Flow Synthesis of Heterocycles

CHAPTER TWO

Flow Synthesis of Heterocycles Marine Movsisyana, Matthias M.A. Moensa, Christian V. Stevens* SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Ghent, Belgium *Corresponding author: E-mail: [email protected]

Contents 1. Introduction 2. Current Challenges 2.1 Dealing with Solids 3. Developing Fields 3.1 Catalysis

26 27 27 29 29

3.1.1 Enzymatic Reactions 3.1.2 Heterogeneous Catalysis

29 30

3.2 Photochemistry 3.3 Electrochemistry 3.4 Tube-In-Tube Reactors 4. Telescoping 4.1 In-line Purification 4.1.1 4.1.2 4.1.3 4.1.4

33 34 35 37 40

Solid Phase-Bound Scavenging Protocol Continuous Separation Distillation Crystallization

40 42 45 45

4.2 Online Analysis and Automation 4.3 Lab-On-A-Chip 5. Conclusion References

46 49 52 53

Abstract Continuous microreactor systems have gained a lot of interest in the field of organic synthesis as these possess enhanced mass and heat transfer properties. Microreactor technology also offers a contemporary way of conducting chemical reactions in a more sustainable fashion due to the miniaturization and increased safety, and also in a technically improved manner due to intensified process efficiency. Recent developments in this area related to the synthesis of heterocyclic compounds are recorded in this chapter. Also, telescoping, in which several subsequent reaction steps (with or without purification) can be achieved by connecting different reactors to each other, is covered.

a

Both authors contributed equally to this work.

Advances in Heterocyclic Chemistry, Volume 119 ISSN 0065-2725 http://dx.doi.org/10.1016/bs.aihch.2015.10.006

© 2016 Elsevier Inc. All rights reserved.

25

j

26

Marine Movsisyan et al.

Keywords: Continuous flow; Heterocycles; Microreactor; Sustainable processes; Telescoping

List of Abbreviations BEMP BPR CMAC CuAAC DBU DCA DIPEA DMAP DMF DMPSi DMPU Dppp ee ETFE FLLEX HPLC MFC MTBE LED PAT PCMM PIFA PS PTFE QP-BZA rt RTU Tf TFA THF TPP TTTA

2-tert-Butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2diazaphosphorine Back pressure regulator Continuous manufacturing and crystallization Copper-catalyzed azide-alkyne cycloaddition reaction 1,8-Diazabicycloundec-7-ene 9,10-Dicyanoanthracene Diisopropyl ethyl amine 4-Dimethylaminopyridine N,N-Dimethylformamide Dimethylpolysilane 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone 1,3-Bis(diphenylphosphino)propane Enantiomeric excess Ethylenetetrafluoroethylene Flow liquideliquid extraction module High-performance liquid chromatography Mass flow controller Methyl tert-butyl ether Light-emitting diode Process analytical technology Portable, continuous, miniature, and modular Phenyliodine bis(trifluoroacetate) Polystyrene Polytetrafluoroethylene (Teflon) Quadrapure benzyl amine Room temperature Residence time unit Trifluoromethanesulfonyl Trifluoroacetic acid Tetrahydrofuran Tetraphenylporphyrin Tris-((1-tert-butyl-1H-1,2,3-triazoyl)methyl)amine

1. INTRODUCTION This chapter is an overview of recent advances that continuous flow chemistry can offer for heterocyclic chemistry. Our discussion is however not an exhaustive sampling of all known examples but rather a compilation of various examples to illustrate the principles, features, and advantages of flow chemistry.

Flow Synthesis of Heterocycles

27

In the last two decades, microfluidic-based systems have emerged as relatively low-cost technologies and small-footprint devices. This technology has become an important tool to implement sustainability in chemical transformations (2010CS675). Modern flow chemistry deals with both micro- and mesoscale devices. Advantages associated with these flow systems include facile automation, process intensification, and optimization. Typically, this technology operates on small volumes of reaction mixtures in controlled environments, which greatly enhances safety (2012GC2776, 2014FC118, 2010TL4189). The laminar flow in microreactors, characterized by a low Reynolds number, results in the diffusion-controlled mixing of the reagents at the interface. Furthermore, the rapid and controlled heat and mass transfer, as well as precise parameter control can lead to an increase in throughput and yields and can guarantee process reliability and reproducibility. Another attractive feature of microfluidic technology is the straightforward scale-up that can be achieved with little or no process reoptimization, by the numberingup principle (multiple systems in parallel) or by scaling-out (changing the reactor characteristics) (2010CS675, 2011CC4583).

2. CURRENT CHALLENGES 2.1 Dealing with Solids Solid particles can be seen both as a blessing and a curse. In terms of purification, precipitation and crystallization of the desired product is highly recommended. For practical reasons most flow chemists however try to avoid reactions with solid particles, as microreactors are prone to clogging. The most common strategies to prevent clogging consist of using a larger-bore passage or manipulation of chemical conditions, such as changing the solvent or adjusting the reagent concentration (2015CET259, 2014COC62). The latter, of course, influences the reactivity and will therefore require a time-consuming re-optimization of the reaction parameters. The perfect one-step flow synthesis, as described above, starts from totally dissolved starting materials, which after reaction give rise to a poorly soluble end product that crystallizes from the reaction mixture after the reactor. In this situation high conversion rates can lead to an accumulation of crystalline product at the end of the microreactor, resulting in clogging of the system. Acke and Stevens (2007GC386) circumvented this problem,

28

Marine Movsisyan et al.

in their multicomponent synthesis toward 3,4-diamino-1H-isochromen-1ones 2 from 2-formyl benzoic acid 1 (Scheme 1), by introducing an immiscible perfluorinated solvent (FluorinertÒ FC-70) between the micromixer and the residence time unit (RTU). The immiscible solvent forms an oily layer between the wall of the microreactor channel and the plug (Figure 1). This layer prevents deposition of crystals on the walls of the reactor and allows the reaction to continue without clogging (2007GC386). When precipitation takes places during the mixing stages of the reaction an alternative approach can be applied, as described by Sedelmeier et al. (2010OL3618). During the Nef oxidation process, in which nitroalkane 3 is transformed to the corresponding aldehyde 4, potassium permanganate (KMnO4) was reduced to manganese dioxide (MnO2). The stoichiometric quantities of MnO2 formed depositions in the reactor and caused fouling of the system. To obtain a truly continuous process the T-piece mixer was submerged in an ultrasound bath (Scheme 2). Ultrasonic cavitation is an often applied technique to control the dispersion of crystals (2010AGI899, 2011CS287). Researches of MIT demonstrated that the use of acoustic irradiation reduced the maximum effective particle size and thus prevented bridging in the reactor (2010OP1347). In that sense acoustic irradiation forms a perfect match to control solid formation in flow chemistry and prevent clogging (2013CES352, 2004US47, 2008JAC2481). The ability of operating under higher pressure conditions is one of the main advantages linked to flow chemistry but currently available back pressure regulators (BPR) for lab scale purposes do not tolerate solid particles and are therefore a common blockage point in any system. The group of Ley designed an effective BPR able to cope with thick chemical slurries under high pressure conditions (2015CET259). Their device consist of a collection vessel that can be pressurized based on the tube-in-tube design. This design allows the process stream to be directly collected in the collection chamber,

Scheme 1 Synthesis of 3,4-diamino-1H-ischromen-1-ones.

