Enabling and accelerating C-H functionalization throughcontinuous-flow chemistryCitation for published version (APA):Gemoets, H. P. L. (2018). Enabling and accelerating C-H functionalization through continuous-flow chemistry.Technische Universiteit Eindhoven.

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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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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

by the B

when th

However,

flowcapil

reactionm

catalyst l

developed

containin

μm,seeS

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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

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Chapter3 

62

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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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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,

J.G.Chem.Rev.2013,113,1499‐1597.18. Moteki, S. A.; Usui, A.; Selvakumar, S.; Zhang, T.; Maruoka, K.Angew. Chem., Int.Ed.

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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

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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

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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

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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

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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

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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

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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.

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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

Figure6.S

NHPiv

5

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Scheme6

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mmI.D.).Bot

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66

Chapter6 

126

slugs turn

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dfromVWR

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Copper

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raction coil,

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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

Figure6.S

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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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REFERENCES

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2. a) Aradi, K.; Tóth, B.; Tolnai, G.; Novák, Z.Synlett2016,27, 1456‐1485; b) Chan, L.;McNally, A.; Toh, Q. Y.; Mendoza, A.; Gaunt, M. J. Chem. Sci. 2015, 6, 1277‐1281; c)Gonda,Z.;Novák,Z.Chem.‐Eur.J.2015,21,16801‐16806.

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5. Jalalian,N.;Ishikawa,E.E.;Silva,L.F.;Olofsson,B.Org.Lett.2011,13,1552‐1555.6. Sandtorv,A.H.;Stuart,D.R.Angew.Chem.Int.Ed.2016,55,15812‐15815.7. Xu,X.;Wang,D.;Ge,C.;Yu,X.;Wan,H.Synlett2016,27,2616‐2620.8. Reitti,M.;Villo,P.;Olofsson,B.Angew.Chem.Int.Ed.2016,55,8928‐8932.9. a)Aggarwal,V.K.;Olofsson,B.Angew.Chem.Int.Ed.2005,44,5516‐5519;b)Wang,D.;

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10. a)Qin,L.;Hu,B.;Neumann,K.D.;Linstad,E.J.;McCauley,K.;Veness,J.;Kempinger,J.J.;DiMagno, S. G. Eur. J.Org. Chem.2015, 2015, 5919‐5924; b)Watts, K.; Gattrell,W.;Wirth, T.Beilstein J.Org.Chem.2011,7, 1108‐1114; c) Hossain,M. D.; Kitamura, T.Tetrahedron 2006, 62, 6955‐6960; d) Carroll, M. A.; Pike, V. W.; Widdowson, D. A.TetrahedronLett.2000,41,5393‐5396;e)Kaźmierczak,P.;Skulski,L.Synthesis1995,,1027‐1032.

11. a) Bielawski,M.; Olofsson, B.Chem.Commun.2007,2, 2521‐2523; b) Bielawski,M.;Zhu,M.;Olofsson,B.Adv.Synth.Catal.2007,349,2610‐2618.

12. Glotz,G.;Knoechel,D.J.;Podmore,P.;Gruber‐Woelfler,H.;Kappe,C.O.Org.ProcessRes.Dev.2017,21,763‐770.

13. Peper‐Bienzeisler,R.;Fickenfrerichs,H.;Jansen,W.Chemkon2012,19,21‐28.14. Hallén,D.J.Chem.Thermodyn.1993,25,519‐524.15. Noël,T.;Su,Y.;Hessel,V.InTop.Organomet.Chem.2015;Vol.57,p1‐41.16. a)Kockmann,N.;Thenée,P.; Fleischer‐Trebes,C.; Laudadio,G.;Noel,T.React.Chem.

Eng.2017,2,258‐280;b)Gemoets,H.P.L.;Su,Y.;Shang,M.;Hessel,V.;Luque,R.;Noel,T.Chem.Soc.Rev.2016,45,83‐117;c)Movsisyan,M.;Delbeke,E.I.P.;Berton,J.K.E.T.;Battilocchio, C.; Ley, S. V.; Stevens, C. V. Chem. Soc. Rev. 2016, 45, 4892‐4928; d)Gutmann,B.;Cantillo,D.;Kappe,C.O.Angew.Chem.Int.Ed.2015,54,6688‐6728.

17. a)Kuhn,S.;Noël,T.;Gu,L.;Heider,P.L.;Jensen,K.F.LabChip2011,11,2488‐2492;b)Noël,T.;Naber,J.R.;Hartman,R.L.;McMullen,J.P.;Jensen,K.F.;Buchwald,S.L.Chem.Sci.2011,2,287‐290.

 

 

 

 

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.