder
reducedpressure, the reactionmixturewas introduced intoa separation
funnel.EthylacetateandsaturatedaqueousNaHCO3solutionwasadded.
Layerswereseparatedand theorganic layerwaswashedwithsaturated
aqueous NaHCO3 and brine solution sequentially. Aqueous phase was
washedtwicewithethylacetate.Remainingorganicphasewasdriedover
MgSO4,filteredandconcentratedunderreducedpressure.Purificationby
flash chromatography afforded the product. The final product was
characterizedby1HNMR,13CNMR,19FNMR(ifapplicable),IRandmelting
pointanalysis.
Experimentalsetupofthecontinuous‐flowmicroreactor.Allcapillary
tubing and microfluidic fittings were purchased from IDEX Health and
Science (Figure 2.S1 and 2.S2). The syringes were connected to the
capillaryusing¼‐28flatbottomflangelessfittings.Asyringepump(Fusion
200 Classic) was used to feed liquid reagents through two high purity
fluorinatedethylenepropylenepolymer(FEP)capillarytubings(ID=500
μm)toafirstTefzel®T‐mixer(ID=500μm).Combinedliquidflowswere
mixedinasingleFEPcapillarytubing(ID=500μm)andfedtoasecond
Tefzel® T‐mixer (ID = 500 μm). A Bronkhorstmass flow controllerwas
usedto introducepureoxygenintothereactionmixtureatthesecondT‐
mixer. Oxygen is was added perpendicular to the reaction mixture flow
directioninordertoproduceastablesegmentedflow.Thereactorconsists
ofa880cmlongFEPcapillarytubing(ID=750μm)withaninnervolume
of4ml.Thereactorwascoiledandsubmergedintoathermostaticoilbath.
Uponexitingthereactor, thereactionmixturewascollected inavialand
analyzedbyTLC,GC‐FIDand/orGC‐MS.
2
Chapter2
40
Figure2.S
Figure 2Microreac
2
S1.Flowsetup.
.S2. 1. Mass fctor.
flow controllerr, 2. Syringe ppump, 3. T‐miixer connection
ns, 4.
AerobicC−HOle inationofIndolesinFlow
41
ASSOCIATEDCONTENT
The Supporting Information is available free of charge on the ACS
PublicationswebsiteatDOI:10.1021/ol502910e.
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4220–4232.53. Noël,T.;Hessel,V.ChemSusChem2013,6,405–407.54. Product3jwaspreparedinbatchwithayieldof70%in14hoursreactiontime,see
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CHAPTER3
Merger of Visible‐Light Photoredox Catalysis
andC−HActivationfortheRoom‐Temperature
C‐2AcylationofIndolesinBatchandFlow
Thischapterisbasedon:
Gemoets,H.P.L.;Sharma,U.K.;Schröder,F.;Noël,T.;VanderEycken,E.V.
ACSCatal.2017,7,3818‐3823
Chapter3
46
ABSTRACT
A mild and versatile protocol for the C−H acylation of indoles via dual
photoredox/transition‐metal catalysiswasestablished inbatchand flow.
TheC−HbondfunctionalizationoccurredselectivelyattheC‐2positionof
N‐pyrimidylindoles. This room‐temperature protocol tolerated a wide
rangeoffunctionalgroupsandallowedforthesynthesisofadiversesetof
acylated indoles. Various aromatic as well as aliphatic aldehydes (both
primary and secondary) reacted successfully. Interestingly, significant
acceleration(20to2h)andhigheryieldswereobtainedundermicroflow
conditions.
MergerofPhotoredoxCatalysisandC−HActivationinFlow
47
INTRODUCTION
Withthegenesisoftransition‐metal‐catalyzedC−Hactivationstrategies,1,2
directCsp2−Hbondacylationhaswitnessedasubstantialgrowthoverthe
past decade.3,4 Despite extensive progress in the field, the low reactivity
and limited selectivity continue to be the two main bottlenecks in this
field. Therefore, the development of mild and widely applicable C−H
acylationmethodologiesareofrelevantimportance.3c
Recently, visible‐light photoredox catalysis has played a tremendous
role for the translation of single‐electron transfer processes into mild
catalytic cycles. Its popularity stems from the access to unique synthetic
pathways which have previously been elusive.5 More specifically, the
power of single‐electron transfer processes enabled by photoredox
catalysis has provided new opportunities for transition‐metal‐catalyzed
cross‐coupling reactions.6,7 In addition, these dual catalytic strategies
allowustocarryoutthereactionatroomtemperature.
(Hetero)arylketones are important structural components present in
variousnaturalproducts, pharmaceuticals, andorganicmaterials (Figure
3.1).8 Palladium‐catalyzed, ligand‐directed C−H acylations of
(hetero)arenes with aldehydes, alcohols, or toluene as acyl surrogates
havebeendescribedoverthepastdecadeasapowerfulandversatiletool
inorganic chemistry.9 In theseexamples, thePdII andPdIV catalytic cycle
appears to be themajor pathway and utilizes stoichiometric amounts of
oxidantsincombinationwithelevatedreactiontemperaturestoenablethe
desiredtransformation.
More recently, single‐electron transfer pathways have been
investigatedtogenerateacylradicalsundermildreactionconditions.10
3
Chapter3
48
Figure3.1.Naturalproductscontaining2‐acylindoleframework.
Hereto, α‐ketoacids have been explored as acyl radical precursors to
enable the room‐temperature acylation of aryl rings via a dual
photoredox/palladium catalytic strategy.11 However, to the best of our
knowledge, aldehydes, while being the most abundant acyl surrogates,
haveneverbeen investigated for theC−Hacylationof (hetero)arenesvia
dualphotoredox/palladiumcatalysisatroomtemperature.Thisprompted
us todevelopanovelmethodologywithaldehydesasacylsurrogates for
the direct C‐2 acylation of indoles at ambient temperature by merging
visible‐lightphotoredoxcatalysisandC−Hactivation.
RESULTSANDDISCUSSION
We commenced our investigations with the C−H acylation of N‐
pyrimidylindole (1a) using 4‐methylbenzaldehyde (2b) as a coupling
partner under standard batch conditions (see SI, Table 3.S1). In the
presence of Pd(OAc)2 (10 mol %), tris(bipyridine)ruthenium chloride
(Ru(bpy)3Cl2, 2 mol %), PivOH (50 mol %), and 4 equiv of tert‐butyl
hydroperoxide (TBHP) in acetonitrile (ACN, 0.1 M) under argon, and
exposedtoa24WCFLlightsource,wewerepleasedtofindselectivelythe
C‐2acylatedproduct3bwitha75% 1HNMRyieldafter20h.Prolonged
reactiontimesresultedinafurtherincreaseinyieldupto84%after36h.
Further optimization was carried out employing 4‐fluorobenzaldehyde
(2i)incombinationwithamoreefficient3.12WblueLED(λmax=465nm)
lightsource(Table3.1).
MergerofPhotoredoxCatalysisandC−HActivationinFlow
49
Table 3.1. Optimization of Reaction Conditions in Batch for the C‐2
AcylationofIndolesa
Entry Changestostandardconditions19F‐NMRYield(%)
1 none 73(72)
2 Ru(bpy)3Cl2,36h 70(66)
3 fac‐[Ir(dF‐ppy)3] 264 fac‐[Ir(ppy)2(dtbpy)]PF6 455 [Ir(dF‐CF3‐ppy)2(dtbpy)]PF6 41
6 [Mes‐Acr]ClO4 38
7 noligand 65
8 PivOH 73
9 Ac‐Ile‐OH 71
10 Ac‐Val‐OH 68
11 Boc‐Ile‐OH 70
aReactionconditions:0.5mmolofN‐pyrimidylindole,10mol%Pd(OAc)2,2mol% fac‐[Ir(ppy)3], 20 mol % Boc‐Val‐OH, 2.0 equiv of 4‐fluorobenzaldehyde and 4.0 equiv ofTBHPinACN(0.1M)for20h,blueLEDlight,isolatedyieldinparentheses.
When screening different photocatalysts, tris[2‐phenylpyridinato‐
C2,N]iridium(fac‐[Ir(ppy)3])was foundtobesuperior(Table3.1,entries
1−5). The use of an organic dye, such as 9‐mesityl‐10‐methylacridinium
perchlorate([Mes‐Acr]ClO4),resultedinamodestyieldof38%(Table3.1,
entry6).Furthermore, replacingPivOHwithmonoprotectedaminoacids
(MPAA) as ligands12 resulted in an improved reactivity and avoided the
observed induction period (entries 8−11 and Figure 3.2). Optimal
reactivitywasobservedusingBoc‐protectedL‐valine(Boc‐Val‐OH):ayield
of73%wasobtainedwithin20hunderbluelightirradiation(Figure3.2).
3
Chapter3
50
Figure3.24‐fluorobe
Oneofth
theso‐cal
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when th
However,
flowcapil
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catalyst l
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containin
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itationsofph
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MergerofPhotoredoxCatalysisandC−HActivationinFlow
51
couldbedoubled(0.2M)withoutanylossofreactivity.Furthermore,with
4equivof2iand6equivofTBHP,animprovedisolatedyieldof89%was
obtainedfor3i(seeTable3.2).Thisdramaticimprovementinthereaction
rate (20 h vs 2 h) and yield (72% vs 89%) can be attributed to the
homogeneousirradiationofthereactionmixture.
Withoptimizedreactionconditionsinhand,weevaluatedthescopeof
thereaction(Table3.2).Theacylationreactiontoleratedawidevarietyof
substituentsonthebenzaldehydecouplingpartner. Indoleacylationwith
benzaldehyde(3a)andaldehydesbearingalkyl/arylsubstituents(3b,3c,
3d)werewell‐toleratedandhigh‐yielding(70−88%yield).Whenusingthe
sterically demanding mesitaldehyde (3e), a moderate yield of 44%was
obtained.Bearinganelectron‐donatingsubstituent (4‐OMe), substrate3f
afforded excellent isolated yields of 73% and 79% in batch and flow,
respectively.Moreover,itwasdemonstratedthatbenzaldehydesbearinga
free hydroxyl group (3g, 3h) showed some reactivity (22−44%).
Aldehydescontainingelectron‐withdrawinggroupssuchas4‐F(3i),4‐CF3
(3j),4‐Br(3k),3‐NO2(3o),and4‐CN(3p)allgavethedesiredproductin
goodyield (54−89%).However,3‐bromobenzaldehyde (3l) gavea lower
yield(28%),whereas4‐nitrobenzaldehyde(3n)didnotyieldanyproduct.
Furthermore,3‐iodobenzaldehyde(3m)gaveamoderateyield(53−56%).
Thelatterexample,togetherwith3gand3h(freehydroxylfunctionality),
showcases themildcharacterofourroomtemperatureprotocolbecause
such functional group tolerability is unprecedented for the high‐
temperature C−H acylation protocols of (hetero)arenes. Moreover,
functional handles such as iodine provide opportunities for further
decorationofthemolecule(e.g.,viacross‐coupling).
3
Chapter3
52
Table3.2:BatchaandFlowbscope
aReactionconditionsbatch:1.0mmolofN‐pyrimidylindole,10mol%Pd(OAc)2,2mol%fac‐[Ir(ppy)3],20mol%Boc‐Val‐OH,2.0equivofaldehydeand4.0equivofTBHPinACN
MergerofPhotoredoxCatalysisandC−HActivationinFlow
53
(0.1M),blueLEDlight,20hreactiontime.nd=notdetected.bReactionconditionsflow:1.0mmolofN‐pyrimidylindole,10mol%Pd(OAc)2,0.5mol%fac‐[Ir(ppy)3],20mol%Boc‐Val‐OH,4.0equivofaldehydeand6.0equivofTBHPinACN(0.2M),blueLEDlight,2h residence time; reported yields are isolated yields. c3 h residence time, 8.0 equiv ofTBHP.d4.36mmolscale.e<2.5equivofaldehyde(duetolimitedsolubility),29%startingmaterialrecovered.
Subsequently,relevantheterocyclicaldehydeswereexploredaspotential
acylsource.Reactionswithfurfural(3q)andthenaldehyde(3s)wereboth
high‐yielding in batch as well as in flow (68−85%). Interestingly, 5‐
hydroxymethylfurfural(3r),aversatileplatformchemical,17showedsome
reactivityalbeitwithalowerisolatedyield(34%).
Next,weexploredthepotentialofaliphaticaldehydestoengageinthe
direct C‐2 acylation protocol. Primary aliphatic aldehydes such as (−)‐
citronellal(3t)and7‐hydroxycitronellal(3u)gavehightoexcellentyields
(up to 95%). Notably, when using cyclohexanecarboxaldehyde (2v) as a
branchedaldehyde,nodecarbonylationwasobserved,despitethefactthis
sidereactionwasdescribedintheliterature.18
Instead, the acyl radical could be successfully trapped, rendering the
desired product 3v in a high yield (81%). N‐Bocpiperidine‐4‐
carboxaldehyde(3w)gaveamoderateyieldof54%inflowconditions.The
loweryieldwasmainlyduetothelimitedsolubilityofthealdehydeinthe
reactionmixture.However, theuseofBoc‐prolinal as a couplingpartner
didnotyieldanyproduct(3x).
Ingeneral,itwasobservedthatinadditiontothereducedreactiontime
and lower catalyst loadings, the obtained isolated yields were higher
undermicro flow conditions when compared to the batch counterparts.
Moreover, in order to demonstrate the practical utility of the developed
protocol,acontinuousflowgram‐scaleexperimentwithN‐pyrimidylindole
(1a)and(−)‐citronellal(2t)wascarriedout.Withasimplenumberedup
3
Chapter3
54
scale‐up procedure19 (2 × 3 mL photomicroreactors), 1.41 g (93%) of
isolatedproduct3tcouldbeobtainedinlessthan9hofoperationtime(2
h residence time). Finally, the scope of various indole derivatives was
evaluated with substituents on the 3, 5, 6, and 7 position (4a−4e).
Moderatetogoodyields(55−75%)wereobtainedforthelattersubstrates.
Moreover, among differentN‐substitution or directing groups evaluated,
theN‐pyrimidylgroupprovedtobesuperior(4f−4h).
Encouraged by the obtained results, we further investigated the
possibilityofusingbenzylalcoholsasacylationreagents.Benzylalcohols
can be readily oxidized into the corresponding benzaldehydes in the
presenceoftheoxidantTBHP.20AsshowninScheme3.1a,benzylalcohol
with4‐OMe(5a)or4‐F(5b)assubstituent,couldbesuccessfullyusedas
acylsurrogates,rendering3fand3iin57%and66%,respectively.
CH2OHN
NN
RN
NN
Ostandard condtitions
batch, 20h, room temp,+
1a
3f: R = OMe, 57%3i: R = F, 66%
5a, 5b
a)
NH
ONaOEt
DMSO
24h, 100 °C3ff, 73%
b)
N
NN
O
3f
R
OMeOMe
Scheme 3.1. a) Evaluation of Benzyl Alcohols as Acyl Surrogates. b) TracelessDeprotection.
To further enhance the syntheticutilityof thisprocess, facile removalof
theN‐pyrimidylgroupwascarriedoutinatracelessfashionusingsodium
MergerofPhotoredoxCatalysisandC−HActivationinFlow
55
ethoxide in DMSO for 24 h at 100 °C, with an overall yield of 73% 3ff
(Scheme3.1b).
In order to gain more insight into the reaction mechanism, some
control experiments were carried out (Scheme 3.2). When the reaction
wascarriedoutwith1a and2i in theabsenceofphotocatalyst,TBHPor
light, only traces of acylated product were observed (Scheme 3.2 a).
Moreover, upon the addition of radical scavengers, such as 2,2,6,6‐
tetramethylpiperidyl‐1‐oxyl(TEMPO)orbutylatedhydroxytoluene(BHT)
to the reaction mixture, suppression of the reaction is taking place,
suggesting that aSET‐typemechanism isathand.Moreover, themassof
the trappedacyl radicalwithTEMPO (Scheme3.3,2i″)wasdetectedvia
GC‐MSanalysis.
Scheme3.2.a)ControlExperiments.b)KIEExperiments.
3
Chapter3
56
Finally, kinetic isotope effect (KIE) experiments of1a and its deuterated
analogue1a‐D1wereperformedunderoptimized conditions revealinga
noticeable KIE (kH/kD = 3.4, Scheme 3.2 b). This indicates that the C−H
bond cleavage might be the rate‐limiting step.21 On the basis of our
observationsandanalogousliteratureprecedents,7,9,11aplausiblereaction
mechanism was proposed (Scheme 3.3). The reaction starts with the
formationofafivememberedpalladacycleA.Meanwhile,anacylradicalis
generated via the photocatalytic process. Herein, the photoexcitation of
the photocatalyst produces the excited state (Ir3+*), which is oxidatively
quenched by t‐BuOOH to generate the key radical intermediate t‐BuO·.
Next a hydrogen abstraction occurs between the t‐BuO· radical and 4‐
fluorobenzaldehyde(2i)toaffordtheacylradical2i′.Theacylradical2i′is
then trapped by the palladacycle A, which results in the formation of
intermediateB.IntermediateBcanundergoasingle‐electronoxidationto
PdIV, which closes the photocatalytic cycle via a back electron donation.
Finally,areductiveeliminationtakesplace,releasingthedesiredproduct
3i and regenerating the PdII catalyst. Further efforts toward a detailed
mechanisticunderstandingof this transformation iscurrentlypursued in
ourlaboratories.
MergerofPhotoredoxCatalysisandC−HActivationinFlow
57
Scheme3.3.ProposedPd(II)/Pd(IV)CyclefortheC‐2AcylationofIndoles.
CONCLUSION
In summary, a room‐temperature C‐2 acylation protocol for indoleswas
developed via a productive merger of visible‐light photoredox catalysis
andC−Hfunctionalization.Thereactionwasconductedbothinbatchand
flow and is compatible with a wide variety of functional groups. The
protocolcouldbeextendedfromaromatictobothprimaryandsecondary
aliphatic aldehydeswith good to excellent yields.Moreover, continuous‐
3
Chapter3
58
flowchemistryproveditseffectivenessbydecreasingthereactiontimeup
to10times(2hvs20h),thecatalystloading4times(0.5mol%vs2mol
%), increasing theyieldsandscaling thereactionconditions. Inaddition,
the scope couldbe further extended tobenzyl alcohols as abundant acyl
surrogates.Finally,KIEexperimentssuggest theC−Hactivationtobe the
rate‐limitingstep.
EXPERIMENTALSECTION
General batch procedure. An oven‐dried 10 mL screw‐cap vial was
chargedwithN‐pyrimidylindole (98mg,0.5mmol,1.0equiv), respective
aldehyde (1.0mmol, 2 equiv), Pd(OAc)2 (11mg, 0.05mmol, 10mol%),
Boc‐Val‐OH (22mg, 0.1mmol, 20mol%) and fac‐[Ir(ppy)3] (6.6mg, 10
µmol, 2mol%) subsequently.Anhydrous acetonitrile (5mL, 0.1M)was
added and then the mixture was put under nitrogen. The solvent was
degassedwith a flowof nitrogenwhile being sonicated (setting: degass)
for 15 min. In most cases a suspension was obtained. The degassed
reactionmixturewasputintothephotoreactorunderaflowofairaround
the reaction tube inorder tokeep the reaction temperatureunder37 °C
andTBHP(364µl,2.0mmol,4equiv)wasaddedinoneportion.After20h
of irradiationunder blue LED light the solventwas evaporated from the
clear orange solution and the mixture was adsorbed onto silica.
Purificationbycolumnchromatographyonsilica(EtOAc:Heptane=1:5
or 1: 10) and subsequent sonication in pentane afforded the desired
products.
Generalflowprocedure.A5mLoven‐driedvolumetricflaskwascharged
with Pd(OAc)2 (22.4mg, 10mol%), fac‐[Ir(ppy)3] (3.3mg, 0.5mol%),
Boc‐Val‐OH(43.4mg,20mol%),N‐pyrimidylindole(195mg,1.0mmol).
The flask was fitted with a septum and was degassed by alternating
vacuumandargonbackfill.Approximately2mLofanhydrousacetonitrile
MergerofPhotoredoxCatalysisandC−HActivationinFlow
59
wasaddedviasyringe.Subsequently, thealdehyde(4.0mmol,4.0equiv)
andTBHP(1.1mLofa5.5Mindecanesolution,6equiv)wereaddedvia
syringe.Finally,anhydrousacetonitrilewasaddedtomakethesolutionup
to 5.0mL. The solutionwas charged in a 10mL BDDiscardit II syringe
underargonandwrappedintoaluminumfoilinordertokeepthesolution
inthedark.Next,thecoveredsyringewasfittedtoasyringepump(Fusion
200 Classic) and connected to the inlet of the 3 mL micro reactor. The
outletofthemicroreactorwasfittedtoanargonfilledcollectionflaskwith
septum via a needle connection. The collection flask was covered with
aluminumforinordertokeepthereactionmixtureinthedark.Anargon
balloonwasattachedinordertoensureaconstantpressure.Thesyringe
pumpwasoperatedataflowrateof0.025mL/min(2hresidencetime).An
extra syringe of 10 mL anhydrous acetonitrile was pumped after the
sample(0.025mL/min)inordertocollectthecomplete5mLsample.The
resulted reaction mixture was monitored using TLC and/or GC‐MS. The
organic mixture was diluted in ethyl acetate and was introduced into a
separation funnel. The organic phase was washed with 3x saturated
aqueousNaHCO3and1xwithbrinesolutionsequentially.Aqueousphase
was backwashed once with ethyl acetate. Collected organic phase was
dried over MgSO4, filtered and concentrated under reduced pressure.
Purification by flash chromatography on silica afforded the product. If
necessary, recrystallization was conducted: solids were dissolved in a
minimum of acetone (or dichloromethane) and petroleum ether was
added. Next, the resulted mixture was kept in the freezer (‐26 °C)
overnight.Formedcrystalswerefilteredoffandwashedwithminimumof
petroleumether.Thefinalproductwasweightedandcharacterizedby1H
NMR, 13C NMR, 19F NMR (if applicable) and melting point analysis (if
applicable).
3
Chapter3
60
Removal ofdirecting group.An oven‐dried 10mL screw‐cap vial was
charged with a mixture of3f (65.8 mg, 0.3 mmol), DMSO (2.0 mL) and
EtONa(61.2mg,0.90mmol),andthereactionmixturewasstirredat100
°C under nitrogen atmosphere for 24 h. After cooling to ambient
temperature, the reaction mixture was diluted with EtOAc and washed
withH2O.TheaqueousphasewasextractedwithEtOAc,andthecombined
organic phase was dried over Na2SO4. After filtration and evaporation
under reduced pressure, the residue was purified by flash column
chromatography (petroleumether/ethyl acetate)on silicagel togive the
product3ff.
Kintetic istope effect (KIE). An oven‐dried 10 mL screw‐cap vial was
chargedwithN‐pyrimidylindole (98mg,0.5mmol,1.0equiv), respective
aldehyde (1.0mmol, 2 equiv), Pd(OAc)2 (11mg, 0.05mmol, 10mol%),
Boc‐Val‐OH (22mg, 0.1mmol, 20mol%) and fac‐[Ir(ppy)3] (6.6mg, 10
µmol, 2 mol %) subsequently. Anhydrous acetonitrile‐d3 (5 mL, 0.1 M)
wasaddedandthenthemixturewasputundernitrogen.Thesolventwas
degassedwith a flowof nitrogenwhile being sonicated (setting: degass)
for15minandthenTBHP(364µl,2.0mmol,4equiv)wasadded inone
portionalongwithinternalstandardα,α,α‐trifluorotoluene(0.5mmol).In
an another reaction tube, deuterated N‐pyrimidylindole23 (98 mg, 0.5
mmol, 1.0 equiv; ~ 90% D), respective aldehyde (1.0 mmol, 2 equiv),
Pd(OAc)2(11mg,0.05mmol,10mol%),Boc‐Val‐OH(22mg,0.1mmol,20
mol %) and fac‐[Ir(ppy)3] (6.6 mg, 10 µmol, 2 mol %) subsequently.
Anhydrousacetonitrile‐d3(5mL,0.1M)wasaddedandthenthemixture
wasputundernitrogen.Thesolventwasdegassedwithaflowofnitrogen
whilebeingsonicated(setting:degass)for15minandthenTBHP(364µl,
2.0mmol,4equiv)wasaddedinoneportionalongwithinternalstandard
(α,α,α‐trifluorotoluene, 0.5 mmol). Two reactions were allowed to stir
under ro
mixturew
with19F‐N
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Chapter3
62
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7. For selectedexamplesonphotoredox/cross‐couplingdual catalysis, see a)Wellin,E.R.;Le,C.;Arias‐Rotondo,D.M.;McCusker,J.K.;MacMillan,D.W.C.Science2017,355,380‐385;b)Johnston,C.P.;Smith,R.T.;Allmendinger,S.;MacMillan,D.W.C.Nature,2016,536,322‐325;c)Tlahuext‐Aca,A.;Hopkinson,M.N.;Sahoo,B.;Glorius,F.Chem.Sci.2016,7,89;d)Fabry,D.C.;Ronge,M.A.;Zoller,J.;Rueping,M.Angew.Chem.,Int.Ed.2015,54,2801‐2805;e)Tasker,S.Z.;Jamison,T.J.Am.Chem.Soc.2015,137,9531‐
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9534;f)Xuan,J.;Zeng,T.‐T.;Feng,Z.‐J.;Deng,Q.‐H.;Chen,J.‐R.;Lu,L.‐Q.;Xiao,W.‐J.;Alper,H.Angew.Chem.,Int.Ed.2015,54,1625‐;g)Tellis,J.C.;Primer,D.N.;Molander,G.A.Science2014,345,433‐436;h)Ye,Y.;Sanford,M.S.J.Am.Chem.Soc.2012,134,9034‐9037;i)Kalyani,D.;McMurtrey,K.B.;Neufeldt,S.R.;Sanford,M.S.J.Am.Chem.Soc.2011,133,18566‐18569.
