The integration of flow reactors into synthetic organic chemistry
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The integration of flow reactors into synthetic organic chemistry The integration of flow reactors into synthetic organic chemistry Document Transcript

  • 519 Review Received: 2 May 2012 Revised: 30 November 2012 Accepted article published: 13 December 2012 Published online in Wiley Online Library: 25 February 2013 (wileyonlinelibrary.com) DOI 10.1002/jctb.4012 The integration of flow reactors into synthetic organic chemistry Ian R. Baxendale∗ Abstract The material presented in this review is based upon discussions and interactions with members of the Department of Chemistry and Biochemistry within the University of Windsor, Ontario, Canada. This article explores the changing face of chemical synthesis with regard to the impact of flow based chemical processing technologies. Highlighted works from the Innovative Technology Centre (ITC), Cambridge, UK, are used to illustrate the alternative synthetic practices available to modern research chemists. The dominant theme of the review is the synergistic effects encountered by combining the advantages of continuous processing regimes with the power of immobilized reagents and scavenger systems for multi-step organic chemistry. c 2012 Society of Chemical Industry Keywords: review; flow chemistry; organic synthesis; heterocycles; automation; technology OUR CURRENT SYNTHESIS CAPABILITY In recent years great advances have been made in our ability to design assemble and test the products derived from chemical synthesis. From the development of drugs in the ongoing fight against disease to the more aesthetic aspects of society with the preparation of perfumes and cosmetics, synthetic chemistry is the pivotal science. Furthermore, the quality and quantity of our food supply relies heavily upon synthesized products, as do almost all otheraspectsofourmodernsocietyrangingfrompaints,pigments and dyestuffs to plastics, polymers and other man-made materials. As chemists our scientific and creative capacity to assemble complex functional molecules from small chemical building blocks has reached an impressive level of sophistication. Much of this has been permitted as a consequence of our greater understanding of chemical mechanics and molecular interactions (e.g. Quantum mechanics, Frontier orbital theory, in silico design). However, the standardization of synthetic route planning using theoretical methodologies such as retro-synthetic analysis or reaction selection and optimization through the use of statistical analysis and factorial design have aided greatly (i.e. Chemometrics, Principle Component Analysis, Design of Experiment methodology).1–5 Another aspect of the synthesis process that has seen tremendous change and progress is the analytical and characterization tools that are now available. It would be unthinkable to most modern molecule markers to embark on a chemical route without having access to high resolution NMR facilities, X-ray crystallography or some form of automated analysis such as LC- or GC-mass spectroscopy. These and related technologies have significantly enriched the information we as chemists can derive from crude chemical reactions helping in reaction profiling or aiding in elucidating the structural specifics of the synthesized compounds. Indeed, characterization and confirmation of a compounds identity that only a decade ago would have been a week’s hard intense manual work can now be processed and validated against literature sources in less than a day. Such resources have as a consequence greatly enhanced the quality and quantity of new chemical structures that can be synthesized. Furthermore, having easier on-line access and the ability to call upon published or in-house archived chemical information at the touch of a button has certainly affected the way in which we approach and conduct chemical synthesis. The large number of chemical search tools and literature- based databases that are routinely available means that a greater degree of precedence can be brought to bear on a chemical problem. This can enable the odds to be stacked in the favour of the chemist by predetermining the most appropriate sequence of reactions or offering alternative strategic bond forming reactions that can provide lower costs, alternative starting points or simply higher yielding processes. To facilitate the searching and recording of new chemical data many institutions and companies are adopting electronic laboratory notebook (ELN)6 systems that will further enhance the level of data retention and information that can be called upon for future chemical syntheses. The combination of many of these features has allowed for the discovery of many new chemical transformations leading to unique chemical architectures and the discovery of several novel reagents with highly specific chemical reactivities. This in turn has propagatedandacceleratedtherapidexpansionofseveralareasof synthesis such as organometallic chemistry, asymmetric synthesis and catalyst promoted processes including organocatalysis.7–11 It is probably not unreasonable to conclude that with the current level of knowledge and synthetic tools almost any molecule that we may wish to prepare could be synthesized in a reasonable timeframe. ∗ Correspondence to: I.R. Baxendale, The Department of Chemistry, Durham Uni- versity. South Road, Durham, DH1 3LE, UK. Email: i.r.baxendale@durham.ac.uk The Department of Chemistry, Durham University, South Road, Durham, DH1 3LE, UK J Chem Technol Biotechnol 2013; 88: 519–552 www.soci.org c 2012 Society of Chemical Industry
  • 520 www.soci.org IR Baxendale Reaction (heat/cool) Quench/Work-up Purify Evaporate Evaporate Purify (distill/recryst) Sequence involving a chemical transformation (involving heating or cooling in a round bottom flask), quenching (neutralisation or decomposition of reactive intermediates), extraction (phase separation), drying, evaporation of the solvent (isolation of the crude material), chromatographic purification (or alternatively distillation, crystallisation or similar additional processing) and finally a further solvent evaporation (isolation of the required pure fractions). Pure product Figure 1. General processing sequence of a chemical reaction. However, despite all the obvious successes resulting from our synthesisprogrammesthefundamentalwayinwhichwephysically conductchemicalsynthesishasremainedrelativelyunchangedfor over two centuries.12–14 Remarkably, apparatus such as standard glass round bottom flasks, condensers, measuring cylinders, test tubes and Bunsen burners are all still commonly in use today despite them being invented over 160 years ago. Consequently laboratory practices have also become standardized to make the best use of these tools and associated pieces of equipment. A standard sequence for a reaction today and over a century ago wouldstillbeeasilyrecognizabletobothbenchchemists(Figure1). From a simple analysis of the individual processing steps it is evident that for a single chemical transformation, which may involve only one bond-forming or bond-breaking event, a series of up to six additional manipulations (work-up and purification) can be required. Interestingly, these supplementary operations, which are essential but costly (in time and resources), add very little intrinsic value to the compounds; they are necessary only because of inefficiencies in our current synthetic practice (removal of spent reagentsandby-products).15 Manyofthesedeficienciesresultfrom poor reactivity, low selectivity, incomplete reaction or extensive by-product formation which is often a result of poor mixing and temperature control in conjunction with the use of highly reactivereagents.Ourcurrentchemicalinclinationisoftentoselect reagents for a particular transformation based on their enhanced (high)reactivitytherebyleadingtoquickchemicaltransformations (short reactions times). However, the flip side of such a selection is that the highly reactive reagents are less stable, being more prone to decomposition and offering a higher potential for side reactions (resulting in more waste). Consequently, a greater emphasis is ultimately placed on purification, often translating into the need to resort to column chromatography to facilitate the removal of numerous small impurities. Interestingly, this is often still the preferred option of many chemists even balanced against a reaction with a longer processing time (no manual intervention) yet then enabling a simple crystallization or distillation as the only required work-up and purification. This philosophy of quick and dirty chemistry coupled with substantial investment in purification technology such as HPLC has largely been driven by a time pressured discovery industry (both pharmaceutical and agrochemicalleaddiscovery)feedingahighthroughputscreening monster.16–20 Unfortunately,suchanapproach,althoughfulfilling a role, does not ideally align itself with performing highly efficient and well optimized chemical synthesis. In addition the physical structure of the apparatus and types of manipulation used in the reactions also impart limitations in terms of the scale at which most synthesis can be conducted. The ease of manual handling and the dimensions of the reaction flasks used in standard laboratories define the practical lower limit range to millilitres and hundreds of milligrams of substances (without utilizing additional specialized equipment). Indeed, even small-scale syntheses are often calibrated not due to a need for such quantities of material but as a consequence of human handling and convenience.21 This can mean that over long synthetic sequences large quantities of starting materials are required in order to elaborate the structures (loss of material through incomplete reaction, by-product formation or manual intervention). Furthermore, testing and optimizing the required synthetic steps involves a significant investment of time and manpower as well as precious substrates/reagents. This is compounded by the complexity of evaluating and tuning the many interlinked variables and parameters (for example, reaction times, temperature, solvents, concentration, catalysts/additives and stoichiometry) that can affect each chemical reactions outcome (i.e. regiochemistry, stereochemistry, purity and yield). Considering all these negative/impinging factors we need to recognize the limitations of current working practice and acknowl- edge the need for improvement. This is especially true if we wish to move to more sustainable chemical practices, as we must, if we are to protect our rapidly dwindling natural resources. Therefore in order to safely respond to the requirements of improving productivity and efficiency we must embrace new opportunities and explore alternative approaches to compound synthesis. The current costs, scale-up issues, lack of reproducibility, manpower wastage through repetitive and or routine tasks are unacceptable; therefore change is inevitable and should be embraced. AN ALTERNATIVE SYNTHESIS STRATEGY During the last decade there has been a steady growth in interestwithinthechemicalcommunityforflowbasedapproaches to synthetic targets due to the inherent benefits such as automated and telescoped reaction sequences, quick reaction optimizations and in-line work-up and purification.22–48 The holistic nature of flow chemistry targets many aspects of both wileyonlinelibrary.com/jctb c 2012 Society of Chemical Industry J Chem Technol Biotechnol 2013; 88: 519–552
