molecules

Review Continuous Flow Synthesis of Heterocycles: A Recent Update on the Flow Synthesis of Indoles

Marco Colella, Leonardo Degennaro * and Renzo Luisi *

Flow Chemistry and Microreactor Technology FLAME-Lab, Department of Pharmacy—Drug Sciences, University of Bari “A. Moro” Via E. Orabona 4, 70125 Bari, Italy; [email protected] * Correspondence: [email protected] (L.D.); [email protected] (R.L.)



Academic Editor: Derek J. McPhee
 Received: 16 June 2020; Accepted: 10 July 2020; Published: 16 July 2020

Abstract: Indole derivatives are among the most useful and interesting heterocycles employed in drug discovery and medicinal chemistry. In addition, flow chemistry and flow technology are changing the synthetic paradigm in the field of modern synthesis. In this review, the role of flow technology in the preparation of indole derivatives is showcased. Selected examples have been described with the aim to provide readers with an overview on the tactics and technologies used for targeting indole scaffolds.

Keywords: flow chemistry; indoles; organic synthesis

1. Introduction Among heterocycles, the indole ring is one of the most ubiquitous in nature as well as in man-made products, such as pharmaceuticals, agrochemicals, dyes, and materials [1,2]. In particular, the indole core appears as a substructure of various biologically active compounds, including the neurotransmitter serotonin; the regulatory hormone melatonin; and various medicines, such as antihypertensive, anti-inflammatory, antimigraine, anti-tumor, and many others (Scheme1)[ 3]. In addition, indole is a privileged scaffold in drug discovery programs targeting new antivirals. Examples of marketed indole-containing antiviral drugs include Arbidol and Delavirdine. Arbidol is used for the treatment and prophylactic prevention of influenza A and B virus and SARS. Delavirdine is a first-generation Molecules 2020, 25, x FOR PEER REVIEW 2 of 28 non-nucleoside reverse transcriptase inhibitor that was approved by the FDA in 1997 for the treatment of human immunodeficiencyreview, recent flow chemistry virus type approaches 1 (HIV-1) developed [4,5]. for strengthening the tactics of indole ring preparation and functionalization will be described.

Scheme 1. Selected examples of indole-containing biologically active compounds. Scheme 1. Selected examples of indole-containing biologically active compounds. 2. Synthesis of Indole Ring under Continuous Flow Conditions Molecules 2020, 25, 3242; doi:10.3390/molecules25143242 www.mdpi.com/journal/molecules 2.1. Fischer Indole Synthesis The Fischer approach, proposed for the first time in 1883 [14], is one of the oldest reactions in organic chemistry [15] but is still the pillar for the preparation of indoles [16]. In the presence of the appropriate acid or acid catalyst, the desired indole is typically obtained by heating ketone 2 (or aldehyde) and arylhydrazine 1 without the need for the isolation of the enolizable N-arylhydrazone intermediate 3. Mechanistically (Scheme 2), it is likely that the tautomer 4 undergoes a [3,3]- sigmatropic rearrangement, giving the bis iminobenzylketone 5 with the loss of aromaticity [16–18]. The latter furnishes the desired indole 8 as a result of rearomatization, cyclization to cyclic aminal 7, and the formation of an indole ring with the loss of ammonia.

Scheme 2. Key steps of the proposed mechanism for the Fischer indolization: (a) N-arylhydrazone generation, (b) enamine formation, (c) [3,3]-sigmatropic rearrangement, (d) re-aromatization, (e) cyclization, (f) indole formation.

The possibility to transfer this transformation in a continuous flow system has attracted different research teams, among which are the groups of Bagley [19] and Kappe [20], whose seminal works demonstrated some important advantages related to the flow technology with respect to the traditional methods. In particular, the adoption of microwave heating or the use of high- temperature/high-pressure flow systems allowed them to improve reaction yields, limiting side-

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Since itsMolecules first 20 isolation20, 25, x FOR PEER by REVIEW Baeyer from the reaction of indigo with oleum (indole2 of 28 = indigo + oleum) [6], many routes have been developed for the indole nucleus preparation, although the review, recent flow chemistry approaches developed for strengthening the tactics of indole ring importancepreparation of this nucleus and functionalization still impels will a be never-ending described. quest to design alternative approaches that are cost-effective, highly productive, and sustainable. For this purpose, not only are “new routes for a classic target” [1] highly demanded, but also the implementation of currently available methods taking advantage of modern technology tools is desired. In pursuing this objective, flow microreactor technology represents a unique resource due to its widely recognized potential in the intensification of synthetic processes. Indeed, the introduction of flow microreactors has paved the way to a breakthrough in different areas of organic synthesis thanks to different advantages over traditional batch processes, such as large surface-to-volume ratio, efficient mass and heat transfer, precise and fast mixing, intrinsic safety, lower solvent and reagent consumption, easier scalability, higher productivity, and reduced footprint and capital investment [7–11]. Moreover, in recent years flow microreactor technology has not only allowed the refinement of various synthetic methodologies but has also disclosed processes which are difficult to perform under batch conditions [12,13]. In this review, recent flow chemistry approaches developed for strengthening the tactics of indole ring preparation and functionalization will be described.

2. Synthesis of Indole Ring under Continuous Flow Conditions

2.1. Fischer Indole SynthesisScheme 1. Selected examples of indole-containing biologically active compounds. The Fischer2. Synthesis approach, of Indole proposed Ring underfor Continuous the first Flow time Conditions in 1883 [14], is one of the oldest reactions in organic chemistry2.1. Fischer [15 Indole] but Synthesis is still the pillar for the preparation of indoles [16]. In the presence of the appropriateThe acid Fischer or acid approach, catalyst, proposed the for desired the first indole time in is1883 typically [14], is one obtained of the oldest by reactions heating in ketone 2 (or aldehyde) andorganic arylhydrazine chemistry [15] but1 without is still the thepillar need for the for preparation the isolation of indoles of [ the16]. In enolizable the presenceN of-arylhydrazone the intermediateappropriate3. Mechanistically acid or acid (Schemecatalyst, the2), desired it is likely indole that is typically the tautomer obtained 4byundergoes heating ketone a [3,3]-sigmatropic2 (or aldehyde) and arylhydrazine 1 without the need for the isolation of the enolizable N-arylhydrazone rearrangement,intermediate giving 3 the. Mechanistically bis iminobenzylketone (Scheme 2), it is 5 likelywith that the the loss tautomer of aromaticity 4 undergoes [16 a [3,3]–18-]. The latter furnishes thesigmatropic desired rearrangement indole 8 as, agiving result the ofbis rearomatization,iminobenzylketone 5 with cyclization the loss of aromaticity to cyclic [ aminal16–18]. 7, and the formation ofThe an latter indole furnishes ring the with desired the indole loss of 8 as ammonia. a result of rearomatization, cyclization to cyclic aminal 7, and the formation of an indole ring with the loss of ammonia.

Scheme 2. Key steps of the proposed mechanism for the Fischer indolization: (a) N-arylhydrazone Scheme 2. Key steps of the proposed mechanism for the Fischer indolization: (a) N-arylhydrazone generation, (b) enamine formation, (c) [3,3]-sigmatropic rearrangement, (d) re-aromatization, (e) generation,cyclization (b) enamine, (f) indole formation, formation. (c) [3,3]-sigmatropic rearrangement, (d) re-aromatization, (e) cyclization, (f) indole formation. The possibility to transfer this transformation in a continuous flow system has attracted different The possibilityresearch teams to transfer, among which this transformationare the groups of Bagley in a continuous[19] and Kappe flow [20], systemwhose seminal has attracted works different demonstrated some important advantages related to the flow technology with respect to the research teams,traditional among methods. which In are particular, the groups the adoption of Bagley of microwave [19] and heating Kappe or [ 20 the], use whose of high seminal- works demonstratedtemperature/high some important-pressure advantages flow systems related allowed to them the flowto improve technology reaction with yields respect, limiting to side the- traditional methods. In particular, the adoption of microwave heating or the use of high-temperature/high-pressure flow systems allowed them to improve reaction yields, limiting side-product formation, and to reduce the reaction time, making this process not only suitable for continuous flow but also superior in terms of productivity with respect to the batch. In the following two sections, various contributions to this field will be presented, highlighting the main aspects and differences between the flow microwave-assisted reactions and conventional heating transformations. Molecules 2020, 25, 3242 3 of 26

2.1.1. Continuous Flow Microwave-Assisted Fischer Indolization From the early experiments conducted in domestic ovens in the 1980s [21,22] to the use of safe and advanced equipment specifically designed for organic reactions [19,23–27], microwave-assisted organic synthesis (MAOS) has proved to be a convenient alternative to conventional heating. Typically, the use of microwave energy ensures a rapid dielectric heating of the reaction mixture to temperatures above the boiling point of the solvent [28,29], thus enabling an increase in reaction rates [30,31]; the fast optimization of reaction procedures [19]; and, in many cases, higher yields [32,33]. Under microwave irradiation, the heating profile is uniform and highly controlled, leading to more reproducible reactions [25]. Moreover, in some cases the use of microwave heating resulted in higher chemo-, regio-, or stereoselectivities as a result of the different absorption and transmission of the energy with respect to conventional heating [34]. However, scaling up microwave-assisted organic reactions is limited by the penetration depth of microwaves (few centimeters), confining this approach to small-scale MW devices [23]. Although the combined use of large multimode MW systems [35,36] and stop-flow synthesis [37] has partially circumvented these limitations, alternative approaches to microwave-mediated large-scale synthesis are highly demanded [38]. In this context, a combination of CF and microwave-assisted organic synthesis (CF-MAOS) was originally proposed by Strauss and coworkers in 1990s [39,40]. In the following years, different groups have applied the CF-MAOS approach also to Fischer synthesis for the preparation of indole scaffolds. The first example was reported by Bagley et al., who designed a CF microwave reactor consisting of a standard pressure-rated glass tube (10 mL) filled with sand (ca. 12 g), which was introduced into the cavity of a self-tunable monomodal microwave synthesizer [19]. The tuning of the microwave power enabled the regulation of the reaction temperature, which was directly measured using an IR sensor. A solution of cyclohexanone 9 and phenylhydrazine 10 in glacial AcOH was introduced into the flow cell at a flow rate of 0.5 mL 1 min− by usingMolecules an 20 HPLC20, 25, x FOR pump, PEER REVIEW and the reaction mixture was heated to 150 ◦C using4 of 28 a microwave power of 150 W. The combined solutions were evaporated, furnishing, after work-up and purification During the collection, to avoid solvent boiling the exit temperature was kept constant by tuning the by recrystallization, the indole 11 in a 91% yield (Scheme3a). irradiation power between 130 and 150 W (Scheme 3c).

Scheme 3. CF-MAOS approach applied to Fischer indole synthesis: (a) first example proposed by Scheme 3. CF-MAOSBagley; (b) nonresonant approach microwave applied system to Fischer for continuous indole flow synthesis: synthesis de (velopeda) first by example Larhed; (c) proposed by Bagley; (b)bench nonresonant-top single-mode microwave microwave system setup presented for continuous by Akai. flow synthesis developed by Larhed; (c) bench-top single-mode microwave setup presented by Akai. In recent years, different works focused on the continuous flow Fischer synthesis for the In the samepreparation field, of Larhed tryptophol and and coworkers derivatives, designedwhich have abeen nonresonant recognized as microwave key intermediates apparatus for the for organic construction of relevant bioactive compounds, such as some antimigraine triptans [41–45] and synthesis, consistingindoramine, ofa selective a helical alpha microwave-1 adrenergic receptor antenna antagonist. of Al-Cu In particular, material in 2017 wrapped Yu and Lv around [46] a tubular reactor madereported of microwave-transparent the application of CF-MAOS methodology borosilicate for glassthe preparation [23]. The of 7- Fischerethyltryptophol indole (7-ET) synthesis was selected, along14, awith relevant other intermediate transformations, en route to the to potent test the non usefulness-steroidal anti- ofinflammatory this setup. and Hence, analgesic a solution of etodolac [47–49]. In this work, using a total flow rate of 200 mL·min−1, a solution of 4-hydroxybutanal cyclohexanone12 (prepared9 and a by solution adding a of drop phenylhydrazine of 4 M hydrochloric10 acidwere to a pumped solution ofthrough 2,3-dihydrofuran) the CF-MAOS in H2O system by a Syrris Asiaand syringe a solution pump. of 2-ethylphenylhydrazine After the optimization hydrochloride study, 13 usingin water/ethylene 230 ◦C as glycol the (EG) temperature preheated and 20 s as the residenceat time,80 °C were indole pumped11 was through obtained the microwave in a 90%-heating yield residence with loop a noteworthy with a residence estimated time of 20 throughputs. of Using these conditions, an exit temperature of 180 °C was achieved. Then, the mixture flowed 9.8 g h 1 (57.2 mmol h 1) (Scheme3b). Some years later, Akai and coworkers developed a bench-top · − through a cooling· − loop with a residence time of 10 s and was diluted with water and extracted with methyl tert-butyl ether (MTBE). After the evaporation of the organic phase, 7-ET was obtained in a 78% isolated yield. In this contribution, the microwave heating enabled the use of a very short residence time (30 s), inhibiting the formation of side-products derived from the reaction of 7-ET with aldehyde excess (Scheme 4).

Scheme 4. Fischer indole synthesis of 7-ET under microwave-assisted continuous flow conditions.

In the same year, Gaikar and co-workers developed a Fischer indolization for the synthesis of tryptophol 17, starting from 2,3-DHF 15 and phenyl hydrazine hydrochloride (PHH) 16 by using the CF-MAOS approach [50]. The initial experiments, performed using conventional oil bath heating, showed that raising the reaction temperature and the flow rates resulted in a higher conversion of

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During the collection, to avoid solvent boiling the exit temperature was kept constant by tuning the single-modeirradiation microwave power apparatus between 130 for and continuous 150 W (Scheme flow 3c). organic synthesis [38]. In this case, the Fischer indolization was selected as a representative transformation to evaluate the apparatus performance. Hence, a solution of cyclohexanone 9 and a solution of phenylhydrazine 10 were separately pumped at the same flow rate through a borosilicate helical glass tube reactor placed into the resonant cavity under a pressure of 25 bar. The optimization study was conducted by changing the solution flow rates (13–17 mL min 1), the irradiation power (130–190 W), and the solution concentrations and · − evaluating the GC yield of product 11. A reaction scale-up was conducted under optimized conditions. In particular, a 2.0 M solution of cyclohexanone 9 in AcOH and a 2.2 M solution of phenylhydrazine 10 in MeCN were flowed into the system using a total flow rate of 15 mL min 1 (corresponding to · − a residence time of 21 s) and using an irradiation power of 145 W. Under steady state conditions at 240 ◦C, 115 g (75%) of product 11 were collected within 60 min. During the collection, to avoid solvent boiling the exit temperature was kept constant by tuning the irradiation power between 130 and 150 W

(Scheme3c). In recent years,Scheme di 3ff. erentCF-MAOS works approach focused applied on to theFischer continuous indole synthesis flow: (a) Fischerfirst example synthesis proposed forby the preparation of tryptophol andBagley; derivatives, (b) nonresonant which microwave have system been for recognized continuous flow as synthesis key intermediates developed by Larhed for;the (c) construction of relevant bioactivebench compounds,-top single-mode such microwave as some setup presented antimigraine by Akai. triptans [41–45] and indoramine, a selective alpha-1 adrenergicIn recent receptor years, antagonist. different works In focused particular, on the in continuous 2017 Yu flowand Fischer Lv [46 synthesis] reported for thethe application of CF-MAOSpreparation methodology of tryptophol for the and preparation derivatives, which of 7-ethyltryptophol have been recognized as (7-ET) key intermediates14, a relevant for the intermediate en route toconstruction the potent of non-steroidalrelevant bioactive anti-inflammatory compounds, such as some and antimigraine analgesic triptans etodolac [41–45 [] 47 and–49 ]. In this indoramine, a selective alpha-1 adrenergic receptor antagonist. In particular, in 2017 Yu and Lv [46] work, using a total flow rate of 200 mL min 1, a solution of 4-hydroxybutanal 12 (prepared by reported the application of CF-MAOS methodology· − for the preparation of 7-ethyltryptophol (7-ET) adding a drop14, aof relevant 4 M hydrochloric intermediate en route acid to to the a potent solution non-steroidal of 2,3-dihydrofuran) anti-inflammatory in and H analgesic2O and a solution etodolac [47–49]. In this work, using a total flow rate of 200 mL·min−1, a solution of 4-hydroxybutanal of 2-ethylphenylhydrazine hydrochloride 13 in water/ethylene glycol (EG) preheated at 80 ◦C were 12 (prepared by adding a drop of 4 M hydrochloric acid to a solution of 2,3-dihydrofuran) in H2O pumped throughand a solution the microwave-heating of 2-ethylphenylhydrazine residence hydrochloride loop 13 in with water/ethylene a residence glycol time (EG) ofpreheated 20 s. Using these conditions, anat 80 exit °C were temperature pumped through of 180 the◦ microwaveC was achieved.-heating residence Then, loop the with mixture a residence flowed time throughof 20 s. a cooling loop with a residenceUsing these time conditions, of 10 s an and exit was temperature diluted of with 180 °C water was andachieved. extracted Then, the with mixture methyl flowed tert-butyl ether through a cooling loop with a residence time of 10 s and was diluted with water and extracted with (MTBE). Aftermethyl the tert evaporation-butyl ether (MTBE). of the After organic the evaporation phase, 7-ET of the was organic obtained phase, 7 in-ET a was 78% obtained isolated in a yield. In this contribution,78% the isolated microwave yield. In heating this contribution, enabled the the microwave use of a heating very enabledshort residence the use of a time very (30 short s), inhibiting the formationresidence of side-products time (30 s), inhibit deriveding the formation from the of side reaction-products of derived 7-ET with from the aldehyde reaction of excess 7-ET with (Scheme 4). aldehyde excess (Scheme 4).