Flow Synthesis of Heterocycles

29

Figure 1 Left: Plug formation; Right: Adjusted set-up. A ¼ Input reagents, B ¼ Microreactor, C ¼ RTU, D ¼ Output reaction mixture, E ¼ Input FluorinertÒ FC-70. Reproduced by permission of The Royal Society of Chemistry.

Scheme 2 Nef oxidation of nitroalkanes to the corresponding carbonyl compounds.

while via the tube-in-tube membrane a gas feed maintains the pressure in the reactor. Despite the ongoing development of dealing with slurries and suspensions on lab scale, such as the V3 pump1 or the CofloreÒ reactor2, the handling of solid materials in flow chemical processes remains a significant challenge.

3. DEVELOPING FIELDS 3.1 Catalysis 3.1.1 Enzymatic Reactions The enzymatic synthesis of cyanohydrin 6 reported by the group of Rutjes, demonstrates several advantages of flow over batch conditions. Toxic HCN, necessary for the enzyme catalyzed addition to aldehyde 5, was 1 2

http://www.vapourtec.co.uk (accessed June 2, 2015). http://www.amtechuk.com (accessed June 1, 2015).

30

Marine Movsisyan et al.

Scheme 3 Chemoenzymatic transformation of piperonal.

safely generated in situ starting from potassium cyanide (Scheme 3) (2015OBC1634). The optimal contact between two immiscible solvents (MTBE/H2O) in the microreactor set-up resulted in a high initial reaction rate and enantioselectivity, comparable to the batch process in which optimized conditions were only obtained under vigorous stirring (2008CEJS89). In-line work-up of the cyanohydrin 6 was achieved via a membrane-based phase separation, allowing the continuation of the two-step reaction approach toward the protected mandelonitrile 7, while both steps have incompatible reaction conditions (2015OBC1634). 3.1.2 Heterogeneous Catalysis The group of Kirschning reported the use of an inductively heated copper wire inside the microreactor (2010SL2009). This copper wire serves as the heat source of the reactor and at the same time as the catalyst that triggers the 1,3-dipolar cycloaddition reaction. To reduce safety issues, the organic azides were prepared in situ by reaction between alkyl halides and sodium azide (NaN3). In this way the azides reacted immediately with the alkynes 8 giving the 1,2,3-triazole 10 (R ¼ Ph; Scheme 4). In fact benzyl bromides were easily transformed into the corresponding triazoles in excellent yields. A contradiction to the batch process was found for methyl 3-(bromomethyl)-5-nitrobenzoate 9, as no conversion was observed (Scheme 4, Reaction 1). The authors proposed the formation of hotspots due to inductive heating, which resulted in the generation of active catalytic species on the surface or its release into solution. This kind of activation does not occur under conventional heating conditions in batch. Besides the synthesis of various triazoles, the synthetic potential of the copper flow system was further demonstrated by the catalytic decarboxylation of the propargylic acid 11 (Scheme 4, Reaction 2) and the CeO coupling in the synthesis of benzopyranone 14 (Scheme 4, Reaction 3) (2010SL2009).

Flow Synthesis of Heterocycles

31

Scheme 4 Continuous copper catalyzed reactions. aBatch conditions: NaN3, DMF-H2O, 100  C, copper wire, 2 h.

Another interesting copper-catalyzed azide-alkyne cycloaddition reaction (CuAAC) was presented by Bogdan and Sach (2009ASC849). The CuAAC was conducted successfully in a continuous-flow mode using a copper coil as reactor, without any additional Cu source. In this way starting from iodoalkynes 15 a variety of 12- to 31-membered rings 16 could be synthesized in good yields (Scheme 4, Reaction 4) (2011OL4060). The enantioselective synthesis of (R)-rolipram 23 was realized by Tsubogo et al. (2015N329) in a multistep chemical transformation under flow conditions without isolation of any intermediates, using only heterogeneous catalysts (Scheme 5, Figure 2). In a first step the commercially available benzaldehyde 17 and nitromethane 18 reacted to give the corresponding nitroalkene 19. The benzaldehyde 17 and nitromethane 18 were pumped together in a stainless steel

32

Marine Movsisyan et al.

Scheme 5 Flow synthesis of (R)-rolipram.

column reactor, filled with a silica-supported amine (Chromatorex DM1020) and finely crushed anhydrous calcium chloride, yielding the desired nitroalkene 19 in excellent yield (>90%). For the subsequent asymmetric 1,4-addition of dimethyl malonate 20 to nitroalkene 19 a polymersupported calcium column (PS-(S)-pybox-calcium chloride) was used as the fixed catalyst. Under the optimized conditions the desired g-nitro ester 21 was obtained in high yields (84%) and high enantioselectivity (ee 94%). The other enantiomer could also be synthesized, simply by replacing the catalyst with its opposing enantiomer (PS-(R)-pybox-calcium chloride) (2015N329).

Figure 2 Diagram of the series of flow reactors used for the synthesis of rolipram. Reprinted by permission from Macmillan Publishers Ltd: Nature (2015N329), Copyright (2015).

Flow Synthesis of Heterocycles

33

The next step involved the reduction of the nitro group to the corresponding amino group. For this purpose a new heterogeneous catalyst (Pd/DMPSi-C) was developed. The mixed solution (crude nitro-ester) and hydrogen gas were pumped through the column reactor at 100  C. Under these conditions a smooth reduction afforded g-lactam 22 in good yields (74%), without epimerization (ee 94%). The final step in the synthesis deals with the hydrolysis and decarboxylation of the ester moiety. The authors noticed that the desired transformations proceeded in the presence of an acidic catalyst. Combining the silica-supported carboxylic acid (SiCOOH, Chromatorex ACD) column at 120  C with the previously optimized set-up resulted in (S)-rolipram 23 in a good yield (50%, four steps). Direct recrystallization of the crude product afforded chemically and enantiomerically pure product without chromatography. The system was able to run continuously for at least one week, without any changes in yields or enantioselectivity for (S)- and (R)-rolipram (2015N329).

3.2 Photochemistry Compared to conventional batch processes, flow processes are far more effective for photochemical synthesis (2015CSC1648). The construction of a photochemical batch reactor that ensures uniform irradiation is very difficult to achieve, as the light intensity quickly decays with increasing distance from the light source. With a relatively simple set-up a homogeneous irradiation of the entire solution can be achieved in flow, due to the small channel size (100e1000 mm) (2007PA1959, 2011CC4583). The emitted wavelength can be fine-tuned to maximize the absorption of the photosensitizer by applying monochromatic LEDs, which are available in various wavelengths, are highly energy efficient and exhibit a long life time (2013CE5450). The important antimalarial drug artemisinin was synthesized by Lévesque and Seeberger (2012AGI1706) via a photochemical continuous flow process, starting from dihydroartemisinic acid 24 (Scheme 6). The crucial step in this pathway is the in situ photochemical preparation of highly reactive singlet oxygen in the presence of 9,10-dicyanoanthracene (DCA) (2013CE5450) or tetraphenylporphyrin (TPP) (2012AGI1706) as photosensitizer. The loading of oxygen gas to the dihydroartemisinic acid 24 mixture was controlled via a mass flow controller and was connected via an ETFE T-mixer. A Schenck ene reaction between dihydroartemisinic acid 24 and singlet oxygen gave rise to allylic hydroperoxide 25. In the next step a catalytic amount of trifluoroacetic acid (TFA) induced Hock

34

Marine Movsisyan et al.