  • 521 Integration of flow reactors into synthetic organic chemistry www.soci.org Figure 2. Cross-discipline synergistic interaction of flow chemical processing. synthesis methodology and process engineering deriving both environmental and economic drivers. Indeed, flow synthesis cuts across several traditional boundaries within the sequential scaling routes of syntheses (research scale, re-synthesis, kilo labs and full scale manufacturing/formulation), combining aspects of both chemical optimization and process intensification (Figure 2). As a result it is a prerequisite to develop a working knowledge of both the science of synthesis and an understanding of chemical engineering principles. Consequently conducting flow chemistry requires significant changes in synthesis planning and execution and so we should be confident that the benefits derived are worth the change in working practice. After all chemists have had over 230 years to perfect current synthesis techniques so why should we suddenly attempt to change all this, what real benefits can be derived? This is a sensible question to pose and one that may take academia and industry several years to fully evaluate and determine where the best returns can be made. In the meantime, it is hope that throughout this article a number of areas can be discussed which can already be adopted by synthesis groups providing definable and tangible benefits. FLOW CHEMISTRY: BACKGROUND Examples of flow-based chemical syntheses have existed for several decades49 and are in fact a well-established practice at manufacturing scales especially for the production of large quantities of a given material. However, the innovative uses of flow in the early stages of synthesis development – laboratory basedsynthesis – arefarlesscommon.Unfortunately,althoughthe concepts of increased mixing efficiency, controlled scaling factors, enhanced safety ratings and continuous processing capabilities have all been well recognized, these benefits have not been generically leveraged into conventional synthetic laboratories (Figure 3).50,51 Over the last 10–12 years there has been a popular resurgent interest in the use of flow based synthesis techniques mainly driven by the availability of several commercial laboratory flow synthesis platforms.52–61 During this period most academic literature within the field has focused primarily upon aspects of flow equipment development or its application to esoteric single step reactions using the expanded processing window capabilities that are available (Figure 4). Significantly less effort has been directed at the more challenging issue of devising general and versatileplatformscapableofperformingmulti-stepsynthesesand leadingtopurefinalproductsthatcanbeuseddirectlyinbiological evaluations or for the determination of some other fundamental physical property.62–64 This is particularly important as it has become increasingly apparent that the task of chemical synthesis must become more closely linked with the immediate testing of the newly prepared product. Working the two aspects in isolation inherently leads to wasted synthesis time and the generation of unwanted materials. Therefore more integrated and continuous relay of information regarding the ongoing synthesis and its products in terms of basic characterization, physical property and biological/physical functions needs to be addressed. This act of immediately gathering and analysing such data will ultimately enablemoreeducatedandresponsivechoicestobemade,varying frommundanefactorssuchasreactionoptimizationtohigherlevel decisions about which molecules should be synthesized next. Although such a change will have a broad impact across all areas of chemical production it will undoubtedly have a more drastic and immediate effect on the production of therapeutic entities. Although flow based chemical processing does provide many advantages it should also be noted it does create certain inherent difficulties when considering multi-step synthesis, such as: (i) compensating for the kinetics of the different reaction steps (integratingreactionsinsequencewithdifferentreactiontimes);(ii) compatibility of the solvent with all reaction steps; hence creating the potential need for solvent switching protocols; (iii) the need J Chem Technol Biotechnol 2013; 88: 519–552 c 2012 Society of Chemical Industry wileyonlinelibrary.com/jctb
  • 522 www.soci.org IR Baxendale Figure 3. Continuous flow synthesis benefits. • Shorter reaction times due to improved mixing and heating. • Higher yields and purities. • Easy Access to increased reaction window enabling access to pressures of 300 bar and superheating of solvents up to 300°C. • Enabled cold reaction zones −120°C. • Multi-stage temperature zones for increased sensitivity processing windows. • Real-time analysis and optimization, incorporated DoE (less waste and more automation). • Scalability (simply increase the quantity made by running for longer). • Improved safety due to containment. Toxic or explosive chemistries can be performed which would be problematic using traditional glassware/apparatus. • Small footprint reactors (more available laboratory space, less expensive glassware). • Direct in-line purificationcan be conducted (less costly purification requirements). Figure 4. Some advantages of flow processing. for intermediate purification by scavenging or in-line preparative purification (preventing by-product build-up); (iv) dilution effects of adding additional downstream flow streams; and (v) monitoring and control of each concurrent operation. As such, although there are many advantages to be gained from adoption of flow synthesis approaches, a strong synthetic experience and good engineering understanding are essential to fully reap the benefits. Flow chemistry for multi-step chemical processing Conceptually,ifasequenceofstepwisereactionscanbeperformed all in the same solvent (or a simple mechanism for solvent exchange is available), and each reaction is highly optimized then the reactions could be easily processed in tandem. In this way the reaction mixture for one step becomes the reactant/s for the next chemical transformation creating a telescoped sequence wileyonlinelibrary.com/jctb c 2012 Society of Chemical Industry J Chem Technol Biotechnol 2013; 88: 519–552
  • 523 Integration of flow reactors into synthetic organic chemistry www.soci.org A B Figure 5. Processing modes of tandem chemical reactions. (Figure 5(a)). In addition moving from a batch based working regime to a continuous flow mode would significantly simplify the processing requirements in terms of scheduling and manipulation ofthesolutions(Figure5(b)).Suchanidealizedscenarioisinreality, not feasible, due to the inevitable lower conversions and the need to quench reactions, work-up intermediates and consequently purify the reaction streams between chemical transformations. It is however, possible to combine another enabling technology, namely, solid-supported reagents and scavengers to facilitate this process and maintain a continuous flowing sequence. Solid-supported reagents and scavengers in flow chemistry Solid supported reagents have been used extensively in multi- step organic syntheses in batch.65–83 Ideally, the use of such reagents should provide clean products without chromatography, crystallization, distillation or any traditional work-up procedures. Supported reagents are reactive species that are associated with a heterogeneous support material.84 They transform a solution resident substrate (or substrates) into a new chemical product (or products), with the excess or spent reagent remaining tethered to the solid matrix making separation a simple processes. In a similar fashion, impurities can be removed from a flow stream using a scavenger species immobilized on a support. This scavenger creates either an electrostatic or covalent interact with the impurity, sequestering it from solution and binding it to the solid matrix thereby effecting purification of the reaction stream. By utilizing these supported components packed into simple columns or reactor cartridges it is immediately possible to perform multi-step organic sequences employing an orchestrated suite of supported reagents to effect all the chemical transformations and purifications. As an illustration we have investigated the formation of 4,5- disubstituted oxazoles in flow facilitated by solid-supported reagents.85 An isocyanide and an acid chloride were mixed using a glass microfluidic chip (274 µL or 1 mL in volume), typically heated to 60◦ C, forming a reactive adduct (the imidoyl chloride); the stream was then passed through a column containing an immobilized P1 base, PS-BEMP, which facilitated cyclization forming the oxazole (Scheme 1). In the sequence a slight excess of the acid chloride starting material was used (1.1–1.2 equiv.) to ensure complete consumption of the corresponding isocyanide coupling partner. The residual acid chloride was later removed by scavenging using a column of QP-BZA (a macroporous benzyl amine resin). Using this approach a small library of 23 compounds was generated, with yields in the range 83–98% and all members being isolated in high purities (>95% as determined by LC- MS and NMR); no further purification or work-up was required. Sulfonates (from the corresponding tosyl substituent) could also be prepared (nine examples, 81–94%) as well as phosphonates (three examples, 84–85%) by using a similar synthetic strategy. Of particular note was that the immobilized BEMP column could be quickly regenerated for repeated use by washing with a solution of BEMP in hexane or either NaOMe or t BuOK in MeOH. Interestingly, when these same oxazoles forming reactions were conducted in batch the yields were generally poor, typically ≤50%. The improvement in flow was ascribed to the different mixing regime used to form the initial imidoyl chloride intermediate under neutral conditions then rapidly processing this species using an in-line base. In addition, the scaled synthesis of these compounds could be achieved by simply using larger columns of supported reagents and allowing the system to run for longer periods of time (∼12 h, generating 10–25 g), clearly illustrating the versatility of the instrumentation and the potential scalability of this technology. In these oxazole forming reactions the reactant concentration was typically of the magnitude of 0.75 mol L–1 concentration. This wasselectedasastandardvalueatwhichtopreparestocksolutions as several of the starting materials and resulting products were highly crystalline and at higher concentrations proved insoluble. The insolubility of materials in flow chemistry is a potential major limitation (due to blockage of the reactors) and obviously needs careful consideration in the planning stages. This aspect can also be compounded by the in-line scavenging process which increases the purity of the reaction stream making crystallization or precipitation a more likely occurrence. Consequently for library preparation using a variety of starting materials with differing solubility remove or when employing a new/unknown reaction it is often advisable to initially run the reaction under increased J Chem Technol Biotechnol 2013; 88: 519–552 c 2012 Society of Chemical Industry wileyonlinelibrary.com/jctb
