Flow Photochemistry Fabrizio Politano, and Gabriela Oksdath-Mansilla Org

Subscriber access provided by UNIV OF CAMBRIDGE Review Light on the horizon: Current research and future perspectives in flow photochemistry Fabrizio Politano, and Gabriela Oksdath-Mansilla Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00213 • Publication Date (Web): 02 Aug 2018 Downloaded from http://pubs.acs.org on August 2, 2018

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1 2 3 4 Light on the horizon: Current research and 5 6 7 8 future perspectives in flow photochemistry 9 10 11 [a] [a] 12 Fabrizio Politano and Gabriela Oksdath-Mansilla* 13 [a] 14 INFIQC-CONICET-UNC, Dpto. de Química Orgánica, Facultad de Ciencias 15 16 Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, X5000HUA 17 Córdoba, Argentina, *[email protected] 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Graphical Abstract 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Abstract 4 5 6 The research area of synthetic organic photochemistry is a powerful tool for creating 7 8 both natural products and molecules with high structural complexity, in a simple way 9 10 and under mild conditions. However, because of the challenges in scaling-up, it has 11 12 13 been difficult to apply a photochemical reaction in an industrial process. Flow chemistry 14 15 provides an opportunity for better control over the conditions of the reaction and, 16 17 additionally, improved reaction selectivity and enhanced reproducibility. Taking into 18 19 20 account that significant interest has focused on the use of flow photochemistry as a 21 22 method for the synthesis of heterocycles and its applications in target-oriented synthesis 23 24 over the last few years, the aim of this review is to highlight the recent efforts to apply 25 26 27 flow photochemistry methodology to diverse reactions as a greener and more scalable 28 29 process for the pharmaceutical and fine chemical industries. Additionally, the review 30 31 highlights future perspectives in the development of scale-up strategies, combining 32 33 photochemical reactions in the continuous flow multistep synthesis of organic 34 35 36 molecules, being of interest for scientists and engineers alike. 37 38 39 40 41 Keywords: flow chemistry, green processes, photochemical synthesis, APIs 42 43 44 45 46 Introduction 47 48 Nowadays, scientist and engineers are increasingly thinking in a sustainable way when 49 50 they design their research programs. It is clear that green chemistry and engineering 51 52 53 principles go beyond concerns over hazards from chemical toxicity and include 54 55 considerations of energy conservation, waste reduction, and lifecycle such as the use of 56 57 more sustainable or renewable feedstocks, and are accordingly being designed for the 58 59 60 entire life cycle of the product. In this context, the fundamentals of photochemistry

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1 2 3 suggest the implementation of this process as sustainable methodology considering the 4 5 photon as a green reagent which is absorbed without leaving residue. Light-induced 6 7 8 activation offers a way for the environmentally mild obtaining of highly reactive 9 10 intermediates, allowing access to molecules with valuable structural complexity which 11 12 otherwise would be difficult to access. Likewise, for activation no additional reagent is 13 14 15 required compared with thermal reaction. Therefore, photochemical transformations 16 17 have been adopted in the rational and efficient design of many synthetic 18 19 methodologies.1 20 21 22 In spite of the numerous advantages mentioned above, different aspects should be 23 24 considered when carrying out a photochemical reaction. Photophysical aspects of the 25 26 reagents such as quantum yield (Φ휆), have to be taken into account in order to increase 27 28 29 reaction efficiency. In addition, the appropriate equipment (lamp, power supply, 30 31 reaction flask with accessories, e.g. for gas inlet) are required for a successful 32 33 photoreaction. In fact, there are a number of aspects in the process related to the 34 35 36 utilization of light itself, some of them regarded as “non-green”, which often reduces 37 38 interest in using it. Several photoreactions involve the use of high-energy and intense 39 40 light sources which are hazardous, and strict risk assessment and operation protocols are 41 42 43 required. For powerful lamps, a forced cooling circulation system is required, and this 44 45 results in a more expensive and sophisticate reactor. Inert and transparent solvents are 46 47 needed, so that the photochemical reactions are carried out in hazardous solvents such 48 49 as benzene, dichloromethane, acetonitrile or methanol.2 50 51 52 However, in the last decade there has been a significant effort made by photochemists to 53 54 carry out reactions with more energy-saving and environmentally benign features. In 55 56 this context, visible-light-induced organic reactions developed rapidly and have gained 57 58 3 59 a considerable interest in both academia and industry. Light-emitting diodes (LEDs) 60

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1 2 3 are successfully used with this purpose, as they are able to provide high-intensity visible 4 5 light over a short wavelength range. Sources of this kind have the advantages of 6 7 8 economy and long life. LEDs emitting in the UVA, down to 320-310 nm are also 9 10 available, although their emission is much less intense, and they are more expensive. In 11 12 the same way, solar light as a more sustainable energy source has been evaluated in 13 14 4 15 photochemical reactions, opening the possibility to explore a greener process. 16 17 Despite continuous progress and technical developments in the use of photochemistry, 18 19 its application in industry has been limited by the scalability of photochemical 20 21 22 processes, which require powerful light sources and reactors of special dimensions and 23 24 shapes to produce large amounts of chemicals per unit of time. Over the last decade, the 25 26 use of continuous-flow chemistry has emerged as a powerful technique for 27 28 photochemical applications, making it possible to overcome the issues associated with 29 30 5 31 batch reactors. Although in the last years a series of reviews have been published 32 33 showing the advantages of flow photochemistry in synthetic application,6,7,8 the aim of 34 35 this review is the development of flow photochemistry as applied to compounds of 36 37 38 pharmaceutical interest. Furthermore, different scale-up strategies of continuous 39 40 multistep synthesis will be discussed, showing future perspectives in flow chemistry. 41 42 43 44 45 Flow Photochemistry 46 47 9,10 48 The Advantages of Continuous-Flow Processes 49 50 With the development of flow chemistry, Organic Photochemistry has gained value for 51 52 the synthetic community and industry due to its interesting applications in milder and 53 54 55 greener conditions. One important problem for photochemical reactions that use 56 57 continuous-flow processes is the ability to scaling it up easily using different reactor 58 59 volumes or parallel multi-reactors (numbering-up).11,12,13 Scalability is directly related 60

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1 2 3 to an efficient and uniform irradiation of the reaction mixture, which can be obtained 4 5 − − 6 according to the well-known Bouguer Lambert Beer law, by using narrow channels in 7 8 the microreactor. Furthermore, with adequate use of refractors or miniaturized light 9 10 sources, the photon flux (number of photons observed per unit time) is more efficient, 11 12 13 resulting in an acceleration of the photochemical reaction (Figure 1). For this reason, a 14 15 reduction of byproducts formation from over-irradiation could be observed, with a 16 17 consequent increment of productivity. Additionally, due to the size of the 18 19 20 microreactor, faster mixing is achieved, enhancing the mass- and heat-transport thus 21 22 providing a high reproducibility of the photochemical conditions and improving the 23 24 selectivity of the reaction.14 25 26 27 28

29 (%) transmittance 30 31 32 33 34 batch flow 35 36 37 38 39 decrease in optical path 40 efficient irradiation 41 42 43 Figure 1. Transmission of light as a function of the optical path according to the 44 45 Bouguer−Lambert−Beer correlation in a photochemical process in batch vs. flow. 46 47 48 49 On the other hand, one interesting advantage of flow chemistry is the fact that 50 51 52 multiphase reactions can be carried out in a simple way and under safe conditions. 53 54 Specifically, the interfacial area is maximized in microreactors because of their size, 55 56 leading to an efficient mass transfer between the two phases (Figure 2). Segmented flow 57 58 59 obtained by liquid slug and elongated bubbles from the immiscible phase has been 60