Scheme 6 Continuous flow synthesis of the antimalarial drug artemisinin.

cleavage of 25 toward the stable enol 26. An excess of (triplet) oxygen in the reaction mixture allowed further oxidation of 26 to generate a new hydroperoxide 27, which after a series of condensation reaction led to the antimalarial drug artemisinin 28. A back pressure regulator (BPR) at the outlet of the system regulated the internal pressure and assisted to increase the oxygen solubility. Further optimization of the reaction conditions showed that conducting the photo oxidation reaction at 20  C minimized the formation of side-products, resulting in an overall yield of 46% (2013CE5450).

3.3 Electrochemistry Extremely fast reactions are uncontrollable under conventional batch conditions or detrimental for the selectivity of the reaction. Microfluidic systems are on the other hand, an excellent alternative for conducting these type of reactions, as highly exothermic reactions can benefit from the efficient heatand mass transfer in microsystems. In that aspect Yoshida (2005CC4509) investigated the electrochemical generation of highly reactive cations. They succeeded in generating and accumulating these cations in the absence of a nucleophile using low temperature electrolysis (“cation pool” method

Flow Synthesis of Heterocycles

35

or in flow: “cation flow” method) (1999JACS9546, 2002CE2650, 2005CC4509). The generation of N-acyliminium ions 30 could be monitored via an FTIR spectrometer (ATR method). The N-acyliminium ions reacted rapidly with a variety of dienophiles to give the [4þ2] cycloaddition product. For example, the reaction of Nacyliminium ion 30 and styrene 31 gave the corresponding cycloadduct 32 in 79% yield together with a polymer side-product (ca. 20%) (Scheme 7). In the batch approach where the cation is added to a solution of styrene, an overall yield of only 20% could be obtained, while for the reverse addition the yield was limited to 57%. Fast and efficient mixing by introducing a micromixer into the system, could be a possible explanation for the higher product selectivity obtained within a continuous flow reactor (2005CC4509).

3.4 Tube-In-Tube Reactors Reactive gases are valuable reagents in chemical transformations, as they can be easily removed from the reaction mixture by venting excess gas from the reaction vessel. High pressure reactions, on the other hand, require expensive specialized equipment as well as additional safety precautions when dealing with toxic, flammable, or corrosive gases. To overcome these hazards, the group of Ley developed a continuous flow gaseliquid reactor. In their design a microporous gas permeable membrane (Teflon AF-2400) was introduced in a larger diameter tubing, where the gas can be either in the inner or outer tube. In this manner the transport of a wide range of gases was possible with significant control of the stoichiometry in a given reaction mixture (2015ACR349). Ammonia gas (NH3) is such a toxic, corrosive gas that can be used under more safe conditions in a continuous flow process. Although ammonia solutions are commercially available, only a limited range of solvents are

Scheme 7 Schematic overview of a microfluidic system for a [4þ2] cycloaddition.

36

Marine Movsisyan et al.

accessible and the concentrations of these solutions can alter due to the volatility of ammonia. Additionally, when higher temperatures are applied, special requirements are necessary to prevent the release of ammonia gas. Cranwell et al. (2012OBC5774) reported the synthesis of pyrroles via the PaaleKnorr reaction of 1,4-diketones 33 with gaseous ammonia (Scheme 8). After diffusion of ammonia through the semipermeable membrane into the reaction mixture, the flow stream passed through an additional reactor at 110  C before passing the BPR (6 bar) at the outlet of the flow system. The compression afforded by the BPR ensured that the gas remained in solution. This approach allowed the safe handling of gaseous ammonia for the synthesis of pyrroles 34 in high yields (33e100%) (2012OBC5774). The abilities of the tube-in-tube design was further expanded by Buba et al. (2013EJOC4509). For the synthesis of the oxazolidinone 36, formaldehyde was used in the gaseous state by heating paraformaldehyde to 80  C. The tube-in-tube reactor needs to be kept at a temperature higher than 80  C to prevent polymerization and subsequent precipitation of paraformaldehyde onto the membrane surface. Formaldehyde reacted with Fmoc-protected alanine 35 in the presence of a catalytic amount of p-toluenesulfonic acid in acetonitrile to achieve N-Fmoc-L-4-methyl-oxazolidin5-one 36 in excellent yield (91%; Scheme 9) (2013EJOC4509). However, the tube-in-tube reactor is not only used for gaseliquid reactions. The group of Kappe used the gas-permeable membrane to prepare the highly toxic and explosive diazomethane (CH2N2) in a safe manner. The diazomethane was formed from N-methyl-N-nitroso-p-toluenesulfonamide (Diazald) and KOH in the inner channel of the microreactor and subsequently diffused through the hydrophobic membrane where it formed the desired products 38, 40, and 42 in the outer chamber. The potential

Scheme 8 Continuous PaaleKnorr pyrrole synthesis.

Flow Synthesis of Heterocycles

37

Scheme 9 Flow tube-in-tube reactor used for the synthesis of oxazolidinones.

Scheme 10 Continuous in situ generation and reaction of diazomethane.

of this method was demonstrated by the methylation of various nucleophiles, a [2þ3] cycloaddition reaction and the cyclopropanation of alkenes (Scheme 10) (2013OL5590).

4. TELESCOPING Multi-step synthesis of complex organic chemicals is today still one of the biggest challenges in organic chemistry. Traditionally, complex molecules are synthesized discontinuously by iterative step-by-step transformation of commercially available starting materials and consist of 6e10

38

Marine Movsisyan et al.

chemical steps. Under batch conditions, the isolation and purification of intermediates is often necessary to avoid undesired reactions in the subsequent synthetic steps. Despite the significant accomplishments, this approach remains to be time-, labor- and resource-consuming. Flow chemistry and continuous processing have nowadays become an important tool for streamlining multi-step syntheses, i.e., telescoping of multi-step reactions. In this approach, different synthetic steps are combined sequentially into a oneflow continuous reactor network. Starting compounds and reagents are pumped uninterruptedly into a series of reactors and the desired product is obtained at the output. Telescoping of multi-step syntheses hence allows the production of complex molecules without the need to isolate intermediate products and can also be beneficial when highly reactive and unstable intermediates are produced (2015N302, 2010CS675, 2011CC4583, 2012ASC17). Integration of multiple subsequent steps to obtain a multi-step flow synthesis appears to be a straightforward extension of the existing flow technology, but various challenges still have to be solved. Challenges such as the number of reaction steps, flow rate control, pressure control, solvent compatibility, dilution effects, and intermediate purification have to be considered when designing an integrated microfluidic network. Initially, researchers need to optimize flow rates, residence time, reaction temperature, and pressure for each flow reactor. Furthermore, the optimization of concentrations, homogeneity, and the choice of reagents per reaction compartment is not enough to establish the desired one-flow synthesis. In an integrated flow process, the conditions of the subsequent reactions have to be taken into account when optimizing a reaction step. Telescoping of multiple subsequent steps will hence proceed smoothly under similar conditions regarding flow rate and solvent (2015OBC1634, 2012ASC17). A pioneering work on the multi-step flow chemistry is the continuous synthesis of ibuprofen, a high-volume, nonsteroidal anti-inflammatory drug. The assembly of the three-step synthesis into one continuous system was envisioned. The researchers first optimized the three reactions separately and then assembled the three steps into a single continuous system. The synthesis of ibuprofen was however seen as an entity, instead of a series of independent reactions. In the design of each reaction, it was taken into account that the synthesized byproducts and excess reagents would not interfere in the subsequent reactions, which eventually eliminated the need for purification and isolation steps. The FriedeleCrafts acylation,