  • 524 www.soci.org IR Baxendale N O EtO O 92% N O O Me Me 99% EtO O N O N N N 92% EtO O Me N O NN Me t Bu 86% EtO O N O ON 92% EtO O N O EtO O NCl 89% N O EtO O 87% N N N O P O EtO OEt 3-NO2; 85% 4-CF3; 84% 4-Br; 85% N O EtO O93% S N O O OEt N O Me Cl F 83% N O O O Cl Cl 90% EtO O N O ON 81% S O O Me N ON N N Me 94% S O O Me N O NN Me t Bu 85% S O O Me N O O Me Me 89% S O O Me N O EtO O R 4-Br; 88% 4-I; 88% 3-Br; 85% 2-Cl; 98% 4-NO2; 83% 3-NO2; 91% 4-F; 94% 2-CF3; 98% 4-CF3; 95% 4-CN; 83% 2,5-F; 94% 3,4-OMe; 83% N O EtO O86% O O N O O OEt N O Me Cl F 83% N O O OEt94% NN Pr Cl N O S O O R = 3-NO2; 84% R = 4-F; 84% R = 4-Br; 84% R Me R N OOO ClCl SO O 88% Me N O EtO O Cl 92% Scheme 1. Synthesis of 4,5-disubstituted oxazoles using a flow reactor. dilution. Running the reaction for longer periods of time can still generate significant quantities of material using this approach or thestocksolutionscanbemademoreconcentratedforsubsequent runs or systematically increased during the same run period. An advantage of flow processing is that stock solutions do not need to be prepared in bulk, consequently with knowledge of the flow rates being used it is possible to prepare additional volumes of stock solution and by judicious modification of the flow rates substitute the new reactant solutions at opportune timings. In this way a staged concentration increase can be applied to the reactor to maximize the throughput for a given reaction. This is particularly beneficial when scaling a chemical transformation and is significantly enhanced when employing in-line monitoring techniques that allow for the rapid re-optimization of the reactor conditions (temperature/flow rate) following a change in reagent concentration thereby establishing a new steady state operation. The accessible chemical structures were further expanded using isothiocyanates and carbon disulfide as electrophiles, providing a bifurcated route for the preparation of thiazoles and imidazoles.86 When aryl isothiocyanates inputs were used, often initially a low yield of the desired thiazole was obtained from the reactor (Scheme 2). However, by eluting the PS-BEMP column with an additional flow stream containing an electrophile (an α-bromo ketone in the example shown), the regioisomeric imidazole adduct could be isolated, providing combined yields of 76–100% (Scheme 3). Investigation of the initially formed intermediate suggested an open chain species was becoming trapped on the resin, and that only after ring closure, instigated by alkylation, was the secondary imidazole product being formed and released. In a similar fashion the reaction between ethyl isocyanide and carbon disulfide furnished a collection of the corresponding S- alkylated thiazoles, again in good yields (72–97%) and excellent purities. We have also adopted similar strategies for the synthesis of peptides in flow, generating rapidly optimized, highly reproducibly, automated sequences that yield the desired product in high purity; and isolated yields of 50–200 mg from a single injection.87 In a standard procedure an N-protected amino acid is pre-treated with PyBrOP, prior to flowing through a column of PS-HOBt. The activated amino acid reacts with the immobilized HOBt thereby becoming sequestered onto the solid phase as the corresponding active ester (Scheme 4, Step 1). During the wileyonlinelibrary.com/jctb c 2012 Society of Chemical Industry J Chem Technol Biotechnol 2013; 88: 519–552
  • 525 Integration of flow reactors into synthetic organic chemistry www.soci.org Scheme 2. Synthesis of thiazoles in flow. Scheme 3. Bifurcated synthesis of imidazole using solid-supported reagents. loading sequence any unreacted starting material or by-products can be washed through the column and directed to waste. The HOBt-supported ester column is then automatically connected in-line to a series of other reagents: PS-DMAP, and PS-SO3H (a polymer-supported sulfonic acid) (Scheme 4, Step 2). A solution of a second, O-protected, amino acid as its hydrochloride salt is then eluted through the column series. The PS-DMAP acts to furnish the free-based in situ, which then progresses through the supported activeester,formingthepeptidebond.Theflowstreamthenenters the PS-SO3H column, scavenging any unreacted amine. Finally, the solvent is evaporated to give the product; several Boc, Fmoc and Cbz N-protected dipeptides were generated in isolated yields of 61–81% without the need for purification by chromatography. This same process can also be extended to the synthesis of polypeptides.BysimplyincorporatingaflowbasedN-deprotection of a Cbz-protected dipeptide (Cbz-Ala-Gly-OEt) using the H-Cube system, the free amine is produced which can be used in a repetition of the above procedure. For example, the tripeptide Cbz-Phe-Ala-Gly-OEt was obtained in 59% overall yield in 6.5 h starting from glycine. Using a flow-based processing regime provides chemists with an expanded range of capabilities and opportunities, providing improved safety considerations, enhanced dispensing and mixing coefficients, and when utilsing in-line real-time diagnostics with the ability to make instant changes creating a new dynamic chemical environment. Throughout these processes, the packed cartridges or reactor coils can also be interacted upon by various physical means such as heating/cooling, oscillation, ultrasound, microwaves, irradiation or electrochemistry giving a full range of chemical activations. Microwave heating of flow reactors has proven particularly beneficial for several chemical transformations.88–90 We and others have shown that it is possible to simply modify standard laboratory microwave reactors to function in continuous flow through mode.91–96 For example, a glass insert reactor can be placed into the microwave cavity allowing solutions to flow through the focused microwave field. By applyingaflowrestrictionbywayofabackpressureregulator(BPR) totheoutputofthereactorsuperheatedreactionconditionscanbe accessed. Illustrative of this process is the high temperature non- metal catalysed intramolecular [2+2+2] alkyne cyclotrimerization reaction shown in Scheme 5.97 A solution of the substrate in DMF, a strongly absorbing microwave solvent, was easily maintained at 200◦ C for the duration of the reaction. An alternative set-up which consists of a simple coil of fluorinated polymer tubing (11.5 m of 0.4 mm i.d. tubing) wound around a central Teflon core provides a flow microwave insert with an internal volume of 1.45 mL (Figure 6).98 The Teflon spigots can be easily spooled to replace a blocked or damaged unit or to allow access to new configurations; for example, wrapping differentlengthsoftubingtoprovidereactorswithvaryinginternal volumes or multiple tubing lengths to accommodate different reactions or flow rates within the same microwave device. The unit is then easily accommodated within the cavity of a commercially available microwave reactor such as the Emrys Optimiser with the input and exit tubes on the underside of the microwave unit (Figure 6(c)). One or more HPLC pumps are then used to deliver the fluidic flows to the system, which is kept under positive pressure through the use of a back-pressure regulator at the exit. This reactor configuration has been successfully used to synthesize a collection of 5-amino-4-cyanopyrazoles as building blocks and starting materials for subsequent transformation into more structurally diverse 4-aminopyrazolopyrimidines by dimerization or the 1H-pyrazolo[3,4-d]pyrimidin-4-amine by condensation with a nitrile (Scheme 6 and 7). To prepare the pyrazole precusors various hydrazines and ethoxymethylene malononitrile were heated together in the flow microwave reactor (flow rates of 0.36–1.75 mL min−1 equating to residence times of 0.8–4.0 min) and then progressed through a scavenging sequence to remove excess ethoxymethylene malononitrile followed by a carbon based decolourising stage. The set-up could be continuously run for periods up to 36 h at temperatures of 100–120◦ C in order to prepare 120–350 g batches of the bulk intermediates in high yields and excellent purities. The design and evaluation of novel microwave reactor inserts is a valuable method of utilizing existing batch based processing capabilities as offered by commercial microwave units and adapting them to enable a more facile scale up. Conventionally the direct scale up of a microwave reactions has been problematic. Typical operating frequency of most commercial microwave J Chem Technol Biotechnol 2013; 88: 519–552 c 2012 Society of Chemical Industry wileyonlinelibrary.com/jctb
  • 526 www.soci.org IR Baxendale Step 1: Loading Step 2: Reaction Scheme 4. Automated peptide synthesis in flow. Scheme 5. Flow microwave aromatization reactions using a glass insert reactor. wileyonlinelibrary.com/jctb c 2012 Society of Chemical Industry J Chem Technol Biotechnol 2013; 88: 519–552