Scheme 4. Fischer indole synthesis of 7-ET under microwave-assisted continuous flow conditions. Scheme 4. Fischer indole synthesis of 7-ET under microwave-assisted continuous flow conditions. In the same year, Gaikar and co-workers developed a Fischer indolization for the synthesis of In the sametryptophol year, 17, Gaikarstarting from and 2,3 co-workers-DHF 15 and phenyl developed hydrazine a hydrochloride Fischer indolization (PHH) 16 by forusing the the synthesis of tryptophol 17CF,-MAOS starting approach from [ 2,3-DHF50]. The initial15 andexperiments, phenyl performed hydrazine using hydrochloride conventional oil bath (PHH) heating,16 by using the showed that raising the reaction temperature and the flow rates resulted in a higher conversion of CF-MAOS approach [50]. The initial experiments, performed using conventional oil bath heating, showed that raising the reaction temperature and the flow rates resulted in a higher conversion of PHH 16 and higher yields of tryptophol 17. However, at higher temperatures two side products—a cinnoline derivative 19 obtained by a different cyclization reaction of the intermediate hydrazine 18, and a bis-indole 20, a dimer formed by a consecutive reaction between 17 and one more molecule of 15—were detected. A kinetic model for this reaction scenario was proposed using experimental data and a COMSOL simulation, determining the activation energies for the generation of derivatives 18 (36.8 kJ/mol), 17 (40.1 kJ/mol), 20 (46.9 kJ/mol), and 19 (67.7 kJ/mol). Hence, while the activation energy for the generation of 18 was low, a higher temperature was necessary to pass the energy barrier of tryptophol 17 formation. On the other hand, an excessive amount of energy promoted the formation of side products. Hence, a microwave heating approach was considered. The efficiency of the microwave heating transfer allowed the researchers to provide the required energy for the effective cyclization Molecules 2020, 25, x FOR PEER REVIEW 5 of 28

PHH 16 and higher yields of tryptophol 17. However, at higher temperatures two side products—a cinnoline derivative 19 obtained by a different cyclization reaction of the intermediate hydrazine 18, and a bis-indole 20, a dimer formed by a consecutive reaction between 17 and one more molecule of 15—were detected. A kinetic model for this reaction scenario was proposed using experimental data Molecules 2020,and25, 3242a COMSOL simulation, determining the activation energies for the generation of derivatives 18 5 of 26 (36.8 kJ/mol), 17 (40.1 kJ/mol), 20 (46.9 kJ/mol), and 19 (67.7 kJ/mol). Hence, while the activation energy for the generation of 18 was low, a higher temperature was necessary to pass the energy barrier of tryptophol 17 formation. On the other hand, an excessive amount of energy promoted the of hydrazineformation18 to tryptophol of side products. in Hence, a shorter a microwave time, limiting heating approach the formation was considered. of by-products. The efficiency of In particular, under optimizedthe microwave conditions heating using transfer a allowed peristaltic the researchers pump, ato solution provide the of required15 and energy a solution for the of 16 (PHH) in environmentallyeffective cyclization friendly of aqueous hydrazine glycerol18 to tryptophol solution in a shorter were separatelytime, limiting introducedthe formation of through by- a quartz products. In particular, under optimized conditions using a peristaltic pump, a solution of 15 and a reactor tube placed in the microwave cavity with a residence time of 300 s. The power input was set solution of 16 (PHH) in environmentally friendly aqueous glycerol solution were separately to 900 W, furnishingintroduced through a temperature a quartz reactor of about tube placed 104 in◦C the at microwave the exit cavity of the with reactor. a residence Using time aof heat300 exchanger, the mixtures. was The po cooled,wer input collected, was set to and900 W after, furnishing work-up a temperature furnished of about the 104 desired °C at the tryptophol exit of the 17 in a 95% yield (Schemereactor.5). Using a heat exchanger, the mixture was cooled, collected, and after work-up furnished the desired tryptophol 17 in a 95% yield (Scheme 5).

Scheme 5. FC-MAOS setup for the preparation of tryptophol. Scheme 5. FC-MAOS setup for the preparation of tryptophol. 2.1.2. Continuous Flow Fischer Indole Synthesis Mediated by Conventional Heating 2.1.2. Continuous Flow Fischer Indole Synthesis Mediated by Conventional Heating As described in the previous section, microwave technology enables a significant improvement As describedof a chemical in the process previous through section, the heating microwave of the reaction technology mixture to enables temperatures a significant that exceed improvement the of a chemical processboiling point through of the the solvent. heating In 2009, of the Kappe reaction presented mixture a seminal to temperatureswork in which the that appealing exceed the boiling possibility to exploit a heated flow system for the indole synthesis was demonstrated [20]. For this point of thestudy, solvent. a high In-temperature/pressure 2009, Kappe presented flow reactor a embeddedseminal withwork HPLC inwhich pumps theto introduce appealing the possibility to exploit areactant heated solution, flow system a stainless for steel the coil indole heated synthesis by an electric was heat demonstrated exchanger (up to [20 350]. °C), For this study, a high-temperaturethermocouples/pressure to measure flow the reactortemperature embedded at the exit of with the coil, HPLC a system pumps pressure to sensor, introduce and a the reactant system pressure valve to set the pressure value were employed (Scheme 6). The use of a high pressure solution, a stainless(up to 200 bar) steel allowed coil researchers heated by to exploit an electric lower boiling heat solvents exchanger in or near (up their to 350supercritical◦C), thermocouples state. to measure theThe temperature authors selected at the Fischer exit of indole the coil,synthesis a system as one of pressure the modelsensor, reactions and for testing a system the flow pressure valve to set the pressuresystem. In value particular, were inspired employed by Bagley’s (Scheme work,6 a). mixture The use of cyclohexanone of a high pressure 9 and phenylhydrazine (up to 200 bar) allowed 10 in acetic acid/iso-propanol (3:1) was introduced with a flow rate of 5 mL min−1 into a 16 mL researchers tostainless exploit steel lower coil heated boiling to 200 solvents °C at 75 inbar. or With near a residence their supercritical time of ca. 3 min, state. the Theindole authors 11 was selected the Fischer indoleobtained synthesis in 96% as yield one with of the productivity model reactions of 25 g·h−1 for. The testing reduced the reaction flow system. time under In the particular, high- inspired by Bagley’stemperature/pressure work, a mixture conditions of cyclohexanone in combination9 and with the phenylhydrazine intrinsic easy scalability10 in of aceticflow chemistry acid/iso-propanol 1 (3:1) was introduced with a flow rate of 5 mL min− into a 16 mL stainless steel coil heated to 200 ◦C at 75 bar. With a residence time of ca. 3 min, the indole 11 was obtained in 96% yield with productivity of 1 25 g h− . The reduced reaction time under the high-temperature/pressure conditions in combination · Molecules 2020, 25, x FOR PEER REVIEW 6 of 28 with the intrinsic easy scalability of flow chemistry makes this approach particularly attractive in terms of productivitymakes with this respect approach to particularly conventional attractive batch in terms procedures. of productivity with respect to conventional batch procedures.

Scheme 6. ContinuousScheme 6. Continuous flow Fischer flow Fischer indole indole synthesis synthesis under under high high-temperature-temperature/pressure/ conditions.pressure conditions. In 2010, Watts and co-workers reported the Fischer synthesis of a series of indoles using three In 2010,different Watts continuous and co-workers flow approaches reported which thewere Fischer compared, synthesis especially in of ter ams series of productivity of indoles [51]. using three different continuousIn this report, flow the approachesauthors described which the first were flow compared,reactor, depicted especially in Scheme in7, which terms was of able productivity to [51]. In this report,merge the the authors solutions described of ketones and the phenylhydrazine first flow reactor, (in DMSO depicted with 10% in of Scheme ethanol) 7into, which a glass was able to microreactor by syringe pumps generating the phenylhydrazone intermediates. The resulting merge the solutionssolution was of subsequently ketones and mixed phenylhydrazine with a solution of MSA (in DMSO (methanesulfonic with 10% acid), of which ethanol) upon into a glass microreactorheating by syringe promoted pumps the cyclization generating of phenylhydrazones the phenylhydrazone via a [3,3]-sigmatropic intermediates. rearrangement, The resultinggiving solutionCommented [M1]: detected 3 before 3. This is wrong order. the substituted indoles. Despite the high conversion for some ketones, the throughput (around 2 mgh−1) was not satisfactory, likely due to the high system backpressure. For this reason, the authors proposed a second approach (Scheme 7b) in which glacial acetic acid and sulfuric acid were respectively selected as the solvent and catalyst. Using these conditions, cyclization occurred faster, allowing the researchers to reduce the length of the reactor and consequently the backpressure of the system. A productivity of 5.7–8.9 mg·h−1 was achieved. The authors proposed a third methodology based on heterogeneous catalyzed Fischer indole synthesis (Scheme 7c). Namely, phenylhydrazones, generated by mixing ketones and phenylhydrazine in ethanol in a T-chip, were cyclized in a capillary packed with Amberlite IR 120H at 70 °C. The low backpressure generated by this setup allowed a significant increase in flow rates, achieving an acid-free throughput of 12.7–20.1 mg·h−1.

Scheme 7. Three different approaches for the continuous flow Fischer synthesis of a series of indoles: (a) initial low-productivity set-up; (b, c) modified versions of the system enabling lower back-pressure and higher productivity.

In 2012, Cosford and co-workers presented an uninterrupted multistep continuous flow synthesis of 2-(1H-indol-3-yl)thiazoles in a Syrris AFRICA® station, consisting of a sequential Hantzsch thiazole synthesis, deketalization, and Fischer indole synthesis. The ketal-protected thioamide 21 was reacted with α-bromoketone 22 in a glass reactor heated to 150 °C, generating ketal thiazole 23. The latter was directly deprotected with HBr, generated during thiazole ring formation, giving the desired ketothiazole 24, which was then mixed with hydrazine hydrochloride 16 in a heated (200 °C) glass reactor, furnishing indolylthiazole 25. The reaction scope was explored by changing both the α-

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makes this approach particularly attractive in terms of productivity with respect to conventional batch procedures.

Molecules 2020, 25, 3242 6 of 26 Scheme 6. Continuous flow Fischer indole synthesis under high-temperature/pressure conditions.

In 2010, Watts and co-workers reported the Fischer synthesis of a series of indoles using three was subsequentlydifferent mixed continuous with flow a solutionapproaches of which MSA were (methanesulfonic compared, especially acid), in terms which of productivity upon heating [51]. promoted the cyclizationIn this of report, phenylhydrazones the authors described via the a first [3,3]-sigmatropic flow reactor, depicted rearrangement, in Scheme 7, which giving was able the to substituted merge the solutions of ketones and phenylhydrazine (in DMSO with 10% of ethanol) into a glass indoles. Despite the high conversion for some ketones, the throughput (around 2 mgh 1) was not microreactor by syringe pumps generating the phenylhydrazone intermediates. The resulting − satisfactory,solution likely due was to subsequently the high system mixed with backpressure. a solution of MSA For this (methanesulfonic reason, the acid), authors which proposed upon a second approach (Schemeheating promoted7b) in which the cyclization glacial of aceticphenylhydrazones acid and via sulfuric a [3,3]-sigmatropic acid were rearrangement, respectively giving selected asCommented the [M1]: detected 3 before 3. This is wrong order. solvent andthe catalyst. substituted Using indoles. these Despite conditions, the high conversion cyclization for some occurred ketones, faster, the throughput allowing (around the researchers2 to mgh−1) was not satisfactory, likely due to the high system backpressure. For this reason, the authors reduce the lengthproposed of a the second reactor approach and (Scheme consequently 7b) in which the backpressure glacial acetic acid of an thed sulfuric system. acid A were productivity of 5.7–8.9 mg hrespectively1 was achieved. selected as the The solvent authors and catalyst. proposed Using athese third conditions, methodology cyclization basedoccurred on faster heterogeneous, · − catalyzed Fischerallowingindole the researchers synthesis to reduce (Scheme the length7c). of the Namely, reactor and phenylhydrazones, consequently the backpressure generated of the by mixing system. A productivity of 5.7–8.9 mg·h−1 was achieved. The authors proposed a third methodology ketones andbased phenylhydrazine on heterogeneous in catalyzed ethanol Fischer in a T-chip,indole synthesis were cyclized(Scheme 7c). in Namely, a capillary phenylhydrazones, packed with Amberlite IR 120H at 70generated◦C. The by lowmixing backpressure ketones and phenylhydrazine generated byin ethanol this setup in a T-chip, allowed were cyclized a significant in a capillary increase in flow packed with Amberlite IR 120H at 70 °C. The low backpressure1 generated by this setup allowed a rates, achieving an acid-free throughput of 12.7–20.1 mg h− . significant increase in flow rates, achieving an acid-free throughput· of 12.7–20.1 mg·h−1.

Scheme 7. Three different approaches for the continuous flow Fischer synthesis of a series of indoles: Scheme 7. Three different approaches for the continuous flow Fischer synthesis of a series of indoles: (a) initial low-productivity set-up; (b, c) modified versions of the system enabling lower back-pressure (a) initial low-productivityand higher productivity set-up;. (b,c) modified versions of the system enabling lower back-pressure and higher productivity. In 2012, Cosford and co-workers presented an uninterrupted multistep continuous flow synthesis of 2-(1H-indol-3-yl)thiazoles in a Syrris AFRICA® station, consisting of a sequential Hantzsch thiazole In 2012, Cosford and co-workers presented an uninterrupted multistep continuous flow synthesis synthesis, deketalization, and Fischer indole synthesis. The ketal-protected thioamide 21 was reacted ® of 2-(1H-indol-3-yl)thiazoleswith α-bromoketone 22 in in a Syrrisa glass reactor AFRICA heated station,to 150 °C, consisting generating ketal of a thiazole sequential 23. The Hantzsch latter thiazole synthesis, deketalization,was directly deprotected and Fischer with HBr, indole generated synthesis. during thiazole The ketal-protected ring formation, giving thioamide the desired21 was reacted with α-bromoketoneketothiazole 2224, whichin a glasswas then reactor mixed with heated hydrazine to 150 hydrochlorideC, generating 16 in a heated ketal (200 thiazole °C) glass23 . The latter reactor, furnishing indolylthiazole 25. The reaction scope ◦ was explored by changing both the α- was directly deprotected with HBr, generated during thiazole ring formation, giving the desired ketothiazole 24, which was then mixed with hydrazine hydrochloride 16 in a heated (200 ◦C) glass reactor, furnishing indolylthiazole 25. The reaction scope was explored by changing both the Molecules 2020, 25, x FOR PEER REVIEW 7 of 28 α-bromoketone and hydrazine hydrochloride portions, resulting in a series of complex drug-like small molecules inbromoketone high yield and (Scheme hydrazine8). hydrochloride portions, resulting in a series of complex drug-like small molecules in high yield (Scheme 8).

Scheme 8. Multistep continuous flow synthesis of various indolylthiazoles. Scheme 8. Multistep continuous flow synthesis of various indolylthiazoles. A very detailed study on the preparation of 7-ethyltryptophol (7-ET) 14 was proposed also by A veryKappe detailed’s group study [52]. onStarting the from preparation previous results of 7-ethyltryptophol reported by Su and co (7-ET)-workers14, concerningwas proposed the also by Kappe’s groupkilogram [52]. scale Starting synthesis from of 14 using previous a flow resultssystem consisting reported of a by three Su-pump and and co-workers, two-reactor flow concerning the system [53], Kappe proposed a new, operationally simpler, single pump one-reactor setup for this kilogram scaletransformation. synthesis Additionally, of 14 using in this a flow work system a precise consistingstudy of the reaction of a three-pump mechanism was and conducted two-reactor flow in order to reduce the formation of several byproducts. In particular, a premixed solution of the hydrazine hydrochloride and DHF (dihydrofuran) in MeOH/H2O (2:1) was pumped using a syringe pump through a system composed of a Hastelloy loop immersed in an oil bath (150 °C), a short stainless steel loop for reaction cooling, and a back-pressure regulator (40 bar). By extraction with MTBE/PE, the majority of byproducts can be removed, obtaining 7-ET in a 41% yield (after column chromatography) with only 3 min of residence time (Scheme 9).

Scheme 9. CF synthesis of 7-ET using conventional heating.

Inspired by Watts’s work, recent articles by Bonjoch and Rutjes emphasized the use of heterogeneous catalysis using the polymeric sulfonic acid resin (Amberlite® IR 120 H) for the continuous flow Fischer indole synthesis of pyrido [2,3-a]carbazoles [54]. For the initial experiments, methanol solutions of cyclohexanone 9 and phenylhydrazine 10, selected as model substrates, were separately driven by syringe pumps through a flow system composed of a T-mixer unit, an ETFE cartridge packed with 100 mg of Amberlite® IR 120 H (placed in oil bath), and a back-pressure regulator. Using a residence time of 10 min or 5 min, respectively, at 50 °C or 90 °C, the full conversion of the starting materials was observed. Additionally, the resin can be reactivated with a 10% H2SO4 solution, when a reduction in efficiency was detected. Similarly, a series of pyrido [2,3-a]carbazoles were prepared by the reaction of 5-oxo-cis-decahydroquinolines with a range of phenylhydrazines. However, adapting this setup for the preparation of pyrido[2,3-a]carbazoles, some slight modifications are needed. Firstly, the adding of AcOH as a cosolvent was necessary to avoid a side reaction mediated by the ammonia liberated during the indolization reaction. In order to avoid solubility problems, in some cases a ternary solvent mixture MeOH-AcOH-DCE (in different proportions) was used. Moreover, the reaction temperature was set at 70 °C and the residence time was tuned for each phenylhydrazine (or its hydrochloride salt) in a range between 20 and 60 min,

Molecules 2020, 25, x FOR PEER REVIEW 7 of 28

bromoketone and hydrazine hydrochloride portions, resulting in a series of complex drug-like small molecules in high yield (Scheme 8).