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1 2 3 successfully used in different photochemical processes. Particularly, photo-oxygenation 4 5 reaction has been improved by using a slug flow with oxygen or air as immiscible 6 7 15 8 phase. Additionally, an improvement in the efficiency of photocycloaddition has been 9 10 observed in slug flow conditions, with water as immiscible phase.16 11 12 13 slug flow 14 15 16 17 immiscible phase 18 (liquid or gas) 19 20 Figure 2. a) Schematic representation of a slug flow for multiphase reactions. b) Real 21 22 picture of a slug flow with colorized water and air as immiscible phase for a photo- 23 24 25 oxygenation reaction. Reprinted with permission from ref 15. Copyright 2015 John 26 27 Wiley and Sons. 28 29 30 31 32 Continuous-Flow Technology 33 34 From their beginning, flow photochemical reactions were carried out using simple 35 36 reactor components that combined pumping systems with different reactor bodies and 37 38 39 available light sources. For the academic, an interesting way of improving 40 41 photochemical reaction and of continuing displaying its synthetic potential is the use of 42 43 available and cheap equipment to access to flow-photoreactor. Even though at present 44 45 17 46 commercial flow photoreactors are available such as Vapourtec UV-150, Corning 47 18 48 Advanced-Flow G1 Photo Reactor or Corning Advanced-Flow Lab Photo Reactor, 49 50 Heraeus Noblelight,19 many efforts are still made to build simple “in-house” designs. 51 52 One of the most commonly used flow photoreactors consists of flexible fluorinated 53 54 55 ethylene propylene (FEP) or polytetrafluoroethylene (PTFE) tubes wrapped around a 56 57 glass cylinder and irradiated by a lamp at its center, which means that it can easily be 58 59 constructed, using cheap and readily available materials.20 In this way, Noël and co- 60

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1 2 3 workers have described a protocol for building a compact, inexpensive modular 4 5 photomicroreactor using commercially available parts, which can be used in a wide 6 7 8 variety of homogeneous visible light photocatalysis or UV-mediated reactions (Figure 9 10 3).21 11 12 13 14 a b c d e 15 16 17 18 19 20 Figure 3. Different parts and sequence for constructing the “in-house” 21 22 23 photomicroreactor. a) LED strips. b) Refractive tape around a 20-ml syringe, followed 24 25 by the PFA microtubing coiled around the syringe (microreactor). c) Large syringe as 26 27 LED place holder. d) LED array and microreactor positioned inside the place holder 28 29 (finished photomicroreactor). e) Holes drilled in the larger-diameter syringe used to 30 31 32 hold the photomicroreactor in place to fit the exit of the microreactor. The nozzle 33 34 provides air cooling. Reprinted with permission from ref 21. Copyright (2016) the 35 36 American Chemical Society. 37 38 39 40 41 Another particular photoreactor design was implemented by Pergantis, 42 43 Vassilikogiannakis and co-workers, base on pneumatically generated aerosols to 44 45 22 46 undertake bi-phasic photooxygenations. This particular reactor works by nebulizing a 47 48 photo-oxidation solution inside a cylindrical chamber, mimicking the earth’s 49 50 atmosphere clouds. A low energy LED strip surrounds the chamber and either oxygen 51 52 or air can be used in excess for efficient nebulization of the reactant solutions. One of 53 54 55 the photo-oxygenation reaction tested was the ene reaction of-citronellol, carried out 56 57 in the presence of 0.8 mol% of rose Bengal as a phtosensitizer, with the ability to 58 59 60

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1 2 3 maximize the surface area to volume ratio between the two phases, and consequently an 4 5 exceptionally high productivities is obtained. 6 7 8 More recently, Booker-Milburn’s group has developed a new flow photoreactor where 9 10 photochemical synthesis can be carried out on a kilogram scale over a 24h processing 11 12 period.23 In addition, a 10-fold reduction of reaction time was achieved compared with a 13 14 15 FEP reactor. The modular reactor consists of an array of a series linked of quartz tubes 16 17 axially arranged around a high power light source (e.g., Hg-lamp or LEDs), with size 18 19 not much larger than a rotary-evaporator condenser. In this way, the reaction solution 20 21 22 enters through an end-cap, flow through one tube into the opposite end-cap, and then 23 24 back through the adjacent tube in the opposite direction (Figure 4a). 25 26 27 a) 28 29 30 31 32 33 34 35 36 b) c) 37 38 39 40 41 42 43 44 45 46 47 48 Figure 4. a) Schematic representation and real picture of an immersion-cooled parallel 49 50 tube flow reactor. Reprinted with permission from ref 23. Copyright (2016) the 51 52 American Chemical Society. b) Schematic and real picture of the vortex fluidic device 53 54 55 (VFD). The image highlights droplet entry into the reactor, its subsequent impact, and 56 57 the creation of the thin film. Reprinted with permission from ref 24. Copyright (2017) 58 59 the John Wiley and Sons. c) Schematic representation and real picture of the reactor 60

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1 2 3 based on a slightly modified lab rotary evaporator. Reprinted with permission from ref 4 5 25. Copyright (2016) the American Chemical Society. 6 7 8 9 10 Another application of flow photochemistry is the use of thin films processing of the 11 12 reaction medium. A thin film can be generated using a vortex fluidic device (VFD). 13 14 15 When a fluid enters the vortex system, the droplet impacts the hemisphere of the 16 17 rotating tube to form a thin film. The film’s effect allows a larger surface-to-volume 18 19 ratio, resulting in a more efficient and homogenous irradiation, rapid heat transfer and 20 21 22 uniform mixing of reagents. In this case, the rotational speed and tilt angle of the tube 23 24 are what define the efficiency of the reaction. This development of VFD has been 25 26 successfully used by Raston’s group in a variety of synthetic applications24 and has been 27 28 extended to photochemistry (Figure 4b).25 29 30 31 Applying the principle of thin film in an elegant way, George and co-worker have been 32 33 able to use a conventional rotary evaporator in photochemical reactions. Additionally, a 34 35 rotary evaporator can be adapted in a simple way for use as flow reactor by the 36 37 38 introduction of two thin PTFE tubes through the rotating neck to allow a solution to be 39 40 pumped in and out of the reactor. A vacuum pump is not necessary and LEDs or any 41 42 other light sources can be placed around the flask. The reactor can be operated in semi- 43 44 45 continuous mode, showing that flow photochemistry is nowadays accessible to any 46 26 47 laboratory group (Figure 4c). 48 49 Building on the pioneering work of Giacomo Ciamician, who was one of the first to 50 51 work with organic chemistry and plant chemistry evaluating photochemical reaction 52 53 27 54 under sunlight, Noël, Debije and co-workers have developed a tree leaf-inspired 55 56 photomicroreactor which may be used in the future to promote solar photochemical 57 58 synthesis (Figure 5).28 Many things have been taken into consideration in order to 59 60

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1 2 3 develop an efficient device in which sunlight reactions can be carried out. The concept 4 5 of “luminescent solar concentrator” (LSC) was used. LSC captures solar light through a 6 7 8 dispersed luminophore (such as a fluorescent dye) in a glass or polymer support. In 9 10 addition, microreactor technology was conveniently used to provide a high surface-to- 11 12 volume ratio of solar light and to improve its large-scale application. LSC is a 13 14 15 polymeric material constituted by Lumogen F Red 305 (LR 305), a perylene bisimide- 16 17 based dye. It has an emission profile that matches the absorption spectrum of the 18 19 methylene blue (MB) photocatalyst used in the reaction system. The luminescent- 20 21 22 concentrated photon flux into the microchannels is more intense than the solar light and 23 24 results in an efficient [4+2] cycloaddition between singlet oxygen and 9,10- 25 26 diphenylanthracene. 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 Figure 5. Leaf-inspired photomicroreactor. A leaf photosystem uses solar energy 50 51 harvesting by means of antenna pigment molecules and a photon transfer process to 52 53 carry out the reaction. Similarly, in a LSC microfluidic reactor chip the photons are 54 55 56 absorbed by the fluorescent molecules and are re-emitted toward the edge of the device 57 58 where a photosensitizer is attached to carry out the photochemical reaction. Reprinted 59 60 with permission from ref 28. Copyright 2017 John Wiley and Sons.