Flow Synthesis of Heterocycles

39

1,2-aryl migration, and hydrolysis were hence performed in an uninterrupted continuous fashion (Scheme 11). Starting from isobutylbenzene 43 within 10 min, a racemic mixture of ibuprofen 46 was obtained in 68% crude yield and 51% isolated yield after off-line acidic work-up and recrystallization. This telescoped process would be rather difficult to perform in batch due to safety issues. The high surface area and efficient heat exchange of the microfluidic system made the rapid change in temperature (150e50  C) and in pH (1e14; exothermic) possible. This procedure also allows an on-demand production of active pharmaceutical ingredients and opens further opportunities in the pharmaceutical industry (2009AGI8547). Recently, Kim et al. (2015AGI1877) reported a three-step integrated microfluidic library synthesis of multifunctionalized and biologically active thioquinazolinones (Scheme 12). The reaction consisted of a Li-halogen exchange of o-bromophenyl isothiocyanate 47, subsequently followed by a two-step reaction with different electrophiles (48, 50) at room temperature. A microfluidic stainless steel network comprising of three T-shaped micromixers (M1, M2, and M3) and three microtube reactors (R1, R2, and R3) were used. The research group succeeded in synthesizing various thioquinazolinone derivatives 52 within 10 s at room temperature in isolated yields between 75% and 98%. The three-step synthesis was performed in THF, which allowed the reactions to be conducted without intermediate work-up or solvent switch. The desired compounds were readily obtained by a simple separation by recrystallization. Furthermore, the gram-scale synthesis of a thioquinazolinone in high productivity was demonstrated in the microfluidic device. On a daily basis, it was possible to produce 360 g of the multifunctionalized (S)-benzyl thioquinazolinone (2015AGI1877).

Scheme 11 Three-step synthesis of ibuprofen.

40

Marine Movsisyan et al.

Scheme 12 Integrated three-step synthesis of a library of multifunctionalized and biologically active thioquinazolines.

4.1 In-line Purification Telescoping multi-step reactions is not without limitations. Often the issues of solvent compatibility and intermediate work-up need to be addressed to avoid product isolation and other purification operations at intermediate stages. Over the last few years, various techniques have been developed to circumvent the additional challenges and thus made it possible to integrate continuous downstream processes with flow synthesis. Every additional step in a continuous process will however result in a more complex network. The utility of the increasingly popular flow technology can hence be expanded by the combination of in-line work-ups and subsequent phase separation with multi-step flow sequences (2010CS675, 2012ASC17). 4.1.1 Solid Phase-Bound Scavenging Protocol Solid-supported scavengers, or catch and release agents, are probably one of the most thoroughly explored methods and are used to quench and/ or scavenge excess reagents and side-products. The group of Ley is a pioneer in the use of flow chemistry combined with solid-supported catalysts, reagents, and scavengers (2011MD613, 2006SL427, 2009AGI4017, 2002NR573, 2010CE12342). One of the earliest examples of multi-step flow synthesis was disclosed by this group. The complex alkaloid natural

Flow Synthesis of Heterocycles

41

product ()-oxomaritidine 58 was synthesized in seven synthetic steps in a continuous operation network in a yield slightly higher than 40% (Scheme 13). The synthesis relied on various columns packed with immobilized reagents, catalysts, and scavengers in series, providing a one-flow-through process. In the first step, a commercially available benzyl bromide 53 was passed through a column packed with a solid-supported azide exchange resin and yielded the corresponding azide in a quantitative yield. The output stream is coupled with a column containing a polymersupported phosphine to yield the corresponding aza-Wittig intermediate which remains trapped on the supported material. Simultaneously and in parallel, an aldehyde was prepared by oxidation of a benzyl alcohol 54 with a prepacked column. This aldehyde was passed through the column containing the immobilized aza-Wittig intermediate, furnishing the desired imine 55 in a solution of THF. This step is actually a catch and release technique where the trapped phosphinimine is released by the aldehyde. In the next step, catalytic hydrogenation in the commercially available H-cube hydrogenator gave the corresponding amine 56. Due to downstream incompatibility of the following reactions in THF as solvent, a manual solvent-switch to dichloromethane was performed using a Vapourtec solvent evaporator. After this solvent-switch procedure, trifluoroacylation of the secondary amine 56 with trifluoroacetic anhydride 57 was performed in a T-shaped microreactor chip at an elevated pressure, followed by continuous removal of excess trifluoroacetic anhydride by a scavenging protocol (with a silica-supported amine). The reaction stream was then directed to a column containing a polymer-supported hypervalent iodine reagent (PS-PIFA) to effect the oxidative phenolic coupling to a seven-membered tricyclic intermediate. In a final deprotection step with a solid-phase bound base, cleavage of the amide bond was promoted, followed by the spontaneous 1,4-conjugate addition which afforded the target product ()-oxomaritidine 58 in more than 40% yield and in above 90% purity. Almost all steps proceeded quantitatively, except for the phenolic oxidation with a yield of 50%. This illustrates again the potential of multi-step processes. The advantages achieved are both cost and efficiency-related. No traditional work-up or purification was required, along with the rapid optimization possibilities and a reduction in manual handling makes this procedure quite efficient. Furthermore, the target compound could be produced in an automated sequence in less than a day, while using traditional methods it would require four days of laboratory manipulation (2006CC2566).

42

Marine Movsisyan et al.

Scheme 13 Microfluidic multi-step synthesis of ()-oxomaritidine with integrated solid-supported scavengers.

4.1.2 Continuous Separation A second approach to in-line purification is the use of liquideliquid extractor modules, providing an operational link between reaction and work-up apparatus comparable to batch chemistry. Traditional continuous extraction is based on the differences in density of two liquid phases. However, phase separation at micro-scale driven by density differences is difficult to accomplish. An alternative driving force appears to be the interfacial surface-tension, as these effects dominate gravitational forces at the micro-scale. The laminar flow characteristics of microfluidic devices can hence be used to realize the extraction of two fluids (2007LC256, 2007AGI5704). Different separation techniques have been reported in the literature, including membrane-based liquideliquid separators (2013IE10802, 2007AGI878, 2007LC256, 2010CE6678). The separation of two fluids is achieved by their wetting properties on the membrane surface. This technique relies on accurately controlling the pressure across the porous membrane so that the wetting phase can flow through the membrane pores while the non-wetting liquid is repelled (2015OBC207). Gl€ ockner et al. (2015OBC207) have reported the rapid synthesis of a range of oxazolines 60 under flow conditions using an in-line separator

Flow Synthesis of Heterocycles

43

Scheme 14 Flow synthesis of a range of oxazolines with an in-line separator.

