catalysts

Review Palladium-Catalyzed Suzuki–Miyaura Cross-Coupling in Continuous Flow

Christophe Len 1,*, Sophie Bruniaux 1, Frederic Delbecq 2 and Virinder S. Parmar 3

1 Centre de Recherche Royallieu, Université de Technologie de Compiègne (UTC), Sorbonne Universités, CS 60319, F-60203 Compiègne CEDEX, France; [email protected] 2 Ecole Supérieure de Chimie Organique et Minérale (ESCOM), 1 rue du Réseau Jean-Marie Buckmaster, F-60200 Compiègne, France; [email protected] 3 Institute of Advanced Sciences, 86-410 Faunce Corner Mall Road, Dartmouth, MA 02747, USA; [email protected] * Correspondence: [email protected]; Tel.: +33-344-234-323

Academic Editor: Ioannis D. Kostas Received: 15 March 2017; Accepted: 25 April 2017; Published: 9 May 2017

Abstract: Carbon–carbon cross-coupling reactions are among the most important processes in organic chemistry and Suzuki–Miyaura reactions are the most widely used protocols. For a decade, green chemistry and particularly catalysis and continuous flow, have shown immense potential in achieving the goals of “greener synthesis”. To date, it seems difficult to conceive the chemistry of the 21st century without the industrialization of continuous flow process in the area of pharmaceuticals, drugs, agrochemicals, polymers, etc. A large variety of palladium Suzuki–Miyaura cross-coupling reactions have been developed using a continuous flow sequence for preparing the desired biaryl derivatives. Our objective is to focus this review on the continuous flow Suzuki–Miyaura cross-coupling using homogeneous and heterogeneous catalysts.

Keywords: palladium; continuous flow; Suzuki–Miyaura; cross-coupling

1. Introduction Among the main reactions in organic chemistry, C–C bond formation via a cross-coupling reaction catalyzed by transition metals is undoubtedly the most important and has been exploited very widely in the recent years. Palladium, the most widely used metal, enables the synthesis of complex and functionalized organic molecules and its chemistry possesses different interesting facets such as heterogeneous and homogeneous catalysis under mild experimental conditions compatible with many functional groups [1–5]. Several palladium catalyzed cross-coupling reactions such as Heck [6–11], Suzuki [12–16], Sonogashira [17–21], Stille [22–25], Hiyama [26], Negishi [27], Kumada [28], Murahashi [29] and Buchwald–Hartwig [30,31] have been developed over the years. Due to current impetus in promoting green chemistry for sustainable development, both for academic and industrial research, chemists have recently established catalytic reactions based on renewable resources, atom economy, less hazardous chemical steps, safer (least toxic) solvents, auxiliaries and alternative technologies such as continuous flow, microwave irradiation, ultrasound irradiation, etc. In the context of green chemistry, catalysis and alternative media, different cross-coupling reactions such as Suzuki–Miyaura in batch reactors have been developed in aqueous media or in water as sole green safer solvent via conventional heating or microwave irradiation [32–43]. Continuous flow chemistry as alternative technology offers significant processing advantages including improved thermal management, mixing control, application to a wider range of reaction conditions, scalability, energy efficiency, waste reduction, safety, use of heterogeneous catalysis, multistep synthesis and much more [44–49]. Two different reactors, micro and meso (or flow) reactors, exist and the devices depend on the channel

Catalysts 2017, 7, 146; doi:10.3390/catal7050146 www.mdpi.com/journal/catalysts Catalysts 2017, 7, 146 2 of 23

dimensions,Catalysts 2017 from, 7, 146 10 to 300 µm for the micro reactor (also called milli or mini) and from 300 µm2 of to 23 more than 5 mm for the meso reactor. Several advantages and disadvantages are associated with the micro and mesoreactors, reactors. exist The and main the advantagesdevices depend for theon the micro cha reactornnel dimensions, are the low from material 10 to 300 input, µm lowfor the waste micro output, excellentreactor mass (also transfer called milli properties, or mini) fast and diffusive from 300 mixingµm to more and thethan disadvantages 5 mm for the meso arethe reactor. low throughput,Several tendencyadvantages to channel and disadvantages blockage and are high associated pressure with drop. the micro In the and case meso of reactors. solid handling The main due advantages to confined for the micro reactor are the low material input, low waste output, excellent mass transfer properties, conditions and increasing of the concentration to have a better productivity, the use of continuous fast diffusive mixing and the disadvantages are the low throughput, tendency to channel blockage sonication could prevent clogging [50]. For the meso reactor, the advantages are the high throughput, and high pressure drop. In the case of solid handling due to confined conditions and increasing of low pressurethe concentration drop and to possibility have a better to handle productivity, solids forthe heterogeneoususe of continuous catalysis. sonication Few could disadvantages prevent for mesoclogging reactors [50]. are For poor the mass meso transfer reactor,property, the advantages slower are mixing, the high etc. throughput, Different studieslow pressure have drop described and the theorypossibility and practicalities to handle solids of scaled-out for heterogeneous micro and catalysi mesos. reactors Few disadvantages but no practical for meso examples reactors of are large-scale poor productionmass transfer have beenproperty, described. slower Palladium-catalyzedmixing, etc. Different cross-coupling studies have described reactions the in continuoustheory and flow reactorspracticalities have been of reportedscaled-out in themicro literature and meso at temperatures reactors but higherno practical than 60 examples◦C[51–63 of], whilelarge-scale only few studiesproduction have described have been micro described. and mesoPalladium-catalyzed reactors for the cross-coupling C–C bond formation reactions in at continuous temperature flow lower thanreactors 60 ◦C. Inhave parallel been withreported the synthesisin the literature of low at molecular temperatures weight higher compounds, than 60 °C this[51–63], technique while only has been appliedfew bystudies academic have described and industrial micro and groups meso for reactors the production for the C–C of bond polymers formation [64–67 at]. temperature For the sake of lower than 60 °C. In parallel with the synthesis of low molecular weight compounds, this technique clarity, this review describes continuous flow selective palladium-catalyzed cross-coupling reactions has been applied by academic and industrial groups for the production of polymers [64–67]. For the having a good energy efficiency at temperatures ranging between 0 ◦C and 80 ◦C. sake of clarity, this review describes continuous flow selective palladium-catalyzed cross-coupling 2. Acceptedreactions Mechanismhaving a good of energy Suzuki efficiency Cross-Coupling at temperatures ranging between 0 °C and 80 °C. 2.The Accepted Suzuki–Miyaura Mechanism cross-couplingof Suzuki Cross-Coupling reaction [12 –16] is one of the most versatile and frequently employedThe method Suzuki–Miyaura for C–C bondcross-coupling formation. reaction It consists [12–16] of is the one coupling of the most of versatile organoboron and frequently compounds (organoborane,employed method organoboronic for C–C bond acid, formation. organoboronate It consists ester of the and coupling potassium of organoboron trifluoroborate) compounds with aryl, alkenyl(organoborane, and alkynyl organoboronic halides. Nowadays, acid, organoboronate a large variety ester of and boronic potassium acids trifluoroborate) are commercially with available.aryl, The generalalkenyl and Suzuki–Miyaura alkynyl halides. catalytic Nowadays, cycle a large occurs vari throughety of boronic oxidative acidsaddition, are commercially transmetallation available. and reductiveThe general elimination Suzuki–Miyaura [13–15,68 catalytic–70]. After cycle formation occurs through of the oxidative catalytic addition, species transmetallation Pd(0), generated and in situ startingreductive from palladiumelimination Pd(II)[13–15,68–70]. or directly After from formation Pd(0) derivatives,of the catalytic oxidative species Pd(0), addition generated of the arylin situ halide ArXstarting furnishes from the palladium palladium Pd(II) complex or directly (ArPdXLn). from Pd(0 The) derivatives, transmetallation oxidative stepaddition occurs of the by aryl conversion halide of ArX furnishes the palladium complex (ArPdXLn). The transmetallation step occurs by conversion of the palladium halide (ArPdXLn) in the presence of the base RO− to a nucleophilic palladium alkoxy the palladium halide (ArPdXLn) in the presence of the base RO− to a nucleophilic palladium alkoxy complex (ArPdORLn). This complex subsequently reacts with a neutral organoboron compound complex (ArPdORLn). This complex subsequently reacts with a neutral organoboron compound Ar’B(OH) to afford the diaryl complex (ArPdAr’Ln) in a cis–trans equilibrium. Then, reductive Ar’B(OH)2 2 to afford the diaryl complex (ArPdAr’Ln) in a cis–trans equilibrium. Then, reductive eliminationelimination of the of thecis cisform form gives gives the the biaryl biaryl derivative derivative Ar–Ar’ Ar–Ar’ and and Pd(0) Pd(0) (Scheme (Scheme 1) 1[15].)[15 ].

Scheme 1. Mechanism of the homogeneous Suzuki–Miyaura reaction. Scheme 1. Mechanism of the homogeneous Suzuki–Miyaura reaction.

Catalysts 2017, 7, 146 3 of 23

Catalysts 2017, 7, 146 3 of 23 Using supported palladium catalysts, Suzuki–Miyaura cross-coupling reaction is a heterogeneous CatalystsUsing 2017, 7,supported 146 palladium catalysts, Suzuki–Miyaura cross-coupling reaction 3is of 23a catalysis [71]. During the reaction, the palladium Pd(II) could be release from the surface of the solid heterogeneous catalysis [71]. During the reaction, the palladium Pd(II) could be release from the support and this leaching palladium could be responsible for the catalysis as a (quasi)homogeneous surfaceUsing of thesupported solid support palladium and this leachingcatalysts, pall Suzukiadium–Miyaura could be responsiblecross-coupling for thereaction catalysis is as a mechanismheterogeneous(quasi)homogeneous (Scheme catalysis2)[72 mechanism– 83[71].]. During (Scheme the reaction,2) [72–83]. the palladium Pd(II) could be release from the surface of the solid support and this leaching palladium could be responsible for the catalysis as a (quasi)homogeneous mechanism (Scheme 2) [72–83].