8. a) Shiri, M.Chem. Rev.2012,112, 3508–3549; b) Kochanowska‐Karamyan, A. J.;Hamann,M.T.Chem.Rev.2010,110,4489–4497;c)Somei,M.;Yamada,F.Nat.Prod.Rep.2005,22,73–103;d)Sundberg,R.J.Indoles,Academic,NewYork,1996.
9. ForselectedexamplesontheC‐2acylationof(hetero)arenes,seea)Kumar,G.;Sekar,G.RSCAdv.2015,5,28292‐28298;b)Wang,W.;Liu,J.;Gui,Q.;Tan,Z.Synlett2015,26,771‐778.c)Li,C.;Zhu,W.;Shu,S.;Wu,X.;Liu,H.Eur.J.Org.Chem.2015,3743–3750;d)Yan,X.‐B.;Shen,Y.‐W.;Chen,D.‐Q.;Gao,P.;Li,Y.‐X.;Song,X.‐R.;Liu,X.‐Y.;Liang,Y.‐M.Tetrahedron2014,70,7490‐7495.e)Pan,C.;Jin,H.;Liu,X.;Cheng,Y.;Zhu,C.Chem.Commun.2013,49, 2933‐2935; f) Zhou, B.; Yang, Y.; Li, Y.Chem.Commun.2012,48,5163–5165; g)Wu,Y.; Li,B.;Mao,F.;Li,X.;Kwong,F.‐Y.Org.Lett.2011,13, 3258‐3261;h)Tang,B.‐X.;Song,R.–J.;Wu,C.–Y.;Liu,Y.;Zhou,M.–B.;Wei,W.–T.;Deng,G.–B.; Yin,D.–L.;Li, J.–H. J.Am.Chem.Soc.2010,132,8900–8902; i) Jia,X.;Zhang,S.;Wang,W.;Luo,F.;Cheng,J.Org.Lett.2009,11,3120‐3123.
10. Forroomtemperaturegenerationofacylradicalfromaldehydes;seea)Li,J.;Wang,D.Z.Org.Lett.2015,17, 5260‐5263;b) Iqbal,N.;Cho,E. J.J.Org.Chem.2016,81, 1905‐1911.
11. Forroomtemperatureacylationofarenes:seea)Xu,N.;Li,P.;Xie,Z.;Wang,L.Chem.‐Eur. J.2016,22, 2236‐2242; b) Zhou, C.; Li, P.; Zhu, X.;Wang, L.;Org.Lett.2015,17,6198‐6201;c)Fang,P.;Li,M.;Ge,H.J.Am.Chem.Soc.2010,132,11898‐11899.
12. a)Cheng,G.‐J.;Yang,Y.‐F.;Liu,P.;Chen,P.;Sun,T.‐Y.;Li,G.;Zhang,X.;Houk,K.N.;Yu,J.‐Q.,Wu,Y.‐D.J.Am.Chem.Soc.2014,136,894‐897;b)Engle,K.M.;Yu,J.–Q.J.Org.Chem.2013,78,8927−8955;c)Engle,K.M.;Thuy‐Boun,P.S.;Dang,M.;Yu,J.‐Q.J.Am.Chem.Soc.2011,133, 18183‐18193; d)Engle,K.M.;Wang,D.‐H.; Yu, J.‐Q. J.Am.Chem.Soc.2010,132,14137‐14151.
13. For selected reviews on flow chemistry; see a) Noël, T., Su, Y.; Hessel, V. Top.Organomet.Chem.2016,57, 1‐41. b)Gemoets,H. P. L.; Su,Y.; Shang,M.;Hessel, V.;Luque,R.;Noël,T.Chem.Soc.Rev.2016,45,83‐117;c)Porta,R.,Benaglia,M.;Puglisi,A.Org. Process Res. Dev.2016,20, 2–25; d)McQuade, D. T.; Seeberger, P. H. J. Org.Chem.2013,78, 6384‐6389; e) Newman, S. G.; Jensen, K. F.Green Chem.2013,15,1456‐1472;f)Glasnov,T.N.;Kappe,C.O.Chem.‐Eur.J.2011,17,11956‐11968.
14. For selected reviews on visible light photoredox catalysis in flow:a)Cambié,D.;Bottecchia, C.;Straathof, N. J.W.;Hessel, V, Noël, T.Chem.Rev.2016,116, 10276–10341;b)Su,Y.;Straathof,N.J.W.;Hessel,V.;Noël,T.Chem.‐Eur.J.2014,20,10562‐10589; c)Garlets,Z. J.;Nguyen, J.D.; Stephenson,C.R. J.Isr. J.Chem.2014,54, 351–360.
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3
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16. Straathof,N.J.W.;Su,Y.;Hessel,V.;Noël,T.Nat.Protoc.2016,11,10‐21.17. vanPutten,R.‐J.;vanderWaal,J.C.;deJong,E.;Rasrendra,C.B.;Heeres,H.J.;deVries,
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7301.
CHAPTER4
MildandSelectiveBase‐FreeC‐HArylationof
Heteroarenes:
Part1:Optimization,ScopeandApplication
Thischapterisbasedon:
Gemoets, H. P. L.; Kalvet, I.; Nyuchev, A. V.; Erdmann, N.; Hessel, V.;
Schoenebeck,F.;Noël,T.Chem.Sci.2017,8,1046‐1055
ABSTRACT
Chapter4
68
Amild and selectiveC–Harylation strategy for indoles, benzofurans and
benzothiophenes is described. The arylation method engages
aryldiazonium salts as arylating reagents in equimolar amounts. The
protocol is operationally simple, base free, moisture tolerant and air
tolerant. It utilizes low palladium loadings (0.5 to 2.0 mol% Pd), short
reaction times,greensolvents (EtOAc/2‐MeTHForMeOH)and is carried
outatroomtemperature,providingabroadsubstratescope(47examples)
and excellent selectivity (C‐2 arylation for indoles and benzofurans, C‐3
arylationforbenzothiophenes).
This chapter includes the reaction optimization, performed scope and
applicationforourdevelopedC−Harylationmethodologyofheteroarenes,
MechanisticstudiesandDFTcalculationsarediscussedinchapter5.
C−HArylationofHeteroarenes:Optimization,ScopeandApplication
69
INTRODUCTION
Theubiquityof theheterobiarylmotif inpharmaceuticals, agrochemicals
andmaterialsillustratesitsscientificandcommercialvalue.1Traditionally,
these moieties have been prepared via cross‐coupling strategies which
require pre‐functionalized substrates.2 However, over the last decade,
transitionmetal‐catalyzedC–Harylationprotocolshavebeendevelopedto
enabletheformationofC–Cbonds.3Incontrasttoclassicalcross‐coupling
chemistry, C–H arylation strategies enable direct functionalization of
simpleheteroarenes.
The direct arylation of heteroarenes can be achieved via radical
pathways,e.g.,visiblelightphotoredoxcatalysis4andMeerweinarylation.5
However,thesemethodssufferfromanumberofdisadvantages,including
long reaction times, large excesses of substrates, selectivity issues and
limited substrate scopes. Recently, there has been an increase in the
number of new methods, particularly in the use of metal‐catalyzed
processes.6 Inparticular, theworkbyGaunt,7Sames,8Sanford,9DeBoef,10
Glorius,11Ackermann,12Fagnou13andLarrosa14hasincreasedthenumber
ofusefulC–Harylationtransformationstoenableheteroaryl‐(hetero)aryl
bond formation. Furthermore, these examples have deepened our
fundamentalunderstandingoftheunderlyingchallengesinherentinsuch
processes.However, thestateof theart isstill far fromcompetitivewith
classical cross coupling strategies, e.g. Suzuki–Miyaura cross coupling.
Currenthurdlesincludeharshreactionconditions(i.e.,hightemperature),
thenecessityofstoichiometricamountsofoxidantsand/oradditives,use
of toxic solvent systems, limited selectivity and high catalyst loadings
(typically5to10mol%).Consequently,thedevelopmentofnew,mildand
broadly applicable C–H arylation strategies is still highly desirable.15We
anticipatedthatthedesignofamildandselectiveC–Harylationprotocol
4
Chapter4
70
Scheme 4.1. Pd‐catalyzedC‐2C–Harylationofindoles.
forheteroaromatics(i.e.,indoles,benzofuransandbenzothiophenes)could
beofhighinterestforAPIsynthesis(e.g.,Bazedoxifene,16Saprisartan17and
Raloxifene18). Recently, Correia et al. described a Pd‐based arylation of
heteroarenesusing aryldiazoniumsalts.6iHowever, theprotocol suffered
from high catalyst loadings (10 to 20 mol% Pd), limited scope and
impractical reaction conditions (e.g., biphasic reaction conditions, large
excessesofreagents,andhighreactiontemperatures).Herein,wedescribe
the development of a mild and selective palladium‐based C–H arylation
strategy(Scheme4.1).Notable featuresofouropen flaskprotocolare its
operational simplicity in conjunction with low catalyst loadings, broad
substrate scope, green solvent system, and short reaction times. No
additionaloxidantsoradditivesarerequired.Thestrategyusesequimolar
amountsorslightexcessesofaryldiazoniumsaltsasconvenientarylating
reagents.6l,19
C−HArylationofHeteroarenes:Optimization,ScopeandApplication
71
OPTIMIZATIONOFREACTIONCONDITIONS
We commenced our optimization studies with the Pd‐catalyzed C–H
arylationof1‐methylindole(1a),whichwasreactedwith1.2equivalents
ofbenzenediazoniumtetrafluoroborate(2a) inthepresenceof10mol%
Pd(OAc)2 inN,N‐dimethylformamide(DMF).Asatisfyingyieldof66%for
1‐methyl‐2‐phenylindole (3a) was obtained within only 30 minutes of
reaction time at room temperature (Table 4.1, entry 1). The main
byproductswere3‐(arylazo)‐1‐methylindole(1aa)and2‐aryl‐3‐(arylazo)‐
1‐methylindole (3aa), due to the uncatalyzed electrophilic substitution
reaction between the highly electrophilic nitrogen of the aryldiazonium
salt and the C‐3 position of 1‐methylindole (Figure 4.1 b). Lowering the
catalystloadingto5mol%Pd(OAc)2inDMFresultedinasignificantdrop
inyield(34%).Anovernightcontrolexperimentshowedthatnoproduct
formationwasobserved in theabsenceofapalladiumcatalyst (entry3).
Using polar protic solvents (e.g., isopropanol) resulted in generally high
reactivity and moderate yields. A considerable amount of byproduct
formationwasconsistentlyobserved(seeSupporting Information (SI)). It
wasgenerally found thatcarryingout thereaction in lesspolar (aprotic)
solvents (e.g., DMF/THF/1,4‐dioxane) resulted in reduced byproduct
formation. After solvent screening, THF was considered to be the best
solvent(77%),combiningboththedesiredreactivityandselectivity(entry
5). A control experiment using Schlenk techniques indicated that the
catalystwasnotaffectedbyairandmoisture(entry5).Therefore,all the
followingexperimentscouldbeperformedasopenflaskreactions,making
this procedure appealing for future scale‐up. A catalyst survey
demonstrated that only Pd(OAc)2, palladium trifluoroacetate (Pd(TFA)2)
and,toalesserextent,tris(dibenzylideneacetone)dipalladium(Pd2(dba)3)
wereactivecatalystsforthischemicaltransformation(Entries6–8).The
4
Chapter4
72
Table4.1.OptimizationfortheC‐2Arylationof1‐Methylindolea
EntryCatalyst(mol%)
SolventReactiontime
YieldGC‐FID(%)
1 Pd(OAc)2(10.0) DMF 30min 662 Pd(OAc)2(5.0) DMF 30min 343 ‐ DMF 16h 04 Pd(OAc)2(5.0) solventb 30min <725 Pd(OAc)2(5.0) THF 30min 77;76c6 catalyst(5.0)d THF 2h 07 Pd(TFA)2(5.0) THF 30min 768 Pd2(dba)3(2.5) THF 30min 689 Pd(OAc)2(0.5) THF 1h 8110 Pd(OAc)2(0.2) THF 1h trace11 Pd(OAc)2(0.5) 2‐MeTHF 2h 8712 Pd(OAc)2(0.5) EtOAc:2‐MeTHF(1:1) 1h 8913 Pd(OAc)2(0.2) EtOAc:2‐MeTHF(1:1) 1h 7814e Pd(OAc)2(0.5) EtOAc:2‐MeTHF(1:1) 30min 93;90f
areaction conditions: catalyst, 0.5 mmol heteroarene and 1.2 equiv. benzenediazoniumtetrafluoroborate in 2.5 mL solvent at rt, open flask. bsolvent: H2O, AcOH, EtOAc,propylene carbonate, DMF, acetone, MeCN, Et2O, 1,4‐dioxane, MeOH, EtOH, i‐PrOH n‐BuOH, DCM, DCE, CHCl3, toluene. cSchlenk line techniques used. dcatalyst: 10% Pd/C,PdCl2, Cu(OAc)2, Cu(OTf)2, Pd[P(C6H5)3]4, (MeCN)2Pd(II)Cl2, PEPPSI‐SIPr. e2hpremixingofPd(OAc)2with1‐methylindole,1.0equiv.ofbenzenediazoniumtetrafluoroborateused.fisolatedyield.
useofPd(OAc)2waspreferredoverPd(TFA)2duetoitscostefficiencyand
stability.Furtheroptimizationstudiesshowedthatitwaspossibletolower
the catalyst loading further to 0.5 mol % in THF (entry 9). Even lower
catalyst loading resulted in only trace amounts of product (entry 10).
Finally, 2‐MeTHF was evaluated. This solvent is recognized as a green
solventforsyntheticorganicchemistrybecauseitcanbereadilyproduced
from furfural, a common biomass material.20 Satisfyingly, 2‐MeTHF
C−HArylationofHeteroarenes:Optimization,ScopeandApplication
73
showedevenbetterselectivityforthedesiredproduct(87%),althoughan
increasedreactiontimeof2hourswasrequiredtoobtainfullconversion
(entry 11). Continued optimization studieswith green solvents revealed
thatthereactiontimecouldbehalvedbyusingEtOAc:2‐MeTHF(1:1)as
a solventmixture (entry12). Indeed, this solvent combinationproved to
be superior, as it enabled further lowering of the catalyst loading to 0.2
mol % Pd(OAc)2 (entry 10 vs. 13). However, in the case of 0.2 mol%
Pd(OAc)2,significantincreasesof1aaand3aawereobservedbecausethe
reactivity toward the desired arylation was diminished. Therefore, 0.5
mol%Pd(OAc)2wasconsideredtobeoptimal.
Inparallelwithouroptimizationstudies,aseriesofreactionprogress
kinetic experimentswereperformed to shedmore lighton theobserved
catalystinductionperiod.Unusualkineticshasoftenbeenreportedinthe
field of C–H functionalization, but has seldom been investigated.21
Therefore,inordertoobtainamorerealisticviewofthisactivationperiod,
wemonitoreda seriesof reactions.As canbe seen fromFigure4.1a, an
inductionperiodofapproximately50minuteswasobservedinthecaseof
Pd(OAc)2 (Figure 4.1 a, blue series). As soon as the reaction began (>50
min),aninitialaccelerationoccurred,resultinginS‐curvebehavior.Itwas
postulated that a possible activation period could be necessary between
the catalyst and the substrate. Therefore, premixing experiments were
conducted.Itwasfoundthatpremixing1‐methylindolewithPd(OAc)2(0.5
mol %) in EtOAc : 2‐MeTHF (1 : 1) for 2 hours could eliminate this
observed induction period (Figure 4.1 a, red series). We surmised that
Pd(II) is first reduced toahomogeneousPd(0)complexand is stabilized
by the π‐donating character of 1‐methylindole and/or by the ligand
exchange of OAc with 2‐MeTHF.22 Indeed, a reaction performed with
Pd2(dba)3asastablehomogenousPd(0)substituteshowedthatneitheran
4
Chapter4
74
Figure4.1series), 1.reactions
4
a) Condition
N
M
1a
N
M
b) Possible
N
M
N
1a
1aa
1.a)Yieldasa.1 equiv. of benoccurringinex
ns for reaction pr
e
[Pd] (0.5
EtOAc:2-MeTH
room temp.,
N
(1.
2a
Me
side-reactions
Me
N N
2a
Pd(OA
functionoftimnzenediazoniumcessbenzenedi
rogress analysis
mol%)
HF (1:1) 0.2 M
open flask
2BF4
0 equiv.)
N2BF4
(in excess)
Ac)2
e.Inthecaseofm tetrafluoroboiazoniumtetraf
N
Me
3a
N
Me
N
Me
N N
3a
3aa
fPd(OAc)2withorate was usedfluoroborate.
hnopremixingd. b) Observed
(blue side‐
C−HArylationofHeteroarenes:Optimization,ScopeandApplication
75
inductionperiodnoran initial accelerationoccurred (Figure4.1a, green
series).However, lower yieldswereobtainedwithPd2(dba)3. This result
givesusafirstglimpseofthepossiblecatalyticmechanism,indicatingthat
palladium in its homogeneous zero state can act as an active catalyst.
FurtherinvestigationofthereactionmechanismisdiscussedinChapter5.
As expected, the product3a was evenmore prone to undergo a side
reaction (i.e., an electrophilic substitution reaction) with
benzenediazonium salt, as the inductive effect of the phenyl substituent
makestheC‐3positionmorenucleophilic.23Thiswasespeciallynoticeable
when a slight excess of benzenediazonium tetrafluoroborate was used
(Figure 4.1 a, blue series). A small yield of approximately 10% was
observed after prolonged reaction time, which accounts for the 0.1
equivalent excess. To counteract this consecutive reaction, an equimolar
amount (1.0 equiv. benzenediazonium tetrafluoroborate)was used. As a
result,90%ofthedesiredproductcouldbeisolated(entry14).Notethat
the reaction time could be halved again, to approximately 30 minutes,
whenusingthepremixingstrategy.Inaddition,aslightlyhigherselectivity
was obtained because side reactionswereminimized.More information
regarding reaction optimization and reaction progress analysis can be
obtainedfromtheSupportingInformation.
Having established a good coupling protocol for indoles, we
subsequently examined the reactivity of benzofuran (1i) with 3‐
trifluoromethylbenzenediazonium salts (2t). A brief optimization in case
of benzofuran was necessary, because optimized conditions for 1‐
methylindoledidnotgivesatisfyingresults(17%,Table4.2,entry1).Since
benzofuranisnotpronetoelectrophilicsubstitution,MeOHcouldbeused
asamorereactivesolvent(42%,entry3).Moreover,itwasobservedthat
the addition of 1.0 equivalent of TFA resulted in an impressive rate
4
Chapter4
76
acceleration (overnight to 30 minutes) while maintaining its selectivity
(Entry4).Next,wequestionedwhether if itwaspossible to increase the
yield of the desired product by using an excess of 2t (Entries 5‐6).
However,onlyaslight increase in theyield to48%wasnoticedwith the
useof1.2equivalents.Highercatalyst loadingwasprobed (Entry7),but
no significant improvementwas observed. The use of the protic solvent
MeOH resulted in the formation of 35% 2‐aryl‐3‐methoxy‐2,3‐
dihydrobenzofuran (6ee), due to MeOH addition (see Chapter 5 for
details).However,asimpleworkupprocedureconsistingof15minutesof
reflux under acidic conditions (i.e., acetyl chloride) was found to be
sufficient to eliminateMeOH from compound6ee, affording the desired
product6ein81%yield(entry8).
Table4.2.OptimizationforthePd‐catalyzedC–HArylationofBenzofurana
Entry Ar‐N2BF4(equiv.)
Pd(OAc)2
(mol%) Solvent
TFA (equiv.)
Reactiontime
IsolatedYield (%)
1b 1.0 0.5 EtOAc:2‐MeTHF ‐ overnight 17
c
2 1.0 0.5 solventd ‐ overnight <25
c
3 1.0 0.5 MeOH ‐ overnight 42c
4 1.0 0.5 MeOH 1.0 30min 42
5 1.2 0.5 MeOH 1.0 30min 48;52c
6 2.0 0.5 MeOH 1.0 30min 48
7 1.2 1.0 MeOH 1.0 30min 49
8e 1.2 0.5 MeOH 1.0 30min 81
areaction conditions: 0.5–1.0mol% Pd(OAc)2, 1.0mmol heteroarene, 1.0–2.0 equiv. 3‐trifluoromethylbenzenediazoniumtetrafluoroborateand0–1.0equiv.TFAin5mLsolventat rt. b2h premixing of Pd(OAc)2 with benzofuran. cF‐NMR yield; dTHF, EtOH, i‐PrOH,CF3CH2OH,EtOAc,MeCN.eafterreaction15minrefluxwithacetylchloride(5equiv.).
C−HArylationofHeteroarenes:Optimization,ScopeandApplication
77
SYNTHETICSCOPE
Withtheoptimizedconditionsinhand,wenextexploredthescopeofour
developed methodology on indoles (Table 4.3). These substrates were
reactedwithequimolaramountsofaryldiazoniumsaltsinthepresenceof
0.5 mol % Pd(OAc)2 in the case of 1‐methylindoles and 1.0 mol % of
Pd(OAc)2forNH‐indoles.A1:1mixtureofEtOAc:2‐MeTHFwasusedas
the solvent. A broad set of substituted aryldiazonium substrates (3a–y)
could be successfully coupledwith 1‐methylindole. Indole arylationwith
aryldiazonium salts bearing alkyl substituents (3c–g, 4a, b) proceeded
well for both N‐protected and free indoles, even in the presence of
stericallydemandingortho‐methyl substituents (3c,3e).Whenusing the
more sterically hindered mesitylenediazonium tetrafluoroborate as the
arylating agent, amixture (C‐2 and C‐3 arylated product)was found for
boththeN‐methylatedandthefreeindoles(3f,4c).Selectivitytowardsthe
C‐3arylatedproductwasprevalent in4c (C‐2 :C‐31 :3.3).Forallother
reactions, complete selectivity towards the C‐2 arylated product was
observed. Next, a scope of aryldiazonium salts containing hydroxy‐,
phenoxy‐ and methoxy‐substituents, was explored (3h–p). It was
demonstrated that aryldiazonium salts bearing a free hydroxyl group
showed some reactivity, although in lower yield (3p, 16%). A para‐
phenoxygroupasanelectron‐donatingsubstituentonthearyldiazonium
saltresultedingoodreactivity(3o,79%).
Moreover, allmethoxy‐containing aryldiazonium salts (3h–n) showed
good to excellent reactivity (69% to 93%), except for 3l, where no full
conversion could be obtained. The yields obtained for compounds3h–n
showcase the applicability of our methodology for the C‐2 arylation of
indoles with arylating agents bearing methoxy‐substituents, which are
often reported tobe cumbersome.7,8b,9bThese substituents are functional
4
Chapter4
78
handles which can be engaged in nickel‐catalyzed cross‐ coupling
chemistry via C–O activation.24 In addition, heterocyclic aryldiazonium
saltswere tolerated in this protocol:3qwas obtained inmoderate yield
(34%)overnight,whilefor3r,agoodyield(71%)wasacquiredwithin1
hour reaction time. Notably, in the case of free NH‐indoles (4a–d), an
ortho‐methyl substituent on the aryldiazonium salt proved necessary to
avoid significant by‐product formation (electrophilic substitution).
However, itwasfoundthatbyblockingtheC‐3positionoftheNH‐indole
(i.e.,viamethylation),thisside‐reactioncouldbecompletelyavoided(4ea
vs.4e).
Next, we explored a more challenging class of aryldiazonium salts
bearing weakly (e.g., F) to highly electron‐withdrawing (e.g., NO2)
substituents (3s–y). Gratifyingly, 4‐fluoro‐ and 3‐iodobenzenediazonium
tetrafluoroboratereadilyreactedwith1‐methylindole(3s,3w).Thelatter
(3w)isparticularlyappealing,sinceitindicatesthatpalladiumundergoes
oxidativeadditionattheelectrophilicdiazoniumsite(insteadofbreaking
the C–I bond) at room temperature. In contrast, aryldiazonium salts
bearing m‐CF3 (3ta), p‐NO2 (3ua), o‐Cl (3va) and p‐Br (3xa) as
substituents did not deliver any arylated product when 1‐methylindole
wasusedasthesubstrate.Itwasobservedthatthesearyldiazoniumsalts
were too prone to electrophilic substitution reactions, resulting in the
rapid formation of 3‐(arylazo)‐1‐methylindoles (see Figure 4.1 b).
However, as in theNH‐indole case, this side reaction couldbe efficiently
overcomebyblockingtheC‐3position.Consequently,thearylationscope
couldbe expanded to electron‐withdrawing substituents (3t,3u,3v,3x)
with high to excellent yields of the desired product (80% to 92%). This
trendwasalsoobservedwhenaryldiazoniumsaltsbearinganacylmoiety
wereused(3yaand3y):58%ofthetargetproduct(3ya)wasobtainedfor
C−HArylationofHeteroarenes:Optimization,ScopeandApplication
79
Table4.3.ScopefortheC–2ArylationofIndoles
a
4
Chapter4
80 a R
eactionconditions:0.5to1.0mol%Pd(OAc)2,1.0mmolheteroareneand1.0equiv.aryldiazonium
saltin5mLEtOAc:2‐MeTHF(1:1)atrt,
openflask,2hpremixingofPd(OAc)2withheteroarene.b Pd 2(dba) 3ascatalyst,1hreaction.c 1mol%Pd(OAc)2,1.2equiv.aryldiazonium
salt.d 4‐
methoxybenzenediazonium
mesylatewasused.eGram‐scaleexperiment(10.0mmol)yielded2.47g(83%),4hreactiontimein2‐MeTHFas
solvent.f 1mol%Pd(OAc)2.g 2mol%Pd(OAc)2.h 2mol%Pd(OAc)2,1.2equiv.aryldiazonium
salt.i 1.2equiv.aryldiazonium
saltat40°C.*nofull
conversionobtained.j 0.01Mand100mol%Pd 2(dba) 3wasused.