(Scheme 14). More specifically, a commercially available liquideliquid membrane module (Zaiput) was used.3 This device allowed an efficient separation of the aqueous and organic phase and the desired oxazolines 60 were obtained in good to excellent yields (60e98%) and in high purity. The Zaiput separator has also been used to perform a solvent switch by Hamlin et al. (2014OP1253). The in-line extraction was performed to remove the water-soluble salts and to swap the solvent by partitioning THF into the aqueous phase and adding hexane as solvent (2014OP1253). An alternative commercially available extraction device is the Flow LiquideLiquid Extraction module (FLLEX) developed by Syrris.4 Delville et al. (2015OBC1634) have used this type of separator to describe an aqueous chemo-enzymatic reaction directly combined with an organic phase protection step for the formation of cyanohydrins in good yields (20e64%) and high to excellent enantioselectivity (ee 62e98%). The group of Jensen has designed microseparators to perform liquide liquid extraction and to separate liquid and gas phases. Both self-assembled microfluidic extraction systems were used in continuous multi-step syntheses of carbamates 62 from acid chlorides 61 without isolation and storage of the intermediate azides and isocyanates (Scheme 15) (2007AGI5704). A more scalable continuous synthesis of ibuprofen 46 was developed by Snead et al. (2015AGI983), which was previously described by the McQuade group (vide supra) (2009AGI8547). A five-stage process was assembled to increase the throughput and to improve the synthesis of ibuprofen in terms of shorter residence time, use of less solvent, minimize

3 4

http://www.zaiput.com/(accessed May 5, 2015). http://www.syrris.com/(accessed May 6, 2015).

44

Marine Movsisyan et al.

Scheme 15 Continuous multi-step synthesis of carbamates with two self-assembled inline extraction devices.

cost and waste. The on-demand production of ibuprofen was performed by three chemical transformations, a work-up and an in-line liquideliquid separation step (Scheme 16). In a total of 3 min, the three chemical steps were conducted with an average yield of above 90% per step. After the Friedele Crafts acylation, an in-line quench of the Lewis acid with HCl was performed to avoid reactor clogging of the aluminum reagent with the subsequent reagents. Subsequently an in-line liquideliquid separation device was integrated into the system to separate the aryl ketone 64 from the aluminum-containing aqueous fraction. Pressurization of this operation was necessary to avoid high volumes of gases (HCl and vaporization of water), which could disrupt membrane separation and thus a smooth separation of the aqueous and organic phases was achieved. In the second chemical transformation step, iodine monochloride was used as promoter of the 1,2-aryl migration leading to the methyl ester 65. The reagent solution for the ICl quench and ester hydrolysis were then mixed with the reaction mixture and within 1 min the synthesis of the sodium-salt of ibuprofen 66 was complete. The continuous synthesis of ibuprofen developed by the

Scheme 16 Five-step synthesis of ibuprofen.

Flow Synthesis of Heterocycles

45

group of McQuade was hence extended and adjusted to develop a more efficient multi-step synthesis (2015AGI983). 4.1.3 Distillation Distillation is another important method for the separation of liquid mixtures to allow both purification and solvent change. The group of Jensen developed an in-line microfluidic distillation device, which was integrated in a multi-step chemical synthesis to exchange reaction solvents. A twostep synthesis for the Heck reaction was performed continuously by using both a liquideliquid extraction unit and an integrated micro-distillation device (Scheme 17). The synthesis starts with the activation of the phenol 67, followed by an in-line membrane-based extraction to remove the aqueous phase and thus any water-soluble components. The purified triflate was further combined with a stream of pure DMF (or toluene) and N2 and the mixture was entered into a micro-distillation unit heated to 70  C which allowed the volatile CH2Cl2 to be evaporated and was carried out of the reactor with a stream of N2. The gaseliquid segmented flow was additionally separated by the difference in surface tensions of the two phases. The micro-distillation device consisted of an integrated gastight PTFE membrane that allowed selective flow of the liquid phase. This solvent switch was necessary to achieve good yields in the subsequent reaction. Hence, a Pd-catalyzed reaction was carried out to form the Heck product 68 in good yields (77%) (2009LC1843, 2010AGI899). 4.1.4 Crystallization Crystallization is a very important unit operation in the pharmaceutical industry. The handling of solids in a continuous manner have however presented greater challenges than the previously discussed downstream

Scheme 17 Two-step synthesis for the Heck reaction with in-line extraction and distillation units.

46

Marine Movsisyan et al.

processes. Various methods for controlled crystallization in continuous systems have been developed, but have not yet been used as an intermediate work-up in an entire continuous multi-step process (2010CGD2219, 2011CGD4392, 2009OP1357, 2013GC1456, 2012CGD3036, 2012CGD5701, 2012OP915, 2007IE8229). The Center for Innovative Manufacturing in Continuous Manufacturing and Crystallization (CMAC) supported by industrial companies such as GlaxoSmithKline, Novartis, and AstraZeneca is focused on the development of continuous manufacturing technologies for crystallization at all stages.5 This group is also interested in the development of tools to achieve precise control of the crystal structure, particle size and shape, and purity of the crystallized chemical products (2015PT38). The direct crystallization of active pharmaceutical ingredients on polymer excipient surfaces and the integration of crystallization in a continuous manufacturing pilot plant has also been investigated by the Novartis-MIT Center for Continuous Manufacturing (2015PT38).

4.2 Online Analysis and Automation The vast number of chemical reactions performed in microreactors show their significance as innovative production units and as promising tools for reaction and kinetic studies. For the development of continuous systems on small, pilot, or industrial scale, real-time monitoring of parameters (such as temperature, pressure, and concentration) or discrete variables (such as catalyst, ligand, and solvent choices) are essential to facilitate optimization, quality control, and to ensure reproducibility. Integration of analytic tools for online process monitoring hence opens new ways for a more reliable optimization of process parameters and yield and further gives the opportunity to perform reaction and kinetic studies (2006CC2566, 2014LC3206, 2011AGI7502, 2012IE14583). Infrared spectroscopy has been found to be one of the most convenient methods for real-time in-line analytical monitoring. The ReactIR flow cell was developed to investigate and solve issues concerning the optimization and control of continuous processing. Depending on the goal of the monitoring, the IR flow cell could be attached in-line at any point in the continuous system. Carter et al. used various common flow chemistry experiments and coupled them to a ReactIR instrument with the goal to overcome 5

http://www.cmac.ac.uk/(accessed May 22, 2015).