Scheme 2. Mechanism of the heterogeneous Suzuki–Miyaura reaction. Scheme 2. Mechanism of the heterogeneous Suzuki–Miyaura reaction. 3. Homogeneous Suzuki–MiyauraScheme 2. Mechanism Cross-Coupling of the heterogene Reactionous Suzuki–Miyaura in Continuous reaction. Flow 3. Homogeneous Suzuki–Miyaura Cross-Coupling Reaction in Continuous Flow 3. HomogeneousBuchwald reported Suzuki–Miyaura an efficient Cross-Couplingsynthesis of biaryls Reaction from aryl in Continuoushalide substrates Flow using a successive Buchwaldlithiation/borylation/Suzuki–Miyaura reported an efficient synthesis cross-coupling of biaryls sequence from aryl in three halide successive substrates mesoreactors using a successive [84]. lithiation/borylation/Suzuki–MiyauraStartingBuchwald from aryl reported bromide, an efficient the bromine-lithium synthesis cross-coupling of biaryls exchange sequence from affordedaryl halide in three the substrates corresponding successive using mesoreactors a aryllithium successive [84]. Startinglithiation/borylation/Suzuki–Miyaurawhich from reacted aryl with bromide, borate theto form bromine-lithium the cross-couplingboronate agent. exchange sequence Conventional afforded in three Suzuki–Miyaura successive the corresponding mesoreactors cross-coupling aryllithium [84]. whichStartingreaction reacted fromusing with aryl homogeneous borate bromide, to form the second-generation thebromine-lithium boronate agent. exchangepalladium Conventional afforded let precatalyst the Suzuki–Miyaura corresponding a furnished aryllithium cross-couplingthe target which reacted with borate to form the boronate agent. Conventional Suzuki–Miyaura cross-coupling reactionbiaryl using derivatives homogeneous (Scheme second-generation 3). One of the main palladiumdrawbacks letof this precatalyst nice concepta furnished was the formation the target of biaryl reaction using homogeneous second-generation palladium let precatalyst a furnished the target derivativessolids such (Scheme as lithium3). One triisopropylarylborate of the main drawbacks during of the this process; nice concept optimization was theof the formation nature of of the solids biarylsolvent derivatives (THF and (SchemeH2O), the 3). concentration One of the main of reagents drawbacks and ofthe this use nice of acoustic concept irradiationwas the formation have been of such as lithium triisopropylarylborate during the process; optimization of the nature of the solvent solidsreported such to avoidas lithium the formation triisopropylarylborate of such solids. during the process; optimization of the nature of the (THFsolvent and H 2(THFO), the and concentration H2O), the concentration of reagents of and reagents the use and of the acoustic use of irradiationacoustic irradiation have been have reported been to avoidreported the formation to avoid of the such formation solids. of such solids.

Scheme 3. Lithiation/borylation/Suzuki–Miyaura cross-coupling sequence for the synthesis of biaryl derivatives. Scheme 3. Lithiation/borylation/Suzuki–Miyaura cross-coupling sequence for the synthesis of biaryl Scheme 3. Lithiation/borylation/Suzuki–Miyaura cross-coupling sequence for the synthesis of derivatives. biaryl derivatives. Catalysts 2017, 7, 146 4 of 23 Catalysts 2017, 7, 146 4 of 23

In thisthis report,report, thethe developmentdevelopment of different reactorsreactors made with a perfluoroalkoxyalkaneperfluoroalkoxyalkane (PFA) tubetube havinghaving the innerinner diameterdiameter of 11 mmmm hashas beenbeen describeddescribed [[84].84]. A solutionsolution of arylbromidearylbromide in THFTHF and a solution of n-butyllithium in hexane (1.6 M or 2.5 M) were injected simultaneously, then mixed at a T-shaped T-shaped mixer mixer and and delivered delivered to to the the first first reactor reactor (reactor (reactor 1) at 1) room at room temperature temperature with with a flow a flow rate −1 rateof 50–78 of 50–78 µL minµL−1 min and a varyingand a varying residence residence time (2–120 time s). (2–120 A solution s). A solutionof diluted of B(OiPr) diluted3 in B(OiPr) THF was3 in −1 THFinjected was with injected a flow with rate a of flow 1 µL rate min of−1 1andµL mixed min withand mixedthe exiting with stream the exiting of aryllithium stream of derivative aryllithium at derivativea T-shape mixer. at a T-shape The mixed mixer. stream The mixed was introduced stream was to introduced the second to reactor the second (reactor reactor 2) at (60reactor °C under 2) at ◦ 60acousticC under irradiation acoustic with irradiation a residence with time a residence of 1 min. time Then, of a 1 solution min. Then, of aqueous a solution KOH of aqueous(0.87 M) KOHand a (0.87solution M) of and aryl a halide solution (1.00 of arylM) and halide XPhos (1.00 precatalyst M) and XPhos(a, 1 mol precatalyst %) in THF ( awere, 1 mol successively %) in THF injected were −1 −1 successivelyinto the exiting injected stream into with the exitinga flow streamrate of with100 µL a flow min rate−1 and of 10021–40µL minµL minand−1, respectively. 21–40 µL min The, ◦ respectively.combined mixture The combined was introduced mixture to wasthe third introduced reactor to (reactor the third 3) at reactor 60 °C (reactorunder acoustic 3) at 60 irradiationC under acousticwith a residence irradiation time with of 10 a residence min (Scheme time 4). of 10Ultrasound min (Scheme chemistry4). Ultrasound was used chemistry for reactors was 2 usedand 3 for to reactorsavoid reactor 2 and clogging 3 to avoid and reactor ensure clogging a good and mixing ensure of reagents a good mixing during of the reagents formation during of the the borate formation and ofthe the Suzuki–Miyaura borate and the cross-coupling Suzuki–Miyaura reaction. cross-coupling reaction.

Scheme 4. Lithiation/borylation/Suzuki–Miyaura cross-coupling sequence for the synthesis of biaryl Scheme 4. Lithiation/borylation/Suzuki–Miyaura cross-coupling sequence for the synthesis of biaryl derivatives in a microflow system. derivatives in a microflow system.

Application of the above methodology was realized with a range of various aryl halides (Figure Application of the above methodology was realized with a range of various aryl halides (Figure1), 1), the limiting step of the process being the lithiation of aryl halides. In their hands, Buchwald the limiting step of the process being the lithiation of aryl halides. In their hands, Buchwald described described that the aryl bromide could be lithiated at room temperature. Whatever the nature of the that the aryl bromide could be lithiated at room temperature. Whatever the nature of the starting starting aryl bromide having different electronic and steric demands in para, meta and ortho positions, aryl bromide having different electronic and steric demands in para, meta and ortho positions, the the aryllithium and then the corresponding lithium arylborate were obtained in good yields. For the aryllithium and then the corresponding lithium arylborate were obtained in good yields. For the third step, the Suzuki–Miyaura cross-coupling reaction with aryl bromide or chloride with both third step, the Suzuki–Miyaura cross-coupling reaction with aryl bromide or chloride with both electron-withdrawing and electron-donating substituents, afforded the target compounds in good electron-withdrawing and electron-donating substituents, afforded the target compounds in good yields. It was noteworthy that non-canonic heteroatomic halides such as quinoline, isoquinoline, yields. It was noteworthy that non-canonic heteroatomic halides such as quinoline, isoquinoline, pyrimidine and benzothiophene were good reagents for the continuous flow reaction. pyrimidine and benzothiophene were good reagents for the continuous flow reaction. It is noteworthy that five-membered 2-heteroaromatic boronic acids are unstable at room It is noteworthy that five-membered 2-heteroaromatic boronic acids are unstable at room temperature and consequently give low yields in the Suzuki–Miyaura cross-coupling reaction [85– temperature and consequently give low yields in the Suzuki–Miyaura cross-coupling reaction [85–90]. 90]. Consequently, Buchwald turned attention to the lithiation/borylation/Suzuki–Miyaura cross- Consequently, Buchwald turned attention to the lithiation/borylation/Suzuki–Miyaura cross-coupling coupling of heteroarenes such as thiophene and furan derivatives; starting from furanic derivatives, of heteroarenes such as thiophene and furan derivatives; starting from furanic derivatives, selective selective deprotonation of the hydrogen atom in position 2 at room temperature afforded the deprotonation of the hydrogen atom in position 2 at room temperature afforded the corresponding corresponding lithium analog which reacted with borate to form the boronate agent. Then, lithium analog which reacted with borate to form the boronate agent. Then, conventional homogeneous conventional homogeneous Suzuki–Miyaura cross-coupling reaction furnished the target biaryl Suzuki–Miyaura cross-coupling reaction furnished the target biaryl derivatives. After optimization derivatives. After optimization of the first continuous flow process (Scheme 4), the borylation was of the first continuous flow process (Scheme4), the borylation was made at room temperature with made at room temperature with a reduced time (6 s vs. 60 s) and acoustic irradiation was not needed a reduced time (6 s vs. 60 s) and acoustic irradiation was not needed for this step in reactor 2 for this step in reactor 2 (Scheme 5) [84]. (Scheme5)[84].

Catalysts 2017, 7, 146 5 of 23 Catalysts 2017, 7, 146 5 of 23 Catalysts 2017, 7, 146 5 of 23

Figure 1. Substrate scope of continuous flow lithiation/borylation/Suzuki–Miyaura cross-coupling Figure 1. Substrate scope of continuous flow lithiation/borylation/Suzuki–Miyaura cross-coupling Figuresequence 1. Substrate starting fromscope aryl of bromides.continuous flow lithiation/borylation/Suzuki–Miyaura cross-coupling sequence starting from aryl bromides. sequence starting from aryl bromides.