C−HArylationofHeteroarenes:Optimization,ScopeandApplication
81
1‐methylindole,whileanimprovedresultwasobtainedfortheC‐3methylatedindole(80%yield,3y).
Subsequently,severalindolederivativesweresubjectedtothereaction
conditions using benzenediazonium tetrafluoroborate as a benchmark
couplingpartner.For5a and5c, the reactionproceededsmoothlyunder
equimolarconditions.5dprovedmorechallenging(22%yield)duetothe
electron‐withdrawingnatureofthemethylcarboxylatesubstituent,which
renders ita lessnucleophilicsubstrate. Interestingly,anexperimentwith
1,2‐dimethylindole and benzenediazonium salt showed that no C‐3
arylatedproductcouldbeformedover5hours.Instead,thesubstratewas
fully converted to theelectrophilic substitutedproduct1bb (93%yield).
Moreover, during a control experiment with a stoichiometric amount of
Pd2(dba)3,no1bbwasformed.This indicatesthatthebenzenediazonium
salt preferably underwent oxidative addition (see SI Section 3.4 and
Chapter5forfurthermechanisticdiscussions).
Next,agramscaleexperimentwasconductedto test thescalabilityof
this mild procedure. The reaction was carried out with equimolar
quantities of reactants (10mmol) and 0.5mol% Pd(OAc)2 in 2‐MeTHF.
Witha slightly longer reaction timeof4hours, a satisfyingyieldof83%
(2.47g)of3kwasachievedunderopenflaskconditions.
Next, we carried out several reactions by coupling benzofuran with
several halogenated aryldiazonium tetrafluoroborates (Table 4.4, 6a–h).
Satisfyingly,all reactionsproceededsmoothly in thepresenceofonly0.5
mol % Pd(OAc)2, thus showcasing the mild reaction conditions of this
protocol.
Finally, we turned our attention towards a more challenging
heteroarene, i.e.benzothiophene (7a‐7b).Becausebenzothiophene is the
4
Chapter4
82
leastnucleophilicheteroareneinvestigatedherein,itwasnecessarytouse
slightly higher catalyst loadings (2.0 mol %) and 2.0 equivalents of
aryldiazoniumsalt inordertoachievefullconversion.Operatingat40°C
wasdecisive toobtaina goodyield forboth7a (80%)and7b (73%). In
agreement with literature reports and density functional theory (DFT)
calculations (see Chapter 5), we observed a complete shift in selectivity
fromC‐2toC‐3arylation.Forcompound7a,asignificantimprovementin
yield(80%vs.69%)andareductioninreactiontime(16hvs.96h)was
observed,highlightingtherelevanceofourmildprotocol.11b
Table4.4.ScopeofAr‐N2BF4onBenzofuranandBenzothiophenea
areaction conditions: 0.5 mol % Pd(OAc)2, 1.0 mmol heteroarene and 1.2 equiv.aryldiazonium tetrafluoroborate in 5 mLMeOH at rt, open flask, after full conversion:reflux with 5.0 equiv. acetyl chloride for 15 min; b2.0 mol % Pd(OAc)2, 2.0 equiv.aryldiazoniumtetrafluoroborateat40°C.
C−HArylationofHeteroarenes:Optimization,ScopeandApplication
83
Taken together, this C–H activation protocol for the direct arylation of
heteroarenes provides a convenient pathway towards a broad range of
heteroaromaticarylatedderivatives.
APPLICATION
Tofurtherillustratetheefficacyofthismildstrategy,weappliedtheC–H
arylation process to the synthesis of methyl 2‐(5‐methylbenzofuran‐2‐
yl)benzoate(8a)(Scheme4.2).Compound8aisakeyintermediateinthe
total synthesis of Saprisartan, an approved drug belonging to the sartan
family.17 Sartansact asangiotensin II receptor (AT1)‐antagonistsandare
among themostprescribeddrugs for the treatmentofhypertension and
heartfailure.25
Scheme4.2.Synthesisofthedrugprecursor8aofSaprisartan.
4
Chapter4
84
Ourmildprocedureallowedustosuccessfullyisolatethekeyintermediate
8ain70%yield,whichcomparesfavorablytothepatentedprocess,which
requires four consecutive steps for the same transformation with an
overalllowyieldof17%.17,26
CONCLUSION
Insummary,wehavedevelopedamildandselectiveprotocolfortheC–H
arylation of heteroarenes, including indoles, benzofurans and
benzothiophenes,witharyldiazoniumsalts. Theprotocol is operationally
simple and is insensitive to air and moisture. It utilizes low palladium
loadings (0.5 to 2 mol% Pd), short reaction times, green solvents
(EtOAc/2‐MeTHF or MeOH) and is carried out at room temperature.
Notably,nooxidantsorotheradditivesarerequired.Thesubstratescope
is broad and displays excellent selectivity (C‐2 arylation for indoles and
benzofurans,C‐3arylationforbenzothiophenes).Toillustratetheefficacy
of this procedure, a key intermediate (8a) for the drug Saprisartanwas
synthesized,comparingfavorablytothepatentedprocess(70%vs.17%).
We expect this protocolwill findwidespread application due to itsmild
characterandexcellentselectivity.
EXPERIMENTALSECTION
General procedure for the synthesis of aryldiazonium
tetrafluoroborates. Procedure A: To a suspension of aniline (9) (10.0
mmol) in5mLwateratrtwasaddedtetrafluoroboricacid(HBF4,48wt%
inwater,3.0equiv.)and thereactionmixturewasstirred for2min.The
mixturewascooledto0°Candasolutionoftert‐butylnitrite(1.2equiv.)
wasaddeddropwise.Afteraddition,thereactionmixturewasstirredat0
°Cfor1hour.Thesolidswerefiltered,washedwithice‐colddiethylether
togivethecrudeproduct.Recrystallizationwasdonebydissolvingcrude
product inaminimumofacetonefollowedbyadditionof ice‐colddiethyl
C−HArylationofHeteroarenes:Optimization,ScopeandApplication
85
ether.Recrystallizationwasrepeateduntilwhitesolidswereacquired(2).
Incasethearyldiazoniumtetrafluoroboratesaltcouldnotbeprecipitated
by following general procedure A, general procedure Bwas carried out.
ProcedureB:Toasolutionofaniline9(10.0mmol)in5mLethanolatrt
wasaddedHBF4(48%inwater,3.0equiv.)andthereactionmixturewas
stirredfor2min.Themixturewascooledto0°Candtert‐butylnitrite(1.5
equiv.)wasaddeddropwise.Afteraddition,themixturewasstirredat0°C
for 2 hours. Diethyl ether was added to the reaction mixture and the
resulting solidswere filtered,washedwith diethyl ether (3 x) and dried
underhighvacuumtogivethetitleproduct(2).
General procedure for the C–H arylation of 1‐methylindole and
derivatives (conditionA). A stock solution was prepared by weighing
Pd(OAc)2(5.6mg,0.5mol%)and1‐methylindole(1a)(656mg,5.0mmol)
intoa50mLround‐bottomflaskequippedwithstirringbar.25mLfreshly
prepared EtOAc:2‐MeTHF (1:1) mixture was added and the resulting
solutionwas stirred for 2 h under air atmosphere at room temperature.
Aryldiazonium salt (1.0 mmol, 1.0 equiv.) was weighted into a 20 mL
reaction tube equipped with stirring bar. 5 mL of stock solution
(containing 1.0 mmol of 1‐methylindole and 0.5 mol% Pd(OAc)2) was
addedimmediatelyviasyringe.Reactionmixturewasstirredvigorouslyat
room temperature until 1‐methylindole was completely consumed
(monitored by TLC). Reaction was quenched by addition of saturated
NaHCO3 solution. The resulting mixture was moved to the separation
funnel.ReactionvialwaswashedwithEtOAcandaddedtotheseparating
funnel. Layers were separated and the organic layer was washed with
saturatedaqueousNaHCO3andbrinesolutionsequentially.Aqueousphase
waswashedwithEtOAc.RemainingorganicphasewasdriedoverMgSO4,
filtered and concentrated under reduced pressure. Purification by flash
4
Chapter4
86
chromatographyaffordedtheproduct.Thefinalproductwascharacterized
by1HNMR,13CNMR,19FNMR(ifapplicable),HRMS,IRandmeltingpoint
analysis(ifapplicable).
GeneralprocedurefortheC–HarylationofNH‐indole(conditionsB).
AstocksolutionwaspreparedbyweighingPd(OAc)2(11.2mg,1.0mol%)
andNH‐indole(1b)(586mg,5.0mmol)intoa50mLround‐bottomflask
equippedwithstirringbar.25mLfreshlypreparedEtOAc:2‐MeTHF(1:1)
mixturewasaddedandtheresultingsolutionwasstirredfor2hunderair
atmosphere at room temperature. Aryldiazonium salt (1.0 mmol, 1.0
equiv.)wasweighted into a 20mL reaction tube equippedwith stirring
bar. 5 mL of stock solution (containing 1.0 mmol of NH‐indole and 1.0
mol% Pd(OAc)2) was added immediately via syringe. Reaction mixture
was stirred vigorously at room temperature until NH‐indole was
completely consumed (monitored by TLC). Reaction was quenched by
additionofsaturatedNaHCO3solution.Theresultingmixturewasmoved
totheseparationfunnel.ReactionvialwaswashedwithEtOAcandadded
totheseparatingfunnel.Layerswereseparatedandtheorganiclayerwas
washedwith saturated aqueousNaHCO3 andbrine solution sequentially.
Aqueous phase was washed with EtOAc. Remaining organic phase was
dried over MgSO4, filtered and concentrated under reduced pressure.
Purification by flash chromatography afforded the product. The final
productwas characterizedby 1HNMR, 13CNMR, 19FNMR(if applicable),
HRMS,IRandmeltingpointanalysis(ifapplicable).
GeneralprocedurefortheC–Harylationofbenzofuran(conditionC).
AstocksolutionwaspreparedbyweighingPd(OAc)2(5.6mg,0.5mol%)
and benzofuran (1g) (591mg, 5.0mmol) into a 25mL volumetric flask.
TFA(370µL,1.0equiv.)wasaddedandthevolumetricflaskwasfilledup
to25mLwithanhydrousMeOH.Aryldiazoniumsalt(1.2mmol,1.2equiv.)
C−HArylationofHeteroarenes:Optimization,ScopeandApplication
87
wasweightedintoa20mLreactiontubeequippedwithstirringbar.5mL
ofstocksolution(containing1.0mmolofbenzofuran,0.5mol%Pd(OAc)2
and 1.0 equiv. of TFA) was added immediately via syringe. Reaction
mixturewasstirredvigorouslyatroomtemperatureuntilbenzofuranwas
completelyconsumed(monitoredbyTLC).Resultingreactionmixturewas
moved to a 50 mL round‐bottom flask and acetyl chloride (350 µL, 5.0
equiv.)was added dropwise. A reflux condenserwasmounted on top of
theround‐bottomflask.Thereactionmixturewasheatedandrefluxedfor
about15minutes.Aftercoolingdown to roomtemperature, the reaction
was quenched by addition of saturated NaHCO3 solution. The resulting
mixture was moved to the separation funnel. Round‐bottom flask was
washed with EtOAc and added to the separating funnel. Layers were
separated and the organic layer was washed with saturated aqueous
NaHCO3andbrinesolutionsequentially.Aqueousphasewaswashedwith
EtOAc. Remaining organic phase was dried over MgSO4, filtered and
concentrated under reduced pressure. Purification by flash
chromatographyaffordedtheproduct.Thefinalproductwascharacterized
by1HNMR,13CNMR,19FNMR(ifapplicable),HRMS,IRandmeltingpoint
analysis(ifapplicable).
General procedure for the C–H arylation of benzothiophene
(conditionD).AstocksolutionwaspreparedbyweighingPd(OAc)2(22.4
mg,2.0mol%)andbenzothiophene(1h)(671mg,5.0mmol)intoa25mL
volumetric flask.TFA (370µL,1.0 equiv.)wasaddedand thevolumetric
flaskwasfilledupto25mLwithanhydrousMeOH.Aryldiazoniumsalt(2.0
mmol,2.0equiv.)wasweightedintoa20mLreactiontubeequippedwith
stirring bar. 5 mL of stock solution (containing 1.0 mmol of
benzothiophene, 2.0 mol% Pd(OAc)2 and 1.0 equiv. of TFA) was added
immediatelyviasyringe.Reactionmixturewasstirredvigorouslyat40°C
4
Chapter4
88
untilbenzothiophenewascompletelyconsumed(monitoredbyTLC).The
reaction was quenched by addition of saturated NaHCO3 solution. The
resultingmixturewasmoved to the separation funnel.Reactionvialwas
washed with EtOAc and added to the separating funnel. Layers were
separated and the organic layer was washed with saturated aqueous
NaHCO3andbrinesolutionsequentially.Aqueousphasewaswashedwith
EtOAc. Remaining organic phase was dried over MgSO4, filtered and
concentrated under reduced pressure. Purification by flash
chromatographyaffordedtheproduct.Thefinalproductwascharacterized
by1HNMR,13CNMR,19FNMR(ifapplicable),HRMS,IRandmeltingpoint
analysis(ifapplicable).
SynthesisofSaprisartanprecursor(8a).Astocksolutionwasprepared
byweighingPd(OAc)2 (11.2mg,1.0mol%)and5‐methylbenzofuran (1i)
(660mg,5.0mmol)intoa25mLvolumetricflask.TFA(370µL,1.0equiv.)
wasaddedandthevolumetricflaskwasfilledupto25mLwithanhydrous
MeOH.o‐COOMe‐benzenediazoniumtetrafluoroborate(2z)(2.0mmol,2.0
equiv.)wasweighted into a 20mL reaction tube equippedwith stirring
bar.5mLof stocksolution (containing1.0mmolof5‐methylbenzofuran,
1.0 mol% Pd(OAc)2 and 1.0 equiv. of TFA) was added immediately via
syringe. Reaction mixture was stirred vigorously at 40 °C until 5‐
methylbenzofuranwascompletelyconsumed(2hours).Thereactionwas
quenchedbyadditionofsaturatedNaHCO3solution.Theresultingmixture
wasmovedtotheseparationfunnel.ReactionvialwaswashedwithEtOAc
andaddedtotheseparatingfunnel.Layerswereseparatedandtheorganic
layer was washed with saturated aqueous NaHCO3 and brine solution
sequentially.AqueousphasewaswashedwithEtOAc.Remainingorganic
phase was dried over MgSO4, filtered and concentrated under reduced
pressure. Purification by flash chromatography on silica (5% EtOAc in
C−HArylationofHeteroarenes:Optimization,ScopeandApplication
89
petroleum ether) afforded methyl 2‐(5‐methylbenzofuran‐2‐yl)benzoate
(8a)(186mg,70%)asayellowoil.
ASSOCIATEDCONTENT
The Supporting Information is available free of charge and can be found
under:https://doi.org/10.1039/c6sc02595a.
4
Chapter4
90
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4
CHAPTER5MildandSelectiveBase‐FreeC‐HArylationofHeteroarenes
Part2:MechanisticInvestigation
Thischapterisbasedon:
Gemoets, H. P. L.; Kalvet, I.; Nyuchev, A. V.; Erdmann, N.; Hessel, V.;Schoenebeck,F.;Noël,T.Chem.Sci.2017,8,1046‐1055
Chapter5
94
ABSTRACT
The mechanistic investigation for the mild and selective C–H arylation
strategy for indoles, benzofurans and benzothiophenes is described.
Mechanistic experiments andDFT calculations support aHeck–Matsuda‐
type coupling mechanism. Moreover, the first experimental results
indicate that BF4 anions could be involved in the anti‐β‐deprotonation
rearomatisationstepofthecatalyticcycle.
ThischapterincludesthemechanisticinvestigationforourdevelopedC−H
arylationmethodologyofheteroarenes,Reactionoptimization, scopeand
applicationarediscussedinchapter4.
C−HArylationofHeteroarenes:MechanisticInvestigation
95
MECHANISTICINVESTIGATION
Since heteroarenes are good nucleophiles, it would be reasonable to
assume a mechanism in which Pd(II) acts as an electrophile, consistent
with numerous literature proposals in the context of C–H
functionalization.1,2SimilartoSEAr,thesereactionsareexpectedtobeC‐3
selective for indoles. However, our methodology yields C‐2 arylated
indolesselectively(seeChapter4)andthusrequiresasubsequentC‐3/C‐2
isomerization. In this context, Gaunt and co‐workers showed that the
presence of acid would facilitate a switch from C‐3 to C‐2 in the Pd‐
catalyzed C–H olefination of indoles,2 proposing that under acidic
conditions, C‐3 deprotonation of the indole moiety would be slowed.
However, such a scenario appears unlikely in our case. For example,
progressive 1H‐NMRspectroscopywithequimolarquantitiesofPd(OAc)2
and 1‐methylindole in d8‐THF showed that neither the HC‐2 or the HC‐3
peaks of 1‐methylindole were affected (see Figure 5.1). Even if C‐H
activationwas to occur under these conditions (i.e., room temperature),
then the introduction of the aryl group would require a subsequent
oxidativeadditionofthediazoniumreagenttoaPd(II)complex,leadingto
a Pd(II)/Pd(IV) catalytic cycle. Calculations, however, are suggesting a
prohibitivelyhighbarrierofaround56kcal/molforsuchtransformation.
Therefore,theemployedPd(OAc)2likelyservesasapre‐catalystandis
reducedtoPd(0)duringtheinitiationperiod.Additionally,sincewehave
shownthatPd(0)iscatalyticallyactivewithoutanyinductionperiod(see
Chapter 4, Figure 4.1 a), it is reasonable to assume that the reaction
proceedsviaaPd(0)/Pd(II)catalyticcycle.3Thiscyclestartswithaninitial
oxidative additionof thehighlyactivatedaryldiazoniumsalt toPd(0) to
yield a cationic Pd(II) complex which should subsequently serve as an
electrophileinthereactionwiththesubstrate(seeScheme5.1).
5
Chapter5
96
Figure5.1.Progress1H‐NMRwaterfallplotofstoichiometricexperimentwithPd(OAc)2and1‐methylindoleind8‐THF.
In order to shed more light on the first step of the catalytic cycle (i.e.,
oxidative addition), a series of test reactionswereperformed (seeTable
5.1). When 1,2‐dimethylindole was mixed with benzenediazonium
tetrafluoroborate (2a) and 0.5mol% (entry 1), only amarginal amount
(0.5mol%)of2awillbeoccupiedinthecatalyticcycle(seeScheme5.2,
Pathway A).* Therefore, the leftover benzenediazonium salt can now
follow the ‘slower’ Pathway B, generating the side‐product 1bb in high
yield(93%).Performingthereaction inpresenceof100mol%Pd(OAc)2
(entry2),aloweramountof1bbwasobtained(42%).Thissuggeststhat
the uncatalyzed electrophilic substitution reaction (Pathway B) is in
competition with the oxidative addition step (Pathway A) (see Scheme
5.2). However, due to the present induction period for the oxidative
*Note,thatforpathwayAthecatalyticcyclecannotbecompletedduetothepresenceofthemethylsubstituentontheC‐2carbon.
C−HArylationofHeteroarenes:MechanisticInvestigation
97
Schem
e5.1.ProposedPd(0)/Pd(II)Heck‐MatsudatypecyclefortheC‐2arylationofheteroarenes(X=NMe,NHorO).
5
Chapter5
98
Table 5.1. Trapping the Aryldiazonium Tetrafluoroborate via Oxidative
Additiona
Entry R Catalyst(mol%)Reactiontime
IsolatedYield(%)
1 R=H Pd(OAc)2(0.5) 2 h 93b,c
2 R=H Pd(OAc)2(100) 16 h 42b
3 R=H Pd2(dba)3(100) 16 h 0d
4 R=F Pd(OAc)2(0.5) 30 min 98c
5 R=F Pd(OAc)2(100) 16 h 0
aReaction conditions: 0.2 mmol 1,2‐dimethylindole and 1.0 equiv. aryldiazoniumtetrafluoroborate in 20 mL EtOAc:2‐MeTHF (1:1) at rt, open flask. b2 h premixing ofPd(OAc)2 with 1,2‐dimethylindole. c0.2 M. d1 h premixing of Pd2(dba)3 withbenzenediazonium tetrafluoroborate. Note: With high palladium loadings, 0.01 M wasusedtoensureahomogeneousreactionconditions.
addition with Pd(II) sources (see Chapter 4, Figure 4.1 a for details),
PathwayBwillstillbefeasibleduringthisinductionperiod.Therefore,itis
reasonable that compound 1bb is still observed, although in a lower
amount (42% vs 93%).When performing the reaction with 100mol%
Pd2(dba)3 (as a Pd(0) source), no side product (1bb) formation was
observed. In order to further illustrate this observation, we conducted
similarexperimentswithamorereactivearyldiazoniumsalt.Knownfrom
previous results (see Chapter 4), 4‐fluorobenzenediazonium
tetrafluoroborate (2s) did not show any induction period when using
Pd(OAc)2asthecatalyst.Performingthereactionwith0.5mol%Pd(OAc)2,
resultedin98%of1cc.However, inpresenceof100mol%Pd(OAc)2,no
side‐product(1cc)wasobserved(Table5.1,entry4‐5).Theaboveresults
describethataninitialoxidativeadditionisathand.
C−HArylationofHeteroarenes:MechanisticInvestigation
99
Scheme 5.2. Competition reaction between oxidative addition (Pathway A) andelectrophilicsubstitution(PathwayB)whenusing1,2‐dimethylindoleassubstrate.
Aftertheoxidativeaddition,theoverallproductselectivitywouldthenbe
determined by the C‐3 to C‐2 migration of Pd.2 However, our efforts to
computationally locate theC‐2Pdcomplexyieldedastructure that is9.1
kcal/mol higher in energy than the preferred η2 π‐complex Int1 (see
Figure5.2),suggestingthatthemigrationisdisfavored.*IntermediateInt1
may alternatively undergo a Heck‐type carbopalladation reaction (see
Scheme 5.1).4 Our calculations suggest this process to be energetically
feasible, being characterized by a relatively facile free energy barrier of *TheC‐2Pdcomplexwas locatedonlyby lockingthePd(II)centertoC‐2.However,uponunfreezing this interaction thestructureconvergedback to theη2π‐complex.ForsimilardifficultiesinlocatingthemigrationofPdfromonecarbontoanotherinthecontextofC‐Hactivationofthiophenesseeref.4a
5
Chapter5
100
17.5 kcal/mol (see Figure 5.2). Thus, we subsequently calculated the
expected selectivities (C‐3 versus C‐2) for C–H arylation for a
carbopalladation mechanism. We considered several possible solvent
coordinations to thecationicPd.Wedetermined that thecoordinationof
twoTHFmolecules is likelypreferred.†Ourcomputedselectivitiesare in
agreementwithexperiments(seeChapter4).CompleteC‐2selectivitywas
experimentally observed for 1‐methylindole and benzofuran, consistent
withourcomputational results(ΔΔG‡=2.4kcal/moland0.7kcal/mol in
favor of C‐2, respectively).‡ By contrast, benzothiophene yielded the C‐3
arylatedproductexclusively,whichwasalsoreproducedbycomputations
(ΔΔG‡=1.9kcal/molinfavorofC‐3)(seeFigure5.3).
As mentioned in Chapter 4, a brief re‐optimization in case of
benzofuranwasnecessary.Sincebenzofuran isnotpronetoelectrophilic
substitution,MeOHcouldbeusedasamorereactivesolvent.Theseresults
areinagreementwiththeliterature.5Felpinetal.demonstratedwithDFT
andexperimentalresultsthatthecationicpalladiumintermediates inthe
HeckcycleareexoergicwithMeOHasthesolvent.6However,theuseofthe
proticsolventMeOHresultedinthesignificantformation(36%)of2‐aryl‐
3‐methoxy‐2,3‐dihydrobenzofuran (6ee) (see Scheme 5.1). It was
speculated that 6ee was formed from the proposed carbopalladation
intermediate II through a SN1 mechanism, resulting in the observed
syn/anti diastereomeric mixture. Hereby, the presence of 6aa, suggests
thattheintermediateIIisexistinginourcatalyticcycle.
†Various ligation states of Pdwere considered: THFmolecules, Indole substrate and thecombinationofboth,withtheTHFmoleculesbeingthepreferredone.‡BenzofuranwasreactedinMeOH,whichoffersvariousdifferentlikelycoordinationstates.Thus, it is challenging to describe this system adequately with computations. For thecoordinationstateconsidered,wepredictselectivitiesinlinewithexperiments.SeeSIforadditionalinformation.
C−HArylationofHeteroarenes:MechanisticInvestigation
101
Figure 5.2. Heck‐type carbopalladation pathway via its transition states at the CPCM(THF) M06L/def2TZVP//wB97X‐D/6‐31G(d) SDD level of theory.7 Free energies areshowninkcal/mol.