Molecules 2020, 25, 3242 7 of 26 Scheme 8. Multistep continuous flow synthesis of various indolylthiazoles. system [53], KappeA very proposed detailed study a new,on the operationallypreparation of 7-ethyltryptophol simpler, single (7-ET) pump 14 was one-reactorproposed also by setup for this transformation.Kappe Additionally,’s group [52]. Starting in this from work previous a precise results reported study ofby theSu and reaction co-workers mechanism, concerning wasthe conducted kilogram scale synthesis of 14 using a flow system consisting of a three-pump and two-reactor flow in order to reducesystem [53 the], Kappe formation proposed of a new, several operationally byproducts. simpler, single In particular, pump one-reactor a premixed setup for solutionthis of the hydrazine hydrochloridetransformation. Additionally, and DHF in (dihydrofuran) this work a precise instudy MeOH of the/ reactionH2O (2:1) mechanism was pumped was conducted using a syringe in order to reduce the formation of several byproducts. In particular, a premixed solution of the pump through a system composed of a Hastelloy loop immersed in an oil bath (150 ◦C), a short hydrazine hydrochloride and DHF (dihydrofuran) in MeOH/H2O (2:1) was pumped using a syringe stainless steelpump loop through for reactiona system comp cooling,osed of and a Hastelloy a back-pressure loop immersed regulator in an oil bath (40 (150 bar). °C), By a short extraction with MTBE/PE, thestainless majority steel loop of byproductsfor reaction cooling, can beand removed, a back-pressure obtaining regulator 7-ET(40 bar). in By a 41%extraction yield with (after column chromatography)MTBE/PE, with the onlymajority 3 minof byproducts of residence can be removed, time (Scheme obtaining9). 7-ET in a 41% yield (after column chromatography) with only 3 min of residence time (Scheme 9).

Scheme 9. CF synthesis of 7-ET using conventional heating. Scheme 9. CF synthesis of 7-ET using conventional heating. Inspired by Watts’s work, recent articles by Bonjoch and Rutjes emphasized the use of Inspiredheterogeneous by Watts’s catalysis work, using recent the polymeric articles sulfonic by Bonjoch acid resin and (Amberlite Rutjes® IR emphasized 120 H) for the the use of heterogeneouscontinuous catalysis flow using Fischer the indole polymeric synthesis sulfonicof pyrido [2,3 acid-a]carbazoles resin (Amberlite [54]. For the® IRinitial 120 experiments, H) for the continuous methanol solutions of cyclohexanone 9 and phenylhydrazine 10, selected as model substrates, were flow Fischerseparately indole synthesisdriven by syringe of pyrido pumps [2,3-througha]carbazoles a flow system [54 composed]. For theof a initialT-mixer experiments,unit, an ETFE methanol solutions ofcartridge cyclohexanone packed with9 and 100 mg phenylhydrazine of Amberlite® IR 12010 H, selected (placed in as oil model bath), and substrates, a back-pressure were separately driven by syringeregulator. pumps Using a through residence time a flow of 10 system min or 5 composedmin, respectively of a, at T-mixer 50 °C or 90 unit, °C, the an full ETFE conversion cartridge packed of the starting materials® was observed. Additionally, the resin can be reactivated with a 10% H2SO4 with 100 mgsolution of Amberlite, when a reductionIR 120 in efficiency H (placed was detected. in oil bath),Similarly, and a series a back-pressure of pyrido [2,3-a]carbazoles regulator. Using a residence timewere of prepared 10 min by or the 5 reaction min, respectively,of 5-oxo-cis-decahydroquinolines at 50 ◦C or 90 with◦C, a therange full of phenylhydrazines. conversion of the starting However, adapting this setup for the preparation of pyrido[2,3-a]carbazoles, some slight materials was observed. Additionally, the resin can be reactivated with a 10% H2SO4 solution, when a modifications are needed. Firstly, the adding of AcOH as a cosolvent was necessary to avoid a side a reduction inreaction efficiency mediated was by detected. the ammonia Similarly, liberated aduring series the of indolization pyrido [2,3- reaction]carbazoles. In order to were avoid prepared by the reactionsolubility of 5-oxo- problemscis-decahydroquinolines, in some cases a ternary with solvent a range mixture ofphenylhydrazines. MeOH-AcOH-DCE (in However, different adapting this setup forproportions) the preparation was used. of Moreover, pyrido[2,3- the reactia]carbazoles,on temperature some was set slight at 70 modifications°C and the residence are time needed. Firstly, was tuned for each phenylhydrazine (or its hydrochloride salt) in a range between 20 and 60 min, the adding of AcOH as a cosolvent was necessary to avoid a side reaction mediated by the ammonia liberated during the indolization reaction. In order to avoid solubility problems, in some cases a ternary solvent mixture MeOH-AcOH-DCE (in different proportions) was used. Moreover, the reaction temperatureMolecules was 20 set20, 2 at5, x 70FOR ◦PEERC and REVIEW the residence time was tuned for each phenylhydrazine8 of 28 (or its hydrochloride salt) in a range between 20 and 60 min, affording different indole derivatives 27 as single diastereoisomersaffording in different satisfactory indole yields.derivatives (Scheme 27 as single 10). diastereoisomers in satisfactory yields. (Scheme 10).

Scheme 10.SchemeAmberlite 10. Amberlite IR IR 120 H- H-catalyzedcatalyzed continuous continuous flow Fischer flowindole synthesis Fischer of indolepyrido[2,3 synthesis- of a]carbazoles. pyrido[2,3-a]carbazoles. Recently, Xu and Lv presented the Fischer indole preparation of 3-methylindole 29 in an ionic Recently,liquid Xu— andnamely Lv, 1- presentedethyl-3-methylimidazolium the Fischer tetrafluoroborate indole preparation ([EMIM] of[BF4]) 3-methylindole—in the presence of29 in an ionic liquid—namely,ZnCl2 as 1-ethyl-3-methylimidazolium a stoichiometric Lewis acid catalyst [55 tetrafluoroborate]. As stated above, also ([EMIM] in this work [BF4])—in a study on the the presence decomposition of the hydrazone intermediate under batch conditions confirmed that the [3,3]- Commented [M2]: detected 3 before 3. This is wrong order. of ZnCl2 assigmatropic a stoichiometric rearrangement Lewis was acid favored catalyst at high [55 ]. temperatures. As stated However, above, also the use in thisof high work a study on the decompositiontemperatures and of long the reaction hydrazone times also intermediate led to an increase under in side batch-reactions. conditions In this contribution, confirmed that the [3,3]-sigmatropicthe authors rearrangement showed how the excellent was favored heat and mass at high transfer temperatures. exhibited in flow microreactors However, enabled the use of high a high-yield preparation of 3-methylindole, with a concomitant decrease in the reaction time and temperaturescontrol and of long by-product reaction formation. times According also led to tooptimized an increase conditions, in a side-reactions. solution of aldehyde In 28 this and a contribution, solution of phenylhydrazine, introduced by two syringe pumps, were mixed and the resulting solution passed into a Corning G1 reactor (functional module I) heated to 60 °C and generating hydrazone. The latter was mixed with a solution of ZnCl2 (60 °C). Subsequently, the mixture was directed through a Corning G1 reactor (functional module II) heated to 200 °C for the indole ring formation. Then, the mixture was cooled into a residence loop, collected, diluted with water, and extracted with toluene. By using a residence time of 4 min, 3-methylindole 29 could be prepared in a a 95% yield with a purity of 96% (net isolated yield of 91%) and eventually further purified by column chromatography or recrystallization. By the extraction of the aqueous phase with dichloromethane, most ionic liquid (85–86%) could be recovered and reused three times in the same transformation without any relevant decrease in the net isolated yield (Scheme 11).

Scheme 11. A continuous-flow Fischer indole synthesis of 3-methylindole in an ionic liquid.

2.2. Hemetsberger-Knittel Indole Synthesis under Continuous Flow Conditions The Hemetsberger-Knittel reaction, presented for the first time in 1969 [56], concerns the thermolysis of α-azidocinnamate esters 30 to give indole-2-carboxylic esters 32 [57]. The precise mechanism of this transformation is still unclear, but it is likely that the thermolysis of 30 leads to the formation of a highly electrophilic singlet nitrene intermediate species 31 [58], which formally

Molecules 2020, 25, x FOR PEER REVIEW 8 of 28

affording different indole derivatives 27 as single diastereoisomers in satisfactory yields. (Scheme 10).

Scheme 10. Amberlite IR 120 H-catalyzed continuous flow Fischer indole synthesis of pyrido[2,3- Molecules 2020, 25, 3242a]carbazoles. 8 of 26

Recently, Xu and Lv presented the Fischer indole preparation of 3-methylindole 29 in an ionic the authors showedliquid—namely how, 1 the-ethyl excellent-3-methylimidazolium heat and masstetrafluoroborate transfer exhibited([EMIM] [BF4]) in— flowin the microreactors presence of enabled ZnCl2 as a stoichiometric Lewis acid catalyst [55]. As stated above, also in this work a study on the a high-yielddecomposition preparation of of the 3-methylindole, hydrazone intermediate with under a concomitant batch conditions decrease confirmed in that the the reaction [3,3]- timeCommented and [M2]: detected 3 before 3. This is wrong order. control of by-productsigmatropic formation. rearrangement According was favored to at optimized high temperatures. conditions, However, a solution the use of ofaldehyde high 28 and a solution of phenylhydrazine,temperatures and long introduced reaction times by also two led syringeto an increase pumps, in side were-reactions. mixed In this and contribution, the resulting solution the authors showed how the excellent heat and mass transfer exhibited in flow microreactors enabled passed intoa high Corning-yield preparation G1 reactor of 3 (functional-methylindole, modulewith a concomitant I) heated decrease to 60 in◦C the and reaction generating time and hydrazone. The latter wascontrol mixed of by with-product a solution formation. of According ZnCl2 (60to optimized◦C). Subsequently, conditions, a solution the mixture of aldehyde was 28 directedand a through solution of phenylhydrazine, introduced by two syringe pumps, were mixed and the resulting a Corning G1 reactor (functional module II) heated to 200 ◦C for the indole ring formation. Then, solution passed into a Corning G1 reactor (functional module I) heated to 60 °C and generating the mixture washydrazone. cooled The into latter a was residence mixed with loop, a solution collected, of ZnCl diluted2 (60 °C). with Subsequently, water, and the extractedmixture was with toluene. By using a residencedirected through time a Corning of 4 min, G1 reactor 3-methylindole (functional module29 could II) heated be to prepared 200 °C for inthe aindole a 95% ring yield with a purity of 96%formation. (net isolated Then, the yield mixture of 91%)was cooled and into eventually a residence further loop, collected, purified diluted by columnwith water, chromatography and extracted with toluene. By using a residence time of 4 min, 3-methylindole 29 could be prepared in a or recrystallization.a 95% yield By with the a purity extraction of 96% (net of isolated the aqueous yield of 91 phase%) and eventually with dichloromethane, further purified by column most ionic liquid (85–86%) couldchromatography be recovered or recrystallization. and reused threeBy the extraction times in of the the sameaqueous transformation phase with dichloromethan withoute, any relevant decrease in themost net ionic isolated liquid (85 yield–86%) (Schemecould be recovered 11). and reused three times in the same transformation without any relevant decrease in the net isolated yield (Scheme 11).

Scheme 11.SchemeA continuous-flow 11. A continuous-flow Fischer Fischer indole indole synthesis of 3 of-methylindole 3-methylindole in an ionic in liquid. an ionic liquid. 2.2. Hemetsberger-Knittel Indole Synthesis under Continuous Flow Conditions 2.2. Hemetsberger-Knittel Indole Synthesis under Continuous Flow Conditions The Hemetsberger-Knittel reaction, presented for the first time in 1969 [56], concerns the The Hemetsberger-Knittelthermolysis of α-azidocinnamate reaction, esters presented30 to give indole for-2 the-carboxylic first time esters 32 in [57 1969]. The [ 56 precise], concerns the thermolysismechanism of α-azidocinnamate of this transformation esters is still30 unclear,to give but it indole-2-carboxylic is likely that the thermolysis esters of 30 leads32 [57 to ].the The precise formation of a highly electrophilic singlet nitrene intermediate species 31 [58], which formally mechanism of this transformation is still unclear, but it is likely that the thermolysis of 30 leads to the formation of a highly electrophilic singlet nitrene intermediate species 31 [58], which formally Molecules 2020, 25, x FOR PEER REVIEW 9 of 28 undergoes a C-H insertion, giving the desired indole nucleus (Scheme 12). Moreover, 2H-azirines, deriving fromundergoes the insertion a C-H insertion of 31 ,to giving the adjacentthe desireddouble indole nucleus bond, (Scheme have been12). Moreover, also proposed 2H-azirines, as the reaction intermediatesderiving [59]. from the insertion of 31 to the adjacent double bond, have been also proposed as the reaction intermediates [59].

Scheme 12. Hemetsberger-Knittel reaction. Scheme 12. Hemetsberger-Knittel reaction. The continuous flow preparation of a series of indoles based on the Hemetsberger–Knittel The continuousreaction was flow presented preparation by Seeberger of a [60 series]. A solution of indoles of the basedazidoacrylate on the 33Hemetsberger–Knittel in toluene was loaded reaction was presentedinto bythe Seebergerreactor via an [injection60]. A solutionloop. The concentration of the azidoacrylate (1.0 or 0.5 M) 33of thein reactant toluene solution was loadedwas into the halved by mixing it with the second pump, which runs at the same flow rate. Then, the resulting reactor via an injection loop. The concentration (1.0 or 0.5 M) of the reactant solution was halved by solution passed through a 2 mL stainless steel heating loop (220 °C). By using these conditions, the mixing it withhigh the-yielding second synthesis pump, of indoles which 34 runs was atachieved the same with a flow residence rate. time Then, of 30 the s (Scheme resulting 13). This solution passed through a 2flow mL approach stainless was steel able to heating address the loop safety (220 issues◦C). related By to using the employment these conditions, of azides; the the use high-yieldingof synthesis ofhigh indoles-boiling34 solvents,was achieved such as mesitylene with a residence and xylenes; timeand the of scalability 30 s (Scheme problem 13s ). encountered This flow approach under traditional batch conditions. In this context, the authors carried out a scalable continuous flow was able tothermolysis address theof azidoacrylates safety issues with relatedthe preparation to the of employment 8.5 g of 35, a precursor of azides; of a DAAO the useinhibitor, of high-boiling solvents, suchwithin as mesitylene21 min (productivity and xylenes;of 2.5 mmol and·min the−1). scalability problems encountered under traditional batch conditions. In this context, the authors carried out a scalable continuous flow thermolysis of azidoacrylates with the preparation of 8.5 g of 35, a precursor of a DAAO inhibitor, within 21 min (productivity of 2.5 mmol min 1). · −

Scheme 13. Hemetsberger–Knittel synthesis under continuous flow conditions.

In 2013, a comparative study between thermolysis, microwave irradiation, and flow approach for the preparation of indole-2-carboxylates via the Hemetsberger–Knittel reaction was presented by Jones [61]. By using microwave irradiation, indole-2-carboxylates were obtained in a higher yield and with a shorter reaction time (200 °C, 10 min) with respect to batch (140 °C, 2 h). By using the flow system, not only were similar reaction yields observed in comparison with the microwave approach, but also a further decrease in the reaction time (165 °C, ca. 1 min) was achieved (Scheme 14).

Scheme 14. Preparation of a series of indoles by Hemetsberger–Knittel synthesis under different conditions.

2.3. Indolization by Reductive Cyclization of Nitro Compounds

Molecules 2020, 25, x FOR PEER REVIEW 9 of 28

undergoes a C-H insertion, giving the desired indole nucleus (Scheme 12). Moreover, 2H-azirines, deriving from the insertion of 31 to the adjacent double bond, have been also proposed as the reaction Molecules 2020, 25, x FOR PEER REVIEW 9 of 28 intermediates [59]. undergoes a C-H insertion, giving the desired indole nucleus (Scheme 12). Moreover, 2H-azirines, deriving from the insertion of 31 to the adjacent double bond, have been also proposed as the reaction intermediates [59].

Scheme 12. Hemetsberger-Knittel reaction.

The continuous flow preparation of a series of indoles based on the Hemetsberger –Knittel reaction was presented by SeebergerScheme [ 6012.]. Hemetsberger A solution of-Knittel the azidoacrylate reaction. 33 in toluene was loaded into the reactor via an injection loop. The concentration (1.0 or 0.5 M) of the reactant solution was halvedThe by continuous mixing it with flow the preparation second pump of a, which series ofruns indoles at the basedsame flow on the rate. Hemetsberger Then, the resulting–Knittel solutionreaction passedwas presented through by a 2Seeberger mL stainless [60]. steel A solution heating of loop the (220azidoacrylate °C). By using 33 in these toluene conditions, was loaded the highinto -theyielding reactor synthesis via an injection of indoles loop. 34 wasThe achievedconcentration with (1.0a residence or 0.5 M) time of theof 30 reactant s (Scheme solution 13). Thiswas flowhalved approach by mixing was it able with to the address second the pump safety, whichissues runsrelated at tothe the same employment flow rate. of Then, azides the; the resulting use of highsolution-boiling passed solvents, through such a 2 asmL mesitylene stainless steel and heating xylenes loop; and (220 the °C). scalability By using problem these conditions,s encountered the Molecules 2020,underhigh25, 3242-yielding traditional synthesis batch conditions. of indoles 34In thiswas c achievedontext, the with authors a residence carried timeout a ofscalable 30 s (Scheme continuous 13). flowThis 9 of 26 thermolysisflow approach of azidoacrylateswas able to address with thethe preparationsafety issues of related 8.5 g ofto 35the, aemployment precursor of of a azidesDAAO; theinhibitor, use of withinhigh-boiling 21 min solvents, (productivity such of as 2.5 mesitylene mmol·min and−1). xylenes; and the scalability problems encountered under traditional batch conditions. In this context, the authors carried out a scalable continuous flow thermolysis of azidoacrylates with the preparation of 8.5 g of 35, a precursor of a DAAO inhibitor, within 21 min (productivity of 2.5 mmol·min−1).