Scheme 5. Lithiation/borylation/Suzuki–Miyaura cross-coupling sequence of heteroarenes with aryl halides in a flow system. Scheme 5. Lithiation/borylation/Suzuki–Miyaura cross-coupling sequence of heteroarenes with aryl Scheme 5. Lithiation/borylation/Suzuki–Miyaura cross-coupling sequence of heteroarenes with aryl halidesApplication in a flow of system. the method was realized to show the scope of the reaction [84]. Starting from halides in a flow system. thiophene, 2-alkylthiophene and 2-alkylfuran, borylation in two steps was efficient: the coupling with differentApplication substituted of the aryls method and heteroaromaticwas realized to halides show afforded the scope the of target the reactioncompounds [84]. in Startinggood yields from thiophene,(SchemeApplication 2-alkylthiophene6). This of novel the methodprocess and allows was2-alkylfuran, realized the use ofborylation to lo showw-cost the heteroarenesin scopetwo steps of the wasinstead reaction efficient: of more [84 the ].expensive coupling Starting and fromwith thiophene,differentunstable substituted 2-alkylthiophene2-heteroaromatic aryls and boronic and heteroaromatic 2-alkylfuran, acids and 2-heteroaromatic borylationhalides afforded in two bromides. the steps target was compounds efficient: the in coupling good yields with different(SchemeIn 6).substituted order This to novel illustrate aryls process andthe syntheticallows heteroaromatic the potential use of halides lo ofw-cost this affordedmethodology, heteroarenes the target Diflunis instead compoundsal of [91,92] more was expensive in good obtained yields and (Schemeunstablein a multi-step6 2-heteroaromatic). This novel sequence process boronic [84]. allows Starting acids the andfrom use of2-heteroaromatic 4-bromoanisole, low-cost heteroarenes thebromides. lithiation/borylation instead of more expensivefollowed by and unstableSuzuki–MiyauraIn order 2-heteroaromatic to illustrate cross-coupling the boronic synthetic with acids potential1-bromo-2, and 2-heteroaromatic of 4-difluorobenzenethis methodology, bromides. permitted Diflunisal the [91,92] synthesis was obtained of the in keya Inmulti-step intermediate order to illustratesequence in the production the[84]. synthetic Starting of potentialDiflunisal from 4-bromoanisole, of(Scheme this methodology, 7). the lithiation/borylation Diflunisal [91,92] was followed obtained by inSuzuki–Miyaura a multi-step sequence cross-coupling [84]. Starting with 1-bromo-2, from 4-bromoanisole, 4-difluorobenzene the lithiation/borylation permitted the synthesis followed of the by Suzuki–Miyaurakey intermediate cross-couplingin the production with of 1-bromo-2, Diflunisal 4-difluorobenzene(Scheme 7). permitted the synthesis of the key intermediate in the production of Diflunisal (Scheme7).

Catalysts 2017, 7, 146 6 of 23

Catalysts 2017, 7, 146 6 of 23 Catalysts 2017, 7, 146 6 of 23

Catalysts 2017, 7, 146 6 of 23

Scheme 6. Substrate scope of continuous flow lithiation/borylation/Suzuki–Miyaura cross-coupling Scheme 6. Substrate scope of continuous flow lithiation/borylation/Suzuki–Miyaura cross-coupling Schemesequence 6. starting Substrate from scope furan of derivatives:continuous [a]flow 0.44 lithiation/borylation/Suzuki–Miyaura M NaF aqueous solution was used instead cross-coupling of KOH; sequence starting from furan derivatives: [a] 0.44 M NaF aqueous solution was used instead of KOH; sequenceand [b] 0.87 starting M KF from aqueous furan solution derivatives: was used [a] 0.44 instead M NaF of KOH.aqueous solution was used instead of KOH; and [b] 0.87 M KF aqueous solution was used instead of KOH. and [b] 0.87 M KF aqueous solution was used instead of KOH. Scheme 6. Substrate scope of continuous flow lithiation/borylation/Suzuki–Miyaura cross-coupling sequence starting from furan derivatives: [a] 0.44 M NaF aqueous solution was used instead of KOH; and [b] 0.87 M KF aqueous solution was used instead of KOH.

Scheme 7. Total synthesis of Diflunisal via lithiation/borylation/Suzuki–Miyaura cross-coupling in a Schememicroflow 7. Totalsystem. synthesis of Diflunisal via lithiation/borylation/Suzuki–Miyaura cross-coupling in a Scheme 7. Total synthesis of Diflunisal via lithiation/borylation/Suzuki–Miyaura cross-coupling in microflow system. a microflowIn order system. to develop an automated, droplet-flow microfluidic system applied to Suzuki–Miyaura Scheme 7. Total synthesis of Diflunisal via lithiation/borylation/Suzuki–Miyaura cross-coupling in a cross-coupling reaction, Buchwald and Jensen reported a systematic methodology including key Inmicroflow order to system.develop an automated, droplet-flow microfluidic system applied to Suzuki–Miyaura Incross-couplingmechanistic order to developinsights reaction, [93]. an automated,Buchwald and droplet-flow Jensen reported microfluidic a systematic system methodology applied to including Suzuki–Miyaura key cross-couplingmechanisticAIn three-steporder reaction,insights to develop flow [93]. Buchwald andiazotization, automated, and droplet-flow Jenseniododediazotization reported microfluidic a systematicand system Suzuki–Miyaura applied methodology to Suzuki–Miyaura cross includingcoupling key reaction has been reported by Organ starting from aniline derivatives [94]. Starting from the mechanisticcross-couplingA three-step insights reaction, [ 93flow]. diazotization,Buchwald and iododediazotization Jensen reported a systematic and Suzuki–Miyaura methodology crossincluding coupling key reactionarylamine, has the been diazotation reported followed by Organ by thestarting introd fructionom aniline of iodide derivatives atom furnished [94]. Starting the iodobenzene from the Amechanistic three-step insights flow diazotization, [93]. iododediazotization and Suzuki–Miyaura cross coupling reaction arylamine,derivatives.A three-step the Then diazotation conventionalflow diazotization, followed Suzuki–Miyaura by theiododediazotization introd crossuction coupling of iodide and afforded Suzuki–Miyauraatom furnished the biphenyl thecross iodobenzene derivativescoupling has been reported by Organ starting from aniline derivatives [94]. Starting from the arylamine, derivatives.(Schemereaction 8).has Then been conventional reported by Suzuki–Miyaura Organ starting frcrossom anilinecoupling derivatives afforded the[94]. biphenyl Starting derivativesfrom the the diazotation(Schemearylamine, 8). followedthe diazotation by the followed introduction by the introd of iodideuction atom of iodide furnished atom furnished the iodobenzene the iodobenzene derivatives. Then conventionalderivatives. Then Suzuki–Miyaura conventional Suzuki–Miyaura cross coupling cross afforded coupling the afforded biphenyl the derivatives biphenyl derivatives (Scheme8 ). (Scheme 8).

Scheme 8. Diazotization/iododediazotization/Suzuki–Miyaura cross coupling sequence for the Schemesynthesis 8. of Diazotization/iododediazotization/Suzuki–Mbiaryl derivatives. iyaura cross coupling sequence for the

synthesis of biaryl derivatives. Scheme 8. Diazotization/iododediazotization/Suzuki–Miyaura cross coupling sequence for the Scheme 8. Diazotization/iododediazotization/Suzuki–Miyaura cross coupling sequence for the synthesis of biaryl derivatives. synthesis of biaryl derivatives.

Catalysts 2017, 7, 146 7 of 23

Catalysts 2017, 7, 146 7 of 23 Three reactors were made with PFA capillary tubing with an inner diameter of 1.52 mm and Three reactors were made with PFA capillary tubing with an inner diameter of 1.52 mm and different volumes. The residence time in reactors was adjusting the length of the reactor tubing. different volumes. The residence time in reactors was adjusting the length of the reactor tubing. A A solution of aniline derivative in CH CN and a solution of tBuONO in CH CN were injected solutionCatalysts of 2017 aniline, 7, 146 derivative in CH33CN and a solution of tBuONO in CH3CN3 were injected7 of 23 simultaneously,simultaneously, followed followed by by mixing mixing with with aa T-mixerT-mixer and injection injection of of a solution a solution of methanesulfonic of methanesulfonic −1 acid inacid CH in3 CHCN.Three3CN. The reactors The three three were solutions solutions made with were were PFA used used capillary withwith atubing flow flow rate ratewith of ofan 22 22 innerµL·minµL diameter min−1. The. Themixedof 1.52 mixed streammm streamand was was introducedintroduceddifferent to the tovolumes. firstthe first reactor The reactor residence at roomat room time temperature temperature in reactors with waswith adjusting a a residence residence the timelength of of 2.7 2.7 the min. min. reactor Then, Then, tubing. a solution a solution A of solution of aniline derivative in CH3CN and a solution of tBuONO in CH3CN were injected nBuNIof innBuNI CH3CN in CH was3CN injected was injected into the into stream the stream with the with same the flow. same The flow. combined The combined mixture mixture was introduced was simultaneously, followed by mixing with a T-mixer and injection of a solution of methanesulfonic to theintroduced second reactor to the second for which reactor is immersedfor which is in immers an ultrasoniced in an ultrasonic bath. The bath. residence The residence time was time 20 was min at acid in CH3CN. The three solutions were used with a flow rate of 22 µL·min−1. The mixed stream was 20 min at room temperature and then the segmented effluent was temporarily collected in an room temperatureintroduced to and the then first thereactor segmented at room temperature effluent was with temporarily a residence collectedtime of 2.7 in min. an intermediateThen, a solution reservoir. intermediate reservoir. Due to the used reservoir a continuous flow unit (CFU) was accommodated. Due to theof nBuNI used reservoir in CH3CN a was continuous injected flowinto the unit stream (CFU) with was the accommodated. same flow. The Acombined solution mixture of [PdCl was2(PPh 3)2], A solution of [PdCl2(PPh3)2], CuI, iPr2NH in CH3CN and a solution of boronic acid in MeOH were CuI, iPr introducedNH in CH toCN the second and a solutionreactor for of which boronic is immers acid ined MeOH in an ultrasonic were injected bath. The simultaneously residence time towas the main injected2 simultaneously3 to the main stream and introduced to the third reactor at 60 °C for 45 min stream and20 min introduced at room totemperature the third reactorand then at the 60 ◦segmenC for 45ted min effluent (Scheme was 9temporarily) [94]. collected in an (Schemeintermediate 9) [94]. reservoir. Due to the used reservoir a continuous flow unit (CFU) was accommodated. A solution of [PdCl2(PPh3)2], CuI, iPr2NH in CH3CN and a solution of boronic acid in MeOH were injected simultaneously to the main stream and introduced to the third reactor at 60 °C for 45 min (Scheme 9) [94].