  • 527 Integration of flow reactors into synthetic organic chemistry www.soci.org A B C Figure 6. (A) Teflon core; (B) spiral coil cavity insert reactor; (C) microwave insert twin tube. Scheme 6. Continuous flow synthesis of pyrazoles under microwave irradiation. Scheme 7. Dimerization of pyrazoles and reaction with nitriles under microwave irradiation. reactors (2.45 GHz) means they have a restricted penetration depth of only a few centimetres into the reaction media. Consequently the heating effect will decrease exponentially from the surface to the inner region of a large reactor leading to non- homogeneous heating. This intrinsic complication has tended to prevent the direct scaling of microwave reactors past a couple of litres inhibiting their use for the production of larger quantities of material. Alternatively exploring the use of continuous flow microwave processing avoids such considerations. Our investigations have led us to construct a number of different reactor designs which make use of existing microwave reactors to establish flow through microwave experiments. As an illistration two basic channel designs are shown in Figure 7.99 These consist of a simple recessed baffled core (with an alternating stepwise inclination) and a classical helical coil unit (easily prepared from Teflon rods using standard machine cutting techniques). These components were then placed into a simple straight glass cylinder capped with Teflon end pieces which allowed connects to be established to the flow stream whilst also securing the device in the microwave camber. By adopting these reactor configurations a series of different chemistries have been successfully processed with regard to scaling the reactions over time and in quantity of material generated. For example, the Hantzsch reaction between 3-nitrobenzaldehyde and ethyl 3-oxobutanoate in the presence of ammoniumacetateandcatalyzedbyphenylboronicacid(5mol%) was preformed. The reactor was operated continuously for 48 h processing a total of 576 mL of reaction solution with a residence time of 12.5 min equating to 349 g of isolated product (following crystallization) (Scheme 8). This gives a good indication of the level of enhanced processing that could be achieved using such simple set-ups. Asimpleglasscolumnorcoilcontaininganimmobilizedreagent can also be utilized to conduct heterogeneous flow catalysis under microwave irradiation. Reactions with metal-tethered catalysts, e.g.polyureamicroencapsulatedpalladiumspecies(PdEnCat)area good example, whereby microwave heating activates the encased palladium species (Figure 8).100 The microencapsulated catalyst can be packed into a simple design U-tube reactor for easy alignment in the microwave cavity. Often with microwave heating accurate and consistent temperature measurement is difficult to achieve therefore to assist in calibrating the system a modified reactor was commissioned that allowed the insertion of a fibre optic probe into the flow stream permitting more detailed thermal readings to be taken (Figure 9). However, it should be noted that this reference point still only supplies a bulk solution value which can be significantly different to the actual localized temperature of a heterogeneous species or catalytic site.101–112 Using this U-tube design in combination with a fixed bed of the PdEnCat catalyst we were able to generate a flow system for the rapid assembly of biaryl units via the Suzuki reaction (Figure 10).113,114 A basic set-up delivered ethanolic solutions of the aryl bromide, boronic acid and tetra-butylammonium acetate as the base to mix prior to passage through the catalyst bed. A final scavengingstepwithapolymer-supportedsulfonicacidfacilitated the clean-up of the reaction stream upon exiting the reactor. This approach gave products which were generally of a higher purity than those generated through the analogous batch reactions. This was ascribed to the fast reaction times; the substrates were only heated for approximately one minute, although during that period the effective catalyst concentration was extremely high. Thus the desired cross-coupling was able to takeplace,buttheshorttimeframeinvolvedavoidsdecomposition and prevents many side reactions from occurring. J Chem Technol Biotechnol 2013; 88: 519–552 c 2012 Society of Chemical Industry wileyonlinelibrary.com/jctb
  • 528 www.soci.org IR Baxendale Figure 7. Microwave reactor Teflon flow tube inserts and dye flow injections highlights. Scheme 8. An example of scaled microwave reaction. Another advantage of this mode of operation was that the same catalyst bed could be used to generate multiple products in a serial fashion. Aliquots of the paired starting materials were introduced in succession to the reactor interspersed by a washing stage to ensure complete elution of the product before the next pair of substrates was coupled (Figure 11). The yields of the products obtained were consistent with those isolated from batch processing and following solvent evaporation gave the desired materialdirectlyinhighpurity.Itwasalsoshownthatmoreefficient use of the catalysts could be achieved when larger quantities of the substrates were processed through the catalyst bed. In batch most reactions required between 3–5 mol% of catalyst to ensure complete conversion of the starting materials. Alternatively, in flow,thereactorcouldbemaintainedundersteadystateoperation resulting in greater catalyst utilization pertaining to an effective catalyst concentration of only 0.2 mol% (Figure 12). This concept of increased efficiency with continued use is a significant benefit of applying immobilized catalysts under flow conditions. Reactive intermediates in multi-step chemical transformations The generation and in situ telescoping of reactive or unstable intermediates directly into a secondary transformation is one of the major processing advantages of flow chemistry. The capacity to constantly produce a manageable quantity of a hazardous chemical entity which remains contained within the reactor for thedurationofitexistenceoffersmaysafetyandhandlingbenefits. Several groups have demonstrated specific advantages in terms of superior overall isolated yields, enhanced purities, increased safety windows and shortened overall reaction times by integrating an initial generation step with a subsequent reaction.115–118 We believe it is also of critical importance to include in-line purification strategies to ensure that no hazardous starting materials or by- products are carried through into the later multi-step processes, thereby causing final product contamination. Some examples of these processes from our laboratory which involve this concept of direct in-line clean-up are illustrated below. Curtius rearrangement The Curtius rearrangement transforms carboxylic acids or acid chlorides to the corresponding isocyanate functionality. The reaction proceeds via an intermediate acyl azide which undergoes rearrangement to give a reactive isocyanate which can in turn be intercepted by a nucleophile to give a modifed product. We have employedaMerrifieldtypeazideion-exchangemonolith119–125 to facilitate this transformation generating reactive acyl azides from variousacidchlorideswhichthenundergoCurtiusrearrangements to give a variety of aryl isocyanates in a subsequent heated coil reactor (Scheme 9).126 Alternatively for larger-scale applications the reactive acyl azide could be generated using diphenylphosporyl azide (DPPA) directly fromcarboxylicacids.127 Inthisprotocolasolutionofthecarboxylic acid with triethylamine plus a suitable nucleophile was loaded as one reaction stream which was then combined with a second stream containing diphenylphosphoryl azide (DPPA) (Scheme 10). In practice an excess of the carboxylic acid was used to ensure complete consumption of the DPPA reagent. On mixing of the streams, an acyl azide was generated which on heating in a convection flow coil (CFC) produced the isocyanate which was quenched immediately with the in situ resident nucleophile to give the desired products. A mixed acid/base scavenger work-up was then used to remove the base, excess carboxylic acid and by-products. For nitrogen-containing heterocyclic carboxylic acid starting materials it was found necessary to use a catch-and-release protocol128,129 to afford the purified products. Fluorination reactions Fluorine is often added to drug molecules to improve binding or provide greater metabolic stability. However, its introduction can be difficult due to the hazards associated with the fluorinating reagents. Using a flow microreactor system with immobilized in-line purification means many of these hazards are eliminated owing to the contained environment and the robustness of the scavenging protocols.130 wileyonlinelibrary.com/jctb c 2012 Society of Chemical Industry J Chem Technol Biotechnol 2013; 88: 519–552
  • 529 Integration of flow reactors into synthetic organic chemistry www.soci.org Figure 8. PdEnCat, an immobilized palladium catalyst. (a) (b) (c) Figure 9. (a) Microencapsulated PdEnCat with the lower image being a TEM recording showing the palladium nano-clusters. (b) Simple U-tube PdEncat packed reactor. (c) Side arm inlet reactor with Fibre optic probe insert for more accurate temperature measurement. Figure 10. Flow microwave Suzuki reactions. J Chem Technol Biotechnol 2013; 88: 519–552 c 2012 Society of Chemical Industry wileyonlinelibrary.com/jctb
  • 530 www.soci.org IR Baxendale Figure11.SequentialprocessingofSuzukicouplingpartnersusingasingle catalyst cartridge in flow. Trifluoromethylationofaldehydeshasbeendemonstratedusing TMS-CF3 (Ruppert’s reagent) as a source of nucleophilic ‘CF3’.131 In particular, a fluoride monolith provided a versatile source of fluo- ride anions (Scheme 11). The reaction stream was purified using a solidsupportedaldehydetotrapanyunreactedRuppert’s reagent, while an acid resin acid deprotects the initially formed intermedi- ate silylated product. Finally, an immobilized hydrazine sequesters any unreacted aldehyde delivering a purified reaction stream. Other flow methods for the introduction of fluorine involve the use of commercially available fluorinating agents such as 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octaneditetra fluoroborate (Selectfluor) and diethylamino sulfurtrifluoride (DAST). The safe work-up of these reactions is particularly important but can again be achieved by the application of immobilized reagents. The α-fluorination of an activated ketone can be conducted using Selectfluor while similarly a fluoro-Ritter reactionwitholefinicsubstratescanberealizedinthesamereactor set-up.132 In the first reaction, a stream of the activated carbonyl was combined with a corresponding stream of Selectfluor and heated (100–120◦ C) (Scheme 12). The product stream then was purified using a combination of an’ immobilized sulfonic acid and dimethylamine resins to scavenge excess reagents and Figure 12. Scaled-up processing of Suzuki reactions in flow using PdEnCat catalyst. by-products. This process afforded the desired products in high yield and excellent purity. The same reactor arrangement was also used for