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Pushing the boundaries of C–H bond functionalization chemistry using flow technology

Pushing the boundaries of C–H bond functionalization chemistry using flow technology C–H functionalization chemistry is one of the most vibrant research areas within synthetic organic chemistry. While most re- searchers focus on the development of small-scale batch-type transformations, more recently such transformations have been carried out in flow reactors to explore new chemical space, to boost reactivity or to enable scalability of this important reaction class. Herein, an up-to-date overview of C–H bond functionalization reactions carried out in continuous-flow microreactors is presented. A comprehensive overview of reactions which establish the formal conversion of a C–Hbondintocarbon–carbon or carbon– heteroatom bonds is provided; this includes metal-assisted C–H bond cleavages, hydrogen atom transfer reactions and C–Hbond functionalizations which involve an S -type process to aromatic or olefinic systems. Particular focus is devoted to showcase the advantages of flow processing to enhance C–H bond functionalization chemistry. Consequently, it is our hope that this review will serve as a guide to inspire researchers to push the boundaries of C–H functionalization chemistry using flow technology. . . . . . Keywords Cross coupling C H activation Catalysis Microreactor Flow chemistry Introduction (Fig. 1a)[6–19]. C–H bonds are the fundamental linkage in organic molecules and, consequently, C–H activation strate- The construction of carbon–carbon and carbon–heteroatom gies would allow for very versatile transformations, even ap- bonds is a key objective for synthetic chemists to build up plicable in late-stage functionalizations enabling rapid diver- complex organic molecules. Such bonds are prevalent in sification of hit molecules. This provides an atom-efficient many materials, medicinally and biologically active com- and cost-effective alternative for the traditional cross- pounds. In the most recent decades, these linkages have been coupling strategies. In 2005, the ACS GCI Pharmaceutical forged through transition metal catalyzed cross coupling be- Roundtable have ranked C–H activation as the top priority tween aryl/alkyl halides or pseudo halides and nucleophiles of the aspirational reactions, i.e. reactions which companies (Fig. 1a)[1, 2]. However, such an approach requires would like to use on the proviso that they are available [20, prefunctionalized substrates and coupling partners, often pre- 21]. While C–H activation has indeed been hailed for its use of pared in a multistep reaction sequence, which is time- unfunctionalized starting materials, the applicability of C–H consuming and inefficient. activation chemistry has been limited mainly by the inert na- Inspired by selective biosynthetic pathways [3–5], C–H ture of the carbon-hydrogen bond (bond dissociation energies −1 activation has emerged as a new and promising area for the of aromatic C–H are around 110 kcal mol and of aliphatic −1 construction of carbon-carbon and carbon-heteroatom bonds C–H around 105 kcal mol ). Consequently, in order to cleave the C–H bond, harsh reaction conditions, long reaction times and high catalyst loadings are typically required. Also, stoi- * Timothy Noel chiometric amounts of toxic oxidants are often needed to close t.noel@tue.nl; https://www.noelresearchgroup.com the catalytic cycle. In the past two decades, continuous-flow microreactors have Department of Chemical Engineering and Chemistry, Micro Flow been increasingly used as an interesting new tool to boost Chemistry and Synthetic Methodology, Eindhoven University of chemical reactions. Advantages, such as excellent heat- and Technology, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands 2 mass-transfer, safety of operation and ease of scale-up, have School of Chemistry, University of Manchester, Oxford Road, attracted the interest of both synthetic and process chemists Manchester M13 9PL, UK 14 J Flow Chem (2020) 10:13–71 Fig. 1 a Comparison between classical cross-coupling and C–H functionalization chemistry. b Advantages provided by flow processing in microreactors and its potential impact on C–H functionalization chemistry and allow to perform reactions under conditions that cannot be inclusion of the latter reaction class is debatable as the cleav- easily achieved in conventional batch reactors (Fig. 1)[22–24]. age of the C–H bond occurs in the final deprotonation step and Since the emergence of flow chemistry, a lot of research thus this class cannot be regarded as a formal C–H activation efforts have been devoted to the development of continuous- reaction. However, for reasons of completeness and due to the flow alternatives for cross-coupling chemistry, which even difficulty in determining the operating C–H scission mecha- served as a benchmark reaction for early reactor concepts nism [28], we have chosen to incorporate radical-based C–H [25, 26]. Notably, despite the fact that C–H activation requires functionalization reactions in this review. The advantages of in general harsher reaction conditions than their cross- flow chemistry have been highlighted when- and wherever coupling counterparts, flow approaches for C–H activation appropriate. Hence, we hope this review will serve as a useful have been comparatively rare. However, as shown in guide for those researchers working in C–Hfunctionalization Fig. 1b, many of the advantages that popularized flow pro- chemistry who aspire to implement flow processing in their cessing are also of great use to boost C–H functionalization experiments. and might deliver a solution to the known shortcomings of the field (Fig. 1a). Herein, we provide an overview of those C–H functionalization processes that have been carried out in flow C − H functionalization in flow [20, 27]. The review is structured by highlighting the different bonds that are formed, including carbon–carbon, carbon–ni- C − C bond formation trogen, carbon–oxygen, carbon–sulfur, carbon–halogen and carbon–hydrogen bonds. We have chosen to include a diverse C − H alkylation set of C–H bond functionalizations, including metal-assisted C–H bond cleavages, hydrogen atom transfer (HAT) reactions The insertion chemistry of carbenes represents an interesting and radical C–H bond functionalizations, which involve the and mechanistically distinct case of C −Hfunctionalization addition of radicals to unsaturated systems. Especially the reaction [18]. While carbenes can be formed in a number of J Flow Chem (2020) 10:13–71 15 ways, one of the most well-known approaches is through the compounds. This allowed for the C −Hfunctionalization of thermal, photochemical or metal-catalyzed decomposition of p-cymene and methyl tert-butyl ether (MTBE, with Rh (S-p- diazo compounds [29]. One of the main advantages of flow BrTCP) )and n-pentane (with a Rh ( R-3,5- 4 2 chemistry, in particular when looking at industrial applica- di)p- BuPh)TPCP) catalyst) via C − H insertion of the tions, is the ability to perform reactions which would ordinar- carbene generated from the parent diazo compound (Scheme ily be considered hazardous in a safe manner, as the reacting 1)in batch [44]. However, both the price of the noble metal volumes at any given time are typically very small [30, 31]. rhodium and the catalyst ligands are a non-negligible cost. Many reports have appeared on the synthesis and chemistry of Provided leaching can be kept to a minimum and high the synthetically useful but unstable diazo compounds in enantioselectivities maintained, catalyst immobilization is an continuous-flow microreactors [32–43]. attractive strategy, both from an economical and environmen- Many routes to access diazo compounds exist, e.g. the di- tal point of view. The Rh (S-p-BrTCP) catalyst in particular 2 4 azo transfer reaction. While a reliable approach, it suffers from shows enantioselectivity for the challenging functionalization poor atom economy as stoichiometric amounts of sulfonamide of primary C − H bonds. As demonstrated by Jones, Davies waste products are formed. A straightforward approach to and co-workers, the catalyst can be grafted on silica particles access diazo compounds is via oxidation of the corresponding by exchanging one of the ligands of the rhodium catalyst with hydrazones. The oxidation can be carried out with insoluble a ligand bearing an alkyne functionality. The silica particle can MnO , or a solid-supported oxidant can be used, such as N- be connected with an azide-bearing silane, allowing covalent iodo-p-toluenesulfonamide potassium salt (PS-SO NIK). linking through the azide-alkyne click reaction with no appar- Using an excess of the supported oxidant PS-NIK (5 equiva- ent loss of selectivity (Scheme 2)[45]. lents), Davies et al. converted hydrazones to donor-acceptor The inside of the PTFE tube is coated with the fiber diazo compounds in flow for subsequent application in C − H containing the silica particles. As such, the liquid is functionalization reactions using enantioselective Rh(II) forced to flow through the fiber in an axial direction. catalysis. Application of the poly(amide-imide) material Torlon rep- Critical to the success of the transformation is the elimina- resents a notable improvement over the previous reported tion of water (which would result in the formation of O − H reactor design, also reported by the groups of Jones and insertion products) and the removal of trace iodine leaching Davies andappliedtoaC − H functionalization reaction from the oxidant column. By constructing a modular flow set- [46], making use of a radial flow through cellulose fibers, up consisting first of an oxidant column, followed by a col- which were incompatible with chlorinated solvents. This umn packed with 4 Å molecular sieves and sodium thiosul- was an important drawback, as this necessitated the use of fate, both water and iodine were removed from the reagent hydrocarbon solvents, e.g. hexane, which can undergo C stream giving access to a series of push-pull diazo − H insertion with carbenes, thereby functioning as an Scheme 1 Enantioselective C − H functionalization in flow through rhodium catalysis 16 J Flow Chem (2020) 10:13–71 4− The polyoxometalate decatungstate (W O ) is a useful 10 32 photocatalyst for the direct activation of hydridic C − Hbonds through hydrogen atom transfer (simultaneous abstraction of a proton and an electron). Upon irradiation with near-UV light (λ TBADT = 323 nm) it undergoes ligand-to-metal charge max transfer (LMCT), giving rise to a first excited state [W O 10 32 ]* with a lifetime of 30 ps. It decays into the second excited state known as wO, in which the bridging oxygen atoms of the cluster have partial radical character, with a lifetime of 55 ± 20 ns. The second excited state can be quenched through participation in both single-electron transfer (SET) or hydro- gen atom transfer (HAT) events [48]. Acting as electrophilic radicals, the bridging oxygen atoms of the cluster are able to engage in selective hydrogen atom transfer (HAT). Decatungstate is usually prepared as the sodium or tetrabutylammonium salt, the latter showing enhanced solu- bility in organic media (acetonitrile or DCM). Upon abstrac- Scheme 2 Silica-immobilized Rh (S-p-BrTCP) (S-p-TPCP) 2 3 tion of the hydrogen atom, the one electron-reduced form of + 5− the catalystisformed, H [W O ] , which has a deep blue 10 32 alkylating agent. Aditionally, the axial hollow-fiber design colour, as well as a carbon [49]or silicon-centered [50]radi- allows to drastically reduce the amount of chlorinated cal. The nucleophilic alkyl radicals thus formed can be trapped solvent necessary, reducing the environmental footprint with suitable electrophilic acceptors, e.g. electron-poor olefins of the reaction, while the turnover number (TON) was (Giese type reaction) or electron-poor (hetero)arenes (Minisci increased (Scheme 3 and 4). type reaction). After formation of the adduct, the resulting After 10 consecutive runs with the same immobilized radical reoxidizes and deprotonates the catalyst to close the catalyst to couple 4-methoxytoluene and hydrazone, the catalytic cycle. Several transformations involving the yield was only slightly lower, dropping from 74% to decatungstate catalyst in continuous-flow will be discussed 65%, while the enantioselectivity remained unchanged in this review, encompassing the C − H activation of alkane (89 to 86% ee). These results are comparable with the substrates, ethers and aldehydes for the direct alkylation, ac- results obtained for the homogeneous catalyst under ylation, fluorination and oxygenation, depending on the radi- batch conditions [47]. cals and the coupling partners involved. Scheme 3 Merger of the flow synthesis of diazo compounds and Rh catalyst immobilization to achieve enantioselective carbene C − Hinsertion J Flow Chem (2020) 10:13–71 17 Scheme 4 Catalytic cycle for decatungstate-catalyzed C − H alkylation Building on previous work on C − H alkylation through state of decatungstate. They can undergo coupling with decatungstate photcatalysis [51–57], Fagnoni et al. reported electron-poor olefinic partners (e.g. maleates, phenyl vinyl the alkylation of a series of electron-poor olefins under flow sulfone and diisopropyl azodicarboxylate, the latter allowing conditions by construction of a 50 ml mesoscale (i.d. 2.1 mm) the formation of C −Nbonds, Scheme 5)[58]. photoflow reactor consisting of a 500 W medium pressure Hg Zuo and co-workers were able to activate light (C -C ) 1 4 vapor lamp and FEP (fluorinated ethylene propylene) tubing, gaseous alkanes using cerium photocatalysis in flow. Their decreasing the required reaction time for the transformation strategy relies on the formation of Ce(IV) alkoxy com- from 6 to 2 h. Alkylating agents include simple cycloalkanes, plexes which undergo ligand-to-metal charge transfer cyclic ethers, e.g. oxetane, and 1,3-benzodioxole, which form (LMCT) under 400 nm irradiation, generating highly elec- nucleophilic alkyl radicals upon quenching of the wO excited trophilic alkoxy radicals (through homolytic fragmentation Scheme 5 Decatungstate catalyzed C − H alkylation of electron-poor olefins 18 J Flow Chem (2020) 10:13–71 Scheme 6 Catalytic cycle for the Minisci alkylation of azines through cerium photocatalysis of the cerium-oxygen bond) and Ce(III). The electrophilic cationic intermediate which rearomatises upon loss of a alkoxy radicals can then operate as HAT catalysts by proton, i.e. a Minisci reaction) rather than through reduc- abstracting hydridic hydrogens, such as those found in tion of the radical adduct to an anionic species (as in the methane and ethane, to form the corresponding nucleophil- case of addition of nucleophilic alkyl radicals to DBAD and ic alkyl radical (polarity matching-strategy). The alkyl rad- electron-poor olefins, the Giese reaction) which undergoes ical can be trapped for the alkylation of electron-poor ole- protonation to form the alkylated product. fins, heteroarenes and DBAD (N-di-Boc azadicarboxylate). All of the linear gaseous alkanes were successfully After addition, the radical adduct reoxidizes Ce(III) to employed in radical alkylation reactions of DBAD, electron- Ce(IV), though an external oxidant, (NH ) S O ,isre- poor olefins and azines. The alkylation of the Boc-protected 4 2 2 8 quired for the rearomatisation of azine substrates DBAD was performed in less than 15 min residence time, (Scheme 6). A plausible explanation for this is that they using both gaseous and liquid alkanes (cyclohexane), in a are functionalized through oxidation of the radical adduct glass microreactor with a volume of 4.5 ml and various alkane formed during the C–Cbondforming-step(resultingina pressures in the range of 400–1800 kPa (Scheme 7)[59]. Scheme 7 C − H functionalization of gaseous alkanes via cerium photocatalysis J Flow Chem (2020) 10:13–71 19 Scheme 8 C − H alkylation through Eosin Y HAT photocatalysis Eosin Y is a common organic photocatalyst in photoredox nucleophilic species, the substrate scope was explored with catalysis because the excited T state formed under visible electron-poor coupling partners. Malononitriles are electro- light irradiation (green light) acts as a one-electron transfer philic olefins and good coupling partners for nucleophilic rad- agent under basic conditions [60]. Recently, two new reactiv- icals (Scheme 8). A series of α,β-unsaturated compounds ity modes of excited state Eosin Y were reported [61]. Wang were tested, the reaction proving to be compatible with amide, and co-workers discovered that Eosin Y can act as a imide, nitro and sulfone functionalities. An interesting cou- photoacid, which allowed the synthesis of 2- pling partner for nucleophilic radicals is 2-vinylpyridine, pro- deoxyglucosides from glycals [62], while Wu and co- viding the hydroalkylated Giese product with THF as the rad- workers discovered Eosin Y can act as a direct hydrogen atom ical coupling partner in 60% yield. 2-vinylthiophene was also transfer (HAT) catalyst under neutral conditions. Under irra- supported in the transformation when the double bond bears diation with white light, the T state of Eosin Y is generated. the electron-withdrawing phenyl ketone moiety. Analogous to decatungstate (vide supra), as an oxygen- The reaction was adapted to flow to enable scale-up, al- centered radical it acts as an electrophilic HAT catalyst suc- though elevated temperatures (50–70 °C) were required with cessfully activating hydridic C − H bonds to create nucleophil- the alkyl coupling partner (THF, i-PrOH) serving as the sol- ic alkyl radicals. The scope of the transformation was explored vent. Further, a polar solvent which does not contain a in regard to the substrate undergoing HAT. Ethers, thioethers, hydridic hydrogen atom is required (t-BuOH was found to amides and alcohols were successfully activated at the α-po- be suitable in the Giese reaction of 2-ethyl-propen-3-one with sition. Acyl radicals could be generated from aldehydes (no- benzaldehyde). The mechanism of the reaction is particularly tably, 2-pyrrole carboxaldehyde was successfully activated) intriguing (Scheme 9), since earlier reports have demonstrated while alcohols undergo functionalization at the hydroxyl Eosin Y to be photoactive as an anion (either the anion or group-bearing carbon. As carbon-centered radicals are dianion) under basic conditions. Scheme 9 Catalytic cycle for the Eosin Y catalysed C − H alkylation via HAT 20 J Flow Chem (2020) 10:13–71 ox − · Several experiments were performed to elucidate the mech- (E (Cl /Cl ) = +2.03 V vs. SCE). Based on these principles, anism. Under irradiation with different wavelengths of light, the Wu and co-workers developed a photocatalytic strategy highest conversions (99%) were achieved with blue and white employing chlorine radical as the HAT catalyst in conjuction light, which corresponds to the absorption maximum of neutral with Mes-Acr as the oxidant. After excitation with 450 nm Eosin Y. The maximum of absorption of the anionic forms is light (blue LEDs), the excited state of Mes-Acr is quenched centred on longer wavelengths, i.e. green light, which in this by chloride delivered to the solution as molecular HCl, forming case resulted in lower conversion (75%). The luminescence of the chlorine radical. As an electrophilic radical species, it is able neutral excited state Eosin Y was not quenched by THF or to activate hydridic C − H bonds in a variety of substrates, e.g. phenyl vinyl sulfone, ruling out the operation of sensitization 3 °C-H and aldehydic C − H bonds, as well as the α C − Hbond or SET as the quenching mechanism. Additionally, cyclic volt- of alcohols, ethers and amides, while preferring a distal ammetry (CV) studies performed in acetone have shown Eosin functionalization in ketones. Y is neither able to oxidise THF nor reduce phenyl vinyl sul- Similar reactivities are observed with other electrophilic radi- fone. The transient intermediates involved in photochemical cal species discussed in this article, i.e. the second excited state of processes can be studied with laser flash photolysis, where the the decatungstate photocatalyst, wO, and oxygen radicals gener- sample is excited with a very short laser pulse (in this particular ated through fragmentation of a labile oxygen-metal bond (like case on the microsecond time scale) after which the absorption cerium, Zuo and co-workers, vide supra), although the selectivity properties and lifetimes of the excited states generated during of HAT depends on the species (polar and steric effects). The the flash can be measured. Moreover, it allows elucidation of nucleophilic alkyl radicals thus formed were trapped with the photochemical reaction pathways as the absorption of the ex- electron-poor olefin benzylidenemalononitrile (Scheme 10). cited states of transient species such as radicals will be Notable is the successful activation of the primary C − H bond quenched due to the shortening of their lifetimes if a suitable in ethane, which was then applied in a series of alkylation reac- reactant is present. After excitation of a THF solution of Eosin tions. Aside from benzylidenemalononitrile, unsaturated phenyl Y with a 470 nm laser, two intermediates were detected with sulfonesalsoprovedtobe suitableradical traps, settingthe stage lifetimes of 20.6 (absorbing at 329 nm) and 21 (absorbing at for C − H allylation reactions as the phenyl sulfone moiety easily 543 nm) μs, which the authors assigned to the T excited state undergoes elimination. of *Eosin Y. After decay of these intermediates, a new interme- The radical adduct formed after trapping of the nucleophil- diate with a lifetime of several milliseconds was detected, indi- ic alkyl radicals with an unsaturated species reoxidises the cating it could be the product formed after HAT to triplet Eosin reduced form of Mes-Acr , closing the catalytic cycle, Y, i.e. H–Eosin Y. Most importantly, the lifetime of this inter- forming a carbanion which is protonated by HCl to release mediate was shortened to 1 ms in the presence of phenyl vinyl chloride (Scheme 11). The cycle involving phenyl sulfones is sulfone which is required for the completion of the catalytic slightly different, as addition of the radical to the unsaturated cycle. Finally, DFT calculations show that two mechanisms moiety of the sulfone yields an olefin product and a sulfonyl could operate in the final step of the catalytic cycle. One is radical, the latter being the species re-oxidising the catalyst the reduction and protonation of the radical adduct by H– and deprotonating hydrochloric acid [67]. −1 Eosin Y (E =32.3 kcal mol ), or an additional THF molecule Due to the ease with which amines are oxidised, amines could be oxidised by the radical adduct, the anion of which then are common substrates in oxidative methodologies. After −1 deprotonates Eosin Y (E =19.9 kcal mol ). Although this initial oxidation of an amine to form an aminium radical, indicates the latter pathway to be more likely, on the basis of deprotonation by another equivalent of amine then leads to deuterium labelling studies direct proton – andelectrontransfer the formation of an α-amino radical, which is itself easily between the adduct and H–EosinYcouldnot be ruledout [63]. oxidised to an iminium ion. The oxidation of amines under An increasing amount of reports on dual catalytic strategies basic or neutral conditions generally yields α-amino radi- have appeared in the scientific literature during the last few cals, unless the reaction is kinetically favourable enough to years [64–66]. Most of these newly developed methodologies compete with this process, which was demonstrated ele- seek to combine the strengths of transition metal catalysis for gantly in a series of challenging photocatalytic cross-coupling reactions with the advantages offered by hydroamination methodologies developed by Knowles photoredox catalysis for the generation of reactive radical inter- and co-workers [68–70]. Additionally, amines are com- mediates, allowing an unprecedented amount of novel reactions monly used as sacrificial oxidants in reductive quenching to be developed to forge carbon-carbon bonds. Seminal contri- cycles of transition metal photocatalysts. The reactivity of butions to the field were made, inparticular,bythe groupof α-amino radicals in particular has been thoroughly ex- MacMillan. The excited state of the Fukuzumi catalyst, 9- plored, especially in the case of tetrahydroisoquinolines, mesityl-10-methylacridinium (Mes-Acr ) perchlorate, is a pow- in which the resulting α-amino radical is benzylic and rel- erful oxidant (excited state reduction potential of +2.06 eV), atively long-lived. As a consequence, many with the ability to oxidise the chloride ion to a chlorine radical functionalizations of this position have been reported J Flow Chem (2020) 10:13–71 21 Scheme 10 C − H functionalization of sp C − H bonds via Mes-Acr /HCl dual catalysis [71–75]. The properties of these radicals were exploited by an oxidative Ugi multicomponent reaction was developed the group of Rueping for the development of a series of combining N,N-dimethylanilines, isocyanides and water as photoredox catalytic cross-dehydrogenative coupling reaction partners giving access to α-amino amides. (CDC) reactions under flow conditions in which tertiary Although recirculation of the mixture proved necessary to aryl amines can be coupled with a variety of nucleophiles. obtain the α-amino amides in high yield, it represents a The organic dye Rose Bengal was identified as the most drastic improvement over batch conditions, e.g. N-butyl- suitable catalyst for the transformation, rendering the pro- 2-(methyl(phenyl)amino)acetamide was formed in 29% cess highly sustainable as H is formally the only waste yield after 3 days of reaction time in batch, whereas an product in a cross-dehydrogenative coupling reaction. A isolated yield of 60% was obtained in flow with recircula- series of substituted N-aryl tetrahydroisoquinolines under- tion after 20 h [77]. go C − H alkylation with nitroalkane and malonate cou- The introduction of fluorine-containing substituents in or- pling partners. Coupling with TMSCN produces α-amino ganic compounds is of great importance in the development of nitriles (yielding α-amino acids upon hydrolysis). pharmaceuticals, as the high electronegativity of fluorine can Phosphonylated products can be accessed through reaction be applied in the modulation of basicity, lipophilicity and bio- with diethyl phosphonate in 3–5 h residence time, availability, as well as increasing metabolic stability [78]. representing an improvement over batch procedures previ- Methods for fluorination and fluoroalkylation are thus contin- ously reported (Scheme 12)[76]. Following these insights, uously being developed. Scheme 11 Catalytic cycle of the Mes-Acr /HCl C − H functionalization 22 J Flow Chem (2020) 10:13–71 Scheme 12 Photoorganocatalysed oxidative CDC of tetrahydroisoquinolines with carbon and phosphorus nucleophiles A traditional approach to aromatic trifluoromethylation is trifluoromethyl radical. The resulting radical adduct is then the Swarts reaction, which is the substitution of a oxidised. Following deprotonation, the trifluoromethylated trichloromethyl group (formed after perchlorination of an ar- silyl enol ether then equilibrates to the ketone. Both the for- omatic methyl group) to trifluoromethyl with SbF .Modern mation of the silyl enol ether and the trifluoromethylation step approaches make use of electrophilic or nucleophilic occur in less than 20 min overall residence time. In these trifluoromethylating agents, such as Togni’s reagent or conditions, both the use of more expensive silylating agents, Umemoto’sreagent [79]. Radical trifluoromethylation strate- gaseous CF I and transition metal photocatalysts are avoided gies are particularly attractive as C − H functionalization reac- by employing Eosin Y as an environmentally benign and in- tions do not require prefunctionalized substrates [80, 81]. A expensive photoorganocatalyst [83]. number of trifluoromethylation methodologies have been de- From the viewpoint of atom economy, CF Iis anat- veloped under continuous-flow conditions, making use of dif- tractive trifluoromethyl source, forming only iodide as ferent kinds of trifluoromethylating agents, and will be waste product. Although perfluoroalkylation starting from discussed below. C-5 chains can be performed under homogeneous reaction Building on the work completed by the group of conditions as the perfluoroiodoalkanes become liquids at MacMillan on the α-trifluoromethylation of carbonyl com- ambient temperatures, CF I is a gaseous reagent, which is pounds with CF I and Ru photocatalysis [82], Kappe and cumbersome to handle under batch conditions, while gas- co-workers applied the liquid reagent triflyl chloride es can be conveniently handled under flow conditions (CF SO Cl) to the α-trifluoromethylation of ketones via a [84]. 