Scheme 9. Diazotization/iododediazotization/Suzuki–Miyaura cross-coupling sequence of aniline Scheme 9. Diazotization/iododediazotization/Suzuki–Miyaura cross-coupling sequence of aniline derivative with aryl halides in a flow system. derivative with aryl halides in a flow system. Scheme 9. Diazotization/iododediazotization/Suzuki–Miyaura cross-coupling sequence of aniline Applicationderivative with of the aryl above halides protocol in a flow with system. little variations to the production of biphenyl compounds Applicationwas reported of(Figure the above 2). In protocolfunction of with the different little variations steric and to electric the production demands ofin biphenylthe aromatic compounds core, was reportedthe couplingApplication (Figure gave2 satisfactory ).of Inthe functionabove yieldsprotocol of [94]. the with different little vari sterications andto the electric production demands of biphenyl in the compounds aromatic core, the couplingwas reported gave satisfactory (Figure 2). In yieldsfunction [94 of]. the different steric and electric demands in the aromatic core, the coupling gave satisfactory yields [94].

Figure 2. Substrate scope of continuous flow diazotization/iododediazotization/Suzuki–Miyaura cross-coupling sequence starting from aniline derivative. Catalysts 2017, 7, 146 8 of 23

Figure 2. Substrate scope of continuous flow diazotization/iododediazotization/Suzuki–Miyaura Catalystscross-coupling2017, 7, 146 sequence starting from aniline derivative. 8 of 23 Catalysts 2017, 7, 146 8 of 23 Application to continuous flow process on a large scale was reported recently and could open Figure 2. Substrate scope of continuous flow diazotization/iododediazotization/Suzuki–Miyaura new wayApplication for industrial to continuous use [95,96]. flow process on a large scale was reported recently and could open cross-coupling sequence starting from aniline derivative. new way for industrial use [95,96]. 4. HeterogeneousApplication Suzuki–Miyaura to continuous flow Cross-Coupling process on a large Reaction scale was in reported Continuous recently Flow and could open 4. Heterogeneousnew way for industrial Suzuki–Miyaura use [95,96]. Cross-Coupling Reaction in Continuous Flow A suitable solid support having Pd(II) species precursors to Pd(0) catalysts are now A suitable solid support having Pd(II) species precursors to Pd(0) catalysts are now commercially commercially4. Heterogeneous available Suzuki–Miyaura but different groups Cross-Coupling prefer to Reaction design theirin Continuous home-made Flow catalysts. In the first partavailable the use but of different Pd(0) reagent groups is preferreported to designand in theirthe second home-made part Pd(II) catalysts. is described. In the first part the use of A suitable solid support having Pd(II) species precursors to Pd(0) catalysts are now Pd(0) Monguchi reagent is reportedand Sajiki and reported in the second a palladium part Pd(II) on iscarbon-catalyzed described. Suzuki–Miyaura coupling commercially available but different groups prefer to design their home-made catalysts. In the first reactionMonguchi using an and efficient Sajiki reported and continuous a palladium flow on sy carbon-catalyzedstem (Scheme 10) Suzuki–Miyaura [97]. To investigate coupling the scope reaction of usingpart an efficientthe use of and Pd(0) continuous reagent is flowreported system and (Schemein the second 10)[ part97]. Pd(II) To investigate is described. the scope of the reaction, the reaction, Monguchi a range and of Sajikiarylboronic reported acids a palladium and ha logenobenzeneon carbon-catalyzed derivatives Suzuki–Miyaura were tested coupling in mild a range of arylboronic acids and halogenobenzene derivatives were tested in mild conditions for 20 s conditionsreaction for using 20 s anduring efficient a sing and le-passcontinuous (Figure flow 3).system The (Schemeauthors 10) have [97]. reported To investigate the detection the scope of of little during a single-pass (Figure3). The authors have reported the detection of little leaching (<1 ppm). leachingthe (<1reaction, ppm). a range of arylboronic acids and halogenobenzene derivatives were tested in mild conditions for 20 s during a single-pass (Figure 3). The authors have reported the detection of little leaching (<1 ppm).

Scheme 10. Suzuki–Miyaura cross coupling in a flow system using H-Cube ®. Scheme 10. Suzuki–Miyaura cross coupling in a flow system using H-Cube®. Scheme 10. Suzuki–Miyaura cross coupling in a flow system using H-Cube®.

Figure 3. Substrate scope of continuous flow Suzuki–Miyaura cross-coupling sequence in a flow system using H-Cube®.

Catalysts 2017, 7, 146 9 of 23 Catalysts 2017, 7, 146 9 of 23 CatalystsFigure2017, 3.7, 146Substrate scope of continuous flow Suzuki–Miyaura cross-coupling sequence in a flow9 of 23 systemFigure using3. Substrate H-Cube scope®. of continuous flow Suzuki–Miyaura cross-coupling sequence in a flow system using H-Cube®. Using the same apparatus H-Cube®, another group reported the Suzuki–Miyaura cross Using the same apparatus H-Cube®, another group reported the Suzuki–Miyaura cross coupling couplingin theUsing presence in the the same presence of apparatus graphene of graphene H-Cube supported®, supportedanother palladium group palladium reported nanoparticles nanoparticles the Suzuki–Miyaura [98]. [98A]. solution Across solution coupling of of4- 4-bromobenzaldehyde and phenylboronic acid dissolved in H2O-EtOH-THF (1:1:1) was injected bromobenzaldehydein the presence of and graphene phenylboronic supported acid dissolvedpalladium in Hnanoparticles2O-EtOH-THF [98]. (1:1:1) A was solution injected of with 4- with a flow rate of 0.2 mL min−1 resulting in a contact time of less than 1 min at 135 ◦C. The target abromobenzaldehyde flow rate of 0.2 mL minand −phenylboronic1 resulting in a acidcontact dissolved time of in less H 2thanO-EtOH-THF 1 min at 135(1:1:1) °C. wasThe injectedtarget biaryl with biarylcompounda flow compound rate wasof 0.2 obtained wasmL min obtained in−1 resultinggood in yield good in wi yielda thcontact a withconversion time a conversion of lessof 96% than of (Scheme 96%1 min (Scheme at 11). 135 °C.11). The target biaryl compound was obtained in good yield with a conversion of 96% (Scheme 11).

Scheme 11. Suzuki–Miyaura cross coupling in a flow system using H-Cube® . Scheme 11. Suzuki–Miyaura cross coupling in a flow system using H-Cube®. Scheme 11. Suzuki–Miyaura cross coupling in a flow system using H-Cube®. In 2006, Canty was the first to develop a macroporous monolith support as a suitable substrate for anchoringInIn 2006,2006, CantyCanty a palladium waswas thethe complex firstfirst toto developdevelop for Suzuki–Miy aa macroporousmacroporousaura cross-coupling monolithmonolith supportsupport continuous asas aa suitablesuitable flow substratesubstratecapillary formicroreactorsfor anchoringanchoring [99]. aa palladiumpalladium Ten years complexcomplex after, Nagaki forfor Suzuki–MiyauraSuzuki–Miy reported anaura efficient cross-couplingcross-coupling three-step continuouscontinuous flow sequence flowflow using capillarycapillary Pd microreactors [99]. Ten years after, Nagaki reported an efficient three-step flow sequence using Pd catalystmicroreactors [100]. The[99]. aryllithium Ten years after,obtained Nagaki from reported arylbromide an efficient reacted three-stepwith B(OMe) flow3; aftersequence the borylation using Pd catalyst [100]. The aryllithium obtained from arylbromide reacted with B(OMe) ; after the borylation reaction,catalyst [100]. the Suzuki–Miyaura The aryllithium obtainedcross coupling from arylbromidereaction in the reacted presence with ofB(OMe) immobilized33; after the Pd(0) borylation on the reaction,polymerreaction, afforded thethe Suzuki–MiyauraSuzuki–Miyaura the target biaryl cross derivatives couplingcoupling reaction(Scheme inin12). thethe presencepresence ofof immobilizedimmobilized Pd(0)Pd(0) onon thethe polymerpolymer affordedafforded thethe targettarget biarylbiaryl derivativesderivatives (Scheme(Scheme 12 12).).

Scheme 12. Halogen/lithium exchange/borylation/Suzuki–Miyaura cross-coupling sequence for the SchemesynthesisScheme 12.12. of Halogen/lithiumbiarylHalogen/lithium derivatives. exchange/borylation/Suzuki–Miyauraexchange/borylation/Suzuki–Miyaura cross-coupling cross-coupling sequence for thethe synthesissynthesis ofof biarylbiaryl derivatives.derivatives. In this report, a solution of bromobenzene in THF (0.10 M) and a solution n-BuLi (0.6 M in hexane)In thiswere report, injected a solutionsimultaneously of bromobenzene with a flow in rate THF of 6.0(0.10 mL M) min and−1 and a solution 1 mL min n-BuLi−1, respectively, (0.6 M in In this report, a solution of bromobenzene in THF (0.10 M) and a solution n-BuLi (0.6 M in inhexane) a micromixer were injected (ID = 500simultaneously µm) and then with in a flowreactor rate (ID of =6.0 1000 mL µm) min −for1 and a residence 1 mL min time−1, respectively, of 1.7 s. A hexane) were injected simultaneously with a flow rate of 6.0 mL min−1 and 1 mL min−1, respectively, solutionin a micromixer of diluted (ID B(OMe) = 500 µm)3 (0.12 and M) then in THF in a wasreactor injected (ID = with1000 aµm) flow for rate a residence of 6.0 mL time min of−1 and1.7 s.the A in a micromixer (ID = 500 µm) and then in a reactor (ID = 1000 µm) for a residence time of 1.7 s. mainsolution stream of diluted was introduced B(OMe)3 (0.12to a micromixerM) in THF was(ID =injected 500 µm) with and a the flow second rate of reactor 6.0 mL (ID min = −10001 and µm) the A solution of diluted B(OMe) (0.12 M) in THF was injected with a flow rate of 6.0 mL min−1 and the formain a streamresidence was time introduced of 2.0 3 sto (Scheme a micromixer 13). After (ID = producing500 µm) and the the boronic second acid reactor solution, (ID = 1000iodoaryl µm) main stream was introduced to a micromixer (ID = 500 µm) and the second reactor (ID = 1000 µm) for derivativefor a residence (0.33 M)time in ofmethanol 2.0 s (Scheme was added 13). Afterand the producing mixture wasthe boronicpassed throughacid solution, the palladium iodoaryl a residence time of 2.0 s (Scheme 13). After producing the boronic acid solution, iodoaryl derivative catalystderivative at 100(0.33 °C M)with in a methanol residence wastime addedof 4.7 minand or the at 120mixture °C with was a passedresidence through time of the 9.4 palladiummin. (0.33 M) in methanol was added and the mixture was passed through the palladium catalyst at 100 ◦C catalyst at 100 °C with a residence time of 4.7 min or at 120 °C with a residence time of 9.4 min. with a residence time of 4.7 min or at 120 ◦C with a residence time of 9.4 min.