Scheme 13.SchemeHemetsberger–Knittel 13. Hemetsberger–Knittel synthesis synthesis under under continuous continuous flow conditions. flow conditions. In 2013, a comparative study between thermolysis, microwave irradiation, and flow approach In 2013, a comparative study between thermolysis, microwave irradiation, and flow approach for the preparationScheme of indole13. Hemetsberger-2-carboxylates–Knittel via synthesis the Hemetsberger under continuous–Knittel flow reaction conditions. was presented by for the preparationJones [61]. of By indole-2-carboxylatesusing microwave irradiation, via indole the-2- Hemetsberger–Knittelcarboxylates were obtained in reactiona higher yield was and presented by Jones [61]. Bywith using Ina shorter2013, microwave a reactioncomparative time irradiation, study(200 °C, between 10 min) indole-2-carboxylates thermolysis, with respect microwave to batch (140 irradiation, were °C, 2 obtained h). and By usingflow in approach the a higherflow yield and system,for the preparation not only were of indolesimilar-2 reaction-carboxylates yields via observed the Hemetsberger in comparison–Knittel with reaction the microwave was presented approach, by with a shorterbutJones reactionalso [61 a]. further By using time decrease microwave (200 in◦ theC, irradiation, reaction 10 min) time indole with (165-2 -°C, respectcarboxylates ca. 1 min) to werewas batch achieved obtained (140 (in◦SchemeC, a higher 2 h). 14 )yield. By and using the flow system, not onlywith a wereshorter similar reaction reactiontime (200 °C, yields 10 min) observed with respect in to comparison batch (140 °C, with2 h). By the using microwave the flow approach, system, not only were similar reaction yields observed in comparison with the microwave approach, but also a further decrease in the reaction time (165 ◦C, ca. 1 min) was achieved (Scheme 14). but also a further decrease in the reaction time (165 °C, ca. 1 min) was achieved (Scheme 14).

Scheme 14. Preparation of a series of indoles by Hemetsberger–Knittel synthesis under different conditions.

2.3. Indolization by Reductive Cyclization of Nitro Compounds Scheme 14.SchemePreparation 14. Preparation of of a a series series of indoles of indoles by Hemetsberger by Hemetsberger–Knittel–Knittel synthesis under different synthesis under conditions. different conditions. 2.3. Indolization by Reductive Cyclization of Nitro Compounds 2.3. Indolization by Reductive Cyclization of Nitro Compounds The reductive cyclization of aromatic nitro compounds is one of the most useful approaches for indole ring construction. The reduction step is generally performed by catalytic hydrogenation over Molecules 2020, 25, x FOR PEER REVIEW 10 of 28 Pd/C, Pt/C, or a combination of Raney nickel and hydrazine [62]. However, other reducing agents such as sodium dithionite,The reductive nickel cyclization boride/hydrazine, of aromatic nitro iron compounds or zinc inis one acetic of the acid, most stannoususeful approaches chloride, for TiCl2-HCl, and TiCl haveindole also ring construction. been employed The reduction [16]. step In is this generally section, performed a classification by catalytic hydrogenation of reductive over cyclizations 3 Pd/C, Pt/C, or a combination of Raney nickel and hydrazine [62]. However, other reducing agents based on diffsucherent as sodium starting dithionite, aromatic nickel nitro boride/hydrazine, compounds iron has or been zinc in proposed. acetic acid, Instannous particular, chloride, the reductive cyclization ofTiClo2--nitrobenzylcarbonyls,HCl, and TiCl3 have also been dinitrostyrenes, employed [16]. In thiso-nitrophenylacetonitriles, section, a classification of reductiveo-nitrostyrenes, and β-(dimethylamino)-2-nitrostyrenescyclizations based on different starting (generated aromatic nitro from compoundso-nitrotoluene has been proposed. in the In Leimgruber–Batchoparticular, the reductive cyclization of o-nitrobenzylcarbonyls, dinitrostyrenes, o-nitrophenylacetonitriles, o- indole synthesis)nitrostyrenes, has been and described. β-(dimethylamino) In recent-2-nitrostyrenes years, the intensification (generated from of o some-nitrotoluene of these in transformations the under continuousLeimgruber flow–Batcho conditions indole synthesis) has been has proposed,been described. and In recent this willyears, be the the intensification topic of thisof some section. In this context,of these transformations the Reissert under indole continuous synthesis flow is condit the classicalions has been method proposed for, and the this reductive will be the cyclization of topic of this section. o-nitrobenzylcarbonylIn this context, compounds. the Reissert Inindole this synthesis reaction, is theo classical-nitrotoluene method for was the reductive reacted cyclization with an oxalic ester to give an o-nitrophenylpyruvateof o-nitrobenzylcarbonyl compounds. derivative In this whichreaction, undergoeso-nitrotoluene reductivewas reacted with cyclization, an oxalic ester furnishing an indole-2-carboxylicto give an acid o-nitrophenylpyruvate derivative (Scheme derivative 15 ).which undergoes reductive cyclization, furnishing an indole-2-carboxylic acid derivative (Scheme 15).

SchemeScheme 15. 15Reissert. Reissert indole indole synthesis. synthesis. In 2011, Guillier and coworkers proposed a study focused on the second step of the Reissert In 2011,indole Guillier synthesis. and coworkersThe authors reported proposed a continuous a study flow focused preparation on the of various second indole step-2- ofcarboxylic the Reissert indole synthesis. Theacid authors ethyl esters reported 37 by the a reduction continuous of the flow nitropreparation group of 36, followe of variousd by spontaneous indole-2-carboxylic cyclization acid ethyl esters 37 by the(Scheme reduction 16) [63]. ofFor the this nitro purpose, group they ofused36 the, followed H-cube system by spontaneous, which ensured cyclization the preparation (Scheme of 16)[63]. indoles 37 in an extremely short time when compared to classical batch Pd/C catalyzed For this purpose,hydrogenation they [ used64]. Moreover, the H-cube with respect system, to other which reduction ensured procedures the, such preparation as Zn/AcOH of [65 indoles] 37 in an extremelyand short microwave time-assisted when hydrogenation compared with to cyclohexene classical [66 batch], the presented Pd/C catalyzed flow approach hydrogenation was able [64]. Moreover, withto prevent respect tedious to other filtration reduction and extraction procedures, steps, suchwhich as may Zn be/AcOH detrimental [65] and for large microwave-assisted-scale production. Once the advantages of the flow approach were established, a series of indoles were prepared by finely selecting the appropriate reaction conditions in terms of catalyst (Pd/C, Ru/C, Raney Ni), temperature (20–100 °C), pressure (1–100 bar), cartridge dimension (s-cart or l-cart), and flow rate (1–3 mL·min−1), depending on the reaction substrate. Furthermore, by means of a design-of- experiments (DoE) approach using the Design-Expert® software [67], a precise process scale-up based on the evaluation of five parameters (temperature, pressure, catalyst type, solvent, and the presence of AcOH) was conducted. In particular, employing optimized conditions (3 mL·min−1, 0.05 M, 50 °C, 100 bars, EtOH/EtOAc 1:1, the absence of AcOH, Pd/C 1-cart), 11.1 g of one indole were produced within 6.75 h (1.6 g·h−1).

Scheme 16. Intensification of the second step of Reissert indole synthesis under CF.

In the context of the reductive cyclization of o-nitrobenzylcarbonyl compounds, Ö rkényi and coworkers described the advantages of the continuous flow approach for the preparation of 40 (Scheme 17), an intermediate en route to 3,9,11-trisubstituted-1H,2H,3H,4H,5H-[1,4]diazepino[1,7- a]indole derivatives of general formula 43, which are melanin-concentrating hormone receptor 1

Molecules 2020, 25, x FOR PEER REVIEW 10 of 28

The reductive cyclization of aromatic nitro compounds is one of the most useful approaches for indole ring construction. The reduction step is generally performed by catalytic hydrogenation over Pd/C, Pt/C, or a combination of Raney nickel and hydrazine [62]. However, other reducing agents such as sodium dithionite, nickel boride/hydrazine, iron or zinc in acetic acid, stannous chloride, TiCl2-HCl, and TiCl3 have also been employed [16]. In this section, a classification of reductive cyclizations based on different starting aromatic nitro compounds has been proposed. In particular, the reductive cyclization of o-nitrobenzylcarbonyls, dinitrostyrenes, o-nitrophenylacetonitriles, o- nitrostyrenes, and β-(dimethylamino)-2-nitrostyrenes (generated from o-nitrotoluene in the Leimgruber–Batcho indole synthesis) has been described. In recent years, the intensification of some of these transformations under continuous flow conditions has been proposed, and this will be the topic of this section. In this context, the Reissert indole synthesis is the classical method for the reductive cyclization of o-nitrobenzylcarbonyl compounds. In this reaction, o-nitrotoluene was reacted with an oxalic ester to give an o-nitrophenylpyruvate derivative which undergoes reductive cyclization, furnishing an indole-2-carboxylic acid derivative (Scheme 15).

Scheme 15. Reissert indole synthesis.

Molecules 2020, 25, 3242In 2011, Guillier and coworkers proposed a study focused on the second step of the Reissert 10 of 26 indole synthesis. The authors reported a continuous flow preparation of various indole-2-carboxylic acid ethyl esters 37 by the reduction of the nitro group of 36, followed by spontaneous cyclization hydrogenation(Scheme with 1 cyclohexene6) [63]. For this purpose, [66], the they presented used the H flow-cube approach system, which was ensured able tothe prevent preparation tedious of filtration indoles 37 in an extremely short time when compared to classical batch Pd/C catalyzed and extractionhydrogenation steps, which [64]. mayMoreover, be detrimental with respect to for other large-scale reduction procedures production., such Once as Zn/AcOH the advantages [65] of the flow approachand weremicrowave established,-assisted hydrogenation a series of with indoles cyclohexene were [ prepared66], the presented by finely flow approach selecting was theable appropriate to prevent tedious filtration and extraction steps, which may be detrimental for large-scale reaction conditions in terms of catalyst (Pd/C, Ru/C, Raney Ni), temperature (20–100 ◦C), pressure production. Once the advantages of the flow approach were established, a series of indoles were (1–100 bar), cartridge dimension (s-cart or l-cart), and flow rate (1–3 mL min 1), depending on the prepared by finely selecting the appropriate reaction conditions in terms of catalyst· −(Pd/C, Ru/C, reaction substrate.Raney Ni), Furthermore,temperature (20–100 by °C), means pressure of (1 a–100 design-of-experiments bar), cartridge dimension (s (DoE)-cart or l approach-cart), and using the Design-Expertflow® ratesoftware (1–3 mL·min [67−1],), adepending precise on process the reaction scale-up substrate. based Furthermore, on the by evaluation means of a design of five-of- parameters experiments (DoE) approach using the Design-Expert® software [67], a precise process scale-up based (temperature,on pressure, the evaluation catalyst of five parameters type, solvent, (temperature, and the pressure, presence catalyst of AcOH)type, solvent, was and conducted. the presence In particular, 1 employing optimizedof AcOH) was conditions conducted. In (3 particular, mL min employing− , 0.05 M, optimized 50 ◦C, conditions 100 bars, (3 EtOHmL·min/EtOAc−1, 0.05 M, 1:1, 50 °C, the absence of 100 bars, EtOH/EtOAc 1:1, the absence· of AcOH, Pd/C 1-cart), 11.1 g of one indole were1 produced AcOH, Pd/C 1-cart), 11.1 g of one indole were produced within 6.75 h (1.6 g h− ). within 6.75 h (1.6 g·h−1). ·

Scheme 16.SchemeIntensification 16. Intensification of the of the second second step of of Reissert Reissert indole indole synthesis synthesis under CF. under CF.

In the context of the reductive cyclization of o-nitrobenzylcarbonyl compounds, Ö rkényi and In the contextcoworkers of described the reductive the advantages cyclization of the continuous of o-nitrobenzylcarbonyl flow approach for the compounds, preparation of 40 Örk ényi and coworkers described(Scheme 1 the7), an advantages intermediate of en the route continuous to 3,9,11-trisubstituted flow approach-1H,2H for,3H,4 theH,5H preparation-[1,4]diazepino[1,7 of 40- (Scheme 17), an intermediatea]indole enderivatives route of togeneral 3,9,11-trisubstituted-1 formula 43, which are melaninH,2H-,3concentratingH,4H,5H -[1,4]diazepino[1,7-a]indole hormone receptor 1 derivatives of general formula 43, which are melanin-concentrating hormone receptor 1 (MCHr1) antagonists [68]. Under traditional batch conditions, 2-(2,3-dihydro-1H-indol-2-yl) acetate 40 can be synthesized by a two-step procedure, starting from 4-(2-nitrophenyl)-3-oxobutanoate 38. The nitro-group reduction and cyclization afforded the indole 39, which can be further reduced to give the indoline derivative 40. In this work, a consecutive catalytic hydrogenation method to obtain 40 in one single-step from ethyl 38, and without the isolation of indole 39, was implemented. According to the optimized conditions, a solution of 38, methanesulfonic acid, and acetic acid was pumped through a H-cube system with a 10 mol% Pd/C catalyst cartridge. By using a temperature of 50 ◦C and a flow rate of 0.5 mL min 1, the full conversion of 4-(2-nitrophenyl)-3-oxobutanoate was observed, with a · − selectivity towards 2-(2,3-dihydro-1H-indol-2-yl) 40 of 73% determined by LC-DAD-MS. Only 3% of indole 39 was detected, whereas the remaining part was composed of side-products (12%). In the same contribution, also the following N-alkylation step for the preparation of 41 was intensified, exploiting flow chemistry tools. Under traditional batch mode, the N-alkylation reaction of 40 to afford the adduct 41 required a high excess (20–60 equiv.) of the carcinogenic 1,2-dibromoethane and used the high dilution technique to prevent the formation of by-products. Moreover, a long reaction time (up to 4 days) is needed. According to optimized conditions, by the DOE approach, a solution of 40, DIPEA, and 1,2-dibromoethane in CH3CN was directed through a home-built 30 mL tube reactor heated at 140 ◦C. The system pressure was controlled using 18 bar back-pressure regulator. In this way, 41 was obtained in a high yield in less than 30 min, with a productivity ca. 200 times better as compared to the slow batch protocol. Moreover, the amounts of 1,2-dibromoethane can be significantly reduced to seven equivalents. Finally, due to the solubility issues of the product, the ring closure step mediated by ammonia was performed under batch conditions, affording the key intermediate 1H,2H,3H,4H,5H,11H,11aH-[1,4]diazepino[1,7-a]indol-2-one 42 in high yield. Molecules 2020, 25, x FOR PEER REVIEW 11 of 28

(MCHr1) antagonists [68]. Under traditional batch conditions, 2-(2,3-dihydro-1H-indol-2-yl) acetate 40 can be synthesized by a two-step procedure, starting from 4-(2-nitrophenyl)-3-oxobutanoate 38.

TheMolecules nitro 20-20group, 25, x FORreduction PEER REVIEW and cyclization afforded the indole 39, which can be further reduced11 of to28 give the indoline derivative 40. In this work, a consecutive catalytic hydrogenation method to obtain 40(MCHr1) in one antagonists single-step [6 from8]. Under ethyl traditional38, and without batch conditions, the isolation 2-(2,3 of -dihydro indole 39-1,H was-indol implemented.-2-yl) acetate According40 can be synthesized to the optimized by a twoconditions,-step procedure a solution, starting of 38, methanesulfonicfrom 4-(2-nitrophenyl) acid, and-3-oxobutanoate acetic acid was 38. pumpedThe nitro through-group reduction a H-cube andsystem cyclization with a 10 afforded mol% Pd/C the indole catalyst 39 cartridge., which can By be using further a temperature reduced to ofgive 50 the°C aindolinend a flow derivative rate of 0.5 40 mL. In· minthis−1 work,, the full a consecutive conversion catalytic of 4-(2-nitrophenyl) hydrogenation-3-oxobutanoate method to obtain was observed,40 in one with single a- step selectivity from ethyl towards 38, 2and-(2,3 without-dihydro - the1H - isolationindol-2-yl) of 40 indole of 73% 39 , determinedwas implemented. by LC- DADAccording-MS. Onlyto the 3% optimized of indole conditions, 39 was detected a solution, whereas of 38 ,the methanesulfonic remaining part acid was, and composed acetic acid of side was- productspumped through(12%). In a the H- cubesame scontribution,ystem with a also 10 mol the% following Pd/C catalyst N-alkylation cartridge. step By for using the preparationa temperature of 41of 50was °C intensified and a flow, exploitingrate of 0.5 mLflow·min chemistry−1, the full tools. conversion Under traditionalof 4-(2-nitrophenyl) batch mode,-3-oxobutanoate the N-alkylation was reactionobserved, of with40 to aafford selectivity the addu towardsct 41 required 2-(2,3-dihydro a high-1H excess-indol (2-20-–yl)60 equiv.)40 of 73% of the determined carcinogenic by LC1,2- dibromoethaneDAD-MS. Only and3% of use indoled the 39 high was dilutiondetected technique, whereas the to preventremaining the part formation was composed of by-products. of side- Moreover,products (12%). a long In reaction the same time contribution, (up to 4 days) also isthe needed. following According N-alkylation to optimized step for conditions,the preparation by t heof DOE41 was approach, intensified a solution, exploiting of 40 flow, DIPEA, chemistry and 1,2tools.-dibromoethane Under traditional in CH batch3CN wasmode, directed the N- throughalkylation a homereaction-built of 4030 tomL afford tube thereactor addu heatedct 41 required at 140 °C. a highThe systemexcess (2pressure0–60 equiv.) was controlledof the carcinogenic using 18 1,2bar- backdibromoethane-pressure regulator. and use dIn the this high way, dilution 41 was techniqueobtained in to a preventhigh yield the in formation less than of30 bymin-products., with a productivityMoreover, a longca. 200 reaction times bettertime (up as comparedto 4 days) tois needed.the slow According batch protocol. to optimized Moreover, conditions, the amounts by t heof 1,2DOE-dibromoethane approach, a solution can be significantlyof 40, DIPEA, reduced and 1,2 -todibromoethane seven equivalents. in CH Finally,3CN was due directed to the throughsolubility a Molecules 2020,issueshome25, 3242- built of the 30 prodmL uct,tube thereactor ring heated closure at step140 °C. mediated The system by ammonia pressure waswas performedcontrolled using under 18 batch bar 11 of 26 conditionsback-pressure, affording regulator. the Inkey this intermediate way, 41 was 1H obtained,2H,3H,4 Hin,5 Ha ,11highH,11a yieldH- [1,4]diazepino[1,7in less than 30 min-a]indol, with-2 a- oneproductivity 42 in high ca. yield 200. times better as compared to the slow batch protocol. Moreover, the amounts of 1,2-dibromoethane can be significantly reduced to seven equivalents. Finally, due to the solubility issues of the product, the ring closure step mediated by ammonia was performed under batch conditions, affording the key intermediate 1H,2H,3H,4H,5H,11H,11aH-[1,4]diazepino[1,7-a]indol-2- one 42 in high yield.