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1 2 3 4 5 It is clear that a control system with different parameters of photochemical reaction is 6 7 8 needed to increase the efficiency and productivity of the reaction. Nowadays, many 9 10 research groups are working on the use of automation platforms, assembling on-line 11 12 analytical techniques or control modules to optimize a photochemical reaction in a very 13 14 15 simple way, and in just few minutes. Following its work; Nöel’s group has employed 16 17 process control technologies which act in real-time to automatically adjust the residence 18 19 time to the solar irradiance variation in the LSC photomicroreactor.29 Additionally, they 20 21 22 development a fully automated continuous-flow platform suitable for luminescence 23 24 screening conditions and Stern-Volmer analysis applied to a photoredox catalysis, in 25 26 which a spectrophotometer and light source are controlled by software and a HPLC 27 28 pumps regulate the stream to the flow cuvette.30 29 30 31 In the same way, Jensen and co-workers were able to screen and optimization (residence 32 33 time, light source power, temperature) a series of visible-light photoredox liquid or gas- 34 35 liquid catalysis in a 15 L scale, using an automated microfluidic platform. An 36 37 38 oscillatory flow is controlled by a computer, enabling a flexible residence time keeping 39 40 mixing and heat transfer efficiently.31,32 41 42 43 44 45 Safer Photo-oxygenations 46 47 Molecular oxygen is a green oxidant and has attractive features: it is inexpensive, 48 49 environmentally benign, and its reactions involve an atom economy. However, one of 50 51 52 the challenges for chemists or the industry is to use oxygen as reagent in large scale 53 54 under controlled and safe conditions. Generally, oxidations reactions which use oxygen 55 56 or air are exothermic, and the heat generated can be difficult to dissipate. In 57 58 59 conventional batch reactors, gas-liquid reaction using organic solvent at a limiting 60

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1 2 3 oxygen concentration (LOC) has to be applied to avoid spontaneous ignition. 4 5 Furthermore, temperature and pressure are difficult to control, which results in a low 6 7 8 selectivity and incomplete reaction. 9 10 With the development of continuous flow technology, aerobic oxidation or even the use 11 12 of oxygen as reagent has become possible without safety hazards. High temperatures 13 14 15 and pressures are easily controlled through the use of high pressure resistant tubing and 16 17 small reaction volumes that can be rapidly cooled. Moreover, a gas-liquid oxidation in 18 19 flow features an excellent mass and heat transfer, minimizing the possibility of 20 21 33 22 explosion when flammable solvent are used. Heterogeneous reactions can be carried 23 24 out using a segmented (slug) flow which allows a more efficient mixing, with improved 25 26 mass transfer between the phases (Figure 2).34 27 28 Specifically, photo-oxygenations involve the participation of singlet oxygen (1O ) as 29 2 30 31 reactive species which can be formed in situ under photosensitizer oxygen conditions. 32 33 Singlet oxygen has a high selectivity, and is in fact a very reactive electrophilic species, 34 35 able to react with unsaturated substrates leading to the formation of endoperoxides, 36 37 38 dioxetanes or allylic hydroperoxides. It can also react with sulphur, selenium, 39 40 phosphorus and nitrogen compounds. Photo-oxygenation represents a powerful strategy 41 42 to obtain oxy functionalized compounds under mild experimental conditions, becoming 43 44 35,36 45 a valuable tool for the synthesis of natural products. 46 .- 47 Another reactive species from molecular oxygen is the superoxide radical anion (O2 ) 48 49 which can be formed by a Singlet Electron Transfer (SET) process from a reduced 50 51 photocatalyst in an air or oxygen atmosphere. These highly reactive species are capable 52 53 54 of oxidizing different substrates such as aryl boronic acids or phenols, and are involved 55 56 in a proton abstraction pathway.2 57 58 59 60

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1 2 3 Many of the intermediate products derived from photo-oxygenation are thermally 4 5 unstable or are explosive peroxides. Furthermore, the concentration of reactive species 6 7 8 from oxygen is very important but due to high reactivity an over-oxidation of products 9 10 can be observed. For all of these, the use of continuous-flow chemistry has a key 11 12 advantage for photochemical transformations, allowing as it does a precise control of 13 14 37,38 15 the parameters of the reaction, and enabling work to be done under safer conditions. 16 17 As an offshoot from this technology, chemists and engineers have developed a 18 19 multitude of flow reactors to generate reactive species from oxygen, carrying out 20 21 22 interesting photochemical applications. In this context, Dreesen, Heinrichs, Monbaliu 23 24 et. al. used a compact commercial glass mesofluidic module (Corning Lab Reactor) to 25 26 carry out a scalable photo-oxygenation of methionine under mild conditions, improving 27 28 chemo-selective and atom-economic, and implementing a safer and sustainable 29 30 39 31 process. The photo-reactor design combines high mixing with an efficient irradiation. 32 33 With an integrated static mixers and sandwiched in a high capacity heat-exchanger, the 34 35 multiphase mass transfer could be optimized and LED panels were put on both sides of 36 37 38 the fluidic device. Additionally, the flow-through module was equipped with an in- and 39 40 offline NMR to analyze the reactor effluent. Under the best conditions a 1mol day-1 of 41 42 methionine sulfoxide was obtained using a very low loading of photocatalyst (0.1% 43 44 45 Rose Bengal) at room temperature with white light irradiation (4000K) and just 0.1 46 47 equivalent of oxygen. 48 49 In the same way, Oelgemöller and coworker demonstrated the utility of a commercially 50 51 available falling film microreactor (IMM, Mainz) by applying it in a photo-oxygenation 52 53 40 54 reaction. The miniaturization of flow devices has the advantage of setting the 55 56 parameters of the reactions under precise control and allowing the reactions’ progress to 57 58 be monitored on-line. Because of that, microfluidic devices can be utilized for the 59 60

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1 2 3 optimization of reactions which involved the use of hazardous reagents. Particularly, the 4 5 6 photo-oxygenation of -terpinene was studied, evaluating reproducibility, oxygen 7 8 sources, solvent, substrate and sensitizer concentration, oxygen flow rate, temperature 9 10 and light sources. Photo-oxygenation takes place in the interface between the liquid and 11 12 13 the gaseous layer, which is obtained in a thin film of the liquid reaction generated by 14 1 15 gravity and counter-currently to the gas phase. Using Rose Bengal (RB) as O2- 16 17 photosensitizer, endoperoxide ascaridole, a natural molecule with important 18 19 bioactivities, was obtained with a yield of up to 89% yield with a productivity of 2.5-3.2 20 21 -1 -1 22 mol L h (Scheme 1). 23 24 25 26 27 28 29 30 31 O2 32 33 light 34 35 36 O2 37 38 39 Scheme 1. Photo-oxygenation of -terpinene in a falling film microreactor. 40 41 42 43 Another recent study involves the use of a vortex reactor to carry out continuous photo- 44 45 46 oxygenations. In this case a rapid rotation generates a Taylor vortices flow presenting 47 48 certain advantages for gas/liquid heterogeneous reactions.41 The high mass transfer 49 50 between both layers allows a more efficient dissolution of gases, owing to which air 51 52 53 from the lab can be used instead of pressurized oxygen. The versatile application of a 54 1 55 vortex reactor could be demonstrated in different photochemical reactions using O2 or 56 .- 57 O2 as reactive species. Phenyl boronic acid was selectively photo-oxidized to the 58 59 60 corresponding phenol; additionally, photo-oxygenations of furfuryl alcohol and -