several fluoro- Ritterreactionswherebyanalkenestartingmaterialinthepresence of wet acetic acid (<5% mol water) reacts with acetonitrile to furnish a monofluorinated product (Scheme 13). DAST (diethylaminosulfur trifluoride) is another useful reagent for substituting fluorine for an alcohol or a carbonyl functionality (aldehyde or activated ketone) yielding the corresponding mono or di-fluorinated products (Scheme 14).130,132 In the process excess DAST along with liberated HF were scavenged using a calcium carbonate quench immediately followed by a silica gel plug to trapinorganicsalts.Althoughthisscavengingprocedureproduces quantities of carbon dioxide this is easily managed using the continuous flow system thus avoiding pressure build-up. While yields were affected by the electronics of the carbonyl moiety, the reaction was found to be tolerant of a wide range of functional groups, e.g. epoxides, alkenes, acetals, amines, esters, amides and various heterocycles creating a very useful protocol. DAST has also found application in the cyclodehydration of β-hydroxy amines which are efficiently converted to the corresponding oxazolines in excellent yields (Scheme 15).130,132 This has also allowed for the construction of a number of chiral PyBOX ligands in flow.133,134 Flow synthesis of novel chemical building blocks Access to a wide array of chemical building blocks is an essential perquisite for many medicinal chemistry synthesis programmes. These compounds can be simple core templates enabling rapid chemical decoration in initial hit finding screens or more specially tailored structures designed to enhance a certain physical characteristic or present a particular functional pattern wileyonlinelibrary.com/jctb c 2012 Society of Chemical Industry J Chem Technol Biotechnol 2013; 88: 519–552
  • 531 Integration of flow reactors into synthetic organic chemistry www.soci.org Scheme 9. Synthesis of acyl azides using a monolith reactor. in later stage compound development. Their availability and cost ultimately determines the scope of their usage, consequently more automated ways of preparing these materials on demand is particularly important. The next sections highlight some of the flowchemistrymethods thatcanbeemployedtogeneratespecific classes of useful building blocks. Ynones and pyrazoles as primary building blocks The flow synthesis of ynones facilitated by in-line purification furnishes reactive building blocks for further transformation to numerous heterocyclic scaffolds.135 The attractive feature of this process is the ability to split the product stream and divert these towards different product outcomes by varying the subsequent coupling agents. Using palladium catalysis an acid chloride and acetylene can undergo a Sonogashira coupling to yield various ynones(Scheme16).Theacidchlorideandacetylenearecombined in flow with a stream containing a catalytic amount of Pd(OAc)2 and H¨unig’s base. The reaction was then heated at 100◦ C for 30 min and the reactor output purified by passage through a series of four solid reagents and scavengers. First, a polyol resin is used to remove excess acid chloride, then a column of CaCO3 to trap HCl formed during the reaction and to deprotonate any ammonium salts. The resultant tertiary amine base (iPr2NEt, H¨unig’s base) was next trapped on a sulfonic acid resin and finally a column of immobilized thiourea removes palladium contamination. The ynone products were thus obtained in high yield (41–95%) and purity following removal of the solvent. The ynones can be further elaborated by combination with an additional input stream containing a nucleophile such as a hydrazine or guanidine derivative. By uniting the flow streams and heating the resultant mixture the corresponding heterocycles can be prepared as a single linked flow sequence (Scheme 17). In this way, a collection of pyrimidines, pyrazoles, oximes, guanidines and flavones have been obtained. Diagnostics integrated with flow processes Owing to the dynamic environment of a flow process it is possible to effect rapid changes in reaction parameters leading to immediate downstream changes in the reaction conditions. Therefore utilizing real-time analysis of the flow stream it is possible to harvest large amounts of data regarding multiple J Chem Technol Biotechnol 2013; 88: 519–552 c 2012 Society of Chemical Industry wileyonlinelibrary.com/jctb
  • 532 www.soci.org IR Baxendale Scheme 10. Curtius rearrangements using DPPA. reaction parameters that can be usefully employed to rapidly optimize the transformation.136–138 Qualitative spectral data can be easily acquired using adjustable wavelength photodiode detectors (or similar spectrometers) placedasin-lineanalysiscells.Otherdiagnosticdevicescanbeused to report on reaction progress, e.g. impedance measurements, Ramanspectroscopy,nearorReactIR,fluorescencemeasurements and various bioassays. Alternatively, or in addition, automated sampling techniques can be used to divert aliquots of reaction media into auxiliary monitoring equipment allowing LCMS or GCMS to be assimilated into the system. Butane-2,3-diacetal protected diols synthesis React IR flow cells can be easily integrated to analyse flow streams in real time including monitoring for the presence of important transient or reactive intermediates (Scheme 18).139,140 We have used such a system to help evolve a flow route to various butane-2,3-diacetals (BDAs) which are key building block in many natural product syntheses. The flow approach allowed the BDA units to be prepared generally in higher yields and with higher reproducibility than the corresponding batch processes.141–145 For example, the BDA protected tartrate was obtained from a mixed stream of dimethyl-L-tartrate and trimethyl orthoformate and a stream containing butane-2,3-dione together with catalytic quantities of camphorsulfonic acid (CSA). Mixing the dimethyl-L- tartrate and trimethylorthoformate resulted in the formation of an intermediate orthoester which was observed using the ReactIR flow cell and was identified as an important reactive species in the diol protection. The processed product stream was finally purified using an immobilized benzylamine scavenger to remove any remaining butanedione and CSA catalyst which could again be confirmed using the React IR flow cell. A periodate resin was then employed to perform a rapid glycol cleavage of the residual tartrateestertogenerateavolatileby-productsthatcouldbeeasily removed. This enabled the generation of multi-gram quantities of the BDA protected adduct in a very reproducible fashion. Only evaporationofvolatileswasrequiredinordertoisolatetheproduct in a crystalline form. This BDA-protected tartrate was further used as a starting material in a two-step transformation first to furnish the unsaturated system by treatment with a strong base in the presence of iodine (Scheme 19). To clean up the reaction stream it wasquenchedwithsimultaneousremovalofthediisopropylamine (HNiPr2) by elution through a sulfonic acid resin whilst the excess iodine was scavenged using a thiosulfate resin. Finally, a short plug of silica gel was used to remove the inorganic salts. Next the selective hydrogenation of the alkene was achieved at scale using the H-cube Midi system (from ThalesNano) yielding the wileyonlinelibrary.com/jctb c 2012 Society of Chemical Industry J Chem Technol Biotechnol 2013; 88: 519–552
  • 533 Integration of flow reactors into synthetic organic chemistry www.soci.org Scheme 11. Synthesis of trifluoromethylated alcohols using a fluoride monolith. Scheme 12. Electrophilic fluorine reactions with Selectfluor. NHAc F NHAc F F OH F Cl NHAc F NHAc F NHAc F O O NHAc F F NHAc 97% 86% 86% 83% 91%96% 91% 89% Scheme 13. Ritter reactions performed using Selectfluor as an activator. J Chem Technol Biotechnol 2013; 88: 519–552 c 2012 Society of Chemical Industry wileyonlinelibrary.com/jctb
  • 534 www.soci.org IR Baxendale N N Cl F F NO2 Cl F O O 73% 97% 87% 83% 65% F NO2 OMe O N F88% F I F 83% F 80% TrtO F 92% OH F 50% 50% DAST, DCM, 0.3 mL/min, 60 °C O OMe F O OMe O OMe Br Br Br O Ph F 96% N N Cl F F N N Cl F F N N F F O O F F F F O2N N O Cl F F F F 86% 87% 89% 96% 75% 75% 83% N H O F FN N O O O O CN F F 71% 94% R H/R O Aldehydes/Ketones N F F 50% Alcohols R OH Scheme 14. Synthesis of mono or di-fluorinated products using DAST. N Cl O NN O RR R = Ph 95% R = iPr 92% R = tBu 90% N O Br N O O MeO 91%O NH HO R Dehydration O NF O N Cl F 87% MeO MeO N O O O 90% Scheme 15. Synthesis of oxazolines using DAST. corresponding meso reduced form in quantitative conversion using a Rh on alumina catalyst. A more challenging sequence was also investigated involving the generation of a BDA protected glyceraldehyde from the corresponding mannitol starting material (Scheme 20). When a small excess of butadione was used with gentle heating of the reaction stream (40◦ C) an optimum yield of the desired product was obtained. Applying the ReactIR system the procedure was quickly optimized to reduced the propensity for the formation of the tris-protected by-product. A column of benzylamine resin was used in-line at the end of the reactor to scavenge excess reagents generating a clean flow stream. From this protected material the half-aldehyde fragment was readily obtained by oxidative cleavage of the diol unit using a resin bound periodate oxidant (Scheme 21). Similarly, the analogous methyl ester could also be formed (via additional oxidation of the intermediate aldehyde) using an immobilized pyridinium perbromide resin. wileyonlinelibrary.com/jctb c 2012 Society of Chemical Industry J Chem Technol Biotechnol 2013; 88: 519–552
  • 535 Integration of flow reactors into synthetic organic chemistry www.soci.org Scheme 16. Synthesis of ynones. Scheme 17. Synthesis of pyrazoles and pyrimidines. In a final sequence a BDA protected glycolate, another useful building block, was synthesized using related procedures (Scheme 22).141,142 Applying similar conditions to those used for the tartrate protection reaction above, enantiomericly pure chloropropanediol was converted to the bis-acetal in 95% yield without racemization. Indeed, this conversion proceeded so efficiently that it was not necessary to incorporate the previously used periodate cleavage protocol to remove unreacted diol (cf. Scheme 18). The resulting chloride substituted product was then treated with a strong base to effect elimination furnishing the exo- alkene, the product stream being in this case collected into water and extracted in a typical batch fashion. Interestingly, the new flow procedure consistently produced high quality product, in an improved ratio of 24:1, exo:endo, compared with variable ratios of between 15:1 and 5:1 in batch. The final double bond cleavage employed a combination of Osmium EnCat and sodium perioidate with N-methyl morpholine as a solution-phase reoxidant to give the corresponding lactone. Clean-up of the reaction stream was affected by passage through a sulfonic acid resin to scavenge the morpholine then an immobilized thiourea to scavenge any leached osmium. Isolation of the pure lactone product involved only solvent evaporation. 3-Nitropyrrolidine building blocks A functionalized heterocycle that is becoming increasingly common in medicinal chemistry projects is the 3-nitropyrrolidine. J Chem Technol Biotechnol 2013; 88: 519–552 c 2012 Society of Chemical Industry wileyonlinelibrary.com/jctb