Catalysts 2017, 7, 146 10 of 23 Catalysts 2017, 7, 146 10 of 23

Catalysts 2017, 7, 146 10 of 23

SchemeScheme 13.13.Halogen/lithium Halogen/lithium exchange/borylation/Suzuki–Miyauraexchange/borylation/Suzuki–Miyaura cross-coupling sequence forfor thethe synthesissynthesis ofof biarylbiaryl derivativesderivatives inin aa microflow microflow system. system. Scheme 13. Halogen/lithium exchange/borylation/Suzuki–Miyaura cross-coupling sequence for the synthesis of biaryl derivatives in a microflow system. Application of the above methodology was successfully applied to the cross-coupling of various Application of the above methodology was successfully applied to the cross-coupling of various functional aryl and heteroaryl iodides (Figure 4) [100]. It was noticeable that cyano derivatives in this functionalApplication aryl and heteroaryl of the above iodides methodology (Figure was4)[ successf100]. Itully was applied noticeable to the that cross-coupling cyano derivatives of various in this processfunctional tolerated aryl the and experimental heteroaryl iodides conditions. (Figure 4) Adapal [100]. Itene, was a noticeable drug used that for cyano the treatment derivatives of in acne, this was process tolerated the experimental conditions. Adapalene, a drug used for the treatment of acne, was producedprocess in tolerated 86% yield the byexperimental applying conditions.this methodology. Adapalene, a drug used for the treatment of acne, was produced in 86% yield by applying this methodology. produced in 86% yield by applying this methodology.

Figure 4. Substrate scope of continuous flow lithiation/borylation/Suzuki–Miyaura cross-coupling Figure 4. Substrate scope of continuous flow lithiation/borylation/Suzuki–Miyaura cross-coupling sequence in a flow system using immobilized Pd on polymer monolith. sequenceFigure 4.in Substrate a flow system scopeusing of continuous immobilized flow Pd lithiation/borylation/Suzuki–Miyaura on polymer monolith. cross-coupling sequenceA large-scale in a flow Suzuki–Miyaurasystem using immobilized cross-coupling Pd on reaction polymer using monolith. solid supported palladium Pd0 Anano/microparticles large-scale Suzuki–Miyaura and ultrasound cross-coupling irradiation was reactionreported in using continuous solid supportedflow by Das palladium [101]. The Pd0 nano/microparticlescontinuousA large-scale flow Suzuki–Miyauratechnique and ultrasound used by thecross-coupling irradiation authors required was reaction a reported syringe, using a inreservoir, solid continuous supported a pump flow and palladiuma by reaction Das [101 Pd].0 Thenano/microparticles continuousvessel. After flowthe introduction and technique ultrasound of used the irradiationaryl by thebromid authors wase, phenylboronic reported required in a acidcontinuous syringe, and potassium a reservoir,flow by carbonate Das a pump [101]. in andThe MeOH-H2O in the reservoir via the syringe a, the reagents were pumped (127 mL min−1) to the acontinuous reaction vessel. flow technique After the used introduction by the authors of the required aryl bromide, a syringe, phenylboronic a reservoir, a acidpump and and potassium a reaction reaction vessel e where the solid supported palladium (0) nano/microparticles (SS-Pd) as vessel. After the introduction of the aryl bromide, phenylboronic acid and potassium carbonate− 1in carbonateheterogeneous in MeOH-H catalyst2O inhad the been reservoir charged. via Ultrason the syringeicationa, of the the reagents mixture were (20 kHz) pumped was realized (127 mL and min ) MeOH-H2O in the reservoir via the syringe a, the reagents were pumped (127 mL min−1) to the to thethe reaction reaction vesselproducte waswhere poured the through solid supported b into the reservoir. palladium Two (0) exits nano/microparticles (d and g) were present (SS-Pd) to as reaction vessel e where the solid supported palladium (0) nano/microparticles (SS-Pd) as heterogeneous catalyst had been charged. Ultrasonication of the mixture (20 kHz) was realized and the reaction product was poured through b into the reservoir. Two exits (d and g) were present to

Catalysts 2017, 7, 146 11 of 23

heterogeneous catalyst had been charged. Ultrasonication of the mixture (20 kHz) was realized and Catalysts 2017, 7, 146 11 of 23 the reaction product was poured through b into the reservoir. Two exits (d and g) were present to Catalysts 2017, 7, 146 11 of 23 recoverrecover thethe mixturemixture after after completion completion of of the the reaction reaction (Scheme (Scheme 14). 14). In comparisonIn comparison with with microreactor microreactor and recovermesoreactor,and mesoreactor, the mixture this this process after process permittedcompletion permitted to of furnishto the furnish reaction biaryl biar derivativesyl(Scheme derivatives 14). on onIn a gramacomparison gram scale scale in inwith continuous continuous microreactor flow.flow. and mesoreactor, this process permitted to furnish biaryl derivatives on a gram scale in continuous flow.

Scheme 14. Continuous flow Suzuki–Miyaura cross-coupling on a gram scale of the substrate. Scheme 14. Continuous flow Suzuki–Miyaura cross-coupling on a gram scale of the substrate. Scheme 14. Continuous flow Suzuki–Miyaura cross-coupling on a gram scale of the substrate. Reactions of various aryl iodides with phenylboronic acids gave excellent yields. Aryl iodides havingReactionsReactions different of of various substitu aryl ents iodides were explored with phenylbo phenylboronic withoutronic significant acids gave change excellent in theiryields. reactivity. Aryl iodides The havinghavingactivation differentdifferent of the substituents substituaryl chlorideents were were was explored moreexplored withoutdifficul withoutt significantthan significant expected, change butchange in theirgave in reactivity. good their yields reactivity. The using activation Thethis activationofmethodology the aryl of chloride the (Scheme aryl was chloride 15) more [101]. difficultwas more than difficul expected,t than but expected, gave good but yields gave usinggood thisyields methodology using this methodology(Scheme 15)[ 101(Scheme]. 15) [101].

Scheme 15. Continuous flow Suzuki–Miyaura cross-coupling reaction of phenyl boronic acid with Schemearyl halides 15. Continuoususing SS-Pd flowas heterogeneous Suzuki–Miyaura catalyst. cross-coupli ng reaction of phenyl boronic acid with Scheme 15. Continuous flow Suzuki–Miyaura cross-coupling reaction of phenyl boronic acid with aryl aryl halides using SS-Pd as heterogeneous catalyst. halides using SS-Pd as heterogeneous catalyst. The catalytic stability in MeOH-H2O under flow conditions was studied by Das and a mechanismThe catalytic was proposed stability (Schemein MeOH-H 16) 2[101].O under No siflowgnificant conditions loss of was activity studied was byobserved Das and after a The catalytic stability in MeOH-H O under flow conditions was studied by Das and a mechanism mechanismrecycling five was times. proposed In their (Scheme hands, the16)2 SEM[101]. anal Noysis significant of SS-Pd lossshowed of activity the presence was observed of Pd(0) nano-after was proposed (Scheme 16)[101]. No significant loss of activity was observed after recycling five times. recyclingmicroparticulates five times. on In the their solid hands, support the SEMwhich anal impliesysis of its SS-Pd reusability showed and the minimum presence ofleaching Pd(0) nano-of Pd In their hands, the SEM analysis of SS-Pd showed the presence of Pd(0) nano-microparticulates on the microparticulatesfrom the solid surface. on the solid support which implies its reusability and minimum leaching of Pd fromsolid the support solid whichsurface. implies its reusability and minimum leaching of Pd from the solid surface.

Catalysts 2017, 7, 146 12 of 23 Catalysts 2017, 7, 146 12 of 23 Catalysts 2017, 7, 146 12 of 23

Scheme 16. A schematic diagram of the Suzuki–Miyaura cross-coupling reaction of phenyl boronic Scheme 16. A schematic diagram of the Suzuki–Miyaura cross-coupling reaction of phenyl boronic acidScheme with 16. aryl A halidesschematic using diagram SS-Pd ofas theheterogeneous Suzuki–Miyaura catalyst. cross-coupling reaction of phenyl boronic acid with aryl halides using SS-Pd as heterogeneous catalyst. acid with aryl halides using SS-Pd as heterogeneous catalyst. Martin-Matute developed a novel strategy using Pd nanoparticles supported in a functionalized mesoporousMartin-Matute Metal-Organic developed Frameworks a novel strategy (MOFs) using [102]. Pd To nanoparticles the best of our supported knowledge, in a functionalized it was the first reportmesoporous on the Metal-Organic Metal-Organic use of metallic Frameworks Frameworks nanoparticles (MOFs) (MOFs) supported [102]. [102 ].To on To the MOFs the best best of in our of flow our knowledge, chemistry knowledge, it forwas it catalytic wasthe first the applications.firstreport report on the on A theusemixture useof metallic of of metallic aryl halide,nanoparticles nanoparticles boronic supportedacid/ester supported and on on KMOFs2 MOFsCO3 inin inwater flow flow andchemistry chemistry ethanol for was catalytic passed throughapplications. a column A mixture of homemade ofof arylaryl halide,halide, 8 wt boronic%boronic Pd@MIL-101-NH acid/esteracid/ester and2 at Kroom2CO3 temperatureinin water water and and forethanol ethanol a residence was was passed passed time ofthrough 35–40 amina columncolumn (Scheme ofof homemadehomemade 17). 8 8 wt wt % % Pd@MIL-101-NH Pd@MIL-101-NH2 2at at room room temperature temperature for for a residencea residence time time of 35–40of 35–40 min min (Scheme (Scheme 17 ).17).