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1 2 3 terpinene were carried out with a high yield and efficiency. In the case of -terpinene 4 5 6 with a rotation speed of 4000 rpm a 91% yield of endoperoxide ascaridole was obtained 7 -1 8 with a productivity of 2.73 mmol h . 9 10 Another interesting application of photo-oxidation in a segmented flow regime was 11 12 3 13 recently developed by Nöel and co-workers. Activated and unactivated C(sp )-H bonds 14 15 were selectively oxidized via decatungstate-photocatalysis (TBADT) with yields 16 17 ranging from (41-91 %) in a short reaction time (45 min). This methodology was 18 19 extended to the oxidation of biologically active compounds, such as (-)-ambroxide, 20 21 22 pregnenolone acetate, (+)-sclareolide, and artemisinin showing its versatility (Scheme 23 24 2).42 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 3 41 Scheme 2. C(sp )-H oxidation enabled by decatungstate photocatalysis (TBADT) in 42 43 slug flow. 44 45 46 47 48 Continuous flow photochemistry for the synthesis of compounds of 49 50 51 pharmaceutical interest 52 53 The strength of the continuous flow process can be demonstrated by its application to 54 55 56 the preparation of fine chemicals such as natural products, but additionally through the 57 58 synthesis of APIs. Puglisi, Benaglia and co-worker reviewed the advances in continuous 59 60 multistep applied to APIs synthesis.43 More recently, Kappe and Dallinger have

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1 2 3 critically reviewed the use of continuous processes in the synthesis of APIs, analyzing 4 5 their impact in terms of sustainability.44 6 7 8 Taking into account that the synthesis of natural products or target molecules which 9 10 display biological activity is an essential part of drug discovery, and that the APIs 11 12 generally have an inherent complexity associated with their molecular framework, the 13 14 15 development of safer and more sustainable synthesis protocols could have a high impact 16 17 on the pharma industry. In this context, the combination of flow and photochemistry is 18 19 an excellent approach which, over recent years, has been employed successfully. In 20 21 22 order to provide new strategies for future transformations applying flow 23 24 photochemistry, selected examples of continuous photochemical transformation of 25 26 natural products or molecules target synthesis from the last three years are presented in 27 28 this section. 29 30 31 32 33 Photocycloaddition Reaction 34 35 One of the photochemical reactions most widely used for natural product access is [2+2] 36 37 45 38 photocycloaddition, which allows the obtaining cyclobutane rings in a simple way. 39 40 Beeler and co-workers successfully synthesized  and -truxinate by means of a head- 41 42 to-head photodimerization from methyl cinnamate.46 These cyclobutane derivatives and 43 44 45 other related molecules, such as the natural products piperarborenine and incarvillateine, 46 47 exhibit antineuroinflammatory activity and act as selective glucose and lipid 48 49 homeostasis PPARγ, becoming an attractive drug target for therapy of type 2 diabetes 50 51 47,48,49 52 mellitus and dyslipidemia. Using a cone photo-flow reactor they could improve 53 54 the [2+2] photocycloaddition increasing yields in a shorter time. Furthermore, when 55 56 bis(thiourea) was used, an increment in the yield and diasteroselectivity was observed. 57 58 59 This can be attributed to an organo-photocatalysis effect (Scheme 3). 60

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Scheme 3: Synthesis of  and -truxinate and analogues by a photocycloaddition [2+2] 22 23 24 25 26 In the same way, Urriolabeitia, Gomez, Cativiela et al., stereoselectively synthesized - 27 28 50 29 isomers of dimethyl esters of 1,3-diaminotruxillic acid in three steps, one of which 30 31 involves a [2+2] photocycloaddition in flow as a key step. The reaction was carried out 32 33 very efficiently by using a LED light source, obtaining quantitative yields in very short 34 35 reaction times (5-20 minutes). This synthesis has the particularity that in the first step an 36 37 38 ortho-palladation of oxazolone is carried out resulting in the formation of dimeric 39 40 ortho-palladated complexes with visible light absorption. In addition, their rigid 41 42 clamshell structure locates the two C=C bonds in close proximity, favoring their 43 44 45 interaction for the [2+2] photocycloaddition and promoting stereoselectivity in the 46 47 palladated truxillic acid product. Finally, the depalladation was induced with molecular 48 49 hydrogen in methanol, obtaining the cyclobutane ring derivative (Scheme 4). 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Scheme 4. [2+2]-Cycloaddition of ortho-palladated oxazolones. 16 17 18 19 20 Photocycloaddition is a well-established way of accessing strained ring scaffolds, which 21 22 can be starting points for drug discovery. Moreover, using continuous flow technology 23 24 25 it is possible to scale-up the reaction so as to generate enough material to carry out 26 27 sequential steps in a complex synthesis.51 Pursuing these objectives, Booker-Milburn et 28 29 al. described the obtaining of tricyclic aziridines in multigram quantities by flow 30 31 32 photocycloaddition. These strained photochemical products can undergo different ring- 33 34 opening/annulation reactions to access a broad range of fused polyheterocycles. In this 35 36 way, using aziridine as a starting point, they could synthesize the alkaloid (±)-3- 37 38 demethoxyerythratidinone with a 68% yields after a 5-step sequence (Scheme 5).52 This 39 40 41 compound belongs to the Erythrina family of alkaloids, which has important 42 43 pharmacological properties including sedative, hypotensive, CNS depressing, 44 45 neuromuscular blocking and curare-like activities.53 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Scheme 5. Synthesis of the alkaloid (±)-3-demethoxyerythratidinone by [2+2] 4 5 photocycloaddition. 6 7 8 9 10 Following a similar approach, Ralph, Booker-Milburn et al. carried out the synthesis of 11 12 (+)-Goniofufurone, a natural product found in Goniothalamus and also isolated from G. 13 14 15 arvensis trees of the plant family Annonaceae, which exhibits promising antitumoral 16 17 properties.54 Strategically, one step of the synthesis involves a Patern -B chi 2] 18 19 photocycloaddition in flow, which enables a very effective scaling up of the reaction 20 21 55 22 (e.g., 150 g/24 h, 97% isolated yield) in a short time. With multigram quantities of the 23 24 key intermediary, the (+)-Goniofufurone could be obtained after five steps in 11.5% 25 26 overall (Scheme 6). 27 28 29 30 31 32 33 34 35 36 37 38 39 Scheme 6. Application of Paterno-Büchi cycloaddition to access (+)-goniofufurone. 40 41 42 43 44 There are other photocycloaddition processes which are often overlooked but which 45 46 have been successfully implemented in natural product synthesis. One of them is [3+2] 47 48 cycloaddition that can involve an excited-state intramolecular proton transfer (ESIPT) 49 50 51 of an adequate substrate to generate a reactive 1,3-dipole intermediate which can be 52 53 trapped by a dipolarophile. Specifically, Beleer’s research group carried out the 54 55 construction of the aglains to generate tetrahydrocyclopenta[b]benzofuran core of the 56 57 56 58 rocaglates and rocaglamides, using a [3+2] photocycloaddition in flow (Scheme 7). 59 60 The Rocaglates are a complex secondary metabolite isolated from Aglaia genus plants.