3 2 two-step continuous-flow strategy (Scheme 13). A mixture Noël et al. developed a photocatalytic protocol for the of the organic photocatalyst Eosin Y, trimethyl silyl triflate trifluoromethylation and perfluoroalkylation of heteroarenes with (TMSOTf) and ketone is mixed with the base, N,N- CF I under continuous-flow with a [Ru(bpy) ]Cl photocatalyst 3 3 2 diisopropyl ethylamine (DIPEA) in a T-mixer allowing both and TMEDA (N,N,N′,N′-tetramethylethane-1,2-diamine) as the the formation of a silyl enol ether and deprotonation of Eosin base. The trifluoromethylation and perfluoroalkylation can be Y (2 min residence time), which is a pH sensitive performed in <1 h of reaction time (Scheme 14)[85]. The scope photocatalyst (basic conditions being required in its use as a of the transformation was expanded, and the organic dye Eosin Y single-electron reductant). Using a second T-mixer, triflyl also proved a viable photocatalyst for the transformation, provid- chloride (1.5 eq. in THF) is added to the reagent stream en ing a greener alternative to Ru photocatalysis [86]. Stern-Volmer route to the photoreactor consisting of FEP tubing coiled kinetics [87] show that the reaction occurs through a reductive around a glass beaker irradiated by a compact fluorescent light quenching cycle of the Ru photocatalyst (Scheme 15)[88]. bulb (CFL) placed inside the beaker. The unsaturated moiety After activation of the Ru(II) photocatalyst through irradi- of the silyl enol ether functions as a radical trap towards the ation with blue light, the excited state is quenched through J Flow Chem (2020) 10:13–71 23 Scheme 13 α-trifluoromethylation of ketones by Eosin Y photocatalysis SETwith TMEDAwhich serves as a sacrificial electron donor, challenging substrates in radical reactions due to their tenden- forming a Ru(I) species which can then reduce the cy towards polymerisation and oxidation. In fact, the low ox- trifluoromethyl iodide, generating the iodide ion and the idation potentials of styrenes allow their anti-Markovnikov trifluoromethyl radical. After addition of the trifluoromethyl functionalization with nucleophiles, an approach pioneered radical to the arene, the resulting adduct is thought to be by the group of Nicewicz [89 –96]. Radical oxidised by the radical cation of TMEDA and then undergoes trifluoromethylations of styrenes were reported requiring rearomatisation through the loss of a proton. electron-donating groups in the ortho position or β-substitu- Leaving the realm of Minisci-type reactions (i.e. the radical tion on the olefin tail [94, 97]. When the trifluoromethylation C − H functionalization of arenes), the conditions were is performed in the presence of the powerfully reducing adapted to the functionalization of styrenes, which are photocatalyst fac-Ir(ppy) , Stern-Volmer kinetics proved the Scheme 14 Photocatalytic trifluoromethylation in flow using CF I 3 24 J Flow Chem (2020) 10:13–71 Scheme 15 Catalytic cycle for the radical trifluoromethylation of heteroarenes with CF Iby 2+ [Ru(bpy) ] photocatalysis reaction occurs through an oxidative quenching cycle via and accelerating the reaction under flow conditions (24–72hin quenching of the excited state with CF I. The benzylic radical batch to 0.5 – 1 h in flow) allows the reaction to occur with high formed after anti-Markovnikov addition of the trifluoromethyl levels of stereocontrol. Indeed, longer reaction times were shown radical to the styrene substrate can be reoxidized by the Ir(IV) to lead to reduced levels of stereoselectivity (Scheme 17)[100]. species formed after oxidative quenching. Following depro- A non-photocatalytic approach to trifluoromethylation un- tonation of the benzylic cation by CsOAc, the olefin function- der flow conditions using CF I as the trifluoromethylating ality is restored (Scheme 16). agent was developed in the group of Kappe by employing Alternatively, if the reaction is performed in the presence of a Fenton-type conditions [101] (developed in the group of the hydrogen donor, the hydrotrifluoromethylated product is obtain- late Francesco Minisci) for the generation of alkyl radicals ed. Thiophenols in particular are frequently applied as hydrogen from alkyl iodides [102]. donors in radical hydrofunctionalization reactions. In this case, 4- By combining catalytic amount of iron(II)sulfate heptahydrate hydroxythiophenol proved optimal. A distinct advantage of and hydrogen peroxide as the oxidant (generally known as performing the transformation under continuous-flow is the fact Fenton’s reagent), the trifluoromethylation of heteroarenes can that the Ir(ppy) photocatalyst, which has a high triplet energy, be performed in a residence time of just a few seconds promotes olefin isomerisation via sensitization of the olefin (Scheme 18). The use of DMSO as solvent is key to the success (triplet-triplet energy transfer, TTET) [98]. As a diradical, the of the transformation, as this allows the reaction to be performed T state of the olefin can undergo rotation leading to the forma- in a more reliable and reproducible way. Fe(II) reduces hydrogen tion of the (Z)-isomer [99]. Due to its higher thermodynamic peroxide, forming Fe(III), a hydroxyl anion and a very reactive stability, the (E)-isomer is thought to be kinetically favoured, hydroxyl radical, the latter which forms an adduct with DMSO. Scheme 16 Catalytic cycle for the trifluoromethylation of styrenes through oxidative quenching of fac-Ir(ppy) with CF I 3 J Flow Chem (2020) 10:13–71 25 Scheme 17 Radical trifluoromethylation of styrenes with CF I through Ir photocatalysis After expelling methylsulfinic acid, a highly reactive meth- the trifluoromethylated analog of dihydroergotamine shows yl radical is formed which then undergoes a thermodynami- promise as a cheap anti-migraine agent with reduced side ef- cally favourable halogen atom transfer reaction with the fects, and is thus an interesting target for the scope of radical perfluoroalkyl iodide present. This leads to the formation of trifluoromethylation methodologies [107]. Due to the short methyl iodide and the comparatively stable perfluoroalkyl rad- residence time of less than 10 s, an impressive amount of ical. After addition to the arene, the resulting adduct is 600 g of dihydroergotamine mesylate could be processed in reoxidized by Fe(III) to form Fe(II) and a cation, which forms 5 h with 98% conversion and a selectivity of 85–86% the desired product after loss of a proton (Scheme 19). (Scheme 20)[108]. As a readily available and low-cost chem- The reaction shows excellent scalability, as shown by the ical reagent, trifluoroacetic acid (TFA) would be an attractive trifluoromethylation of the pharmaceutically relevant anti- source of the trifluoromethyl radical. Although the oxidation migraine agent, dihydroergotamine. It is a semi-synthetic de- of TFA has been reported to generate trifluoromethyl radicals rivative of ergotamine, a natural product found in the ergot rye by electrochemical means, harsh conditions are required due fungus, Claviceps purpurea [103, 104]. Due to nausea being a to the high oxidation potential of TFA, which drastically limits common side effect, dihydroergotamine treatment is being the scope of these methodologies. Hence, trifluoromethylation superseded by application of the more selective via an oxidative decarboxylation approach commonly follow- sulfonamide-bearing tryptamines, known as the triptan drugs, ed in photoredox catalysis [109] to generate alkyl radicals is of which sumatriptan is a prominent example, which also have impractical in the case of TFA. By installing a redox auxiliary a higher cost associated with their use [105, 106]. However, group, Stephenson and co-workers managed to bring the Scheme 18 Fe-catalyzed trifluoromethylation – and perfluoroalkylation of arenes with CF I 3 26 J Flow Chem (2020) 10:13–71 Scheme 19 Catalytic cycle for the Fe-catalyzed trilfluoromethylation with CF I oxidation potential of TFA within the electrochemical poten- excited state of the Ru photocatalyst is quenched by the 2+ tial range of [Ru(bpy) ] . The redox auxiliary approach relies trifluoroacetoxy pyridinium adduct, delivering the in this case on the reaction between pyridine N-oxide and trifluoroacetate radical, forming the trifluoromethyl radical trifluoroacetic anhydride (TFAA), forming an adduct in which upon decarboxylation (Scheme 21). the weak N-O bond can be cleaved reductively. Stern-Volmer As is common for photochemical transformations, the re- kinetics point to an oxidative quenching cycle in which the action showed limited scalability in batch. When scaling up Scheme 20 Scale-up of the Fe(II)/CF I/H O radical trifluoromethylation for the production of a trifluoromethylated ergotamine derivative on 600 g 3 2 2 scale J Flow Chem (2020) 10:13–71 27 Scheme 21 Radical trifluoromethylation with TFAA/pyridine N-oxide via Ru photocatalysis the trifluoromethylation of N-Boc pyrrole to 100 g scale, the presented, opening up another possibility for the fragmentation product was obtained in a modest yield of 35% after a reaction of the trifluoroacetylated pyridines, although this is limited to a time of 62 h. few specific cases, e.g. mesitylene [117]. As discussed previously, one of the main advantages of flow Sodium trifluoromethanesulfinate (CF SO Na), common- 3 2 photochemistry is its inherent scalability [110–115]. ly known as the Langlois reagent, has found wide application Performing the reaction under flow conditions yielded 71% of in radical trifluoromethylation reactions, including in the the trifluoromethylated N-Boc pyrrole (20 g scale, 10 min Minisci-type functionalization of heteroarenes [118–122]. residence time, Scheme 22), compared to 57% yield on 20 g Multiple equivalents of an external oxidant, such as t- scale in batch (15 h reaction time) [116]. A later report elabo- BuOOH, are usually required to oxidise the sulfinate and ef- rating on the mechanistic aspects of the reaction includes scale- fect SO extrusion to form the trifluoromethyl radical up of the trifluoromethylation of an N-Boc protected pyrrole [123–125]. As a bench-stable solid, it is one of the most con- bearing a methyl ester functionality to 1 kg scale (V =150 mL), venient to handle trifluoromethylation agents [119]. Long re- −1 in which a productivity of 20 g h was achieved. Additionally, action times and multiple additions of the sulfinate salt are evidence for the formation of EDA (electron donor-acceptor) usually required. The conditions originally reported by complexes between the pyridine-N-oxide and arenes is Langlois and co-workers make use of a Cu(I) additive to Scheme 22 Radical trifluoromethylation with TFAA/pyridine N-oxide via Ru photocatalysis 28 J Flow Chem (2020) 10:13–71 Scheme 23 Trifluoromethylation of coumarins by Duan et al promote cleavage of the peroxide bond, which initiates the oxidation of the sulfinate by the T state of 4,4′- reaction. Duan et al. adapted the conditions of the original dimethoxybenzophenone forming the trifluoromethyl radical Langlois trifluoromethylation reaction to continuous-flow (vide supra) and a ketyl radical which deprotonates the acidic (60 °C, 40 min residence time) to generate a library of HFIP. The radical adduct formed after addition of the trifluoromethyl-substituted coumarins (Scheme 23)[126]. trifluoromethyl radical to the double bond of the maleimide is Rueping and co-workers applied the Langlois reagent to then proposed to abstract a hydrogen atom from the alcohol, the hydrotrifluoromethylation of maleimides (representing resulting in the hydrotrifluoromethylation of the olefin and electron-poor olefins) and heteroarenes with 4,4′- regenerating the ketone functionality of the catalyst closing dimethoxybenzophenone as an organic HAT catalyst under the catalytic cycle (Scheme 25). The strongly oxidising iridium near-UV irradiation (350 nm) (Scheme 24). photocatalyst [Ir(dF(CF )ppy) ](dtbpy)]PF was also found to 3 2 6 The reaction requires the presence of hexafluoroisopropanol be a suitable visible light photocatalyst for this transformation, (HFIP) as an additive, a reaction medium with high polarity improving the yields under similar reaction conditions [130]. known to stabilize polar intermediates such as radicals Through application of the luminescence screening ap- [127–129]. The authors propose a mechanism based on the proach developed in the group of Glorius [131], Noël, Scheme 24 Photoorganocatalytic trifluoromethylation of maleimides and arenes J Flow Chem (2020) 10:13–71 29 Scheme 25 Catalytic cycle for radical trifluoromethylation with CF SO Na under benzophenone 3 2 catalysis Alcaza r a n d co-workers confirmed t he cycle, forming bromide ion and the malonyl radical [133, 134]. [Ir(dF(CF )ppy) ](dtbpy)]PF photocatalyst is quenched effi- The transformation was also reported using organic photoredox 3 2 6 ciently by the Langlois reagent. On the basis of these findings, catalysts (e.g., Th-BT-Th) [135]. By calculating the spectro- a continuous-flow trifluoromethylation of highly functional- scopic properties and reduction potentials with DFT at the ized heteroarenes was developed. Although the reaction pro- M06-2X / 6-31G+(d) level of theory using the continuum sol- ceeds in 30 min of residence time, 1 equivalent of an external vation model PCM, a series of alkynylated bithiophenes were oxidant, (NH ) S O , is required for the reaction to occur in synthesized for their evaluation as potential photocatalysts by 4 2 2 8 synthetically useful yields, since two consecutive oxidations Alcazar, Noël and co-workers, the alkynes functionalized with are required (Scheme 26)[132]. phenyl substituents bearing both electron-releasing and Stephenson and co-workers reported the alkylation of electron-withdrawing groups. To benchmark their performance, 2+ heteroarenes by quenching of excited state [Ru(bpy) ] by the thiophene photocatalysts were applied in the C −Halkyl- bromomalonate through an oxidative Ru(III)/Ru(II) quenching ation of heteroarenes with bromomalonate and Ph Nas the Scheme 26 Trifluoromethylation of heteroarenes with CF SO Na 3 2 via Ir photocatalysis 30 J Flow Chem (2020) 10:13–71 2+ base, proving viable alternatives to [Ru(bpy) ] .Five- Ravelli and co-workers trapped the acyl radicals with phe- membered heterocycles such as pyrrole, thiophene and furan nyl vinyl sulfone under flow conditions to form the derivatives can be alkylated with 1 mol% of the photocatalyst hydroacylated product. Using a modular set-up, the sulfonyl (PC) through irradiation with purple LEDs (400 nm), as well as moiety can be removed in a second flow module with base benzofurans and indole derivatives, including N-Boc-Trp-OMe (tetramethylguanidine, TMG or triazabicyclododecene (55% isolated yield, Scheme 27). The alkylation of 3- supported on polystyrene, TBD-PS) to form an α,β-unsatu- methylindole was performed in continuous flow and afforded rated ketone, which can then undergo conjugate addition. This the alkylated product in 70% yield in 7 min residence time. The was applied to the synthesis of γ-nitroketones and β-(3- catalysts were also applied to other C − H alkylations of indolyl)ketones with nitroalkanes and indole as nucleophiles, heteroarenes, ie. trifluoromethylation (with CF Iand respectively. Starting from O-Boc protected salicylaldehyde TMEDA, 20 min residence time, 450 nm LEDs) and followed by acylation of phenyl vinyl sulfone, both the sulfo- difluoromethylation (using BrCF CO Et as the reagent) [136]. nyl and the carbonate protecting group are cleaved under basic 2 2 conditions, after which the product undergoes an intramolec- ular cyclization to afford chromanone (35% overall yield, C − Hacylation Scheme 29)[140]. In contrast to the C-3 formation of β-(3-indolyl)ketones ac- Aldehydes are excellent hydrogen atom donors in decatungstate complished through decatungstate photocatalysis, the C-2 acyla- HAT photocatalysis [137, 138]. By irradiation with near UV light tion of indoles to yield α-(2-indolyl)ketones in flow via a dual (λ TBADT = 323 nm), acyl radicals are formed via HAT with max catalytic cycle with Pd and Ir involving acyl radicals at room the decatungstate catalyst (we refer to Scheme 4 for the catalytic temperature was reported by Noël, Van der Eycken, and co- cycle, R = acyl radical) (Scheme 28). workers. The acyl radicals are formed from aldehydes through Fagnoni and co-workers used α,β-unsaturated esters as HAT with the tert-butoxyl radical. The tert-butoxyl radical is radical traps to form γ-ketoesters. The reaction was performed formed by engaging t-BuOOH in an oxidative Ir(III)/Ir(IV) in 2 h of residence time in a photoflow reactor constructed quenching cycle with the iridium photocatalyst (i.e. photocata- from PTFE tubing (12 ml reactor volume), a medium pressure lytic Fenton initiation). Pd(OAc) activates the C-2 position of Hg lamp and a HPLC pump. By introducing a second reagent 2 the indole assisted by a pyrimidine directing group and is hy- stream containing 0.4 M of NaBH in EtOH as a reductant to pothesized to react with the acyl radical to form an acylated the product stream exiting the photoflow reactor, the ketone Pd(III) species, which is oxidised by Ir(IV) to a Pd(IV) species, functionality is reduced to an alcohol and undergoes intramo- closing the photocatalytic cycle. Upon reductive elimination, the lecular cyclisation to form a γ-lactone product, e.g. the lactone C-2 acylated product is formed and the Pd(II) center is regener- condensation product obtained from heptan-2-one and diethyl maleiate is formed in a 65% overall yield [139]. ated, closing the “dark” catalytic cycle (Scheme 30). Scheme 27 C − H alkylation of heteroarenes with bithiophene photocatalysts J Flow Chem (2020) 10:13–71 31 Scheme 28 Flow synthesis of γ-lactones via decatungstate photocatalyzed C-H acylation followed by reductive intramolecular cyclization A range of aromatic, heteroaromatic (including furfural, a C − Hcarboxylation andC − H cyanation biomass-derived feedstock) and aliphatic aldehydes undergo ac- ylation with several substituents being tolerated on the indole The selective activation of carbon dioxide has long stood as one ring, although the absence of a directing group (e.g. pym, py) of the holy grails of chemistry [142–145]. The reduction of CO was not tolerated (Scheme 31). By performing the reaction in using the organic photoredox catalyst p-terphenylene under UV continuous flow, both the catalytic loadings and the reaction time irradiation was achieved by Jamison and co-workers and ap- couldbedecreased (20min residencetimeinflowfrom20h plied to the synthesis of amino acids in flow (Scheme 32). The under batch conditions) improving the sustainability of the pro- synthesis occurs through radical-radical coupling of the carbon cess [141]. dioxide radical anion with a benzylic α-amino radical, which is Scheme 29 Decatungstate-catalyzed hydroacylation of phenyl vinyl sulfone followed by derivatization through elimination and conjugate addition 32 J Flow Chem (2020) 10:13–71 Scheme 30 C-2 acylation of indoles via Ir/Pd dual catalysis formed from the single-electron oxidation and deprotonation of an α-amino radical upon deprotonation by the base potassium a benzylic amine in a segmented flow regime, compellingly trifluoroacetate (CF CO K). The radical anion of the 3 2 combining the advantages of flow chemistry in gas-liquid and photocatalyst is then able to reduce CO ,closing thecatalytic photochemical transformations. To increase the selectivity of cycle, while the resulting carboxylate is formed by radical- the reaction, a UV filter was applied with a cut-off at 280 nm radical coupling with the stabilized (and hence, somewhat (λ p-terphenylene = 283 nm) (Scheme 33). persistent) α-amino benzylic radical [146]. max Stern-Volmer kinetics show the S excited state of p- Using magnetite (Fe O ) nanoparticles as a heterogeneous 1 3 4 terphenylene is quenched by the amine, forming the radical catalyst, Varna et al. were able to activate the methyl group of a anion of p-terphenylene and an aminium radical, which forms series of N,N-dimethylanilines in an oxidative cyanation reaction Scheme 31 Room temperature C-2 acylation of indoles through Pd/Ir dual catalysis J Flow Chem (2020) 10:13–71 33 Scheme 32 Coupling of CO with benzylic α-amino radicals by UV photooorganocatalysis with H O and NaCN in aqueous methanol (1:1) as the solvent. to an iminium ion, which reacts with HCN to form the α- 2 2 The reaction is performed in a stainless steel microreactor with a aminonitrile product (Scheme 34)[147]. reactor volume of 5 ml and i.d. of 0.8 mm. The coil was submerged in an oil bath to keep the reactor at a C − H alkenylation temperature of 50 °C allowing a series of N-methylanilines to be monocyanated in less than 10 min residence time (Scheme The Fujiwara-Moritani reaction or oxidative Heck reaction rep- 35). After exiting the reactor, the nanoferrites can be separated resents one of the earliest examples of Pd-catalysed C −Hac- conveniently from the product stream with a magnet. The tivation [148, 149]. In contrast to the Mizoroki-Heck reaction, mechanism suggested by the authors occurs through the forma- in which prefunctionalization of the vinyl or arene coupling tion of an Fe(IV) oxo-species from Fe(II) through oxidation partner is required to allow oxidative addition to Pd(0) to occur, with hydrogen peroxide. The Fe(IV) species oxidises the amine the Fujiwara-Moritani reaction starts from Pd(II). While the Scheme 33 Catalytic cycle for the carboxylation of α-amino radicals by terphenylene photocatalysis 34 J Flow Chem (2020) 10:13–71 Scheme 34 Oxidative α- cyanation of N-methylanilines catalyzed by Fe O 3 4 production of stoichiometric amounts of halide waste can be gases in continuous flow offers a number of distinct advan- avoided by employing diazonium salts as the coupling partners tages including precise control of pressure and flow rate (i.e., in the Heck-Matsuda reaction, the Fujiwara-Moritani reaction the stoichiometry of the gaseous reagents) [152, 153]. as a cross-dehydrogenative coupling reaction represents a more Moreover, the establishment of a segmented flow regime pro- atom-economical approach [150]. vides a high gas-liquid interfacial area and assists in Because of its higher reactivity, Pd(II) is frequently used as preventing precipitation of Pd . Due to better heat dissipation, the catalyst in combination with an external oxidant to close the reaction can be run at higher temperatures without catalyst the catalytic cycle and prevent the formation of Pd(0) parti- degradation. Using Pd(OAc) in combination with TFA and cles. The reactions are performed in the presence of acid, as O as the oxidant, these principles were applied for the devel- they are able to coordinate to the Pd(II) center, rendering it opment of a C-3 vinylation of indoles, yielding alkenylated more electron-poor, which favours the C-H activation step and indoles in a residence time of 10–20 min (Scheme 37)[154]. allows for the deprotonation of the targeted C-H bond A variant of the Fujiwara-Moritani reaction allowing the (Scheme 36)[151]. ortho-functionalization of acetanilides with Pd/C as a reusable From an environmental point of view, one of the attractive heterogeneous catalyst and benzoquinone as an external oxi- aspects of the Fujiwara-Moritani reaction is the possibility to dant in the presence of TsOH as the acid was reported by the use oxygen as an external oxidant. The use of oxygen in batch group of Vaccaro making use of the acetamide directing group. processes can be hazardous and is limited in its efficiency due The use of a green solvent derived from lignocellulosic bio- to the poor solubility of oxygen in organic media. The use of mass, γ-valerolactone (GVL), is notable, as it is both a less toxic Scheme 35 Oxidative cyanation of N-methylanilines J Flow Chem (2020) 10:13–71 35 Scheme 36 Catalytic cycle for the Fujiwara-Moritani reaction and more sustainable alternative to traditional polar aprotic sol- Combining Brønsted acid catalysis and C − H activation vents, e.g. DMF. Although leaching is a requirement for the with Mn(I), Ackermann and co-workers performed a C − H reaction to occur with Pd(II) as the active catalytic species, alkenylation of indoles, thiophenes, pyrroles, tryptophans and Pd(0) formed at the end of the catalytic cycle is hypothesized pyridones through the use of a pyridine directing group. The to be redeposited on the support, overall resulting in minimal alkene functionality is furnished by the hydroarylation of an amounts of palladium leaching (4 ppm). Apart from this, alkyne bearing a carbonate leaving group. leaching is also decreased when using GVL compared to DMF The carbonate is left untouched, in contrast to previous re- or NMP. Under batch conditions, the catalyst can be reused for ports where hydroarylation occurred with β-elimination. Using five runs with little decrease of performance. Performing the a cheap and air-stable manganese carbonyl catalyst, reaction in a continuous-flow packed bed reactor allows scaling MnBr(CO) , allylic carbonates and ethers can be synthesized −1 up the reaction to a productivity of 4 g h (Scheme 38)[155]. from alkynes bearing these functionalities through C − H Scheme 37 Fujiwara-Moritani C-3 vinylation of indoles with O as oxidant 2 36 J Flow Chem (2020) 10:13–71 Scheme 38 Fujiwara-Moritani alkenylation of acetanilides activation of the heterocyclic ring directed by pyridine. The clogging and accelerate the reaction [157]. Starting from func- reaction is accelerated under flow conditions, from 16 h in batch tionalized phenyl ethers and N-functionalized indoles, the meth- to 1–20 min residence time in flow, which can be coupled with od allows the construction of polycyclic ether systems and fused an in-line catalyst separation. The scalability of the method was indolines (Scheme 40)[158]. demonstrated by the production of 2.24 g of the alkenylated Mihovilovic and co-workers reported the first intermolec- product using indole as the coupling partner in 1 h ular C − H activation process under continuous-flow condi- (Scheme 39)[156]. tions. Starting from aryl bromides and aryl boronic acids, they performed the Suzuki-Miyaura reaction in flow using Pd(PPh ) catalyst and K CO as the base allowing for the C − H arylation 3 4 2 3 synthesis of 2-phenylpyridines in 20 min residence time. Notably, they found the reaction was sensitive to the material Li and co-workers reported a direct intramolecular C − H of the flow reactor coil used, with PFA performing better than arylation of aryl bromides using Pd(OAc) under ultrasonication stainless steel. With pyridine acting as the directing group, the without requiring the presence of any additional ligands. By ortho-position to the pyridyl substituent in 2-phenylpyridine immersing the coil in an ultrasonic cleaning bath, as in this case, can be selectively targeted for C − H activation in a second ultrasound irradiation can be applied to prevent microreactor Scheme 39 Alkenylation of heterocycles through pyridine-directed Mn-catalysed C − H activation J Flow Chem (2020) 10:13–71 37 Scheme 40 Intermolecular ligand-free C − H arylation under ultrasound irradiation in flow step using dichloro(p-cymene)ruthenium(II) as the and para positions (i.e. the more traditional electrophilic aro- precatalyst, PPh and DBU as the base under an atmosphere matic substitution reactions) of the arene moiety [166]. For of air allowing the synthesis of bis – or trisarylated products in this transformation, diaryliodonium salts, a class of 1 h residence time (Scheme 41)[159]. hypervalent iodine compounds, are used concomitantly as Another class of cross-dehydrogenative coupling arylating agents and for the oxidation of Cu(I) to Cu(III). (CDC) reaction in which two unfunctionalized aryl rings Mechanistic studies indicate the first step is an oxidative ad- are coupled via C − H activation under aerobic oxidation dition to copper followed by a C − H activation step in which was extensively investigated by Stahl and co-workers deprotonation of the adduct by triflate occurs. Reductive elim- [160–162]. The coupling of o-xylene, specifically, holds ination forges the aryl-aryl bond to yield the meta-functional- promise in the preparation of monomers used in the pro- ized amide and regenerates Cu(I) (Scheme 44). duction of the polyimide resin Upilex [163]and metal- Although diaryliodonium salts are now commonly used organic frameworks [164]. as arylating reagents [167], their synthesis requires both Mechanistically, two separate Pd(II) metal centers allow the use of the superacid TfOH and m-CPBA as an oxi- the C − H activation of two xylene molecules, followed by a dant, rendering the transformation highly exothermic and transmetalation step leading to a single Pd(II) center with two potentially hazardous. For these reasons, Noël and co- arene ligands. Upon reductive elimination, the biphenyl moi- workers developed a continuous-flow synthesis of ety and Pd(0) are formed, which is then reoxidized with O diaryliodonium triflates. As mentioned earlier, heat trans- (Scheme 42). Although the reaction shows remarkable selec- fer to the environment is more efficient and the active tivity for the desired product, it is limited by low yields (8%) volume of reactants reacting in a microreactor is typically and the requirement for long reaction times. very small greatly decreasing the potential explosive haz- Noël and co-workers increased the yield of the ard of the reaction. By submerging the reactor coil into an homocoupled product to 41% (60% selectivity) by applying ultrasonic bath, clogging of the microreactor is prevented. 