Scheme 17. Suzuki–Miyaura cross coupling in a flow system using Pd MOF. Scheme 17. Suzuki–Miyaura cross coupling in a flow system using Pd MOF. Scheme 17. Suzuki–Miyaura cross coupling in a flow system using Pd MOF. Variations of the aryl halides and boronic acid derivatives permitted the production of a mini- libraryVariations (Figure 5). of Thethe arylauthors halides always and used boronic the sameacid derivativescartridge for permitted the preparation the production of the mini-library of a mini- oflibrary biarylVariations (Figure derivatives. 5). of The the Itauthors arylis noticeable halides always thatandused after boronicthe samethe acidreaction, cartridge derivatives the for recovery the preparation permitted catalystthe of was the production mini-libraryfound to be of partiallyaof mini-librarybiaryl crystallinederivatives. (Figure with It5). is a Theremainingnoticeable authors Pfthat always content after used theof 6.81 reaction, the wt same % (initiallythe cartridge recovery 7.29 for wtcatalyst the %) preparation[102]. was found of to the be mini-librarypartially crystalline of biaryl with derivatives. a remaining It isPf noticeablecontent of that6.81 wt after % the(initially reaction, 7.29 thewt %) recovery [102]. catalyst was found to be partially crystalline with a remaining Pf content of 6.81 wt % (initially 7.29 wt %) [102].

Catalysts 2017, 7, 146 13 of 23 CatalystsCatalysts 20172017,, 77,, 146146 1313 ofof 2323

Figure 5. Substrate scope of continuous flow Suzuki–Miyaura cross-coupling sequence using FigureFigure 5.5. Substrate scope of continuouscontinuous flowflow Suzuki–MiyauraSuzuki–Miyaura cross-couplingcross-coupling sequencesequence usingusing immobilizedimmobilizedimmobilized PdPdPd ononon MOFs.MOFs.MOFs.

AA veryvery nicenice strategystrategy basedbased onon dendrimer-encapsuldendrimer-encapsulatedated PdPd nanoparticlesnanoparticles asas catalystcatalyst inin flowflow A very nice strategy based on dendrimer-encapsulated Pd nanoparticles as catalyst in flow reactorreactor waswas developeddeveloped byby VerboomVerboom [103,104].[103,104]. InIn contrastcontrast withwith thethe conventionalconventional heterogeneousheterogeneous reactor was developed by Verboom [103,104]. In contrast with the conventional heterogeneous Suzuki–MiyauraSuzuki–Miyaura cross-couplingcross-coupling reactionreaction usingusing cartridgecartridge filledfilled withwith solidsolid catalysts,catalysts, Verboom’sVerboom’s Suzuki–Miyaura cross-coupling reaction using cartridge filled with solid catalysts, Verboom’s method methodmethod anchoredanchored PdPd nanoparticlesnanoparticles ontoonto thethe innerinner wallswalls ofof thethe flowflow reactor.reactor. ArylAryl halideshalides (10(10 mM)mM) anchored Pd nanoparticles onto the inner walls of the flow reactor. Aryl halides (10 mM) were mixed werewere mixedmixed withwith boronicboronic acidacid derivativesderivatives (15(15 mM)mM) inin ethanolethanol atat 8080 °C°C usingusing n-Bun-Bu44NOHNOH (20(20 mM)mM) asas with boronic acid derivatives (15 mM) in ethanol at 80 ◦C using n-Bu NOH (20 mM) as base at 80 ◦C. basebase atat 8080 °C.°C. TheThe solutionsolution waswas passedpassed throughthrough thethe catalyticcatalytic microreactormicroreactor4 withwith aa residenceresidence timetime ofof 1313 The solution was passed through the catalytic microreactor with a residence time of 13 min (Scheme 18). minmin (Scheme(Scheme 18).18).

SchemeScheme 18.18. Suzuki–MiyauraSuzuki–MiyauraSuzuki–Miyaura crosscross cross couplingcoupling coupling inin inaa flow aflow flow systemsystem system usingusing using dendrimer-encapsulateddendrimer-encapsulated dendrimer-encapsulated PdPd Pdnanoparticles.nanoparticles. nanoparticles.

TheThe electronicelectronic substituentssubstituents effectseffects havehave beenbeen ststudiedudied andand differentdifferent biarylbiaryl compoundscompounds havehave beenbeen The electronic substituents effects have been studied and different biaryl compounds have been obtainedobtained (Figure(Figure 6).6). ThisThis strategystrategy demonstrateddemonstrated thethe influenceinfluence ofof dendrimersdendrimers inin thethe stabilizationstabilization ofof thethe obtained (Figure6). This strategy demonstrated the influence of dendrimers in the stabilization of the PdPd NPsNPs withwith lowlow metalmetal leachingleaching [103,104].[103,104]. Pd NPs with low metal leaching [103,104].

Catalysts 2017, 7, 146 14 of 23

Catalysts 2017, 7, 146 14 of 23

Catalysts 2017, 7, 146 14 of 23

Figure 6. Substrate scope of continuous flow Suzuki–Miyaura cross-coupling sequence using Pd Figure 6.dendrimersSubstrate encapsulated scope of microreactor. continuous flow Suzuki–Miyaura cross-coupling sequence using Pd dendrimers encapsulated microreactor. Another group developed dendrimers for continuous flow Suzuki–Miyaura cross-coupling reaction [105]. Variation was noticeable since the authors described magnetic Fe3O4 fixation of Another group developed dendrimers for continuous flow Suzuki–Miyaura cross-coupling dendron-functionalized iron oxide nanoparticles containing Pd nanoparticles. In this process, the Figure 6. Substrate scope of continuous flow Suzuki–Miyaura cross-coupling sequence using Pd reactionnon-covalent [105]. Variation magnetic was fixation noticeable of solid material since inside the authors the glass describedreactor microstructures magnetic was Fe3 Oapplied4 fixation of dendrimers encapsulated microreactor. dendron-functionalizedusing external magnetic iron forces oxide and nanoparticles the reversible immobilization containing Pd of nanoparticles.catalyst materials Inonto this the process, wall the non-covalentof microchannelsAnother magnetic group was fixation developed possible. ofsolid Application dendrimers material of for this inside continuous methodology the glass flow was reactorSuzuki–Miyaura realized microstructures to produce cross-coupling only was oneapplied compound using 4-methoxy-1-bromobenzene and boronic acid. using externalreaction magnetic[105]. Variation forces was and noticeable the reversible since the immobilization authors described of catalystmagnetic materials Fe3O4 fixation onto of the wall of microchannelsdendron-functionalizedAnother was strategy possible. used iron palladium Applicationoxide nanoparticles nanoparticles of this cont methodology immobilizedaining Pd nanoparticles. in was a polymer realized In membrane this to produceprocess, for the only one Suzuki–Miyaura cross-coupling reaction but this particular area has not been developed in this compoundnon-covalent using 4-methoxy-1-bromobenzene magnetic fixation of solid material and inside boronic the glass acid. reactor microstructures was applied review. As examples, some works have been written recently in this field and are just quoted in this Anotherusing external strategy magnetic used palladiumforces and the nanoparticles reversible immobilization immobilized of catalyst in a polymer materials onto membrane the wall for the reviewof microchannels for interested was researchers possible. Application wishing to gainof this deeper methodology knowledge was of realizedthe field to[106–108]. produce only one Suzuki–MiyauracompoundAlcazar cross-couplingusing reported 4-methoxy-1-bromobenzene an efficient reaction cross-coupling but this and particular reboronicaction acid.using area hascommercial not been heterogeneous developed insilica- this review. As examples,supportedAnother some palladium worksstrategy have catalystused beenpalladium and written a mesoreactor nanoparticles recently [109]. in immobilized this The field authors and in a areusedpolymer just a simple quoted membrane and in efficient this for reviewthe for interestedexperimentalSuzuki–Miyaura researchers set-up wishingcross-coupling using to a gain6.6 reaction mm deeper (internal but knowledge this diameter)particular of theareaOmnifit field has column [not106 been–108 containing ].developed 1in g thisof Alcazarheterogeneousreview. reportedAs examples, catalyst an some and efficient commercialworks have cross-coupling boronicbeen written acids andrecently reaction aryl halidesin this using field (Scheme and commercial are19). just A solution quoted heterogeneous ofin arylthis halide in THF and a solution of boronic acid and base in water were pumped at 0.2 mL min−1 with silica-supportedreview for palladiuminterested researchers catalyst andwishing a mesoreactor to gain deeper [109 knowledge]. The authors of the field used [106–108]. a simple and efficient two independentAlcazar reported pumps. an efficientThe flow cross-coupling streams met atre actiona T-shaped using mixer commercial and then heterogeneous passed through silica- a experimental set-up using a 6.6 mm (internal diameter) Omnifit column containing 1 g of heterogeneous columnsupported containing palladium SiliaCa catalystt DPP-Pd and aas mesoreactor diphenylphosphine [109]. The pallad authorsium (II)used heterogeneous a simple and catalyst efficient at catalyst60experimental and °C with commercial a residence set-up boronic usingtime of a acids5 min.6.6 mmandA biphasic aryl(internal halides solvent diameter) system (Scheme Omnifitsuch 19 as). THF-H Acolumn solution2O containingwas of used aryl to halide1ensure g of in THF −1 and a solutioncompleteheterogeneous of dissolution boronic catalyst acid of andany and commercialsolid base and in avoiding waterboronic were anyacids subsequent pumpedand aryl halides atclogging. 0.2 (Scheme mL min 19). Awith solution two of independent aryl pumps.halide The flowin THF streams and a solution met at of a boronic T-shaped acid mixerand base and in water then passedwere pumped through at 0.2 a mL column min−1 with containing SiliaCattwo DPP-Pd independent as diphenylphosphine pumps. The flow palladiumstreams met (II) at a heterogeneous T-shaped mixer catalyst and then at passed 60 ◦C withthrough aresidence a column containing SiliaCat DPP-Pd as diphenylphosphine palladium (II) heterogeneous catalyst at time of 5 min. A biphasic solvent system such as THF-H2O was used to ensure complete dissolution of 60 °C with a residence time of 5 min. A biphasic solvent system such as THF-H2O was used to ensure any solid and avoiding any subsequent clogging. complete dissolution of any solid and avoiding any subsequent clogging.

Scheme 19. Continuous flow Suzuki–Miyaura cross-coupling sequence using SiliaCat DPPP-Pd as supported catalyst.

Scheme 19. Continuous flow Suzuki–Miyaura cross-coupling sequence using SiliaCat DPPP-Pd as Scheme 19. Continuous flow Suzuki–Miyaura cross-coupling sequence using SiliaCat DPPP-Pd as supported catalyst. supported catalyst.

