The integration of ﬂow reactors into synthetic organic chemistry

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ReviewReceived: 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 syntheticorganic chemistryIan R. Baxendale∗

Abstract

The material presented in this review is based upon discussions and interactions with members of the Department of Chemistryand Biochemistry within the University of Windsor, Ontario, Canada. This article explores the changing face of chemicalsynthesis with regard to the impact of flow based chemical processing technologies. Highlighted works from the InnovativeTechnology Centre (ITC), Cambridge, UK, are used to illustrate the alternative synthetic practices available to modern researchchemists. The dominant theme of the review is the synergistic effects encountered by combining the advantages of continuousprocessing 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 CAPABILITYIn recent years great advances have been made in our ability todesign assemble and test the products derived from chemicalsynthesis. From the development of drugs in the ongoing fightagainst disease to the more aesthetic aspects of society with thepreparation of perfumes and cosmetics, synthetic chemistry is thepivotal science. Furthermore, the quality and quantity of our foodsupply relies heavily upon synthesized products, as do almost allother aspects of our modern society ranging from paints, pigmentsand dyestuffs to plastics, polymers and other man-made materials.

As chemists our scientific and creative capacity to assemblecomplex functional molecules from small chemical buildingblocks has reached an impressive level of sophistication.Much of this has been permitted as a consequence of ourgreater understanding of chemical mechanics and molecularinteractions (e.g. Quantum mechanics, Frontier orbital theory,in silico design). However, the standardization of synthetic routeplanning using theoretical methodologies such as retro-syntheticanalysis or reaction selection and optimization through the useof 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 seentremendous change and progress is the analytical andcharacterization tools that are now available. It would beunthinkable to most modern molecule markers to embark ona chemical route without having access to high resolutionNMR facilities, X-ray crystallography or some form of automatedanalysis such as LC- or GC-mass spectroscopy. These and relatedtechnologies have significantly enriched the information we aschemists can derive from crude chemical reactions helping inreaction profiling or aiding in elucidating the structural specificsof the synthesized compounds. Indeed, characterization andconfirmation of a compounds identity that only a decade agowould have been a week’s hard intense manual work can nowbe processed and validated against literature sources in less than

a day. Such resources have as a consequence greatly enhancedthe quality and quantity of new chemical structures that can besynthesized.

Furthermore, having easier on-line access and the ability tocall upon published or in-house archived chemical informationat the touch of a button has certainly affected the way in whichwe approach and conduct chemical synthesis. The large numberof chemical search tools and literature- based databases that areroutinely available means that a greater degree of precedence canbe brought to bear on a chemical problem. This can enable theodds to be stacked in the favour of the chemist by predeterminingthe most appropriate sequence of reactions or offering alternativestrategic bond forming reactions that can provide lower costs,alternative starting points or simply higher yielding processes. Tofacilitate the searching and recording of new chemical data manyinstitutions and companies are adopting electronic laboratorynotebook (ELN)6 systems that will further enhance the level ofdata retention and information that can be called upon for futurechemical syntheses.

The combination of many of these features has allowed forthe discovery of many new chemical transformations leading tounique chemical architectures and the discovery of several novelreagents with highly specific chemical reactivities. This in turn haspropagated and accelerated the rapid expansion of several areas ofsynthesis such as organometallic chemistry, asymmetric synthesis

and catalyst promoted processes including organocatalysis.7–11

It is probably not unreasonable to conclude that with the currentlevel of knowledge and synthetic tools almost any molecule thatwe may wish to prepare could be synthesized in a reasonabletimeframe.

∗ Correspondence to: I.R. Baxendale, The Department of Chemistry, Durham Uni-versity. South Road, Durham, DH1 3LE, UK. Email: [email protected]

The Department of Chemistry, Durham University, South Road, Durham, DH13LE, UK

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www.soci.org IR Baxendale

Reaction(heat/cool)

Quench/Work-upPurify

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, evaporationof 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 requiredpure fractions).

Pureproduct

Figure 1. General processing sequence of a chemical reaction.

However, despite all the obvious successes resulting from oursynthesis programmes the fundamental way in which we physicallyconduct chemical synthesis has remained relatively unchanged for

over two centuries.12–14 Remarkably, apparatus such as standardglass round bottom flasks, condensers, measuring cylinders, testtubes and Bunsen burners are all still commonly in use todaydespite them being invented over 160 years ago. Consequentlylaboratory practices have also become standardized to make thebest use of these tools and associated pieces of equipment. Astandard sequence for a reaction today and over a century agowould still be easily recognizable to both bench chemists (Figure 1).