  • 536 www.soci.org IR Baxendale MeO2C CO2Me OH OH O O OO OMe OMe MeO2C MeO2C CH(OMe)3 MeO MeO MeO MeO Scheme 18. Mettler Toledo ReactIR Flow Cell and flow synthesis of BDA protected tartrate. Scheme 19. Flow synthesis of a BDA-protected tartate derivative. This versatile motif can be readily prepared using TFA (trifluoroacetic acid) or a fluoride source to generate a dipolar structure from N-(methoxymethyl)-N-(trimethylsilyl)benzylamine which will undergo cycloaddition with an alkene.143–145 Under flow conditions a stream of the nitroalkene with TFA can be combined with a second stream containing the coupling partner (Scheme 23).146,147 The united flow stream is then heated to facilitate the reaction and purified by scavenging with a benzylamine resin and a short plug of silica gel thereby removing any unreacted nitroalkene and releasing the product from its initially formed TFA salt. Optimization studies revealed that nitropyrrolidines could also be obtained under milder conditions when a fluoride monolith was used to generate the dipole component. Here the starting materials flowed through a heated fluoride monolith prior to scavenging with a benzylamine resin to afford pure products in high yields. Using the H-Cube flow hydrogenator (ThalesNano) selective reduction of the nitro group to the amine while retaining the benzyl group could be performed using a Raney nickel catalyst. This selective reduction ultimately enabled libraries of derivatives to be rapidly assembled for biological testing (Figure 13).148 Alternatively both the nitro reduction and benzyl deprotection could be achieved simultaneously when a Pd/C catalyst system was employed. Scheme 20. Flow synthesis of BDA protected glyceraldehyde. wileyonlinelibrary.com/jctb c 2012 Society of Chemical Industry J Chem Technol Biotechnol 2013; 88: 519–552
  • 537 Integration of flow reactors into synthetic organic chemistry www.soci.org Scheme 21. BDA protected glyceraldehyde aldehyde or ester. Scheme 22. Synthesis of BDA protected glycolate. Scheme 23. Synthesis of 3-nitropyrrolidines from the nitroalkene. J Chem Technol Biotechnol 2013; 88: 519–552 c 2012 Society of Chemical Industry wileyonlinelibrary.com/jctb
  • 538 www.soci.org IR Baxendale Figure 13. A small sample set of pyrrolidine templates prepared in flow. Triazoles 1,4-disubstituted triazole formation by copper(I) mediated [3+2] Huisgen cycloadditions of an organic azide with a terminal acetylene is of much current interest, with applications in many different areas from cell biology to materials science. Our group has used a series of immobilized reagent to prepare the triazoles products in flow (Scheme 24).149 The cycloaddition was catalysed using Amberlyst 21 (a benzylic dimethyl amine functionalized resin) preloaded with copper(I) iodide with the flow stream being directedthroughacartridgeofQP-TU(athioureametalscavenger) to remove any leached copper residues. Finally, an immobilized triphenylphosphine equivalent, PS-PPh2, was used to scavenge excess organic azide. This system afforded the desired compounds in high purity without the need for chromatography and with no Glaser homo-coupled acetylene products being observed. Although this type of ‘Click chemistry’ is synthetically very valuable it is restricted by the commercial availability of the starting materials. In addition the azide and acetylene coupling componentshaveassociatedsafetyconsiderationsregardingtheir synthesis and use especially at scale. Consequently it would be preferable to generate such species in situ and immediate use them without isolation. We therefore devised a set of protocols that allow the preparation of the individual units that can be readily telescoped into our previously described cycloadditions flow sequence as as shown in scheme 24. Azide formation We modified a set of batch conditions developed by Moses and coworkers150 as a convenient starting point for the development of a flow process for aryl azides (Scheme 25). However, in this transformation the resulting azide products are potentially contaminated with unreacted trimethylsilyl azide and aniline starting materials both of which are toxic. The trimethylsilyl azide can also be readily hydrolysed to toxic, volatile and highly explosive hydrazoic acid. Thus, contamination with unreacted starting material is not only a concern in terms of product purity, but presents an unacceptable risk in terms of process safety, particularly for large scale synthesis. Therefore, a scavenging protocol was developed to purify in-line the azide product stream usingreadilyavailableandinexpensivescavengerresins.Asshown in Scheme 25, following azide synthesis, the reaction stream passes through a scavenging column containing PS-sulfonic acid, followed by PS-dimethylamine. The PS-sulfonic acid traps any unreacted aniline (red band) while at the same time converting any remaining trimethylsilyl azide to hydrazoic acid, which is in turn trapped onto the QP-DMA (orange colouration). Having established a reliable sequence to these azide inter- mediates they can be telescoped into a number of additional transformations for example a Staudinger aza-Wittig reaction employing a monolithic triphenylphosphine reagent or cycload- ditions reactions to form 5-amino-4-cyano-1,2,3-triazoles.151,152 Acetylene formation The Seyferth–Gilbert homologation of an aldehyde using the Bestmann–Ohira reagent has been successfully run in a flow microreactor leading to the formation of acetylenes (Scheme 26).153 The aldehyde starting material along with the Bestmann–Ohirareagentwerecombinedwithasecondarystream of potassium tert-butoxide and introduced to a heated flow coil. The reaction stream was first scavenged with immobilized benzylamine to remove excess aldehyde, then a sulfonic acid resin to both remove excess base and protonate any phosphoric residues. Finally, a dimethylamine resin was employed to remove acidic impurities. The acetylene could then be collected in high yield. A small modification to the sequence was necessary for nitrogen-containing starting materials where the sulfonic acid resin was substituted for an alumina packed cartridge to avoid capture of the newly formed product. Demonstrating the full utility of working in a multi-step regime the Bestmann–Ohira reagent was further used in the direct transformation of an alcohol through to the corresponding triazoles in a single continuous sequence (Scheme 27). The wileyonlinelibrary.com/jctb c 2012 Society of Chemical Industry J Chem Technol Biotechnol 2013; 88: 519–552
  • 539 Integration of flow reactors into synthetic organic chemistry www.soci.org Scheme 24. Copper catalysed [3+2] Huisgen cycloadditions. Scheme 25. Formation of aryl azides in flow. benzyl alcohol starting material was first selectively oxidized upon passage through a column of immobilized TEMPO, with the resulting aldehyde reacting with the Bestmann–Ohira reagent under subsequently established basic conditions. The freshly generated acetylene was immediately coupled with the in situ azide (Cu catalysed) and progressed through the previously described train of scavenger and reaction cartridges to finally afford the triazole in high purity and 55% isolated yield after crystallization. Target orientated synthesis As has been aptly demonstrated flow chemistry is ideally suited to the rapid production of small building blocks enhancing the diversity of available structures by making use of the improved safety profile and extended processing windows inherent with the contained reactor design. The inclusion of high levels of automation and an improved safety profile also allow the option of preforming several traditionally ‘forbidden chemistries’ further expanding the chemical repertoire available to the operator. However, this is only a small component part of the wider task of a synthesis chemist who must also assemble these molecular fragments into more elaborate constructs. Here again, flow chemistry can be used to assist in the multi-step assembly process. Indeed, it is often more apparent what the true processing potential of flow chemistry provides when viewed in the context of a target driven synthesis. Preparation of casein kinase inhibitors As an illustration a four-step flow assisted synthesis of a series of casein inhibitors has been described.154 The route was developed J Chem Technol Biotechnol 2013; 88: 519–552 c 2012 Society of Chemical Industry wileyonlinelibrary.com/jctb
  • 540 www.soci.org IR Baxendale N OMe Cl H 78% N N H Cl 64% N H Me 71% H H H NO2 H Br Ph H H MeO2C H NO2 84% 79% >90% 77% 65% Cl O O 81% 82%73% H F3C H 88% Scheme 26. Synthesis of acetylenes using the Bestmann–Ohira reagent in flow. Scheme 27. Synthesis of a triazole direct from an alcohol starting material in a multi-step sequence. to allow variations of the substituents at positions 2, 3 and 6 of the imidazopyridazine core, in total a collection of 20 analogues were rapidly assembled. The sequence necessitated the development of a continuous flow method to safely scale up an organometallic reaction conducted at low temperature (Scheme 28). To provision the reactor a dual loop filling system was devized that enabled a constant supply of a butyllithium solution (or LiHMDS) to the reaction stream. By using a simple valve selection system one sample loop could be filled while the second fed the reactor. A rapid exchange between the two loops permitted an essentially seamless feed of the organometallic solution. In the second step an immobilized perbromide was used to enable mono-bromination through controlled contact time of the solution passing through the polymeric packed bed reactor (Scheme 29). The resulting mono-bromo intermediate was immediately subjected to a high temperature condensation reaction with 6-chloro-3-pyridazinamine to furnish the bicyclic imidazopyridazine core. Finally, a liquid handler was used to wileyonlinelibrary.com/jctb c 2012 Society of Chemical Industry J Chem Technol Biotechnol 2013; 88: 519–552