Scheme 17. CF reductive cyclization of o-nitrobenzylcarbonyl en route to indole derivatives of general Scheme 17. CF reductive cyclization of o-nitrobenzylcarbonyl en route to indole derivatives of general formula 43. formula 43. In the 1960s, the preparation of indoles by the reductive cyclization of o-nitrostyrenes was In the 1960s,reportedScheme the by preparation Cadogan17. CF reductive [69,70 ofcyclization] and indoles Sundberg of o by-nitrobenzylcarbonyl [ the71,72 reductive] (Scheme en18 cyclization )route. This to deoxygenative indole derivatives of o-nitrostyrenes cyclization of general was was reported by Cadogantypically [69,formula70] perf and 43.ormed Sundberg by heating [71 the,72 aromatic] (Scheme nitro 18compounds). This deoxygenative in the presence of cyclizationboiling trivalent was typically phosphorus compounds, such as triethyl phosphite. However, this methodology suffered from the performed byuse heating ofIn extreme the 1960s, the conditions aromatic the preparation along nitro with of thecompounds indoles generation by the of in largereductive the quantities presence cyclization of phos of of boilingp horouso-nitrostyrenes waste. trivalent Later was, phosphorus compounds,transitionreported such as by metal triethyl Cadogan-catalyzed phosphite.[69,70 ] versions and Sundberg However, of this [ 71,72 reaction this] (Scheme usingmethodology 1 8 carbon). This deoxygenative monoxide suffered (CO) cyclization from as terminal the was use of extreme conditions alongreductanttypically with perfwereormedthe proposed generationby heating as suitable the of aromaticmethodologies large nitro quantities compounds for indole of ring in phosphorous theconstruction presence of[73 boiling waste.–84]. Despite trivalent Later, its transition syntheticphosphorus utility, compounds, this multiphase such as deoxygetriethyl phosphite.nation is limited However, by thethis employment methodology of suffered highly toxicfrom COthe metal-catalyzedunderuse of versionselevatedextreme conditionspressure of this and along reaction temperature with the using generation [16]. carbon of large monoxide quantities of (CO) phosp ashorous terminal waste. Later reductant, were proposed astransition suitable metal methodologies-catalyzed versions for indole of this ring reaction construction using carbon [73 monoxide–84]. Despite (CO) as its terminal synthetic utility, this multiphasereductant deoxygenation were proposed as is suitable limited methodologies by the employment for indole ring construction of highly [73 toxic–84]. Despite CO under its elevated synthetic utility, this multiphase deoxygenation is limited by the employment of highly toxic CO pressure and temperature [16]. under elevated pressure and temperature [16]. Scheme 18. Reductive cyclization of o-nitrostyrenes.

SchemeScheme 18. Reductive 18. Reductive cyclization cyclization of o of-nitrostyrenes.o-nitrostyrenes.

In this regard, in 2017 Kappe and Roberge reported a continuous flow preparation of various

2-aryl-substituted indoles by the palladium-catalyzed reductive cyclization of o-vinylnitrobenzenes (o-nitrostilbenes and -styrenes), employing carbon monoxide as the stoichiometric reducing agent [85] (Scheme 19). Due to the larger specific interfacial area with respect to batch reactors, the availability of mass flow controllers to finely dose the gases following stoichiometry, and the possibility to improve the solubility of the gas in the liquid phase, adopting pressurized systems, continuous flow microreactors emerge as an enabling technology to boost this type of gas-liquid transformations. By using optimized conditions, a solution of nitrostilbene, Pd(OAc)2, and 1,10-phenanthroline/tributylamine in MeCN was loaded into an injection loop and introduced into the reactor at a 0.5 mL min 1 flow rate. The · − mixture was combined in a glass static mixer at 140 C with the CO stream (8 mL min 1), which was ◦ · − directed from a gas cylinder to the system by using a mass flow controller. By using a fluoropolymer tubing, the mixer was connected with the residence coil reactor heated at 140 ◦C. Finally, the solution passed through a short cooling loop and a back-pressure regulator. The total residence time was 15 min, though some reaction output was reprocessed (total residence time of 30 min) using the same reaction conditions to improve the conversion. Immediately after the contact with CO, palladium (II) acetate was reduced to palladium (0), which partly deposited inside the channels of the flow device. According to the authors, this irreversible event induced the stopping of the reaction, explaining the low conversion observed in the case of less reactive nitrostilbenes. However, using this approach various 2-aryl-substituted indoles were prepared within 15 to 30 min, which is a significantly reduced reaction time with respect to the reported batch processes. In many cases, by HPLC-UV/Vis analysis the desired indole was identified as the only product in the crude mixture and therefore was easily isolated in high purity without needing column chromatography. Furthermore, the reaction was scaled up by employing a slightly different setup, in which the injection loop was removed and a high-pressure syringe pump were used instead of the HPLC pumps. Hence, by using methyl 2-nitrocinnamate as a starting material and 1 mol% catalyst loading, the corresponding indole was obtained in an 84% isolated yield with a throughput of 1.3 g h 1 (Scheme 19). · − Molecules 2020, 25, x FOR PEER REVIEW 1211 of 28

(MCHr1)In this antagonists regard, in 2017[68]. UnderKappe traditionaland Roberge batch reported conditions, a continuous 2-(2,3-dihydro flow preparation-1H-indol -of2- yl)various acetate 2- aryl40 can-substituted be synthesized indoles by by a thetwo palladium-step procedure-catalyzed, starting reductive from cyclization 4-(2-nitrophenyl) of o-vinylnitrobenzenes-3-oxobutanoate 38(o-. nitrostilbenesThe nitro-group and reduction -styrenes) and, employing cyclization carbon afforded monoxide the indole as the 39 stoichiometric, which can be reducing further reduced agent [85 to] (giveScheme the indoline19). Due derivative to the larger 40 .specific In this work, interfacial a consecutive area with catalytic respect tohydrogenation batch reactors, method the availability to obtain of40 massin one flow single controllers-step from to ethylfinely 38 dose, and the without gases following the isolation stoichiometry, of indole 39 and, was the implemented. possibility to improveAccording the to solubility the optimized of the conditions,gas in the liquid a solution phase of, adopting 38, methanesulfonic pressurized systems,acid, and continuous acetic acid flowwas microreactorspumped through emerge a H -ascube an senablingystem with technology a 10 mol to% boostPd/C thiscatalyst type cartridge. of gas-liquid By using transformations. a temperature By usingof 50 ° C a optimizednd a flow rate conditions, of 0.5 mL· min a−1 , the solution full conversion of nitrostilbene, of 4-(2-nitrophenyl) Pd(OAc)-3-oxobutanoate2, and 1,10was- pobserved,henanthroline/tributylamine with a selectivity towards in MeCN 2- (2,3was-dihydro loaded -in1Hto- indolan injection-2-yl) 40 loop of 73%and determinedintroduced into by LCthe- reactorDAD-MS. at aOnly 0.5 mL 3%·min of indole−1 flow 39rate. was The detected mixture, whereas was combined the remaining in a glass part static was mixer composed at 140 °Cof sidewith- theproducts CO stream (12%). (8 In mL the·min same−1), contribution,which was directed also the from following a gas Ncylinder-alkylation to the step system for the by preparation using a mass of flow41 was controll intensifieder. By, exploitingusing a fluoropolymer flow chemistry tubing, tools. the Under mixer traditional was connected batch mode,with the the residence N-alkylation coil reactorreaction heated of 40 toat 140afford °C. theFinally, addu thect 41solution required passed a high through excess a short(20–60 cooling equiv.) loop of the and carcinogenic a back-pressure 1,2- regulator.dibromoethane The total and residence used the time high was dilution 15 min technique, though some to prevent reactio n the output formation was reprocessed of by-products. (total residenceMoreover, time a long of 30reaction min) using time the(up same to 4 days)reaction is needed.conditions According to improve to optimized the conversion. conditions, Immediately by the afterDOE theapproach, contact witha solution CO, palladium of 40, DIPEA, (II) acetate and 1,2 was-dibromoethane reduced to palladium in CH3CN (0) ,was which directed partly throughdeposited a insidehome- builtthe channels 30 mL tube of the reactor flow device.heated Accordingat 140 °C. Theto the system authors, pressure this irreversible was controlled event usinginduced 18 barthe stopbackping-pressure of the regulator. reaction In, explaining this way, 41 the was low obtained conversion in a observedhigh yield in in theless casethan of30 lessmin , reactive with a nitrostilbenes.productivity ca. However, 200 times usingbetter as this compared approach to variousthe slow 2 batch-aryl- substitutedprotocol. Moreover, indoles wtheere amounts prepared of within1,2-dibromoethane 15 to 30 min ,can which be significantlyis a significantly reduced reduced to seven reaction equivalents. time with Finally,respect todue the to reported the solubility batch processes.issues of theIn many product, cases, the by ring HPLC closure-UV/Vis step analysis mediated the by desired ammonia indole was was performed identified under as the batchonly productconditions in ,the affording crude mixture the key and intermediate therefore w 1asH ,2easilyH,3H isolated,4H,5H,11 in Hhigh,11a purityH-[1,4]diazepino[1,7 without needing-a]indol column-2- chromatographyone 42 in high yield. Furthermore,. the reaction was scaled up by employing a slightly different setup, in which the injection loop was removed and a high-pressure syringe pump were used instead of the Molecules 2020,HPLC25, 3242 pumps. Hence, by using methyl 2-nitrocinnamate as a starting material and 1 mol% catalyst 12 of 26 loading, the corresponding indole was obtained in an 84% isolated yield with a throughput of 1.3 g·h−1 (Scheme 19).

Scheme 17. CF reductive cyclization of o-nitrobenzylcarbonyl en route to indole derivatives of general formula 43.

In the 1960s, the preparation of indoles by the reductive cyclization of o-nitrostyrenes was reported by Cadogan [69,70] and Sundberg [71,72] (Scheme 18). This deoxygenative cyclization was typicallyScheme perf 19ormed. CF reductive by heating cyclization the aromatic of o-vinylnitrobenzenes nitro compounds using in CO the as apresence stoichiometric of boiling reductant. trivalent Schemephosphorus 19. CF reductive compounds, cyclization such as triethyl of o-vinylnitrobenzenes phosphite. However, using this methodology CO as a stoichiometric suffered from the reductant. use ofAs extreme mentioned conditions in the along introduction with the generation of this section, of large o-nitrophenylacetonitriles quantities of phosphorous have waste. also Laterbeen, As mentionedsuccessfullytransition metalin employed the-catalyzed introduction for the versions preparation of of this this of reactionthe section, indole using ringo-nitrophenylacetonitriles by carbon reductive monoxide cyclization, (CO) in as particular terminal have also been successfullyaccreductant employedessing 2,3were-unsubstituted forproposed the preparation as and suitable 3-substituted methodologies of the indoles indole for (Scheme indole ring 20ring) by. construction reductive [73 cyclization,–84]. Despite its in particular synthetic utility, this multiphase deoxygenation is limited by the employment of highly toxic CO accessing 2,3-unsubstituted and 3-substituted indoles (Scheme 20). under elevated pressure and temperature [16].

Scheme 20. Reductive cyclization of o-nitrophenylacetonitriles. Scheme 18. Reductive cyclization of o-nitrostyrenes. BaxendaleScheme and coworkers 20. Reductive presented cyclization the continuous of o-nitrophenylacetonitriles. flow preparation of indole-3-carboxylic ester 47 by the Pd-catalyzed reductive cyclization of o-nitrophenylacetonitrile 46 [86]. The indole 47 Baxendale and coworkers presented the continuous flow preparation of indole-3-carboxylic ester

47 by the Pd-catalyzed reductive cyclization of o-nitrophenylacetonitrile 46 [86]. The indole 47 was then employed for the production of a novel mimic-based herbicide 49. Firstly, for the synthesis of o-nitrophenylacetonitrile 46, a base-mediated SNAr was performed. A solution of DBU (base) and a solution of ethyl cyanoacetate 44 were mixed and then combined with a solution of 2-chloronitrobenzene 45. The resulting mixture was directed into the Coflore ACR device, which was agitated at 8 Hz and maintained at the temperature of 65 ◦C to give adduct 46. The combined stream was quenched with a 2 M hydrochloric using an inline static mixing element, and the biphasic mixture was collected. EtOAc was selected as the best solvent for the first step, due to its compatibility with the following Pd-catalyzed reductive cyclization. Hence, after the dilution with EtOH and the adding of AcOH (10 mol%), the organic phase was drawn and pumped through a 10 mol% Pd/C catalyst cartridge placed into an H-cube. The cartridge was heated to 50 ◦C and pressurized at 15 bar, giving the desired indole 47 with a productivity of 3.7 g h 1. Next, 47 was purified and functionalized by a telescoped · − two-step sequence (Scheme 21). In particular, the substitution of the ethoxy group by hydrazine was achieved by mixing a THF solution of 47 with a THF solution of hydrazine. The resulting solution was passed through a FEP flow coil heated to 100 ◦C, using a back-pressure regulator of 100 psi to control the system pressure. The resulting acyl hydrazine 48 was directly reacted with a solution of CDI in a FEP flow coil (heated to 75 ◦C) giving, after passing through a scavenging cartridge of QP-SA (a sulfonic acid functionalized polymer), the desired 3H-[1,3,4]oxadiazol-2-one 49 in an 82% yield. Alternatively, the latter cyclization can be achieved by combining acyl hydrazine 48 with an input of triphosgene (in CHCl3 solution) and directing it through a packed bed scavenging cartridge containing QP-DMA (N,N-dimethylbenzylamine polystyrene), obtaining, after solvent evaporation, the desired final product 49 in a 91% yield, without the need for further purification. Molecules 2020, 25, x FOR PEER REVIEW 13 of 28

was then employed for the production of a novel mimic-based herbicide 49. Firstly, for the synthesis of o-nitrophenylacetonitrile 46, a base-mediated SNAr was performed. A solution of DBU (base) and a solution of ethyl cyanoacetate 44 were mixed and then combined with a solution of 2- chloronitrobenzene 45. The resulting mixture was directed into the Coflore ACR device, which was agitated at 8 Hz and maintained at the temperature of 65 °C to give adduct 46. The combined stream was quenched with a 2 M hydrochloric using an inline static mixing element, and the biphasic mixture was collected. EtOAc was selected as the best solvent for the first step, due to its compatibility with the following Pd-catalyzed reductive cyclization. Hence, after the dilution with EtOH and the adding of AcOH (10 mol%), the organic phase was drawn and pumped through a 10 mol% Pd/C catalyst cartridge placed into an H-cube. The cartridge was heated to 50 °C and pressurized at 15 bar, giving the desired indole 47 with a productivity of 3.7 g·h−1. Next, 47 was purified and functionalized by a telescoped two-step sequence (Scheme 21). In particular, the substitution of the ethoxy group by hydrazine was achieved by mixing a THF solution of 47 with a THF solution of hydrazine. The resulting solution was passed through a FEP flow coil heated to 100 °C, using a back-pressure regulator of 100 psi to control the system pressure. The resulting acyl hydrazine 48 was directly reacted with a solution of CDI in a FEP flow coil (heated to 75 °C) giving, after passing through a scavenging cartridge of QP-SA (a sulfonic acid functionalized polymer), the desired 3H- [1,3,4]oxadiazol-2-one 49 in an 82% yield. Alternatively, the latter cyclization can be achieved by combining acyl hydrazine 48 with an input of triphosgene (in CHCl3 solution) and directing it through a packed bed scavenging cartridge containing QP-DMA (N,N-dimethylbenzylamine Molecules 2020, 25, 3242 13 of 26 polystyrene), obtaining, after solvent evaporation, the desired final product 49 in a 91% yield, without the need for further purification.