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1 2 3 There are family members such as rocaglamide, silvestrol, rocaglaol, which exhibits 4 5 potent cytotoxicity for a number of cancer cell lines.57 With a numbering-up approach, a 6 7 8 multigram scale from ESIPT [3+2] photocycloaddition was developed to successfully 9 10 generate aglain derivatives up to 12g in 10h. Finally, the rocaglate skeleton was 11 12 achieved after subsequent -ketol rearrangement and hydroxyl-directed reduction. 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 Scheme 7. [3+2] photocycloaddition to obtaining rocaglate derívate. 30 31 32 33 Photocyclization Reaction 34 35 36 Photocyclization is another kind of photo-induced reaction used to access heterocyclic 37 38 skeletons of many natural products. Tranmer et al. have developed a continuous flow 39 40 synthesis of substituted-6(5H)-phenanthridinones.58 The phenanthridinones family have 41 42 43 been known to be inhibitor of Poly(ADP-ribose) polymerase (PARP) and are currently 44 58 45 being used in clinical trials as potential cancer therapies. The method involves a two- 46 47 step process where 2-halobenzanilide derivatives are generated from an aniline, 48 49 50 followed by photocyclization to obtain a substituted-6(5H)-phenanthridinone in yields 51 52 of up to 99%. 53 54 55 56 57 58 59 60

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1 2 3 4 5 6 7 8 9 10 11 12 13 Scheme 8. Synthesis of substituted-6(5H)-phenanthridinones by photocyclization. 14 15 16 17 18 Koolman and co-worker carried out the synthesis of vabicaserin analogues by 19 59 20 photocyclization reaction, using a mesoscale and a microfluidic flow photoreactor. 21 22 Vabicaserin is a polycyclic system with a 1,2,3,4-tetrahydroquinoline core, which has 23 24 60 25 been clinically investigated as a 5-HT2C agonist for the treatment of schizophrenia. 26 27 Furthermore, 1,2,3,4-tetrahydroquinoline are the substructure of many biologically 28 29 active compounds and natural products, and as a consequence.61 Using photochemistry, 30 31 Koolman’s group could access 4′-dialkyl or spirocylic-substituted tetrahydroquinoline 32 33 34 as part of a diazepino-annulated heterocycle. Particularly, 4,4′-disubstituted 35 36 tetrahydroquinolines were obtained effectively using a mesoscale tube-based flow 37 38 reactor in acetone as solvent and Pyrex as a filter. The Vabicaserin analogues could be 39 40 41 synthesized in good yields after reduction with borane and subsequent Boc deprotection 42 43 with trifluoroacetic acid. Furthermore, 4-spirosubstituted dihydroquinoline moiety was 44 45 synthesized for the first time by photocyclization reaction in a microfluidic reactor with 46 47 48 a 50% of isolated yield (Scheme 9). 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 Scheme 9. Obtaining vabicaserin analogues through photocyclization reaction. 15 16 17 18 19 Czarnocki and Lisiecki have reported the use of photocyclization as a crucial step in the 20 62 21 total synthesis of (+)-epigalcatin. The galcatin structure is present in many natural 22 23 products with potential biological activity. Podophyllotoxin and semisynthetic 24 25 derivatives are antiviral and cytotoxic compounds of clinical use and additionally are 26 27 63 28 used as anticancer agents. The authors achieved the synthesis starting from 29 30 commercially available and cheap materials including piperonal, 3,4- 31 32 dimethylbenzaldehyde, and diethyl succinate to obtain (+)-epigalcatin in a highly 33 34 35 stereoselective way. Using L-prolinol as chiral auxiliary, an 8-membered ring was 36 37 obtained via macrolactonization, setting the stage for the continuous flow 38 39 photocyclization of the chiral atropisomeric 1,2-bisbenzylidenesuccinate amide ester 40 41 42 with an isolated yield of 65%. By chiral auxiliary removal and subsequent reductions, 43 44 (+)-epigalcatin was achieved with an overall yield of 5% (Scheme 10). 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Scheme 10. Total synthesis of (+)-epigalcatin employing photocyclization as a key 18 19 strategic step. 20 21 22 23 24 Coombs and co-worker have developed a method to generate furan-fused 25 26 cyclopentanones using a flow photochemical approach.64 Particularly, a photo-Nazarov 27 28 reaction was employed as a key strategic step to access the corresponding heterocyclic 29 30 31 motif which is present in the core structures of different alkaloid or flavonoid natural 32 33 products with important biological activity.65 Starting with the 2-furyl or 2-thiophenyl 34 35 enones and using a FEP tubing reactor, photocycloaddition was conducted using acetic 36 37 38 acid (AcOH) or hexafluoroisopropanol (HFIP) as solvent, giving cyclic products in 45- 39 40 97% yields, with exposure times of 3.4−6.8 min (Scheme 11). 41 42 43 44 45 46 47 48 49 50 51 52 53 54 Scheme 11. Easy access to furan-fused cyclopentanones via photo-Nazarov reaction. 55 56 57 58 59 Photoredox Catalysis Reaction 60

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1 2 3 Visible-light photoredox catalysis has emerged as an attractive strategy, as opposed to 4 5 conventional methods to generate radical intermediates in an efficient and sustainable 6 7 66 8 way. Starting with the fact that most organic molecules normally absorb in the UV- 9 10 visible range (254-350 nm), the employment of photoredox catalysts which can be 11 12 excited selectively in the visible-light range allows access to radicals and radical ions 13 14 15 reactive species, by a Single Electron Transfer (SET) pathway, in mild and controlled 16 17 conditions. In the last decade the use of visible-light photoredox catalysis has been 18 19 applied in numerous organic transformations, and even in heterocyclic chemistry,67 and 20 21 68 22 this catalysis has also been successfully applied to obtain known APIs. For this reason, 23 24 it is not a surprising that flow photochemistry has been extended to photoredox catalysis 25 26 in order to improve reaction times, yields and selectivity, as well as productivity. 27 28 Maintaining this approach, Collins and co-workers have extended their photochemical 29 30 31 strategies for the construction of carbazoles to the use of visible-light photoredox and 32 33 flow chemistry. In a previous study, the authors successfully synthesized carprofen 34 35 analogues employing a continuous flow UV-reactor.69 Carprofen is a carbazole-based 36 37 70 38 drug used in the treatment of pain in veterinary science. However, more recently, the 39 40 visible-light-mediated synthesis of carbazoles with a Cu-based sensitizer and the use of 41 42 continuous-flow conditions resulted in an approximately 12-fold decrease in reaction 43 44 71 45 time (Scheme 12a). In an alternative approach to carbazoles, aryl azides were used as 46 47 a photochemical reagent allowing access to more complex heterocycles under UV-LED 48 49 irradiation in a continuous flow reactor.72 Specifically, the anti-inflamatory Carprofen 50 51 could be obtained with a residence time of 4h with a 64% of isolated yield (Scheme 52 53 54 12b). 55 56 57 58 59 60

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 Scheme 12. Synthesis of carbazoles derivatives. a) Using photoredox catalysis with a 15 16 17 Cu-based sensitizer. b) Using aryl azides as photochemical reagent. 18 19 20 21 In another synthetic strategy for building heterocycles, Stephenson and co-workers 22 23 24 reported coupling of tertiary alkyl bromomalonate with electron-rich arenes, such 25 26 asindole, thiopene or pyrrol, via visible-light protoredox catalysis.73 Furthermore, 27 28 quaternary carbon centers were efficiently prepared in high yields and could be scaled 29 30 31 up in a flow photoreactor. Taking into account that substituted malonate esters are key 32 33 intermediates in the biologically active molecule synthesis, and have themselves shown 34 35 antimycrobacterial properties, using this photochemical method it is possible to access 36 37 interesting molecules such as bioactive thiophene malonate derivative, with therapeutic 38 39 40 potential in cardiovascular and neurological diseases. The bioactive thiophene malonate 41 42 derivative is an ion-channel modulating agent and it is known to modulate Ca2+- 43 44 activated K+ channels with subtypes SK/IK/BK (Scheme 13).74 45 46 47 48 49 50 51 52 53 54 55 56 57 58 Scheme 13. Visible light photoredox-mediated coupling of tertiary alkyl 59 60 bromomalonate with electron-rich arenes.