40 bar of O pressure in a stainless steel capillary microreactor A variety of diaryliodonium triflates were synthesized on requiring a reaction time of 40 min, compared to 17 h under a gram-scale in a residence time of a few seconds [168]. batch conditions (Scheme 43)[165]. Apart from the availability of diaryliodonium salts, the The meta-selective arylation of anilines under copper ca- synthesis of meta-arylated anilines makes use of amides talysis was reported by Phipps and Gaunt, offering an orthog- as protected amines, resulting in the necessity of a onal approach to functionalizations of arenes targeting mainly deprotection step. For pharmaceutical production, Cu the ortho positions (as in many palladium-catalyzed C − H levels are required to be below a threshold of 25 ppm, activation methodologies making use of a directing group) – requiring the removal of copper. The different steps were 38 J Flow Chem (2020) 10:13–71 Scheme 41 Ortho C − H arylation of pyridines with aryl bromides under continuous-fllow conditions integrated in a modular flow set-up by Noël and co- to the initially reported copper(II)triflate. Copper leaching workers using a copper tubular flow reactor (CTFR) for from the coil can be removed from the mixture by a the arylation reaction, where copper leaching from the membrane separator in a continuous liquid-liquid extrac- reactor walls acts as a catalyst for the transformation, tion with aqueous NH . Finally, the resulting pivalanilides based on the initial observation that the reaction was ac- can be deprotected in continuous flow with a 1:1 mixture celerated with powdered copper as the catalyst, compared of HCl:1,4-dioxane. Due to the modularity of the process, Scheme 42 Catalytic cycle for the CDC of o-xylene J Flow Chem (2020) 10:13–71 39 Scheme 43 o-Xylene coupling under flow conditions the meta-arylated anilines can be obtained in <1 h without moiety and the metal center, bringing the Pd(II) in proxim- the necessity of chromatographic separation, reducing itytothe ortho C − H bond, which is then softly downstream processing (Scheme 45)[169]. deprotonated to form a palladacycle intermediate. A second During the last decade, many reports on C − H activa- oxidative addition to the palladacycle occurs, bringing pal- tion processes using transient directing groups as a strat- ladium to its tetravalent oxidation state. After reductive egy to selectively target C − H bonds have appeared in the elimination, the ortho position to the original site of the scientific literature [170–172]. A notable transient oxidative addition has been selectively functionalized. directing group is the bicyclic olefin norbornene This is followed by norbornene extrusion. Although [173–175]. Catellani and co-workers first reported the norbornene, in principle, acts as an organocatalyst, stoi- use of norbornene and Pd(II) for an ortho di – or chiometric amounts are necessary for the reaction to occur trifunctionalization of aryl iodides in 1997 [176]. at a reasonable rate [177]. The resulting ArPd(II)X species Starting from Pd(0), an oxidative addition of the aryl can then undergo further functionalization (e.g. through an- iodide occurs. This is followed by a carbopalladation step, other cross-coupling cycle), with many possibilities having inserting norbornene via its double bond between the arene been reported [178–182]. This brings the catalytic Pd Scheme 44 Catalytic cycle for the Cu-catalyzed meta-arylation of anilines 40 J Flow Chem (2020) 10:13–71 Scheme 45 meta-Arylation of anilines employed in a modular flow set-up species back to its original zerovalent oxidation state and termination pathway is the Heck reaction. In this case, com- closes the catalytic cycle (Scheme 46). A common petition between coupling of the desired olefin and Scheme 46 Catalytic cycle for the Catellani reaction with termination via a Heck pathway J Flow Chem (2020) 10:13–71 41 norbornene is a known issue which can be addressed by Grignard reagent. After ligand exchange, Mn(II) undergoes a controlling the stoichiometry of the olefinic reagents. In single-electron oxidation to Mn(III) which is arylated by the principle, the transformation can also be performed using Grignard reagent in a transmetalation step. Reductive elimi- gaseous olefins. nation from Mn(III) forges the C-C bond, generating Mn(I). Due to the difficulties arising from the volatility of The external oxidant DCIB (1,2-dichloro-2-methylpropane), norbornene and poor control of the stoichiometry of the gas- is required to form the Mn(III) species and close the catalytic eous reagents, these transformations can be challenging to cycle, reoxidising Mn(I) to Mn(II). perform under batch conditions, in particular when attempting Using this methodology, both azines and diazines can be to perform the reaction using two distinct arene coupling part- arylated with arenes, thiophene and the sterically hindered ners. In the first report on gas-liquid Catellani reactions, Noël, mesityl moiety. Avariety of substituents on the amide nitrogen Della Ca′ and co-workers reported an increase in selectivity were also tolerated. The reaction can be performed in flow in for a heterocoupling from 12% yield in batch to 66% under 100 min compared to 16 h under batch conditions, which can −1 flow conditions, due to the accurate control over the stoichi- be scaled-up with a productivity of 1.12 g h (Scheme 48). ometry of the gaseous reagents and the high gas-to-liquid The Pd-catalyzed intermolecular C − H activation of the mass transfer under flow conditions (Scheme 47)[183]. C-5 position in 1,2,3-triazoles to give arylated products with C − H activation chemistry employing Earth-abundant aryl halides as the coupling partners was reported in 2016 by metals such as Ni, Mn and Co is becoming more common- Vaccaro and Ackermann, using the green solvent γ- place as alternatives are sought to the precious metals tradi- valerolactone (GVL) and palladium on charcoal (Pd/C) as a tionally employed in C − H activation catalysis [184]. heterogeneous catalyst [185]. The methodology was also Ackermann and co-workers reported the ortho C − Harylation adapted to flow conditions, mainly for the intramolecular C of substituted azines with an amide directing group under − H arylation to yield triazole-fused chromanes and triazole- continuous-flow conditions with MnCl salt combined with fused isoindolines. As in their report on a Fujiwara-Moritani a neocuproine ligand, a Grignard species as the arylating agent reaction in flow (vide supra), Pd/C was immobilized in a flow (Kumada-type coupling), TMEDA as the base and DCIB as reactor and combined with GVL resulting in minimal amounts an oxidant. of leaching, making the transformation highly sustainable. After forming the complex and coordination of Mn(II) by Starting from Pd(0), oxidative addition to the aryl halide the amide functionality, the Grignard reagent undergoes occurs, followedbythe C − H activation of the triazole transmetalation. The amide directing group brings the metal through deprotonation. Reductive elimination then delivers center in proximity of the ortho C − H bond for the C − H the final product (Scheme 49). As well as intramolecular cy- activation step occurring through deprotonation with the clization products, intermolecular C − H arylation with aryl Scheme 47 Continuous-flow Catellani reaction employing gaseous olefin partners 42 J Flow Chem (2020) 10:13–71 Scheme 48 Mn-catalyzed C − H arylation of azines with Grignard reagents bromides is also possible under these conditions. The reaction oxidant for the oxidative cyclization of diaryl – and was scaled to 100 mmol scale under flow conditions, yielding triarylamines to form carbazoles (Scheme 51). 24 g of product after 44 h, corresponding to a productivity of Surprisingly, the copper catalyst was found to outper- −1 2+ 0.55 g h (Scheme 50). form Ru(bpy) , however, a reaction time of 14 days was Several reports have been published on the application of required to obtain the N-phenylcarbazole in 85% yield. For copper complexes as photoredox catalysts for C − H this reason, a flow set-up was constructed allowing the functionalization reactions [186]. reaction to be performed in a residence time of 20 h. The Collins et al. applied the in situ formed copper photoredox authors propose a mechanism based on the oxidative catalyst [Cu(Xantphos)(dmp)]BF in conjunction with I as an quenching of the Cu(I) catalyst by molecular iodine. The 4 2 Scheme 49 Pd-catalyzed cross coupling via C − H activation in 1,2,3-triazoles J Flow Chem (2020) 10:13–71 43 Scheme 50 C-H activation with Pd/C of 1,2,3-triazoles functionalized with aryl halides in γ-valerolactone Cu(II) species then formed oxidises the carbazole which 190]. Due to the relatively small band gap of semiconductor allows the cyclization to occur through homolytic aromatic materials, electrons can be excited from the valence band to substitution. After oxidation, the aromaticity of the carba- the conduction band, creating an electron-hole pair, in which zole is restored (Scheme 52)[187]. the electron can effect one-electron reduction, and the hole can In the Meerwein-type C − H arylation reaction, aryl diazo- act as a one-electron oxidant [191]. For this reason, TiO is nium salts are used to generate aryl radicals via one-electron frequently used for the oxidative solar decontamination of reduction [188]. Several photocatalytic variants of this reac- waste water [192]. As an abundant, non-toxic and heteroge- tion have been developed for selective C − H arylation, in- neous photocatalyst, it is a very attractive material for sustain- cluding the use of the inorganic photocatalyst TiO able chemistry [193], the downside being the band gap of (Scheme 53). unmodified TiO is too large for the creation of electrons The behaviour of semiconductor nanoparticles as and holes through visible light irradiation. This problem is photocatalysts is well-described, representing one of the ear- generally solved through the use of modified TiO [194], liest and most important examples of photocatalysis [189, e.g. employing Pt and Pd as co-catalysts, bringing the Scheme 51 Copper-catalyzed synthesis of carbazoles 44 J Flow Chem (2020) 10:13–71 Scheme 52 Proposed cycle for the copper-catalyzed intramolecular arylation to form carbazoles absorption of the material from the ultraviolet into the visible pyridine, thiophene and furfural with a range of aryl diazoni- range through the creation of intra-bandgap states in which the um salts (Scheme 54)[196]. size of the electronic transitions fall within the energetic range The group of Ackermann used another 3d earth-abundant of visible light [195]. Rueping et al. have shown that the metal, manganese, to perform a visible light-photocatalyzed combination of TiO with aryl diazonium salts results in the C − H arylation of heteroarenes with diazonium salts under formation of a TiO azoether with a strong absorption at flow conditions. Inexpensive CpMn(CO) proved to be the 2 3 450 nm (corresponding to the blue part of the visible spec- most effective catalyst for the transformation. trum) to create aryl radicals. To allow the use of heterogeneous On the basis of mechanistic studies, the authors suggest a titania in flow, a falling film microreactor (FFMR) was con- radical mechanism starting with the exchange of one CO ligand structed by Rehm, Rueping and co-workers. An open stainless for the arene substrate, followed by coordination of the aryl dia- steel flow cartridge, equipped with a quartz window, is coated zonium salt to the Mn(I) center. After irradiation with blue light with TiO nanoparticles and irradiated on one side with blue (450 nm LEDs), metal-to-ligand charge transfer (MLCT) leads to light. The performance of the FFMR markedly improved the electron transfer from Mn(I) to the diazonium ligand, forming reaction compared to batch conditions, and was successfully Mn(II) and an aryl radical with extrusion of N . The aryl radical appliedtothe C − H arylation of heteroarenes such as adds to the arene substrate to forge the aryl-aryl bond, whereupon Scheme 53 Mechanism of the titania-catalyzed Meerwein C − H arylation J Flow Chem (2020) 10:13–71 45 Scheme 54 Titania-catalyzed Meerwein arylation in a falling-film microreactor the radical adduct formed is oxidised to form a cation, either by Apart from the photocatalytic C − H arylations of reaction with the oxidised Mn(II) complex or another equivalent (hetero)arenes which have been described using Eosin Y 2+ of diazonium salt. Deprotonation then restores the aromaticity of [198], dual catalysis by [Ru(bpy) ] in conjunction with the system (Scheme 55 and 56). Pd(OAc) [199], TiO [200] and Mn photocatalysis (vide su- 2 2 Flow conditions proved to be highly beneficial for the re- pra), a catalyst-free arylation would be attractive from the action, accelerating the reaction time to 60 min residence time viewpoint of sustainability and atom-economy. Exploiting and drastically improving the yield. For p - the advantages offered by the implementation of microreactor trifluoromethylbenzenedizonium tetrafluoroborate and ben- technology for the generation of highly reactive, explosive zene, by switching to flow, an improvement in yield from intermediates, Kappe and co-workers developed a catalyst- −1 25% to 64% was noted with a productivity of 1.42 g h . free radical C − H arylation through photochemical means. The methodology was also applied to the synthesis of a pre- The so-called diazo anhydrides (Ar-N=N-O-N=N-Ar), which cursor of the hyperthermia drug Dantrolene, starting from fur- are nitrosamine dimers, fragment homolytically under irradi- fural derived from biomass [197]. ation with near-UV light (> 300 nm) to yield aryl radicals Scheme 55 Catalytic cycle for the Mn photocatalytic C − H arylation of (hetero)arenes 46 J Flow Chem (2020) 10:13–71 Scheme 56 C − H arylations of heteroarenes with aryl diazonium salts under Mn photocatalysis which can be applied in the C − H arylation reaction of only N ,H Oand t-BuOH as waste in a metal-free process 2 2 (hetero)arenes. Although these intermediates are highly unsta- (Scheme 58)[201]. ble, they can be safely generated and consumed in situ by Another application of α-amino radicals was reported by performing the reaction in a microreactor. Nitrosamines are Vega, Trabanco and co-workers at Janssen Pharmaceuticals formed through the nitrosation reaction of anilines with tert- for the C − H arylation of the α-position in N,N- butyl nitrite (t-BuONO, Scheme 57). dialkylhydrazones. To decrease the formation of byproducts formed from the The authors propose an oxidative quenching cycle based spontaneous decomposition of diazo compounds, t-BuONO on the reductive abilities of the Ir(ppy) photocatalyst and the arene coupling partners are fed via two separate reagent (Scheme 59). Upon excitation with blue light (455 nm), excit- streams to a T-mixer before entering the photoreactor, equipped ed Ir(III) undergoes SET with an electron-poor arene substrate with a medium pressure Hg lamp (125 W, although a reduction (e.g., 2,4-dicyanobenzene), forming Ir(IV) and the one- to 75 W was found to be suitable for certain substrates) and UV- electron reduced form of the arene (radical anion). Ir(IV) is filter (cut-off at 300 nm). The substrate scope includes thio- then reduced to Ir(III) to restart the cycle by oxidising the phenes, furan and N-protected pyrroles, as well as electron-rich hydrazone, generating a hydrazinium radical, which readily phenyl derivatives and azines (including pyridine N-oxide) undergoes deprotonation by LiOAc to form the stabilized α- whichwere arylatedinaresidencetimeof45min, producing amino radical. The α-amino radical forms an anionic adduct Scheme 57 Catalytic cycle for the C − H arylation of (hetero)arenes employing diazo anhydrides as the aryl radical precursors J Flow Chem (2020) 10:13–71 47 Scheme 58 Metal-free photochemical C − H arylation of (hetero)arenes through radical-radical coupling with the radical anion of the cyanobenzenes, azines were also successfully employed as electron-poor arene. With cyanide acting as the leaving group electron-poor arene coupling partners (Scheme 60)[202]. in the adduct, the product is then formed. Through the use of continuous-flow, the arylation could be accelerated in 20– C − N bond formation 40 min allowing the gram-scale synthesis of arylated dialkylhydrazones. Repeating the reaction after the first Activation of the beta C − H bond in hindered aliphatic amines arylation with another flow reactor allowed for a regioselec- to yield aziridines (or beta-lactams in the presence of carbon tive second arylation step on the same substrate, though more monoxide) was reported by Gaunt and co-workers in 2014 forcing conditions (increase of catalyst loading, residence time [203] and was later adapted to a continuous-flow process by and reaction temperature) were required. Apart from Lapkin and co-workers [204]. Starting from palladium(II) Scheme 59 Ir-catalyzed alpha C − H arylation of N,N- dialkylhydrazones 48 J Flow Chem (2020) 10:13–71 Scheme 60 Continuous-flow synthesis of arylated N,N- dialkylhydrazones via Ir photoredox catalysis acetate, the hindered amine coordinates to the metal. This can monocoordinated variant. This dissociation is more favoured happen a second time to form a Pd(II) center coordinated by when hindered amines are used. The monocoordinated com- two amines. The steric bulk on the amine is critical to achieve plex can then undergo the C − H activation step (rate-deter- activation of the C − H bond, since the C − H activation step mining), i.e. deprotonation of the beta C − H bond through a requires dissociation of this complex to the less stable concerted metalation-deprotonation (CMD) mechanism to Scheme 61 Catalytic cycle for the beta C − H activation in hindered aliphatic amines J Flow Chem (2020) 10:13–71 49 yield a cyclometalated Pd(II) complex. This can undergo ox- the mechanistic investigations were combined in a kinetic mod- idation by the hypervalent iodine oxidant PhI(OAc) resulting el and applied to the design of a process model for an ideal plug in a Pd(IV) complex. The nitrogen is then deprotonated to flow reactor, with the limitation that T = 120 °C (stability max form a four-membered Pd(IV) intermediate which undergoes limit of Pd(OAc) ) and that the space-time yield be large reductive elimination, liberating the aziridine and Pd(II), enough (full conversion within 10 min). Optimization experi- thereby closing the catalytic cycle. ments were performed and yielded conditions with 0.5 mol% The mechanism of the reaction was investigated in detail loading of Pd catalyst for which t =10 min. (Scheme 61). The rate of the reaction was shown to increase Next, further development of the flow process for gram- over time, which could have two causes: either the rate was scale production of aziridines was carried out by incorporating affected negatively by increasing the concentration of the modules to remove the catalyst as well as the desired aziridine amine, or the reaction rate was increased by one of the product. Separation of the homogeneous catalyst was accom- byproducts of the reaction (autoinduction). The latter was ruled plished through the use of an amine-functionalized QuadraSil out by starting the reaction at 20% conversion. Essentially, the AP column (which coordinates and retains the Pd(II) catalyst), reaction is performed with the same equivalent ratios, but with a leaving the eluent with <1 ppm of Pd. The aziridine was re- smaller amount of the reagents. Because less byproducts are moved from the mixture by incorporating a column packed formed, an autocatalyzed reaction should then be slower. with Isolute SCX-3 gel (sulfonic acid-functionalized silica When factoring in the different starting concentrations, the rates gel). Washing the column with a basic eluent subsequently were shown to be identical, suggesting instead that the rate was elutes the aziridine yielding the product without further puri- negatively affected by the concentration of amine (its consump- fication required. Performing the reaction in a commercial −1 tion during the reaction then leads to an increase in the reaction Vapourtec R-Series allowed a productivity of 0.77 g h −1 −1 rate). The effect of adding reaction products as additives to the (space-time yield 0.463 kg V h ,Scheme 62). reaction (PhI, aziridine, and HOAc) was investigated as well. In A derivatization in flow of the resulting aziridines by reac- this case, increasing the amount of HOAc showed a small in- tion with nucleophiles was also developed. In the case of non- crease in the rate. The rate at t was shown by comparison to t activated aziridines and weak nucleophiles, this generally re- 0 1/2 to be inversely proportional to the concentration of amine. quires activation by (Lewis) acids. Hence, aziridines retained Apart from this, the reaction was shown to be zeroth order in on the acidic column are susceptible to nucleophilic attack and PhI(OAc) andfirst orderinPd(OAc) . these principles were applied to the in-line derivatization with 2 2 The kinetic isotope effect (KIE) can be applied to the study MeOH, H O and in-situ generated HN , yielding the function- 2 3 of reaction mechanisms by isotopic labeling. In C − Hactiva- alized amine products in good yield (Scheme 63)[204]. tion, deuterium labeling of the target C − H bond can change The direct C − H amination of arenes (Minisci-type the rate of the reaction (a primary kinetic isotope effect) which amination) is a challenging transformation, requiring strongly shows the C − H activation to be the rate-limiting step (k ), oxidizing conditions [207, 208]orthe installmentofaredox which proved to the case for the C − H aziridination, auxiliary or electrophoric group [209]. The group of Leonori explaining the first order dependence on Pd(OAc) . The oxi- recently reported the application of O-aryl hydroxylamines as a dative addition of PhI(OAc) following this step then does not redox auxiliary to generate aminium radicals for late stage C − alter the rate. The negative first order dependence on the H amination [210, 211]. Building on this work while eliminat- amine can be rationalized by the increased reversible forma- ing the need for prefunctionalization, a visible light photocata- tion of the square planar bisaminated Pd(II) complex (k ), lytic approach to generate aminium radicals from amines direct- which is unproductive, since the C − H activation step requires ly via the in situ formation of an N-chloroamine with N- a vacant coordination site [205, 206]. As the protonated amine chlorosuccinimide (NCS) was developed (Scheme 64). cannot coordinate to Pd(II), increasing the amount of HOAc Under acidic conditions, the protonated N- (k ) decreases the effective concentration of amine available to chloroamines can engage in an oxidative quenching cy- coordinate the metal which shifts the k equilibrium towards cle with the photocatalyst [Ru(bpy) ]Cl , generating the 2 3 2 the desired monoaminated complex. The optimal amount of chloride ion and an electrophilic aminium radical, which HOAc was determined to be 20 equiv., since higher concen- undergoes addition to an arene. The radical adduct trations of acid lead to degradation of the aziridine product. formed after addition is then oxidised to a carbocation Another piece of evidence in the puzzle is the rate with by Ru(III), closing the catalytic cycle and generating the which more sterically congested amines react. Increasing the aminofunctionalized arene after loss of a proton. Key to steric bulk makes the formation of the bisaminated complex the para-selectivity of the aromatic amination is the less favorable, increasing the rate, which was shown by a com- polarity of the medium combine with the highly polar- petition experiment between two amines of which one was ized aminium radical. Under these conditions, the aro- more substituted. The selectivity and the mechanism of C − H matic chlorination which is a competing pathway when activation were further probed by DFT calculations. Data from using N-chloroamine reagents is suppressed in favour of 50 J Flow Chem (2020) 10:13–71 Scheme 62 Palladium-catalysed synthesis of aziridines in continuous-flow thearomaticC − H amination. Using HFIP as a solvent phenyl moiety in a Phe residue, which is underexplored also allowed expanding of the substrate scope to more in bioconjugation chemistry. electron-poor arenes, e.g. fluorobenzene, and improves The method was adapted to flow in collaboration with selectivity towards the para-position. The scope of the AstraZeneca with piperidine and iodobenzene as reacting reaction is very broad, including the direct partners to furnish the para-substituted building block −1 functionalization of the organometallic compound 1-(4-iodophenyl)piperidine in a productivity of 3.8 g h [Ru(ppy)(bpy) ]PF , polystyrene (degree of (Scheme 65)[212]. A different photochemical approach 2 6 functionalization: 19%) and a tetrapeptide, the latter un- was followed by Marsden and co-workers, performing an dergoing selective amination in the para-position of the intramolecular C − H amination in a mixture of acetic acid Scheme 63 Derivatization of aziridine in continuous-flow J Flow Chem (2020) 10:13–71 51 Scheme 64 Catalytic cycle for the direct C − H amination of arenes through photocatalytic reduction of protonated N- chloroamines and sulfuric acid and fragmenting the protonated N- [215–217]. The first 1,5-HAT reaction, the classic Hoffmann- chloroamine homolytically using UV light [213]. Löffler-Freytag reaction, originated in 1883 and involves pho- The reaction was performed in flow, in which the N- tolysis of a protonated N-chloroamine after which the resulting chloroamine could be synthesized from the amine and NCS aminium radical abstracts a hydrogen from a carbon five atoms followed by cleaving the nitrogen-chlorine bond homolytically away, resulting in δ-chlorination. The 1,5-radical translocation under irradiation of a 125 W UV lamp. This was then applied to is thermodynamically favourable because the abstraction of the intramolecular C − H amination reactions in flow to synthesize hydridic hydrogen atom is exergonic and occurs through a six- a range of tetrahydroquinolines (Scheme 66). Although higher membered transition state, although 1,6- and 1,7-translocations isolated yield was obtained in both batch and flow conditions involving sulfamates and sulfamides have also been reported by when both steps were performed separately, integrating the the group of Roizen [218, 219]. Following the translocation of chlorination of the amine and the intramolecular C − H the halide, an intramolecular nucleophilic substitution reaction amination reaction in a modular fashion gave N- then furnishes pyrrolidine products. Recently, different electro- methyltetrahydroquinoline in an overall yield of 34% [214]. chemical variations of the Hoffmann-Löffler-Freytag reaction A myriad of reports on reactions involving a 1,5-hydrogen were reported. Lei and co-workers reported a halide-free HLF atom transfer step have recently appeared in the literature reaction of tosylamides in the presence of acetate and HFIP Scheme 65 Functionalization of iodobenzene with piperidine via direct C − H amination under flow conditions 52 J Flow Chem (2020) 10:13–71 Scheme 66 Intramolecular C − H amination with N-chloroamines and UV light involving amidyl radical intermediates. Different pathways (in- amides to generate the photolabile N-iodoamides leading to volving ionic or radical reactivity) were proposed to arrive at amidyl radicals [222–225]. Using imines, iminyl radicals can the amidyl radical, which generates a carbon-centered radical be accessed as well. This was applied to the synthesis of after the intramolecular remote hydrogen atom transfer. The oxazolines and 1,2-amino alcohols. With bromide as the medi- carbon-centered radical is then oxidised to a carbocation, which ator, Rueping and co-workers developed an electrochemical cyclizes to form pyrrolidines [220]. A complementary approach cross-dehydrogenative approach to the Hoffmann-Löffler- involving both the use of electrochemistry and light to cleave Freytag reaction for the synthesis of pyrrolidines under both the N-haloamides was reported by Stahl and co-workers [221]. batch and flow conditions. The mechanistic pathways through Iodide ion is oxidised to iodine at the anode, which reacts with which the reaction occurs are again complicated, since several Scheme 67 Mechanism of electrochemical cyclization of Ts- protected amines to pyrrolidines J Flow Chem (2020) 10:13–71 53 species and pathways (both occuring at the anode or cathode in photochemical C − H oximation occuring through the homo- the undivided cell) can be involved in the generation of the key lytic photolysis of a nitrite functional group in which a nitroxy amidyl radical intermediate (Scheme 67). - and alkoxy radical are formed. The electrophilic alkoxy rad- The amidyl radical undergoes intramolecular HAT to yield ical then engages in a 1,5-HAT leading to the radical translo- the carbon-centered radical which can form the pyrrolidine in cation of a nitroxide functionality which equilibrates to an a number of different ways. First, the carbon radical can trap oxime (Scheme 69, right part). bromine (generated under oxidative conditions from bromide) The group of Ryu reported a Barton reaction under flow which can undergo an intramolecular nucleophilic substitu- conditions. An alcohol is transformed into a nitrite by reaction tion. Alternatively, the carbon-centered radical can undergo with nitrosyl chloride (NOCl) and the labile N-O bond is direct oxidation to the carbocation followed by cyclization. cleaved by irradiation with near-UV light (365 nm proving The presence of base (methoxide, which is also formed from sufficient). The reaction was performed in a stainless steel MeOH through the cathodic reduction of protons to hydrogen microreactor with a glass cover to allow irradiation of the in a divided cell) was found necessary for the reaction to reaction mixture (Scheme 68, left part). Different parameters occur, as the amidyl radical can be accessed through the of the reaction were investigated, e.g. light source combina- deprotonated tosylamide. The reaction was scaled under both tions with different glasses (cut-offs being at different wave- batch (50 g scale) and flow conditions. Flow chemistry is an lengths depending on the material). Out of these combina- attractive option for the scale-up of electrochemical reactions tions, the application of a 15 W black light in combination due to the fast reaction rates and decrease of the necessary with Pyrex glass performed best for small-scale reactions. amount of supporting electrolyte (a non-neglible factor during While the Barton reaction is usually run in acetone as the scale-up). A commercial Asia Flux module manufactured by solvent, the limited solubility of the steroid in acetone neces- Syrris was used in conjuction with a graphite anode and 316 sitated switching to DMF. The reaction was scaled-up to gram alloy stainless steel cathode. The desired pyrrolidines were scale, combining two microreactors and 8 × 20 W black lights, formed in high yields under both conditions of constant cur- yielding 3.1 g of the oxime after 20 h (32 min residence time), −2 rent (5 mA cm ) and constant potential (2.8 V). Accurate an intermediate in the synthesis of myriceric acid A [227]. control of residence time in flow reactions generating gases is difficult, since the formation of gas bubbles (slugs) de- C − O bond formation creases the residence time during the reaction. Hence, a back-pressure regulator was included in the system to solubi- Pasau and co-workers at UCB developed a benzylic photo- lize the majority of hydrogen formed at the cathode (1 to chemical C − H oxidation in continuous flow (Scheme 70). 