  • 541 Integration of flow reactors into synthetic organic chemistry www.soci.org Scheme 28. Organolithium deprotonation in flow. automate sequential compound generation through an SNAr reaction to give amine diversified imidazopyridazine derivatives (Figure 14). The ability to access low temperature domains for chemical processing is a vital prerequisite for many selective chemical transformations. As well as impacting upon selectivity it can also influence the stability of many chemical reagents such as organometallic reagents and facilitates control of reaction rates reducing the propensity for uncontrolled run away reactions. This therefore becomes particularly important when considering process development routes and scaled manufacture where cryogenic temperatures also become expensive and challenging engineering problems. It has therefore been of significant general interest to the chemical community that as a consequence of their high surface to volume ratios many microreactor systems display excellent heat transfer charactoristics.155–158 This often means a greater stability in reaction temperature especially when mixing reactive reagents. As a consequence many reactions can be effectively conducted at higher temperatures than would be possible under the corresponding classical batch set-ups (a lower temperature is often used in batch to compensate for the formation of hot-spots, mixing fluctuations and inherent reactor gradients – cooling from the outside of the reactor towards the centre). Because of the high surface to volume ratio encountered in many flow systems (coil and chip reactors) cooling is very efficient. We have evaluated the potential of scaling processes under reduced temperatures for example the formation of the versatile coupling components aryl boronic acids (Scheme 30).159 Two independent flow streams were pre-cooled in a short length of tubing prior to being combined and reacted at −60◦ C. The halogenated aromatic underwent lithium halogen exchange and then rapidly quenched upon the pinicol boranate ester in situ. The newly formed ate species was decomposed under acid conditions using an in-line sulfonic acid quench. To conveniently establish the cryogenic conditions we made use of a polar bear flow reactor (Figure 15). The device allowed the continual running of the reactor at low temperatures for several days with a consistent and stable temperature, there is no need to supply coolant or dose the device with liquid nitrogen or dry ice and so maintenance and user involvement is minimal. Consequently we were able to generate libraries of boronic acid components and also conduct scaled experiments by simply running the reactor for a longer period of time. Target orientated synthesis of a 5HT1B antagonist A seven-step batch synthesis of the potent 5HT1B antagonist developed by AstraZeneca160 was previously described in an overall yield of 7%. This synthesis consequently became a benchmark for the evaluation of the potential benefits of using flow chemistry for target development (Figure 16). Our flow synthesis of this pharmaceutical was instigated by combining streams of 3-fluoro-4-nitroanisole and piperizine at 135◦ C to promote the SNAr. The exiting reaction was scavenged with a benzylamine resin to remove the liberated hydrofluoric acid priortoitstransmissiontoacontinuousflowhydrogenation.161 The outflow containing the aniline intermediate was scavenged with a thiourea resin to ensure complete removal of any potentially leached palladium species (Scheme 31). Following a solvent switch, from ethanol to toluene, the flow stream containing the newly formed aniline was combined with a solution of dimethyl acetylenedicarboxylate and heated. An in-line scavenge for residual dicarboxylate and the use of anhydrous potassium carbonate to remove traces of water allowed the stream to be telescoped into a high temperature cyclo-condensation reaction. An in-line BPR operating at 250 psi was fitted to the system to maintainthesystempressureunderthesesuperheatedconditions. The output stream from the stainless steel reactor coil was rapidly cooled to ambient temperature and mixed with a third input flow of THF/H2O. The combined flow stream was then progressed through a column containing an ion exchange hydroxide resin which promoted ester hydrolysis and simultaneous capture of the resulting carboxylic acid on the basic resin. The final step involved J Chem Technol Biotechnol 2013; 88: 519–552 c 2012 Society of Chemical Industry wileyonlinelibrary.com/jctb
  • 542 www.soci.org IR Baxendale Scheme 29. Construction of a series of imidazopyridazine compounds in flow. Figure 14. Compound collection of casein kinase inhibitors. an amide coupling reaction and a catch-and-release purification. This was conducted by flowing a solution of O-(benzotriazol- 1-yl)-N,N,N ,N -tetramethyluronium tetrafluoroborate (TBTU) and HOBt (hydroxybenzotriazole) through the column containing the immobilized carboxylate intermediate. This resulted in activation ofthecarboxylatebyformationoftheactiveestertherebyreleasing it from the resin. The flow stream containing the HOBt-activated ester was directed to merge with an additional stream of 4-morpholinoaniline leading to amide coupling. Purification of the reaction stream was achieved using a ‘catch-and-release’ strategy with a sulfonic acid containing column. This resulted in trapping of the product which was washed and subsequently released by eluting with methanolic ammonia. The final solution was concentrated and the crude inhibitor isolated by recrystallization wileyonlinelibrary.com/jctb c 2012 Society of Chemical Industry J Chem Technol Biotechnol 2013; 88: 519–552
  • 543 Integration of flow reactors into synthetic organic chemistry www.soci.org Scheme 30. Synthesis of aryl boronic acids at reduced temperatures. Figure 15. The polar bear cold flow reactor from Cambridge Reactor Design. Figure 16. AstraZeneca’s 5HT1B antagonist. to obtain an 18% overall yield of the product effectively trebling that of the original batch process. δ-opioid receptor agonist The use of a React IR flow cell to evaluate reaction progression greatly aided in the construction of the multi-step synthe- sis of N,N-diethyl-4-(3-fluorophenylpiperidin-4-ylidenemethyl)- benzamide, a potent δ-opioid receptor agonist originally devel- oped by AstraZeneca (Scheme 32).162 A twofold excess of the Grignard reagent, diisopropylmagnesium bromide, was used as a base to catalyse amide formation between diethylamine and the methyl ester and then to further deprotonate the bridg- ing methylene group which was subsequently added into a Boc-protected piperidinone. The resulting tertiary alcohol was quenched and scavenged by passage through a sulfonic acid con- taining cartridge, with any residual piperidinone being removed via a hydrazine functional resin. The React IR cell was positioned in the flow path at the end of this series to determine the disper- sion and effective concentration of the passing alcohol product stream. This enabled the controlled and automatically regulated introduction of a solution of Burgess’ reagent to meet the alcohol inducing the dehydration at an elevated temperature. The final stage of the process involved a ‘catch-and-release’ purification on a additional column of sulfonic acid resin which at 60◦ C also pro- moted the cleavage of the Boc-protecting group. The release step was conducted with a solution of ammonia in methanol allowing the isolation of the target molecule in an impressive 35% overall yield and in high purity. Imatinib (Gleevec) The synthesis of the tyrosine kinase inhibitor Gleevec, a treatment for chronic myeloid leukaemia and gastrointestinal stromal tumours, proved an interesting test of the capabilities of flow J Chem Technol Biotechnol 2013; 88: 519–552 c 2012 Society of Chemical Industry wileyonlinelibrary.com/jctb
  • 544 www.soci.org IR Baxendale Scheme 31. Flow synthesis of 5HT1B antagonist. chemistry since all the previous batch syntheses involved the generation of very insoluble intermediates.163,164 This is an issue which is often raised as a significant hurdle for the wider adoption of flow processing. Nevertheless, a flow synthesis was realized through a reverse coupling strategy to that employed in the batch route.165,166 Following Scheme 33, solutions of the appropriate acid chloride and aniline coupling partner were united prior to entering a flow coil generating the corresponding amide. The product stream was collected using an automated fraction collector (triggered by a UV detector) after its passage through an in-line acid and base scavenger sequence. The product aliquot was collected into an incubated vial which already contained a known concentration of N-methylpiperazine in DMF. A nitrogen gas purge was then used to evaporate the volatile DCM solvent producing a homogeneous DMF mixture of known relative stoichiometry ready for the next transformation. Both the collection and reintroduction of the reaction solution into the system was automated via the use of an autosampler. Passage of the reaction mixture through a heated column containing calcium carbonate, as a basic media, promotedthesubstitutionofthebenzylicchloride.Animmobilized isocyanatespeciesplacedin-lineensuredcompleteremovalofany excess N-methylpiperazine allowing the product to be efficiently caught onto a column of silica-supported sulfonic acid. After washing, the product was released from the silica support by elution with a solution of DBU (the base for the next step). The solution was then subjected to a Buchwald-Hartwig coupling with an advanced amine fragment prepared as described in Scheme 17. Following an extensive screening study the most effective catalyst system was found to be the ligand stabilized BrettPhos Pd pre- catalyst. It was further discovered that the introduction of an additional water stream input just prior to the reactor exit aided dissolution of precipitate salts ensuring easy separation at the end of the sequence. The organic output was concentrated in vacuo and directly loaded onto a silica samplet cartridge for automated flash chromatography to give imatinib in 32% yield and greater than 95% purity. Using the same sequence but modifying the various inputs also allowed the generation of several derivatives (Figure 17). Running the reactor set-up in a fully automated mode allowed a new compound to be generated on average every 8 hours. Grossamide As an example of using directed feedback routines to optimize and facilitate the synthesis of new materials the assembly of the natural product grossamide is a key defining synthesis (Scheme34).167 Anumberofimportanttechniquesandprocedures were brought together in this work that have been significant in influencing many recent multi-step syntheses: (a) both the input of starting materials and the product elution were controlled using liquid handlers; (b) throughout the optimization process, the reactions were monitored using in-line LC-MS analysis enabling flow rates and stoicheiometries of reagents to be changed in order to deliver the product in maximum yield and purity; and wileyonlinelibrary.com/jctb c 2012 Society of Chemical Industry J Chem Technol Biotechnol 2013; 88: 519–552