Scheme 21. CF synthesis of indole-3-carboxylic ester by reductive cyclization and its derivatization to Scheme 21. anCF auxin synthesis mimic. of indole-3-carboxylic ester by reductive cyclization and its derivatization to an auxin mimic. 2.4. Heumann Indole Synthesis [87] 2.4. Heumann IndoleVery Synthesisrecently, Lubell and coworkers reported the continuous flow intensification of the Heumann indole synthesis. This transformation was initially proposed for the preparation of indigo, Very recently, Lubell and coworkers reported the continuous flow intensification of the Heumann a relevant dyestuff, although a different protocol was selected for the industrial preparation of this indole synthesis.molecule, This the transformationso-called Heumann−Pfleger was initially method [ proposed88]. Almost forgotten, for the preparation in the following of decades, indigo, a relevant dyestuff, althoughthe Heumann a di ff indoleerent synthesis protocol has wasbeen selected sporadically for utilized the industrial for the preparation preparation of substituted of this molecule, the so-calledindoles Heumann [89–95]. PflegerIn this paper, method a useful [87 reaction]. Almost was forgotten,successfully exploited in the following for the preparation decades, of thea Heumann series of 3-substituted− indoles by three consecutive flow steps. The sequence was optimized for the indole synthesispreparation has been of 3-(but sporadically-3-enyl)indole utilized 53a (Scheme for 2 the2a). preparationIn the first step, ofmethyl substituted bromoacetate indoles and 1- [[288- –94]. In this paper, a usefulaminophenyl]pent reaction was-4 successfully-en-1-one 50 were exploited premixed forin DMF the and preparation loaded into ofan ainjection series loop. of 3-substituted By using indoles by three consecutiveDMF as the flow elution steps. solvent, The the sequence mixture was was directed optimized into a PFA for reactor the preparation heated to 110 of °C. 3-(but-3-enyl)indole After a residence time of 90 min, the N-alkylated intermediate methyl [2-(pent-4-enoyl)phenyl]glycinate 51 53a (Schemewas 22a). obtained In the in firsta quantitative step, methyl yield, which bromoacetate was a remarkable and result 1-[2-aminophenyl]pent-4-en-1-one when compared to the best result 50 were premixed inobtained DMF and under loaded batch conditions into an (57%). injection The subsequent loop. By saponification using DMF could as the be effectively elution solvent,achieved the mixture using both the batch and flow approaches. The latter was performed by loading a methanol mixture was directed into a PFA reactor heated to 110 ◦C. After a residence time of 90 min, the N-alkylated of 51 and aqueous NaOH solution (10 N) into an injection loop. MeOH was used as a solvent to flow intermediate methyl [2-(pent-4-enoyl)phenyl]glycinate 51 was obtained in a quantitative yield, which was a remarkable result when compared to the best result obtained under batch conditions (57%). The subsequent saponification could be effectively achieved using both the batch and flow approaches. The latter was performed by loading a methanol mixture of 51 and aqueous NaOH solution (10 N) into an injection loop. MeOH was used as a solvent to flow the mixture into a PFA reactor heated to 60 ◦C with a residence time of 15 min, obtaining the 2-[(pent-4-enoyl)phenyl)glycine 52 in a Molecules 2020, 25, x FOR PEER REVIEW 14 of 28 quantitative yield (Scheme 22b). The latter was mixed with acetic anhydride and Et3N in AcOEt and the mixturethe was mixture injected into a into PFA reactor an injection heated to loop. 60 °C with The a residence same solvent time of 15 was min, used obtaining to introducethe 2-[(pent- the mixture through a stainless4-enoyl)phenyl)glycine steel reactor, 52 in allowing a quantitative the yield Heumann (Scheme 2 cyclization2b). The latter for was the mixe preparationd with acetic of desired 1-acetyl-3-(but-3-enyl)indoleanhydride and Et3N in53 AcOEtin aand 90% the yieldmixture (Scheme was injected 22 intoc), whichan injection was loop. also The in same this solvent case higher with was used to introduce the mixture through a stainless steel reactor, allowing the Heumann cyclization respect to thefor batch the preparation reaction of desired (74%). 1- Theacetyl same-3-(but- protocol3-enyl)indole was 53 in extended a 90% yield ( forScheme the 2 preparation2c), which was of different 3-substitutedalso indoles in this case53b higher–f. Moreover, with respect byto the using batch thisreaction flow (74%). protocol, The same the protocol indoles was extended were synthesized for in a high purity withoutthe preparation needing of different chromatography 3-substituted indoles purification. 53b–f. Moreover, by using this flow protocol, the indoles were synthesized in a high purity without needing chromatography purification.

Scheme 22. CF intensification of three-step Heumann indole synthesis: (a) alkylation of aniline 50; (b) Scheme 22. saponificationCF intensification; (c) Heumann of three-stepcyclization. Heumann indole synthesis: (a) alkylation of aniline 50; (b) saponification; (c) Heumann cyclization. 2.5. Indole Synthesis through Photochemical Benzannulation It is well established that the advent of flow chemistry enables researchers to face the longstanding restrictions of batch photochemistry, such as limited scale-up, inefficient light transmission, and prolonged reaction times [96,97]. Flow microreactors are typically characterized by a high surface-to-volume ratio, which permits a more uniform irradiation of the entire reaction mixture, often allowing a decrease in photocatalyst loadings, along with a considerable reduction in the reaction time from hours/days in batch to seconds/mins in flow. The latter is not only convenient for the process productivity but is also important in preventing side-reactions. In 2013, Danheiser proposed a flow photochemical benzannulation for the preparation of various aromatic and heteroaromatic compounds [98]. Among them, two highly functionalized indole derivatives were also obtained. By using a continuous flow photochemical reactor, a solution of diazoketone of type 54a–b and ynamide 55 in DCE was pumped through the system by a syringe pump (Scheme 23). The light-promoted Wolff rearrangement of diazo ketone furnished vinylketene 56. According to the proposed “pericyclic cascade” mechanism, vinylketene 56 reacted with ynamides 55, leading to vinylcyclobutenone 57. The latter undergoes an electrocyclic cleavage triggered by light, giving dienylketene 58, which furnished indole derivative 59 after a rapid 6-π electrocyclic ring-closure and tautomerization. Due to the uncomplete conversion of vinylcyclobutenone 57 into the desired indole derivative 59, the reaction mixture was collected in a pear-shaped flask, concentrated, dissolved in toluene, and refluxed for 2 h. Due to its air sensitivity, indole 59b was converted into the relative triflate adduct 60 to facilitate the purification step.

Molecules 2020, 25, 3242 14 of 26

2.5. Indole Synthesis through Photochemical Benzannulation It is well established that the advent of flow chemistry enables researchers to face the longstanding restrictions of batch photochemistry, such as limited scale-up, inefficient light transmission, and prolonged reaction times [95,96]. Flow microreactors are typically characterized by a high surface-to-volume ratio, which permits a more uniform irradiation of the entire reaction mixture, often allowing a decrease in photocatalyst loadings, along with a considerable reduction in the reaction time from hours/days in batch to seconds/mins in flow. The latter is not only convenient for the process productivity but is also important in preventing side-reactions. In 2013, Danheiser proposed a flow photochemical benzannulation for the preparation of various aromatic and heteroaromatic compounds [97]. Among them, two highly functionalized indole derivatives were also obtained. By using a continuous flow photochemical reactor, a solution of diazoketone of type 54a–b and ynamide 55 in DCE was pumped through the system by a syringe pump (Scheme 23). The light-promoted Wolff rearrangement of diazo ketone furnished vinylketene 56. According to the proposed “pericyclic cascade” mechanism, vinylketene 56 reacted with ynamides 55, leading to vinylcyclobutenone 57. The latter undergoes an electrocyclic cleavage triggered by light, giving dienylketene 58, which furnished indole derivative 59 after a rapid 6-π electrocyclic ring-closure and tautomerization. Due to the uncomplete conversion of vinylcyclobutenone 57 into the desired indole derivative 59, the reaction mixture was collected in a pear-shaped flask, concentrated, dissolved in toluene, and refluxed for 2 h. Due to its air sensitivity, indole 59b was converted into the relative triflate adduct 60 to facilitate the purification step. Molecules 2020, 25, x FOR PEER REVIEW 15 of 28

Scheme 23. CF synthesis of highly substituted indoles by photochemical benzanullation. Scheme 23. CF synthesis of highly substituted indoles by photochemical benzanullation. 3. Derivatization of Indole Ring under Continuous Flow Conditions 3. Derivatization of Indole Ring under Continuous Flow Conditions In recent years, flow chemistry has been applied not only for the construction of the indole In recentnucleus years, but flow also for chemistry its efficient has derivatization. been applied Hence, not in the only following for the sections, construction the attention of thewill indolebe nucleus but also for itsfocused effi cient on the derivatization. efforts made by different Hence, groups in the in following the intensification sections, of indolethe attention derivatization will be focused procedures using flow approach emphasizing the advantages over traditional batch chemistry. on the efforts made by different groups in the intensification of indole derivatization procedures using flow approach3.1. emphasizingIndole Ring Derivatization the advantages Mediated by V overisible L traditionalight-Photoredox batch Catalysis chemistry. in Flow Mode As briefly described in Section 2.5, flow chemistry offers some technological features that arise 3.1. Indole Ringas extremely Derivatization useful in Mediatedview of an byintensification Visible Light-Photoredox of photochemical processes. Catalysis In in the Flow field Modeof indole photochemical derivatization, Chen et al. reported a continuous flow preparation of tricyclo-1,4- As brieflybenzoxazines described by the in intramolecular Section 2.5 cyclization, flow chemistry of indole derivatives offers somevia visible technological-light photoredox features that arise as extremelycatalysis [9 useful9]. For this in study, view a homemade of an intensification capillary photoreactor of photochemical consisting of two quartz processes. glass tubes In the field connected in series, described and named by the authors as “reaction towers”, was used. A of indole photochemicalfluorinated ethylene derivatization, propylene FEP tube Chen was wrapped et al. around reported each reaction a continuous tower which held flow a LED preparation of tricyclo-1,4-benzoxazinescorn light bulb (34 W) by in the the center, intramolecular thus providing cyclization the reaction mixture of indole irradiation derivatives [100]. According via visible-light photoredox catalysisto the optimized [98]. protocol, For this indole study, derivative a homemade 61, p-toluensulfonic capillary acid photoreactor (TsOH), a catalytic consisting amount of of two quartz methylene blue (MB), and the selected alcohol were mixed in a round bottom flask. The resulting glass tubes connectedmixture was sucked in series, into the described reactor at one and end named and returned by the at the authors other (rpm as = “reaction 50, flow rate towers”,is about was used. A fluorinated10 ethylene mL·min−1). propyleneThe transformation FEP tube was performed was wrapped under O around2, giving eachthe hydroperoxide reaction tower intermed whichiate held a LED corn light bulb62 which, (34 W) in the in presence the center, of acid thus (TsOH), providing provided the the desired reaction tricyclo mixture-1,4-benzoxazine irradiation 63. A series [99]. According of tricyclo-1,4-benzoxazines were obtained by varying the starting indole derivative 61 (N- 61 p to the optimizedmonosubstituted protocol, tryptamines indole derivative or tryptophol were, used)-toluensulfonic and the alcohol acid(methanol, (TsOH), ethanol, a catalyticpropanol, amount of methylene blueand isopropanol). (MB), and the Moreover, selected carrying alcohol out werethe transformation mixed in a in round CH3CN bottom and adopting flask. 2The- resulting methoxyethan-1-ol as the nucleophile, a moderate yield of the corresponding tricyclo-1,4- benzoxazine 63b was observed. It is noteworthy that the transformation is complete in 1–3 h rather than the 24 h required by the batch protocol. Furthermore, a gram-scale experiment was performed, obtaining the desired product 63a in a 78% yield in 5 h (Scheme 24).

Molecules 2020, 25, x FOR PEER REVIEW 15 of 28

Scheme 23. CF synthesis of highly substituted indoles by photochemical benzanullation.

3. Derivatization of Indole Ring under Continuous Flow Conditions In recent years, flow chemistry has been applied not only for the construction of the indole nucleus but also for its efficient derivatization. Hence, in the following sections, the attention will be focused on the efforts made by different groups in the intensification of indole derivatization procedures using flow approach emphasizing the advantages over traditional batch chemistry.

3.1. Indole Ring Derivatization Mediated by Visible Light-Photoredox Catalysis in Flow Mode As briefly described in Section 2.5, flow chemistry offers some technological features that arise as extremely useful in view of an intensification of photochemical processes. In the field of indole photochemical derivatization, Chen et al. reported a continuous flow preparation of tricyclo-1,4- Molecules 2020, benzoxazines25, 3242 by the intramolecular cyclization of indole derivatives via visible-light photoredox 15 of 26 catalysis [99]. For this study, a homemade capillary photoreactor consisting of two quartz glass tubes connected in series, described and named by the authors as “reaction towers”, was used. A fluorinated ethylene propylene FEP tube was wrapped around each reaction tower which held a LED mixture wascorn sucked light bulb into (34 W) the in reactorthe center, at thus one providing end andthe reaction returned mixture at irradiation the other [100 (rpm]. According= 50, flow rate is about 10to mL themin optimized1). Theprotocol, transformation indole derivative was61, p-toluensulfonic performed acid under (TsOH), O a, catalytic giving amount the hydroperoxide of · − 2 intermediatemethylene62 which, blue in (MB), the and presence the selected of acid alcohol (TsOH), were mixed provided in a round the bottom desired flask. tricyclo-1,4-benzoxazine The resulting mixture was sucked into the reactor at one end and returned at the other (rpm = 50, flow rate is about 63. A series of tricyclo-1,4-benzoxazines were obtained by varying the starting indole derivative 10 mL·min−1). The transformation was performed under O2, giving the hydroperoxide intermediate 61 (N-monosubstituted62 which, in the tryptaminespresence of acid or(TsOH), tryptophol provided the were desired used) tricyclo and-1,4 the-benzoxazine alcohol 63 (methanol,. A series ethanol, of tricyclo-1,4-benzoxazines were obtained by varying the starting indole derivative 61 (N- propanol, and isopropanol). Moreover, carrying out the transformation in CH3CN and adopting monosubstituted tryptamines or tryptophol were used) and the alcohol (methanol, ethanol, propanol, 2-methoxyethan-1-ol as the nucleophile, a moderate yield of the corresponding tricyclo-1,4-benzoxazine and isopropanol). Moreover, carrying out the transformation in CH3CN and adopting 2- 63b was observed.methoxyethan It is- noteworthy1-ol as the nucleophile, that the transformation a moderate yield is of complete the corresponding in 1–3 h tricyclo rather-1,4 than- the 24 h required bybenzoxazine the batch protocol.63b was observed. Furthermore, It is notewor athy gram-scale that the transformation experiment is complete was performed, in 1–3 h rather obtaining the than the 24 h required by the batch protocol. Furthermore, a gram-scale experiment was performed, desired product 63a in a 78% yield in 5 h (Scheme 24). obtaining the desired product 63a in a 78% yield in 5 h (Scheme 24).

Scheme 24. CF preparation of tricyclo-1,4-benzoxazines library via metal-free visible-light photoredox catalysis.

A further proof of the benign effect of the homogenous irradiation ensured by continuous photoflow synthesis has been furnished by Noël, Van der Eycken, and coworkers [100]. These authors Molecules 2020, 25, x FOR PEER REVIEW 16 of 28 reported the C-2 acylation of N-pyrimidylindoles 64 using aldehydes as acyl surrogates by merging visible-light photoredoxScheme 24. catalysis CF preparation and palladium of tricyclo-1,4- catalyzedbenzoxazines C-H library activation. via metal-free The visible pyrimidyl-light ring linked to the indole nitrogenphotoredox acted catalysis. as a directing group assisting the C-2 functionalization, and could be removed at the endA further of the proof sequence. of the benign The effect transformation of the homogenous was irradiationperformed ensured at room by continuous temperature under batch and flowphotoflow conditions. synthesis Regarding has been furnished theflow by Noël, approach, Van der Eycken, a 3 mL and PFAcoworkers capillary [101]. These reactor authors was wrapped reported the C-2 acylation of N-pyrimidylindoles 64 using aldehydes as acyl surrogates by merging around the innervisible-light cylinder photoredox of a catalysis 3D-printed and palladium photomicroreactor catalyzed C-H activation. in combination The pyrimidyl ring with linked a 3.12 W blue LED (λmax =to 465the indole nm) lightnitrogen source. acted as Using a directing a syringe group assisting pump, the a C solution-2 functionalization of 64, Pd(OAc), and could2, be fac-[Ir(ppy) 3] as a photocatalyst,removed Boc-protectedat the end of the sequence.l-valine The (Boc-Val-OH), transformation was aldehyde performed 65at ,room and temperature tert-butyl under hydroperoxide batch and flow conditions. Regarding the flow approach, a 3 mL PFA capillary reactor was wrapped (TBHP) as thearound oxidant the inner in anhydrous cylinder of a 3D acetonitrile-printed photomicroreactor were introduced in combination into the with photomicroreactor a 3.12 W blue LED at a flow 1 rate of 0.025(λ mL maxmin = 465 nm), corresponding light source. Using to a asyringe residence pump, timea solution of 2 of h. 64 Aromatic, Pd(OAc)2, fac and-[Ir(ppy) aliphatic3] as a aldehydes · − were successfullyphotocatalyst, employed Boc-protected as acylating L-valine partners, (Boc-Val-OH), obtaining aldehyde 65 the, and functionalized tert-butyl hydroperoxide indoles 66 in good (TBHP) as the oxidant in anhydrous acetonitrile were introduced into the photomicroreactor at a flow to excellent yields. Moreover, the reaction scope could be extended by using a series of differently rate of 0.025 mL·min−1, corresponding to a residence time of 2 h. Aromatic and aliphatic aldehydes substituted Nwere-pyrimidylindoles successfully employed64 as. acylating By a systematic partners, obtaining comparison the functionalized with theindoles traditional 66 in good to batch setup, the authors demonstratedexcellent yields. Moreover, that the the designed reaction scope flow could approach be extended enabled by using the a acceleration series of differently of the reaction time from 20substituted h to 2 h, theN-pyrimidylindoles reduction in 64 catalyst. By a systematic loading comparison from 2 mol% with the to traditional 0.5 mol%, batch and setup, a general the increase authors demonstrated that the designed flow approach enabled the acceleration of the reaction time in isolated yields. In addition, by using a numbering-up approach (2 3 mL), the continuous flow from 20 h to 2 h, the reduction in catalyst loading from 2 mol% to 0.5 mol%, and× a general increase in C-2 acylationisolated of N-pyrimidylindole yields. In addition, by using64 using a numbering ( )-citronellal-up approach as (2 a × coupling 3 mL), the continuous partner wasflow C accomplished,-2 − obtaining 1.41acylation g (93%) of N of-pyrimidylindole the desired product64 using ( within−)-citronellal less as than a coupling 9 h (Scheme partner was25). accomplished, obtaining 1.41 g (93%) of the desired product within less than 9 h (Scheme 25).