From a simple analysis of the individual processing steps itis evident that for a single chemical transformation, which mayinvolve only one bond-forming or bond-breaking event, a series ofup to six additional manipulations (work-up and purification) canbe required. Interestingly, these supplementary operations, whichare essential but costly (in time and resources), add very littleintrinsic value to the compounds; they are necessary only becauseof inefficiencies in our current synthetic practice (removal of spentreagents and by-products).15 Many of these deficiencies result frompoor reactivity, low selectivity, incomplete reaction or extensiveby-product formation which is often a result of poor mixingand temperature control in conjunction with the use of highlyreactive reagents. Our current chemical inclination is often to selectreagents for a particular transformation based on their enhanced(high) reactivity thereby leading to quick chemical transformations(short reactions times). However, the flip side of such a selection isthat the highly reactive reagents are less stable, being more proneto decomposition and offering a higher potential for side reactions(resulting in more waste). Consequently, a greater emphasis isultimately placed on purification, often translating into the needto resort to column chromatography to facilitate the removalof numerous small impurities. Interestingly, this is often stillthe preferred option of many chemists even balanced againsta reaction with a longer processing time (no manual intervention)yet then enabling a simple crystallization or distillation as theonly required work-up and purification. This philosophy ofquick and dirty chemistry coupled with substantial investmentin purification technology such as HPLC has largely been drivenby a time pressured discovery industry (both pharmaceutical andagrochemical lead discovery) feeding a high throughput screening

monster.16–20 Unfortunately, such an approach, although fulfilling

a role, does not ideally align itself with performing highly efficientand well optimized chemical synthesis.

In addition the physical structure of the apparatus and typesof manipulation used in the reactions also impart limitations interms of the scale at which most synthesis can be conducted.The ease of manual handling and the dimensions of the reactionflasks used in standard laboratories define the practical lowerlimit range to millilitres and hundreds of milligrams of substances(without utilizing additional specialized equipment). Indeed, evensmall-scale syntheses are often calibrated not due to a needfor such quantities of material but as a consequence of humanhandling and convenience.21 This can mean that over longsynthetic sequences large quantities of starting materials arerequired in order to elaborate the structures (loss of materialthrough incomplete reaction, by-product formation or manualintervention). Furthermore, testing and optimizing the requiredsynthetic steps involves a significant investment of time andmanpower as well as precious substrates/reagents. This iscompounded by the complexity of evaluating and tuning themany interlinked variables and parameters (for example, reactiontimes, temperature, solvents, concentration, catalysts/additivesand stoichiometry) that can affect each chemical reactionsoutcome (i.e. regiochemistry, stereochemistry, purity and yield).

Considering all these negative/impinging factors we need torecognize the limitations of current working practice and acknowl-edge the need for improvement. This is especially true if we wishto move to more sustainable chemical practices, as we must, if weare to protect our rapidly dwindling natural resources. Thereforein order to safely respond to the requirements of improvingproductivity and efficiency we must embrace new opportunitiesand explore alternative approaches to compound synthesis. Thecurrent costs, scale-up issues, lack of reproducibility, manpowerwastage through repetitive and or routine tasks are unacceptable;therefore change is inevitable and should be embraced.

AN ALTERNATIVE SYNTHESIS STRATEGYDuring the last decade there has been a steady growth ininterest within the chemical community for flow based approachesto synthetic targets due to the inherent benefits such asautomated and telescoped reaction sequences, quick reaction

optimizations and in-line work-up and purification.22–48 Theholistic nature of flow chemistry targets many aspects of both

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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 bothenvironmental and economic drivers. Indeed, flow synthesis cutsacross several traditional boundaries within the sequential scalingroutes of syntheses (research scale, re-synthesis, kilo labs andfull scale manufacturing/formulation), combining aspects of bothchemical optimization and process intensification (Figure 2). Asa result it is a prerequisite to develop a working knowledge ofboth the science of synthesis and an understanding of chemicalengineering principles. Consequently conducting flow chemistryrequires significant changes in synthesis planning and executionand so we should be confident that the benefits derived are worththe change in working practice. After all chemists have had over230 years to perfect current synthesis techniques so why shouldwe suddenly attempt to change all this, what real benefits canbe derived? This is a sensible question to pose and one that maytake academia and industry several years to fully evaluate anddetermine where the best returns can be made. In the meantime,it is hope that throughout this article a number of areas canbe discussed which can already be adopted by synthesis groupsproviding definable and tangible benefits.