Figure5.3. Predictionof selectivity for theHeck‐type carbopalladationpathway via itstransition states at theCPCM (THF)M06L/def2TZVP//wB97X‐D/6‐31G(d) SDD level oftheory.7Freeenergiesareshowninkcal/mol.
5
Chapter5
102
Thecarbopalladationstep in the traditionalHeck‐typereactionwouldbe
followed by syn‐β‐hydride elimination. Due to the rigidity of the ring
system, however, there is no possibility of conventional syn‐β‐hydride
eliminationfromtheformedintermediateII(seeScheme5.1).Incontrast,
it has been previously suggested that a base or solvent assisted anti‐β‐
deprotonationrearomatisationcouldoccur.4b,8 ,9Whilethatstepmayalso
be involved in our case, due to the ionic and complex natures of the
intermediates involved, an adequate computational description of the
systemwouldposeanumberofdifficulties.4b,10However, insitu19FNMR
analysisofthereactionhasgivenusinitialinsightsintothelikelynatureof
theprocesses involved(seeFigure5.4).Thedata indicate thatadditional
signals,assignedasBF3∙2Me‐THF(‐155.82ppm)andHF(‐192.44ppm),
Figure5.4. Progress 19F‐NMRwaterfallplotof the reaction for6‐fluoro‐1‐methylindole(1e)with4‐F‐PhN2BF4(2s)inEtOAc:2‐MeTHF(1:1).
C−HArylationofHeteroarenes:MechanisticInvestigation
103
appear in the 19FNMRspectrumat thesamerateas theproduct5b (see
Figure 5.5 and SI for further details). Derived from these experimental
observations, we can postulate that the BF4‐ (which stabilizes the
carbopalladationintermediateII)andthesolvent2‐MeTHFbothassist in
the anti‐β‐deprotonation rearomatisation, through the formation of HF
and BF3.2‐MeTHF (see Scheme 5.3). Moreover, when using alternative
counterions for thearyldiazoniumsalt (i.e., 4‐methoxybenzenediazonium
mesylateandtosylate),noproductwasobserved(seeTable5.2).Incaseof
4‐methoxybenzenediazonium tosylate, 0.5 equiv. of BF4‐ (as an 48 wt%
HBF4 aqueous solution) was added to the reaction mixture after 15
minutes. Upon addition, immediate gas formation and color changewas
observed.After2hours,thereactionwascompletedandthedesired
Figure5.5.ConversionandYieldwasmonitoredby the 19Fsignalsof reactionmixture.α,α,α‐trifluorotoluene(‐63.72ppm)wasusedasinternalstandard.
0 20 40 60
0
20
40
60
80
100
F-N
MR
Yie
ld (
%)
Time (min)
Conversion of 1e Yield of 5b Yield of BF
3.2-MeTHF
Yield of HF
5
Chapter5
104
product was obtained in 62% isolated yield (entry 3). It is therefore
hypothesizedthatproduct3hwastheBF4counterionofthearyldiazonium
saltplaysanon‐negligiblerole in thereactionmechanism, i.e.actingasa
pseudo‐baseintheanti‐β‐deprotonationrearomatisationstep.Inaddition,
a crude 1H‐NMRspectrumacquired from the reactionmixture (usingd8‐
THFassolvent) indicatesthatthe lostprotonappearsquantitativelyasa
broadsignalat9.0ppm(seeFigure5.6).
Scheme5.3. Proposedanti‐β‐deprotonationrearomatisationassistedby theBF4‐ anion.BothBF3.2‐MeTHFandHFwereobserved in 19F‐NMR inquantitative correlation to thedesiredproduct(5b).
Table5.2.ControlExperimentswithOtherCounterionsa
N
Me
N
Me
Pd(OAc)2 (2.0 mol%)
EtOAc:2-MeTHF (1:1) 0.2 M
room temp., open flask
N2X
(1.0 equiv.)
MeO
OMe
1a 2 3h
+
Entry Counterion(X) reactiontime isolatedYield(%)
1 BF4‐ 2 h 82b
2 OMs‐ 16 h 0
3 OTs‐ 2 h 0c;62d
aReaction conditions: 2.0 mol % Pd(OAc)2, 0.5 mmol 1‐methylindole and 1.0 equiv. 4‐methoxybenzenediazoniumsaltin2.5mLEtOAc:2‐MeTHF(1:1)atrt,openflask.b0.5mol%Pd(OAc)2;cnoreactionobserved.dadditionof0.5equiv.BF4‐(fromanHBF448wt%inH2Osolution).
C−HArylationofHeteroarenes:MechanisticInvestigation
105
Figure 5.6. 1H‐NMR taken of crude reaction mixture. Reaction conditions: 1.0 mol %Pd(OAc)2,1.0mmol1‐methylindoleand1.0equiv.benzenediazoniumsaltin5mLd8‐THFat rt, open flask,1h reaction.With this crude 1H‐NMRwewould like toemphasize thecleannatureofouroptimizedreactionconditions.
Alternatively, a radical mechanism could be envisioned for this
transformation. However, a large excess (5 to 100 equiv.) of the
heteroarene substrate is generally required to obtain satisfying results
under such conditions. In our case, optimal results were achieved with
equimolarquantities. Inaddition, testreactionsviatheradicalpathway11
did not lead to the desired product. Moreover, radical scavenging tests
failed to trap any radical intermediates (see Table 5.3). Both scavengers
(i.e., TEMPO and Galvinoxyl) were not able to trap any radical
intermediates. Note, that upon addition of the radical scavenger, the
reactionstoppedimmediately(seeTable5.3,entries2‐4).However,itwas
speculated that the highly reactive scavenger poisoned the catalyst.
Finally, in radical chemistry, mixtures of C‐2 and C‐3 arylation are
5
Chapter5
106
frequentlyobserved,12whileoursystemdisplayscompleteselectivity(C‐2
forindoleandbenzofuran,whileC‐3forbenzothiophene).
Table5.3.RadicalScavengingExperiments
EntryRadicalscavenger
(equiv.)
Additionradical
scavenger
Yieldbbeforeaddition(%)
Yieldbafter30min(%)
CommentsforGC‐MS
1 ‐ ‐ ‐ 76 ‐
2 TEMPO(1.0) 5min 5 5 Notrappedint.
3 Galvinoxyl(1.0) 5min 5 5 Notrappedint.
4 TEMPO(1.0) 15min 21 21 Notrappedint.
areactionconditions:5.0mol%Pd(OAc)2,0.5mmolheteroareneand1.0equiv.diazoniumsalt in2.5mLsolvent, rt,0.1equiv.decafluorobiphenylas internalstandard forGC‐FID,open flask, 1.0 equiv. of radical scavenger added at indicated reaction time. bYielddeterminedbyGC‐FID.Int.=intermediates.
CONCLUSION
Mechanistic experiments andDFT calculations support aHeck–Matsuda‐
type coupling mechanism. Moreover, the first experimental results
indicate that BF4 anions could be involved in the anti‐β‐deprotonation
rearomatisationstepofthecatalyticcycle.
ASSOCIATEDCONTENT
The Supporting Information is available free of charge and can be foundunder:https://doi.org/10.1039/c6sc02595a.
C−HArylationofHeteroarenes:MechanisticInvestigation
107
REFERENCES
1. a)Lane,B.S.;Brown,M.A.;Sames,D.J.Am.Chem.Soc.2005,127,8050‐8057;2. Grimster,N.P.;Gauntlett,C.;Godfrey,C.R.A.;Gaunt,M.J.Angew.Chem.Int.Ed.2005,
44,3125‐3129.3. a)Yamashita,R.;Kikukawa,K.;Wada,F.;Matsuda,T. J.Organomet.Chem.1980,201,
463‐468;b)Kikukawa,K.;Matsuda,T.Chem.Lett.1977,,159‐162.4. a)Tang,S.Y.;Guo,Q.X.;Fu,Y.Chem.‐Eur.J.2011,17,13866‐13876;b)Steinmetz,M.;
Ueda,K.;Grimme,S.;Yamaguchi, J.;Kirchberg,S.; Itami,K.;Studer,A.Chem. ‐Asian J.2012,7,1256‐1260;c)Glover,B.;Harvey,K.A.;Liu,B.;Sharp,M.J.;Tymoschenko,M.F.Org.Lett.2003,5,301‐304;d)Maeda,K.;Farrington,E.J.;Galardon,E.;John,B.D.;Brown,J.M.Adv.Synth.Catal.2002,344,104‐109.
5. b)Felpin,F.X.;Nassar‐Hardy,L.;LeCallonnec,F.;Fouquet,E.Tetrahedron2011,67,2815‐2831;
6. Felpin, F.‐X.; Miqueu, K.; Sotiropoulos, J.‐M.; Fouquet, E.; Ibarguren, O.; Laudien, J.Chem.‐Eur.J.2010,16,5191‐5204.
7. a)Frisch,M.J.etal.;Gaussian09,RevisionD.01,Gaussian,Inc.:WallingfordCT,2009;b)Sperger,T.;Sanhueza,I.A.;Kalvet,I.;Schoenebeck,F.Chem.Rev.2015,115,9532‐9586.
8. a) Colletto, C.; Islam, S.; Julia‐Hernandez, F.; Larrosa, I. J.Am.Chem. Soc.2016, 138,1677‐1683;
9. Ikeda,M.;A.A.ElBialy,S.;Yakura,T.Heterocycles1999,51,1957.10. a) Sperger, T.; Fisher, H. C.; Schoenebeck, F.WIREs Comput. Mol. Sci. 2016, DOI:
10.1002/wcms.1244;b)Bonney,K.J.;Schoenebeck,F.Chem.Soc.Rev.2014,43,6609.11. Kalyani,D.;McMurtrey,K.B.;Neufeldt,S.R.;Sanford,M.S.J.Am.Chem.Soc.2011,133,
18566‐18569.12. Hari,D.P.;Hering,T.;König,B.Org.Lett.2012,14,5334‐5337
5
CHAPTER6
AModularFlowDesign forthemeta‐Selective
C−HArylationofAnilines
Thischapterisbasedon:
Gemoets, H. P. L.; Laudadio, G.; Verstraete K.; Hessel, V.; Noël, T.Angew.
Chem.Int.Ed.2017,56,7161‐7165
Chapter6
110
ABSTRACT
Describedhereinisaneffectiveandpracticalmodularflowdesignforthe
meta‐selective C−H arylation of anilines. The design consists of four
continuous‐flow modules (i.e., diaryliodonium salt synthesis, meta‐
selectiveC−Harylation,inlinecopperextraction,andanilinedeprotection)
which can be operated either individually or consecutively to provide
direct access tometa‐arylated anilines.With a total residence time of 1
hour, the desired product could be obtained in high yield and excellent
purity without the need for column chromatography, and the residual
copper content meets the standards for parenterally administered
pharmaceuticalsubstances.
AModularFlowDesignforthemeta‐SelectiveC−HArylationofAnilines
111
INTRODUCTION
Site‐selective C−H bond functionalization strategies are of paramount
importance in modern organic synthesis.1 However, because of the
ubiquitouspresenceofC−Hbondsinorganicmolecules,theregioselective
assembly of substituted arenes remains amajor challenge. Traditionally,
theortho and, to someextent, theparasubstitutionof areneshavebeen
thoroughly explored with the use of Friedel–Crafts chemistry. More
recently,muchworkhasbeencarriedoutonthetransitionmetalcatalyzed
ortho‐functionalization of arenes, and it proceeds by a cyclometalation
strategy.2 Incontrast, thedevelopmentofmeta‐selective transformations
has required much more scientific investigation. Besides traditional
approaches which rely on tuning steric and electronic properties of
aromatic substrates,novel robust catalytic strategieshaveemerged.3For
example, the incorporation of directing‐group templates4 or the use of
transient ligandmediators5 (e.g., Pd/norbornene)havebeenexploited to
carefullynavigatetransitionmetalstothemeta‐position.
Among the reported meta‐selective C−H functionalization strategies,
the meta‐arylation of electron‐rich arenes is of high interest to access
novelbiarylmotifs,whichrepresentacommonmoietywithinmedicines,
agrochemicals, and functional materials.6 In particular, Gaunt and co‐
workers first reported the meta‐selective C−H arylation of protected
anilines.7 This transformation was believed to proceed via a highly
electrophilicCuIII/arylintermediate,obtainedfromCuI,andinpresenceof
diaryliodonium salts as both oxidant and arylating agent.8 However,
despite being shelf‐stable, nontoxic, and synthetically useful,
diaryliodonium salts have limited availability and are expensive.9 The
main cause is associated with its cumbersome preparation. Hereto,
stoichiometricamountsofhazardousreagents(e.g.,m‐CPBAandTfOH)are
6
Chapter6
112
necessary to oxidize iodine to its hypervalent state (i.e., I+III) and the
greatlyexothermicnatureofthereactionmakeshot‐spotformationhighly
probable, thus resulting in reduced selectivities and safety issues on a
largescale.
Acentralthemeofourresearchistodevelopcontinuousflowmethods,
thus delivering a set of new tools to facilitate challenging synthetic
transformationsandprovideadditionaladvantagesoverbatchintermsof,
forexample,safety,10scalability,11 time‐reduction,12orselectivity.13Given
the importance of meta‐arylated anilines and its limited scalability
potential inbatch,we felt that a continuous‐flowstrategy to access such
compounds would represent an important advance. To prepare these
compounds, we identified four key steps in its synthesis, including the
synthesisofthediaryliodoniumsalt,themeta‐selectiveC−Harylation,and
the removal of both the copper catalyst and the directing group (see
Scheme 6.1). While all these modules have great potential on its own,
combiningthemwouldallowstraightforwardaccesstothemeta‐arylated
anilineswithinareasonabletimescaleandeffort.
Scheme6.1.ModularFlowDesignforthedirectaccesstometa‐arylatedanilines.
AModularFlowDesignforthemeta‐SelectiveC−HArylationofAnilines
113
RESULTSANDDISCUSSION
In taking on this challenge, we anticipated that diaryliodonium salt
synthesis as the first module could highly benefit from continuous‐flow
processing to alleviate the current safety limitations (i.e., highly
exothermic nature and hazardous reagents handling).14 The one‐pot
synthesisdevelopedby thegroupofOlofssonwas identifiedas themost
convenientstrategytoproduceadiversesetofdiaryliodoniumsalts.14bA
0.1mLPFAreactorcoil(750mmI.D.)wasconstructedandreagentswere
introducedbythreeseparatefeedstreams(i.e.,reagentfeed,oxidantfeed,
and acid feed; see Figure 6.S1 and Scheme 6.S1 in the Experimental
Section). To preventmicroreactor clogging and to ensure excellent heat
dissipation, the reactor assembly was submerged in an ultrasonic bath
kept at room temperature.After initial optimization (seeTable S1 in the
Supporting Information (SI)), it was found that the target di‐p‐
tolyliodonium triflate (4a) could be obtained, after only a two‐seconds
residence time, in excellent yield (89%) after crystallization (Table 6.1).
Notably, our flow protocol was highly reproducible and the yields were
typicallyhigherthanthoseobtainedwithconventionalbatchlabware(52–
67%).14b, 15 The procedure can be readily scaled and, as an example,we
obtained2.04gramsof4a(5mmolscale,89%).
Next,asmalllibraryofsymmetricalandunsymmetricaldiaryliodonium
saltswasestablishedinflow(Table6.1).Awidevarietyofunsymmetrical
diaryliodonium triflates bearing diverse substituents and mesitylene as
thecounterligandweresuccessfullysynthesizedonagramscale(3a–l).In
particular, the compounds 3d (80%) and 3i (85%) were obtained in
significantly higher yields than previously reported.7, 16 Moreover, the
unsymmetricaldiaryliodoniumtriflatesbearingelectron‐richsubstituents
(3cand3l)weresynthesizedforthefirsttimebythisone‐stepprocedure.
6
Chapter6
114
Table6.1.ScopefortheSynthesisof(un)SymmetricalDiaryliodoniumSalts
inFlowa
aReactionconditions:Syringe1:5.0mmolofaryliodide(1)and5.5mmolofarene(2)in25mL DCE at 0.75mL/min, syringe 2: 5.5mmol ofm‐CBPA in 25mL of DCE at 0.75mL/min,syringe3:10.0mmolTfOHin50mLDCEat1.5mL/min.Addedtothereactorviasyringepump.bmesityliodidewasused.c3mLreactorvolumewithtr=60s,6.5mmolm‐CBPAand15mmolTfOH.Note:3seriesrefertounsymmetricaldiaryliodoniumsaltswithmesitylene as arene, 4 series to symmetrical diaryliodonium salts. m‐CPBA = meta‐chloroperbenzoicacid,Tf=trifluoromethanesulfonyl.
Webelievethatthismoduleprovidesausefultooltoenablethelarge‐scale
preparationofvaluableandcostlydiaryliodoniumsaltsinasafeandtime‐
efficientfashion.FurtherexplorationofscopeispresentedinChapter7.
We next addressed the development ofmodule 2,which involves the
continuous‐flowmeta‐selective C−H arylation of anilines. It is generally
acceptedthatthereportedmeta‐selectiveC−Harylationreactionoperates
by a homogeneous mechanism, thus making the use of heterogeneous
catalysts superfluous. Nevertheless, the use of heterogeneous precursor
materials, which can serve as cheap and convenient reservoirs for the
releaseofhomogeneouscatalyticallyactivespecies,canbeofhighlyadded
AModularFlowDesignforthemeta‐SelectiveC−HArylationofAnilines
115
value.17 We hypothesized that the catalytically active species could be
readily formed from Cu0 in the presence of highly electrophilic
diaryliodonium salts.18 Preliminary batch investigations revealed that
inexpensive copper powder enabled the meta‐arylation of N‐(o‐
tolyl)pivalamide(5a)withdi‐p‐tolyliodoniumtriflate(4a;seeTableS2in
SI).Moreover, theseexperimentsrevealedthatcopperpowderwasmore
active than the benchmark Cu(OTf)2 catalyst source reported by Gaunt,
thusreducingthebatchreactiontimefrom24to2hours(seeFigureS1in
SI). In addition, reactions with surface‐treated copper turnings revealed
that both Cu0 and CuI can be used as catalyst source (see Figure S1b in
SI).19
Translating this concept to continuous manufacturing, we speculated
thatthemeta‐selectiveC−Harylationcouldhighlybene itfromtheuseof
copper tube flowreactors (CTFRs),20whichwouldallow for a significant
breakthroughinoperationalsimplicityforC−Hactivationchemistry.21To
test thishypothesis, a20mLCTFR (1.65mmI.D.)was constructed from
cheap and commercially available copper tubing (see Figure 6.S2 and
Scheme6.S2intheExperimentalSection).Afterinitialoptimizationofthe
reactionparameters,fullconversionwasobtainedwithinonly20minutes
residencetime,thusyielding88%of6a(seeTable6.2andTablesS3and
S4 in SI).Next, variouspivanilideswith4a as the couplingpartnerwere
subjected to our flow protocol (Table 6.2). Pivanilides bearing either
ortho‐alkyl,ortho‐aryl,orortho‐methoxysubstituentswerewelltolerated
andyieldedthemonoarylatedcompounds6b,6c,and6d respectively, in
excellentyields(86–91%).Intheabsenceoforthosubstituents,bothmeta
positionsbecamehighlyaccessible,thusresultinginahigh‐yielding
6
Chapter6
116
Table6.2.ScopewithRespecttoAnilinesaandDiaryliodoniumSaltsbforthe
meta‐SelectiveC−HArylationinFlow
aReaction conditions: 0.5mmol aniline (5) and 2.0 equiv [Tol‐I‐Tol]OTf (4a) in 5.0mLDCE. bReaction conditions: 0.5 mmol N‐(o‐tolyl)pivalamide (5a) and 2.0 equiv [Ar‐I‐Mes]OTf(3)in5.0mLDCE.AddedtotheCTFRbysyringepump.c40minresidencetime.d5.03mmolscalereaction:1.384g(98%)ofdesiredproductobtained.eSymmetrical[Ar‐I‐Ar]OTf(4)wasused.Piv=pivaloyl.
mixture of both mono‐ and diarylated products 6e/6e’ (80% yield,
mono/di 1:2.3). Also, the heterocyclic substrate indoline was readily
convertedinto6finourflowreactor,thusyieldingthepurecompoundin
AModularFlowDesignforthemeta‐SelectiveC−HArylationofAnilines
117
80% yield upon isolation. Generally, meta‐substituted substrates are
perceived as more challenging substrates but could nevertheless be
acquired in flow within 20 minutes (6g,h). More complex ortho,para‐
disubstituted pivanilides were also compatible (6i–l), thus obtaining 6i
and a 6j/6j’ mixture in high yields (85–86%). Modest yields (30–42%)
wereobtainedfor6kand6lbecauseofincompleteconversion.
Next,adiversesetofdiaryliodoniumsalts,allpreparedonagramscale
in flow by module 1, were evaluated as coupling partners with N‐(o‐
tolyl)pivalamide (5a) asabenchmarksubstrate (Table6.2).The transfer
ofvariousarylgroupswaseffectiveforabroadrangeofsymmetricaland
unsymmetrical diaryliodonium triflates (6m–w) bearing either electron‐
neutral, electron‐donating, or electron‐withdrawing substituents, thus
yieldingthedesiredmeta‐arylatedproductsinfairtoexcellentyields(21–
90%). Note that for unsymmetrical diaryliodonium salts, the sterically
hindered mesitylene could be successfully used as a “dummy ligand”
allowingselectivetransferofthefunctionalizedarylgroups.Interestingly,
agram‐scalereactionwasreadilycarriedoutandresultedintheformation
of 6a in near quantitative yield (1.384 g, 98%), thus highlighting the
excellent scale‐uppotentialofourcontinuous‐flowprotocol. It shouldbe
noted that the complete scope (6a–w)wasperformedwithonlya single
copper capillary without any apparent loss of reactivity. Moreover, the
acceleratedreactionconditions(20minvs.24–48h)andimprovedyields
highlightthepotentialoftheseCTFRs,asreadilyavailableflowreactors,to
enable copper‐catalyzed C−H activation chemistry for gram‐scale drug
manufacturing.
Operating themeta‐arylation reaction in a continuous flow manner,
evidently raised thequestionofwhether significant copper leachingwas
taking place. Leaching can become apparent at longer operation times,
6
Chapter6
118
since copperwill beprogressively chromatographed through the reactor
tubing as a result of subsequent leaching/redeposition cycles.17 To
investigate the leaching behavior, Inductively coupled plasma optical
emission spectroscopy (ICP‐OES) analysis was conducted on reaction
samples (seeSection2.3 inSI).Ascanbeseen fromTable6.3, thecrude
reactionsamplefrommodule2containedabout4720ppmofCu,andisin
the same range as previously reported transformations in CFTRs.20a To
remove the leached copper from the target compound,we considered a
continuous‐flow inline extraction module (module 3).22 The extraction
module consisted of a 5mL PFA coil (1.65 mm I.D.) connected to a
commercially available Zaiput liquid‐liquid membrane separator (see
Figure 6.S3 and Scheme 6.S3 in the Experimental Section). The aqueous
ammoniasolution(32wt%)wasmergedwiththeorganicstreamexiting
theCTFR.Thecombinedliquid‐liquidphaseprovidedarapidextractionof
copper through complexation with ammonia, and could be visually
confirmedbythedeep‐bluecoloredaqueousphase.
Table6.3.InlineCopperExtractionandPhaseSeparationa
aCrude phase from module 2 and NH3 (32wt%) aqueous solution was pumped withsyringe pump and mixed together in a T‐mixer. A Zaiput membrane separator wasconnectedattheendofthe5mLPFAextractioncoil.OrganicphasewascheckedforCucontentviaICP‐OESanalysis.
AModularFlowDesignforthemeta‐SelectiveC−HArylationofAnilines
119
Theorganicstreamwassubsequentlyseparatedfromtheaqueousstream
in the Zaiput device. ICP‐OES analysis revealed that 99.7% of copper
contentcouldbereadilyextractedwithasinglepassthroughthemodule.
This step leads to a residual 14.3 ppm of Cu, and is far below the
recommended limit for parenterally administered pharmaceutical
substances(<25ppmaccordingtotheEuropeanMedicinesAgency(EMA)
Guidelines).23
The finalstep inourreactionsequenceconstitutes theremovalof the
pivalicprotectinggroup.Notably,thecleavageofpivanilidesprovedtobe
extremelychallenging.Literatureproceduresutilizerefluxconditionsand
prolonged reaction times ranging from 1–3 days.7, 24 Such extended
reaction times are not suitable for continuous‐flow processing and a
thorough screening of potential deprotection strategies was carried out
(seeTables S6andS7 inSI).The flowmodule consistedof a20mLPFA
capillary(1.65mmI.D.)equippedwitha140psibackpressureregulator
(BPR) to enable superheated reaction conditions (see Figure 6.S4 and
Scheme6.S4 in theExperimental Section). Eventually,we found that the
deprotectionof6acouldberealizedwithin40minutesusinganHCl/1,4‐
dioxane(1:1)mixtureat130°C(Table6.4),thusyieldingthefreeaniline
7a in excellent yield (94%). A final extraction procedure was used to
circumvent chromatography (see SI Section 4.4). This continuous‐flow
deprotection protocol appeared to be generally applicable (7a–h) and
constitutes a significant improvement compared to the literature
procedures.