  • 545 Integration of flow reactors into synthetic organic chemistry www.soci.org Scheme 32. Preparation of a δ-opioid receptor agonist. Scheme 33. Flow synthesis of the tyrosine kinase inhibitor Gleevec. J Chem Technol Biotechnol 2013; 88: 519–552 c 2012 Society of Chemical Industry wileyonlinelibrary.com/jctb
  • 546 www.soci.org IR Baxendale Figure 17. Gleevec derivatives formed using the automated flow reactor. (c) the system employed a number of automated exchangeable reagent columns, and an in-line UV detector was used to monitor the flow stream’s progress. This enabled many valve switching operations to be performed automatically under computer control. For the initial amide bond forming reaction we built upon our previous work constructing peptides in flow (Scheme 4).87 In this case (Scheme 34) the desired amide was synthesized by coupling tyramine and ferulic acid using the immobilized HOBt protocol previously described. Following elution from the sulfonic acid scavenging column the product stream was diluted (3:1) with a second input solution containing a hydrogen peroxide–ureacomplexandsodiumdihydrogenphosphatebuffer (pH 4.5). The entire mixture was then passed through a pre- packed column containing the enzyme horseradish peroxidase (type II) supported on silica to perform the oxidative dimerization and intramolecular cyclization to yield grossamide. This compact synthesis demonstrates many advantages of drawing together enabling technologies such as automation, immobilized reagents, enzymatic reagents and flow chemistry to generate complex chemical structures. One major advantage of flow chemistry and the level of automation that is involved is that once a synthetic sequence has been worked out and implemented, it is relatively trivial to perform the same reaction again. Indeed, many of the operational parameters can be simply reloaded into the software from the original run providing duplicate reaction conditions. We have used this approach to repeatedly prepare quantities of various coumarin-8-carbaldehydes as selective IRE1-binders for investigations of mRNA splicing (Scheme 35).168 Having access to freshly prepared material has been benifical for the biological work as the aldehyde substrates tend to undergo auto oxidation upon storage. One particular route to these molecules is depicted in the scheme as shown below. The synthesis provides clean, easily isolated material (via filteration) which requires only drying prior to use. Furthermore, the operation of the reactor can be performed by numberous people and actually requires very little chemical experience in order to conduct the repeat synthesis. This significantly increases access times to these compounds when scheduling time allocation in a busy synthesis laboratory.169,170 Oxmaritadine A further convincing showcase for this mode of working is the total synthesis of the biologically interesting natural product oxomaritidine which utilizes a combination of scavengers and five different immobilized reagents to conduct each of the eight contiguous steps of the sequence (Scheme 36).171 The initial step of the synthesis involved the transformation of 4-(2-bromoethyl)phenol to its corresponding azide which was achieved by the action of a packed bed azide exchange resin. The output stream containing the organic azide was then directed into a second column containing an immobilized phosphine species; this resulted in the formation of a solid- phase aza-Wittig intermediate. In a convergent sequence the aldehyde, 3,4-dimethoxybenzaldehyde, was prepared. For this reaction a column of polymer-supported tetra-N-ethylammonium perruthenate (PSP) was used to oxidize the prerequisite alcohol, and the aldehyde product stream was passed directly into the column containing the aza-Wittig intermediate, reacting to yield the imine adduct. This imine-containing solution flowed on and was next subjected to continuous flow hydrogenation using an H-Cube system, to yield the resultant secondary amine. A solvent exchange was affected using a V-10 solvent evaporator and the crude material re-dissolved in DCM for continued processing. The amine solution was next passed into a microfluidic reaction chip to combine with an additional stream of trifluoroacetic anhydride (TFAA) resulting in trifluoroacetylation of the amine. The reaction stream was directed through a column of polymer- supported (ditrifluoroacetoxyiodo)benzene (PS-PIFA) which acted to perform the phenolic oxidative coupling, generating the seven-membered spirodieneone. Finally, removal of the amide protecting group was conducted with a column of hydroxide ion-exchange resin, acting to facilitate deprotection of the secondary amine which spontaneously undergoes cyclization to give oxomaritidine in 40% overall yield and 90% purity. The entire route took only approximately 6 h of flow processing time which compares favourably with the batch run time of about 4 days. CONCLUSION Althoughflowchemistryhasalreadyprovenitselfasavaluabletool in manufacturing settings its adoption for small-scale laboratory applications or within research environments has until recently only been via a small number of enthusiastic pioneers and innovators.However,thereisarapidlyexpandingbodyofscientific evidence which continues to demonstrate the tremendous benefits and enhanced processing capabilities inherent to the wileyonlinelibrary.com/jctb c 2012 Society of Chemical Industry J Chem Technol Biotechnol 2013; 88: 519–552
  • 547 Integration of flow reactors into synthetic organic chemistry www.soci.org Scheme 34. Flow synthesis of Grossamide using in-line LC-MS monitoring. Scheme 35. Synthetic flow route to coumarin-8-carbaldehyde. J Chem Technol Biotechnol 2013; 88: 519–552 c 2012 Society of Chemical Industry wileyonlinelibrary.com/jctb
  • 548 www.soci.org IR Baxendale Scheme 36. The multi-step flow synthesis of oxomaritidine using solid-supported reagents. bench chemist by embracing flow processing. Consequently, even many of the original sceptics are now exhorting the merits of flow synthesis. However, despite the growing acceptance and adoption of this technology it is certainly true there are still a number of limitations that need to be overcome in order for it to be truly accepted as a mainstream chemistry technique. For example, one important pre-requisite in flow chemistry is the choice of an effective solvent that avoids precipitation that can lead to blockages in the flow pathway. Although this is often over-emphasized as a critical issue (as it can be easily avoided) it does still require careful consideration as part of the synthesis planning stage and so imparts certain restrictions. Furthermore, in many synthetic routes it is also essential to be able to modify concentrationsorfullyexchangesolventsbetweensteps,therefore to harness the full benefits of continuous flow synthesis this should ideally be accomplished as part of an in-line telescoped sequence in a fully automated fashion. Without this facility to make adjustments to the reaction solution the complex multi-step synthetic transformations which are currently regularly performed in batch will always remain difficult to translate to flow. Therefore a greater degree of development is urgently needed with regard to procedures and equipment for direct solvent exchange and in- line evaporation. In fact the whole area of downstream chemical work-up and purification is becoming an increasingly important aspect of flow processing. Currently very few practical solutions to continuous reaction quenching and aqueous extractions are available within research environments despite these already existing for use at large scale (i.e. counter current extraction methodologies). This is obviously limiting the scope and wider adoption of flow technologies. Heavily linked to synthesis in the future will be a direct increase in the real time monitoring and analysis of each stage of the chemical process. Advances in the integration of diagnostic tools will enable greater use of smart automated monitoring routines capable of first harvesting comprehensive reaction data and then interpreting the results to make informed decisions regarding the minor calibration and tailoring or full optimization of an operation. This work is currently a major research area which will rapidly expand the capabilities of many flow operations. In the long term, the future of flow chemistry hinges, more, upon its ability to adapt rapidly to the demands of changing scale, allowing the reproducible production of varying quantities of final product for multiple applications in short time frames. New flow platforms will be required to generate both large numbers of structural diversity products albeit in small quantities for high- throughput screens yet also simplify the operational up-scaling of theroutestofurnishhundredsofgramstokilogramsforearlystage physiochemical profiling and toxicology testing. Of additional interest will be the concept of ‘make and screen’ which attempts to remove a traditional bottleneck in the discovery process by link- ing the synthesis component to rapid in-line biological evaluation or property determination. Indeed, the processing requirements to only prepare and then evaluation a microgram or less of a final material would considerably reduce cycle times, streamline wileyonlinelibrary.com/jctb c 2012 Society of Chemical Industry J Chem Technol Biotechnol 2013; 88: 519–552
  • 549 Integration of flow reactors into synthetic organic chemistry www.soci.org compound logistics and ultimately lead to reduced synthesis cost. In addition it becomes entirely possible to address several biolog- ical or physical assays at once. For example, a single experiment could provide kinetics in terms of on- and off-rates directly yielding a comparable measure of affinity and activity. Simultaneously in another part of the system measurements of other physical char- acteristics such as pKa, log P or solubility could be taken by simply diverting part of the synthesis product flow stream. Many of the fundamental requirements in terms of information retrieval and flexibility of synthetic implementation seem ideally suited to a flow based approach to chemical synthesis. 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