FLOW CHEMISTRY: BACKGROUNDExamples of flow-based chemical syntheses have existed forseveral decades49 and are in fact a well-established practiceat manufacturing scales especially for the production of largequantities of a given material. However, the innovative uses offlow in the early stages of synthesis development – laboratorybased synthesis – are far less common. Unfortunately, although theconcepts of increased mixing efficiency, controlled scaling factors,enhanced safety ratings and continuous processing capabilitieshave all been well recognized, these benefits have not beengenerically 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 techniquesmainly driven by the availability of several commercial laboratory

flow synthesis platforms.52–61 During this period most academicliterature within the field has focused primarily upon aspects offlow equipment development or its application to esoteric singlestep reactions using the expanded processing window capabilitiesthat are available (Figure 4). Significantly less effort has beendirected at the more challenging issue of devising general andversatile platforms capable of performing multi-step syntheses andleading to pure final products that can be used directly in biologicalevaluations or for the determination of some other fundamentalphysical property.62–64 This is particularly important as it hasbecome increasingly apparent that the task of chemical synthesismust become more closely linked with the immediate testing ofthe newly prepared product. Working the two aspects in isolationinherently leads to wasted synthesis time and the generation ofunwanted materials. Therefore more integrated and continuousrelay of information regarding the ongoing synthesis and itsproducts in terms of basic characterization, physical propertyand biological/physical functions needs to be addressed. This actof immediately gathering and analysing such data will ultimatelyenable more educated and responsive choices to be made, varyingfrom mundane factors such as reaction optimization to higher leveldecisions about which molecules should be synthesized next.Although such a change will have a broad impact across all areasof chemical production it will undoubtedly have a more drasticand immediate effect on the production of therapeutic entities.

Although flow based chemical processing does provide manyadvantages it should also be noted it does create certain inherentdifficulties when considering multi-step synthesis, such as: (i)compensating for the kinetics of the different reaction steps(integrating reactions in sequence with different reaction times); (ii)compatibility of the solvent with all reaction steps; hence creatingthe potential need for solvent switching protocols; (iii) the need

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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 preparativepurification (preventing by-product build-up); (iv) dilution effectsof adding additional downstream flow streams; and (v) monitoringand control of each concurrent operation. As such, although thereare many advantages to be gained from adoption of flow synthesisapproaches, a strong synthetic experience and good engineeringunderstanding are essential to fully reap the benefits.

Flow chemistry for multi-step chemical processingConceptually, if a sequence of stepwise reactions can be performedall in the same solvent (or a simple mechanism for solventexchange is available), and each reaction is highly optimizedthen the reactions could be easily processed in tandem. In thisway the reaction mixture for one step becomes the reactant/s forthe next chemical transformation creating a telescoped sequence


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A

B

Figure 5. Processing modes of tandem chemical reactions.

(Figure 5(a)). In addition moving from a batch based workingregime to a continuous flow mode would significantly simplify theprocessing requirements in terms of scheduling and manipulationof the solutions (Figure 5(b)). Such an idealized scenario is in reality,not feasible, due to the inevitable lower conversions and the needto quench reactions, work-up intermediates and consequentlypurify the reaction streams between chemical transformations. Itis however, possible to combine another enabling technology,namely, solid-supported reagents and scavengers to facilitate thisprocess and maintain a continuous flowing sequence.

Solid-supported reagents and scavengers in flow chemistrySolid supported reagents have been used extensively in multi-

step organic syntheses in batch.65–83 Ideally, the use of suchreagents should provide clean products without chromatography,crystallization, distillation or any traditional work-up procedures.

Supported reagents are reactive species that are associatedwith a heterogeneous support material.84 They transform asolution resident substrate (or substrates) into a new chemicalproduct (or products), with the excess or spent reagent remainingtethered to the solid matrix making separation a simple processes.In a similar fashion, impurities can be removed from a flowstream using a scavenger species immobilized on a support. Thisscavenger creates either an electrostatic or covalent interact withthe impurity, sequestering it from solution and binding it to thesolid matrix thereby effecting purification of the reaction stream.By utilizing these supported components packed into simplecolumns or reactor cartridges it is immediately possible to performmulti-step organic sequences employing an orchestrated suite ofsupported reagents to effect all the chemical transformations andpurifications.