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1 2 3 4 5 Chen and co-workers have implemented a strategy by photoredox catalysis to generate 6 7 75 8 tricyclo-1,4-benzoxazines in continuous flow. Numerous pharmacological compounds 9 10 have benzoxazines as scaffolds in their structure, conferring important bio-activities 11 12 such as antitumor, anti-inflammatory, antihypertensive, neuroprotective as well as 13 14 76 15 antithrombotic. Additionally, the same group has observed a potent anticancer activity 16 17 in tricyclo-1,4-benzoxazine derivatives. Correspondingly, they reported a one-pot 18 19 synthesis of benzoxazines starting with 3-subtituted indoles in the presence of 20 21 22 methylene blue (MB) as a photocatalyst to generate singlet oxygen, followed by a 23 24 rearrangement induced by p-toluenesulfonic acid (TsOH). Using white LEDs light, after 25 26 1h in a continuous flow reactor, a family of 1,4-bezoxazines were obtained in yields 27 28 ranging from 52-99% (scheme 14). 29 30 31 32 33 34 35 36 37 38 39 40 41 42 Scheme 14. Access to benzoxazines derivatives via photoredox catalysis. 43 44 45 46 Jamison and co-workers have used photoredox catalysis in flow for amino acid 47 48 77 49 synthesis, by activation of carbon dioxide. Despite its abundance, availability and 50 51 sustainability, the use of CO2 as a carbon building block is limited by its low reactivity 52 53 and high stability. However, carbon-carbon bond formation could be carried out through 54 55 56 a single-electron reduction of CO2 using para-terphenyl as photoredox catalysts. The 57 58 CO2 radical anion intermediate is coupled with an -amino radical formed by SET and 59 60 subsequent deprotonation. Additionally, the protocol involves a continuous segmented

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1 2 3 photo-flow setup, which is generated with a liquid solution that contains the amine 4 5 substrate and the catalyst mixed with CO gas in line (Scheme 15). 6 2 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Scheme 15. Generation of -amino acid via photoredox catalysis using CO as carbon 23 2 24 25 building block. 26 27 28 29 Bode et al., have reported the synthesis of morpholines, piperazines, thiomorpholines, 30 31 32 diazepanes, and oxazepanes heterocycle derivatives, using photoredox catalysis. This 33 34 protocol involves the use of commercially available SnAP reagents and aldehydes to 35 36 obtain saturated N-heterocycles under continuous flow photocatalysis conditions. The 37 38 39 methodology showed excellent functional group tolerance, allowing the scale-up of N- 40 41 heterocycles in good yield (17-57 % yield) after 9 min (Scheme 16). 42 43 44 45 46 47 48 49 50 51 52 53 54 Scheme 16. Synthesis of Saturated N-heterocycles with SnAP reagent under photoredox 55 56 catalysis in flow. 57 58 59 60

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1 2 3 Miscellaneous Photochemical Reaction 4 5 One of the photochemical reactions widely used in the synthesis of a valuable APIs are 6 7 8 photo-oxygenation reactions, which have great relevance for the pharmaceutical 9 10 industry. In this context, the advance in adoption of continuous processing to carry out 11 12 oxidation has been significant.78 In this sense, Rossen, Poliakoff, George, and co- 13 14 15 worker, carried out a photo-oxygenation reaction to synthesize the Artemisinin 16 17 antimalarial drug.79 Making use of the principles of green chemistry, the authors 18 19 proposed two synthetic strategies with a continuous flow photoreactor. One of them 20 21 22 (Method A) involves the use of liquid CO2 as solvent, toluene as co-solvent and a dual- 23 24 function solid acid/photocatalyst. Commercially available porphyrins straightforward 25 26 onto the sulfonated crosslinked polystyrene ion-exchange resin Amberlyst-15 were 27 28 applied, given a dual function of the Brønsted acidic and photo-catalytic needed to 29 30 1 31 obtain Artemisinin via O2 photo-oxygenation starting from dihydroartemisinic acid 32 33 (Scheme 16). The second one (Method B) involves the use of an aqueous mixture of 34 35 organic solvent, [Ru(bpy) ]2+ as photocatalyst and H SO as acid in a tubular 36 3 2 4 37 38 photoreactor. The mixtures result in a spontaneous crystallization of pure photoproduct 39 40 Artemisinin, while the photocatalyst used plus H2SO4 remains in water phase and could 41 42 be recycled (Scheme 17). 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Scheme 17. Synthesis of Artemisinin carrying out photo-oxygenation reaction. Method 4 5 A: Heterogeneous synthesis using liquid CO as solvent and a dual-function solid 6 2 7 8 acid/photocatalyst. Method B: Homogeneous synthesis using recycled acid and 9 10 photocatalysts. 11 12 13 14 15 Cochran et al. described a photochemical rearrangement of chiral oxaziridines in 16 17 continuous flow to obtain chiral bicyclic lactams (Scheme 18).80 Alternatively to 18 19 Schmidt and Beckmann’s rearrangements, prochiral ketones can be converted to chiral 20 21 22 oxaziridines which undergo a stereoselective photolytic rearrangement to produce the 23 24 chiral lactam. Caprolactams derivatives have been reported as -secretase inhibitors, 25 26 which are involved in Alzheimer’s disease.81 Furthermore, their heterocyclic structure is 27 28 29 present in compounds which show potent angiotensin-converting enzyme (ACE) 30 31 inhibition activity. The authors carried out the photolysis in a continuous flow reactor, 32 33 demonstrating its potential usefulness to perform this type of photochemical reaction on 34 35 36 a larger scale. 37 38 39 40 41 42 43 44 45 46 47 48 49 Scheme 18. Photo-rearrangement of chiral oxaziridines to obtain chiral bicyclic 50 51 lactams. 52 53 54 55 Photo-rearrangements are an interesting strategy for accessing the scaffold structure in a 56 57 58 simple way. This is the cases of photo-Favorskii rearrangement, which involves an 59 60 elimination reaction coupled with a 1,2-carbon migration and subsequent nucleophilic

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1 2 3 attack to obtain carboxylic acid from -substituted ketone. In this context, Baxendale 4 5 6 and co-worker carried out a successful synthesis of ibuprofen under continuous-flow 7 82 8 photochemistry. Ibuprofen (isobutylphenyl propionic acid) is a nonsteroidal anti- 9 10 inflammatory drug widely used to alleviate pain, fever and inflammation. The strategy 11 12 13 is based on the photo-Favorskii rearrangement of the appropriate halopropiophenone (a- 14 15 chloropropiophenone) using a commercially available Vapourtec E-series flow system. 16 17 Evaluating different reaction conditions such as different filters, residence times and 18 19 concentration, after 20 minutes of irradiation it was possible to generate a 75% yield of 20 21 22 ibuprofen (Scheme 19). 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 Scheme 19. Photo-Favorskii rearragenment to access ibuprofen. 41 42 43 44 Monbaliu and co-workers have reported a photochemical radical addition of 45 46 ‑ 47 isopropanol-derived to maleic or fumaric acid to obtain γ butyrolactone scaffolds under 48 49 scalable continuous-flow conditions.83 -Butyrolactones are reported to be building 50 51 blocks for the preparation of biologically relevant molecules, and are present in many 52 53 54 natural products, such as paraconic acids, trisubstituted -butyrolactones which show 55 56 antibiotic and antitumor properties.84 With a simple methodology, this kind of 57 58 59 heterocyclic compound could be synthesized using a lab-scale mesofluidic reactor with 60