Finally, with all the individualmodules fully explored and optimized,
the different modules were combined to enable direct access tometa‐
arylatedanilines(Scheme6.2).Inmodule1,4‐iodotoluene(1a)and
6
Chapter6
120
Table6.4.AnilineDeprotectioninFlowa
aReaction conditions: 0.5mmol product (6) in 5.0mLHCl (32wt%)/1,4‐dioxane (1:1),added to the PFA reactor by syringe pump (for 7a–f R1=Me, for 7g,h R2=Me). Anilineobtainedafterextractionprocedure(nochromatography).
toluene (2a) where readily converted into the corresponding iodonium
salt 4a within a 2 second residence time. After crystallization, 4a was
combined with N‐(o‐tolyl)pivalamide (5a) and introduced in module 2.
UponexitingtheCTFR,thereactionmixturewasmergedwiththeaqueous
NH3solutionphasetoremovetheleachedcopperinmodule3.Theorganic
phase containing 6a was subsequently evaporated and re‐dissolved in
HCl/1,4‐dioxane(1:1).Thismixturewasfedtothelastmoduletoobtain
the fullydeprotectedmeta‐arylatedaniline7a inanoverallyieldof80%
and99%purityafterafinalextractionprocedure.Itshouldbenotedthat
theoverallprocedurecouldbecarriedoutwithina1hourresidencetime
andrequirednochromatographicpurification.
AModularFlowDesignforthemeta‐SelectiveC−HArylationofAnilines
121
Z
NH2
7a
80% overal yield
no chromatography
99% purity
Me
Me
Cu
NHPiv
Me
Me
I
Me
NH3 (aq.)
2. meta-selectiveC-H arylation
4. anilinedeprotection
3. copperextraction
1. iodonium salt synthesis
5a
2a
1a
4a
6a
Scheme6.2.Overviewofmodularflowexperimentforthesynthesisof7a.Solidarrowsindicatedirectconnectionsanddashedarrowsindicateindirectconnections(forexample,precipitationorsolventexchange).
CONCLUSION
Inconclusion,wehavedevelopedamodularandefficientcontinuous‐flow
approach which allows direct access to valuablemeta‐arylated anilines.
Module1 provides a unique, safe, and scalable flow method to prepare
highlyvaluablediaryliodoniumsalts,withina2secondresidencetime(15
examples).Inmodule2,acoppertubeflowreactorwasusedforthefirst
timetoenablecopper‐catalyzedmeta‐selectiveC−Harylationofprotected
anilineswithina20minuteresidencetime(23examples).Effectiveinline
copper removal in module 3 led to values suitable for meeting the
standards of parenterally administered pharmaceutical substances (i.e.,
residualCucontent<25ppm).Finally,deprotectionofthepivanilideswas
realizedinmodule4,thusdeliveringthedesiredmeta‐arylatedanilinesin
a straightforward fashionwithin40minutes.Orchestratingall individual
modules in an integrated process allowed preparation ofmeta‐arylated
anilineswithina total time frameof1hour inexcellentyieldandpurity,
andwithouttheneedofchromatography.Webelievethattheeachofthe
6
Chapter6
122
developedmodulesareofhighvalueandwillfindwidespreaduseinboth
academiaandindustry.
EXPERIMENTALSECTION
Module 1: Diaryliodonium salts synthesis. A 25 mL oven‐dried
volumetric flask was chargedwith 4‐iodotoluene (1a, 1.09 g, 5.0mmol)
and toluene (2a, 506 mg, 5.5 mmol). Next, a second 25 mL oven‐dried
volumetric flask was charged with meta‐chloroperbenzoic acid (≤ 77%)
(1.24 g, 5.5mmol). Both the flaskswere fittedwith a septum andwere
degassed by alternating vacuum and argon backfill. Anhydrous
dichloroethanewasaddedviasyringetomakea25.0mLsolutioninboth
flasks. Both the solutionswere charged in 30mL NORM‐JECT® syringes
and were fitted to a single syringe pump. After, a 50 mL oven‐dried
volumetricflaskwaschargedwitharound20mLdichloroethane.Theflask
was fitted with a septum and was degassed by alternating vacuum and
argon backfill. Trifluoromethanesulfonic acid (1.50 g, 10.0 mmol) was
addedcarefullywitha syringeandanhydrousdichloroethanewasadded
viasyringetomakea50.0mLsolution.Thesolutionwaschargedina60
mLNORM‐JECT®syringeandfittedtoasecondsyringepump.Allsyringes
wereconnectedtoapolyetheretherketone(PEEK)cross‐mixer(500µm
I.D.)andsubsequentlyconnected to the inletof the0.1mLPFAcapillary
tubing(750µmI.D.).Thecross‐mixerandmicroreactorweresubmerged
in a sonication bath and sonication was applied during operation. First
syringepump(containing2syringes)wasoperatedat2x0.75mL/minand
the second syringe pumpwas operated at 1.5mL/min (total 3mL/min
flowrate,2secondsresidencetime).Theoutletofthereactorwasfittedto
anargonfilledroundbottomflaskwithseptumviaaneedleconnection.An
argon filledballoonwasattached inorder toensureaconstantpressure.
The reaction mixture was evaporated under reduced pressure at the
AM
rotavap.
the rotav
wasdisso
diethyl e
mixturew
filteredo
was weig
applicabl
Figure6.Sunderargmixer,5.P
R
I
1
m-C
Tf
Scheme6
ModularFlow
Residuewas
vap.Thispro
olved in am
ether until
waskeptint
ffandwashe
ghted and c
e)andmeltin
S1.A)SetupofgonB)MicroreaPFAcoil.
+ R/Mes
2
CBPA
fOH
6.S1.Schematic
Designforth
s dissolved i
ocedurewas
minimumamo
cloudy solu
thefreezer(
edwithamin
characterize
ngpointanal
module1:1.Syactorandcross‐
75
rt, s
representation
hemeta‐Selec
ndiethyl eth
repeated th
ount of acet
tion was ob
(‐26°C)over
nimumofdie
d by 1H NM
lysis.
yringepumps,2‐mixersubmerg
1. iodonium
salt synthesis
PFA tubing
50 µm ID, 0.1 mL
sonication, tr = 2 s
nofmodule1.
ctiveC−HAry
her and evap
hree times.T
tone, followe
btained. Ne
rnight.Form
ethylether.T
MR, 13C NM
2.Sonicationbatgedinthesonic
R
ylationofAni
porated aga
Then, the res
edby additio
ext, the resu
medcrystalsw
Thefinalpro
MR, 19F NMR
th,3.Collectioncationbath:4.C
I
OTf
3 (Mes) or 4 (R)
RR/Mes
ilines
123
in at
sidue
on of
ulted
were
oduct
R (if
nflaskCross‐
66
Chapter6
124
Module2:meta‐selectiveC−Harylationofanilines.A5mLoven‐dried
volumetric flaskwas chargedwithN‐(o‐tolyl)pivalamide (5a, 95mg, 0.5
mmol) and di‐p‐tolyliodonium triflate (4a, 458mg, 1.0mmol). The flask
was fitted with a septum and was degassed by alternating vacuum and
argonbackfill.Anhydrousdichloroethanewasaddedviasyringetomakea
5.0 mL solution. The solution was charged in a 10 mL BD Discardit II®
syringe.Next, thesyringewas fitted toa syringepumpandconnected to
theinletofthe20mLCTFR.TheCTFRwassubmergedintoathermostatic
oil bath and kept at 70 °C during operation. The outlet of the CTFRwas
fittedtoanErlenmeyercollectionflask.Thesyringepumpwasoperatedat
a flow rate of 1.0 mL/min (20 minutes residence time). Three extra
syringesofeach10mLanhydrousdichloroethanewerepumpedafterthe
sample(1.0mL/min)inordertocollectthecompletesample.Theresulted
reaction mixture was monitored using TLC and/or GC‐MS. The organic
mixturewasdilutedinDCMandwasintroducedintoaseparationfunnel.
Theorganicphasewaswashedwith2xsaturatedaqueousNaHCO3and1x
with brine solution sequentially. Aqueous phase was backwashed once
with DCM. Collected organic phase was dried over MgSO4, filtered and
concentrated under reduced pressure. Purification by flash
chromatography on silica afforded the product. The final product was
weightedandcharacterizedby1HNMR,13CNMR,19FNMR(ifapplicable),
HRMSandmeltingpointanalysis(ifapplicable).
AM
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Chapter6
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AModularFlowDesignforthemeta‐SelectiveC−HArylationofAnilines
127
Module4:Deprotectionofanilines.A5mLoven‐driedvolumetricflask
was charged with N‐(4,4'‐dimethyl‐[1,1'‐biphenyl]‐3‐yl)pivalamide (6a,
141mg,0.5mmol)andHCl(37wt%):1,4‐dioxane(1:1)mixturewasadded
viasyringetomakea5.0mLsolution.Thesolutionwaschargedina10mL
BDDiscardit II® syringe.Next, the syringewas fitted to a syringepump
andconnected to the inletof the20mLPFAdeprotectioncoil (1.65mm
I.D.).Thereactorwassubmergedintoathermostaticoilbathandkeptat
130 °C during operation. The outlet of the reactor was fitted to an
Erlenmeyercollectionflask.Thesyringepumpwasoperatedataflowrate
of0.5mL/min(40minutesresidencetime).Threeextrasyringesofeach
10mLanhydrous1,4‐dioxanewerepumpedafter thesample inorder to
collectthecompletesample.Theresultedreactionmixturewasmonitored
usingTLCand/orGC‐MS.Theorganicmixturewasdilutedinethylacetate
and was introduced into a separation funnel. The organic phase was
washed with aqueous 1M NaOH solution. Next the organic phase was
extractedatleast3xwithaqueous1MHClsolutionuntilaldesiredproduct
4,4'‐dimethyl‐[1,1'‐biphenyl]‐3‐amine (7a) was extracted to the aqueous
phase (monitored by TLC ninhydrin stain to detect the primary amine
functionality). Finally, the aqueous phase was made basic by careful
addition of NaOHpellets, and ethyl acetatewas added in order to back‐
extract7atotheorganicphase.Thecollectedorganicphasewasdriedover
MgSO4, filtered and concentrated under reduced pressure in order to
obtain the desired product. The final product was weighted and
characterized by 1H NMR, 13C NMR, 19F NMR (if applicable), HRMS and
meltingpointanalysis(ifapplicable).
6
Chapter6
128
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AModularFlowDesignforthemeta‐SelectiveC−HArylationofAnilines
129
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CHA
FlowS
Thischap
Gemoets,
11735‐11
HAPT
Synthesi
terisbasedo
H.P.L.;Lau
1741.
TER
isofDia
on:
udadio,G.;H
7
ryliodon
Hessel,V.;No
niumTri
oël,T. J.Org.
iflates
Chem.2017
7,82,
Chapter7
134
ABSTRACT
A safe and scalable synthesis of diaryliodonium triflates was achieved
usingapracticalcontinuous‐flowdesign.Awidearrayofelectron‐richto
electron‐deficientarenescouldreadilybetransformedtotheirrespective
diaryliodoniumsaltsonagramscale,withresidencetimesvaryingfrom2
to60s(44examples).
Inthischapterafurtherexplorationofthescopefortheflowsynthesisof
diaryliodoniumtriflates ispresented.The initialdevelopmentof the flow
reactorandpreliminaryscopeisdiscussedinChapter6.
FlowSynthesisofDiaryliodoniumTriflates
135
INTRODUCTION
In recent years, the applications of aryl electrophile sources, such as
hypervalentiodinatedcompounds,havebecomeincreasinglyimportantin
synthetic organic chemistry.1 Inparticular, diaryl‐λ3‐iodanes, also known
asdiaryliodoniumsalts,havebeenextensivelyusedinnumerousarylation
procedures.2Suchdiaryliodoniumsalts canbeconsideredasbothstrong
electrophiles and powerful oxidants, which allows chemists to reach
higher oxidation states with Pd or Cu complexes and to carry out the
targeted transformations at milder reaction conditions.3 Furthermore,
diaryliodoniumsaltscanbeusedasanelectrophilicarylsourcetocouple
withawidevarietyofnucleophiles,allowingthepreparationofsulfides,4
ethers,5amines,6esters,7andnitrocompounds8aswellastheα‐arylation
onenolates.9
Given the apparent importance of diaryliodonium salts (Scheme 7.1),
manysyntheseshavebeendevelopedtopreparethesecompounds.10The
mostpracticalreactionconditionsinvolvethereactionofiodoareneswith
Scheme7.1.Advantagesanddisadvantagesofdiaryliodoniumsalts.
7
Chapter7
136
asuitableoxidanttogiveI+IIIfollowedbyaligandexchangewithanarene.
Animprovedone‐potversionwasdevelopedbyOlofssonetal.usingmeta‐
chloroperbenzoic acid (m‐CPBA) as the oxidant and
trifluoromethanesulfonic acid (TfOH) to yield diaryliodonium triflates
directly.11However, suchoxidative reaction conditionsare typically very
exothermicandthusrepresentasubstantialsafetyriskwhencarriedout
on a large scale. Herein, we present a flow synthesis of diaryliodonium
triflateswhichisfastandscalableandprovidesabroadsubstratescope.
RESULTSANDDISCUSSION
To quantify the thermodynamic data of highly exothermic reactions,
reactioncalorimetryistypicallyused.12Inordertorapidlydeterminethe
unknownreactionenthalpy(ΔHR)ofthediaryliodoniumsaltsynthesis,we
developed an operationally simple adiabatic continuous‐flow device that
allowed us to calculate ΔHR values via in‐line ΔT measurements (see
Scheme 7.2 a). Hereto, a custom‐made glass tubewas designed, and the
cross‐micromixerandmicroreactorwereplacedinside.Highvacuumwas
applied to the system in order to create adiabatic conditions (for more
detailsaboutthesetup,seetheSupportingInformation(SI).Assumingfull
conversion, we calculated the reaction enthalpy using the following
equation,ΔHR=m×Cp×ΔT,wherem andCp are themassand theheat
capacity of the solvent, respectively (Cp values of substrates were
neglected,whichisfairgiventhedilution).Athermocouplewasconnected
totheT‐mixerattheendofthemicroreactor,whichallowedustohavein‐
line temperaturemeasurements. The calibration of the adiabatic system
was performed using the well‐known neutralization reaction of sodium
hydroxidewithhydrochloricacid.13Next,wecarriedout the synthesisof
diphenyliodoniumtriflateanddi‐p‐tolyliodoniumtriflate intheadiabatic
microfluidic device, and ΔT values were measured (reactions were
FlowSynthesisofDiaryliodoniumTriflates
137
performedthreetimeseach).WiththeCpvalueofDCEknown(Cp=129.4
J·mol−1·K−1),14wewere able to directly calculate the respective enthalpy
values.Interestingly,veryhighΔHRvaluesbetween−160and−180kJ/mol
were observed, highlighting the need for a safe and reliable method to
scale the reaction conditions (see Scheme 7.2 b).15 Such exothermic
transformations can be carried out safely in continuous‐flow
microreactors as the microenvironment results in an excellent heat
dissipationrate.16
Scheme7.2.a)Adiabaticmicroflowsetupforenthalpymeasurements.b)Enthalpyvaluesobtainedfortheone‐potsynthesisofdiaryliodoniumtriflates.
Wecommencedourinvestigationsbydesigningasuitablecontinuous‐flow
setup (Scheme 7.3). Our design consists of three individual feeds that
allow separation of the hazardous reagents and control of the reaction
stoichiometrybyadjustingtheindividualflowrates.Thedifferentreagent
streamsweremergedinacross‐micromixerandsubsequentlyintroduced
7
Chapter7
138
Feed
Feed
Feed
Scheme7
in a perfl
avoidmic
ultrasonic
(2a)inth
for our r
obtained
dichloroe
was rem
Notably,t
gramsca
crystals (
yield(69%
Figure7.triflate(3a
7
1.5 mL/min
0.75 mL/min
0.75 mL/min
m-CPBA
Ar-I + Ar'-H
d 3:
d 2:
d 1:
TfOH
7.3.Schematicr
luoroalkoxy
croreactorcl
c bath.17 The
hepresence
reaction opti
with 1.1 eq
ethane(DCE)
markably fast
thedesiredd
le (2.04g,8
(Figure 7.1).
%yield)of3
1.Comparisona)producedeit
n
n
n
H
representationo
capillary rea
logging,them
e reaction b
ofm‐CPBAa
imization stu
quiv of 2a a
)asthesolve
t and was
di‐p‐tolyliod
9%) inexce
. Analogous
3aasaninfer
of the solids otherinbatch(le
PFA750 µm I.
room tem
Ultrasonicat
ofthemicroflow
actor (PFA, 7
mixerandre
between 4‐io
andTfOHwa
udies. Optim
and m‐CPBA
entina100μ
completed
oniumtriflat
ellentyielda
batch exper
rior‐qualityp
obtained aftereft)orflow(righ
A tubingD., 0.1 - 3.0 mL
mp., tr = 2 - 60 s
tion
wsetup.
750μm i.d.,
eactorweres
odotoluene (
asselectedas
mal reaction
A, and 2 equ
μLmicroreac
within 2 s
te3acouldb
aspureands
riments resu
powderpreci
precipitation oht).
0.1−3.0mL)
submergedi
(1a) and tolu
sthebenchm
conditions w
uiv of TfOH
ctor.Thereac
residence t
beobtained
simple toha
ulted in a lo
ipitate.
of di‐p‐tolyliodo
). To
inan
uene
mark
were
and
ction
time.
ona
andle
ower
onium
FlowSynthesisofDiaryliodoniumTriflates
139
With the optimized conditions in hand, we sought to demonstrate the
generality of our flow protocol (Table 7.1).Within 2 s residence time, a
diverse set of both symmetrical and unsymmetrical diaryliodonium
triflateswas synthesized in fair to excellent yieldon a gram scale (5−10
mmolscale).Symmetricaldiaryliodoniumtriflateswerereadilyproduced
ingoodtoexcellentyields(3a−3c).Usingdifferent(hetero)‐arenes,
Table 7.1. Scope ofDiaryliodonium Triflates Using Electron‐Neutral and
Electron‐RichArylIodidesa
1.1 equiv. m-CPBA 2.0 equiv. TfOH
V = 0.1 mL, tr = 2s3
+R
I
1 2
1.1 equiv.
R' R
I+
R'
-OTf
3a (90%, 92%b)
I+
-OTf
3b (87%)
I+
-OTf
3c (58%)
I+
-OTf
3e (43%)
I+-OTf
3d (75%)
I+
-OTf
3g (85%)
I+
-OTf
3f (87%)
I+-OTf
3i (78%)
I+-OTf
MeMe F F
S
Me
Me
Me Me
Me
MeMe
Me
Me
Me
3j (75%)c
I+-OTf
I
Me
Me MeF
3l (88%)
I+-OTf Me
Me Me
Me
3n (80%)
I+-OTf
3o (72%)
I+-OTf
3p (56%)
I+-OTfMe
Me Me Me
Me
Me
Me
Me
Me
I
3k (61%)
I+-OTf Me
Me Me
Me
Me MeMe
Ph
3q (21%)
I+-OTf
3r (49)%)
I+-OTf
S
3m (37%)
I+-OTf Me
MeMe
F
OMeMe
Me
Me Me
Me
Me
Me
Me
3h (28%)
I+-OTf
Me
Me
MeAcHN
aReactionconditions:feed1:5.0mmolofaryliodide(1),5.5mmolofarene(2)in25mLofDCE;feed2:5.5mmolofm‐CPBAin25mLofDCE;feed3:10mmolofTfOHin50mLof DCE. Throughput distribution feed 1 / feed 2 / feed 3 was 1:1:2.; b10 mmol scalereaction;Isolatedyieldsarereported.
7
Chapter7
140
unsymmetrical diaryliodonium salts were synthesized (3d, 3e).
Furthermore,theuseofstericallyhinderedmesitylenewaswell‐tolerated,
providingaccesstoadiversesetofarylmesityliodoniumtriflates(3f−3p).
Thesecompoundsareofhighinterestincross‐couplingandC−Harylation
chemistrybecausetheyallowselective transferof the functionalizedaryl
groups to the substrate. Aryl iodides bearing strong electron‐ donating
substituents (e.g., anisoles) or electron‐rich heteroaromatic iodides (e.g.,
thiophene) were incompatible with the reaction conditions. However,
these diaryliodonium triflates could be accessedwhen using themesityl
iodidewith thecorresponding(hetero)arenes,albeit ina loweryield(3q
and3r).
Aryl iodides with electron‐withdrawing functional groups proved
particularly challenging. However, after a minor re‐optimization of the
reactionconditions(seetheSI),itwasfoundthatthesecompoundscould
beobtained ingoodyieldsby increasingthereactorvolumeto3mLand
usinganexcessofm‐CPBA(1.3equiv)andTfOH(3.0equiv).Aryliodides
bearing ortho, meta, and para electron withdrawing substituents (e.g.,
halogens, nitro, esters, ketones) were all well‐tolerated, yielding the
targeted diaryliodonium triflates in synthetically useful yields (32−90%
yield) (Table 7.2). Also, 3‐iodopyridine (3x and 3ai) and 1‐
iodoanthraquinone (3s) could be subjected to the flow conditions,
resultinginthedesiredcompoundsinfairyields(19−47%yield).
Finally,withtheaimofdevelopinga flowprotocolutilizingcheapand
easilyavailablestartingmaterials,wechosetooxidizesimplearenesusing
molecular iodine to yield the corresponding symmetrical diaryliodonium
triflates.Optimalresultswereobtainedusingiodineasthelimitingreagent
alongwith3equivofm‐CPBA,4.1−10equivofarene,and5equivofTfOH
(seetheSI).Moderatetoexcellentyieldswereobtainedforthesynthesis
FlowSynthesisofDiaryliodoniumTriflates
141
ofsymmetricaldiaryliodoniumsalts(38−90%)(Table7.3).Inmostcases,
thepara−parasubstituteddiaryliodoniumanalogueswereobtainedasthe
only regioisomer.However,whenusing tolueneas the substrate, several
other regioisomerswere obtainedwith theortho−para isomer being the
mostabundant(3ak).However,theselectivitycouldbecompletelytuned
towardtheortho−paraisomerbydecreasingthereactiontemperatureto0
°C.
Table 7.2. Scope of Diaryliodonium Triflates with Electron‐Deficient
Substratesa
aReactionconditions:feed1:5.0mmolof1,5.5mmol2in25mLofDCE;feed2:6.5mmolof m‐CPBA in 25mL of DCE; feed 3: 15mmol of TfOH in 50mL of DCE. Throughputdistributionfeed1/feed2/feed3was1:1:2.Isolatedyieldsarereported.
7
Chapter7
142
Table 7.3. Scope of Symmetric Diaryliodonium Triflates Derived from
ArenesandMolecularIodinea
aReactionconditions: feed1:2.0mmolof4,10equiv.of2 in10mLofDCE; feed2:6.0mmolofm‐CPBAin10mLofDCE;feed3:10mmolofTfOHin10mLofDCE.Throughputdistributionfeed1/feed2/feed3was1:1:2.b4.1equiv.ofareneareused.cSelectivityatroomtemperature:ortho‐para90%para‐para5%andortho‐ortho5%.dSelectivityat0°C:ortho‐para>96%.Alltheyieldsreportedareisolated.
CONCLUSION
Insummary,wehavedevelopedafast,scalable,andsafecontinuous‐flow
protocol to prepare various symmetrical and unsymmetrical
diaryliodoniumtriflates.Ourprotocoldisplayedabroadsubstratescopeof
electron‐rich to electron‐deficient substrates (44 examples, yields up to
92%). Notably, the reaction could be completed in a matter of seconds,
allowingthepreparationthediaryliodoniumtriflatesonagramscalewith
excellentpurityinatime‐efficientfashion.Webelievethatthedeveloped
flow protocol will find widespread use in both academia and industry
giventhesyntheticrelevanceofdiaryliodoniumsalts.
FlowSynthesisofDiaryliodoniumTriflates
143
EXPERIMENTALSECTION.
General Procedure for the Diaryliodonium Salt Synthesis with
Electron‐NeutralandElectron‐RichSubstrates (GP1). A 25mL oven‐
dried volumetric flask was charged with 4‐iodotoluene (1a, 1.09 g, 5.0
mmol) and toluene (2a, 506mg,5.5mmol).Next, a second25mLoven‐
dried volumetric flask was charged with meta‐chloroperbenzoic acid
(≤77%)(1.24g,5.5mmol).Boththeflaskswerefittedwithaseptumand
weredegassedbyalternatingvacuumandargonbackfill.Dichloroethane
wasaddedviasyringetomakea25.0mLsolutioninbothflasks.Boththe
solutionswerechargedin30mLNORM‐JECT®syringesandwerefittedtoa
single syringe pump. Afterwards, a 50 mL oven‐dried volumetric flask
fittedwithaseptumandwasdegassedbyalternatingvacuumandargon
backfill and charged with 20 mL of dichloroethane.
Trifluoromethanesulfonic acid (0.9 mL, 10.0mmol) was added carefully
withasyringe,anddichloroethanewasaddedviasyringetomakea50.0
mL solution. The solutionwas charged in a 60mLNORM‐JECT® syringe
and fitted to a second syringe pump. All syringes were connected to a
PEEKcross‐mixer(500μmi.d.)andsubsequentlyconnectedtotheinletof
the 0.1 mL PFA capillary tubing (750 μm i.d.). The cross‐mixer and
microreactor were submerged in a sonication bath, and sonication was
applied during operation. The first syringe pump (containing two
syringes)wasoperatedat2×0.75mL/min,andthesecondsyringepump
was operated at 1.5 mL/min (total 3 mL/min flow rate, 2 s residence
time).Theoutletofthereactorwasfittedtoanargon‐filledround‐bottom
flask with septum via a needle connection. An argon filled balloon was
attachedinordertoensureaconstantpressure.Thereactionmixturewas
evaporatedunderreducedpressureattherotavap.Residuewasdissolved
indiethyletherandevaporatedagainattherotavap.Thisprocedurewas
repeated three times, and then the residuewas dissolved in aminimum
7
Chapter7
144
amount of acetone, followed by addition of diethyl ether until a cloudy
solutionwasobtained.Next,theresultingmixturewaskeptinthefreezer
(−26 °C) overnight. Formedcrystalswere ilteredoff andwashedwith a
minimumofdiethylether.