As an illustration we have investigated the formation of 4,5-disubstituted oxazoles in flow facilitated by solid-supportedreagents.85 An isocyanide and an acid chloride were mixed usinga glass microfluidic chip (274 µL or 1 mL in volume), typicallyheated to 60◦C, forming a reactive adduct (the imidoyl chloride);the stream was then passed through a column containingan immobilized P1 base, PS-BEMP, which facilitated cyclizationforming the oxazole (Scheme 1). In the sequence a slight excess

of the acid chloride starting material was used (1.1–1.2 equiv.) toensure complete consumption of the corresponding isocyanidecoupling partner. The residual acid chloride was later removedby scavenging using a column of QP-BZA (a macroporous benzylamine resin). Using this approach a small library of 23 compoundswas generated, with yields in the range 83–98% and all membersbeing 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 alsobe 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 columncould be quickly regenerated for repeated use by washingwith a solution of BEMP in hexane or either NaOMe or tBuOKin MeOH.

Interestingly, when these same oxazoles forming reactions wereconducted in batch the yields were generally poor, typically ≤50%.The improvement in flow was ascribed to the different mixingregime used to form the initial imidoyl chloride intermediateunder neutral conditions then rapidly processing this speciesusing an in-line base. In addition, the scaled synthesis of thesecompounds could be achieved by simply using larger columnsof supported reagents and allowing the system to run for longerperiods of time (∼12 h, generating 10–25 g), clearly illustratingthe versatility of the instrumentation and the potential scalabilityof this technology.

In these oxazole forming reactions the reactant concentrationwas typically of the magnitude of 0.75 mol L–1 concentration. Thiswas selected as a standard value at which to prepare stock solutionsas several of the starting materials and resulting products werehighly crystalline and at higher concentrations proved insoluble.The insolubility of materials in flow chemistry is a potential majorlimitation (due to blockage of the reactors) and obviously needscareful consideration in the planning stages. This aspect canalso be compounded by the in-line scavenging process whichincreases the purity of the reaction stream making crystallizationor precipitation a more likely occurrence. Consequently for librarypreparation using a variety of starting materials with differingsolubility remove or when employing a new/unknown reactionit is often advisable to initially run the reaction under increased


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N

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EtO

O92%

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3-NO2; 85%4-CF3; 84%4-Br; 85%

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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

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R

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Scheme 1. Synthesis of 4,5-disubstituted oxazoles using a flow reactor.

dilution. Running the reaction for longer periods of time can stillgenerate significant quantities of material using this approach orthe stock solutions can be made more concentrated for subsequentruns or systematically increased during the same run period. Anadvantage of flow processing is that stock solutions do not needto be prepared in bulk, consequently with knowledge of the flowrates being used it is possible to prepare additional volumes ofstock solution and by judicious modification of the flow ratessubstitute the new reactant solutions at opportune timings. Inthis way a staged concentration increase can be applied to thereactor to maximize the throughput for a given reaction. Thisis particularly beneficial when scaling a chemical transformationand is significantly enhanced when employing in-line monitoringtechniques that allow for the rapid re-optimization of the reactorconditions (temperature/flow rate) following a change in reagentconcentration thereby establishing a new steady state operation.

The accessible chemical structures were further expanded usingisothiocyanates and carbon disulfide as electrophiles, providing abifurcated route for the preparation of thiazoles and imidazoles.86

When aryl isothiocyanates inputs were used, often initially alow yield of the desired thiazole was obtained from the reactor

(Scheme 2). However, by eluting the PS-BEMP column with anadditional flow stream containing an electrophile (an α-bromoketone in the example shown), the regioisomeric imidazoleadduct could be isolated, providing combined yields of 76–100%(Scheme 3). Investigation of the initially formed intermediatesuggested an open chain species was becoming trapped on theresin, 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 andcarbon disulfide furnished a collection of the corresponding S-alkylated thiazoles, again in good yields (72–97%) and excellentpurities.