5 bar), allowing the synthesis of the tosylpyrrolidine com- Oxygen gas is used as the oxidant in conjunction with the pound methyl 4-methyl-1-tosylpyrrolidine-2-carboxylate in organic photocatalyst riboflavin tetraacetate (RFT) under −1 76% yield with a productivity of 0.37 mmol h UV light irradiation with an Fe(III) salt, the latter being nec- (Scheme 68)[226]. essary for the reduction of hydrogen peroxide which causes Another reaction of historical importance involving such a decomposition of the riboflavin [228]. After irradiation with translocation is the Barton reaction. It can be classified as a UV light, the riboflavin can abstract a hydrogen atom from the Scheme 68 Electrochemical HLF reaction in flow conditions 54 J Flow Chem (2020) 10:13–71 Scheme 69 Barton rearrangement under flow conditions benzylic position to generate a benzylic radical. Since ribofla- reduced by the catalytic amount of the iron(II)perchlorate ad- vin is a known photosensitizer for oxygen, the authors pro- ditive (Scheme 71). pose the formation of singlet oxygen, O , which would then To synthesize a series of acetals, Kappe and co-workers react with the benzylic radical to give a peroxo radical, which used Cu(OAc) and t-BuOOH as the oxidant for the oxidative can engage in HAT forming a hydroperoxide. The hydroper- coupling of ethers and enols (from phenols and β-ketoesters), oxides can form either ketone or alcohol products. The re- in which a bond is formed between the enol oxygen and the α- duced riboflavin can then be reoxidised by O ,returning to carbon of an ether (Scheme 72). To avoid the dangers associ- its ground state, while the H O formed during the oxidation is ated with heating a mixture of peroxides and ethers, a feed 2 2 Scheme 70 Continuous flow benzylic oxidation with RFT as photocatalyst J Flow Chem (2020) 10:13–71 55 Scheme 71 Catalytic cycle for benzylic oxidation by RFT/Fe(II) catalysis containing a non-aqueous solution of t-BuOOH in n-decane is the formation of the acetal products in less than 20 min at 130 °C premixed in a glass static mixer with a feed containing the compared to 3 h reflux under batch conditions [229]. copper catalyst, the ether and the substrate. Flow chemistry offers several advantages when dealing with The reaction is performed in a stainless steel reactor coil with exothermic reactions (e.g., oxidations) due to excellent heat a volume of 20 ml and an internal diameter of 1 mm leading to transfer to the environment, while the small reacting volumes Scheme 72 Continuous flow acetal synthesis via oxidation by alkyl peroxide 56 J Flow Chem (2020) 10:13–71 decrease explosion and combustion hazards [31, 230, 231]. Schultz and co-workers at Merck Sharpe and Dohme Thus, it becomes possible to operate in novel process windows, (MSD) reported the remote C − H oxidation of amines using i.e. conditions of high temperature and pressure not safely acces- sodium decatungstate (NaDT) as a HAT photocatalyst sible in batch. The MC system is a highly effective mixture of (Scheme 74). The reaction is carried out in a 1:1 mixture of Co, Mn and bromide salts for the synthesis of carbonyl com- acetonitrile and water in the presence of 1.5 equivalents of pounds through aerobic oxidation [232, 233]. Kappe and co- H SO to protonate the amine (neutral amines being incom- 2 4 workers studied the oxidation of ethylbenzene to acetophenone patible with the decatungstate photocatalyst [237]) and or benzoic acid under flow conditions using 2.5 mol% of CoBr 2.5 equivalents of H O as the oxidant. Acidic conditions 2 2 2 and Mn(OAc) and air as the oxidant (Scheme 73). are important to the remote functionalization, as the radical Air, delivered from a gas bottle connected to a mass-flow is preferentially formed on a distal position to the protonated controller is mixed with the liquid reagent stream (1 M ethyl- amine, as exemplified by the β-selective functionalization of benzene, 2.5 mol% CoBr and 2.5 mol% Mn(OAc) in pyrrolidine, and the γ-selective functionalization of piperidine 2 2 HOAc) pumped with a HPLC pump to the reactor, a 50 m and azepane. These building blocks are useful but costly in (V = 25 mL) PFA coil placed inside a GC oven (100–150 °C). drug discovery. The reaction was performed in a 10 ml flow The system is kept under pressure through the use of a 12 bar reactor with an FEP coil using oxygen as the oxidant under back-pressure regulator (BPR). Acetophenone can be obtain- 4.5–5 bars of pressure with 365 nm LEDs. As >1 h of resi- ed in a residence time of 4–8 min in 66% yield without chro- dence time was required, recirculating the mixture during 22 h matography. 2-bromoacetophenone present in the reaction was necessary for the scale-up of a pyrrolidine oxidation on mixture can be removed by reduction through treatment of 5 g scale [238]. the crude with Zn metal. Alternatively, doubling the residence Noël and co-workers employed tetrabutylammonium time to 16 min allows the production of benzoic acid in 71% decatungstate (TBADT) with a mixture (2.5:1) of acetonitrile yield (purification with acid-base extraction, no chromatogra- and 1 M aqueous HCl for the oxidation of activated and phy necessary) [234]. unactivated C − H bonds in flow using oxygen gas (2.5 equiv- The oxidation of unactivated sp C − H bonds is a highly alents) as the oxidant (Scheme 75). The reaction was carried challenging transformation [235]. Several approaches to the out in a 5 ml PFA capillary reactor at atmospheric pressure in oxidation of methylene or methine groups exist, including 45 min residence time under 365 nm LED irradiation. The metal catalysis (e.g., the Chen-White oxidation or the use of methodology was applied to the oxidation of terpenoid natural metal porphyrins, vide infra), biocatalysis, photocatalysis and products, including the gram scale oxidation (1.5 h residence electrochemistry [236]. Examples of these oxidation chemis- time, 10 ml reactor volume) of the sesquiterpene antimalarial, tries performed in flow will be discussed below. artemisinin [239]. Due to the electrophilic nature of the Scheme 73 Air oxidation of ethylbenzene to acetophenone or benzoic acid in flow J Flow Chem (2020) 10:13–71 57 Scheme 74 Photocatalytical oxidation with oxygen with recirculation in flow catalyst, both methods allow the site-selective oxidation of a (alcohols further being oxidised to ketones having previously methylene group to a ketone [240, 241]. The alkyl radical been described) [242]. The reduced form of the catalyst is then formed after HATwith decatungstate is trapped by O to form re-oxidised by a second equivalent of oxygen, closing the an alkyl hydroperoxide intermediate, which leads to alcohol catalytic cycle [243, 244]. and ketone products, though ketones are the major product Scheme 75 Mild and selective C(sp )-H oxidation in flow 58 J Flow Chem (2020) 10:13–71 Scheme 76 Continuous-flow oxidation of Csp -H bond by in situ generated dioxirane Another approach to C(sp )–H hydroxylation involves the compared to 2% in batch). The method also proved scaleable, use of strong oxidants, e.g. hypervalent iodine reagents or as exemplified by the production of 2.7 g 1-adamantanol from dioxiranes (DMDO or TFDO). While dioxiranes such as adamantane using two 20 mL reactors equipped with static −1 TFDO are highly effective oxidants, they are cumbersome to mixer coils (96% yield, productivity 1.17 g h )[245]. work with: TFDO, for instance, is a gaseous reagent which Aside from the applications of C–H oxidation to deliver decomposes above 10 °C. As such, despite its potential, its use oxygenated building blocks or as a biomimetic strategy in is limited to small-scale batch reactions. As discussed previ- total synthesis, another interesting application of C–Hoxida- ously, one of the main advantages offered by flow chemistry is tion can be found in the practice of drug discovery. One of the the potential to generate and consume small quantities of haz- key aspects in the development of a new drug is the study of ardous intermediates in situ, improving both the safety of the its metabolic stability. The first step in the metabolism of process and opening the doors to scale-up. drugs in vivo is first pass hepatic oxidation by Cytochrome Ley, Pasau and co-workers developed an in situ formation P450 oxidase liver enzymes, which contain an Fe porphyrin. of the oxidant TFDO under flow conditions, starting from Oxidative methodologies which are able to mimic drug me- 1,1,1-trifluoromethylacetone (Scheme 76). A mixture of the tabolism are thus in high demand [246, 247]. substrate and 1,1,1-trifluoromethylacetone in DCM (feed 1) The field of organic electrochemistry has recently seen a are mixed with an aqueous solution of sodium bicarbonate resurgence in attention [248] and can benefit greatly from the (feed 2), followed by the addition of a third reagent (feed 3) implementation of microreactor technology [249]. stream containing the oxidant (aqueous solution of Oxone) Electrochemical processes require long reaction times as they which are then pumped to a microreactor filled with glass are typically highly mass-transfer limited, being limited both beads and kept at 25 °C. The system is kept under pressure by the dimensions of the electrode surface available for the through the use of a back-pressure regulator (75 psi), allowing reaction to occur, as well as the fact that electron-transfer both the oxidation of unactivated and activated C − Hbonds in processes are absent in the bulk of the solution as they only a residence time of 80 s. occur in a very thin layer near the surface of the electrode 19 1 The formation of TFDO was detected by F NMR and H (Helmholtz layer). While the use of electrons as green and NMR spectroscopy, after in-line phase separation of the or- traceless reagents justifies the classifcation of electrochemical ganic phase with a liquid-liquid membrane separator (Zaiput), reactions under the moniker ‘green chemistry’,an important proving the yield to be higher in flow than batch (5% in flow, drawback of organic electrochemistry is the poor conductivity J Flow Chem (2020) 10:13–71 59 −1 of organic solvents necessitates the use of large (commonly hydroxylation. At 8 F mol with the use of reducing sodium stoichiometric) amounts of supporting electrolyte, which can bisulfite as supporting electrolyte, the metabolite 5- be either reduced or eliminated entirely in a microreactor due hydroxyldiclofenac was isolated in 46% yield, a notable im- to the very small inter-electrode spacing [250–254]. provement compared to earlier syntheses requiring both mul- Aditionally, the potential applied can be used to perform ox- tiple transformations and expensive reagents. An interesting idations in a in a more reliable and reproducible way and quinone by-product was also isolated which can undergo con- several electrochemical C–H oxidation methodologies have jugation with glutathione, one of the strategies followed by the already been reported [255, 256]. liver to eliminate toxic electrophiles. This can be easily imple- Although electrochemistry has already seen application mented in a modular flow set-up by connecting the output of in the mimicry of drug metabolism through the use of the electrochemical microreactor to a T-junction and introduc- coupled techniques such as electrochemical-mass spec- ing a second stream containing glutathione to synthesize con- trometry (EC-MS), these methods typically do not allow jugates. Unsurprisingly (vide supra), tolbutamide underwent the delivery of useful amounts of drug metabolites, which oxidation at the α-position to the amide nitrogen yielding a can be problematic, in case their full characterization by product which is not a known tolbutamide metabolite. NMR spectroscopy is required [257, 258]. Hence, flow Primidone was oxidised electrochemically to phenobarbital, electrochemical oxidation is an attractive tool for the a barbiturate drug known to be one of the two first-pass me- preparation of drug metabolites. tabolites of primidone. Phenobarbital was isolated in 24% −1 Stalder and Roth studied the oxidation of five drugs yield, although its productivity was limited (7 mg h )by (diclofenac, tolbutamide, primidone, albendazole, and chlor- solubility issues. Albendazole (ABZ), a sulfide drug, has promazine) by electrochemical means (Scheme 77). While two first-pass metabolites corresponding to the sulfoxide and diclofenac, tolbutamide and primidone undergo C–Hoxida- the sulfone, both of which can be accessed electrochemically. tion, albendazole and chlorpromazine are sulfide drugs which The sulfoxide was isolated in 38% yield (productivity −1 undergo facile electrochemical oxidation to sulfoxides [259]. 65 mg h ) while chlorpromazine, an antipsychotic drug, also Diclofenac, a non-steroidal anti-inflammatory drug (NSAID), underwent S-oxidation to yield a sulfoxide (83% yield, −1 undergoes first-pass hepatic oxidation via aromatic 33 mg h ), which is one of its hepatic metabolites [259]. Scheme 77 Flow oxygenative electrolysis of approved drugs 60 J Flow Chem (2020) 10:13–71 Scheme 78 Electrochemical synthesis of thiazoles by intramolecular C-S bond formation C − S bond formation only reagents in the reaction, requiring only a mixture of ace- tonitrile and methanol as the solvent and a C anode/Pt cathode The heterocyclic motifs thiazole and thiazine account for 15% couple, the methodology is highly sustainable. The electro- of all sulfur-containing drugs approved by the US Food and chemical method is also compatible with thioamide- Drug Administration (FDA) [260]. These compounds are tra- substituted pyridines, leading to thiazolopyridine products. ditionally accessed from the parent N-aryl thioamides through The method is tolerant of a large variety of functional groups the use of chemical oxidants, while complementary catalytic including free alkyl alcohols. The synthesis of 2- approaches have also been developed involving the use of phenylbenzothiazole was performed on gram-scale with a pro- −1 palladium [261] and photoredox catalysis [262, 263]. As men- ductivity of 0.3 g h , yielding 2.4 g after 7.2 h (Scheme 78). tioned before, performing oxidative reactions in an electro- Due to the presence of methanol, hydrogen evolution is ob- chemical cell can avoid both the necessity of using highly served at the counter-electrode. The authors propose a mech- oxidising conditions and the use of transition metals. anism based on the one-electron oxidation of the Although the first report on electrochemical oxidation for (deprotonated) thioamide to a thiamidyl radical in which the the synthesis of benzothiazoles was published in 1979 [264], sulfur atom has partial radical character. This intermediate can due to renewed interest in the field of electrochemistry more then undergo a dimerisation (observed in some cases) or un- methodologies are being reported in literature, including im- dergo an intramolecular cyclization with the arene. Following provements in the electrosynthesis of benzothiazoles via oxidation of the radical adduct after intramolecular cycliza- dehydrogenative C-S coupling [265, 266]. The group of tion, a carbocation is formed yielding the aromatic thiazole Wirth reported the synthesis of thiazoles using flow electro- after deprotonation (Scheme 79)[267]. chemistry. As before, the advantages associated with the use Apart from thiazoles, six-membered heterocycles (e.g., thi- of flow electrochemistry are exploited. In this case, the reac- azines) incorporating a sulfur atom can also be accessed tion could be performed without mediator and without through oxidative methodologies, although their electrochem- supporting electrolyte. Taking into account electrons are the ical synthesis was hitherto underexplored. Again through an Scheme 79 Proposed mechanism of electrochemical synthesis of thiazoles by intramolecular C-S bond formation J Flow Chem (2020) 10:13–71 61 Scheme 80 Electrochemical continuous flow synthesis of 1,4- benzoxathiins and 1,4- benzothiazines oxidative dehydrogenative C-S coupling, Xu and co-workers microreactor technology is an obvious choice. Moreover, C − developed the synthesis of 1,4-thiazines and 1,4- H halogenations are frequently initiated by the homolytic cleav- benzoxathiins using a flow electrolysis cell (Scheme 80). age of a halogen-halogen bond using light, with the advantages The reaction is run in the presence of the Lewis acid of performing photochemistry in flow having been previously Sc(OTf) with a mixture of acetonitrile and TFA (9:1) as the highlighted, while elemental halogens (or equivalent sources of solvent with a Pt cathode (the reduction of protons being the electrophilic halogens, “X ”) can be safely generated under flow reaction occuring at the counter electrode) and a carbon-filled conditions. The halogenation of organic compounds was com- polyvinylidene fluoride anode. The mechanism of the reaction prehensively reviewed by Cantillo et al. (2017) [269]. is similar to the cyclization to form thiazoles (vide supra), analogously occuring via oxidation of the thioamide to a C − Hfluorination thiamidyl radical intermediate. Particular to this transforma- tion is the use of a catalytic amount of the Lewis acid Sc(OTf) 3 Although the carbon-fluorine bond has many attractive prop- and the strong Bronsted acid TFA. The use of acids is impor- erties, due to the difficulties associated with working with tant to promote the formation of the cyclic products with good fluoride salts (low solubility in organic media), elemental fluo- selectivity, as protonation allows for the formation of the rine and hydrofluoric acid, the development of novel fluori- thiamidyl radical at lower voltages and protonation of the nating agents is an active field. Depending on their reactivity, cyclized product prevents it from undergoing further oxida- the reagents can be classified as being either electrophilic or tion, as demonstrated by cyclic voltammetry studies [268]. nucleophilic. One such nucleophilic reagent is Because the protonated thiamidyl radical is more electrophilic, diethylaminosulfur trifluoride (DAST). A downside of its its polarity matches the arene coupling partner more closely use is the fact that it decomposes above 90 °C, which makes promoting the desired intramolecular cyclization reaction and applying microreactor technology an attractive choice when allowing for the synthesis of substituted 1,4-benzothiazines working with this reagent. Aside from the explosive aspect, and 1,4-benzoxathiins bearing both electron-withdrawing perfluorinated tubing is not affected by the hydrofluoric acid and electron-donating groups [211]. formed during the reaction, which can be quenched by intro- ducing a bicarbonate solution as the reagent stream exits the C − X bond formation reactor. Seeberger et al. applied DAST to the fluorination of aldehydes to form acyl fluorides [270]. Transforming a carbon-hydrogen bond to a carbon-halogen bond A different approach to acyl fluorides was followed by is a key transformation in organic synthesis. As many dangers are Britton et al. using the decatungstate photocatalyst and the associated with the use of elemental halogens, for the C − H electrophilic fluorinating agent N-fluorobenzenesulfonimide halogenation of organic compounds the application of (NFSI) [271]. Through decatungstate photocatalysis, site- 62 J Flow Chem (2020) 10:13–71 Scheme 81 Decatungstate catalysed C − H fluorination with the electrophilic fluorinating reagent NFSI selective C − H fluorination was achieved for both unactivated In collaboration with Merck, the methodology was and activated C − H bonds, the methodology also being ap- applied to the fluorination of leucine methyl ester, a plied to the synthesis of tracers for Positron Emission key component of Odanacatib, an osteoporosis drug Tomography (PET) studies by the labelling of amino acids candidate [276]. Under flow conditions, the reaction and peptides with [ F]NFSI [272–274]. Notable is the differ- could be accelerated from 16 h to 2 h, allowing the ence in selectivity obtained when using photocatalysis when production of γ-fluoroleucine in 90% yield (> 20 g compared to a thermal radical chain reaction initiated with scale, Scheme 82)[237]. AIBN, exemplified by the functionalization of 4- An organocatalytic approach towards benzylic fluori- ethyltoluene bearing two distinct benzylic positions, with nation was followed by Kappe and co-workers by ap- AIBN favouring methyl functionalization (kinetic control). plication of xanthone as a photoorganocatalyst, The reaction was performed under flow conditions for the Selectfluor as the fluorinating agent and irradiation with fluorination of ibuprofen methyl ester (Scheme 81)[275]. a 105 W CFL bulb (Scheme 83). Scheme 82 Application of the work of Britton and co-workers to the synthesis of a precursor of the osteoporosis drug candidate Odanacatib (Merck) J Flow Chem (2020) 10:13–71 63 Scheme 83 Benzylic fluorination with a xanthone photoorganocatalyst in conjunction with the Selectfluor reagent The T excited state of xanthone functions as a HAT Ibuprofen methyl ester was fluorinated at the benzylic catalyst to generate benzylic radicals [277, 278]. This position with >90% selectivity in 80% isolated yield, allowed the fluorination of a variety of benzylic sub- while the natural product celestolide, a common fra- strates at room temperature in a residence time of less grance component, was fluorinated in 9 min in 88% than 30 min, although for more challenging substrates, isolated yield. Processing of 100 ml of solution allowed an elevated reaction temperature of 60 °C was required. theproductionof2.3gofproduct [279]. Scheme 84 Free radical chain chlorination driven by light irradiation 64 J Flow Chem (2020) 10:13–71 Scheme 85 In situ generation and on site consumption of chlorine in continuous-flow C − H chlorination functionalization in the chemical research literature. Apart from the obvious hazards associated with storing chlorine The C − H photochlorination in continuous flow reported by gas in its elemental form, one of the downsides of using Cl Jähnisch and co-workers using Cl gas in a FFMR is one of for radical chlorinations is the occurrence of electrophilic ar- the earliest examples of continuous-flow radical C − H omatic substitution as a side-reaction, especially when Scheme 86 Benzylic chlorination by in situ generated chlorine J Flow Chem (2020) 10:13–71 65 working with electron-rich substrates. Through the use of a glass microreactor and irradiation with 352 nm light quartz window, irradiation of the reaction mixture in the through the use of a 15 W black light (Scheme 87)[284]. FFMR with short wavelength UV light (190–250 nm) coming An additional benefit of microreactor technology is the fact from a 1000 W Xenon lamp became possible, supressing the that the product stream leaves the reactor, hence, the formation ionic reactivity and providing the desired chlorinated product of polybrominated side products is avoided. The use of solar −1 −1 in a spacetime yield of 400 mol L h (Scheme 84)[280]. light as a sustainable energy source for photochemistry is of Ryu et al. developed a photochlorination of alkanes with a interest [285–287], and was applied to photobromination by 15 W CFL black light (Scheme 85). Sulfuryl chloride was also Park and co-workers [288]. The photochemical bromination is used as a chlorinating agent. Due to the dangers associated frequently performed in CCl , a toxic solvent which use being with chlorine gas, in situ generation of molecular chlorine is phased out due to health and environmental concerns [289]. highly desirable. Several reports have appeared on photo- By using the electrophilic brominating agent N- chemical oxidative chlorination. Hydrochloric acid is then bromosuccinimide, the photobromination can be performed mixed with bleach to form chlorine in situ, which is then in acetonitrile as the solvent as demonstrated by Kappe and homolytically cleaved in a photoreactor, as demonstrated by co-workers who developed a continuous-flow C − Hbenzylic the groups of Ryu and Kappe (Scheme 86)[281, 282]. bromination with NBS using FEP tubing and CFL bulb [290]. This was also applied to the synthesis of 5- bromomethylpyrimidine by Casar and co-workers, applied C − H bromination in the synthesis of Rosuvastatin [291]. O’Brien et al. solved the problem of possible microreactor clogging due to the for- Although elemental bromine is easier to handle than chlo- mation of succinimide by performing the reaction in a slug rine and bromine radicals are more selective when flow with an aqueous phase, allowing in-line separation with a performing HAT, bromination is electronically less liquid-liquid separator [292]. deactivating than chlorination. For this reason, photochem- ical C − H bromination suffers more frequently from C − D bond formation polybromination in unbiased substrates such as cycloalkanes [283]. Through the use of microreactor tech- Deuteration and tritiation of pharmaceutical drug candidates is of nology, Ryu et al. performed the C − H bromination of great importance in the field of drug discovery for the study of cycloalkanes in a residence time of a few minutes using a drug metabolism and pharmacokinetics [293, 294]. Specifically, Scheme 87 Photochemical bromination of aliphatic C(sp )-H bonds in flow 66 J Flow Chem (2020) 10:13–71 Scheme 88 Ir-catalysed ortho-deuteration in flow the synthesis of stable isotopically labelled standards for detec- addressedbyincreasingthemixing efficiency andbycontrolling tion with mass spectrometry techniques is of interest. Stable iso- the reaction temperature carefully. Moreover, the reaction mix- topically labelled standards are usually prepared via a hydrogen ture can be quenched efficiently in flow, limiting the time that isotope exchange reaction in which C − H activation leads to a H sensitive molecules need to be exposed to harsh reaction condi- −DorH − T exchange. The benefits of using gases in flow tions and thus offering options to avoid overreaction due to chemistry have been highlighted extensively in this review. The multiple, consecutive C–H functionalization events. The reac- mass-transfer and safety aspects are of particular importance tivity of C–H bonds can be enhanced by selecting the right when considering the use of D . Noël, Vliegen and co-workers catalyst and use of high reaction temperatures. In flow, such developed a continuous-flow approach to the deuteration of a conditions can be easily reached due to so-called superheating model compound (N-4-methoxyphenyl)-N-methylbenzamide of the reaction mixture (heating above the boiling point) through using an immobilized iridium catalyst (Scheme 88). Starting use of back pressure regulators. In some cases, such boosting of from polystyrene beads functionalized with a diphenylphosphine reaction kinetics allows to even lower the catalyst loading which group, ligand exchange with Crabtree’s catalyst allowed for the is another common hurdle associated with batch C–H immobilization the catalyst. Several reactor designs were tested, functionalization chemistry. Moreover, multiphase reaction mix- including a CSTR, packed bed reactor and the commercial H- tures can be easily carried out in flow allowing to explore new Cube Pro™. In the CSTR, the catalyst particles are suspended as chemical space, e.g. use of gaseous reagents and safe use of a fluidized bed but only allowed deuterium incorporation up to oxygen as a cheap and green oxidant. Also, photochemical M + 2. In the micro-packed bed reactor, deuteration up to M + 7 HAT reactions can be substantially accelerated in flow due to was obtained up to 64% conversion after two runs under 40 bars the homogeneous irradiation of the entire reaction mixture. of pressure. M + 7 only for normal pressure with 54% conver- Due to these apparent advantages of flow C–H sion, 64% conversion has only M + 3 product Employing the functionalization, we anticipate that microreactor tech- commercial H-Cube Pro™ system allows for the direct genera- nology will be more frequently used in the future. tion of deuterium gas from deuterated water, as well as deutera- While some notable advances have been made in recent tion up to M + 7 [295]. years, we believe that the field has barely scratched the surface of what is technologically possible. Moreover, new flow technologies are currently developed in aca- demic and industrial settings, which should allow to Conclusion and outlook provide new and unanticipated opportunities to this promising field. Thus, it is our hope that this review The main limitations of C–H functionalization chemistry arise will serve as a useful starting point for those aspiring from the selectivity and reactivity of C–H bonds. Herein, we to carry out their C–H functionalization chemistry in have shown that continuous-flow processing is able to address flow. at least in part those aspects. Selectivity problems can be J Flow Chem (2020) 10:13–71 67 Acknowledgements We acknowledge financial support from the Dutch 25. Cantillo D, Kappe CO (2014). Chem Cat Chem 6:3286–3305 Science Foundation (NWO) for a VIDI grant for T.N. (SensPhotoFlow, 26. Noel T, Buchwald SL (2011). Chem Soc Rev 40:5010–5029 No. 14150). S.G. is grateful to the European Union for receiving 27. G. Laudadio, T. Noël (2017) In Strategies for Palladium-Catalyzed Erasmus+ grant. A.N. and T.N. acknowledge financial support from Non-Directed and Directed CH Bond Functionalization, Elsevier, AbbVie. pp. 275–288 28. Gemoets HPL, Kalvet I, Nyuchev AV, Erdmann N, Hessel V, Schoenebeck F, Noel T (2017). Chem Sci 8:1046–1055 Open Access This article is licensed under a Creative Commons 29. de Frémont P, Marion N, Nolan SP (2009). 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KaHo Sint-Lieven in Ghent. He then moved to Ghent University to obtain a PhD under the super- Sebastian Govaerts studied vision of Professor Johan Van der chemistry at the Katholieke Eycken (2005-2009). Next, he Hogeschool Leuven and the KU moved to Massachusetts Institute Leuven, Belgium. During his of Technology (MIT) as a bachelor, he worked on radical Fulbright Postdoctoral Fellow trifluoromethylation in the group with Professor Stephen L. of Prof. Wim De Borggraeve. He Buchwald. He currently holds a moved to Eindhoven University position as an associate professor of Technology as an Erasmus+ and he chairs the Micro Flow exchange student during his mas- Chemistry & Synthetic Methodology group at Eindhoven University of ter studies to work in the group of Technology. His research interests are flow chemistry, homogeneous ca- Dr. Timothy Noël, where he talysis and organic synthesis. His research on photochemistry in worked on photocatalytic sp3 C– microfluidic reactors was awarded the DECHEMA award 2017 and the H oxidation chemistry and elec- Hoogewerff Jongerenprijs 2019. He is currently the editor in chief of the trochemical sulfonamide synthe- Journal of Flow Chemistry. sis. He is currently pursuing PhD studies with Dr. Daniele Leonori at the University of Manchester, UK. He is mainly interested in organic reactions involving radicals and the application of enabling technologies to their development. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Flow Chemistry Springer Journals

Pushing the boundaries of C–H bond functionalization chemistry using flow technology

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Springer Journals
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Copyright © The Author(s) 2020
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2062-249X
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2063-0212
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10.1007/s41981-020-00077-7
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Abstract