Scheme 25. CF C-2 acylation of indoles via dual photoredox/palladium catalysis at room temperature. Scheme 25. CF C-2 acylation of indoles via dual photoredox/palladium catalysis at room temperature. 3.2. Continuous Flow Functionalization of Indole Nitrogen As described in Section 2.2, the attractive possibility of translating efficient microwave batch protocols into high-temperature/high-pressure scalable continuous flow process was extensively investigated. This kind of approach has been applied to the functionalization of the indole ring by Kappe and Holbrey. These authors reported an efficient N-methylation of indole 67 with dimethylcarbonate (DMC), using tributylmethylammonium methylcarbonate, an ionic liquid, as the catalytic base [102]. Initially, this transformation was carefully optimized under microwave batch mode, finding that, at reaction temperatures below 150 °C, the major reaction product was N- (methoxycarbonyl)indole 69, and the desired N-methylindole 70 could not be detected. In order to selectively drive the transformation toward the formation of 70, the use of a temperature of 230 °C for 20 min at a pressure of ~17 bar was necessary. Moreover, given that tributylmethylammonium methylcarbonate is prepared by the treatment of tributylamine with DMC [103], the authors successfully proposed to generate the catalyst in situ by adding tributylamine to a solution of indole 67 in DMC–DMF (10:1, v/v) and subjecting the mixture to microwave heating. Once the optimized conditions under batch microwave mode were established, the transformation was transferred into a high-temperature/high-pressure continuous flow reactor (X-Cube Flash) containing a stainless steel

Molecules 2020, 25, 3242 16 of 26

3.2. Continuous Flow Functionalization of Indole Nitrogen As described in Section 2.2, the attractive possibility of translating efficient microwave batch protocols into high-temperature/high-pressure scalable continuous flow process was extensively investigated. This kind of approach has been applied to the functionalization of the indole ring by Kappe and Holbrey. These authors reported an efficient N-methylation of indole 67 with dimethylcarbonate (DMC), using tributylmethylammonium methylcarbonate, an ionic liquid, as the catalytic base [101]. Initially, this transformation was carefully optimized under microwave batch mode, finding that, at reaction temperatures below 150 ◦C, the major reaction product was N-(methoxycarbonyl)indole 69, and the desired N-methylindole 70 could not be detected. In order to selectively drive the transformation toward the formation of 70, the use of a temperature of 230 ◦C for 20 min at a pressure of ~17 bar was necessary. Moreover, given that tributylmethylammonium methylcarbonate is prepared by the treatment of tributylamine with DMC [102], the authors successfully proposed to generate the catalyst in situ by adding tributylamine to a solution of indole 67 in DMC–DMF (10:1, v/v) and subjecting the mixture to microwave heating. Once the optimized conditions under batch microwave mode were established, the transformation was transferred into a high-temperature/high-pressure continuous flow reactor (X-Cube Flash) containing a stainless steel coil, a heat exchanger, and a system pressure valveMolecules to set2020, the25, x FOR pressure PEER REVIEW value. Firstly, by using a 16 mL stainless steel coil17 andof 28 a flow rate of 1.2 mL min 1, the optimized microwave batch conditions (230 C, 20 min) were translated to the · coil,− a heat exchanger, and a system pressure valve to set the pressure◦ value. Firstly, by using a 16 flow apparatus,mL stainless obtaining steel coil the and total a flow conversion rate of 1.2 mL·min of−1 indole, the optimized67 into microwave70. Subsequently, batch conditions the (230 process was further intensified°C, 20 min) by were pumping translated the to the mixture flow apparatus of 67 ,and obtaining tributylamine the total conversion in DMC-DMF of indole 67 into (10:1) 70. with a flow Subsequently, the process was further intensified by pumping the mixture of 67 and tributylamine rate of 1.3 mL min 1 (~3 min of residence time) through a 4 mL stainless steel coil heated to 285 C and in· DMC−-DMF (10:1) with a flow rate of 1.3 mL·min−1 (~3 min of residence time) through a 4 mL ◦ with the pressurestainless set steel to coil 150 heated bar. to The 285 methylation°C and with the protocolpressure set was to 150 extended bar. The methylation to indole protocol68 derivative and amines, phenols,was extended thiophenols, to indole and68 derivative carboxylic and amines, acids. phenols, In all thethiophenols, cases, theand fullcarboxylic conversion acids. In all of the starting material wasthe observed. cases, the full Using conversion this of protocol, the starting 250–370 material was mg observed. of product Using couldthis protocol, be obtained 250–370 mg within 3 min, which correspondedof product could to a calculatedbe obtained within throughput 3 min, which of ~100corresponded g per dayto a calculated (Scheme throughput 26). of ~100 g per day (Scheme 26).

Scheme 26. CF N-methylation of indole derivatives. Scheme 26. CF N-methylation of indole derivatives. 3.3. Continuous Flow Functionalization of C-3 Position of Indole Ring 3.3. Continuous Flow Functionalization of C-3 Position of Indole Ring In recent years, different groups have reported the decoration of the indole ring at the C-3 In recentposition years, by di usingfferent continuous groups have flow approaches. reported the In this decoration context, O’Shea of the designed indole ring an inspiring at the C-3 position by using continuousautomated sequential flow approaches. approach for the In construction this context, of a 3- O’Sheaindolylmethyl designed derivatives an library inspiring [104]. automated Firstly, 12 3-hydroxymethylindoles were prepared by the iodo–magnesium exchange of four 3- sequential approachiodoindoles, followed for the by construction trapping with three of different a 3-indolylmethyl aldehydes. The halogen derivatives-magnesium library exchange [103 ]. Firstly, 12 3-hydroxymethylindolesreaction was performed were by prepared introducingby indole the solutions iodo–magnesium 72 and iPrMgCl·LiCl exchange with of automated four 3-iodoindoles, followed byinjection trapping loops with into threea reactor di chipfferent at 0 °C aldehydes. with a residence The time halogen-magnesium of 12 min. The output flow exchange containing reaction was the 3-metallated indoles 73 was reacted with solutions of aldehydes 74 in a second reactor chip, using performed by introducing indole solutions 72 and iPrMgCl LiCl with automated injection loops into a residence time of 7 min at 0 °C. Then, the resulting mixture was· combined with an aqueous solution a reactor chipof NHat 04Cl◦ C in with a liquid a– residenceliquid extraction time chip. of 12 The min. collection The of output the organic flow phase containing furnished,the after 3-metallated indoles 73 waspurification, reacted the with desired solutions 3-hydroxymethylindoles of aldehydes 75. It74 is noteworthyin a second that this reactor system chip,setup was using able a residence to perform the 12 metalations, electrophile additions, in-line extractions, and product collections time of 7 minautomatically. at 0 ◦C. Then, The entire the resulting system wasmixture controlled was by a combined computer software with an program aqueous to judiciously solution of NH4Cl in a liquid–liquidcalibrate extraction the sequential chip. reagents The injections, collection extraction, of the and organic collection, phase and to furnished,set any other process after purification, the desired 3-hydroxymethylindolesparameter. Subsequently, exploiting75. again It is multi noteworthy-microreactor that setups this in combination system setup with inline was ableflow to perform liquid/liquid extractors, the obtained indoles were employed for the preparation of indole derivatives the 12 metalations,77 and 78 electrophilethrough acid-catalyzed additions, elimination in-line–addition extractions, sequences and via the product intermediate collections electrophilic automatically. The entire systemindolium cations was controlled 76, using allyltrimethylsilane by a computer and methanol software as nucleophiles. program Hence, to judiciously a collection of calibrate the sequential reagents36 indole derivatives injections, was obtained extraction, starting and from collection, only four indoles and byto merging set any continuous other multi process-step parameter. systems and continuous-flow extraction technology (Scheme 27). Subsequently, exploiting again multi-microreactor setups in combination with inline flow liquid/liquid extractors, the obtained indoles were employed for the preparation of indole derivatives 77 and 78 through acid-catalyzed elimination–addition sequences via the intermediate electrophilic indolium

Molecules 2020, 25, 3242 17 of 26 cations 76, using allyltrimethylsilane and methanol as nucleophiles. Hence, a collection of 36 indole derivatives was obtained starting from only four indoles by merging continuous multi-step systems and continuous-flow extraction technology (Scheme 27). Molecules 2020, 25, x FOR PEER REVIEW 18 of 28

Molecules 2020, 25, x FOR PEER REVIEW 18 of 28

Scheme 27. CF automated multi-step generation of 3-hydroxymethylindoles and their conversion to Scheme 27. CF automated multi-step generation of 3-hydroxymethylindoles and their conversion to 77 77 and 78 via acid-catalyzed nucleophilic substitution. and 78 via acid-catalyzed nucleophilic substitution. In 2017, Ley and coworkers furnished a contribution to the field, reporting the scandium triflate In 2017,(Sc(OTf) Ley and3) catalyzed coworkers preparation furnished of a series a of contribution bis(indolyl)methanes to the (BIM field,S) [105 reporting], which are the biological scandium triflate relevant derivatives [106,107]. In this article, the batch protocol previously reported by Sato et al. (Sc(OTf)3) catalyzed preparation of a series of bis(indolyl)methanes (BIMS)[104], which are biological [108]Scheme was translated 27. CF automated to flow mode multi -withstep generationthe careful of optimizat 3-hydroxymethylindolesion of the reaction and theirsolvent, conversion solution to flow relevant derivativesrates77 and and concentrations,78 [105 via acid,106-cataly]. reactorz Ined nucleophilic this volume, article, substitution. reaction the time,batch and protocol temperature. previously According to reported the best by Sato et al. [107] wasconditions, translated a solution to flow of indole mode 79 withand aldehyde the careful 80 and optimizationa Sc(OTf)3 solution of were the mixed reaction in a T- solvent,piece, solution flow rates andand the concentrations,In 2017, resultin Leyg andmixture coworkers reactorwas directed furnished volume, through a contribution a reaction 20 mL reactor to th time,e field coil and,using reporting temperature.a reaction the scandium time of 60 Accordingtriflate min, to the (Sc(OTf)which is3 ) convenientcatalyzed preparation with respect of ato series the of reported bis(indolyl)methanes batch protocol. (BIM TheS) [ designed105], which flow are approach,biological best conditions,relevantcharacterized a solutionderivatives by short of[106 reaction indole,107]. Intime 79this andand article, easy aldehyde thework batch-up operations,protocol80 and previously aallowed Sc(OTf) the reported 3rapidsolution explorationby Sato were et al.of mixed in a T-piece, and[the108 the reaction] was resulting translated scope.mixture Hence, to flow by mode wasusing with directedvarious the careful indoles through optimizat and aldehydes, aion 20 of mL the a library reactorreaction of 18solvent, coil BIM usingS wassolution obtained a reactionflow, time of 60 min, whichratesincluding is and convenient concentrations,four novel withstructures reactor respect, providing volume, to the reactionthe reported opportunity time, batch and to temperature.expand protocol. the biological According The designed utility to the of bestthis flow approach, conditions,class of molecules. a solution Moreover, of indole 79 using and aldehyde a slightly 80 differentand a Sc(OTf) setup,3 solution the gram were-scale mixed preparation in a T-piece of, characterizedandbis(indolyl)methanes by the shortresultin reactiong mixture derivative was time directed 81a and was through easy performed, work-up a 20 mL obtaining reactor operations, 12.4coil gusing with a allowedanreaction operation time the time of rapid60 of min 5 h, exploration of the reactionwhichand 46 scope. ismin convenient (Scheme Hence, 28 with). by respect using to various the reported indoles batch protocol. and aldehydes, The designed a flowlibrary approach, of 18 BIMS was obtained, includingcharacterized four by novelshort reaction structures, time and providing easy work-up the operations, opportunity allowed tothe expand rapid exploration the biological of utility the reaction scope. Hence, by using various indoles and aldehydes, a library of 18 BIMS was obtained, of this classincluding of molecules. four novel Moreover, structures, providing using a the slightly opportunity different to expand setup, the biological the gram-scale utility of this preparation of bis(indolyl)methanesclass of molecules. derivative Moreover,81a was using performed, a slightly different obtaining setup, 12.4 the g gram with-scale an operation preparation time of of 5 h and 46 min (Schemebis(indolyl)methanes 28). derivative 81a was performed, obtaining 12.4 g with an operation time of 5 h and 46 min (Scheme 28).

Scheme 28. Sc(OTf)3 catalyzed continuous flow synthesis of BIMS 81.

A further contribution by Palmieri and coworkers presented the oxidative transformation of sulfonyl indoles 82 into 3-alkylidene-2-oxindoles 83 using the continuous flow approach [109]. The reaction involved indole ring oxidation mediated by N-chlorosuccinimide (NCS), followed by the elimination of arylsulfinic acid to introduce exocyclic unsaturation. Interestingly, the initial

experiments under Schemetraditional 28. Sc(OTf) batch conditions3 catalyzed continuous revealed only flow asynthesis low yield of BIMof theS 81. expected product 83 along withScheme side-products 28. Sc(OTf) probably3 catalyzed derived from continuous overoxidation flow pathways. synthesis Hence, of BIM in orderS 81. to reduce the contactA further time contribution between theby Palmieriobtained and unsaturated coworkers oxindole presented 83 the and oxidative the oxidizing transformation reagent, of a A furthersulfonylcontinuous contribution indoles flow 82approach into by 3-alkylidene was Palmieri evaluated.-2-oxindoles and A flow coworkers apparatus83 using the, consistingpresented continuous of twoflow the reservoirs, approach oxidative two[109 HPLC]. transformationThe of sulfonyl indolesreaction involved82 into indole 3-alkylidene-2-oxindoles ring oxidation mediated by N83-chlorosuccinimideusing the continuous (NCS), followed flow by approach the [108]. elimination of arylsulfinic acid to introduce exocyclic unsaturation. Interestingly, the initial N The reactionexperiments involved under indole traditional ring oxidation batch conditions mediated revealed by only-chlorosuccinimide a low yield of the expected (NCS), product followed 83 by the elimination ofalong arylsulfinic with side-products acid to probably introduce derived exocyclic from overoxidation unsaturation. pathways. Interestingly, Hence, in order the to initial reduce experiments under traditionalthe contact batch time conditions between the revealed obtained unsaturated only a low oxindole yield of83 theand expectedthe oxidizing product reagent, 83 a along with side-productscontinuous probably flow derived approach fromwas evaluated. overoxidation A flow apparatus pathways., consisting Hence, of two in reservoirs, orderto two reduce HPLC the contact time between the obtained unsaturated oxindole 83 and the oxidizing reagent, a continuous flow approach was evaluated. A flow apparatus, consisting of two reservoirs, two HPLC pumps, a T-mixer, Molecules 2020, 25, 3242 18 of 26 a PTFE coil reactor, and a back-pressure regulator, was designed for the optimization study. A careful evaluation of the solvent mixture, reactant concentrations, solution flow rates, and reaction temperature Molecules 2020, 25, x FOR PEER REVIEW 19 of 28 was conducted. Moreover, the authors showed how the use of a protecting-group on the indole nitrogen waspumps, essential a T-mixer, for this a PTFE transformation, coil reactor, and identifying a back-pressure the benzyl regulator group, was designed as the most for the suitable one. optimization study. A careful evaluation of the solvent mixture, reactant concentrations, solution By using bestflow conditions rates, and reaction (Scheme temperature 29), the was sulfonyl conducted. indoles Moreover,82 theand authors NCS showed solutions how the were use directedof from each reservoira protecting to the reactor-group on coil the heatedindole nitrogen to 60 was◦C, essential obtaining for this various transformation 3-alkylidene-2-oxindole, identifying the benzyl derivatives in moderategroup to satisfactory as the most suitable yields. one. The By using obtained best conditions products (Scheme possessed 29), the ansulfonyl E configuration, indoles 82 and except for NCS solutions were directed from each reservoir to the reactor coil heated to 60 °C, obtaining various derivatives bearing3-alkylidene a- methyl2-oxindole group derivatives at the in moderate C-4 position to satisfactory of the indole yields. The ring, obtained which products were obtained as Z stereoisomers.possessed Remarkably, an E configuration, this contribution except for derivatives represented bearing a the methyl first group approach at the C-4 for position the direct of the conversion of 3-functionalizedindole ring indole, which derivatives were obtained intoas Z stereoisomers. 3-alkylidene-2-oxindoles, Remarkably, this contribution and it was represented achievable the only under first approach for the direct conversion of 3-functionalized indole derivatives into 3-alkylidene-2- flow conditions. oxindoles, and it was achievable only under flow conditions.

Scheme 29. NCS-mediated oxidative conversion of sulfonyl indoles 82 into 3-alkylidene-2-oxindoles Scheme 29. NCS-mediated83 under CF conditions. oxidative conversion of sulfonyl indoles 82 into 3-alkylidene-2-oxindoles 83 under CF conditions. Very recently, the same group presented the continuous flow preparation of 3-alkylindoles 85 Very recently,through the the polymer same-supported group presented sodium borohydride the continuous reduction of flow 3-(1-arylsulfonylalkyl) preparation ofindoles 3-alkylindoles 84 85 (sulfonyl indoles) [110]. The reaction stoichiometry, reactant concentrations, residence time, and through thesolvent polymer-supported were judiciously optimized sodium by borohydride using a flow system reduction composed of of 3-(1-arylsulfonylalkyl)two syringe pumps, a three- indoles 84 (sulfonyl indoles)way valve, [109 ]. a Thepacked reaction bed reactor, stoichiometry, and a back-pressure reactant regulator. concentrations, According residence to the optimized time, and solvent were judiciouslyconditions, optimized the transformation by using was a performed flow system by directing composed a 0.05 M of ethanolic two syringe solution pumps,of sulfonyl a three-way indole 84 through a packed bed reactor containing six equivalents of PS-BH4 resin using a residence valve, a packedtime of bed 20 min. reactor, Once the and 84 ainfusion back-pressure was finished, regulator. the three-way According valve was switched to the, permitting optimized the conditions, the transformationethanol was entrance performed, which pushe by directingd the residual a 0.05 sulfonyl M ethanolic indole into solution the system. of sulfonyl By using indole these 84 through conditions, a collection of 3-alkylindoles 85 was obtained in good yields. 2-MeTHF was added as a a packed bed reactor containing six equivalents of PS-BH4 resin using a residence time of 20 min. cosolvent when solubility issues were encountered, although a doubling of reaction time (halving the Once the 84 infusionflow rate) was was required finished, in these the cases three-way (Scheme 30 valvea). The was authors switched, stated that permitting previous methodologies the ethanol entrance, which pushedadopted theresidual for sulfonyl sulfonyl indole reduction indole into usingthe sodium system. borohydride By using suffer these from conditions, tedious work-up a collection of 3-alkylindolesoperations,85 was with obtained consequent in goodsolvent yields.consumption 2-MeTHF and waste was production. added In as this a cosolventwork, by merging when solubility the flow chemistry and the employment of solid supported species, the work-up was limited to issues were encountered,solvent evaporation although, reducing a the doubling operational of time reaction and thus time increasing (halving the theproductivity. flow rate) Since was required in these casessulfonyl (Scheme indoles 30 84a). can The be prepared authors by stateda three-component that previous coupling methodologies of indoles with aldeh adoptedydes and for sulfonyl indole reductionarylsulfinic using acids, sodium the authors borohydride designed an su integratedffer from flow tedious setup for work-up the synthesis operations, of sulfonyl indoles with consequent 84 and subsequent inline sodium borohydride reduction (Scheme 30b). In this way, the one-pot solvent consumption and waste production. In this work, by merging the flow chemistry and the generation of three 3-alkylindoles 85 directly from their remote precursors, indoles, and aldehydes employmentwas of solidachievable. supported For this purpose, species, the the flow work-up apparatus wasschematized limited in Scheme to solvent 30b was evaporation, used. Sulfonyl reducing the operational timeindoles and 84 were thus obtained increasing by pumping the productivity. a solution of indole Since and aldehyde sulfonyl and indoles a solution84 ofcan pTolSO be prepared3H by a three-componentand pTolSO coupling2H into a of reactor indoles coil using with a residence aldehydes time andof 3 h. arylsulfinic Then, the resulting acids, mixture the was authors passed designed an through a packed bed reactor containing Amberlyst A21 to remove acidic species. Finally, the passage integrated flowthrough setup the for packed the bed synthesis reactor containing of sulfonyl PS-BH indoles4 resin afforded84 and the subsequent desired 3-alkylindoles inline sodium 85. borohydride reduction (Scheme 30b). In this way, the one-pot generation of three 3-alkylindoles 85 directly from their remote precursors, indoles, and aldehydes was achievable. For this purpose, the flow apparatus schematized in Scheme 30b was used. Sulfonyl indoles 84 were obtained by pumping a solution of indole and aldehyde and a solution of pTolSO3H and pTolSO2H into a reactor coil using a residence time of 3 h. Then, the resulting mixture was passed through a packed bed reactor containing Amberlyst A21 to remove acidic species. Finally, the passage through the packed bed reactor containing PS-BH4 resin afforded the desired 3-alkylindoles 85. Molecules 2020, 25, 3242 19 of 26