General Procedure for the Diaryliodonium Salt Synthesis with
Electron‐Deficient Substrates (GP2). A 25 mL oven‐dried volumetric
flask was charged with 4‐iodonitrobenzene (1b, 1.25 g, 5.0 mmol) and
mesitylene (2b, 0.76 mL, 5.5 mmol). Next, a second 25 mL oven‐dried
volumetric flask was charged with meta‐chloroperbenzoic acid (≤77%)
(1.5 g, 6.5 mmol). Both the flasks were fitted with a septum and were
degassed by alternating vacuum and argon backfill. Dichloroethane was
added via syringe to make a 25.0 mL solution in both flasks. Both the
solutionswerechargedin30mLNORM‐JECT®syringesandwerefittedto
a single syringe pump. Afterwards, a 50mL oven‐dried volumetric flask
was fitted with a septum and was degassed by alternating vacuum and
argon backfill and charged with 40 mL of dichloroethane.
Trifluoromethanesulfonic acid (1.3 mL, 15 mmol) was added carefully
withasyringe,anddichloroethanewasaddedviasyringetomakea50.0
mL solution. The solutionwas charged in a 60mLNORM‐JECT® syringe
and fitted to a second syringe pump. All syringes were connected to a
PEEKcross‐mixer(500μmi.d.)andsubsequentlyconnectedtotheinletof
the 3.0 mL PFA capillary tubing (750 μm i.d.). The cross‐mixer and
microreactor were submerged in a sonication bath, and sonication was
applied during operation. The first syringe pump (containing two
syringes)wasoperatedat2×0.75mL/min,andthesecondsyringepump
was operated at 1.5 mL/min (total 3 mL/min flow rate, 60 s residence
time).Theoutletofthereactorwasfittedtoanargon‐filledround‐bottom
flask with septum via a needle connection. An argon‐filled balloon was
FlowSynthesisofDiaryliodoniumTriflates
145
attachedinordertoensureaconstantpressure.Thereactionmixturewas
evaporatedunderreducedpressureattherotavap.Residuewasdissolved
indiethyletherandevaporatedagainattherotavap.Thisprocedurewas
repeated three times, and then the residuewas dissolved in aminimum
amount of acetone, followed by addition of diethyl ether until a cloudy
solutionwasobtained.Next,theresultingmixturewaskeptinthefreezer
(−26 °C) overnight. Formedcrystalswere filteredoff andwashedwith a
minimumofdiethylether.
GeneralProcedurefortheDiaryliodoniumSaltSynthesiswithIodine
(GP3).A10mLoven‐driedvolumetric flaskwas chargedwith iodine (4,
507mg,2mmol)and thearene(2,8.2−20mmol).Next,asecond10mL
oven‐driedvolumetricflaskwaschargedwithmeta‐chloroperbenzoicacid
(≤77%) (1.5 g, 6 mmol). Both the flasks were fitted with a septum and
weredegassedbyalternatingvacuumandargonbackfill.Dichloroethane
wasaddedvia syringe tomakea10mLsolution inboth flasks.Both the
solutionswerechargedin10mLNORM‐JECT®syringesandwerefittedto
a single syringe pump. Afterwards, a 25mL oven‐dried volumetric flask
was fitted with a septum and was degassed by alternating vacuum and
argon backfill and charged with around 15 mL of dichloroethane.
Trifluoromethanesulfonic acid (0.9 mL, 10.0mmol) was added carefully
withasyringe,anddichloroethanewasaddedviasyringetomakea20.0
mL solution. The solutionwas charged in a 20mLNORM‐JECT® syringe
and fitted to a second syringe pump. All syringes were connected to a
PEEKcross‐mixer(500μmi.d.)andsubsequentlyconnectedtotheinletof
the 3 mL PFA capillary tubing (750 μm i.d.). The cross‐mixer and
microreactor were submerged in a sonication bath, and sonication was
applied during operation. The first syringe pump (containing two
syringes)wasoperatedat2×0.75mL/min,andthesecondsyringepump
7
Chapter7
146
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CHAPTER8
ACriticalAssessmentofC−HFunctionalization
forAPISynthesis:ACaseStudy
Thischapterisbasedon:
Gemoets,H.P.L.;Schouten,A.;Hessel,V.;Noël,T.2017,unpublishedwork
0
0,2
0,4
0,6
0,8
1PMI
EMY
E‐Factor
Yield
AE
Mod.EcoScale
Suzuki‐Miyaura coupling (Judd 1994, Glaxo Group Limited)
C‐H arylation (Gemoets 2016, BF4‐)
C‐H arylation (Gemoets 2017, MsO‐)
Chapter8
152
ABSTRACT
In this chapter, a critical assessment of the C‐2 arylation protocol
described in Chapter 4 is performed. The methodology elucidated in
Chapter4wasevaluatedforitsapplicationinthesynthesisofsaprisartan,
aprescriptiondrugemployedinthetreatmentofhypertensionandheart
failure.Moreover,aholisticevaluationoftheC‐Hactivationmethodology
reported herein was conducted. Based on experimental results, cost
analysis and green chemistry metrics, our C−H activation methodology
was compared to the patented synthesis of the same API (saprisartan).
Specifically, the formation of the key intermediate methyl 2‐(5‐
methylbenzofuran‐2‐yl)benzoate, was found to be the bottleneck in the
patentedsyntheticrouteandwasusedasthepointofcomparisonbetween
the two methodologies. Compared to the patented route, the
implementationofourC‐2arylationmethodologyfortheformationofthe
samekey intermediate resulted in a significant increase inproduct yield
(65% vs 17%) and in a projected cost reduction of around 92% for
chemicals and solvent. Moreover, the assessment of Green Chemistry
Metrics revealed the enhanced green profile of our C−H activation
methodology.OursyntheticroutescoredmuchlowerontheProcessMass
Intensity(PMI)index(68vs326),thusmakingthisprocedureacceptable
for the pharmaceutical sector, where PMI values lower than 100 are
recommendedforeverysyntheticstep.Lastly,withtheaimtoimprovethe
safety and the potential for industrial scale up of our methodology, we
attempted to translate the batch procedure into a continuous‐flow
protocol.
ACriticalAssessmentofC−HFunctionalizationforAPISynthesis
153
INTRODUCTION
Heterocyclic moieties are often present in active pharmaceutical
ingredients(API).1Specifically,nitrogen‐containingheterocyclesaloneare
presentinalmost60%ofallAPIsapprovedbytheUnitedStatesFoodand
Drugs Administration (U.S. FDA).2 Within heterocycles, heteroarene
moieties and in particular heterobiaryl structures are among the most
important and recurring motifs in marketed APIs, agrochemical
compoundsandadvancedmaterials.Asexample,fourdrugAPIsbasedon
benzo‐fused heterobiaryl motifs are presented in Figure 8.1.3 Notably,
raloxifenewaslistedinthetop200drugssoldworldwidein2013.4
Figure 8.1. Selected examples of APIs containing benzo‐fused heterobiaryl corestructures.
WhileinvestigatingthepossibilitytoapplyourC‐2arylationmethodology
in the preparation of an API, we identified the anti‐hypertensive drug
saprisartan as an ideal candidate.5 Saprisartan contains a C‐2 arylated
benzofurancore,andshouldthereforefallwithinthedemonstratedscope
ofourC‐2arylationmethodology.Uptodate,theSuzuki‐Miyauracoupling
8
Chapter8
154
remains the most widely used cross‐coupling arylation reaction in
industry,1b and is also reported in a 1994 patent (Judd, Glaxo Group
Limited)6 describing the C‐2 arylation step toward the synthesis of
saprisartan (Figure 8.2). However, despite its popularity, the Suzuki‐
Miyaura coupling remains far from ideal in termsof sustainabilityof the
process. First of all, this method requires pre‐functionalization of both
couplingpartners(aboronicacidandanorganohalide).Theneedforthe
presence of a boronic acid results in an undesired extra step in the
reaction process. Furthermore, the synthesis of boronic esters requires
harshreagents(e.g.,lithiumcontainingreagents),whilethepresenceofan
organohalide coupling partner is associated with the production of
halogen‐containingchemicalwaste.Moreover,thecouplingreactionitself
requires harsh conditions in terms of temperature and relatively long
reactiontimes,whichmayleadtoalimitedfunctionalgrouptolerability.
Figure 8.2. Retrosynthetic analysis of patented synthetic routes to saprisartan andraloxifene,bothinvolvingaSuzuki‐Miyauracouplingstrategy.
Incontrasttotheclassicalcross‐couplingstrategies,theimplementationof
a C–H activation strategy would circumvent the need for pre‐
functionalizationof the substrates.Over the last years, several transition
metal‐catalyzedmethodsforthedirectC‐2arylationofheteroareneshave
been developed.7 However, these methods still necessitate high
temperatures, stoichiometricamountsofoxidantsand/oradditives, toxic
solventsystemsandlimitedselectivityandhighcatalystloadings.
ACriticalAssessmentofC−HFunctionalizationforAPISynthesis
155
In order to compare our developedmethod (described in chapter 4)
with the state of the art procedure for the synthesis of saprisartan, we
performedacostanalysiscomparingbothprocedures.Strategicdecisions
in the manufacturing industry are mostly driven by economic interests.
Thus,areliableindicatoronthepossibilitytoapplyanovelsyntheticroute
isacostanalysiscomparingtheeconomicaspectsofanewprocesstothe
established one. Because of the difficulty in accessing and deriving data
fromtheindustrialscaleproductionofsaprisartan,wedecidedtoconduct
a cost analysis on the lab‐scale. Such lab‐scale cost evaluation can be
regardedasasimplifiedversionofthemethodreportedbyKressireretal.8
A detailed explanation on the approach adopted for the cost analysis is
givenintheExperimentalSection.
Moreover,besidestheeconomicaspect,weassessedtheenvironmental
impactof the twoproceduresviadifferentgreenmetrics.During the last
decades, sustainability of chemical processes has become a topic of
increasing interest.Therefore, the termgreenchemistry, referring to the
design of chemical processes and products to minimize the use and/or
generation of hazardous materials, was created.9 The fundamentals of
green chemistry were further clarified and explained in a list of twelve
principleswhichprovideacohesiveframeworkforthedesignofchemical
processeswithareducedeffectontheenvironment.Fortoolongtimethe
environmental effects of chemical processes were considered as a
“necessary evil” that must be tolerated in order to obtain optimized,
efficientandinexpensiveprocesses.However,oneoftherationalesbehind
greenchemistryisthatthedesignofamoresustainableprocesswillalso
result in increased profits for the industry. The principles of green
chemistryshouldthereforenotbeseenasasetofrulestoberespectedto
8
Chapter8
156
meet theguidelinesof regulatoryagencies,butalsoasanopportunity to
continuouslyinnovate.10
A comprehensive way to evaluate the environmental impact of
products and processes across their entire life cycle is the so‐called Life
CycleAssessment (LCA).11 This analytic toolwould be a suitable one for
thecomparisonoftheproposedstrategywithconventionalcross‐coupling
chemistries. However, a large number of data concerning the industrial
productionofsaprisartanwouldberequiredtoconductaproperLCA.Due
to the impossibility of gathering such data, we decided to compare the
methodologies of interested by employing green metrics, which can be
regardedassimplifiedenvironmentalscreeningtools.12Thegreenmetrics
we used for the assessment of the environmental effects of the two
methodologies are: atom economy (AE),13 environmental factor (E‐
factor),14processmassintensity(PMI),15effectivemassyield(EMY)16and
EcoScale (original and modified).17 A brief discussion and definition of
thesemetricsisgivenintheExperimentalSection.
ACriticalAssessmentofC−HFunctionalizationforAPISynthesis
157
RESULTSANDDISCUSSION
Saprisartansynthesis:Identifyingthebottleneck
In1994,onbehalfofGlaxoGroupLimited,Juddetal.patentedaneleven‐
step procedure for the synthesis of saprisartan starting from 5‐
methylbenzofuran.3d,6 In order to identify the bottleneck of the synthetic
route,weperformedaretrosyntheticanalysis,asdepictedinScheme8.1.
Scheme 8.1. Retrosynthesis of saprisartan as reported by Judd (1994). a) 1. n‐BuLi,TMEDA,ether, ‐60°C,2.B(Oi‐Pr)3, ‐60°C,3.HCl;b)methyl2‐bromobenzoate,Pd(PPh3)4,DME,Na2CO3 (aq),N2, reflux;c)Br2,CCl4,0°C;d)NaOH,MeOH,reflux;e)DPPA,Et3N, t‐BuOH, 1,4‐dioxane, N2, reflux; f) NBS, (PhCO2)2, CCl4, reflux; g) ethyl 4‐cyclopropyl‐2‐ethyl‐1H‐imidazole‐5‐carboxylate, K2CO3, DMF, RT, N2; h) TFA, CH2Cl2, 3°C, N2; i)CF3(SO2)2O,CH2Cl2,Et3N, ‐70°C,N2; j)NaOH,MeOH,50°C;k)1.CDI,THF,RT,N2,2.NH3,EtOH,reflux.
In order to determine the efficiency of each synthetic step, the process
mass intensity (PMI) was calculated and used as key metric (see Table
8.1).15b The first two steps a) (i.e., lithiation followed by borylation and
acidic work‐up) and b) (i.e., Suzuki‐Miyaura coupling) of this procedure
aredirectlyconnectedtotheC‐2arylationof5‐methylbenzofuran.Ascan
beseenfromtheresultsinTable8.1,comparedtoallothersyntheticsteps,
8
Chapter8
158
thecombinationof stepaandbaffords thehighestPMIvalue (326)and
was therefore identified as the bottleneck of this synthetic route. Apart
fromthehighestprocessmass intensity, thecombinationofstepaandb
also resulted in the lowest yields (17% overall yield). Therefore, taking
into account these observations, it becomes clear that a significant
improvement in thesynthesisofsaprisartancould lie in thereplacement
ofthecurrentC‐2arylationstrategywithourC−Hactivationmethodology.
Table8.1.CalculatedPMIforeachoftheElevenSteps intheProcedureof
SaprisartanSynthesisPublishedbyJuddetal.in1994.3d,a
Step Yield(g)
Yield(%)
PMI Step Yield(g) Yield(%)
PMI
a 13.80 56 68 f 3.50 68 109
bb 4.31 30 131 gb 19.70 62 173
(a+b)b,e 4.31 17 326 h 16.20 98 48
c 57.97 95 31 i 10.00 100 40
dc 22.00 92 69 j 18.50 95 83
eb 1.95 18 124 kc,d 0.33 64 293
aSome of the purification steps in the procedurewere not clearly quantified andwerethereforenottakenintoaccount:bcolumnchromatography,cacidification,dcrystallization;eThe PMIs of the first two steps (a+b) were combined considering the proposedchemistry,whichcomprisesbothsteps.
In chapter 4, thismild and selective C−H arylation of heteroarenes (i.e.,
indoles, benzofurans and benzothiophenes) was described.5 The open
flaskprocedureemployedtheuseofaryldiazoniumtetrafluoroboratesas
highlyelectrophilicarylatingagents, lowpalladium loadings (0.5‐2.0mol
% Pd) and green solvents (EtOAc/2‐MeTHF or MeOH). To illustrate the
efficacyofthismildstrategyforthesynthesisofsaprisartan,weemployed
ourmethodforthesynthesisoftheC‐2arylatedintermediatemethyl2‐(5‐
methylbenzofuran‐2‐yl)benzoate (8a) (see Scheme 8.2). Starting from 5‐
ACriticalAssessmentofC−HFunctionalizationforAPISynthesis
159
methylbenzofuran, a two‐step procedure involving the preparation of 2‐
(methoxycarbonyl)benzenediazonium tetrafluoroborate and followed by
theC‐2arylation,affordedtheisolatedkeyintermediate8ain67%overall
yield. Such a result compares positively to the patentedprocess, both in
termsofyieldandsustainability,especiallywhentakingintoaccountthat
thepatentedprocesswouldrequirefourformaltransformationstoobtain
thesameproduct(i.e.,stepa inScheme8.1actuallyconsistsof lithiation,
borylationandacidificationwhilestepbisthecross‐couplingmethod).
Scheme8.2.Comparisonforthesynthesisofthesaprisartandrugprecursor8ausingthepatentedorourdirectC−Harylationmethod(asdescribedinChapter4).
WhenapplyingourC‐2arylationstrategytothesynthesisofcompound8a,
aryldiazonium tetrafluoroborates were employed. The use of the BF4‐
counterionisoftenrecommendedforthesynthesisofaryldiazoniumsalts
asitdisplaysanincreasedsafetyprofilecomparedtoaryldiazoniumsalts
bearing a chloride counterion.18 However, aryldiazonium
tetrafluoroborates exhibit poor solubility in many organic solvents. In
addition, the counterion has a significant impact on the nucleofugic
propertiesofaryldiazoniumsalts,and,therefore,ontheirreactivityinthe
reaction medium.19 With the aim of developing a safe, scalable and
environmentallybenignC−Harylationstrategyforthesynthesisof8a,we
reasoned that the implementation of a more soluble and more reactive
diazonium salt, would be of high importance. Based on the ease of
preparation and shelf stability of the salts, we prepared an array of
8
Chapter8
160
aryldiazoniumsaltspossessingalternativecounterions(seeTable8.2).2‐
(methoxycarbonyl)benzenediazonium salts bearing the mesylate (2za),
tosylate(2zb)20andtriflate(2zc)counterionallprovedtobeshelfstable
andcouldbereadilyaccessed,viarecrystallization,infairtoexcellentyield
(28‐92%). Notably, the aryldiazonium sulfonates (2za and 2zc) were
successfully isolated for the first time via the above procedure. Using
trifluoroaceticacid, theresultingaryldiazoniumsalt2zdwasobtained in
loweryield (11%).21Moreover, thesaltdemonstrated instabilityat room
temperature,andslowlydecomposedwithinfewdays.Asexpected,when
attempting the synthesis of 2‐(methoxycarbonyl)benzenediazonium
acetate(2ze),22nosolidscouldbeobtainedduetorapiddecomposition.
Table 8.2. Scope of Synthesized 2‐(methoxycarbonyl)benzenediazonium
SaltswithAlternativeCounterionsa
aSynthesis and purification methods employed for compounds 2z to 2ze are reportedbetween brackets and described in Table 8.S1; bThese aryldiazonium salts tend todecomposeatroomtemperature.
Next,weperformedaseriesofreactionstofurtheroptimizethedirectC‐2
arylation of 5‐methylbenzofuran (see Table 8.3). In our previously
ACriticalAssessmentofC−HFunctionalizationforAPISynthesis
161
reportedresults(entry1), trifluoroaceticacidwasused instoichiometric
amount as additive in order to accelerate the reaction (see Chapter 4,
Table 4.2 for further details). However, in order to aim for the highest
possible atom economy, we chose to omit the addition of any additive.
Whenperformingthereaction intheabsenceof trifluoroaceticacid,a16
hours reaction time (overnight)was necessary to obtain full conversion
and amoderate yield of8a (49%, Table 8.3, entry 2). Furthermore, the
reactions performed with 2‐(methoxycarbonyl)benzenediazonium
tosylate, triflate and mesylate all compared favorably to the previously
reported results (entry 3‐5 vs 1). Considering that the counterion is not
participating in the reaction, it can be considered as waste when
calculating the environmental impact of our process. Therefore, while
evaluating the green chemistry metrics of our process (see Green
Chemistry Metrics section), the molecular weight of the employed
counterions becomes relevant. Mesylate possesses the lowest molecular
weightwhencomparedtotosylateandtriflate(seeTable8.3.Moreover,in
contrast to tetrafluoroborate and triflate, mesylate counterions do not
contain any halogen atoms, thus making their waste treatment less
demanding. Lastly, further optimization of the reaction conditions
demonstrated that theequivalentsofdiazoniumsaltcouldbereduced to
1.2 equiv and that the reaction could be operated at room temperature
without loss of reactivity (entry 6). Moreover, the optimized conditions
allowed for a facilework‐procedure that allowedus to avoid the former
extractionanddryingstep(seeExperimentalSectionforfurtherdetails).
8
Chapter8
162
Table 8.3. FurtherBatchOptimization for theDirect C−H arylation of 5‐
MethylbenzofurantothekeyIntermediate8aa
Entry X‐ MWx‐(g/mol)
DiazoniumSalt(equiv)
T(°C)
t GCYield
1b BF4‐ 86.80 2.0 40 2 h 70%c
2 BF4‐ 86.80 2.0 40 16 h 49%
3 TfO‐ 149.60 2.0 40 16 h 82%
4 TsO‐ 171.19 2.0 40 16 h 93%
5 MsO‐ 95.09 2.0 40 16 h 93%
6 MsO‐ 95.09 1.2 rt 16 h 94%;89%c
aReaction conditions: 1.0mol%Pd(OAc)2, 1.0mmol 5‐methylbenzofuran and 1.2 – 2.0equiv aryldiazonium salt in 5mLMeOH at rt – 40 °C; b1 equiv of TFA as additive (forfurtherdetailsseechapter4);cisolatedyield.
Unlike all other counterions, the 2‐(methoxycarbonyl)benzenediazonium
mesylate was highly soluble in MeOH, therefore making it a suitable
reagent for a continuous flow protocol. Because of the safety risks
associatedwith diazonium salts,we considered that performing our C‐2
arylation reaction in continuous‐flow would considerably enhance the
operational safety and increase the scale‐up potential. Bearing this in
mind, a continuous‐flow reactor was constructed from PFA capillary
tubing (750 µm i.d., 3 mL) in order to investigate our C−H arylation
protocolinmicroflow.Translatingtheoptimizedbatchreactioncondition
to flowyielded30%ofthedesiredproduct8awithinonly30minutesof
residencetimeat40°C(Scheme8.3a).Furtheroptimizationtowardsthe
ACriticalAssessmentofC−HFunctionalizationforAPISynthesis
163
development of a continuous‐flow process appropriate for multi‐gram
scale production is currently underway in our laboratory. Specifically,
these efforts focus on the implementation of a 2‐stage telescoped flow
system that would allow us to perform the in situ formation of the
diazoniumsaltpriortotheC−Harylationstep,thusfurtherimprovingthe
safetyprofileofourprocedure(scheme8.3b).23
Scheme8.3.a)FlowExperimentsfortheDirectC−HArylationof5‐MethylbenzofurantothekeyIntermediate8a.b)Telescopedflowexperimentincludingtheinsituformationofaryldiazoniumsaltonmulti‐gramscale.
8
Chapter8
164
Costanalysis
Thesecondpartofthischaptercomprisesacostanalysisofthepreviously
mentionedsyntheticroutestowardthesaprisartanprecursor8a.Inorder
toprovideacomprehensivecomparison,thecostanalysisreportedherein
is performed on lab scale procedures and the evaluation of the cost
assessments is based on the method reported by Kressirer et al.8 For
furtherdetailsonthemethodofcostanalysisseeExperimentalSection.
AscanbeseenfromScheme8.2,thepatentedprocedurefromJuddet
al. reports a rather low overall yield of 17%. On the other hand, our
procedure shows a 67% and 65% overall yield for the aryldiazonium
tetrafluoroborate andmesylate respectively.* It is evident that the large
improvements obtained in the yields also reflects in a reduction of
materialcosts.Thecostanalysisrevealedthat,comparedto thepatented
process, savings from 86% and up to 92% were obtained with our
methodology (seeTable8.4 for summary). This remarkable reduction in
the costs could be attributed to an improvement of several different
aspects.Firstly,duetobetteryieldsandhigherreactionefficiency,alower
amountofchemicalsisrequiredtoproducethesamequantityofthetarget
compound.Furthermore,thechemicalsusedinourprocessarelesscostly.
Thirdly, by circumventing the need for pre‐functionalization of the
substrates as well as and the need to either cool or heat the reaction
mixture,ourprocessrepresentsamorestraightforwardapproach.Finally,
themassive reduction of solvent use is largely explained by the simpler
work‐up procedures. Easier work‐up procedures also contribute in
reducing the laborcostsassociatedwithourprocedure (e.g.,noneed for
*Sincetheemployedaryldiazoniumsaltsarenotcommerciallyavailable,wehavetaken into account the yield of the diazotisation step into the overall yield (seeScheme8.4).
ACriticalAssessmentofC−HFunctionalizationforAPISynthesis
165
extraction, washing or drying steps). A detailed description of the cost
analysiscanbefoundinScheme8.4andTable8.5to8.7.
Table8.4.CostAnalysison theLabScaleProcedures from Juddetal.and
Gemoetsetal.forthesynthesisofthesaprisartanprecursor8aa
aThecostsarebasedontheproductionof10gramsoftargetcompound.PatentedreferstotheprocessbyJuddetal..Tetrafluoroboratereferstothereactionconditionsreportedin chapter 4 using 2z as arylating reagent. Mesylate refers to the further improvedproceduredescribedwithinthischapterusing2zaasarylatingreagent.
CostaspectPatented Tetrafluoroborate MesylateCosts(€) Costs(€) Reduction Costs(€) Reduction
Chemicals 122.65 15.05 88% 9.70 92%
Solvents 8.24 2.69 67% 1.27 85%
Total 130.89 17.74 86% 10.97 92%
Energy o ++ +
Labor o + ++
8
Chapter8
166
NH
2
CO
OM
e
8a
0.18
6 g
(70
%)
N2B
F4
CO
OM
e
(2.1
1 m
mol
)
Co
nd
itio
ns
tBu
ON
O (
3.1
6 m
mol
), H
BF
4 (5
.26
mm
ol),
Me
OH
(2.