Flow Synthesis of Heterocycles

47

different challenges. The formation of oxazole 71 from an isocyanide 70 and acid chloride 69 was, for example, performed and monitored by the IR flow cell (Scheme 18). Ethyl isocyanoacetate 70 and 3-nitrobenzoyl chloride 69 were combined in a glass reactor chip to form the intermediate addition adduct. The reaction mixture was subsequently flowed through a packed cartridge of base (PS-BEMP) to facilitate the base-catalyzed intramolecular cyclization. Afterward, surplus acid chloride was removed by a scavenging system (QP-BZA), which resulted in the completion of the reaction. Monitoring of the product output was possible by the detection of the ester carbonyl bands versus that of the original isocyanide. The results also showed the effectiveness of the scavenging resin to remove the excess of acid chloride (2006OL5231, 2010OP393). The group of Ley employed a sequence of flow-based microreactors with integrated solid-supported reagents and an in-line ReactIR flow cell to design, optimize, and develop a continuous flow synthesis of a heterocyclic benzamide 74 (Scheme 19). N,N-Diethyl-4-(3-fluorophenylpiperdin4-ylidenemethyl)benzamide 74 was hence synthesized from the ester 72 and 1-Boc-4-piperidone 73. The in-line IR device was used to detect the desired signal and hence to synchronize pumping of a late input stream to match with the reactive components (2010SL505). Another automated process developed by the Ley group deals with the continuous synthesis of imatinib, the active ingredient of gleevec (Scheme 20). The synthesis sequence starts with a catch and release protocol, in which an acid chloride 75 is trapped on a DMAP-immobilized cartridge, followed by pumping a stream of amine 76 that resulted in the release of the corresponding amide. A subsequent basic column is present to scavenge any remaining acid chloride and the reaction mixture is then collected in a vial containing 1-methylpiperazine 77 at 50  C, which facilitates the evaporation of CH2Cl2 and thus a switch to DMF as solvent. Because in the next step a different concentration of the amide is required, an in-line UV

Scheme 18 Flow synthesis of oxazoles, monitored by the ReactIR flow cell.

48

Marine Movsisyan et al.

Scheme 19 Flow synthesis of N,N-Diethyl-4-(3-fluorophenylpiperdin-4-ylidenemethyl) benzamide with solid-supported reagents and in-line ReactIR flow cell.

spectrometer is used to monitor the formation of the amide. Once a particular amount of amide is obtained, this solution is collected and pumped by an autosampler through an immobilized base to induce a nucleophilic substitution with the piperazine, followed by an in-line scavenge of the latter. A catch and release technique with a solid-supported sulphonic acid is further used. The immobilized acid is used to catch the amine through protonation, while unreacted amide goes to the waste. In the following step, DBU is used to release the amine 78 by deprotonation. Subsequently the addition of a 2aminopyrimidine 79 and a palladium catalyst furnished the Buchwalde Hartwig cross-coupling, giving the crude product. Integrated silica gel chromatography is performed to further purify the desired compound and give imatinib 80 in 32% yield and above 95% purity (2013OBC1822, 2013GC1456). Microreactors have also been combined with fluorescence, Raman, X-ray, and NMR spectroscopy. A review published by Yue et al. (2012IE14583) provides an overview of the spectroscopic detection techniques, such as fluorescence, UVevis, IR, Raman, X-ray, and NMR

Flow Synthesis of Heterocycles

49

Scheme 20 Multi-step synthesis of imatinib with in-line scavengers and reagent an in-line UV-monitoring.

spectroscopy, in combination with microreactors for online reaction monitoring as well as catalyst characterization.

4.3 Lab-On-A-Chip The ultimate objective of miniaturization would be to integrate all aspects of laboratory processes into a single location or device; so-called micro-totalanalysis or lab-on-a-chip systems, in which for example synthesis, separation, detection, and data-analysis can be performed. The potential advantages of integrated continuous manufacturing are the typical benefits of miniaturization including reduced reagent consumption, improved portability, and safety. Furthermore, the potential for high-throughput screening, accelerated speed of reaction, and analysis are important features of integrated systems (2006AGI2463, 2006N705, 2013CR2550). Compared to the conventional batch facilities, lab-on-a-chip systems require smaller and cheaper infrastructure which makes it possible to ship the equipment to other manufacturing facilities. The development of portable, continuous, miniature, and modular (PCMM) manufacturing processes hence opens a wide

50

Marine Movsisyan et al.

variety of opportunities for flow technology in the synthesis of pharmaceuticals (2015N302). Belder et al. (2006AGI2463) have developed a microfluidic chip for integrated chemical reaction and analysis combined on a single device (Figure 3). This set-up was used to test the enantioselectivity of fungal enzyme mutants. The substrate, glycidyl phenyl ether 81, and various mutant epoxide hydrolase catalysts were mixed and reacted in the meandering channels of the microfluidic device (Scheme 21). The reaction products 82/83 were isolated from the remaining substrate via electrophoretic separation in the separation channel and the proportions of the respective enantiomers were monitored by fluorescence detection, using a deep UV-laser. This system proved to be successful for testing the enantioselectivity of enzyme mutants from Aspergillus niger (2006AGI2463, 2006N705). Another important paper on this topic was published by Wang et al. (2009LC2281) for the synthesis and screening of 1024 reactions. A microfluidic platform was assembled to perform and screen in situ click chemistry reaction between 8 acetylenes and 16 azides. The computer-controlled system consisted of a solid-phase extraction procedure for purification and electrospray ionization mass spectrometry (Figure 4). The integrated platform hence enhanced the sensitivity for hit identification and throughput of the downstream analysis, resulting in reduced reagent consumption and screening time. The first example of an end-to-end integrated continuous manufacturing plant for a pharmaceutical drug was reported by the Trout group. The target active pharmaceutical ingredient, aliskiren hemifumarate,

Figure 3 Schematic overview of the integrated catalysis and analysis chip. Reprinted by permission from Macmillan Publishers Ltd: Nature (2006N705), Copyright (2006).

51

Flow Synthesis of Heterocycles

Scheme 21 Testing the enantioselectivity of fungal enzyme mutants.

(a)

(b)

(c)

Figure 4 (a) An integrated microfluidic platform for in situ click chemistry, controlled by computer software using color-coded pressure-driven valves: Red (dark gray in print versions)dpositive pressure, off/on; Yellow (light gray in print versions)dperistaltic pumping; Green (gray in print versions)dvacuum. (b) Imagine of the actual device, where the various channels are loaded with different dyes. (c) PTFE tubing for offchip incubation and storage of the reaction products. Red (dark gray in print versions) and blue (black in print versions) dyes are used for visualization. Black scale bars are 3 mm. Reproduced from 2009LC2281 with permission of The Royal Society of Chemistry.

was obtained through multi-step synthesis including separations, crystallizations, drying, and formulation, resulting in a final tablet that met the specifications for drug-product quality (Figure 5). The continuous crystallization was done in a single integrated extrusion and molding device, which made it possible to avoid several solid-handling steps such as mixing and granulation. The number of unit operations were hence reduced from 21 for the batch process to 14 for the flow process, resulting in shorter production times. The

52

Marine Movsisyan et al.