Molecules 2020, 25, x FOR PEER REVIEW 20 of 28

Scheme 30. (a) CF preparation of 3-alkylated indoles by the reduction of sulfonyl indoles and (b) Scheme 30. (aintegrate) CF preparation flow setup for the of synthesis 3-alkylated of 3-alkylindoles indoles directly by from the their reduction remote precursor’ of sulfonyl indoles indoles and (b) integrate flowand setup aldehydes. for the synthesis of 3-alkylindoles directly from their remote precursor’ indoles and aldehydes. In 2017, Liu and Cui reported the use of chiral metal−organic frameworks (MOFs) for the enantioselective Friedel-Crafts alkylation of indoles with a series of ketoesters under batch and flow In 2017, Liuconditions and [ Cui111]. In reported this contribution, the the use authors of chiral demonstrated metal howorganic the chemical frameworks stability, catalytic (MOFs) for the − enantioselectiveactivity, Friedel-Crafts and stereoselectivity alkylation of MOFs ofcan indoles be boosted with by tuning a series the ligand of structures. ketoesters In particular, under batch and flow among three porous chiral MOFs with the framework formula [Mn2L(H2O)2], outstanding results conditions [110].were In furnished this contribution, by a porous chiral the CF3- authorscontaining MOF demonstrated 86. By using a syringe how pump, thechemical a solution of N stability,- catalytic activity, and stereoselectivitymethylindole 70 and ofβ,γ MOFs-unsaturated can α- beketoesters boosted 87 in CHCl by tuning3 was introduced the ligand into a stainless structures. steel In particular, column filled with 86 (ground with a diameter of around 0.4–5 μm) and quartz sands (20–40 mesh) among three porouswith a residence chiral time MOFs of 12 h with obtaining the the framework Friedel-Crafts addition formula products [Mn 882 L(Hin 89–292O)% yield2], outstanding with results 91–94% of enantioselectivity. With respect to batch experiments, a slight decrease in were furnished by a porous chiral CF3-containing MOF 86. By using a syringe pump, a solution of enantioselectivity probably related to the presence of silica used for the reactor packing was observed. N-methylindoleHowever,70 and underβ,γ-unsaturated flow conditions, aα slight-ketoesters increase in87 catalyticin CHCl activity3 waswas achieved. introduced The authors into a stainless steel column filled withstated86 that(ground the fixed- withbed reactor a diameter can be reused of aroundup to seven 0.4–5 times withoutµm) and any significant quartz sands worsening (20–40 mesh) with of system performance. Notably, this work represented the first example of the use of MOF-mediated a residence timeheterogeneous of 12 h obtaining asymmetric the catalysis Friedel-Crafts under continuous addition flow conditions products (Scheme88 31in). 89–92% yield with 91–94% of enantioselectivity. With respect to batch experiments, a slight decrease in enantioselectivity probably related to the presence of silica used for the reactor packing was observed. However, under flow conditions, a slight increase in catalytic activity was achieved. The authors stated that the fixed-bed reactor can be reused up to seven times without any significant worsening of system performance. Notably, this work represented the first example of the use of MOF-mediated heterogeneous asymmetric catalysis under continuous flow conditions (Scheme 31). Molecules 2020, 25, x FOR PEER REVIEW 21 of 28

Scheme 31. CF Friedel–Crafts alkylations of N-methylindole with β,γ-unsaturated α-ketoesters Scheme 31. CFcatalyzed Friedel–Crafts by a metal-organic alkylations framework (copyright of N-methylindole of Reference [7]). with β,γ-unsaturated α-ketoesters catalyzed by a metal-organic framework (copyright of Reference [7]). In 2018, the continuous flow preparation of C-3 dicarbonyl indoles via the I2/DMSO-mediated oxidative coupling of aryl acetaldehydes with indoles was proposed by Fang and Guo [112]. Initial batch experiments were conducted, using phenylacetaldehyde 89 and N-methylindole 70 as starting materials. According to the optimal batch conditions, a mixture of I2 (1.5 equivalents) and phenylacetaldehyde in DMSO was heated for 4 h. Then, N-methylindole was added and the solution was heated for 11 h, obtaining the dicarbonyl indole 90a in a 59% yield (Scheme 32a). Despite the fact that N-methylindole 70 was added after phenylacetaldehyde 89, the formation of by-product 91, derived from dehydration between the acetaldehydes and indoles, was not negligible (13%). To face this limitation, a two-step continuous flow system was designed (Scheme 32b). In the first microreactor, the aryl acetaldehyde was subjected to Kornblum oxidation to produce the key intermediate phenyl glyoxal C 92. In the second microreactor, 92 goes through a Friedel–Crafts-type reaction with indole, followed by an oxidation process to afford the desired dicarbonyl indole. The two reaction steps were separately optimized. According to the best conditions, a DMSO solution of 89 and a DMSO solution of I2 were introduced in the first reactor heated to 110 °C using a residence of time of 6.25 min, producing the phenyl glyoxal C intermediate. The latter was reacted with a DMSO solution of 70 in a second reactor heated to 120 °C with a residence time of 7.5 min, obtaining a high yield (88%) of 90a with only traces of byproduct 91. Therefore, the developed flow protocol ensured higher yields and a reduced reaction time and iodine dosage (0.5 equivalents), reducing the byproduct formation with respect to the batch setup. The reaction scope was then explored by varying both the aryl acetaldehydes and indole derivatives, producing a collection of dicarbonyl indoles. Notably, using this approach the use of a high iodine amount and the employment of amine catalyst, which are the main drawbacks of previously reported batch protocols, could be overcome.

Molecules 2020, 25, 3242 20 of 26

In 2018, the continuous flow preparation of C-3 dicarbonyl indoles via the I2/DMSO-mediated oxidative coupling of aryl acetaldehydes with indoles was proposed by Fang and Guo [111]. Initial batch experiments were conducted, using phenylacetaldehyde 89 and N-methylindole 70 as starting materials. According to the optimal batch conditions, a mixture of I2 (1.5 equivalents) and phenylacetaldehyde in DMSO was heated for 4 h. Then, N-methylindole was added and the solution was heated for 11 h, obtaining the dicarbonyl indole 90a in a 59% yield (Scheme 32a). Despite the fact that N-methylindole 70 was added after phenylacetaldehyde 89, the formation of by-product 91, derived from dehydration between the acetaldehydes and indoles, was not negligible (13%). To face this limitation, a two-step continuous flow system was designed (Scheme 32b). In the first microreactor, the aryl acetaldehyde was subjected to Kornblum oxidation to produce the key intermediate phenyl glyoxal C 92. In the second microreactor, 92 goes through a Friedel–Crafts-type reaction with indole, followed by an oxidation process to afford the desired dicarbonyl indole. The two reaction steps were separately optimized. According to the best conditions, a DMSO solution of 89 and a DMSO solution of I2 were introduced in the first reactor heated to 110 ◦C using a residence of time of 6.25 min, producing the phenyl glyoxal C intermediate. The latter was reacted with a DMSO solution of 70 in a second reactor heated to 120 ◦C with a residence time of 7.5 min, obtaining a high yield (88%) of 90a with only traces of byproduct 91. Therefore, the developed flow protocol ensured higher yields and a reduced reaction time and iodine dosage (0.5 equivalents), reducing the byproduct formation with respect to the batch setup. The reaction scope was then explored by varying both the aryl acetaldehydes and indole derivatives, producing a collection of dicarbonyl indoles. Notably, using this approach the use of a high iodine amount and the employment of amine catalyst, which are the main drawbacks of previously reported batch protocols, could be overcome. Molecules 2020, 25, x FOR PEER REVIEW 22 of 28

Scheme 32. (a) Batch and (b) flow synthesis of dicarbonyl indoles via I2/DMSO-mediated oxidative Scheme 32.coupling.(a) Batch and (b) flow synthesis of dicarbonyl indoles via I2/DMSO-mediated oxidative coupling. 3.4. Continuous Flow Functionalization of C-2 Position of Indole Ring 3.4. Continuous FlowAs described Functionalization above in this review, of C-2 flow Position chemistry of offers Indole the Ring possibility to access highly complex molecular structures through continuous flow multi-step strategies applicable for industrial As described above in this review, flow chemistry offers the possibility to access highly purposes. In this context, Pollet and France reported a tandem, bicatalytic continuous flow complex molecularcyclopropanation structures-homo-Nazarov through-type ringcontinuous-opening cyclization flow multi-step for the preparation strategies of applicablea for industrial purposes.hydropyrido[1 In,2- thisa]indole context, framework, Pollet which and is France present in reported various bioactive a tandem, compounds bicatalytic [113]. continuous flow cyclopropanation-homo-Nazarov-typeRemarkably, this contribution was the first ring-opening example in the literature cyclization of a homo for-Nazarov the preparation-type of a cyclization under continuous flow conditions. The two steps of the sequence, cyclopropanation and hydropyrido[1,2-ring-openinga]indole cyclization, framework, were separately which optimized is present in batch in with various great accuracy bioactive to develop compounds an [112]. Remarkably,industrial this contribution-viable proce wasss in terms the first of solvent example selection in the and literature catalyst loading of ahomo-Nazarov-type in order to transfer the cyclization under continuousprocess flowin flow conditions. mode. An integrated, The two two steps-step setup of the was sequence, designed (Scheme cyclopropanation 33). The first step, and the ring-opening Rh-catalyzed cyclopropanation, was performed by reacting a solution of diazoester 93 with a mixture cyclization,of were Rh2(esp) separately2 catalyst and optimized styrene 94 in a batch stainless with-steel greatreactor accuracycoil heated to 50 develop °C. The outcoming an industrial-viable solution, characterized by an irregular volumetric flow rate due to the N2 generation, was mixed with a solution of In(OTf)3 in a mixing bed packed with 2 mm borosilicate glass beads. The resulting mixture was directed through a second stainless steel reactor coil heated to 50 °C to achieve the ring- opening cyclization. In the case of hydropyrido[1,2-a]indole 95a, the continuous flow tandem approach ensured a higher yield when compared to the batch and an impressive throughput of 4.7 g·h−1. Otherwise, probably due to the flow irregularity observed during the cyclopropanation step and solubility issues, a lower yield was observed in the case of hydropyrido[1,2-a]indole 95b in comparison to the batch result. However, a relevant throughput of 2.8 g·h−1 was achievable.

Molecules 2020, 25, 3242 21 of 26 process in terms of solvent selection and catalyst loading in order to transfer the process in flow mode. An integrated, two-step setup was designed (Scheme 33). The first step, the Rh-catalyzed cyclopropanation, was performed by reacting a solution of diazoester 93 with a mixture of Rh2(esp)2 catalyst and styrene 94 in a stainless-steel reactor coil heated to 50 ◦C. The outcoming solution, characterized by an irregular volumetric flow rate due to the N2 generation, was mixed with a solution of In(OTf)3 in a mixing bed packed with 2 mm borosilicate glass beads. The resulting mixture was directed through a second stainless steel reactor coil heated to 50 ◦C to achieve the ring-opening cyclization. In the case of hydropyrido[1,2-a]indole 95a, the continuous flow tandem approach ensured a higher yield when compared to the batch and an impressive throughput of 4.7 g h 1. Otherwise, · − probably due to the flow irregularity observed during the cyclopropanation step and solubility issues, a lower yield was observed in the case of hydropyrido[1,2-a]indole 95b in comparison to the batch 1 result. However, a relevant throughput of 2.8 g h− was achievable. Molecules 2020, 25, x FOR PEER REVIEW · 23 of 28

Scheme 33.SchemeCF tandem,33. CF tandem, bicatalytic bicatalytic cyclopropanation-ring-opening cyclopropanation-ring-opening cyclization. cyclization. 4. Conclusions 4. Conclusions The relevance of indole, a biologically accepted pharmacophore in medicinal compounds, and The relevanceits derivatives, of indole, requires a biologicallya continuous improvement accepted pharmacophoreof their preparation. inIn medicinalthis review article, compounds, we and its derivatives,have requires tried to a report continuous the contribut improvemention of flow chemistry of their in the preparation. reinforcement of In synthetic this review strategies article, for we have the indole nucleus construction and its functionalization, emphasizing the convenience of flow tried to reporttranslation the contribution with respect to of traditional flow chemistry batch procedures. in the We reinforcement highlighted some of aspects synthetic on the strategiesuse of for the indole nucleusenabling construction flow technol andogies its in functionalization,the synthesis of indole core emphasizings, reporting representative the convenience examples of using flow translation with respectdifferent to traditional microreactor batch devices procedures., trying to show We how highlighted the flow performance some surpassed aspects the on traditional the use of enabling batch approach. The application of continuous flow chemistry for the fast generation of libraries of flow technologiesindole derivative in the synthesiss, useful for of biological indole cores, screening reporting, is foreseen representative for the future. Inexamples addition, usingthe different microreactorincorporation devices, trying of in- toline show biological how assays the flow of indole performance derivatives surpassed will speed up the the traditional process of drug batch approach. The applicationdiscovery, of continuous placing continuous flow chemistryflow chemistry for at the the fastfrontier generation of modern ofmedicinal libraries chemistry. of indole Our derivatives, perspective is that enabling technologies such as flow chemistry will become irreplaceable tools for useful for biologicalmodern chemical screening, synthesis. is foreseen for the future. In addition, the incorporation of in-line biological assays of indole derivatives will speed up the process of drug discovery, placing continuous Author Contributions: Writing-Original Draft Preparation, (M.C.); Writing-Review & Editing, (L.D., R.L.). All flow chemistryauthors at have the read frontier and agreed of to the modern published medicinal version of the manuscript chemistry.. Our perspective is that enabling technologies such as flow chemistry will become irreplaceable tools for modern chemical synthesis. Funding: We thank the University of Bari for support; Fondi Ateneo 2019–Degennaro. Author Contributions:Conflicts of InterestWriting—Original: The authors declare Draft no Preparation,conflict of interest (M.C.);. Writing—Review & Editing, (L.D., R.L.). All authors have read and agreed to the published version of the manuscript. References Funding: We thank the University of Bari for support; Fondi Ateneo 2019—Degennaro. 1. Vicente, R. Recent advances in indole syntheses: New routes for a classic target. Org. Biomol. Chem. 2011, 9, Conflicts of Interest:6469–The6480. authors declare no conflict of interest. 2. Gribble, G.W. Indole Ring Synthesis: From Natural Products to Drug Discovery; Wiley-VCH: Chichester, UK, 2016. References 3. Kaushik, N.K.; Kaushik, N.; Attri, P.; Kumar, N.; Kim, C.H.; Verma, A.K.; Choi, E.H. Biomedical importance of indoles. Molecules 2013, 18, 6620–6662. 1. Vicente,4. R. RecentGhinea, advancesI.O.; Dinica, inR.D. indole Breakthoughts syntheses: in Indole New and routes Indolizine for Chemistry, a classic target.New SyntheticOrg. Pathways, Biomol. Chem. 2011, 9, 6469–6480. [NewCrossRef Applications,][PubMed In Scope] of Selective Heterocycles from Organic and Pharmaceutical Perspective; Varala, V., 2. Gribble, G.W.Ed.;Indole Intech Ring Open: Synthesis: Rijeka, Croatia, From 2016; Natural Chapter Products 5, pp. 1043 to–1561. Drug Discovery; Wiley-VCH: Chichester, UK, 2016. 5. Zhang, M.Z.; Chen, Q.; Yang, G.-F. A review on recent developments of indole-containing antiviral agents. 3. Kaushik, N.K.;Eur. Kaushik,J. Med. Chem. N.; 2015 Attri,, 89, 421 P.;–441. Kumar, N.; Kim, C.H.; Verma, A.K.; Choi, E.H. Biomedical importance of indoles.6. MoleculesBaeyer, A. Ue2013ber die, 18 beziehungen, 6620–6662. der zimmtsäure [CrossRef zu][ derPubMed indigogruppe.] Chem. Ber. 1880, 13, 2254–2263. 4. Ghinea,7. I.O.; Colella, Dinica, M.; Carlucci, R.D. Breakthoughts C.; Luisi, R. Supported in Indolecatalysts andfor continuous Indolizine flow s Chemistry,ynthesis. Top. Curr. New Chem. Synthetic 2018, Pathways, 376, 46. New Applications. In Scope of Selective Heterocycles from Organic and Pharmaceutical Perspective; Varala, V., Ed.; 8. Gutmann, B.; Cantillo, D.; Kappe, C.O. Continuous‐flow technology—A tool for the safe manufacturing of Intech Open:active Rijeka, pharmaceutical Croatia, ingredients. 2016; Chapter Angew. 5, Chem. pp. Int. 1043–1561. 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