11 m
L),
0 °C
, 2
h
Pu
rifi
cati
on
Ace
tone
(6
.33
mL)
, E
t 2O
(1
5.8
3 m
L)
Co
nd
itio
ns
5-M
e b
en
zofu
ran
(0.1
32 g
)
Pd(
OA
c)2
(2.2
4 m
g),
TF
A (
0.11
4 g
)
Me
OH
(5
mL)
, 4
0 °
C,
2 h
Pu
rifi
cati
on
NaH
CO
3 aq
(10
mL)
, E
tOA
c (1
0 m
L),
2z
0.49
9 g
(95
%)
NH
2
CO
OM
e
8a
0.23
7 g
(89
%)
N2O
Ms
CO
OM
e
(1.6
4 m
mol
)
Co
nd
itio
ns
tBu
ON
O (
2.4
7 m
mol
), M
sOH
(4.1
1 m
mol
),
Me
OH
(1.
64 m
L),
0 °C
, 2h
Pu
rifi
cati
on
Me
OH
(4.
92 m
L),
Et 2
O (
8.2
mL)
,
liq.
N2
(82
mL)
Co
nd
itio
ns
5-M
e b
en
zofu
ran
(0.1
32 g
)
Pd(
OA
c)2
(2.2
4 m
g),
Me
OH
(5
mL)
RT
, 16
h
Pu
rifi
cati
on
-
2za
0.31
0 g
(73
%)
O
Me
8a
4.31
g (
30%
)
Co
nd
itio
ns
I) n
BuL
i (1.
6 M
, 81
.6 m
L),
TM
ED
A (
20.9
mL)
,
E2O
(2
77
.2 m
L),
-60
°C
, 1
.25
h
II) B
(O-i
Pr)
3(3
9.7
mL)
. -6
0 °C
III)
HC
l (2
M,
69.3
mL)
, R
T
Pu
rifi
cati
on
Et 2
O (
13
8.6
mL)
, H
Cl (
2 M
, 3
69
.6 m
L)
Co
nd
itio
ns
Me
thyl
2-b
rom
ob
en
zoat
e
(11
.7 g
)
Pd(
PP
h3)
4(1
.0 g
), N
a2C
O3
(2 M
, 6
0 m
L)
DM
E (
300
mL)
, re
flux,
6.5
h
Pu
rifi
cati
on
Et 2
O (
300
mL)
12.7
5 g
(56
%)
O
Me
B(O
H) 2
(18.
5 g
)
a) b)
c)
Schem
e8.4.Detailedschematicforthesynthesisof8avia:a)processreportedbyJuddetal.,b)processreportedbyGem
oetsetal.in
chapter4andc)im
provedprocessreportedbyGem
oetsetal.em
ploying2‐(methoxycarbonyl)benzenediazoniummesylate.
Table8.5.CostAnalysisforthePatentedProcedureofJuddetal.fortheSynthesisof8aa
ACriticallAssessmentofC−HFuncttionalizationforAPISynt
a HCl(37%,d=1.2g/m
L)asstocksolutionisconsideredforthecostanalysis;bThe
massofthesolutionisconsideredforthePM
Icalculation.Themassofthesolutionisnotedbetweenthebrackets;cOnlythemassofthesoluteisconsideredforthecostanalysis;
thesis
167
d Chemicalsutilizedforacoolingbath(notincludedinPMIcalculations).
88
Chapter8
168
Table8.6.CostAnalysisfortheDevelopedProcedureofGem
oetsetal.fortheSynthesisof8ausingArN
2BF 4salta
8
\aThe
massofthesolution
isconsidered
forthePM
Icalculation
The
massofthesolution
isnotedbetweenthebrackets
b Onlythe
\aThemassofthesolutionisconsideredforthePM
Icalculation.Themassofthesolutionisnotedbetweenthebrackets;bOnlythe
massofthesoluteisconsideredforthecostanalysisforasaturatedNaHCO
3solutioninwater(96g/L).
Table8.7.CostAnalysisfortheImprovedProcedureofGem
oetsetal.fortheSynthesisof8ausingArN
2OMssalta
ACritical
lAssessment
ofC−HFuncttionalization
a ThemassofthesolutionisconsideredforthePM
Icalculation.Themassofthesolutionisnotedbetweenthebrackets;bChem
icals
utilizedforacoolingbath(notincludedinPMIcalculations).
forAPISyntthesis
169
88
Chapter8
170
Because of the fact that the energy and labor costs to compare the two
procedures could not be determined easily,we decided to discuss these
aspectsonaqualitativebase.Withregardtotheenergycosts,bothresults
obtainedwithourmethodologyarefavorablecomparedtotheprocedure
reportedbyJuddetal. Infact, thelatterrequirescryogenictemperatures
for the lithiation‐borylation methodology, while the subsequent Suzuki‐
Miyauracouplingisperformedunderrefluxconditionsfor6.5hours.
A significant reduction in labor costs is expected for bothprocedures
involving our C‐2 arylation strategy, especially in the case of
aryldiazoniummesylate.Thiscaneasilybeexplainedbythe fact thatour
procedure ismore user‐friendly and requires less process steps (e.g., no
needforextraction,washingordryingsteps)comparedtotheprocedure
by Juddetal.Obviously, lessoperational steps translate ina lower labor
costs.
In summary, a cost analysis performed on the patented literature
procedureandtheproceduredevelopedinourgroupshowsareductionof
one order of magnitude both for the chemicals and solvent costs.
Moreover, a cost reduction for what concerns energy and labor costs is
plausible, thusgiving to theproposedchemistryan intrinsicvalue for its
potentialapplicationinthepharmaceuticalindustry.
ACriticalAssessmentofC−HFunctionalizationforAPISynthesis
171
GreenChemistryMetrics
The last part of this chapter focuses on the evaluation of the
environmental impact of both thepatented literatureprocedure andour
proposed chemistry. The comparison between the two processes was
carriedoutbymeansofGreenChemistryMetrics.Specifically,sevengreen
metrics were chosen and employed for the assessment of the
environmentaleffects(Table8.8).Abriefbackgroundanddefinitionofthe
usedmetricsisgivenintheExperimentalSection;whilethequantification
ofeachmetricisbrieflydiscussedinthefollowingparagraphs.
Table8.8.CalculatedGreenMetricsforthePatentedLiteratureProcedure
andtheProposedChemistryfromourGroupa
aPatented refers to the process by Judd et al.. Tetrafluoroborate refers to the reactionconditions reported in chapter 4. Mesylate refers to the further improved proceduredescribedwithinthischapter.
Determinationoftheatomeconomyisquitestraightforwardandthenoted
differences result from the sums of the molecular weights of all used
reactants.ComparedtothedirectC−Harylationwitharyldiazoniumsalts,
the Suzuki‐Miyaura cross coupling methodology reported by Judd et al.
requiresmorereactants,hence itsatomeconomyis lowerthantheatom
economy of the chemistry proposed herein. Moreover, when looking at
atom economy, a marginal difference between the employment of
aryldiazonium tetrafluoroborate andmesylate canbeobserved.This can
GreenMetric Patented Tetrafluoroborate Mesylate
Yield(%) 17 67 65AE(%) 42 56 55
E‐Factor(‐) 325 229 67PMI(‐) 326 230 68EMY(%) 0.301 0.567 1.46
EcoScale(%) 0 39.5 41.5Mod.EcoScale(%) 44 66 63
8
Chapter8
172
be justified by the fact that although methanesulfonic acid possesses a
slightlyheaviermolecularweightthantetrafluoroboricacid(87.81g/mol
vs96.11g/molrespectively),lessequivofdiazoniumsaltarenecessary.
As described in the experimental section, the E‐factor and PMI green
metricsonlydifferbytheadditionofone.Therefore,thesemetricswillbe
discussed simultaneously. It is important to underline that for these
calculationsonly the chemicals involved in the reactionwere considered
as relevant,while all chemicals used, for example, for the cooling of the
reactionmediumwere not accounted for. The values calculated for both
thesemetrics can be found in Tables 8.8. It can easily be noticed that a
slight decrease in the values of both metrics was obtained for the C‐2
arylation employing aryldiazonium tetrafluoroborate (230 vs 326).
However, this result does not satisfy the criteria yet necessary for
pharmaceuticalproduction(seeTable8.9).Though,thisresultscanbeput
in perspective by considering that the difference between the reaction
scaleofourmethodologyandthereportedprocedurebyJudd,differswith
afactorof140.Specifically,reactionsperformedonasmallerscale(such
asourC‐2arylationprocess)requirethereforearelativelylargeramount
ofsolvent,comparedtoreactionsperformedonbiggerscale.
On the other hand, in the case of the C‐2 arylation employing
aryldiazonium mesylate the difference with the patented procedure for
what concerns E‐factor and PMI is striking (68 vs 326). A remarkable
difference can also be observed when compared to the experiment
employing aryldiazonium tetrafluoroborate (68 vs 230). The large
decrease in the E‐factor and PMI values can be attributedmostly to the
simpler purification method of the target compound, which does not
requireanyextractionorwashingstep.Notably,E‐factorandPMIvaluesin
thisrangerenderourstrategyextremelyvaluableintermsofapplicability
ACriticalAssessmentofC−HFunctionalizationforAPISynthesis
173
in thepharmaceutical industry.Generally, E‐factors values calculated for
the pharmaceutical industry fall within a range of 25 to 100 (see Table
8.9), thusmakingthecalculatedvalueforourchemistryof67acceptable
forthemanufacturingindustry.
Table 8.9. E‐factor Estimates forDifferent Chemical Industries based on
Sheldon’sOriginalFindings14e
Industrysector Annualproduction(tonnes) E‐factorOilrefining 106–108 <0.1
Bulkchemicals 104–106 1–5Finechemistry 102–104 5–50Pharmaceuticals 101–103 25–100
The difference in the reaction scales also plays a major role in the
determination of the effective mass yield. However, despite the values
beingsomewhatunfairtowardourprocess,thecalculatedvaluesforEMY
favorourproposedchemistry,especiallyinthecaseofC‐2arylationwith
aryldiazonium mesylate. Although almost all involved chemicals are
specified as hazardous according to the MSDS sheets, the significant
increase in EMY for our strategy can be attributed to the fact that a
diminishedamountofreagentsandsolventsisused(e.g.,lessequivalents
ofacid,noTFA).
Both the calculation and determination of the EcoScale and the
Modified EcoScale are clearly in Table 8.10 and 8.11, andwill therefore
only briefly be discussed herein. The large increase obtained on the
EcoScale for our proposed chemistry is mainly caused by the large
increase in the reaction yield and in the use of less hazardous reagents.
With regard to the Modified EcoScale, which is an indicator for the
applicabilityofalaboratoryprocedureinindustry,thevaluesareclearlyin
favorof theproceduredeveloped inourgroupemployingaryldiazonium
8
Chapter8
174
tetrafluoroborate as arylating agent. In fact, in comparison to the
procedure reported by Judd et al., our method is much simpler. On the
otherhand,theprocedureemployingaryldiazoniummesylateasarylating
agentshowsaslightlowervalueof63%ontheModifiedEcoScale,which
could be attributed to the fact that the isolation of the relative unstable
aryldiazoniummesylaterequiresamoredifficultcrystallizationmethod.
AsdepictedinFigure8.3,theproposedC−Hactivationprotocolforthe
synthesis of key intermediate8a is in high favorwhen compared to the
patented cross‐coupling method. The illustrated areas give a
representation of the “environmental footprint” of the procedures
normalizedagainstthepatentedprocess.Thesmallertheillustratedarea,
the“greener”theprocess.
Figure8.3.GreenChemistryMetricsradarchartofallthediscussedscenariosfortheC‐2arylationof5‐methylbenzofuranleadingtomethyl2‐(5‐methylbenzofuran‐2‐yl)benzoate(8a),akey intermediate in theroute tosaprisartan.Allvalueswerenormalizedagainstthe patented process (Judd et al. 1994, Glaxo Group Limited). See Table 8.8 for theabsolutevaluesforalltheGreenMetricsused.
0
0,2
0,4
0,6
0,8
1PMI
EMY
E‐Factor
Yield
AE
Mod.EcoScale
Suzuki‐Miyaura coupling (Judd 1994, Glaxo Group Limited)
C‐H arylation (Gemoets 2016, BF4‐)
C‐H arylation (Gemoets 2017, MsO‐)
ACriticalAssessmentofC−HFunctionalizationforAPISynthesis
175
Table8.10.CalculationsofEcoScaleforallThreeCasesa
Patented Tetrafluoroborate MesylateParameter Value PP Value PP Value PP1.Yield 17% 41.5 67% 16.5 65% 17.5
2.Pricereaction expensive 3 inexpensive 0 inexpensive 03.Safety nBuLi(N,T,F)
TMEDA(F)Et2O(F+)
B(O‐iPr)3(F)DME(F,T)
15510510
tBuONO(F)MeOH(F,T+)TFA(N)
5155
tBuONO(F)MeOH(F,T+)MsOH(T)
5155
4.Technicalset. Inertatm. 1 Common 0 Common 05.Temp./time Cooling<0°C 5 Cooling0°C 4 Cooling0°C 46.Workupandpurification
Chromato.L/Lextr.
103
Chromato.Sphaseextr.L/Lextr.
1023
Chromato.Sphaseextr.
102
Totalpenaltyp.EcoScalescore
108.5
0 60.5
39.5 58.5
41.5
aFormoredetailsregardingtheCalculationofEcoScale,seeTable8.S2.
Table8.11.CalculationsofModifiedEcoScaleforallThreeCases
Patented Tetrafluoroborate MesylateParameter Value Points Value Points Value Points
1.Yield 17% 0 67% 3 65% 32.Quality >98% 10 >98% 10 >98% 103.WorkupandpurificationFiltr.beforefinalcryst.?Easysep.ofsuspension?Easydrying?
No/NoNo/Non/a
00
Yes/NoYes/Non/a
55
Yes/NoYes/Non/a
55
4.EquipmentMultipurposereactors? n/a n/a n/a 5.Reactiontime >10h 5 3‐6h 7 >10h 36.Reactiontemperature <‐10°C 3 <90°C 8 <90°C 87.RawmaterialsChlorinatedsolvent?Pricesolvents<$7/kg?Allreagentscommod.?
NoYesYes
101010
NoYesYes
101010
NoYesYes
101010
8.EHSExtremelyexothermic?Hazardousortoxic?Flammableorexplosive?
Yes/NoYesYes
500
Yes/NoYesYes
740
Yes/NoYesYes
740
TotalpointsModifiedEcoScalescore
5344
7966
7563
8
Chapter8
176
CONCLUSION
Basedonexperimentalresults,costanalysisandgreenchemistrymetrics,
a holistic comparison was made between cross‐coupling chemistry and
C−Hactivationmethodology.Speci ically,theC‐2arylationofabenzofuran
precursor towards the synthesis of the API saprisartan was chosen as
model reaction to compare a classic Suzuki‐Miyaura coupling (patented
synthesis by Judd, Glaxo Group Limited, 1994) and our developed C−H
arylation methodology. With the aim on sustainability, further
optimization of our previously reported C−H arylation procedure (see
Chapter 4) was performed. Overall, a combined 65% isolated yield was
obtained for our two steps (i.e., diazotization and C−H arylation), which
comparedfavorabletothe17%yieldobtainedforthepatentedprocedure.
Moreover, when assessing the cost calculations, an impressive 92%
reductionofchemicalandsolventcostswasfound.Furthermore,because
of the room temperature conditions and the relatively simple
experimental procedure,we anticipate that ourmethodologywould also
require lower costs in terms of energy and labor costs. Besides the
economicalaspect,theassessmentofGreenChemistryMetricsrevealedan
enhanced green profile. As example, a PMI value of 68 (vs 326 of the
patented process), renders the present methodology acceptable for the
pharmaceutical industry. Finally, preliminary studies showed that the
implementation of continuous‐flow would considerably enhance the
operational safety scalability of the procedure. Further optimization
towards the development of a continuous‐flow process appropriate for
multi‐gramscaleproductioniscurrentlyunderwayinourlaboratory.
ACriticalAssessmentofC−HFunctionalizationforAPISynthesis
177
EXPERIMENTALSECTION
GeneralProcedures
General procedure for the synthesis of aryldiazonium salts. The
respective aniline (10.0 mmol) was dissolved in 10 mL of solvent. The
solutionwascooledto0°Candacid(1.1‐2.5equiv)wasadded.Tert‐butyl
nitrite (1.4‐1.5 equiv) was added dropwise over a period of 5 minutes.
Afteraddition,themixturewasstirredat0°Cfor2hours.Purificationwas
performedbyrecrystallization.Theresultingsolidsweredriedunderhigh
vacuum to give the pure crystalline product. Detailed description of the
differentsynthesisandpurificationmethodsaregiveninTable8.S1.
Table8.S1.OverviewofMethodsusedfortheSynthesisandPurificationof
DiazoniumSaltsa
SynthesisMethod Solvent Acid(equiv) tBuONO(equiv)
A MeOH 2.5 1.5B THF:AcOH(1:2) 1.1 1.4C THF:AcOH(1:2.6) 1.4 1.5D DCM 2.1 1.5
PurificationMethod Explanation
A Addeddiethyletherforcrystallization.Filteredoffcrystals.Recrystallized2to3timesfromacetonebyadditionofdiethyletheratRT
B Reactionmixturewascooledto‐78°Canddiethyletherwasaddedforcrystallization.Liquidphasewasdecanted.Precipitatewasrecrystallized2to3timesfrommethanolbyadditionofdiethyletherat‐78°C.
aThe synthesis and purification methods are shown between brackets respectively inTable8.2.
Synthesis of 5‐methylbenzofuran (1i) substrate. A 250 mL round‐
bottom flask was charged with p‐cresol (5.4 g, 50 mmol),
8
Chapter8
178
Dimethylacetamide(DMA,100mL)andKOH(5.6g,100mmol), followed
by dropwise addition of 2‐bromoacetaldehyde diethyl acetal (14.8 g, 75
mmol) at room temperature. After the addition, themixturewas stirred
underreflux for2hoursuntil thereactionwascompleted(monitoredby
TLC). Then, themixture was cooled to room temperature and extracted
with EtOAc and saturated brine solution. Next, the organic layer was
washedwith5%NaOHaqueoussolution,10%HClaqueoussolutionand
saturatedNaHCO3 solution.The remainingorganicphasewasdriedover
MgSO4,filteredandconcentratedunderreducedpressure.Purificationby
flashchromatographyonsilica(5%EtOAcinpetroleumether)afforded1‐
(2,2‐diethoxyethoxy)‐4‐methylbenzene (10,6 g, 95% yield). The latter
intermediateandpoly‐phosphoricacid(10.2g)werecombinedin200mL
of benzene and brought to reflux for 2 days. The reaction mixture was
cooledtoroomtemperatureandextractedwithEtOAcandsaturatedbrine
solution.Next,theorganiclayerwaswashedsubsequentlywith5%NaOH
aqueous solution, 10% HCl aqueous solution and saturated NaHCO3
solution.TheremainingorganicphasewasdriedoverMgSO4,filteredand
concentrated under reduced pressure. Purification by flash
chromatographyonsilica(petroleumether)afforded5‐methylbenzofuran
(1i)(2.0g,36%yield).
Improved synthesis of saprisartan precursor (8a) with 2‐
(methoxycarbonyl)benzenediazoniummesylate.A stock solutionwas
prepared by weighing Pd(OAc)2 (11.2 mg, 1.0 mol%) and 5‐
methylbenzofuran(1i)(660mg,5.0mmol)intoa25mLvolumetricflask.
2‐(methoxycarbonyl)benzenediazonium mesylate (2za) (1.2 mmol, 1.2
equiv.)wasweighted into a 20mL reaction tube equippedwith stirring
bar.5mLof stocksolution (containing1.0mmolof5‐methylbenzofuran,
1.0mol%Pd(OAc)2)wasaddedimmediatelytothevialviaasyringe.The
ACriticalAssessmentofC−HFunctionalizationforAPISynthesis
179
reactionmixturewas stirred overnight (16 hours) at room temperature
until5‐methylbenzofuranwascompletelyconsumed.Thereactionmixture
was concentrated under reduced pressure. The remaining residue was
purifiedbyflashchromatographyonsilica(5%EtOAcinpetroleumether)
andaffordedmethyl2‐(5‐methylbenzofuran‐2‐yl)benzoate(8a) (237mg,
89%)asayellowoil.
CostAnalysis
Like mentioned before, the cost analysis performed on the comparison
betweenclassic theSuzuki‐Miyaura cross‐couplingandourC‐2arylation
strategy, for the synthesis of the saprsartan precursor 8a, is based on
laboratoryscalecosts.Thisisduetothefactthatdetailedinformationon
thecostofindustrialscaleprocessingarehardtoobtain.Thislabscalecost
evaluationcanthereforebeconsideredasimplifiedversionofthemethod
reportedbyKressireretal.8
For the proposed laboratory‐scale cost analysis, a batch procedure is
assumed, and the production price per gram of compound produced is
calculatedandcomparedforbothprocesses.Threemajorcostfactorsare
considered: chemicals cost, energy cost and labor cost. Fixed costs, (e.g,.
glassware and laboratoryequipment)werenot taken into consideration.
Furthermore,thecostanalysisincludesthelaboratoryprocedurestarting
fromthepreparationofreactionuntilthefirstworkupprocedure.Further
purification,suchascolumnchromatography,wasnotaccountedfor.
Chemicals are divided into two categories: reagents and solvents.
Reagentscostsarebasedonthemostaffordablepricesfromsuppliersfor
laboratory use. The following suppliers were consulted: Sigma‐Aldrich,
Tokyo Chemical Industry, Alfa Aesar, Fisher Scientific and VWR
International.Moreover, solventsare treatedasbulkchemicalsand their
8
Chapter8
180
bulk quantity prices are obtained from the websites of Platts and
LookChem.
Unlike the chemicals and solvent costs, the energy and labor costs
proved more difficult to determine and only a rough estimate could be
made. Therefore, although a possible approach for the determination of
energy and labor costs is briefly discussed, both cost factors were
eventuallyexcludedfromthequantitativecostanalysis.
Energycostscouldbeestimatedbythetheoreticalpowerconsumption
of theused laboratoryequipment. In caseofheatingelements, suchas a
heating plate and a rotary evaporator, a percentage of the maximum
power that these equipment can consumed was considered for the
calculations. Though excluded from the quantitative cost analysis, the
energy costs of different laboratory procedures will be compared
qualitatively.
Thelastcostaspectthatcouldbeaccountedforistherequiredhuman
labor.Thelaborcostswereestimatedbytakingintoaccountallthosesteps
that require an intervention by the operator, such as weighing the
reagents and work‐up extractions. The labor time is then calculated by
multiplyingeachoperationbyanestimatedtimeneededtocompleteit.A
gross hourlywage of € 27.44was assumed, based on the average gross
yearly salary of a development chemist in theNetherlands as of 2015.24
Similarly towhatdiscussedwith theenergycosts, the costsof laborwill
onlybecomparedqualitatively.
ACriticalAssessmentofC−HFunctionalizationforAPISynthesis
181
GreenChemistryMetrics
AtomEconomy (AE). First reported in 1991 by Trost, AE is one of the
most fundamental and important tools for the assessment of
environmental effects of chemical processes.13 Simply put, calculation of
theatomeconomyrevealshowmanyatomsofthereactantsarepresentin
the finalproduct.Thecalculationof atomeconomy is reasonably simple,
doesnotaccountforexcessesofreactants,solventsandreagentsandcould
beused for a single reaction (1), aswell as for amultiple step synthesis
(2).
→
∙ 100%
(1)
→
∙ 100%
(2)
Environmental Factor (E‐factor). In contrast to atom economy, the E‐
factoralsoincludesreagentsandsolventsinthecalculationoftheamount
of product produced compared to the amount of waste generated to
produce it.Specifically, in1992SheldonfirstproposedtheE‐factorasan
indicator for the quantity ofwaste that is produced for a givenmass of
product.14 In this context waste includes all kinds of materials, such as
reactants, reagents, solvents used for reaction and purification and , if
applicable,catalysts.Therefore,theE‐factorisdefinedbytheequation(3).
‐
(3)
While calculating the E‐factor, divergent opinions might arise on what
aspects should be accounted for in thewaste calculation. In this specific
case,wasteisconsideredasthemassofunusedchemicalsinthereaction.
8
Chapter8
182
Chemicalsusedforcooling(e.g.,coolingbathconsistingofliquidnitrogen
andethylacetate)werenotaccountedfor.
ProcessMassIntensity(PMI). In1998Heinzleetal.proposedPMIasa
greenmetric forglobalefficiency.15aPMIresembles theE‐factorandonly
differs from it by a value of 1. Moreover, PMI has been chosen by The
American Chemical Society Green Chemistry Institute’s Pharmaceutical
Roundtableasthekey,high‐levelmetricforevaluatingandbenchmarking
progresses towards a more sustainable manufacturing.15b This decision
hasbeenmadebasedonbothphilosophical (e.g., generationof revenue)
and technical (e.g., better surrogate for the cumulative environmental
impacts) grounds. Both E‐factor and PMI stand out as widely used
parameter, but statistics show that the latter is slightly preferred in
chemical industry.15c In order to align our results with the most used
parameter,wechosetousePMIasthekeymetric inthe identificationof
thebottleneckstepinthesaprisartansynthesisreportedbyJuddetal.