Figure 5 Schematic overview of the ICM process for the production of tablets containing aliskiren hemifumarate. Automated control loops and PAT devices are indicated in green (light gray in print versions). P, pump; TC, temperature controller; CT, concentration transmitter; FT, flow transmitter; RC, ratio controller; S, separation; Cr, crystallization vessel; LC, level controller; PT, pressure transmitter; W, filter/wash; D, dilution tank; DC, density controller; CC, concentration controller; FC, flow controller; E, extruder; MD, mold; sp, control set point. Reprinted with permission from 2014CGD2148. Copyright (2014) American Chemical Society.

researchers further investigated the performance of the crystallization step operated for an extended period of time within the integrated continuous manufacturing. The determination of the process analytical technology (PAT) tools and the design of the automated control strategy appears to be vital for integrated continuous manufacturing of pharmaceuticals. Trout and co-workers succeeded in performing the continuous crystallization for more than 100 h in the integrated process, furnishing the drug in 91.4% yield and with a purity over 99% (2014OP402, 2013AGI12359, 2014CGD2148).

5. CONCLUSION Since microreactor technology was first seen as an effective method for the synthesis of chemical compounds, enormous advances have been made in this area. The examples discussed in this chapter and many other illustrations in the literature, prove the potential of flow chemistry in chemical and pharmaceutical production and confirm the expected benefits and the intensification of chemical processes. The above-mentioned flow processes furthermore illustrate the flexibility of microfluidic devices, as flow chemistry allows the linking of individual reactions into multi-step reactions as well as preparing a series of analogues by simple modifications. A variety of technical approaches can additionally be considered for the implementation of flow processes, such as the automated and real-time in-line analysis and

Flow Synthesis of Heterocycles

53

in-line purification devices, which facilitate rapid optimization and ensure reproducibility. Despite much progress, flow chemistry is a relatively new area of research and thus a number of hurdles still have to be overcome. The advantageous possibilities associated with this technology, however, make it an intensively researched topic and an exponential increase in published work is expected in the near future.

REFERENCES 1999JACS9546 J.-I. Yoshida, S. Suga, S. Suzuki, N. Kinomura, A. Yamamoto, and K. Fujiwara, J. Am. Chem. Soc., 121, 9546e9549 (1999). 2002CE2650 J.-I. Yoshida and S. Suga, Chem. Eur. J., 8, 2650e2658 (2002). 2002NR573 S.V. Ley and I.R. Baxendale, Nat. Rev. Drug Discovery, 1, 573e586 (2002). 2004US47 A. Gedanken, Ultrason. Sonochem., 11, 47e55 (2004). 2005CC4509 J. Yoshida, Chem. Commun., 4509e4516 (2005). 2006AGI2463 D. Belder, M. Ludwig, L.-W. Wang, and M.T. Reetz, Angew. Chem. Int. Ed., 45, 2463e2466 (2006). 2006CC2566 I.R. Baxendale, J. Deeley, C.M. Griffiths-Jones, S.V. Ley, S. Saaby, and G.K. Tranmer, Chem. Commun., 24, 2566e2568 (2006). 2006N705 S.J. Haswell, Nature, 441, 705 (2006). 2006OL5231 M. Baumann, I.R. Baxendale, S.V. Ley, C.D. Smith, and G.K. Tranmer, Org. Lett., 8, 5231e5234 (2006). 2006SL427 I.R. Baxendale, C.M. Griffiths-Jones, S.V. Ley, and G.K. Tranmer, Synlett, 2006, 427e430 (2006). 2007AGI878 A. Aota, M. Nonaka, A. Hibara, and T. Kitamori, Angew. Chem. Int. Ed., 46, 878e880 (2007). 2007AGI5704 H.R. Sahoo, J.G. Kralj, and K.F. Jensen, Angew. Chem. Int. Ed., 46, 5704e5708 (2007). 2007GC386 D.R.J. Acke and C.V. Stevens, Green Chem., 9, 386e390 (2007). 2007IE8229 H. Zhao, J.-X. Wang, Q.-A. Wang, J.-F. Chen, and J. Yun, Ind. Eng. Chem. Res., 46, 8229e8235 (2007). 2007LC256 J.G. Kralj, H.R. Sahoo, and K.F. Jensen, Lab Chip, 7, 256e263 (2007). 2007PA1959 Y. Matsushita, T. Ichimura, N. Ohba, S. Kumada, K. Sakeda, T. Suzuki, H. Tanibata, and T. Murata, Pure Appl. Chem., 79, 1959e1968 (2007). 2008CEJS89 K. Koch, R.J.F. van den Berg, P.J. Nieuwland, R. Wijtmans, M.G. Wubbolts, H.E. Schoemaker, F.P.J.T. Rutjes, and J.C.M. van Hest, Chem. Eng. J., 135(Supplement 1), S89eS92 (2008). 2008JAC2481 K. Sato, J.-G. Li, H. Kamiya, and T. Ishigaki, J. Am. Ceram. Soc., 91, 2481e2487 (2008). 2009AGI4017 I.R. Baxendale, S.V. Ley, A.C. Mansfield, and C.D. Smith, Angew. Chem. Int. Ed., 48, 4017e4021 (2009). 2009AGI8547 A.R. Bogdan, S.L. Poe, D.C. Kubis, S.J. Broadwater, and D.T. McQuade, Angew. Chem. Int. Ed., 48, 8547e8550 (2009). 2009ASC849 A.R. Bogdan and N.W. Sach, Adv. Synth. Catal., 351, 849e854 (2009). 2009LC1843 R.L. Hartman, H.R. Sahoo, B.C. Yen, and K.F. Jensen, Lab Chip, 9, 1843e1849 (2009). 2009LC2281 Y. Wang, W.-Y. Lin, K. Liu, R.J. Lin, M. Selke, H.C. Kolb, N. Zhang, X.-Z. Zhao, M.E. Phelps, C.K.F. Shen, K.F. Faull, and H.-R. Tseng, Lab Chip, 9, 2281e2285 (2009).

54

2009OP1357 2010AGI899 2010CS675 2010CE6678 2010CE12342 2010CGD2219 2010OL3618 2010OP1347 2010OP393 2010SL505 2010SL2009 2010TL4189 2011AGI7502 2011CC4583 2011CGD4392 2011CS287 2011MD613 2011OL4060 2012AGI1706 2012ASC17 2012CGD3036 2012CGD5701 2012GC2776 2012IE14583 2012OBC5774 2012OP915 2013AGI12359

Marine Movsisyan et al.