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1 2 3 inline NMR spectroscopy, enabling fast optimization of the reaction parameters. Under 4 5 6 optimized conditions, a family of -butyrolactones was obtained on a scale-up 7 -1 8 methodology to 12 g day in a short time, with moderate to high isolated yields (47-76 9 10 %) (Scheme 20). 11 12 13 14

15 16 17 18 19 20 21

22 23 24 Scheme 20. Synthesis of trisubstituted -butyrolactones via photochemical radical 25 26 addition reaction. 27 28 29 30 Interestedly, the group from Monbaliu reported inter- and intramolecular strategies for 31 32 33 the diasteroselective preparation of threo-methylphenidate hydrochloride which 34 35 involves a continuous-flow Rh-catalyzed intermolecular C-H carbene insertion or a 36 37 thermal or photochemical intramolecular C-H carbene insertion. Specifically, in the last 38 39 40 example, the photochemical intramolecular insertion originates β-lactam intermediate, 41 42 which, after methanolysis processing under acidic conditions, forms methylphenidate 43 44 hydrochloride.85 The interest of methylphenidate lies in its pharmacological properties 45 46 47 when acting as a norepinephrine–dopamine reuptake inhibitor, and is widely uses to 48 49 treat attention deficit hyperactivity disorder (ADHD) and narcolepsy. Furthermore, the 50 51 different stereoisomers have different pharmacological profiles. For this reason, the 52 53 54 development of new processes for the stereoselective preparation of methylphenidate 55 56 are very important. In this way, the photochemical decomposition of tosylhydrazone is 57 58 carried out in presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), resulting in 97% 59 60

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1 2 3 of the conversion after 60 minutes of residence time, and with a productivity of 0.3 g h-1 4 5 (Scheme 21) 6 7 8 9 10 11 12 13 14

15 16 Scheme 21. Employing photochemical intramolecular insertion C-H carbene insertion 17 18 19 to obtain methylphenidate. 20 21 22 23 24 Multi-step Continuous-Flow Synthetic Applications involving a 25 26 27 Photochemical Step 28 29 The art of total synthesizing to access complex organic molecules such as natural 30 31 product is defined by the concept of “ideal synthesis”, which should be the focus in 32 33 34 providing large quantities of complex products, minimizing work and materials 35 36 expenses. In this way, the use of multistep flow sequences has allowed to improvement 37 38 of several synthetic applications.86 Besides, numerous single-step photo-flow 39 40 41 transformations have been reported in recent years, dealing with the generation of 42 43 unstable diazo compounds for use in divergent proto-deboronative and oxidative C(sp2)- 44 45 87 C(sp3) cross-coupling processes; such as arylation of cysteine by photoredox 46 47 88 48 catalysis; decarboxylative coupling of amino acids with aryl halides using a dual 49 89 50 catalysis methodology (combination of photoredox and Ni catalysis); preparation of 51 52 organosilanes through hydrosilylation by tetrabutylammonium decatungstate- 53 54 photocatalyzed activation of the Si-H bond.90 55 56 57 In spite of this, only a few examples of synthetic sequences in flow which include at 58 59 least one photochemical step were found in the literature. In this section, multistep 60

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1 2 3 continuous-flow photochemical transformations are surveyed, in order to provide a 4 5 perspective, and hopefully an inspiration for future research, in the quest for the ideal 6 7 8 synthesis. 9 10 The real challenge of multi-step continuous-flow reactions involves the ability to 11 12 combine different reactions, taking into account solvent compatibility, flow-rate 13 14 15 synergy and by-product effects. In this context, Jamison and co-worker have developed 16 17 an interesting three-step-in-one-flow protocol to produce ’-deoxy and 2’,3’- 18 19 dideoxynucleosides (Scheme 22).91 Nucleosides and nucleoside analogs have long been 20 21 92,93 22 an important class of medicinal agents, possessing anticancer and antiviral activity. 23 24 The synthesis protocol involves a sequence of glycosylation, photo-sensitized 25 26 deoxygenation and deprotection reactions. In the first step, ’-m- 27 28 trifluoromethylbenzoate ribose together with 5 mol-% of pyridinium triflate salts as 29 30 31 catalysts and a silylated nucleoside base were introduced into the T-mixer, to carry out 32 33 the Vorbrüggen glycosilation. The 2-O-deoxyribonuleoside obtained was directly mixed 34 35 with the 3,6-dimethoxy-9-ethylcarbazole photosensitizer to bring about the 36 37 38 photoinduced electron transfer deoxygenation reaction. Finally, a solution of NaOH was 39 40 introduced via a T-mixer to the exiting stream from the second step to carry out the 41 42 deprotection reaction. With the continuous multi-step, one-flow sequence the thymidine 43 44 45 and anti-HIV drug edoxudine were successfully synthesized with 72% and 66% yields 46 47 respectively. 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Scheme 22. Synthesis of ’-deoxy and ’,3’-dideoxynucleosides via a sequence of 20 21 22 glycosylation, photo-sensitized deoxygenation and deprotection reactions. 23 24 25 26 Very recently, a review has been published of photochemical Wolff rearrangements and 27 28 94 29 their application in integrated microflow syntheses. In the photo-Wolff rearrangement, 30 31 an -diazocarbonyl compound undergoes rearrangement, obtaining a ketene 32 33 intermediate, which can react with different nucleophiles. In this way, an interesting 34 35 36 application based on an Arndt–Eistert homologation sequence was developed by Kappe 37 38 et al. for the synthesis of -amino acids from the respective protected -amino acids 39 40 (Scheme 23).95 The process involves a fully continuous 4 successive reaction: amino 41 42 43 acid activation by anhydride, acylation of diazomethane, the photo-induced Wolf 44 45 rearrangement, and nucleophilic addition. Without any doubt, one of the challenges of 46 47 Arndt–Eistert homologation is the safe use of diazomethane (CH2N2), which is a very 48 49 50 toxic reagent, highly irritating, a carcinogenic compound, volatile and exceedingly 51 52 sensitive to heat, light, and shock, leading to explosive decomposition. For this reason, 53 54 carrying out the Arndt-Eistert homologation in the continuous-flow sequence has 55 56 allowed solution of the problems associated with the handling of a dangerous reagent 57 58 59 and with photochemistry, such as scalability and over-irradiation. Therefore, for the 60

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1 2 3 activation of -amino acid, a solution of the corresponding amino acid and base (Bu3N) 4 5 6 were mixed in a T-shaped mixer with an anhydride chloride to generate anhydride 7 8 derivatives. Later, the anhydride was combined with CH2N2 which was previously 9 10 formed by treating Diazald (commercially available) with KOH, to finally generate the 11 12 13 α-diazoketone. The remaining diazomethane was removed by introducing the reaction 14 15 solutions into a gas-permeable tube (AF 2400) which was immersed in acetic acid. 16 17 Before performing the photo-induced Wolf rearrangement, the corresponding 18 19 diazoketone was mixed with a solution of H O/THF, and then sent through the 20 2 21 22 photoreactor, obtaining the corresponding -amino acid. 23 24

25 26 27 28 29 30 31 32 33 34 35 Scheme 23. Preparation of -amino acids through four successive reactions: amino acid 36 37 38 activation by anhydride, acylation of diazomethane, photo-induced Wolf rearrangement, 39 40 and nucleophilic addition. 41 42 43 44 45 Beeler et al. developed an efficient photo-deprotection group of amine, and afterwards 46 47 they applied it in a multistep flow synthesis.96 Then 2-methoxy-hydroxymethylxanthene 48 49 was used as protecting group and chromophore, showing an overall stability under a 50 51 52 variety of conditions and compatibility with organic solvent. Particularly, a 53 54 piperazinylcarbonyl-piperidine derivative was synthesized by a three-step-in-one-flow 55 56 protocol, which includes amidation, photo-deprotection and acylation reactions. In the 57 58 first step an activated ester and diisopropylethylamine (DIPEA) were combined with a 59 60