1 (4)
EffectiveMassYield (EMY). In addition to the E‐factor, Hudlicky et al.
proposedacomparablemetricthatconsidersasnegligibleallwastethatis
generated in a chemical processes and not associated to any
environmental risk. This EMY is defined as ‘themass of desired product
comparedtothemassofallnon‐benignmaterialsusedinitssynthesis’.16
Mathematically,theEMYisdefinedbyequation(5)
%
‐∙ 100 %
(5)
In contrast to the earlier discussed metrics, the advantage of the EMY
metricisthatitisagoodindicationofthehazardousmaterialsusedinthe
synthesis.However,thedefinitionof ‘non‐benign’ isnotunivocallystated
ACriticalAssessmentofC−HFunctionalizationforAPISynthesis
183
in the literature, therefore leaving room for interpretation. For our
purposes,MSDSsheetsprovidedbyChemWatchwereemployedasbases
toassessthehazardousofadeterminedcompound.
EcoScale.In2006,VanAkenetal.introducedtheEcoScaleasananalysis
toolforassessingthequalityofaspecificorganicreactionconductedinthe
laboratory.17a While other metrics focus mainly on one aspect of a
determinedprocess,EcoScaleisconceivedasabroadermetric.Basedona
penaltysysteminwhichyield,cost,safety,conditionsandeaseofworkup
and purification are considered, the overall greenness of a chemical
transformationisevaluatedwithatotalmaximumscoreof100points(see
Table8.S2).
Modified EcoScale. While the original EcoScale has proven its value in
comparing laboratory procedures, its simplistic nature and limitations
prevented it from being largely adopted by the chemical industry.
However, in 2012, Dach et al. developed a so‐called Modified EcoScale
which is based on eight criteria and currently utilized by Boehringer
IngelheimPharmaceuticals (seeTable8.S3).17bThe industrial application
of this modified EcoScale adds significant value to this specific green
metric,whichrepresentsagoodindicatoroftheindustrialapplicabilityof
a laboratoryprocedure.ThescoreforthemodifiedEcoScale iscalculated
asapercentageof thescoredpointsrelative to the totalpoints.Both the
original EcoScale from Van Aken et al. and the Modified EcoScale green
metricswerecalculatedinthisinvestigation.
8
Chapter8
184
Table8.S2.TheEcoScalePenaltySystemasProposedbyVanAkenetal.
Parameter Penaltypoints1.Yield (100‐%yield)/22.Priceofreaction(toobtain10mmolofendproduct)Inexpensive(<$10)Expensive(>$10and<$50)Veryexpensive(>$50)
035
3.SafetyN(dangerousforenvironment)T(toxic)F(highlyflammable)E(explosive)F+(extremelyflammable)T+(extremelytoxic)
555101010
3.TechnicalsetupCommonsetupInstrumentsforcontrolledadditionofchemicalsUnconventionalactivationtechniquePressureequipment,>1atmAnyadditionalspecialglassware(Inert)gasatmosphereGlovebox
0123113
4.Temperature/timeRoomtemperature,<1hRoomtemperature<24hHeating,<1hHeating>1hCoolingto0°CCooling,<0°C
012345
5.WorkupandpurificationNoneCoolingtoroomtemperatureAddingsolventSimplefiltrationRemovalofsolventwithbp<150°CCrystallizationandfiltrationRemovalofsolventwithbp>150°CSolidphaseextractionDistillationSublimationLiquid‐liquidextractionClassicalchromatography
0000001223310
EcoScalescore=100%‐(penaltypoints)%
ACriticalAssessmentofC−HFunctionalizationforAPISynthesis
185
Table8.S3.ThemodifiedEcoScaleTemplateDevelopedbyDachetal. for
StepEvaluationatBoehringerIngelheimPharmaceuticals
Parameter Points1.Yield>95%80‐95%60‐80%
1073
2.Quality(AorWt%)ofproductbyGC,HPLC,etc.>98%95‐98%<95%
1073
3.WorkupandpurificationFiltrationbeforefinalcrystallizationpossible?Easyseparationofsuspension?Easydryingintumbleorpaddledryerpossible?
Yes:10.No:0‐9Yes:10.No:0‐9Yes:10.No:0‐9
4.EquipmentMultipurposereactorssuitable?
Yes:10.No:0‐9
5.Reactiontime<3h3‐6h>10h
1073
6.ReactiontemperatureRT<90°C90‐150°C>150°C<‐10°C
108533
7.RawmaterialsIschlorinatedsolventused?Priceforsolvents<$7/kg?Allcomponentsarecommodities?
No:10.Yes:0‐9No:10.Yes:0‐9No:10.Yes:0‐9
8.EHSReactionextremelyexothermic?Hazardousortoxicmaterialsneeded?Highlyflammableorexplosivematerialneeded?
No:10.Yes:0‐9No:10.Yes:0‐9No:10.Yes:0‐9
ModifiedEcoScalescore=(scoredpoints/totalpoints)*100%
8
Chapter8
186
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8
SUMMARY
Summary
190
The work presented in this thesis focused on the development of
continuous‐flowstrategies for enablingandaccelerating challengingC−H
functionalizations, thus providing additional advantages over batch in
termsofsafety,scalability,reactiontimeandselectivity.
The main research line gravitated around the selective C−H
functionalizationofheteroarenes.InChapter2,afastandstraightforward
continuous‐flow protocol for the dehydrogenative C‐3 olefination of
indoleswasdeveloped. Thanks to the enhancedgas‐liquidmass transfer
providedbymicroflowtechnology,molecularoxygencouldbeemployed
as sole oxidant, boosting reaction kinetics and accelerating hour‐scale
reactionsinbatchtotheminuterangeinflow.
In Chapter 3, a mild and versatile protocol for the C−H acylation of
indoles, via a dual photoredox/palladium catalysis, was established.
Various aromatic and aliphatic (primary and secondary) aldehydeswere
successfully employed as acylating reagents. The room temperature
procedure tolerated a wide variety of functional groups resulting in a
diversesetofselectiveC‐2acylatedindoles(28examples).Moreover,the
implementation of continuous‐flow technology significantly decreased
reactiontimes(2hvs20hinbatch),iridiumcatalystloading(0.5mol%vs
2mol% in batch), and afforded increased yieldswhile allowing an easy
scale‐upofthereactionconditions.
Chapter4describesamildandselectiveC‐Harylationofheteroarenes
through experiment and computation. This open flask arylation method
relies on equimolar amounts of aryldiazonium tetrafluoroborates as
arylating agents and requires low palladium loadings (0.5 – 2 mol%).
Moreover, optimization of the reaction conditions resulted in the use of
green solvents (EtOAc:2‐MeTHF or MeOH) and room temperature
191
operation.Abroad substrate scopewasobtainedwithperfect selectivity
(C‐2 for indoles and benzofurans, C‐3 for benzothiophenes, total 46
examples).
Toachieveabetterunderstandingofthearylationreaction,mechanistic
investigationthroughDFTcalculationsandmechanisticexperimentswere
conductedinChapter5.Experimentalandcomputationalresultssupport
aHeck‐Matsuda‐typecoupling,withpreliminaryresults indicatinganon‐
innocentbehavioroftheBF4‐counterionsofthediazoniumsalts.
Aparallelresearchlinefocusedonthedevelopmentofintegratedmulti‐
step flow processes to access valuable intermediates in a streamline
manner. Therefore, a practical and effective modular flow process was
designed for the continuous manufacturing of meta‐arylated anilines.
Chapter 6 describes the development of four continuous‐flow modules
(i.e., diaryliodonium salt synthesis, meta‐selective C−H arylation, inline
copperextractionandanilinedeprotection).Eachmodulewasoptimized
andcanbeoperatedindividuallyorinseries,thusprovidingdirectaccess
tometa‐arylatedanilineswithatotalresidencetimeof1hour.Thedesired
meta‐arylatedanilineswereobtainedinexcellentyieldandpurity,without
theneedforanychromatographymethod.
The flowsynthesisofdiaryliodoniumtriflateswas furtherexplored in
Chapter7.Flowcalorimetryrevealedthehighlyexothermicnatureofthe
reaction(ΔHupto‐180kJ/mol).Thereactionscopewasthenexpandedto
abroadspectrumofbothelectron‐richandelectron‐deficientcompounds
withexcellentscalability(44examples).Aproductivityofupto3.8g/hfor
asingle100µLreactorwasachieved.
InChapter8,acriticalassessmentontheenvironmentalimpactofour
developedC−Harylationprotocolwasconducted.Basedonexperimental
Summary
192
results, cost analysis and green chemistry metrics, the C−H activation
methodology was compared to an existing patented procedure for the
synthesis of saprisartan. The implementation of our C‐2 arylation
methodology for the formation of the key intermediate methyl 2‐(5‐
methylbenzofuran‐2‐yl)benzoate resulted in a significant increase in
productyield (65%vs17%)and inaprojectedcostreductionofaround
92% for chemicals and solvent. Moreover, the assessment of Green
Chemistry Metrics revealed the enhanced green profile of our C−H
activation methodology, thus making this procedure acceptable for the
pharmaceutical sector (PMI < 100). Finally, preliminary studies showed
that the implementation of continuous‐flowwould considerably enhance
theoperationalsafetyscalabilityoftheprocedure.
LISTOFABBREVIATIONS
ListofAbbreviations
196
(MeCN)2Pd(II)Cl2 Bis(acetonitrile)dichloropalladium(II)[(Mes‐Acr)ClO4] 9‐Mesityl‐10‐methylacridiniumperchlorate2‐MeTHF 2‐methyltetrahydrofuranAc‐Ile‐OH N‐(acetyl)‐L‐isoleucineACN AcetonitrileAcOH AceticacidACSGCI AmericanchemicalsocietygreenchemistryinstituteAE AtomefficiencyAPI ActivepharmaceuticalingredientAT AngiotensinBDE BonddissociationenergyBHT ButylatedhydroxytolueneBoc‐Val‐OH N‐(tert‐Butoxycarbonyl)‐L‐valineBPR BackpressureregulatorCDC Cross‐dehydrogenativecouplingCF3CH2OH 2,2,2‐TrifluoroethanolCHCl3 ChloroformCp HeatcapacityCTFR Continuous‐flowcopperreactorCTFR Coppertubeflowreactordba DibenzylideneacetoneDCE DichloroethaneDCM DichloromethaneDFT DensityfunctionaltheoryDMA DimethylacetamideDME DimethoxyethaneDMF N,N‐DimethylformamideDMSO DimethylsulfoxideDPPA DiphenylphosphorylazideE‐factor EnvironmentalfactorEMA EuropeanMedicinesAgencyEMY EffectivemassyieldEtOAc EthylacetateEtONa Sodiumethoxidefac‐[Ir(ppy)3] Tris[2‐phenylpyridinato‐C2,N]iridium(III)FDA FoodanddrugadministrationFEP FluorinatedethylenepropyleneGC‐FID GaschromatographyflameionizationdetectorGC‐MS Gaschromatography‐massspectrometryHBF4 TetrafluoroboricacidHRMS Highresolutionmassspectroscopyi.d.orID InternaldiameterICP‐OES Inductivelycoupledplasmaopticalemissionspectroscopyi‐PrOH IsopropanolIR InfraredKIE Kineticisotopeeffect
197
KOH PotassiumhydroxideLCA LifecycleassessmentLED LightemittingdiodeLSF Latestagefunctionalizationm‐CBPA meta‐ChloroperbenzoicacidMeOH MethanolMPAA MonoprotectedaminoacidsMSDS MaterialsafetydatasheetNBS N‐Bromosuccinimiden‐BuLi n‐butyllithiumn‐BuOH n‐ButanolNMR NuclearmagneticresonanceOAc AcetateOTf TriflateP(C6H5)3orPPh3 Tetrakis(triphenylphosphine)PEEK PolyetheretherketonePEPPSI‐SIPr (1,3‐Bis(2,6‐diisopropylphenyl)imidazolidene)(3‐chloropyridyl)
palladium(II)dichloridePFA PerfluoroalkoxyalkanePhCOOH BenzoicacidPivOH PivalicacidPMI ProcessmassintensityPTFE Polytetrafluoroethylenep‐TsOH p‐toluenesulfonicacidRTorrt RoomtemperatureRu(bpy)3Cl2 Tris(bipyridine)ruthenium(II)chlorideSET SingleelectrontransferSI SupportinginformationTBHP tert‐butylhydroperoxidet‐BuONO tert‐butylnitriteTEMPO 2,2,6,6‐Tetramethylpiperidine1‐oxylTFA TrifluoroaceticacidTfOH TrifluoromethanesulfonicacidTHF TetrahydrofuranTLC ThinlayerchromatographyTMEDA Tetramethylethylenediaminetr ResidencetimeΔHr Reactionenthalpy
ACKNOWLEDGEMENTS
Acknowledgements
200
Here Iamsittingbehindmydesk lookingbackat thepast4yearsofmy
life.Uptotoday,IremembervividlythemomentwhenIwasstaringdown
atmynoteswereI listedthe ‘prosandcons’ofpursuingaPh.D. ‘abroad’.
Today I want to thank my younger self for making that brave decision.
“Thebestthings in lifeareoftenwaitingforyouat theexitrampofyour
comfortzone.”KarenSalmansohnoncesaid. Ihavetoadmit thatthere is
much truth in that saying.Evidently, Iwouldhavenotbeenable towalk
this journey without the support of the many wonderful and inspiring
people,whichIammostgratefultohavemet.
Firstandforemost,Iwouldliketothankmyfavoritecolleague,bestfriend,
lovingpartner,andpresent‐daywife,CeciliaBottecchia.Sincethemoment
wefirstmet(inthelab)youhavebeenonmyside.Iknowthatwithoutyou
IwouldnothavebeenwhereIamtoday.Youencouragedme intimesof
doubtandcalmedmedowninmomentsofstress.Afterworkinglatehours
youwouldalwaysknowhowtocheermeupwithyour incredibleItalian
cuisineand surprises.Youweremypersonal editor, proofreading allmy
papers,andcelebratingtheiracceptancewith thebestsushi in town!We
sharedallourhappinessand(nerdy)successtogether.Cecilia, thankyou
forbeingthemostawesomepartner.YoumademebelieveinmyselfandI
amforevergratefulthatourpathshavecrossed.Graziemilleamoremio!
I would like to express my sincere gratitude to my promoter and co‐
promoter, Volker Hessel and Timothy Noël. Without their collaborative
agreement, Iwouldhaveneverhad theopportunity topursuit aPh.D. at
the Eindhoven University of Technology. I would like to thank Volker
Hesseltotrustinmycapabilitiesandallowmetoworkanddevelopmyself
freely.Andthankyouforalwaystakingthetimefromyourbusyschedule
to help and listen. Moreover, I will never forget your awesome Science,
Philosophy,Psychology,LiteratureandRock‐n‐Rolllecture!
201
On a personal note, I would like to express my special gratitude to
Timothy,mydailysupervisorandwhoIconsidermyprimementor.Since
wefirstmetduringtheinterviewfortheErasmusexchangeprogram,we
made an immediate connection. Our common roots brought us together
and swiftly what supposed to be an interview, changed into a relaxed
conversation with jokes and laughter. I cannot express enough how
grateful IamfortheopportunityyougavemetopursuemyPh.D.within
your researchgroup.Youhave alwaysbelieved inmeandmotivatedme
non‐stopthroughoutmyPh.D.Youhavetaughtmedeterminationandthe
courage tobelieve inmycapabilities,bothasascientistaswellas inmy
personallife.Timothy,youarethecatalystthateveryPh.D.studentshould
have to yield a dissertationwith great success!Over the years you have
becomemuchmore thanmy daily supervisor, you have become a close
friend.Wehavesharednumerousunforgettablemoments together that I
willalwayscherish.
IwouldliketothankallthemembersofmyPh.D.defensecommittee,Prof.
EmielHensen,Prof.TroelsSkrydstrup,Prof.FlorisRutjes,Prof.BertMaes,
Prof. JanvanMaarseveenandProf.Albert Schenning for sacrificing their
valuabletimetoreadandcommentonmydissertation,andfortakingpart
inthedefenseceremony.
IwouldliketothanktheNetherlandsOrganisationforScientificResearch
(NWO) for providing the financial support necessary to conduct my
research(ECHOgrantnr.713.013.001).
For themanycollaborationduringmyPh.D. Iwould like to thank Indrek
Kalvet and Prof. Franziska Schoenebeck from RWTH Aachen for the
excellent computational studies they performed, Dr. Upendra Sharma,
Acknowledgements
202
FelixSchröderandErikvanderEyckenfromKULeuvenfortheiressential
collaborationonthedualcatalysisproject.
Iwanttoexpressmygratitudetoallmycolleagues.ToDario,youarethe
colleague everybody should have. You intelligence and curiosity for
science still baffles me. Thank you for the numerous moments you
dedicatedyourtimetoexplainanddiscussworkwithme.Andthankyou
andNadia for themanynice dinners andparties at your place. ToXiao‐
Jing,thankyouforyouromnipresentsmileinthelabandyourinteresting
stories about Asian culture. And I promise that Iwill domy best not to
makeanymisplacedjokesanymoreabout‘Chinesepeople’:‐).ToKoen,the
engineerofourgroup,thankyouforalwaysorganizingallthenicegroup
activitiesandforkeepingthegroupmoralhighwhennecessary.Istillhave
nice memories of our challenging pub quiz nights and your awesome
rooftop parties! To Gabriele, our hardcore chemist, thank you for the
tremendous amountofwork youdidduringour collaborations! Itwas a
greatpleasuretoworkwithyou.Yourfearlessanddeterminedattitudein
thelabreallyinspiredme.To,Alessandra,thankyousomuchforallyour
enthusiasmandeffort. Itwasapleasureto introduceyoutotheworldof
flowchemistry.Andthankyouforneverlosingfaithinourflowreactors,
even if it theywere clogging numerous times. I wish you all the best in
finishing yourPh.D. in Parma. ToFangZhao, thank you for being such a
pleasantofficemate, and Iwillnever forgetyourboldenthusiasmduring
theTU/esportsdays.
To Natan, our first graduated Ph.D., thank you for all the time you
dedicatedtomeasmymasterthesissupervisor.Wehadsomegreattimes
together back in ‘the old days’! To Lana, the most awesome, crazy
colleagueandfriendIhaveevermet!Thankyou forall thesillyandnice
memories,fromthe10kDommelruntothelongnightconversationswith
203
you,MarkandMiro.ToNico,thepostdoceverygroupshouldhave!Thank
youforbeingthe‘godfather’ofourgroup.Youtaughtmesomuchduring
myfirstyears inthelab. Iamforevergrateful.ToYuanhai, thankyoufor
makingme smileevery timeagain. Itwasagreatpleasureworkingwith
you. You always made sure we would have ‘another paper’. To Sasha,
thank you for your tremendous help on finalizing the endless substrate
scopeofourproject.YouareoneofthebestorganicchemistsIhavemet.
Can’t wait to share another водка with you (but don’t tell Timothy).
Dannie,thankyouforalltheamusingtimewehadtogether,fromoursilly
conversationintheF.O.R.T.toourthoughtfulconversationsduringsquash
games.Thankyouoncemoreforallyoursupportandthebestofluckwith
finishingyourPh.D.!
Ialsowant tosharemygratitude toall thestaffmembersof theSCR‐sfp
group.A special thanks toPeter formaking sure all orders always came
throughandthatallequipmentwasalwaysoperationalandrunning.Also
thank you for the many pleasant conversations we had at the F.O.R.T.
Thank you Carlo for always keeping an eye on our lab safety and
cleanliness.WithoutyouIbelievethelabwouldhavebeenahugemessby
now.ThankyouMarliesforyoursupportwithGC‐MSandorders.ToErik,
abig thankyou forallyourhelpwith ‘upgrading’my fumehoodandthe
manypleasantconversationswehad!
A big thanks to secretaries of our group. Thank you José for all your
splendid work. You made sure everything was always taken care of
properly.Denise,thankyouforyourprofessionalismwhichIcouldrelyon.
TomypreviousofficematesJanneliesandMinjinginSTW1.50.Thankyou
somuch for the great times I hadwith you guys. Thank youMinjing for
teaching me my first Chinese sentences. Thank you Jannelies for the
Acknowledgements
204
abundantenjoyableconversations,andforyourgreathelpwithfilingmy
Dutchtaxletters.
I deeply appreciate the support of all the SCR‐sfp colleagues whom
providedalovelyenvironmentinwhichtowork.DearJohn,thankyoufor
the interesting scientific discussions and the witty conversation at the
F.O.R.T. Thank you Carlos for our countless pleasant meetings in the
corridor.Marcthanksforthemanydiscussions.
Toallthestudentsofourresearchgroup,whomhaveallbeenessentialfor
oursuccess.ThankyouLiesbeth,Sieuwert,BartandBenjamin.Thankyou
KirstenforlayingthegroundworkofourAngewandtepaper.Arian,your
optimismandkindnesstoeverybodyissomethingIwillneverforget.Ali,
thankyouforyourboldenthusiasmandworkinglatehours.
Finally, I would like to thank my family and closest friends for always
beingthereforme.Thankyoumomanddadforalwaysbelievinginme.To
my brother Tim, thank you for always listening tomy long and ‘boring’
complaintsaboutwork.Youcouldalwaysrelatetothelateworkinghours.
Floris, thanks for your interest andmotivation. AndBenoit, Chapter 5 is
dedicatedtoyou;‐).
LISTOF
PUBLICATIONS
ListofPublications
208
PEERREVIEWEDARTICLES
1. Gemoets,H.P.L.;Laudadio,G.;Hessel,V.;Noël,T.,AFlowSynthesisof
Diaryliodonium Triflates. Journal of Organic Chemistry 2017, 82,
11735‐11741.
2. Gemoets, H. P. L.; Laudadio, G.; Verstraete, K.; Hessel, V.;. Noël, T., A
ModularFlowDesignfortheMeta‐selectiveC−HArylationofAnilines.
AngewandteChemieInternationalEdition2017,56,7161‐7165.
3. Gemoets,H.P.L.;Sharma,U.K.;Schroder,F.;NoelT.;VanderEycken,
E.V.,MergerofVisible‐LightPhotoredoxCatalysisandC–HActivation
fortheRoom‐TemperatureC‐2AcylationofIndolesinBatchandFlow.
ACSCatalysis2017,7,3818‐3823.
4. Gemoets, H. P. L.; Kalvet, I.; Nyuchev, A. V.; Erdmann, N.; Hessel, V.;
Schoenebeck,F.;Noël,T.,MildandSelectiveBase‐FreeC–HArylation
of Heteroarenes: Experiment and Computation. Chemical Science,
2017,8,1046‐1055.
5. Gemoets,H.P.L.;Su,Y.;Shang,M.;Hessel,V.;Luque,R.;Noel,T.,Liquid
Phase Oxidation Chemistry in Continuous‐Flow Microreactors.
ChemicalSocietyReviews2016,45,83‐117
6. Gemoets,H.P.L.;Hessel,V.;Noël,T.,AerobicC–HOlefinationofIndoles
via a Cross‐Dehydrogenative Coupling in Continuous Flow. Organic
Letters2014,16,5800‐5803
Outsidethescopeofthisthesis
7. Straathof,N. J.;Gemoets,H.P.L.;Wang,X.; Schouten, J.C.;Hessel,V.;
Noel, T.,Rapid Trifluoromethylation and Perfluoroalkylation of Five‐
MemberedHeterocyclesbyPhotoredoxCatalysis inContinuousFlow.
ChemSusChem,2014,7,1612‐1617
209
Futurepublications
8. Gemoets, H. P. L.; Schouten, A.; Hessel, V.; Noël, T., A Critical
assessmentofC−HFunctionalization forAPISynthesis:ACaseStudy.
2017,manuscriptinpreparation
Bookchapters
9. Gemoets, H. P. L.; Hessel, V.; Noel, T. Reactor Concepts for Aerobic
Liquid‐phase Oxidation: Microreactors and tube reactors. In Liquid
PhaseAerobicOxidationAnalysis:IndustrialApplicationsandAcademic
Perspectives;Stahl,S.,Alsters,P.L.,Eds.;Wiley‐VCH:Weinheim,2016;
pp397‐419.
CONFERENCEPROCEEDINGS
Oralpresentations
1. Enabling and Accelerating C−H Bond Functionalization Through
Continuous‐Flow Chemistry. Invited speaker at FROST 6, 18‐20th
October2017,Budapest,Hungary
2. Mild and selective base‐free C−H arylation of Heteroarenes:
Computation and Experiment. NCCC XVIII, 6‐8th March 2017,
Noordwijkerhout,TheNetherlands.
3. Breaking the Unbreakable: C−H Functionalization in micro low.
IndustrymeetsScienceFocusSessionatCHAINS,6‐8thDecember2016,
Veldhoven,TheNetherlands.
4. Aerobic C−H ole ination of indoles via a cross‐dehydrogenative
coupling in continuous flow. NCCC XVI, 2‐4th March 2015,
Noordwijkerhout,TheNetherlands.
ListofPublications
210
Posterpresentations
5. A Modular Flow Design for the Meta‐selective C−H Arylation of
Anilines.CHAINS,5‐7thNovember2017,Veldhoven,TheNetherlands.
6. Enabling and Accelerating C−H Bond Functionalization through
Continuous‐FlowChemistry.FlowChemistryEurope,SELECTBIO,7‐8th
February2017,Cambridge,UnitedKingdom.
7. Aerobic C−H ole ination of indoles via a cross‐dehydrogenative
coupling in continuous flow. CHAINS, 17‐18th November 2014,
Veldhoven,TheNetherlands.
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