S. Lawton, G. Steele, P. Shering, L. Zhao, I. Laird, and X.-W. Ni, Org. Process Res. Dev., 13, 1357e1363 (2009). R.L. Hartman, J.R. Naber, S.L. Buchwald, and K.F. Jensen, Angew. Chem. Int. Ed., 49, 899e903 (2010). D. Webb and T.F. Jamison, Chem. Sci., 1, 675e680 (2010). T. Tricotet and D.F. O’Shea, Chem. Eur. J., 16, 6678e6686 (2010). Z. Qian, I.R. Baxendale, and S.V. Ley, Chem. Eur. J., 16, 12342e 12348 (2010). A.J. Alvarez and A.S. Myerson, Cryst. Growth Des., 10, 2219e2228 (2010). J. Sedelmeier, S.V. Ley, I.R. Baxendale, and M. Baumann, Org. Lett., 12, 3618e3621 (2010). R.L. Hartman, J.R. Naber, N. Zaborenko, S.L. Buchwald, and K.F. Jensen, Org. Process Res. Dev., 14, 1347e1357 (2010). C.F. Carter, H. Lange, S.V. Ley, I.R. Baxendale, B. Wittkamp, J.G. Goode, and N.L. Gaunt, Org. Process Res. Dev., 14, 393e404 (2010). Z. Qian, I.R. Baxendale, and S.V. Ley, Synlett, 2010, 505e508 (2010). S. Ceylan, T. Klande, C. Vogt, C. Friese, and A. Kirschning, Synlett, 2010, 2009e2013 (2010). T.S.A. Heugebaert, B.I. Roman, A. De Blieck, and C.V. Stevens, Tetrahedron Lett., 51, 4189e4191 (2010). R.L. Hartman, J.P. McMullen, and K.F. Jensen, Angew. Chem. Int. Ed., 50, 7502e7519 (2011). J. Wegner, S. Ceylan, and A. Kirschning, Chem. Commun., 47, 4583e4592 (2011). A.J. Alvarez, A. Singh, and A.S. Myerson, Cryst. Growth Des., 11, 4392e4400 (2011). T. Noel, J.R. Naber, R.L. Hartman, J.P. McMullen, K.F. Jensen, and S.L. Buchwald, Chem. Sci., 2, 287e290 (2011). M. Baumann, I.R. Baxendale, and S.V. Ley, Mol. Diversity, 15, 613e630 (2011). A.R. Bogdan and K. James, Org. Lett., 13, 4060e4063 (2011). F. Lévesque and P.H. Seeberger, Angew. Chem. Int. Ed., 51, 1706e1709 (2012). J. Wegner, S. Ceylan, and A. Kirschning, Adv. Synth. Catal., 354, 17e57 (2012). J.L. Quon, H. Zhang, A. Alvarez, J. Evans, A.S. Myerson, and B.L. Trout, Cryst. Growth Des., 12, 3036e3044 (2012). S.Y. Wong, A.P. Tatusko, B.L. Trout, and A.S. Myerson, Cryst. Growth Des., 12, 5701e5707 (2012). F.E.A. Van Waes, J. Drabowicz, A. Cukalovic, and C.V. Stevens, Green Chem., 14, 2776e2779 (2012). J. Yue, J.C. Schouten, and T.A. Nijhuis, Ind. Eng. Chem. Res., 51, 14583e14609 (2012). P.B. Cranwell, M. O’Brien, D.L. Browne, P. Koos, A. Polyzos, M. PenaLopez, and S.V. Ley, Org. Biomol. Chem., 10, 5774e5779 (2012). H. Zhang, J. Quon, A.J. Alvarez, J. Evans, A.S. Myerson, and B. Trout, Org. Process Res. Dev., 16, 915e924 (2012). S. Mascia, P.L. Heider, H. Zhang, R. Lakerveld, B. Benyahia, P.I. Barton, R.D. Braatz, C.L. Cooney, J.M.B. Evans, T.F. Jamison, K.F. Jensen, A.S. Myerson, and B.L. Trout, Angew. Chem. Int. Ed., 52, 12359e12363 (2013).

Flow Synthesis of Heterocycles

2013CE5450 2013CES352 2013CR2550 2013EJOC4509 2013GC1456 2013IE10802 2013OBC1822 2013OL5590 2014CGD2148 2014COC62 2014FC118 2014LC3206 2014OP402 2014OP1253 2015AGI983 2015AGI1877 2015ACR349 2015CET259 2015CSC1648 2015N302 2015N329 2015OBC207 2015OBC1634 2015PT38

55

D. Kopetzki, F. Levesque, and P.H. Seeberger, Chem. Eur. J., 19, 5450e5456 (2013). F. Castro, S. Kuhn, K. Jensen, A. Ferreira, F. Rocha, A. Vicente, and J.A. Teixeira, Chem. Eng. Sci., 100, 352e359 (2013). P.N. Nge, C.I. Rogers, and A.T. Woolley, Chem. Rev., 113, 2550e2583 (2013). A.E. Buba, S. Koch, H. Kunz, and H. L€ owe, Eur. J. Org. Chem., 2013, 4509e4513 (2013). S.G. Newman and K.F. Jensen, Green Chem., 15, 1456e1472 (2013). A. Adamo, P.L. Heider, N. Weeranoppanant, and K.F. Jensen, Ind. Eng. Chem. Res., 52, 10802e10808 (2013). M.D. Hopkin, I.R. Baxendale, and S.V. Ley, Org. Biomol. Chem., 11, 1822e1839 (2013). F. Mastronardi, B. Gutmann, and C.O. Kappe, Org. Lett., 15, 5590e5593 (2013). H. Zhang, R. Lakerveld, P.L. Heider, M. Tao, M. Su, C.J. Testa, A.N. D’Antonio, P.I. Barton, R.D. Braatz, B.L. Trout, A.S. Myerson, K.F. Jensen, and J.M.B. Evans, Cryst. Growth Des., 14, 2148e2157 (2014). K.J. Wu and S. Kuhn, Chim. Oggi-Chem. Today, 32, 62e66 (2014). F.E.A. Van Waes, S. Seghers, W. Dermaut, B. Cappuyns, and C.V. Stevens, J. Flow Chem., 4, 118e124 (2014). K.F. Jensen, B.J. Reizman, and S.G. Newman, Lab Chip, 14, 3206e3212 (2014). P.L. Heider, S.C. Born, S. Basak, B. Benyahia, R. Lakerveld, H. Zhang, R. Hogan, L. Buchbinder, A. Wolfe, S. Mascia, J.M.B. Evans, T.F. Jamison, and K.F. Jensen, Org. Process Res. Dev., 18, 402e409 (2014). T.A. Hamlin, G.M.L. Lazarus, C.B. Kelly, and N.E. Leadbeater, Org. Process Res. Dev., 18, 1253e1258 (2014). D.R. Snead and T.F. Jamison, Angew. Chem. Int. Ed., 54, 983e987 (2015). H. Kim, H.-J. Lee, and D.-P. Kim, Angew. Chem. Int. Ed., 54, 1877e1880 (2015). M. Brzozowski, M. O’Brien, S.V. Ley, and A. Polyzos, Acc. Chem. Res., 48, 349e362 (2015). B.J. Deadman, D.L. Browne, I.R. Baxendale, and S.V. Ley, Chem. Eng. Technol., 38, 259e264 (2015). T.S.A. Heugebaert, C.V. Stevens, and C.O. Kappe, ChemSusChem, 8, 1648e1651 (2015). J.M. Hawkins, Nature, 520, 302e303 (2015). T. Tsubogo, H. Oyamada, and S. Kobayashi, Nature, 520, 329e 332 (2015). S. Gl€ ockner, D.N. Tran, R.J. Ingham, S. Fenner, Z.E. Wilson, C. Battilocchio, and S.V. Ley, Org. Biomol. Chem., 13, 207e214 (2015). M.M.E. Delville, K. Koch, J.C.M. van Hest, and F.P.J.T. Rutjes, Org. Biomol. Chem., 13, 1634e1638 (2015). C.A. Challener, Pharm. Technol., 39, 38e40 (2015).