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1 2 3 protected piperazine at a T-junction, and subsequently the reaction mixture was made to 4 5 flow into the photochemical reactor to carry out the photo-deprotection. Finally, a 6 7 8 solution of benzoyl chloride in dicloroethane was introduced to exiting stream from the 9 10 second step to conduct the acylation reaction, obtaining the piperazinylcarbonyl- 11 12 piperidine derivative in a 42% yield with an overall residence time of 55 min (Scheme 13 14 15 24). 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 Scheme 24. Continuous-flow multistep synthesis of piperazinylcarbonyl-piperidine via 35 36 amidation, photo-deprotection and acylation reactions. 37 38 39 40 41 Once again, the synthesis of the natural product artemisinin plays an important role in 42 43 the development of different methods and technologies for industrial-scale production.97 44 45 46 Taking into account that about 1% of artemisinin is extracted from the Artemisia annua 47 48 plant, numerous efforts have been made to implement processes that mimic the 49 50 biosynthetic pathway. For this reason, considering that reagents and catalysts can be 51 52 found in natural sources, the plant waste material has also been used to prepare 53 54 55 artemisinin or another artemisinin-derived APIs, and to carry the desired transformation 56 57 out directly. With these in mind, Seeberger, Gilmore et al. have developed a green 58 59 chemical protocol to synthesize artemisinin which involves the use of 60

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1 2 3 dihydroartemisinic acid (DHAA) as well as chlorophyll (as photosensitizer) contained 4 5 in the plant extract.98 In a two-step-in-one-flow protocol, the crude extract containing 6 7 8 DHAA in presence of trifluoroacetic acid was combined with oxygen in a T-shaped 9 10 mixer and the photoreaction was conducted under visible light irradiation at -20 °C. The 11 12 second reaction line was kept at room temperature and after 10 min of residence time, 13 14 15 the corresponding artemisinin is generated (Scheme 25). 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 Scheme 25. Two-step-in-one-flow protocol to prepare Arthemisinin antimalarial drug. 34 35 36 37 38 The oxidant singlet oxygen is a key reactive intermediate involved in the photo- 39 40 oxidation of natural products. Particularly, primary or secondary amines can be photo- 41 1 42 oxidized by O2 to generate imine intermediate, and if this imine is trapped by cyanide 43 44 45 anion, -amino-nitrile is obtained as final product. Using this synthetic strategy, 46 47 Gilmore et al. built hydantoins heterocycles with a two-step continuous-flow sequence 48 49 of photo-oxidation and carboxylation rearrangement.99 Hydantoin derivatives possess 50 51 52 important biochemical and pharmacological properties such as anti-inflammatory, anti- 53 54 HIV, anticonvulsant, antihypertensive and are used to treat many human diseases. 55 56 Taking into account the relevance of this heterocycle, its synthetic approach in 57 58 continuous-flow chemistry suggests an alternative framed within the principles of green 59 60

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1 2 3 chemistry, carrying out biphasic gas/liquid reactions with an O2 and CO2 source and 4 5 with a highly atom economy, using light as a traceless reagent and an eco-friendly 6 7 8 solvent. After of a residence time of 24 minutes, different benzylic and aliphatic 9 10 unprotected hydantoins were obtained in good yields (Scheme 26). 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 Scheme 26. Two-step continuous-flow sequence to access hydantoins derivatives. 27 28 29 30 31 In the previous section we explained a protocol developed by Collins and co-workers to 32 33 synthesize a family of carzabazole heterocycles (Scheme 12). Currently, the same group 34 35 is extending its strategy to access a more complex carbazole structure using two-step 36 37 100 38 continuous-flow processes. Via photochemical decomposition of azides, a variety of 39 40 carbazoles can be obtained, which are involved in a subsequent transformation to 41 42 generate a family of the alkaloid clausine C, with interesting biological properties such 43 44 45 as antimalarial, antibacterial and anti-HIV. On the one hand, a bromide-substituted 46 47 azide is photo-decomposed under continuous flow process using purple LEDs. 48 49 Subsequent Suzuki cross-coupling with heterogeneous palladium-based catalyst 50 51 52 (SiliaCat) and boronic acids was carried out, obtaining a family of aryl and heteroaryl 53 54 carabazoles with good yield (36-74%) after approximately 4h (Scheme 27, Protocol 1). 55 56 On the other hand, exploiting the bromo functionality of carabazole derivatives, Collins 57 58 et al. carried out a second two-step protocol, attaching a subsequent dual-photocatalyst 59 60

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1 2 3 reaction. For this purpose a Ni-catalysis cross-coupling with bromo-carbazole, 4 5 potassium alkyl trifluoroborates and organic dye 4CzIPN as photoredox-catalyst were 6 7 8 performed. Under blue LEDs irradiation, after 3h approximately, a new carbazole 9 10 derivative was generated (Scheme 27, Protocol 2). 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 Scheme 27. Two-step protocols in continuous flow. Protocol 1: with a Suzuki cross- 36 37 38 coupling step. Protocol 2: with a Nickel/photoredox cross-coupling. 39 40 41 42 Outlook 43 44 45 It is clear that photochemistry has earned an important place in organic synthesis, 46 47 showing its versatility to access complex molecular structures in a simple way. 48 49 Furthermore, considering that its applications have been found to be framed within the 50 51 52 green chemistry and engineering principles, activation with light of different organic 53 54 compounds has emerged as an attractive synthetic tool. In this context, flow chemistry 55 56 has acted as a bridge between the past and the future of organic synthesis. The challenge 57 58 59 to photochemists and engineers was the development of methodologies or processes 60

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1 2 3 relevant for the pharmaceutical industry. The use of flow photochemistry has allowed 4 5 the overcoming of some setbacks, leading to the acquisition of APIs in milder, safer and 6 7 8 more sustainable conditions. Additionally, with the technological advances, 9 10 photochemical reactions have demonstrated that they can successfully be introduced in 11 12 multi-step processes. Today it only remains for us to calculate the best route to drive 13 14 15 total synthesis. For this reason, future challenges will be related to the combination, in 16 17 individual modules, of multi-catalysis methodologies (photocatalysis, enzymatic 18 19 catalysis, organocatalysis and metal catalysis) under continuous flow conditions, to 20 21 22 access chiral compounds with biological interest. Using nature as a source of inspiration 23 24 and applying flow chemistry, scientists should only look at the light on the horizon, 25 26 order their steps, and keep walking. 27 28 29 30 31 Acknowledgements 32 33 34 This work was supported in part by Consejo Nacional de Investigaciones Científicas y 35 36 Técnicas (CONICET), Secretaría de Ciencia y Tecnología (SeCyT), Universidad 37 38 39 Nacional de Córdoba (UNC) and Fondo para la Investigación Científica y Tecnológica 40 41 Argentina (FONCyT). FP gratefully acknowledges receipt of a fellowship from 42 43 CONICET. 44 45 46 47 References 48 49 50 (1) Kärkäs, M. D.; Porco, J. A.; Stephenson, C. R. J. Photochemical Approaches to 51 52 Complex Chemotypes: Applications in Natural Product Synthesis. Chem. Rev. 53 54 2016, 116, 9683-9747. 55 56 57 58 (2) Handbook of Synthetic Photochemistry; Albini, A., Fagnoni, M., Eds.; Wiley- 59 60 VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2009.

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