Catalysts 2017, 7, 146 15 of 23

ApplicationCatalysts 2017, 7 of, 146 this strategy permitted the synthesis of the biaryl derivatives starting15 of 23 from halides/pseudohalides and (4-methoxyphenyl) boronic acid in excellent yields (Scheme 20)[109]. Application of this strategy permitted the synthesis of the biaryl derivatives starting from WhateverCatalysts the 2017 leaving, 7, 146 group on the benzene ring, the target biphenyl derivatives were15 obtained of 23 in halides/pseudohalides and (4-methoxyphenyl) boronic acid in excellent yields (Scheme 20) [109]. high yields. Of course, the use of aromatic ring bearing electron-donor groups such as 2,4-dimethoxy WhateverApplication the leaving of this group strategy on the permitted benzene thering, synthe the targetsis of biphenyl the biaryl derivatives derivatives were starting obtained from in analogs gave lower yields (50%). It was notable that bromo- and chloropyridines provided good yields halides/pseudohalideshigh yields. Of course, theand use (4-methoxyphenyl) of aromatic ring be boroniaring celectron-donor acid in excellent groups yields such (Scheme as 2,4-dimethoxy 20) [109]. and theWhateveranalogs ester functionality gave the leavinglower yields wasgroup tolerated(50%). on the It benzenewas despite notable ring, the thatth usee targetbromo- of KOH biphenyl an asd chloropyridines strong derivatives base. Usingwere provided obtained this good process, in the authorshighyields claimed yields. and that theOf course,ester the crudefunctionality the use products of aromatic was aretolerated ring clean be dearing andspite electron-donor free the ofuse phosphine of KOH groups as ligandstrong such asbase. avoiding 2,4-dimethoxy Using thethis need of chromatographicanalogsprocess, gave the purification.authors lower claimedyields Moreover,(50%). that the It crudewas low notable products leaching that are ofbromo- clean palladium and an dfree chloropyridines fromof phosphine the support ligand provided and avoiding good the stability of the catalystyieldsthe need and after of the chromatographic moreester functionality than 30 purification. cycles was was tolerated Moreover observed. despite, low leachingthe use of of KOHpalladium as strong from thebase. support Using andthis process,the stability the authors of the catalyst claimed after that more the crude than 30products cycles wasare cleanobserved. and free of phosphine ligand avoiding the need of chromatographic purification. Moreover, low leaching of palladium from the support and the stability of the catalyst after more than 30 cycles was observed.

Scheme 20. Substrate scope of continuous flow Suzuki–Miyaura cross-coupling sequence with Scheme 20. Substrate scope of continuous flow Suzuki–Miyaura cross-coupling sequence with different different aryl bromides and 4-methoxyphenylboronic acid. aryl bromides and 4-methoxyphenylboronic acid. SchemeIn order 20. to furtherSubstrate explore scope theof continuous scope of the flow reac Suzuki–Miyauration, Alcazar reported cross-coupling the use sequenceof bromobenzene with and differentphenyltriflate aryl bromides as starting and 4-methoxyphenylboronicmaterials with different acid. boronic acid derivatives (Scheme 21) [109]. In order to further explore the scope of the reaction, Alcazar reported the use of bromobenzene Excellent yields were obtained with commercial boronic acids and boronic ester, borane and borate In order to further explore the scope of the reaction, Alcazar reported the use of bromobenzene and phenyltriflatefreshly prepared as from starting the corresponding materials with bromo different derivatives boronic by metalation acid derivatives [110]. (Scheme 21)[109]. Excellentand yields phenyltriflate were obtained as starting with materials commercial with diff boronicerent boronic acids acid and deriva boronictives ester, (Scheme borane 21) [109]. and borate Excellent yields were obtained with commercial boronic acids and boronic ester, borane and borate freshly prepared from the corresponding bromo derivatives by metalation [110]. freshly prepared from the corresponding bromo derivatives by metalation [110].

Scheme 21. Substrate scope of continuous flow Suzuki–Miyaura cross-coupling reaction with different aryl bromides/triflate and phenylboronic acid derivatives.

Scheme 21. Substrate scope of continuous flow Suzuki–Miyaura cross-coupling reaction with SchemeRecently, 21. Substrate Kappe scope presented of continuous a comparative flow Suzuki–Miyaura investigation cross-couplingof four commercial reaction immobilized with different phosphine-baseddifferent aryl bromides/triflate Pd catalyst [111]. and phenylboronic One of them acid was derivatives. SiliaCat DPP-Pd as diphenylphosphine aryl bromides/triflate and phenylboronic acid derivatives. palladium (II) heterogeneous catalyst developed by Pagliaro [112–114]. In this work, the best process usedRecently, two stock Kappesolutions. presented The first asolution comparative contained investigation aryl halide (0.83of four M) incommercial THF and the immobilized second one phosphine-based Pd catalyst [111]. One of them was SiliaCat DPP-Pd as diphenylphosphine Recently,phenylboronic Kappe acid presented (0.45 M) and a K2 comparativeCO3 (0.55 M) in a investigation mixture of H2O-EtOH of four (1:1). commercial These two solutions immobilized palladium (II) heterogeneous catalyst developed−1 by Pagliaro [112–114].−1 In this work, the best process phosphine-basedwere pumped Pd in catalyst different [111 feeds,]. One 0.055 of mL them min was and SiliaCat 0.155 mL DPP-Pd min , respectively, as diphenylphosphine and mixed in a palladium T- used two stock solutions. The first solution contained aryl halide (0.83 M) in THF and the second one (II) heterogeneousmixer and then catalyst introduced developed to the catalyst by Pagliarocartridge of [112 the– X-cube114]. flow In this reactor work, at 80 the °C (Scheme best process 22). used phenylboronicUnder these conditions, acid (0.45 M)full and conversion K2CO3 (0.55 was M) obtained in a mixture in less of than H2O-EtOH 20 min (1:1). and almostThese two quantitative solutions two stockwereyield solutions. pumped of the biaryl in Thedifferent target first compound feeds, solution 0.055 was containedmL reported. min−1 and aryl 0.155 halide mL min (0.83−1, respectively, M) in THF and and mixed the in second a T- one phenylboronicmixer and acid then (0.45 introduced M) and to Kthe2CO catalyst3 (0.55 cartridge M) in a of mixture the X-cube of Hflow2O-EtOH reactor at (1:1). 80 °C These (Scheme two 22). solutions were pumpedUnder these in differentconditions, feeds, full conversion 0.055 mL was min obtained−1 and in 0.155 less than mL min20 min−1 ,and respectively, almost quantitative and mixed in a T-mixeryield and of the then biaryl introduced target compound to the catalyst was reported. cartridge of the X-cube flow reactor at 80 ◦C (Scheme 22). Under these conditions, full conversion was obtained in less than 20 min and almost quantitative yield of the biaryl target compound was reported. Catalysts 2017, 7, 146 16 of 23

Catalysts 2017, 7, 146 16 of 23 Catalysts 2017, 7, 146 16 of 23 Catalysts 2017, 7, 146 16 of 23

Scheme 22. Suzuki–Miyaura cross coupling in a flow system X-Cube using commercial Siliacat DPP- Scheme 22. Suzuki–Miyaura cross coupling in a flow system X-Cube using commercial Siliacat DPP-Pd. Pd. SchemeScheme 22. 22. Suzuki–Miyaura Suzuki–Miyaura cross cross coupling coupling in in aa flowflow system X-CubeX-Cube using using commercial commercial Siliacat Siliacat DPP- DPP- BuarquePd.BuarquePd. and Estevesand Esteves reported reported an an interesting interesting work using using heterogeneous heterogeneous catalyst catalyst from Covalent from Covalent OrganicOrganic Frameworks Frameworks (COFs) (COFs) [[115],115], COFs COFs are are differen differentt than MOFs than since MOFs COFs since do not COFs contain do metallic not contain ionsBuarque Buarqueor heavy and and Esteveselements Esteves reported reportedas part an anof interesting interestingtheir structures. work usingusing In heterogeneousthisheterogeneous study, the catalyst catalystauthors from from developed Covalent Covalent metallicOrganic ions orFrameworks heavy elements (COFs) [115], as partCOFs of are their differen structures.t than MOFs In since this COFs study, do not the contain authors metallic developed OrganicPd(OAc) Frameworks2@COF-300 (COFs)for the Suzuki–Miyaura [115], COFs are cross-couplingdifferent than MOFsreaction since in continuous COFs do notflow contain (Scheme metallic 23). Pd(OAc)ions2@COF-300 or heavy forelements the Suzuki–Miyaura as part of their cross-coupling structures. In reactionthis study, in continuousthe authors flowdeveloped (Scheme 23). ionsThe or mixture heavy of elements bromobenzene, as part phenylboronic of their structures. acid in a solutionIn this of study, MeONa the (2 M)authors in MeOH developed was The mixtureinjectedPd(OAc) of on2 bromobenzene,@COF-300 to a glass for column the phenylboronicSuzuki–Miyaura (Omnifit column acidcross-coupling with in a a volume solution reaction of of6.3 MeONamL), in continuous which (2 M)was flow in filled MeOH (Scheme with wasglass 23). injected Pd(OAc)2@COF-300 for the Suzuki–Miyaura cross-coupling reaction in continuous flow (Scheme 23). The mixture of bromobenzene, phenylboronic acid in a solution of MeONa (2 M) in MeOH was on toThe abeads glass mixture (2 column mm) of andbromobenzene, (Omnifit Pd(OAc)2@COF-300 column phenylboronic with (100 mg). a volume acidThe residencein ofa 6.3solution mL),time wasof which MeONa 20 min was and (2 filled M)the intemperature with MeOH glass was beads injected on to a glass column (Omnifit column with a volume of 6.3 mL), which was filled with glass (2 mm)injectedwas and maintained on Pd(OAc) to a glass 2at@COF-300 60column °C; under (Omnifit (100 these mg). columnconditions, The with residence the a maximalvolume time ofconversion 6.3 was mL), 20 min whichwas andobtained was the filled temperaturebetween with glass20 was beads (2 mm) and Pd(OAc)2@COF-300 (100 mg). The residence time was 20 min and the temperature maintainedand 40 at min 60 with◦C; undera very high these degree conditions, of selectivity. the maximal conversion was obtained between 20 and beadswas (2 maintained mm) and Pd(OAc)at 60 °C; 2under@COF-300 these (100conditions, mg). The the residence maximal conversiontime was 20 was min obtained and the between temperature 20 40 minwasand with maintained 40 a min very with highat a60 very degree°C; highunder ofdegree these selectivity. of conditions, selectivity. the maximal conversion was obtained between 20 and 40 min with a very high degree of selectivity.