C–H functionalization chemistry is one of the most vibrant research areas within synthetic organic chemistry. While most re- searchers focus on the development of small-scale batch-type transformations, more recently such transformations have been carried out in flow reactors to explore new chemical space, to boost reactivity or to enable scalability of this important reaction class. Herein, an up-to-date overview of C–H bond functionalization reactions carried out in continuous-flow microreactors is presented. A comprehensive overview of reactions which establish the formal conversion of a C–Hbondintocarbon–carbon or carbon– heteroatom bonds is provided; this includes metal-assisted C–H bond cleavages, hydrogen atom transfer reactions and C–Hbond functionalizations which involve an S -type process to aromatic or olefinic systems. Particular focus is devoted to showcase the advantages of flow processing to enhance C–H bond functionalization chemistry. Consequently, it is our hope that this review will serve as a guide to inspire researchers to push the boundaries of C–H functionalization chemistry using flow technology. . . . . . Keywords Cross coupling C H activation Catalysis Microreactor Flow chemistry Introduction (Fig. 1a)[6–19]. C–H bonds are the fundamental linkage in organic molecules and, consequently, C–H activation strate- The construction of carbon–carbon and carbon–heteroatom gies would allow for very versatile transformations, even ap- bonds is a key objective for synthetic chemists to build up plicable in late-stage functionalizations enabling rapid diver- complex organic molecules. Such bonds are prevalent in sification of hit molecules. This provides an atom-efficient many materials, medicinally and biologically active com- and cost-effective alternative for the traditional cross- pounds. In the most recent decades, these linkages have been coupling strategies. In 2005, the ACS GCI Pharmaceutical forged through transition metal catalyzed cross coupling be- Roundtable have ranked C–H activation as the top priority tween aryl/alkyl halides or pseudo halides and nucleophiles of the aspirational reactions, i.e. reactions which companies (Fig. 1a)[1, 2]. However, such an approach requires would like to use on the proviso that they are available [20, prefunctionalized substrates and coupling partners, often pre- 21]. While C–H activation has indeed been hailed for its use of pared in a multistep reaction sequence, which is time- unfunctionalized starting materials, the applicability of C–H consuming and inefficient. activation chemistry has been limited mainly by the inert na- Inspired by selective biosynthetic pathways [3–5], C–H ture of the carbon-hydrogen bond (bond dissociation energies −1 activation has emerged as a new and promising area for the of aromatic C–H are around 110 kcal mol and of aliphatic −1 construction of carbon-carbon and carbon-heteroatom bonds C–H around 105 kcal mol ). Consequently, in order to cleave the C–H bond, harsh reaction conditions, long reaction times and high catalyst loadings are typically required. Also, stoi- * Timothy Noel chiometric amounts of toxic oxidants are often needed to close t.noel@tue.nl; https://www.noelresearchgroup.com the catalytic cycle. In the past two decades, continuous-flow microreactors have Department of Chemical Engineering and Chemistry, Micro Flow been increasingly used as an interesting new tool to boost Chemistry and Synthetic Methodology, Eindhoven University of chemical reactions. Advantages, such as excellent heat- and Technology, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands 2 mass-transfer, safety of operation and ease of scale-up, have School of Chemistry, University of Manchester, Oxford Road, attracted the interest of both synthetic and process chemists Manchester M13 9PL, UK 14 J Flow Chem (2020) 10:13–71 Fig. 1 a Comparison between classical cross-coupling and C–H functionalization chemistry. b Advantages provided by flow processing in microreactors and its potential impact on C–H functionalization chemistry and allow to perform reactions under conditions that cannot be inclusion of the latter reaction class is debatable as the cleav- easily achieved in conventional batch reactors (Fig. 1)[22–24]. age of the C–H bond occurs in the final deprotonation step and Since the emergence of flow chemistry, a lot of research thus this class cannot be regarded as a formal C–H activation efforts have been devoted to the development of continuous- reaction. However, for reasons of completeness and due to the flow alternatives for cross-coupling chemistry, which even difficulty in determining the operating C–H scission mecha- served as a benchmark reaction for early reactor concepts nism [28], we have chosen to incorporate radical-based C–H [25, 26]. Notably, despite the fact that C–H activation requires functionalization reactions in this review. The advantages of in general harsher reaction conditions than their cross- flow chemistry have been highlighted when- and wherever coupling counterparts, flow approaches for C–H activation appropriate. Hence, we hope this review will serve as a useful have been comparatively rare. However, as shown in guide for those researchers working in C–Hfunctionalization Fig. 1b, many of the advantages that popularized flow pro- chemistry who aspire to implement flow processing in their cessing are also of great use to boost C–H functionalization experiments. and might deliver a solution to the known shortcomings of the field (Fig. 1a). Herein, we provide an overview of those C–H functionalization processes that have been carried out in flow C − H functionalization in flow [20, 27]. The review is structured by highlighting the different bonds that are formed, including carbon–carbon, carbon–ni- C − C bond formation trogen, carbon–oxygen, carbon–sulfur, carbon–halogen and carbon–hydrogen bonds. We have chosen to include a diverse C − H alkylation set of C–H bond functionalizations, including metal-assisted C–H bond cleavages, hydrogen atom transfer (HAT) reactions The insertion chemistry of carbenes represents an interesting and radical C–H bond functionalizations, which involve the and mechanistically distinct case of C −Hfunctionalization addition of radicals to unsaturated systems. Especially the reaction [18]. While carbenes can be formed in a number of J Flow Chem (2020) 10:13–71 15 ways, one of the most well-known approaches is through the compounds. This allowed for the C −Hfunctionalization of thermal, photochemical or metal-catalyzed decomposition of p-cymene and methyl tert-butyl ether (MTBE, with Rh (S-p- diazo compounds [29]. One of the main advantages of flow BrTCP) )and n-pentane (with a Rh ( R-3,5- 4 2 chemistry, in particular when looking at industrial applica- di)p- BuPh)TPCP) catalyst) via C − H insertion of the tions, is the ability to perform reactions which would ordinar- carbene generated from the parent diazo compound (Scheme ily be considered hazardous in a safe manner, as the reacting 1)in batch [44]. However, both the price of the noble metal volumes at any given time are typically very small [30, 31]. rhodium and the catalyst ligands are a non-negligible cost. Many reports have appeared on the synthesis and chemistry of Provided leaching can be kept to a minimum and high the synthetically useful but unstable diazo compounds in enantioselectivities maintained, catalyst immobilization is an continuous-flow microreactors [32–43]. attractive strategy, both from an economical and environmen- Many routes to access diazo compounds exist, e.g. the di- tal point of view. The Rh (S-p-BrTCP) catalyst in particular 2 4 azo transfer reaction. While a reliable approach, it suffers from shows enantioselectivity for the challenging functionalization poor atom economy as stoichiometric amounts of sulfonamide of primary C − H bonds. As demonstrated by Jones, Davies waste products are formed. A straightforward approach to and co-workers, the catalyst can be grafted on silica particles access diazo compounds is via oxidation of the corresponding by exchanging one of the ligands of the rhodium catalyst with hydrazones. The oxidation can be carried out with insoluble a ligand bearing an alkyne functionality. The silica particle can MnO , or a solid-supported oxidant can be used, such as N- be connected with an azide-bearing silane, allowing covalent iodo-p-toluenesulfonamide potassium salt (PS-SO NIK). linking through the azide-alkyne click reaction with no appar- Using an excess of the supported oxidant PS-NIK (5 equiva- ent loss of selectivity (Scheme 2)[45]. lents), Davies et al. converted hydrazones to donor-acceptor The inside of the PTFE tube is coated with the fiber diazo compounds in flow for subsequent application in C − H containing the silica particles. As such, the liquid is functionalization reactions using enantioselective Rh(II) forced to flow through the fiber in an axial direction. catalysis. Application of the poly(amide-imide) material Torlon rep- Critical to the success of the transformation is the elimina- resents a notable improvement over the previous reported tion of water (which would result in the formation of O − H reactor design, also reported by the groups of Jones and insertion products) and the removal of trace iodine leaching Davies andappliedtoaC − H functionalization reaction from the oxidant column. By constructing a modular flow set- [46], making use of a radial flow through cellulose fibers, up consisting first of an oxidant column, followed by a col- which were incompatible with chlorinated solvents. This umn packed with 4 Å molecular sieves and sodium thiosul- was an important drawback, as this necessitated the use of fate, both water and iodine were removed from the reagent hydrocarbon solvents, e.g. hexane, which can undergo C stream giving access to a series of push-pull diazo − H insertion with carbenes, thereby functioning as an Scheme 1 Enantioselective C − H functionalization in flow through rhodium catalysis 16 J Flow Chem (2020) 10:13–71 4− The polyoxometalate decatungstate (W O ) is a useful 10 32 photocatalyst for the direct activation of hydridic C − Hbonds through hydrogen atom transfer (simultaneous abstraction of a proton and an electron). Upon irradiation with near-UV light (λ TBADT = 323 nm) it undergoes ligand-to-metal charge max transfer (LMCT), giving rise to a first excited state [W O 10 32 ]* with a lifetime of 30 ps. It decays into the second excited state known as wO, in which the bridging oxygen atoms of the cluster have partial radical character, with a lifetime of 55 ± 20 ns. The second excited state can be quenched through participation in both single-electron transfer (SET) or hydro- gen atom transfer (HAT) events [48]. Acting as electrophilic radicals, the bridging oxygen atoms of the cluster are able to engage in selective hydrogen atom transfer (HAT). Decatungstate is usually prepared as the sodium or tetrabutylammonium salt, the latter showing enhanced solu- bility in organic media (acetonitrile or DCM). Upon abstrac- Scheme 2 Silica-immobilized Rh (S-p-BrTCP) (S-p-TPCP) 2 3 tion of the hydrogen atom, the one electron-reduced form of + 5− the catalystisformed, H [W O ] , which has a deep blue 10 32 alkylating agent. Aditionally, the axial hollow-fiber design colour, as well as a carbon [49]or silicon-centered [50]radi- allows to drastically reduce the amount of chlorinated cal. The nucleophilic alkyl radicals thus formed can be trapped solvent necessary, reducing the environmental footprint with suitable electrophilic acceptors, e.g. electron-poor olefins of the reaction, while the turnover number (TON) was (Giese type reaction) or electron-poor (hetero)arenes (Minisci increased (Scheme 3 and 4). type reaction). After formation of the adduct, the resulting After 10 consecutive runs with the same immobilized radical reoxidizes and deprotonates the catalyst to close the catalyst to couple 4-methoxytoluene and hydrazone, the catalytic cycle. Several transformations involving the yield was only slightly lower, dropping from 74% to decatungstate catalyst in continuous-flow will be discussed 65%, while the enantioselectivity remained unchanged in this review, encompassing the C − H activation of alkane (89 to 86% ee). These results are comparable with the substrates, ethers and aldehydes for the direct alkylation, ac- results obtained for the homogeneous catalyst under ylation, fluorination and oxygenation, depending on the radi- batch conditions [47]. cals and the coupling partners involved. Scheme 3 Merger of the flow synthesis of diazo compounds and Rh catalyst immobilization to achieve enantioselective carbene C − Hinsertion J Flow Chem (2020) 10:13–71 17 Scheme 4 Catalytic cycle for decatungstate-catalyzed C − H alkylation Building on previous work on C − H alkylation through state of decatungstate. They can undergo coupling with decatungstate photcatalysis [51–57], Fagnoni et al. reported electron-poor olefinic partners (e.g. maleates, phenyl vinyl the alkylation of a series of electron-poor olefins under flow sulfone and diisopropyl azodicarboxylate, the latter allowing conditions by construction of a 50 ml mesoscale (i.d. 2.1 mm) the formation of C −Nbonds, Scheme 5)[58]. photoflow reactor consisting of a 500 W medium pressure Hg Zuo and co-workers were able to activate light (C -C ) 1 4 vapor lamp and FEP (fluorinated ethylene propylene) tubing, gaseous alkanes using cerium photocatalysis in flow. Their decreasing the required reaction time for the transformation strategy relies on the formation of Ce(IV) alkoxy com- from 6 to 2 h. Alkylating agents include simple cycloalkanes, plexes which undergo ligand-to-metal charge transfer cyclic ethers, e.g. oxetane, and 1,3-benzodioxole, which form (LMCT) under 400 nm irradiation, generating highly elec- nucleophilic alkyl radicals upon quenching of the wO excited trophilic alkoxy radicals (through homolytic fragmentation Scheme 5 Decatungstate catalyzed C − H alkylation of electron-poor olefins 18 J Flow Chem (2020) 10:13–71 Scheme 6 Catalytic cycle for the Minisci alkylation of azines through cerium photocatalysis of the cerium-oxygen bond) and Ce(III). The electrophilic cationic intermediate which rearomatises upon loss of a alkoxy radicals can then operate as HAT catalysts by proton, i.e. a Minisci reaction) rather than through reduc- abstracting hydridic hydrogens, such as those found in tion of the radical adduct to an anionic species (as in the methane and ethane, to form the corresponding nucleophil- case of addition of nucleophilic alkyl radicals to DBAD and ic alkyl radical (polarity matching-strategy). The alkyl rad- electron-poor olefins, the Giese reaction) which undergoes ical can be trapped for the alkylation of electron-poor ole- protonation to form the alkylated product. fins, heteroarenes and DBAD (N-di-Boc azadicarboxylate). All of the linear gaseous alkanes were successfully After addition, the radical adduct reoxidizes Ce(III) to employed in radical alkylation reactions of DBAD, electron- Ce(IV), though an external oxidant, (NH ) S O ,isre- poor olefins and azines. The alkylation of the Boc-protected 4 2 2 8 quired for the rearomatisation of azine substrates DBAD was performed in less than 15 min residence time, (Scheme 6). A plausible explanation for this is that they using both gaseous and liquid alkanes (cyclohexane), in a are functionalized through oxidation of the radical adduct glass microreactor with a volume of 4.5 ml and various alkane formed during the C–Cbondforming-step(resultingina pressures in the range of 400–1800 kPa (Scheme 7)[59]. Scheme 7 C − H functionalization of gaseous alkanes via cerium photocatalysis J Flow Chem (2020) 10:13–71 19 Scheme 8 C − H alkylation through Eosin Y HAT photocatalysis Eosin Y is a common organic photocatalyst in photoredox nucleophilic species, the substrate scope was explored with catalysis because the excited T state formed under visible electron-poor coupling partners. Malononitriles are electro- light irradiation (green light) acts as a one-electron transfer philic olefins and good coupling partners for nucleophilic rad- agent under basic conditions [60]. Recently, two new reactiv- icals (Scheme 8). A series of α,β-unsaturated compounds ity modes of excited state Eosin Y were reported [61]. Wang were tested, the reaction proving to be compatible with amide, and co-workers discovered that Eosin Y can act as a imide, nitro and sulfone functionalities. An interesting cou- photoacid, which allowed the synthesis of 2- pling partner for nucleophilic radicals is 2-vinylpyridine, pro- deoxyglucosides from glycals [62], while Wu and co- viding the hydroalkylated Giese product with THF as the rad- workers discovered Eosin Y can act as a direct hydrogen atom ical coupling partner in 60% yield. 2-vinylthiophene was also transfer (HAT) catalyst under neutral conditions. Under irra- supported in the transformation when the double bond bears diation with white light, the T state of Eosin Y is generated. the electron-withdrawing phenyl ketone moiety. Analogous to decatungstate (vide supra), as an oxygen- The reaction was adapted to flow to enable scale-up, al- centered radical it acts as an electrophilic HAT catalyst suc- though elevated temperatures (50–70 °C) were required with cessfully activating hydridic C − H bonds to create nucleophil- the alkyl coupling partner (THF, i-PrOH) serving as the sol- ic alkyl radicals. The scope of the transformation was explored vent. Further, a polar solvent which does not contain a in regard to the substrate undergoing HAT. Ethers, thioethers, hydridic hydrogen atom is required (t-BuOH was found to amides and alcohols were successfully activated at the α-po- be suitable in the Giese reaction of 2-ethyl-propen-3-one with sition. Acyl radicals could be generated from aldehydes (no- benzaldehyde). The mechanism of the reaction is particularly tably, 2-pyrrole carboxaldehyde was successfully activated) intriguing (Scheme 9), since earlier reports have demonstrated while alcohols undergo functionalization at the hydroxyl Eosin Y to be photoactive as an anion (either the anion or group-bearing carbon. As carbon-centered radicals are dianion) under basic conditions. Scheme 9 Catalytic cycle for the Eosin Y catalysed C − H alkylation via HAT 20 J Flow Chem (2020) 10:13–71 ox − · Several experiments were performed to elucidate the mech- (E (Cl /Cl ) = +2.03 V vs. SCE). Based on these principles, anism. Under irradiation with different wavelengths of light, the Wu and co-workers developed a photocatalytic strategy highest conversions (99%) were achieved with blue and white employing chlorine radical as the HAT catalyst in conjuction light, which corresponds to the absorption maximum of neutral with Mes-Acr as the oxidant. After excitation with 450 nm Eosin Y. The maximum of absorption of the anionic forms is light (blue LEDs), the excited state of Mes-Acr is quenched centred on longer wavelengths, i.e. green light, which in this by chloride delivered to the solution as molecular HCl, forming case resulted in lower conversion (75%). The luminescence of the chlorine radical. As an electrophilic radical species, it is able neutral excited state Eosin Y was not quenched by THF or to activate hydridic C − H bonds in a variety of substrates, e.g. phenyl vinyl sulfone, ruling out the operation of sensitization 3 °C-H and aldehydic C − H bonds, as well as the α C − Hbond or SET as the quenching mechanism. Additionally, cyclic volt- of alcohols, ethers and amides, while preferring a distal ammetry (CV) studies performed in acetone have shown Eosin functionalization in ketones. Y is neither able to oxidise THF nor reduce phenyl vinyl sul- Similar reactivities are observed with other electrophilic radi- fone. The transient intermediates involved in photochemical cal species discussed in this article, i.e. the second excited state of processes can be studied with laser flash photolysis, where the the decatungstate photocatalyst, wO, and oxygen radicals gener- sample is excited with a very short laser pulse (in this particular ated through fragmentation of a labile oxygen-metal bond (like case on the microsecond time scale) after which the absorption cerium, Zuo and co-workers, vide supra), although the selectivity properties and lifetimes of the excited states generated during of HAT depends on the species (polar and steric effects). The the flash can be measured. Moreover, it allows elucidation of nucleophilic alkyl radicals thus formed were trapped with the photochemical reaction pathways as the absorption of the ex- electron-poor olefin benzylidenemalononitrile (Scheme 10). cited states of transient species such as radicals will be Notable is the successful activation of the primary C − H bond quenched due to the shortening of their lifetimes if a suitable in ethane, which was then applied in a series of alkylation reac- reactant is present. After excitation of a THF solution of Eosin tions. Aside from benzylidenemalononitrile, unsaturated phenyl Y with a 470 nm laser, two intermediates were detected with sulfonesalsoprovedtobe suitableradical traps, settingthe stage lifetimes of 20.6 (absorbing at 329 nm) and 21 (absorbing at for C − H allylation reactions as the phenyl sulfone moiety easily 543 nm) μs, which the authors assigned to the T excited state undergoes elimination. of *Eosin Y. After decay of these intermediates, a new interme- The radical adduct formed after trapping of the nucleophil- diate with a lifetime of several milliseconds was detected, indi- ic alkyl radicals with an unsaturated species reoxidises the cating it could be the product formed after HAT to triplet Eosin reduced form of Mes-Acr , closing the catalytic cycle, Y, i.e. H–Eosin Y. Most importantly, the lifetime of this inter- forming a carbanion which is protonated by HCl to release mediate was shortened to 1 ms in the presence of phenyl vinyl chloride (Scheme 11). The cycle involving phenyl sulfones is sulfone which is required for the completion of the catalytic slightly different, as addition of the radical to the unsaturated cycle. Finally, DFT calculations show that two mechanisms moiety of the sulfone yields an olefin product and a sulfonyl could operate in the final step of the catalytic cycle. One is radical, the latter being the species re-oxidising the catalyst the reduction and protonation of the radical adduct by H– and deprotonating hydrochloric acid [67]. −1 Eosin Y (E =32.3 kcal mol ), or an additional THF molecule Due to the ease with which amines are oxidised, amines could be oxidised by the radical adduct, the anion of which then are common substrates in oxidative methodologies. After −1 deprotonates Eosin Y (E =19.9 kcal mol ). Although this initial oxidation of an amine to form an aminium radical, indicates the latter pathway to be more likely, on the basis of deprotonation by another equivalent of amine then leads to deuterium labelling studies direct proton – andelectrontransfer the formation of an α-amino radical, which is itself easily between the adduct and H–EosinYcouldnot be ruledout [63]. oxidised to an iminium ion. The oxidation of amines under An increasing amount of reports on dual catalytic strategies basic or neutral conditions generally yields α-amino radi- have appeared in the scientific literature during the last few cals, unless the reaction is kinetically favourable enough to years [64–66]. Most of these newly developed methodologies compete with this process, which was demonstrated ele- seek to combine the strengths of transition metal catalysis for gantly in a series of challenging photocatalytic cross-coupling reactions with the advantages offered by hydroamination methodologies developed by Knowles photoredox catalysis for the generation of reactive radical inter- and co-workers [68–70]. Additionally, amines are com- mediates, allowing an unprecedented amount of novel reactions monly used as sacrificial oxidants in reductive quenching to be developed to forge carbon-carbon bonds. Seminal contri- cycles of transition metal photocatalysts. The reactivity of butions to the field were made, inparticular,bythe groupof α-amino radicals in particular has been thoroughly ex- MacMillan. The excited state of the Fukuzumi catalyst, 9- plored, especially in the case of tetrahydroisoquinolines, mesityl-10-methylacridinium (Mes-Acr ) perchlorate, is a pow- in which the resulting α-amino radical is benzylic and rel- erful oxidant (excited state reduction potential of +2.06 eV), atively long-lived. As a consequence, many with the ability to oxidise the chloride ion to a chlorine radical functionalizations of this position have been reported J Flow Chem (2020) 10:13–71 21 Scheme 10 C − H functionalization of sp C − H bonds via Mes-Acr /HCl dual catalysis [71–75]. The properties of these radicals were exploited by an oxidative Ugi multicomponent reaction was developed the group of Rueping for the development of a series of combining N,N-dimethylanilines, isocyanides and water as photoredox catalytic cross-dehydrogenative coupling reaction partners giving access to α-amino amides. (CDC) reactions under flow conditions in which tertiary Although recirculation of the mixture proved necessary to aryl amines can be coupled with a variety of nucleophiles. obtain the α-amino amides in high yield, it represents a The organic dye Rose Bengal was identified as the most drastic improvement over batch conditions, e.g. N-butyl- suitable catalyst for the transformation, rendering the pro- 2-(methyl(phenyl)amino)acetamide was formed in 29% cess highly sustainable as H is formally the only waste yield after 3 days of reaction time in batch, whereas an product in a cross-dehydrogenative coupling reaction. A isolated yield of 60% was obtained in flow with recircula- series of substituted N-aryl tetrahydroisoquinolines under- tion after 20 h [77]. go C − H alkylation with nitroalkane and malonate cou- The introduction of fluorine-containing substituents in or- pling partners. Coupling with TMSCN produces α-amino ganic compounds is of great importance in the development of nitriles (yielding α-amino acids upon hydrolysis). pharmaceuticals, as the high electronegativity of fluorine can Phosphonylated products can be accessed through reaction be applied in the modulation of basicity, lipophilicity and bio- with diethyl phosphonate in 3–5 h residence time, availability, as well as increasing metabolic stability [78]. representing an improvement over batch procedures previ- Methods for fluorination and fluoroalkylation are thus contin- ously reported (Scheme 12)[76]. Following these insights, uously being developed. Scheme 11 Catalytic cycle of the Mes-Acr /HCl C − H functionalization 22 J Flow Chem (2020) 10:13–71 Scheme 12 Photoorganocatalysed oxidative CDC of tetrahydroisoquinolines with carbon and phosphorus nucleophiles A traditional approach to aromatic trifluoromethylation is trifluoromethyl radical. The resulting radical adduct is then the Swarts reaction, which is the substitution of a oxidised. Following deprotonation, the trifluoromethylated trichloromethyl group (formed after perchlorination of an ar- silyl enol ether then equilibrates to the ketone. Both the for- omatic methyl group) to trifluoromethyl with SbF .Modern mation of the silyl enol ether and the trifluoromethylation step approaches make use of electrophilic or nucleophilic occur in less than 20 min overall residence time. In these trifluoromethylating agents, such as Togni’s reagent or conditions, both the use of more expensive silylating agents, Umemoto’sreagent [79]. Radical trifluoromethylation strate- gaseous CF I and transition metal photocatalysts are avoided gies are particularly attractive as C − H functionalization reac- by employing Eosin Y as an environmentally benign and in- tions do not require prefunctionalized substrates [80, 81]. A expensive photoorganocatalyst [83]. number of trifluoromethylation methodologies have been de- From the viewpoint of atom economy, CF Iis anat- veloped under continuous-flow conditions, making use of dif- tractive trifluoromethyl source, forming only iodide as ferent kinds of trifluoromethylating agents, and will be waste product. Although perfluoroalkylation starting from discussed below. C-5 chains can be performed under homogeneous reaction Building on the work completed by the group of conditions as the perfluoroiodoalkanes become liquids at MacMillan on the α-trifluoromethylation of carbonyl com- ambient temperatures, CF I is a gaseous reagent, which is pounds with CF I and Ru photocatalysis [82], Kappe and cumbersome to handle under batch conditions, while gas- co-workers applied the liquid reagent triflyl chloride es can be conveniently handled under flow conditions (CF SO Cl) to the α-trifluoromethylation of ketones via a [84]. 3 2 two-step continuous-flow strategy (Scheme 13). A mixture Noël et al. developed a photocatalytic protocol for the of the organic photocatalyst Eosin Y, trimethyl silyl triflate trifluoromethylation and perfluoroalkylation of heteroarenes with (TMSOTf) and ketone is mixed with the base, N,N- CF I under continuous-flow with a [Ru(bpy) ]Cl photocatalyst 3 3 2 diisopropyl ethylamine (DIPEA) in a T-mixer allowing both and TMEDA (N,N,N′,N′-tetramethylethane-1,2-diamine) as the the formation of a silyl enol ether and deprotonation of Eosin base. The trifluoromethylation and perfluoroalkylation can be Y (2 min residence time), which is a pH sensitive performed in <1 h of reaction time (Scheme 14)[85]. The scope photocatalyst (basic conditions being required in its use as a of the transformation was expanded, and the organic dye Eosin Y single-electron reductant). Using a second T-mixer, triflyl also proved a viable photocatalyst for the transformation, provid- chloride (1.5 eq. in THF) is added to the reagent stream en ing a greener alternative to Ru photocatalysis [86]. Stern-Volmer route to the photoreactor consisting of FEP tubing coiled kinetics [87] show that the reaction occurs through a reductive around a glass beaker irradiated by a compact fluorescent light quenching cycle of the Ru photocatalyst (Scheme 15)[88]. bulb (CFL) placed inside the beaker. The unsaturated moiety After activation of the Ru(II) photocatalyst through irradi- of the silyl enol ether functions as a radical trap towards the ation with blue light, the excited state is quenched through J Flow Chem (2020) 10:13–71 23 Scheme 13 α-trifluoromethylation of ketones by Eosin Y photocatalysis SETwith TMEDAwhich serves as a sacrificial electron donor, challenging substrates in radical reactions due to their tenden- forming a Ru(I) species which can then reduce the cy towards polymerisation and oxidation. In fact, the low ox- trifluoromethyl iodide, generating the iodide ion and the idation potentials of styrenes allow their anti-Markovnikov trifluoromethyl radical. After addition of the trifluoromethyl functionalization with nucleophiles, an approach pioneered radical to the arene, the resulting adduct is thought to be by the group of Nicewicz [89 –96]. Radical oxidised by the radical cation of TMEDA and then undergoes trifluoromethylations of styrenes were reported requiring rearomatisation through the loss of a proton. electron-donating groups in the ortho position or β-substitu- Leaving the realm of Minisci-type reactions (i.e. the radical tion on the olefin tail [94, 97]. When the trifluoromethylation C − H functionalization of arenes), the conditions were is performed in the presence of the powerfully reducing adapted to the functionalization of styrenes, which are photocatalyst fac-Ir(ppy) , Stern-Volmer kinetics proved the Scheme 14 Photocatalytic trifluoromethylation in flow using CF I 3 24 J Flow Chem (2020) 10:13–71 Scheme 15 Catalytic cycle for the radical trifluoromethylation of heteroarenes with CF Iby 2+ [Ru(bpy) ] photocatalysis reaction occurs through an oxidative quenching cycle via and accelerating the reaction under flow conditions (24–72hin quenching of the excited state with CF I. The benzylic radical batch to 0.5 – 1 h in flow) allows the reaction to occur with high formed after anti-Markovnikov addition of the trifluoromethyl levels of stereocontrol. Indeed, longer reaction times were shown radical to the styrene substrate can be reoxidized by the Ir(IV) to lead to reduced levels of stereoselectivity (Scheme 17)[100]. species formed after oxidative quenching. Following depro- A non-photocatalytic approach to trifluoromethylation un- tonation of the benzylic cation by CsOAc, the olefin function- der flow conditions using CF I as the trifluoromethylating ality is restored (Scheme 16). agent was developed in the group of Kappe by employing Alternatively, if the reaction is performed in the presence of a Fenton-type conditions [101] (developed in the group of the hydrogen donor, the hydrotrifluoromethylated product is obtain- late Francesco Minisci) for the generation of alkyl radicals ed. Thiophenols in particular are frequently applied as hydrogen from alkyl iodides [102]. donors in radical hydrofunctionalization reactions. In this case, 4- By combining catalytic amount of iron(II)sulfate heptahydrate hydroxythiophenol proved optimal. A distinct advantage of and hydrogen peroxide as the oxidant (generally known as performing the transformation under continuous-flow is the fact Fenton’s reagent), the trifluoromethylation of heteroarenes can that the Ir(ppy) photocatalyst, which has a high triplet energy, be performed in a residence time of just a few seconds promotes olefin isomerisation via sensitization of the olefin (Scheme 18). The use of DMSO as solvent is key to the success (triplet-triplet energy transfer, TTET) [98]. As a diradical, the of the transformation, as this allows the reaction to be performed T state of the olefin can undergo rotation leading to the forma- in a more reliable and reproducible way. Fe(II) reduces hydrogen tion of the (Z)-isomer [99]. Due to its higher thermodynamic peroxide, forming Fe(III), a hydroxyl anion and a very reactive stability, the (E)-isomer is thought to be kinetically favoured, hydroxyl radical, the latter which forms an adduct with DMSO. Scheme 16 Catalytic cycle for the trifluoromethylation of styrenes through oxidative quenching of fac-Ir(ppy) with CF I 3 J Flow Chem (2020) 10:13–71 25 Scheme 17 Radical trifluoromethylation of styrenes with CF I through Ir photocatalysis After expelling methylsulfinic acid, a highly reactive meth- the trifluoromethylated analog of dihydroergotamine shows yl radical is formed which then undergoes a thermodynami- promise as a cheap anti-migraine agent with reduced side ef- cally favourable halogen atom transfer reaction with the fects, and is thus an interesting target for the scope of radical perfluoroalkyl iodide present. This leads to the formation of trifluoromethylation methodologies [107]. Due to the short methyl iodide and the comparatively stable perfluoroalkyl rad- residence time of less than 10 s, an impressive amount of ical. After addition to the arene, the resulting adduct is 600 g of dihydroergotamine mesylate could be processed in reoxidized by Fe(III) to form Fe(II) and a cation, which forms 5 h with 98% conversion and a selectivity of 85–86% the desired product after loss of a proton (Scheme 19). (Scheme 20)[108]. As a readily available and low-cost chem- The reaction shows excellent scalability, as shown by the ical reagent, trifluoroacetic acid (TFA) would be an attractive trifluoromethylation of the pharmaceutically relevant anti- source of the trifluoromethyl radical. Although the oxidation migraine agent, dihydroergotamine. It is a semi-synthetic de- of TFA has been reported to generate trifluoromethyl radicals rivative of ergotamine, a natural product found in the ergot rye by electrochemical means, harsh conditions are required due fungus, Claviceps purpurea [103, 104]. Due to nausea being a to the high oxidation potential of TFA, which drastically limits common side effect, dihydroergotamine treatment is being the scope of these methodologies. Hence, trifluoromethylation superseded by application of the more selective via an oxidative decarboxylation approach commonly follow- sulfonamide-bearing tryptamines, known as the triptan drugs, ed in photoredox catalysis [109] to generate alkyl radicals is of which sumatriptan is a prominent example, which also have impractical in the case of TFA. By installing a redox auxiliary a higher cost associated with their use [105, 106]. However, group, Stephenson and co-workers managed to bring the Scheme 18 Fe-catalyzed trifluoromethylation – and perfluoroalkylation of arenes with CF I 3 26 J Flow Chem (2020) 10:13–71 Scheme 19 Catalytic cycle for the Fe-catalyzed trilfluoromethylation with CF I oxidation potential of TFA within the electrochemical poten- excited state of the Ru photocatalyst is quenched by the 2+ tial range of [Ru(bpy) ] . The redox auxiliary approach relies trifluoroacetoxy pyridinium adduct, delivering the in this case on the reaction between pyridine N-oxide and trifluoroacetate radical, forming the trifluoromethyl radical trifluoroacetic anhydride (TFAA), forming an adduct in which upon decarboxylation (Scheme 21). the weak N-O bond can be cleaved reductively. Stern-Volmer As is common for photochemical transformations, the re- kinetics point to an oxidative quenching cycle in which the action showed limited scalability in batch. When scaling up Scheme 20 Scale-up of the Fe(II)/CF I/H O radical trifluoromethylation for the production of a trifluoromethylated ergotamine derivative on 600 g 3 2 2 scale J Flow Chem (2020) 10:13–71 27 Scheme 21 Radical trifluoromethylation with TFAA/pyridine N-oxide via Ru photocatalysis the trifluoromethylation of N-Boc pyrrole to 100 g scale, the presented, opening up another possibility for the fragmentation product was obtained in a modest yield of 35% after a reaction of the trifluoroacetylated pyridines, although this is limited to a time of 62 h. few specific cases, e.g. mesitylene [117]. As discussed previously, one of the main advantages of flow Sodium trifluoromethanesulfinate (CF SO Na), common- 3 2 photochemistry is its inherent scalability [110–115]. ly known as the Langlois reagent, has found wide application Performing the reaction under flow conditions yielded 71% of in radical trifluoromethylation reactions, including in the the trifluoromethylated N-Boc pyrrole (20 g scale, 10 min Minisci-type functionalization of heteroarenes [118–122]. residence time, Scheme 22), compared to 57% yield on 20 g Multiple equivalents of an external oxidant, such as t- scale in batch (15 h reaction time) [116]. A later report elabo- BuOOH, are usually required to oxidise the sulfinate and ef- rating on the mechanistic aspects of the reaction includes scale- fect SO extrusion to form the trifluoromethyl radical up of the trifluoromethylation of an N-Boc protected pyrrole [123–125]. As a bench-stable solid, it is one of the most con- bearing a methyl ester functionality to 1 kg scale (V =150 mL), venient to handle trifluoromethylation agents [119]. Long re- −1 in which a productivity of 20 g h was achieved. Additionally, action times and multiple additions of the sulfinate salt are evidence for the formation of EDA (electron donor-acceptor) usually required. The conditions originally reported by complexes between the pyridine-N-oxide and arenes is Langlois and co-workers make use of a Cu(I) additive to Scheme 22 Radical trifluoromethylation with TFAA/pyridine N-oxide via Ru photocatalysis 28 J Flow Chem (2020) 10:13–71 Scheme 23 Trifluoromethylation of coumarins by Duan et al promote cleavage of the peroxide bond, which initiates the oxidation of the sulfinate by the T state of 4,4′- reaction. Duan et al. adapted the conditions of the original dimethoxybenzophenone forming the trifluoromethyl radical Langlois trifluoromethylation reaction to continuous-flow (vide supra) and a ketyl radical which deprotonates the acidic (60 °C, 40 min residence time) to generate a library of HFIP. The radical adduct formed after addition of the trifluoromethyl-substituted coumarins (Scheme 23)[126]. trifluoromethyl radical to the double bond of the maleimide is Rueping and co-workers applied the Langlois reagent to then proposed to abstract a hydrogen atom from the alcohol, the hydrotrifluoromethylation of maleimides (representing resulting in the hydrotrifluoromethylation of the olefin and electron-poor olefins) and heteroarenes with 4,4′- regenerating the ketone functionality of the catalyst closing dimethoxybenzophenone as an organic HAT catalyst under the catalytic cycle (Scheme 25). The strongly oxidising iridium near-UV irradiation (350 nm) (Scheme 24). photocatalyst [Ir(dF(CF )ppy) ](dtbpy)]PF was also found to 3 2 6 The reaction requires the presence of hexafluoroisopropanol be a suitable visible light photocatalyst for this transformation, (HFIP) as an additive, a reaction medium with high polarity improving the yields under similar reaction conditions [130]. known to stabilize polar intermediates such as radicals Through application of the luminescence screening ap- [127–129]. The authors propose a mechanism based on the proach developed in the group of Glorius [131], Noël, Scheme 24 Photoorganocatalytic trifluoromethylation of maleimides and arenes J Flow Chem (2020) 10:13–71 29 Scheme 25 Catalytic cycle for radical trifluoromethylation with CF SO Na under benzophenone 3 2 catalysis Alcaza r a n d co-workers confirmed t he cycle, forming bromide ion and the malonyl radical [133, 134]. [Ir(dF(CF )ppy) ](dtbpy)]PF photocatalyst is quenched effi- The transformation was also reported using organic photoredox 3 2 6 ciently by the Langlois reagent. On the basis of these findings, catalysts (e.g., Th-BT-Th) [135]. By calculating the spectro- a continuous-flow trifluoromethylation of highly functional- scopic properties and reduction potentials with DFT at the ized heteroarenes was developed. Although the reaction pro- M06-2X / 6-31G+(d) level of theory using the continuum sol- ceeds in 30 min of residence time, 1 equivalent of an external vation model PCM, a series of alkynylated bithiophenes were oxidant, (NH ) S O , is required for the reaction to occur in synthesized for their evaluation as potential photocatalysts by 4 2 2 8 synthetically useful yields, since two consecutive oxidations Alcazar, Noël and co-workers, the alkynes functionalized with are required (Scheme 26)[132]. phenyl substituents bearing both electron-releasing and Stephenson and co-workers reported the alkylation of electron-withdrawing groups. To benchmark their performance, 2+ heteroarenes by quenching of excited state [Ru(bpy) ] by the thiophene photocatalysts were applied in the C −Halkyl- bromomalonate through an oxidative Ru(III)/Ru(II) quenching ation of heteroarenes with bromomalonate and Ph Nas the Scheme 26 Trifluoromethylation of heteroarenes with CF SO Na 3 2 via Ir photocatalysis 30 J Flow Chem (2020) 10:13–71 2+ base, proving viable alternatives to [Ru(bpy) ] .Five- Ravelli and co-workers trapped the acyl radicals with phe- membered heterocycles such as pyrrole, thiophene and furan nyl vinyl sulfone under flow conditions to form the derivatives can be alkylated with 1 mol% of the photocatalyst hydroacylated product. Using a modular set-up, the sulfonyl (PC) through irradiation with purple LEDs (400 nm), as well as moiety can be removed in a second flow module with base benzofurans and indole derivatives, including N-Boc-Trp-OMe (tetramethylguanidine, TMG or triazabicyclododecene (55% isolated yield, Scheme 27). The alkylation of 3- supported on polystyrene, TBD-PS) to form an α,β-unsatu- methylindole was performed in continuous flow and afforded rated ketone, which can then undergo conjugate addition. This the alkylated product in 70% yield in 7 min residence time. The was applied to the synthesis of γ-nitroketones and β-(3- catalysts were also applied to other C − H alkylations of indolyl)ketones with nitroalkanes and indole as nucleophiles, heteroarenes, ie. trifluoromethylation (with CF Iand respectively. Starting from O-Boc protected salicylaldehyde TMEDA, 20 min residence time, 450 nm LEDs) and followed by acylation of phenyl vinyl sulfone, both the sulfo- difluoromethylation (using BrCF CO Et as the reagent) [136]. nyl and the carbonate protecting group are cleaved under basic 2 2 conditions, after which the product undergoes an intramolec- ular cyclization to afford chromanone (35% overall yield, C − Hacylation Scheme 29)[140]. In contrast to the C-3 formation of β-(3-indolyl)ketones ac- Aldehydes are excellent hydrogen atom donors in decatungstate complished through decatungstate photocatalysis, the C-2 acyla- HAT photocatalysis [137, 138]. By irradiation with near UV light tion of indoles to yield α-(2-indolyl)ketones in flow via a dual (λ TBADT = 323 nm), acyl radicals are formed via HAT with max catalytic cycle with Pd and Ir involving acyl radicals at room the decatungstate catalyst (we refer to Scheme 4 for the catalytic temperature was reported by Noël, Van der Eycken, and co- cycle, R = acyl radical) (Scheme 28). workers. The acyl radicals are formed from aldehydes through Fagnoni and co-workers used α,β-unsaturated esters as HAT with the tert-butoxyl radical. The tert-butoxyl radical is radical traps to form γ-ketoesters. The reaction was performed formed by engaging t-BuOOH in an oxidative Ir(III)/Ir(IV) in 2 h of residence time in a photoflow reactor constructed quenching cycle with the iridium photocatalyst (i.e. photocata- from PTFE tubing (12 ml reactor volume), a medium pressure lytic Fenton initiation). Pd(OAc) activates the C-2 position of Hg lamp and a HPLC pump. By introducing a second reagent 2 the indole assisted by a pyrimidine directing group and is hy- stream containing 0.4 M of NaBH in EtOH as a reductant to pothesized to react with the acyl radical to form an acylated the product stream exiting the photoflow reactor, the ketone Pd(III) species, which is oxidised by Ir(IV) to a Pd(IV) species, functionality is reduced to an alcohol and undergoes intramo- closing the photocatalytic cycle. Upon reductive elimination, the lecular cyclisation to form a γ-lactone product, e.g. the lactone C-2 acylated product is formed and the Pd(II) center is regener- condensation product obtained from heptan-2-one and diethyl maleiate is formed in a 65% overall yield [139]. ated, closing the “dark” catalytic cycle (Scheme 30). Scheme 27 C − H alkylation of heteroarenes with bithiophene photocatalysts J Flow Chem (2020) 10:13–71 31 Scheme 28 Flow synthesis of γ-lactones via decatungstate photocatalyzed C-H acylation followed by reductive intramolecular cyclization A range of aromatic, heteroaromatic (including furfural, a C − Hcarboxylation andC − H cyanation biomass-derived feedstock) and aliphatic aldehydes undergo ac- ylation with several substituents being tolerated on the indole The selective activation of carbon dioxide has long stood as one ring, although the absence of a directing group (e.g. pym, py) of the holy grails of chemistry [142–145]. The reduction of CO was not tolerated (Scheme 31). By performing the reaction in using the organic photoredox catalyst p-terphenylene under UV continuous flow, both the catalytic loadings and the reaction time irradiation was achieved by Jamison and co-workers and ap- couldbedecreased (20min residencetimeinflowfrom20h plied to the synthesis of amino acids in flow (Scheme 32). The under batch conditions) improving the sustainability of the pro- synthesis occurs through radical-radical coupling of the carbon cess [141]. dioxide radical anion with a benzylic α-amino radical, which is Scheme 29 Decatungstate-catalyzed hydroacylation of phenyl vinyl sulfone followed by derivatization through elimination and conjugate addition 32 J Flow Chem (2020) 10:13–71 Scheme 30 C-2 acylation of indoles via Ir/Pd dual catalysis formed from the single-electron oxidation and deprotonation of an α-amino radical upon deprotonation by the base potassium a benzylic amine in a segmented flow regime, compellingly trifluoroacetate (CF CO K). The radical anion of the 3 2 combining the advantages of flow chemistry in gas-liquid and photocatalyst is then able to reduce CO ,closing thecatalytic photochemical transformations. To increase the selectivity of cycle, while the resulting carboxylate is formed by radical- the reaction, a UV filter was applied with a cut-off at 280 nm radical coupling with the stabilized (and hence, somewhat (λ p-terphenylene = 283 nm) (Scheme 33). persistent) α-amino benzylic radical [146]. max Stern-Volmer kinetics show the S excited state of p- Using magnetite (Fe O ) nanoparticles as a heterogeneous 1 3 4 terphenylene is quenched by the amine, forming the radical catalyst, Varna et al. were able to activate the methyl group of a anion of p-terphenylene and an aminium radical, which forms series of N,N-dimethylanilines in an oxidative cyanation reaction Scheme 31 Room temperature C-2 acylation of indoles through Pd/Ir dual catalysis J Flow Chem (2020) 10:13–71 33 Scheme 32 Coupling of CO with benzylic α-amino radicals by UV photooorganocatalysis with H O and NaCN in aqueous methanol (1:1) as the solvent. to an iminium ion, which reacts with HCN to form the α- 2 2 The reaction is performed in a stainless steel microreactor with a aminonitrile product (Scheme 34)[147]. reactor volume of 5 ml and i.d. of 0.8 mm. The coil was submerged in an oil bath to keep the reactor at a C − H alkenylation temperature of 50 °C allowing a series of N-methylanilines to be monocyanated in less than 10 min residence time (Scheme The Fujiwara-Moritani reaction or oxidative Heck reaction rep- 35). After exiting the reactor, the nanoferrites can be separated resents one of the earliest examples of Pd-catalysed C −Hac- conveniently from the product stream with a magnet. The tivation [148, 149]. In contrast to the Mizoroki-Heck reaction, mechanism suggested by the authors occurs through the forma- in which prefunctionalization of the vinyl or arene coupling tion of an Fe(IV) oxo-species from Fe(II) through oxidation partner is required to allow oxidative addition to Pd(0) to occur, with hydrogen peroxide. The Fe(IV) species oxidises the amine the Fujiwara-Moritani reaction starts from Pd(II). While the Scheme 33 Catalytic cycle for the carboxylation of α-amino radicals by terphenylene photocatalysis 34 J Flow Chem (2020) 10:13–71 Scheme 34 Oxidative α- cyanation of N-methylanilines catalyzed by Fe O 3 4 production of stoichiometric amounts of halide waste can be gases in continuous flow offers a number of distinct advan- avoided by employing diazonium salts as the coupling partners tages including precise control of pressure and flow rate (i.e., in the Heck-Matsuda reaction, the Fujiwara-Moritani reaction the stoichiometry of the gaseous reagents) [152, 153]. as a cross-dehydrogenative coupling reaction represents a more Moreover, the establishment of a segmented flow regime pro- atom-economical approach [150]. vides a high gas-liquid interfacial area and assists in Because of its higher reactivity, Pd(II) is frequently used as preventing precipitation of Pd . Due to better heat dissipation, the catalyst in combination with an external oxidant to close the reaction can be run at higher temperatures without catalyst the catalytic cycle and prevent the formation of Pd(0) parti- degradation. Using Pd(OAc) in combination with TFA and cles. The reactions are performed in the presence of acid, as O as the oxidant, these principles were applied for the devel- they are able to coordinate to the Pd(II) center, rendering it opment of a C-3 vinylation of indoles, yielding alkenylated more electron-poor, which favours the C-H activation step and indoles in a residence time of 10–20 min (Scheme 37)[154]. allows for the deprotonation of the targeted C-H bond A variant of the Fujiwara-Moritani reaction allowing the (Scheme 36)[151]. ortho-functionalization of acetanilides with Pd/C as a reusable From an environmental point of view, one of the attractive heterogeneous catalyst and benzoquinone as an external oxi- aspects of the Fujiwara-Moritani reaction is the possibility to dant in the presence of TsOH as the acid was reported by the use oxygen as an external oxidant. The use of oxygen in batch group of Vaccaro making use of the acetamide directing group. processes can be hazardous and is limited in its efficiency due The use of a green solvent derived from lignocellulosic bio- to the poor solubility of oxygen in organic media. The use of mass, γ-valerolactone (GVL), is notable, as it is both a less toxic Scheme 35 Oxidative cyanation of N-methylanilines J Flow Chem (2020) 10:13–71 35 Scheme 36 Catalytic cycle for the Fujiwara-Moritani reaction and more sustainable alternative to traditional polar aprotic sol- Combining Brønsted acid catalysis and C − H activation vents, e.g. DMF. Although leaching is a requirement for the with Mn(I), Ackermann and co-workers performed a C − H reaction to occur with Pd(II) as the active catalytic species, alkenylation of indoles, thiophenes, pyrroles, tryptophans and Pd(0) formed at the end of the catalytic cycle is hypothesized pyridones through the use of a pyridine directing group. The to be redeposited on the support, overall resulting in minimal alkene functionality is furnished by the hydroarylation of an amounts of palladium leaching (4 ppm). Apart from this, alkyne bearing a carbonate leaving group. leaching is also decreased when using GVL compared to DMF The carbonate is left untouched, in contrast to previous re- or NMP. Under batch conditions, the catalyst can be reused for ports where hydroarylation occurred with β-elimination. Using five runs with little decrease of performance. Performing the a cheap and air-stable manganese carbonyl catalyst, reaction in a continuous-flow packed bed reactor allows scaling MnBr(CO) , allylic carbonates and ethers can be synthesized −1 up the reaction to a productivity of 4 g h (Scheme 38)[155]. from alkynes bearing these functionalities through C − H Scheme 37 Fujiwara-Moritani C-3 vinylation of indoles with O as oxidant 2 36 J Flow Chem (2020) 10:13–71 Scheme 38 Fujiwara-Moritani alkenylation of acetanilides activation of the heterocyclic ring directed by pyridine. The clogging and accelerate the reaction [157]. Starting from func- reaction is accelerated under flow conditions, from 16 h in batch tionalized phenyl ethers and N-functionalized indoles, the meth- to 1–20 min residence time in flow, which can be coupled with od allows the construction of polycyclic ether systems and fused an in-line catalyst separation. The scalability of the method was indolines (Scheme 40)[158]. demonstrated by the production of 2.24 g of the alkenylated Mihovilovic and co-workers reported the first intermolec- product using indole as the coupling partner in 1 h ular C − H activation process under continuous-flow condi- (Scheme 39)[156]. tions. Starting from aryl bromides and aryl boronic acids, they performed the Suzuki-Miyaura reaction in flow using Pd(PPh ) catalyst and K CO as the base allowing for the C − H arylation 3 4 2 3 synthesis of 2-phenylpyridines in 20 min residence time. Notably, they found the reaction was sensitive to the material Li and co-workers reported a direct intramolecular C − H of the flow reactor coil used, with PFA performing better than arylation of aryl bromides using Pd(OAc) under ultrasonication stainless steel. With pyridine acting as the directing group, the without requiring the presence of any additional ligands. By ortho-position to the pyridyl substituent in 2-phenylpyridine immersing the coil in an ultrasonic cleaning bath, as in this case, can be selectively targeted for C − H activation in a second ultrasound irradiation can be applied to prevent microreactor Scheme 39 Alkenylation of heterocycles through pyridine-directed Mn-catalysed C − H activation J Flow Chem (2020) 10:13–71 37 Scheme 40 Intermolecular ligand-free C − H arylation under ultrasound irradiation in flow step using dichloro(p-cymene)ruthenium(II) as the and para positions (i.e. the more traditional electrophilic aro- precatalyst, PPh and DBU as the base under an atmosphere matic substitution reactions) of the arene moiety [166]. For of air allowing the synthesis of bis – or trisarylated products in this transformation, diaryliodonium salts, a class of 1 h residence time (Scheme 41)[159]. hypervalent iodine compounds, are used concomitantly as Another class of cross-dehydrogenative coupling arylating agents and for the oxidation of Cu(I) to Cu(III). (CDC) reaction in which two unfunctionalized aryl rings Mechanistic studies indicate the first step is an oxidative ad- are coupled via C − H activation under aerobic oxidation dition to copper followed by a C − H activation step in which was extensively investigated by Stahl and co-workers deprotonation of the adduct by triflate occurs. Reductive elim- [160–162]. The coupling of o-xylene, specifically, holds ination forges the aryl-aryl bond to yield the meta-functional- promise in the preparation of monomers used in the pro- ized amide and regenerates Cu(I) (Scheme 44). duction of the polyimide resin Upilex [163]and metal- Although diaryliodonium salts are now commonly used organic frameworks [164]. as arylating reagents [167], their synthesis requires both Mechanistically, two separate Pd(II) metal centers allow the use of the superacid TfOH and m-CPBA as an oxi- the C − H activation of two xylene molecules, followed by a dant, rendering the transformation highly exothermic and transmetalation step leading to a single Pd(II) center with two potentially hazardous. For these reasons, Noël and co- arene ligands. Upon reductive elimination, the biphenyl moi- workers developed a continuous-flow synthesis of ety and Pd(0) are formed, which is then reoxidized with O diaryliodonium triflates. As mentioned earlier, heat trans- (Scheme 42). Although the reaction shows remarkable selec- fer to the environment is more efficient and the active tivity for the desired product, it is limited by low yields (8%) volume of reactants reacting in a microreactor is typically and the requirement for long reaction times. very small greatly decreasing the potential explosive haz- Noël and co-workers increased the yield of the ard of the reaction. By submerging the reactor coil into an homocoupled product to 41% (60% selectivity) by applying ultrasonic bath, clogging of the microreactor is prevented. 