Scheme 23. Suzuki–Miyaura cross coupling in a flow system using Pd(OAc)2@COF-300.

An efficientScheme approach 23. Suzuki–Miyaura was reported cross for coupling the prod in auction flow system of furan-based using Pd(OAc) biaryls2@COF-300. [116]. A mixture Scheme 23. Suzuki–Miyaura cross coupling in a flow system using Pd(OAc)2@COF-300. of aryl halide,Scheme boronic 23. Suzuki–Miyaura acid derivative cross and coupling TBAF in amethanol flow system (0.37 using M) Pd(OAc)was injected2@COF-300. through an X- cube Anfitted efficient with a approachFC1032 catalyst was reported at flow forrate the of 0.5prod mLuction min− 1of at furan-based 120 °C for 2 biarylsh (Scheme [116]. 24). A mixture Anof efficient aryl halide, approach boronic wasacid reportedderivative forand the TBAF production in methanol of (0.37 furan-based M) was injected biaryls through [116]. A an mixture X- of An efficient approach was reported for the production of furan-based biaryls [116]. A mixture cube fitted with a FC1032 catalyst at flow rate of 0.5 mL min−1 at 120 °C for 2 h (Scheme 24). arylof halide, aryl halide, boronic boronic acid derivativeacid derivative and and TBAF TBAF in methanol in methanol (0.37 (0.37 M) M) was was injected injected through through anan X-cubeX- −1 ◦ fittedcube with fitted a FC1032 with a catalystFC1032 catalyst at flow at rate flow of rate 0.5 of mL 0.5 min mL minat−1 120 at 120C °C for for 2 h2 (Schemeh (Scheme 24 24).).

Scheme 24. Suzuki–Miyaura cross coupling in a flow system X-Cube using FC1032 catalyst.

OverScheme to catalyst 24. Suzuki–Miyaura cycles, the furan cross couplingderivatives in a wereflow system obtained X-Cube in goodusing FC1032yields catalyst.(82–92%) using FC1032 catalyst as t-butyl based palladium polymer (Figure 7) [116]. Over to catalyst cycles, the furan derivatives were obtained in good yields (82–92%) using TheScheme same 24.process Suzuki–Miyaura was developed cross couplingafter su bstitutionin a flow system of FC1032 X-Cube catalyst using FC1032by PdCl catalyst.2(PPh3) 2 DVB FC1032Scheme catalyst 24. Suzuki–Miyaura as t-butyl based palladium cross coupling polymer in a (Figure flow system 7) [116]. X-Cube using FC1032 catalyst. catalyst at flow rate of 0.3 mL min−1 at 120 °C for 3 h. It is well known that PdCl2(PPh3)2 DVB catalyst is Overa moreThe to sameefficient catalyst process catalyst cycles, was than thedeveloped FC1032furan derivatives aftercatalyst. substitution In werethis regard; ofobtained FC1032 starting incatalyst good with by yieldsthe PdCl deactivated (82–92%)2(PPh3)2 DVB arylusing catalyst at flow rate of 0.3 mL min−1 at 120 °C for 3 h. It is well known that PdCl2(PPh3)2 DVB catalyst FC1032Overbromides to catalyst catalyst or aryl as cycles,t -butylchlorides thebased in furan the palladium presence derivatives polymer of PdCl were2 (PPh(Figure obtained3)2 DVB 7) [116]. incatalyst good afforded yields (82–92%) the target usingfuran- FC1032 is a more efficient catalyst than FC1032 catalyst. In this regard; starting with the deactivated aryl catalystbased asThet-butyl biarylssame basedprocessin 83–92% palladium was yields developed (Figure polymer 8)after [116]. (Figure su bstitution7)[116 of]. FC1032 catalyst by PdCl2(PPh3)2 DVB bromides or aryl chlorides in the−1 presence of PdCl2(PPh3)2 DVB catalyst afforded the target furan- catalystThe same at flow process rate of was 0.3 mL developed min at 120 after °C substitutionfor 3 h. It is well of known FC1032 that catalyst PdCl2(PPh by PdCl3)2 DVB2(PPh catalyst3)2 DVB based biaryls in 83–92% yields (Figure 8) [116]. is a more efficient catalyst than FC1032−1 catalyst.◦ In this regard; starting with the deactivated aryl catalyst at flow rate of 0.3 mL min at 120 C for 3 h. It is well known that PdCl2(PPh3)2 DVB catalystbromides is a more or aryl efficient chlorides catalyst in the than presence FC1032 of PdCl catalyst.2(PPh3 In)2 DVB this regard;catalyst startingafforded withthe target the deactivated furan- based biaryls in 83–92% yields (Figure 8) [116]. aryl bromides or aryl chlorides in the presence of PdCl2(PPh3)2 DVB catalyst afforded the target furan-based biaryls in 83–92% yields (Figure8)[116]. Catalysts 2017, 7, 146 17 of 23 Catalysts 2017, 7, 146 17 of 23

Catalysts 2017, 7, 146 17 of 23

Figure 7. Substrate scope of continuous flow Suzuki–Miyaura cross-coupling sequence using FC1032 Figure 7. Substrate scope of continuous flow Suzuki–Miyaura cross-coupling sequence using catalyst. FC1032Figure catalyst. 7. Substrate scope of continuous flow Suzuki–Miyaura cross-coupling sequence using FC1032 catalyst.

Figure 8. Substrate scope of continuous flow Suzuki–Miyaura cross-coupling sequence using

PdCl2(PPh3)2 DVB catalyst. Figure 8. Substrate scope of continuous flow Suzuki–Miyaura cross-coupling sequence using Figure 8. Substrate scope of continuous flow Suzuki–Miyaura cross-coupling sequence using 5. ConcludingPdCl2(PPh 3Remarks)2 DVB catalyst. PdCl2(PPh3)2 DVB catalyst. 5. ConcludingThe main focusRemarks of this review has been the observance of the continuous flow chemistry and 5. ConcludingSuzuki–Miyaura Remarks cross-coupling reactions. Homogeneous Suzuki–Miyaura cross-coupling reactions have Thebeen main focusreported of this reviewin two has beendifferent the ob servanceelegant of theand continuous modular flow strategies: chemistry and(i) The main focus of this review has been the observance of the continuous flow chemistry lithiation/borylation/homogeneousSuzuki–Miyaura cross-coupling reactions. Suzuki–Miyaura Homogeneous sequence Suzuki–Miyaura using a three-step cross-coupling triphasic reactions flow and Suzuki–Miyaura cross-coupling reactions. Homogeneous Suzuki–Miyaura cross-coupling system;have andbeen (ii) diazotization/iododediazotization/homogeneousreported in two different elegant and Suzuki–Miyaura modular sequencestrategies: using (i) a reactionsthree-steplithiation/borylation/homogeneous have triphasic been reportedflow system. in twoMore Suzuki–Miyaura different examples elegant have sequence been and reported modularusing a inthree-step strategies:heterogeneous triphasic (i) lithiation/Suzuki– flow borylation/homogeneousMiyaurasystem; and cross-coupling (ii) diazotization/iododediazotization/homogeneous reactions. Suzuki–Miyaura Some groups sequence used usingPd(0) as a three-stepthe Suzuki–Miyaura active catalyst triphasic and sequence flow some system; usinggroups anda (ii)preferredthree-step diazotization/iododediazotization/homogeneous totriphasic start with flow Pd(II) system. as precursor More examples of Pd(0). have Whatever Suzuki–Miyaura been reportedthe type sequenceinof catalyst,heterogeneous using homogeneous, a three-stepSuzuki– triphasicheterogeneous,Miyaura flow cross-coupling system. Pd(II) or More Pd(0),reactions. examplesthe residenceSome groups have times been used were reportedPd(0) less thanas the in one active heterogeneous hour catalyst and the and Pd Suzuki–Miyaura loadingsome groups were cross-couplinglowpreferred compared to reactions.start with with the SomePd(II)conversion, groupsas precursor yield used and Pd(0)of selectivity.Pd as(0). the Whatever active As mentioned catalyst the type and by of Kappe, somecatalyst, groups “ palladiumhomogeneous, preferred which to startisheterogeneous, leached with Pd(II) from the as Pd(II) precursorsupport or Pd(0),is most of Pd(0).th likelye residence responsible Whatever times for the were the type catalysis, less of than catalyst, th oneus suggesting hour homogeneous, and athe (quasi)homogeneous Pd heterogeneous,loading were Pd(II)mechanismlow orcompared Pd(0),”. In the withthis residence regard,the conversion, timeshomogeneous were yield less and metal than selectivity. catalyst/ligand one hour Asand mentioned thesystem Pd loadingbyshould Kappe, wereprobably “palladium low be compared whichmore withefficientis leached the conversion, if from the recyclingthe support yield of andis the most selectivity. catalyst likely responsiblecould As mentionedbe improved. for the catalysis, by Kappe, thus “palladium suggesting which a (quasi)homogeneous is leached from the supportmechanism is most”. likelyIn this responsible regard, homogeneous for the catalysis, metal thus suggestingcatalyst/ligand a (quasi)homogeneous system should probably mechanism be”. more In this efficient if the recycling of the catalyst could be improved.

Catalysts 2017, 7, 146 18 of 23 regard, homogeneous metal catalyst/ligand system should probably be more efficient if the recycling of the catalyst could be improved. Depending on the parameters used (concentrations, temperature, pressure, etc.), the lifetime of all the elements of the process, pumps, pipes and reactors, is longer or shorter. To date, no realistic study has been published on this aspect. Varying the nature of the materials, and the designs of the reactor with the microfluidic system, the possibilities to work in high concentrations are new avenues to explore in the future. Chemists and chemical engineers have the means to pave the way to a more widespread implementation of continuous flow strategies for the production of industrially relevant products in the future. Importantly, we hope that these demonstrated advantages of combining Suzuki–Miyaura cross-coupling reaction and flow processes can stimulate further advances in the field from the younger generations for the benefit of the chemical industry in the future.

Author Contributions: S.B. and F.D. analyzed the data; C.L. and V.S.P. wrote the paper. Conflicts of Interest: The authors declare no conflict of interest.

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