40 bar of O pressure in a stainless steel capillary microreactor A variety of diaryliodonium triflates were synthesized on requiring a reaction time of 40 min, compared to 17 h under a gram-scale in a residence time of a few seconds [168]. batch conditions (Scheme 43)[165]. Apart from the availability of diaryliodonium salts, the The meta-selective arylation of anilines under copper ca- synthesis of meta-arylated anilines makes use of amides talysis was reported by Phipps and Gaunt, offering an orthog- as protected amines, resulting in the necessity of a onal approach to functionalizations of arenes targeting mainly deprotection step. For pharmaceutical production, Cu the ortho positions (as in many palladium-catalyzed C − H levels are required to be below a threshold of 25 ppm, activation methodologies making use of a directing group) – requiring the removal of copper. The different steps were 38 J Flow Chem (2020) 10:13–71 Scheme 41 Ortho C − H arylation of pyridines with aryl bromides under continuous-fllow conditions integrated in a modular flow set-up by Noël and co- to the initially reported copper(II)triflate. Copper leaching workers using a copper tubular flow reactor (CTFR) for from the coil can be removed from the mixture by a the arylation reaction, where copper leaching from the membrane separator in a continuous liquid-liquid extrac- reactor walls acts as a catalyst for the transformation, tion with aqueous NH . Finally, the resulting pivalanilides based on the initial observation that the reaction was ac- can be deprotected in continuous flow with a 1:1 mixture celerated with powdered copper as the catalyst, compared of HCl:1,4-dioxane. Due to the modularity of the process, Scheme 42 Catalytic cycle for the CDC of o-xylene J Flow Chem (2020) 10:13–71 39 Scheme 43 o-Xylene coupling under flow conditions the meta-arylated anilines can be obtained in <1 h without moiety and the metal center, bringing the Pd(II) in proxim- the necessity of chromatographic separation, reducing itytothe ortho C − H bond, which is then softly downstream processing (Scheme 45)[169]. deprotonated to form a palladacycle intermediate. A second During the last decade, many reports on C − H activa- oxidative addition to the palladacycle occurs, bringing pal- tion processes using transient directing groups as a strat- ladium to its tetravalent oxidation state. After reductive egy to selectively target C − H bonds have appeared in the elimination, the ortho position to the original site of the scientific literature [170–172]. A notable transient oxidative addition has been selectively functionalized. directing group is the bicyclic olefin norbornene This is followed by norbornene extrusion. Although [173–175]. Catellani and co-workers first reported the norbornene, in principle, acts as an organocatalyst, stoi- use of norbornene and Pd(II) for an ortho di – or chiometric amounts are necessary for the reaction to occur trifunctionalization of aryl iodides in 1997 [176]. at a reasonable rate [177]. The resulting ArPd(II)X species Starting from Pd(0), an oxidative addition of the aryl can then undergo further functionalization (e.g. through an- iodide occurs. This is followed by a carbopalladation step, other cross-coupling cycle), with many possibilities having inserting norbornene via its double bond between the arene been reported [178–182]. This brings the catalytic Pd Scheme 44 Catalytic cycle for the Cu-catalyzed meta-arylation of anilines 40 J Flow Chem (2020) 10:13–71 Scheme 45 meta-Arylation of anilines employed in a modular flow set-up species back to its original zerovalent oxidation state and termination pathway is the Heck reaction. In this case, com- closes the catalytic cycle (Scheme 46). A common petition between coupling of the desired olefin and Scheme 46 Catalytic cycle for the Catellani reaction with termination via a Heck pathway J Flow Chem (2020) 10:13–71 41 norbornene is a known issue which can be addressed by Grignard reagent. After ligand exchange, Mn(II) undergoes a controlling the stoichiometry of the olefinic reagents. In single-electron oxidation to Mn(III) which is arylated by the principle, the transformation can also be performed using Grignard reagent in a transmetalation step. Reductive elimi- gaseous olefins. nation from Mn(III) forges the C-C bond, generating Mn(I). Due to the difficulties arising from the volatility of The external oxidant DCIB (1,2-dichloro-2-methylpropane), norbornene and poor control of the stoichiometry of the gas- is required to form the Mn(III) species and close the catalytic eous reagents, these transformations can be challenging to cycle, reoxidising Mn(I) to Mn(II). perform under batch conditions, in particular when attempting Using this methodology, both azines and diazines can be to perform the reaction using two distinct arene coupling part- arylated with arenes, thiophene and the sterically hindered ners. In the first report on gas-liquid Catellani reactions, Noël, mesityl moiety. Avariety of substituents on the amide nitrogen Della Ca′ and co-workers reported an increase in selectivity were also tolerated. The reaction can be performed in flow in for a heterocoupling from 12% yield in batch to 66% under 100 min compared to 16 h under batch conditions, which can −1 flow conditions, due to the accurate control over the stoichi- be scaled-up with a productivity of 1.12 g h (Scheme 48). ometry of the gaseous reagents and the high gas-to-liquid The Pd-catalyzed intermolecular C − H activation of the mass transfer under flow conditions (Scheme 47)[183]. C-5 position in 1,2,3-triazoles to give arylated products with C − H activation chemistry employing Earth-abundant aryl halides as the coupling partners was reported in 2016 by metals such as Ni, Mn and Co is becoming more common- Vaccaro and Ackermann, using the green solvent γ- place as alternatives are sought to the precious metals tradi- valerolactone (GVL) and palladium on charcoal (Pd/C) as a tionally employed in C − H activation catalysis [184]. heterogeneous catalyst [185]. The methodology was also Ackermann and co-workers reported the ortho C − Harylation adapted to flow conditions, mainly for the intramolecular C of substituted azines with an amide directing group under − H arylation to yield triazole-fused chromanes and triazole- continuous-flow conditions with MnCl salt combined with fused isoindolines. As in their report on a Fujiwara-Moritani a neocuproine ligand, a Grignard species as the arylating agent reaction in flow (vide supra), Pd/C was immobilized in a flow (Kumada-type coupling), TMEDA as the base and DCIB as reactor and combined with GVL resulting in minimal amounts an oxidant. of leaching, making the transformation highly sustainable. After forming the complex and coordination of Mn(II) by Starting from Pd(0), oxidative addition to the aryl halide the amide functionality, the Grignard reagent undergoes occurs, followedbythe C − H activation of the triazole transmetalation. The amide directing group brings the metal through deprotonation. Reductive elimination then delivers center in proximity of the ortho C − H bond for the C − H the final product (Scheme 49). As well as intramolecular cy- activation step occurring through deprotonation with the clization products, intermolecular C − H arylation with aryl Scheme 47 Continuous-flow Catellani reaction employing gaseous olefin partners 42 J Flow Chem (2020) 10:13–71 Scheme 48 Mn-catalyzed C − H arylation of azines with Grignard reagents bromides is also possible under these conditions. The reaction oxidant for the oxidative cyclization of diaryl – and was scaled to 100 mmol scale under flow conditions, yielding triarylamines to form carbazoles (Scheme 51). 24 g of product after 44 h, corresponding to a productivity of Surprisingly, the copper catalyst was found to outper- −1 2+ 0.55 g h (Scheme 50). form Ru(bpy) , however, a reaction time of 14 days was Several reports have been published on the application of required to obtain the N-phenylcarbazole in 85% yield. For copper complexes as photoredox catalysts for C − H this reason, a flow set-up was constructed allowing the functionalization reactions [186]. reaction to be performed in a residence time of 20 h. The Collins et al. applied the in situ formed copper photoredox authors propose a mechanism based on the oxidative catalyst [Cu(Xantphos)(dmp)]BF in conjunction with I as an quenching of the Cu(I) catalyst by molecular iodine. The 4 2 Scheme 49 Pd-catalyzed cross coupling via C − H activation in 1,2,3-triazoles J Flow Chem (2020) 10:13–71 43 Scheme 50 C-H activation with Pd/C of 1,2,3-triazoles functionalized with aryl halides in γ-valerolactone Cu(II) species then formed oxidises the carbazole which 190]. Due to the relatively small band gap of semiconductor allows the cyclization to occur through homolytic aromatic materials, electrons can be excited from the valence band to substitution. After oxidation, the aromaticity of the carba- the conduction band, creating an electron-hole pair, in which zole is restored (Scheme 52)[187]. the electron can effect one-electron reduction, and the hole can In the Meerwein-type C − H arylation reaction, aryl diazo- act as a one-electron oxidant [191]. For this reason, TiO is nium salts are used to generate aryl radicals via one-electron frequently used for the oxidative solar decontamination of reduction [188]. Several photocatalytic variants of this reac- waste water [192]. As an abundant, non-toxic and heteroge- tion have been developed for selective C − H arylation, in- neous photocatalyst, it is a very attractive material for sustain- cluding the use of the inorganic photocatalyst TiO able chemistry [193], the downside being the band gap of (Scheme 53). unmodified TiO is too large for the creation of electrons The behaviour of semiconductor nanoparticles as and holes through visible light irradiation. This problem is photocatalysts is well-described, representing one of the ear- generally solved through the use of modified TiO [194], liest and most important examples of photocatalysis [189, e.g. employing Pt and Pd as co-catalysts, bringing the Scheme 51 Copper-catalyzed synthesis of carbazoles 44 J Flow Chem (2020) 10:13–71 Scheme 52 Proposed cycle for the copper-catalyzed intramolecular arylation to form carbazoles absorption of the material from the ultraviolet into the visible pyridine, thiophene and furfural with a range of aryl diazoni- range through the creation of intra-bandgap states in which the um salts (Scheme 54)[196]. size of the electronic transitions fall within the energetic range The group of Ackermann used another 3d earth-abundant of visible light [195]. Rueping et al. have shown that the metal, manganese, to perform a visible light-photocatalyzed combination of TiO with aryl diazonium salts results in the C − H arylation of heteroarenes with diazonium salts under formation of a TiO azoether with a strong absorption at flow conditions. Inexpensive CpMn(CO) proved to be the 2 3 450 nm (corresponding to the blue part of the visible spec- most effective catalyst for the transformation. trum) to create aryl radicals. To allow the use of heterogeneous On the basis of mechanistic studies, the authors suggest a titania in flow, a falling film microreactor (FFMR) was con- radical mechanism starting with the exchange of one CO ligand structed by Rehm, Rueping and co-workers. An open stainless for the arene substrate, followed by coordination of the aryl dia- steel flow cartridge, equipped with a quartz window, is coated zonium salt to the Mn(I) center. After irradiation with blue light with TiO nanoparticles and irradiated on one side with blue (450 nm LEDs), metal-to-ligand charge transfer (MLCT) leads to light. The performance of the FFMR markedly improved the electron transfer from Mn(I) to the diazonium ligand, forming reaction compared to batch conditions, and was successfully Mn(II) and an aryl radical with extrusion of N . The aryl radical appliedtothe C − H arylation of heteroarenes such as adds to the arene substrate to forge the aryl-aryl bond, whereupon Scheme 53 Mechanism of the titania-catalyzed Meerwein C − H arylation J Flow Chem (2020) 10:13–71 45 Scheme 54 Titania-catalyzed Meerwein arylation in a falling-film microreactor the radical adduct formed is oxidised to form a cation, either by Apart from the photocatalytic C − H arylations of reaction with the oxidised Mn(II) complex or another equivalent (hetero)arenes which have been described using Eosin Y 2+ of diazonium salt. Deprotonation then restores the aromaticity of [198], dual catalysis by [Ru(bpy) ] in conjunction with the system (Scheme 55 and 56). Pd(OAc) [199], TiO [200] and Mn photocatalysis (vide su- 2 2 Flow conditions proved to be highly beneficial for the re- pra), a catalyst-free arylation would be attractive from the action, accelerating the reaction time to 60 min residence time viewpoint of sustainability and atom-economy. Exploiting and drastically improving the yield. For p - the advantages offered by the implementation of microreactor trifluoromethylbenzenedizonium tetrafluoroborate and ben- technology for the generation of highly reactive, explosive zene, by switching to flow, an improvement in yield from intermediates, Kappe and co-workers developed a catalyst- −1 25% to 64% was noted with a productivity of 1.42 g h . free radical C − H arylation through photochemical means. The methodology was also applied to the synthesis of a pre- The so-called diazo anhydrides (Ar-N=N-O-N=N-Ar), which cursor of the hyperthermia drug Dantrolene, starting from fur- are nitrosamine dimers, fragment homolytically under irradi- fural derived from biomass [197]. ation with near-UV light (> 300 nm) to yield aryl radicals Scheme 55 Catalytic cycle for the Mn photocatalytic C − H arylation of (hetero)arenes 46 J Flow Chem (2020) 10:13–71 Scheme 56 C − H arylations of heteroarenes with aryl diazonium salts under Mn photocatalysis which can be applied in the C − H arylation reaction of only N ,H Oand t-BuOH as waste in a metal-free process 2 2 (hetero)arenes. Although these intermediates are highly unsta- (Scheme 58)[201]. ble, they can be safely generated and consumed in situ by Another application of α-amino radicals was reported by performing the reaction in a microreactor. Nitrosamines are Vega, Trabanco and co-workers at Janssen Pharmaceuticals formed through the nitrosation reaction of anilines with tert- for the C − H arylation of the α-position in N,N- butyl nitrite (t-BuONO, Scheme 57). dialkylhydrazones. To decrease the formation of byproducts formed from the The authors propose an oxidative quenching cycle based spontaneous decomposition of diazo compounds, t-BuONO on the reductive abilities of the Ir(ppy) photocatalyst and the arene coupling partners are fed via two separate reagent (Scheme 59). Upon excitation with blue light (455 nm), excit- streams to a T-mixer before entering the photoreactor, equipped ed Ir(III) undergoes SET with an electron-poor arene substrate with a medium pressure Hg lamp (125 W, although a reduction (e.g., 2,4-dicyanobenzene), forming Ir(IV) and the one- to 75 W was found to be suitable for certain substrates) and UV- electron reduced form of the arene (radical anion). Ir(IV) is filter (cut-off at 300 nm). The substrate scope includes thio- then reduced to Ir(III) to restart the cycle by oxidising the phenes, furan and N-protected pyrroles, as well as electron-rich hydrazone, generating a hydrazinium radical, which readily phenyl derivatives and azines (including pyridine N-oxide) undergoes deprotonation by LiOAc to form the stabilized α- whichwere arylatedinaresidencetimeof45min, producing amino radical. The α-amino radical forms an anionic adduct Scheme 57 Catalytic cycle for the C − H arylation of (hetero)arenes employing diazo anhydrides as the aryl radical precursors J Flow Chem (2020) 10:13–71 47 Scheme 58 Metal-free photochemical C − H arylation of (hetero)arenes through radical-radical coupling with the radical anion of the cyanobenzenes, azines were also successfully employed as electron-poor arene. With cyanide acting as the leaving group electron-poor arene coupling partners (Scheme 60)[202]. in the adduct, the product is then formed. Through the use of continuous-flow, the arylation could be accelerated in 20– C − N bond formation 40 min allowing the gram-scale synthesis of arylated dialkylhydrazones. Repeating the reaction after the first Activation of the beta C − H bond in hindered aliphatic amines arylation with another flow reactor allowed for a regioselec- to yield aziridines (or beta-lactams in the presence of carbon tive second arylation step on the same substrate, though more monoxide) was reported by Gaunt and co-workers in 2014 forcing conditions (increase of catalyst loading, residence time [203] and was later adapted to a continuous-flow process by and reaction temperature) were required. Apart from Lapkin and co-workers [204]. Starting from palladium(II) Scheme 59 Ir-catalyzed alpha C − H arylation of N,N- dialkylhydrazones 48 J Flow Chem (2020) 10:13–71 Scheme 60 Continuous-flow synthesis of arylated N,N- dialkylhydrazones via Ir photoredox catalysis acetate, the hindered amine coordinates to the metal. This can monocoordinated variant. This dissociation is more favoured happen a second time to form a Pd(II) center coordinated by when hindered amines are used. The monocoordinated com- two amines. The steric bulk on the amine is critical to achieve plex can then undergo the C − H activation step (rate-deter- activation of the C − H bond, since the C − H activation step mining), i.e. deprotonation of the beta C − H bond through a requires dissociation of this complex to the less stable concerted metalation-deprotonation (CMD) mechanism to Scheme 61 Catalytic cycle for the beta C − H activation in hindered aliphatic amines J Flow Chem (2020) 10:13–71 49 yield a cyclometalated Pd(II) complex. This can undergo ox- the mechanistic investigations were combined in a kinetic mod- idation by the hypervalent iodine oxidant PhI(OAc) resulting el and applied to the design of a process model for an ideal plug in a Pd(IV) complex. The nitrogen is then deprotonated to flow reactor, with the limitation that T = 120 °C (stability max form a four-membered Pd(IV) intermediate which undergoes limit of Pd(OAc) ) and that the space-time yield be large reductive elimination, liberating the aziridine and Pd(II), enough (full conversion within 10 min). Optimization experi- thereby closing the catalytic cycle. ments were performed and yielded conditions with 0.5 mol% The mechanism of the reaction was investigated in detail loading of Pd catalyst for which t =10 min. (Scheme 61). The rate of the reaction was shown to increase Next, further development of the flow process for gram- over time, which could have two causes: either the rate was scale production of aziridines was carried out by incorporating affected negatively by increasing the concentration of the modules to remove the catalyst as well as the desired aziridine amine, or the reaction rate was increased by one of the product. Separation of the homogeneous catalyst was accom- byproducts of the reaction (autoinduction). The latter was ruled plished through the use of an amine-functionalized QuadraSil out by starting the reaction at 20% conversion. Essentially, the AP column (which coordinates and retains the Pd(II) catalyst), reaction is performed with the same equivalent ratios, but with a leaving the eluent with <1 ppm of Pd. The aziridine was re- smaller amount of the reagents. Because less byproducts are moved from the mixture by incorporating a column packed formed, an autocatalyzed reaction should then be slower. with Isolute SCX-3 gel (sulfonic acid-functionalized silica When factoring in the different starting concentrations, the rates gel). Washing the column with a basic eluent subsequently were shown to be identical, suggesting instead that the rate was elutes the aziridine yielding the product without further puri- negatively affected by the concentration of amine (its consump- fication required. Performing the reaction in a commercial −1 tion during the reaction then leads to an increase in the reaction Vapourtec R-Series allowed a productivity of 0.77 g h −1 −1 rate). The effect of adding reaction products as additives to the (space-time yield 0.463 kg V h ,Scheme 62). reaction (PhI, aziridine, and HOAc) was investigated as well. In A derivatization in flow of the resulting aziridines by reac- this case, increasing the amount of HOAc showed a small in- tion with nucleophiles was also developed. In the case of non- crease in the rate. The rate at t was shown by comparison to t activated aziridines and weak nucleophiles, this generally re- 0 1/2 to be inversely proportional to the concentration of amine. quires activation by (Lewis) acids. Hence, aziridines retained Apart from this, the reaction was shown to be zeroth order in on the acidic column are susceptible to nucleophilic attack and PhI(OAc) andfirst orderinPd(OAc) . these principles were applied to the in-line derivatization with 2 2 The kinetic isotope effect (KIE) can be applied to the study MeOH, H O and in-situ generated HN , yielding the function- 2 3 of reaction mechanisms by isotopic labeling. In C − Hactiva- alized amine products in good yield (Scheme 63)[204]. tion, deuterium labeling of the target C − H bond can change The direct C − H amination of arenes (Minisci-type the rate of the reaction (a primary kinetic isotope effect) which amination) is a challenging transformation, requiring strongly shows the C − H activation to be the rate-limiting step (k ), oxidizing conditions [207, 208]orthe installmentofaredox which proved to the case for the C − H aziridination, auxiliary or electrophoric group [209]. The group of Leonori explaining the first order dependence on Pd(OAc) . The oxi- recently reported the application of O-aryl hydroxylamines as a dative addition of PhI(OAc) following this step then does not redox auxiliary to generate aminium radicals for late stage C − alter the rate. The negative first order dependence on the H amination [210, 211]. Building on this work while eliminat- amine can be rationalized by the increased reversible forma- ing the need for prefunctionalization, a visible light photocata- tion of the square planar bisaminated Pd(II) complex (k ), lytic approach to generate aminium radicals from amines direct- which is unproductive, since the C − H activation step requires ly via the in situ formation of an N-chloroamine with N- a vacant coordination site [205, 206]. As the protonated amine chlorosuccinimide (NCS) was developed (Scheme 64). cannot coordinate to Pd(II), increasing the amount of HOAc Under acidic conditions, the protonated N- (k ) decreases the effective concentration of amine available to chloroamines can engage in an oxidative quenching cy- coordinate the metal which shifts the k equilibrium towards cle with the photocatalyst [Ru(bpy) ]Cl , generating the 2 3 2 the desired monoaminated complex. The optimal amount of chloride ion and an electrophilic aminium radical, which HOAc was determined to be 20 equiv., since higher concen- undergoes addition to an arene. The radical adduct trations of acid lead to degradation of the aziridine product. formed after addition is then oxidised to a carbocation Another piece of evidence in the puzzle is the rate with by Ru(III), closing the catalytic cycle and generating the which more sterically congested amines react. Increasing the aminofunctionalized arene after loss of a proton. Key to steric bulk makes the formation of the bisaminated complex the para-selectivity of the aromatic amination is the less favorable, increasing the rate, which was shown by a com- polarity of the medium combine with the highly polar- petition experiment between two amines of which one was ized aminium radical. Under these conditions, the aro- more substituted. The selectivity and the mechanism of C − H matic chlorination which is a competing pathway when activation were further probed by DFT calculations. Data from using N-chloroamine reagents is suppressed in favour of 50 J Flow Chem (2020) 10:13–71 Scheme 62 Palladium-catalysed synthesis of aziridines in continuous-flow thearomaticC − H amination. Using HFIP as a solvent phenyl moiety in a Phe residue, which is underexplored also allowed expanding of the substrate scope to more in bioconjugation chemistry. electron-poor arenes, e.g. fluorobenzene, and improves The method was adapted to flow in collaboration with selectivity towards the para-position. The scope of the AstraZeneca with piperidine and iodobenzene as reacting reaction is very broad, including the direct partners to furnish the para-substituted building block −1 functionalization of the organometallic compound 1-(4-iodophenyl)piperidine in a productivity of 3.8 g h [Ru(ppy)(bpy) ]PF , polystyrene (degree of (Scheme 65)[212]. A different photochemical approach 2 6 functionalization: 19%) and a tetrapeptide, the latter un- was followed by Marsden and co-workers, performing an dergoing selective amination in the para-position of the intramolecular C − H amination in a mixture of acetic acid Scheme 63 Derivatization of aziridine in continuous-flow J Flow Chem (2020) 10:13–71 51 Scheme 64 Catalytic cycle for the direct C − H amination of arenes through photocatalytic reduction of protonated N- chloroamines and sulfuric acid and fragmenting the protonated N- [215–217]. The first 1,5-HAT reaction, the classic Hoffmann- chloroamine homolytically using UV light [213]. Löffler-Freytag reaction, originated in 1883 and involves pho- The reaction was performed in flow, in which the N- tolysis of a protonated N-chloroamine after which the resulting chloroamine could be synthesized from the amine and NCS aminium radical abstracts a hydrogen from a carbon five atoms followed by cleaving the nitrogen-chlorine bond homolytically away, resulting in δ-chlorination. The 1,5-radical translocation under irradiation of a 125 W UV lamp. This was then applied to is thermodynamically favourable because the abstraction of the intramolecular C − H amination reactions in flow to synthesize hydridic hydrogen atom is exergonic and occurs through a six- a range of tetrahydroquinolines (Scheme 66). Although higher membered transition state, although 1,6- and 1,7-translocations isolated yield was obtained in both batch and flow conditions involving sulfamates and sulfamides have also been reported by when both steps were performed separately, integrating the the group of Roizen [218, 219]. Following the translocation of chlorination of the amine and the intramolecular C − H the halide, an intramolecular nucleophilic substitution reaction amination reaction in a modular fashion gave N- then furnishes pyrrolidine products. Recently, different electro- methyltetrahydroquinoline in an overall yield of 34% [214]. chemical variations of the Hoffmann-Löffler-Freytag reaction A myriad of reports on reactions involving a 1,5-hydrogen were reported. Lei and co-workers reported a halide-free HLF atom transfer step have recently appeared in the literature reaction of tosylamides in the presence of acetate and HFIP Scheme 65 Functionalization of iodobenzene with piperidine via direct C − H amination under flow conditions 52 J Flow Chem (2020) 10:13–71 Scheme 66 Intramolecular C − H amination with N-chloroamines and UV light involving amidyl radical intermediates. Different pathways (in- amides to generate the photolabile N-iodoamides leading to volving ionic or radical reactivity) were proposed to arrive at amidyl radicals [222–225]. Using imines, iminyl radicals can the amidyl radical, which generates a carbon-centered radical be accessed as well. This was applied to the synthesis of after the intramolecular remote hydrogen atom transfer. The oxazolines and 1,2-amino alcohols. With bromide as the medi- carbon-centered radical is then oxidised to a carbocation, which ator, Rueping and co-workers developed an electrochemical cyclizes to form pyrrolidines [220]. A complementary approach cross-dehydrogenative approach to the Hoffmann-Löffler- involving both the use of electrochemistry and light to cleave Freytag reaction for the synthesis of pyrrolidines under both the N-haloamides was reported by Stahl and co-workers [221]. batch and flow conditions. The mechanistic pathways through Iodide ion is oxidised to iodine at the anode, which reacts with which the reaction occurs are again complicated, since several Scheme 67 Mechanism of electrochemical cyclization of Ts- protected amines to pyrrolidines J Flow Chem (2020) 10:13–71 53 species and pathways (both occuring at the anode or cathode in photochemical C − H oximation occuring through the homo- the undivided cell) can be involved in the generation of the key lytic photolysis of a nitrite functional group in which a nitroxy amidyl radical intermediate (Scheme 67). - and alkoxy radical are formed. The electrophilic alkoxy rad- The amidyl radical undergoes intramolecular HAT to yield ical then engages in a 1,5-HAT leading to the radical translo- the carbon-centered radical which can form the pyrrolidine in cation of a nitroxide functionality which equilibrates to an a number of different ways. First, the carbon radical can trap oxime (Scheme 69, right part). bromine (generated under oxidative conditions from bromide) The group of Ryu reported a Barton reaction under flow which can undergo an intramolecular nucleophilic substitu- conditions. An alcohol is transformed into a nitrite by reaction tion. Alternatively, the carbon-centered radical can undergo with nitrosyl chloride (NOCl) and the labile N-O bond is direct oxidation to the carbocation followed by cyclization. cleaved by irradiation with near-UV light (365 nm proving The presence of base (methoxide, which is also formed from sufficient). The reaction was performed in a stainless steel MeOH through the cathodic reduction of protons to hydrogen microreactor with a glass cover to allow irradiation of the in a divided cell) was found necessary for the reaction to reaction mixture (Scheme 68, left part). Different parameters occur, as the amidyl radical can be accessed through the of the reaction were investigated, e.g. light source combina- deprotonated tosylamide. The reaction was scaled under both tions with different glasses (cut-offs being at different wave- batch (50 g scale) and flow conditions. Flow chemistry is an lengths depending on the material). Out of these combina- attractive option for the scale-up of electrochemical reactions tions, the application of a 15 W black light in combination due to the fast reaction rates and decrease of the necessary with Pyrex glass performed best for small-scale reactions. amount of supporting electrolyte (a non-neglible factor during While the Barton reaction is usually run in acetone as the scale-up). A commercial Asia Flux module manufactured by solvent, the limited solubility of the steroid in acetone neces- Syrris was used in conjuction with a graphite anode and 316 sitated switching to DMF. The reaction was scaled-up to gram alloy stainless steel cathode. The desired pyrrolidines were scale, combining two microreactors and 8 × 20 W black lights, formed in high yields under both conditions of constant cur- yielding 3.1 g of the oxime after 20 h (32 min residence time), −2 rent (5 mA cm ) and constant potential (2.8 V). Accurate an intermediate in the synthesis of myriceric acid A [227]. control of residence time in flow reactions generating gases is difficult, since the formation of gas bubbles (slugs) de- C − O bond formation creases the residence time during the reaction. Hence, a back-pressure regulator was included in the system to solubi- Pasau and co-workers at UCB developed a benzylic photo- lize the majority of hydrogen formed at the cathode (1 to chemical C − H oxidation in continuous flow (Scheme 70). 5 bar), allowing the synthesis of the tosylpyrrolidine com- Oxygen gas is used as the oxidant in conjunction with the pound methyl 4-methyl-1-tosylpyrrolidine-2-carboxylate in organic photocatalyst riboflavin tetraacetate (RFT) under −1 76% yield with a productivity of 0.37 mmol h UV light irradiation with an Fe(III) salt, the latter being nec- (Scheme 68)[226]. essary for the reduction of hydrogen peroxide which causes Another reaction of historical importance involving such a decomposition of the riboflavin [228]. After irradiation with translocation is the Barton reaction. It can be classified as a UV light, the riboflavin can abstract a hydrogen atom from the Scheme 68 Electrochemical HLF reaction in flow conditions 54 J Flow Chem (2020) 10:13–71 Scheme 69 Barton rearrangement under flow conditions benzylic position to generate a benzylic radical. Since ribofla- reduced by the catalytic amount of the iron(II)perchlorate ad- vin is a known photosensitizer for oxygen, the authors pro- ditive (Scheme 71). pose the formation of singlet oxygen, O , which would then To synthesize a series of acetals, Kappe and co-workers react with the benzylic radical to give a peroxo radical, which used Cu(OAc) and t-BuOOH as the oxidant for the oxidative can engage in HAT forming a hydroperoxide. The hydroper- coupling of ethers and enols (from phenols and β-ketoesters), oxides can form either ketone or alcohol products. The re- in which a bond is formed between the enol oxygen and the α- duced riboflavin can then be reoxidised by O ,returning to carbon of an ether (Scheme 72). To avoid the dangers associ- its ground state, while the H O formed during the oxidation is ated with heating a mixture of peroxides and ethers, a feed 2 2 Scheme 70 Continuous flow benzylic oxidation with RFT as photocatalyst J Flow Chem (2020) 10:13–71 55 Scheme 71 Catalytic cycle for benzylic oxidation by RFT/Fe(II) catalysis containing a non-aqueous solution of t-BuOOH in n-decane is the formation of the acetal products in less than 20 min at 130 °C premixed in a glass static mixer with a feed containing the compared to 3 h reflux under batch conditions [229]. copper catalyst, the ether and the substrate. Flow chemistry offers several advantages when dealing with The reaction is performed in a stainless steel reactor coil with exothermic reactions (e.g., oxidations) due to excellent heat a volume of 20 ml and an internal diameter of 1 mm leading to transfer to the environment, while the small reacting volumes Scheme 72 Continuous flow acetal synthesis via oxidation by alkyl peroxide 56 J Flow Chem (2020) 10:13–71 decrease explosion and combustion hazards [31, 230, 231]. Schultz and co-workers at Merck Sharpe and Dohme Thus, it becomes possible to operate in novel process windows, (MSD) reported the remote C − H oxidation of amines using i.e. conditions of high temperature and pressure not safely acces- sodium decatungstate (NaDT) as a HAT photocatalyst sible in batch. The MC system is a highly effective mixture of (Scheme 74). The reaction is carried out in a 1:1 mixture of Co, Mn and bromide salts for the synthesis of carbonyl com- acetonitrile and water in the presence of 1.5 equivalents of pounds through aerobic oxidation [232, 233]. Kappe and co- H SO to protonate the amine (neutral amines being incom- 2 4 workers studied the oxidation of ethylbenzene to acetophenone patible with the decatungstate photocatalyst [237]) and or benzoic acid under flow conditions using 2.5 mol% of CoBr 2.5 equivalents of H O as the oxidant. Acidic conditions 2 2 2 and Mn(OAc) and air as the oxidant (Scheme 73). are important to the remote functionalization, as the radical Air, delivered from a gas bottle connected to a mass-flow is preferentially formed on a distal position to the protonated controller is mixed with the liquid reagent stream (1 M ethyl- amine, as exemplified by the β-selective functionalization of benzene, 2.5 mol% CoBr and 2.5 mol% Mn(OAc) in pyrrolidine, and the γ-selective functionalization of piperidine 2 2 HOAc) pumped with a HPLC pump to the reactor, a 50 m and azepane. These building blocks are useful but costly in (V = 25 mL) PFA coil placed inside a GC oven (100–150 °C). drug discovery. The reaction was performed in a 10 ml flow The system is kept under pressure through the use of a 12 bar reactor with an FEP coil using oxygen as the oxidant under back-pressure regulator (BPR). Acetophenone can be obtain- 4.5–5 bars of pressure with 365 nm LEDs. As >1 h of resi- ed in a residence time of 4–8 min in 66% yield without chro- dence time was required, recirculating the mixture during 22 h matography. 2-bromoacetophenone present in the reaction was necessary for the scale-up of a pyrrolidine oxidation on mixture can be removed by reduction through treatment of 5 g scale [238]. the crude with Zn metal. Alternatively, doubling the residence Noël and co-workers employed tetrabutylammonium time to 16 min allows the production of benzoic acid in 71% decatungstate (TBADT) with a mixture (2.5:1) of acetonitrile yield (purification with acid-base extraction, no chromatogra- and 1 M aqueous HCl for the oxidation of activated and phy necessary) [234]. unactivated C − H bonds in flow using oxygen gas (2.5 equiv- The oxidation of unactivated sp C − H bonds is a highly alents) as the oxidant (Scheme 75). The reaction was carried challenging transformation [235]. Several approaches to the out in a 5 ml PFA capillary reactor at atmospheric pressure in oxidation of methylene or methine groups exist, including 45 min residence time under 365 nm LED irradiation. The metal catalysis (e.g., the Chen-White oxidation or the use of methodology was applied to the oxidation of terpenoid natural metal porphyrins, vide infra), biocatalysis, photocatalysis and products, including the gram scale oxidation (1.5 h residence electrochemistry [236]. Examples of these oxidation chemis- time, 10 ml reactor volume) of the sesquiterpene antimalarial, tries performed in flow will be discussed below. artemisinin [239]. Due to the electrophilic nature of the Scheme 73 Air oxidation of ethylbenzene to acetophenone or benzoic acid in flow J Flow Chem (2020) 10:13–71 57 Scheme 74 Photocatalytical oxidation with oxygen with recirculation in flow catalyst, both methods allow the site-selective oxidation of a (alcohols further being oxidised to ketones having previously methylene group to a ketone [240, 241]. The alkyl radical been described) [242]. The reduced form of the catalyst is then formed after HATwith decatungstate is trapped by O to form re-oxidised by a second equivalent of oxygen, closing the an alkyl hydroperoxide intermediate, which leads to alcohol catalytic cycle [243, 244]. and ketone products, though ketones are the major product Scheme 75 Mild and selective C(sp )-H oxidation in flow 58 J Flow Chem (2020) 10:13–71 Scheme 76 Continuous-flow oxidation of Csp -H bond by in situ generated dioxirane Another approach to C(sp )–H hydroxylation involves the compared to 2% in batch). The method also proved scaleable, use of strong oxidants, e.g. hypervalent iodine reagents or as exemplified by the production of 2.7 g 1-adamantanol from dioxiranes (DMDO or TFDO). While dioxiranes such as adamantane using two 20 mL reactors equipped with static −1 TFDO are highly effective oxidants, they are cumbersome to mixer coils (96% yield, productivity 1.17 g h )[245]. work with: TFDO, for instance, is a gaseous reagent which Aside from the applications of C–H oxidation to deliver decomposes above 10 °C. As such, despite its potential, its use oxygenated building blocks or as a biomimetic strategy in is limited to small-scale batch reactions. As discussed previ- total synthesis, another interesting application of C–Hoxida- ously, one of the main advantages offered by flow chemistry is tion can be found in the practice of drug discovery. One of the the potential to generate and consume small quantities of haz- key aspects in the development of a new drug is the study of ardous intermediates in situ, improving both the safety of the its metabolic stability. The first step in the metabolism of process and opening the doors to scale-up. drugs in vivo is first pass hepatic oxidation by Cytochrome Ley, Pasau and co-workers developed an in situ formation P450 oxidase liver enzymes, which contain an Fe porphyrin. of the oxidant TFDO under flow conditions, starting from Oxidative methodologies which are able to mimic drug me- 1,1,1-trifluoromethylacetone (Scheme 76). A mixture of the tabolism are thus in high demand [246, 247]. substrate and 1,1,1-trifluoromethylacetone in DCM (feed 1) The field of organic electrochemistry has recently seen a are mixed with an aqueous solution of sodium bicarbonate resurgence in attention [248] and can benefit greatly from the (feed 2), followed by the addition of a third reagent (feed 3) implementation of microreactor technology [249]. stream containing the oxidant (aqueous solution of Oxone) Electrochemical processes require long reaction times as they which are then pumped to a microreactor filled with glass are typically highly mass-transfer limited, being limited both beads and kept at 25 °C. The system is kept under pressure by the dimensions of the electrode surface available for the through the use of a back-pressure regulator (75 psi), allowing reaction to occur, as well as the fact that electron-transfer both the oxidation of unactivated and activated C − Hbonds in processes are absent in the bulk of the solution as they only a residence time of 80 s. occur in a very thin layer near the surface of the electrode 19 1 The formation of TFDO was detected by F NMR and H (Helmholtz layer). While the use of electrons as green and NMR spectroscopy, after in-line phase separation of the or- traceless reagents justifies the classifcation of electrochemical ganic phase with a liquid-liquid membrane separator (Zaiput), reactions under the moniker ‘green chemistry’,an important proving the yield to be higher in flow than batch (5% in flow, drawback of organic electrochemistry is the poor conductivity J Flow Chem (2020) 10:13–71 59 −1 of organic solvents necessitates the use of large (commonly hydroxylation. At 8 F mol with the use of reducing sodium stoichiometric) amounts of supporting electrolyte, which can bisulfite as supporting electrolyte, the metabolite 5- be either reduced or eliminated entirely in a microreactor due hydroxyldiclofenac was isolated in 46% yield, a notable im- to the very small inter-electrode spacing [250–254]. provement compared to earlier syntheses requiring both mul- Aditionally, the potential applied can be used to perform ox- tiple transformations and expensive reagents. An interesting idations in a in a more reliable and reproducible way and quinone by-product was also isolated which can undergo con- several electrochemical C–H oxidation methodologies have jugation with glutathione, one of the strategies followed by the already been reported [255, 256]. liver to eliminate toxic electrophiles. This can be easily imple- Although electrochemistry has already seen application mented in a modular flow set-up by connecting the output of in the mimicry of drug metabolism through the use of the electrochemical microreactor to a T-junction and introduc- coupled techniques such as electrochemical-mass spec- ing a second stream containing glutathione to synthesize con- trometry (EC-MS), these methods typically do not allow jugates. Unsurprisingly (vide supra), tolbutamide underwent the delivery of useful amounts of drug metabolites, which oxidation at the α-position to the amide nitrogen yielding a can be problematic, in case their full characterization by product which is not a known tolbutamide metabolite. NMR spectroscopy is required [257, 258]. Hence, flow Primidone was oxidised electrochemically to phenobarbital, electrochemical oxidation is an attractive tool for the a barbiturate drug known to be one of the two first-pass me- preparation of drug metabolites. tabolites of primidone. Phenobarbital was isolated in 24% −1 Stalder and Roth studied the oxidation of five drugs yield, although its productivity was limited (7 mg h )by (diclofenac, tolbutamide, primidone, albendazole, and chlor- solubility issues. Albendazole (ABZ), a sulfide drug, has promazine) by electrochemical means (Scheme 77). While two first-pass metabolites corresponding to the sulfoxide and diclofenac, tolbutamide and primidone undergo C–Hoxida- the sulfone, both of which can be accessed electrochemically. tion, albendazole and chlorpromazine are sulfide drugs which The sulfoxide was isolated in 38% yield (productivity −1 undergo facile electrochemical oxidation to sulfoxides [259]. 65 mg h ) while chlorpromazine, an antipsychotic drug, also Diclofenac, a non-steroidal anti-inflammatory drug (NSAID), underwent S-oxidation to yield a sulfoxide (83% yield, −1 undergoes first-pass hepatic oxidation via aromatic 33 mg h ), which is one of its hepatic metabolites [259]. Scheme 77 Flow oxygenative electrolysis of approved drugs 60 J Flow Chem (2020) 10:13–71 Scheme 78 Electrochemical synthesis of thiazoles by intramolecular C-S bond formation C − S bond formation only reagents in the reaction, requiring only a mixture of ace- tonitrile and methanol as the solvent and a C anode/Pt cathode The heterocyclic motifs thiazole and thiazine account for 15% couple, the methodology is highly sustainable. The electro- of all sulfur-containing drugs approved by the US Food and chemical method is also compatible with thioamide- Drug Administration (FDA) [260]. These compounds are tra- substituted pyridines, leading to thiazolopyridine products. ditionally accessed from the parent N-aryl thioamides through The method is tolerant of a large variety of functional groups the use of chemical oxidants, while complementary catalytic including free alkyl alcohols. The synthesis of 2- approaches have also been developed involving the use of phenylbenzothiazole was performed on gram-scale with a pro- −1 palladium [261] and photoredox catalysis [262, 263]. As men- ductivity of 0.3 g h , yielding 2.4 g after 7.2 h (Scheme 78). tioned before, performing oxidative reactions in an electro- Due to the presence of methanol, hydrogen evolution is ob- chemical cell can avoid both the necessity of using highly served at the counter-electrode. The authors propose a mech- oxidising conditions and the use of transition metals. anism based on the one-electron oxidation of the Although the first report on electrochemical oxidation for (deprotonated) thioamide to a thiamidyl radical in which the the synthesis of benzothiazoles was published in 1979 [264], sulfur atom has partial radical character. This intermediate can due to renewed interest in the field of electrochemistry more then undergo a dimerisation (observed in some cases) or un- methodologies are being reported in literature, including im- dergo an intramolecular cyclization with the arene. Following provements in the electrosynthesis of benzothiazoles via oxidation of the radical adduct after intramolecular cycliza- dehydrogenative C-S coupling [265, 266]. The group of tion, a carbocation is formed yielding the aromatic thiazole Wirth reported the synthesis of thiazoles using flow electro- after deprotonation (Scheme 79)[267]. chemistry. As before, the advantages associated with the use Apart from thiazoles, six-membered heterocycles (e.g., thi- of flow electrochemistry are exploited. In this case, the reac- azines) incorporating a sulfur atom can also be accessed tion could be performed without mediator and without through oxidative methodologies, although their electrochem- supporting electrolyte. Taking into account electrons are the ical synthesis was hitherto underexplored. Again through an Scheme 79 Proposed mechanism of electrochemical synthesis of thiazoles by intramolecular C-S bond formation J Flow Chem (2020) 10:13–71 61 Scheme 80 Electrochemical continuous flow synthesis of 1,4- benzoxathiins and 1,4- benzothiazines oxidative dehydrogenative C-S coupling, Xu and co-workers microreactor technology is an obvious choice. Moreover, C − developed the synthesis of 1,4-thiazines and 1,4- H halogenations are frequently initiated by the homolytic cleav- benzoxathiins using a flow electrolysis cell (Scheme 80). age of a halogen-halogen bond using light, with the advantages The reaction is run in the presence of the Lewis acid of performing photochemistry in flow having been previously Sc(OTf) with a mixture of acetonitrile and TFA (9:1) as the highlighted, while elemental halogens (or equivalent sources of solvent with a Pt cathode (the reduction of protons being the electrophilic halogens, “X ”) can be safely generated under flow reaction occuring at the counter electrode) and a carbon-filled conditions. The halogenation of organic compounds was com- polyvinylidene fluoride anode. The mechanism of the reaction prehensively reviewed by Cantillo et al. (2017) [269]. is similar to the cyclization to form thiazoles (vide supra), analogously occuring via oxidation of the thioamide to a C − Hfluorination thiamidyl radical intermediate. Particular to this transforma- tion is the use of a catalytic amount of the Lewis acid Sc(OTf) 3 Although the carbon-fluorine bond has many attractive prop- and the strong Bronsted acid TFA. The use of acids is impor- erties, due to the difficulties associated with working with tant to promote the formation of the cyclic products with good fluoride salts (low solubility in organic media), elemental fluo- selectivity, as protonation allows for the formation of the rine and hydrofluoric acid, the development of novel fluori- thiamidyl radical at lower voltages and protonation of the nating agents is an active field. Depending on their reactivity, cyclized product prevents it from undergoing further oxida- the reagents can be classified as being either electrophilic or tion, as demonstrated by cyclic voltammetry studies [268]. nucleophilic. One such nucleophilic reagent is Because the protonated thiamidyl radical is more electrophilic, diethylaminosulfur trifluoride (DAST). A downside of its its polarity matches the arene coupling partner more closely use is the fact that it decomposes above 90 °C, which makes promoting the desired intramolecular cyclization reaction and applying microreactor technology an attractive choice when allowing for the synthesis of substituted 1,4-benzothiazines working with this reagent. Aside from the explosive aspect, and 1,4-benzoxathiins bearing both electron-withdrawing perfluorinated tubing is not affected by the hydrofluoric acid and electron-donating groups [211]. formed during the reaction, which can be quenched by intro- ducing a bicarbonate solution as the reagent stream exits the C − X bond formation reactor. Seeberger et al. applied DAST to the fluorination of aldehydes to form acyl fluorides [270]. Transforming a carbon-hydrogen bond to a carbon-halogen bond A different approach to acyl fluorides was followed by is a key transformation in organic synthesis. As many dangers are Britton et al. using the decatungstate photocatalyst and the associated with the use of elemental halogens, for the C − H electrophilic fluorinating agent N-fluorobenzenesulfonimide halogenation of organic compounds the application of (NFSI) [271]. Through decatungstate photocatalysis, site- 62 J Flow Chem (2020) 10:13–71 Scheme 81 Decatungstate catalysed C − H fluorination with the electrophilic fluorinating reagent NFSI selective C − H fluorination was achieved for both unactivated In collaboration with Merck, the methodology was and activated C − H bonds, the methodology also being ap- applied to the fluorination of leucine methyl ester, a plied to the synthesis of tracers for Positron Emission key component of Odanacatib, an osteoporosis drug Tomography (PET) studies by the labelling of amino acids candidate [276]. Under flow conditions, the reaction and peptides with [ F]NFSI [272–274]. Notable is the differ- could be accelerated from 16 h to 2 h, allowing the ence in selectivity obtained when using photocatalysis when production of γ-fluoroleucine in 90% yield (> 20 g compared to a thermal radical chain reaction initiated with scale, Scheme 82)[237]. AIBN, exemplified by the functionalization of 4- An organocatalytic approach towards benzylic fluori- ethyltoluene bearing two distinct benzylic positions, with nation was followed by Kappe and co-workers by ap- AIBN favouring methyl functionalization (kinetic control). plication of xanthone as a photoorganocatalyst, The reaction was performed under flow conditions for the Selectfluor as the fluorinating agent and irradiation with fluorination of ibuprofen methyl ester (Scheme 81)[275]. a 105 W CFL bulb (Scheme 83). Scheme 82 Application of the work of Britton and co-workers to the synthesis of a precursor of the osteoporosis drug candidate Odanacatib (Merck) J Flow Chem (2020) 10:13–71 63 Scheme 83 Benzylic fluorination with a xanthone photoorganocatalyst in conjunction with the Selectfluor reagent The T excited state of xanthone functions as a HAT Ibuprofen methyl ester was fluorinated at the benzylic catalyst to generate benzylic radicals [277, 278]. This position with >90% selectivity in 80% isolated yield, allowed the fluorination of a variety of benzylic sub- while the natural product celestolide, a common fra- strates at room temperature in a residence time of less grance component, was fluorinated in 9 min in 88% than 30 min, although for more challenging substrates, isolated yield. Processing of 100 ml of solution allowed an elevated reaction temperature of 60 °C was required. theproductionof2.3gofproduct [279]. Scheme 84 Free radical chain chlorination driven by light irradiation 64 J Flow Chem (2020) 10:13–71 Scheme 85 In situ generation and on site consumption of chlorine in continuous-flow C − H chlorination functionalization in the chemical research literature. Apart from the obvious hazards associated with storing chlorine The C − H photochlorination in continuous flow reported by gas in its elemental form, one of the downsides of using Cl Jähnisch and co-workers using Cl gas in a FFMR is one of for radical chlorinations is the occurrence of electrophilic ar- the earliest examples of continuous-flow radical C − H omatic substitution as a side-reaction, especially when Scheme 86 Benzylic chlorination by in situ generated chlorine J Flow Chem (2020) 10:13–71 65 working with electron-rich substrates. Through the use of a glass microreactor and irradiation with 352 nm light quartz window, irradiation of the reaction mixture in the through the use of a 15 W black light (Scheme 87)[284]. FFMR with short wavelength UV light (190–250 nm) coming An additional benefit of microreactor technology is the fact from a 1000 W Xenon lamp became possible, supressing the that the product stream leaves the reactor, hence, the formation ionic reactivity and providing the desired chlorinated product of polybrominated side products is avoided. The use of solar −1 −1 in a spacetime yield of 400 mol L h (Scheme 84)[280]. light as a sustainable energy source for photochemistry is of Ryu et al. developed a photochlorination of alkanes with a interest [285–287], and was applied to photobromination by 15 W CFL black light (Scheme 85). Sulfuryl chloride was also Park and co-workers [288]. The photochemical bromination is used as a chlorinating agent. Due to the dangers associated frequently performed in CCl , a toxic solvent which use being with chlorine gas, in situ generation of molecular chlorine is phased out due to health and environmental concerns [289]. highly desirable. Several reports have appeared on photo- By using the electrophilic brominating agent N- chemical oxidative chlorination. Hydrochloric acid is then bromosuccinimide, the photobromination can be performed mixed with bleach to form chlorine in situ, which is then in acetonitrile as the solvent as demonstrated by Kappe and homolytically cleaved in a photoreactor, as demonstrated by co-workers who developed a continuous-flow C − Hbenzylic the groups of Ryu and Kappe (Scheme 86)[281, 282]. bromination with NBS using FEP tubing and CFL bulb [290]. This was also applied to the synthesis of 5- bromomethylpyrimidine by Casar and co-workers, applied C − H bromination in the synthesis of Rosuvastatin [291]. O’Brien et al. solved the problem of possible microreactor clogging due to the for- Although elemental bromine is easier to handle than chlo- mation of succinimide by performing the reaction in a slug rine and bromine radicals are more selective when flow with an aqueous phase, allowing in-line separation with a performing HAT, bromination is electronically less liquid-liquid separator [292]. deactivating than chlorination. For this reason, photochem- ical C − H bromination suffers more frequently from C − D bond formation polybromination in unbiased substrates such as cycloalkanes [283]. Through the use of microreactor tech- Deuteration and tritiation of pharmaceutical drug candidates is of nology, Ryu et al. performed the C − H bromination of great importance in the field of drug discovery for the study of cycloalkanes in a residence time of a few minutes using a drug metabolism and pharmacokinetics [293, 294]. Specifically, Scheme 87 Photochemical bromination of aliphatic C(sp )-H bonds in flow 66 J Flow Chem (2020) 10:13–71 Scheme 88 Ir-catalysed ortho-deuteration in flow the synthesis of stable isotopically labelled standards for detec- addressedbyincreasingthemixing efficiency andbycontrolling tion with mass spectrometry techniques is of interest. Stable iso- the reaction temperature carefully. Moreover, the reaction mix- topically labelled standards are usually prepared via a hydrogen ture can be quenched efficiently in flow, limiting the time that isotope exchange reaction in which C − H activation leads to a H sensitive molecules need to be exposed to harsh reaction condi- −DorH − T exchange. The benefits of using gases in flow tions and thus offering options to avoid overreaction due to chemistry have been highlighted extensively in this review. The multiple, consecutive C–H functionalization events. The reac- mass-transfer and safety aspects are of particular importance tivity of C–H bonds can be enhanced by selecting the right when considering the use of D . Noël, Vliegen and co-workers catalyst and use of high reaction temperatures. In flow, such developed a continuous-flow approach to the deuteration of a conditions can be easily reached due to so-called superheating model compound (N-4-methoxyphenyl)-N-methylbenzamide of the reaction mixture (heating above the boiling point) through using an immobilized iridium catalyst (Scheme 88). Starting use of back pressure regulators. In some cases, such boosting of from polystyrene beads functionalized with a diphenylphosphine reaction kinetics allows to even lower the catalyst loading which group, ligand exchange with Crabtree’s catalyst allowed for the is another common hurdle associated with batch C–H immobilization the catalyst. Several reactor designs were tested, functionalization chemistry. Moreover, multiphase reaction mix- including a CSTR, packed bed reactor and the commercial H- tures can be easily carried out in flow allowing to explore new Cube Pro™. In the CSTR, the catalyst particles are suspended as chemical space, e.g. use of gaseous reagents and safe use of a fluidized bed but only allowed deuterium incorporation up to oxygen as a cheap and green oxidant. Also, photochemical M + 2. In the micro-packed bed reactor, deuteration up to M + 7 HAT reactions can be substantially accelerated in flow due to was obtained up to 64% conversion after two runs under 40 bars the homogeneous irradiation of the entire reaction mixture. of pressure. M + 7 only for normal pressure with 54% conver- Due to these apparent advantages of flow C–H sion, 64% conversion has only M + 3 product Employing the functionalization, we anticipate that microreactor tech- commercial H-Cube Pro™ system allows for the direct genera- nology will be more frequently used in the future. tion of deuterium gas from deuterated water, as well as deutera- While some notable advances have been made in recent tion up to M + 7 [295]. years, we believe that the field has barely scratched the surface of what is technologically possible. Moreover, new flow technologies are currently developed in aca- demic and industrial settings, which should allow to Conclusion and outlook provide new and unanticipated opportunities to this promising field. Thus, it is our hope that this review The main limitations of C–H functionalization chemistry arise will serve as a useful starting point for those aspiring from the selectivity and reactivity of C–H bonds. Herein, we to carry out their C–H functionalization chemistry in have shown that continuous-flow processing is able to address flow. at least in part those aspects. Selectivity problems can be J Flow Chem (2020) 10:13–71 67 Acknowledgements We acknowledge financial support from the Dutch 25. Cantillo D, Kappe CO (2014). Chem Cat Chem 6:3286–3305 Science Foundation (NWO) for a VIDI grant for T.N. (SensPhotoFlow, 26. Noel T, Buchwald SL (2011). Chem Soc Rev 40:5010–5029 No. 14150). S.G. is grateful to the European Union for receiving 27. G. Laudadio, T. Noël (2017) In Strategies for Palladium-Catalyzed Erasmus+ grant. A.N. and T.N. acknowledge financial support from Non-Directed and Directed CH Bond Functionalization, Elsevier, AbbVie. pp. 275–288 28. Gemoets HPL, Kalvet I, Nyuchev AV, Erdmann N, Hessel V, Schoenebeck F, Noel T (2017). Chem Sci 8:1046–1055 Open Access This article is licensed under a Creative Commons 29. de Frémont P, Marion N, Nolan SP (2009). 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Chem A 105:10890– University (Nizhny Novgorod, Russia). Then he worked on his 284. Manabe Y, Kitawaki Y, Nagasaki M, Fukase K, Matsubara H, PhD project at the same university Hino Y, Fukuyama T, Ryu I (2014). Chem Eur J 20:12750–12753 under the supervision of Prof. 285. Cambié D, Noël T (2018). Top Curr Chem 376:45 Alexei Yu Fedorov and partly at 286. Schultz DM, Yoon TP (2014). Science 343:1239176 University of Cologne (Germany, 287. Protti S, Ravelli D, Fagnoni M, Albini A (2009). Chem Commun: Group of Prof. H.-G. Schmalz). 7351–7353 After obtaining his PhD in 2013, 288. Kim YJ, Jeong MJ, Kim JE, In I, Park CP (2015). Aust J Chem 68: he worked as Young Researcher 1653–1656 at the Lobachevsky University. 289. Henderson RK, Jimenez-Gonzalez C, Constable DJC, Alston SR, After that, he worked in Inglis GGA, Fisher G, Sherwood J, Binks SP, Curzons AD (2011). Michelin (R&D Department, Green Chem 13:854–862 2014-2015) and in the group of 290. Cantillo D, de Frutos O, Rincon JA, Mateos C, Kappe CO (2014). Prof. V. Hessel at TU Eindhoven (2015). In 2016-2018, he worked at J Organomet Chem 79:223–229 the Lobachevsky University as an Assistant Professor. From 2019, 291. Šterk D, Jukič M, Časar Z (2013). Org Process Res Dev 17:145– Alexander returned to TU Eindhoven, where he is currently working on flow photochemistry. His current scientific interest is the development of 292. O’Brien M, Cooper D (2016). Synlett 27:164–168 continuous-flow methodology for organic synthesis. 293. Sawama Y, Monguchi Y, Sajiki H (2012). Synlett 23:959–972 294. Lockley WJS, McEwen A, Cooke R, Labelled Compd J (2012). Radiopharm. 55:235–257 295. Habraken E, Haspeslagh P, Vliegen M, Noël T (2014). J Flow Chem 5:2–5 Timothy Noel received in 2004 his MSc degree (Industrial Publisher’snote Springer Nature remains neutral with regard to jurisdic- Chemical Engineering) from the tional claims in published maps and institutional affiliations. KaHo Sint-Lieven in Ghent. He then moved to Ghent University to obtain a PhD under the super- Sebastian Govaerts studied vision of Professor Johan Van der chemistry at the Katholieke Eycken (2005-2009). Next, he Hogeschool Leuven and the KU moved to Massachusetts Institute Leuven, Belgium. During his of Technology (MIT) as a bachelor, he worked on radical Fulbright Postdoctoral Fellow trifluoromethylation in the group with Professor Stephen L. of Prof. Wim De Borggraeve. He Buchwald. He currently holds a moved to Eindhoven University position as an associate professor of Technology as an Erasmus+ and he chairs the Micro Flow exchange student during his mas- Chemistry & Synthetic Methodology group at Eindhoven University of ter studies to work in the group of Technology. His research interests are flow chemistry, homogeneous ca- Dr. Timothy Noël, where he talysis and organic synthesis. His research on photochemistry in worked on photocatalytic sp3 C– microfluidic reactors was awarded the DECHEMA award 2017 and the H oxidation chemistry and elec- Hoogewerff Jongerenprijs 2019. He is currently the editor in chief of the trochemical sulfonamide synthe- Journal of Flow Chemistry. sis. He is currently pursuing PhD studies with Dr. Daniele Leonori at the University of Manchester, UK. He is mainly interested in organic reactions involving radicals and the application of enabling technologies to their development.

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Published: Mar 14, 2020

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