We have also adopted similar strategies for the synthesisof peptides in flow, generating rapidly optimized, highlyreproducibly, automated sequences that yield the desired productin high purity; and isolated yields of 50–200 mg from a singleinjection.87 In a standard procedure an N-protected amino acidis pre-treated with PyBrOP, prior to flowing through a column ofPS-HOBt. The activated amino acid reacts with the immobilizedHOBt thereby becoming sequestered onto the solid phase asthe corresponding active ester (Scheme 4, Step 1). During the


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Scheme 2. Synthesis of thiazoles in flow.

Scheme 3. Bifurcated synthesis of imidazole using solid-supportedreagents.

loading sequence any unreacted starting material or by-productscan be washed through the column and directed to waste. TheHOBt-supported ester column is then automatically connectedin-line to a series of other reagents: PS-DMAP, and PS-SO3H (apolymer-supported sulfonic acid) (Scheme 4, Step 2). A solution ofa second, O-protected, amino acid as its hydrochloride salt is theneluted through the column series. The PS-DMAP acts to furnish thefree-based in situ, which then progresses through the supportedactive ester, forming the peptide bond. The flow stream then entersthe PS-SO3H column, scavenging any unreacted amine. Finally, thesolvent is evaporated to give the product; several Boc, Fmoc andCbz N-protected dipeptides were generated in isolated yields of61–81% without the need for purification by chromatography.

This same process can also be extended to the synthesis ofpolypeptides. By simply incorporating a flow based N-deprotectionof a Cbz-protected dipeptide (Cbz-Ala-Gly-OEt) using the H-Cubesystem, the free amine is produced which can be used in a

repetition of the above procedure. For example, the tripeptideCbz-Phe-Ala-Gly-OEt was obtained in 59% overall yield in 6.5 hstarting from glycine.

Using a flow-based processing regime provides chemists withan expanded range of capabilities and opportunities, providingimproved safety considerations, enhanced dispensing and mixingcoefficients, and when utilsing in-line real-time diagnostics withthe ability to make instant changes creating a new dynamicchemical environment. Throughout these processes, the packedcartridges or reactor coils can also be interacted upon byvarious physical means such as heating/cooling, oscillation,ultrasound, microwaves, irradiation or electrochemistry givinga full range of chemical activations. Microwave heating of flowreactors has proven particularly beneficial for several chemical

transformations.88–90 We and others have shown that it is possibleto 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 cavityallowing solutions to flow through the focused microwave field. Byapplying a flow restriction by way of a back pressure regulator (BPR)to the output of the reactor superheated reaction conditions can beaccessed. Illustrative of this process is the high temperature non-metal catalysed intramolecular [2+2+2] alkyne cyclotrimerizationreaction shown in Scheme 5.97 A solution of the substrate in DMF,a strongly absorbing microwave solvent, was easily maintained at200◦C for the duration of the reaction.

An alternative set-up which consists of a simple coil offluorinated polymer tubing (11.5 m of 0.4 mm i.d. tubing) woundaround a central Teflon core provides a flow microwave insertwith an internal volume of 1.45 mL (Figure 6).98 The Teflon spigotscan be easily spooled to replace a blocked or damaged unitor to allow access to new configurations; for example, wrappingdifferent lengths of tubing to provide reactors with varying internalvolumes or multiple tubing lengths to accommodate differentreactions or flow rates within the same microwave device. The unitis then easily accommodated within the cavity of a commerciallyavailable microwave reactor such as the Emrys Optimiser withthe input and exit tubes on the underside of the microwave unit(Figure 6(c)). One or more HPLC pumps are then used to deliver thefluidic flows to the system, which is kept under positive pressurethrough the use of a back-pressure regulator at the exit.

This reactor configuration has been successfully used tosynthesize a collection of 5-amino-4-cyanopyrazoles as buildingblocks and starting materials for subsequent transformationinto more structurally diverse 4-aminopyrazolopyrimidines bydimerization or the 1H-pyrazolo[3,4-d]pyrimidin-4-amine bycondensation with a nitrile (Scheme 6 and 7). To prepare thepyrazole precusors various hydrazines and ethoxymethylenemalononitrile were heated together in the flow microwave reactor(flow rates of 0.36–1.75 mL min−1 equating to residence times of0.8–4.0 min) and then progressed through a scavenging sequenceto remove excess ethoxymethylene malononitrile followed bya carbon based decolourising stage. The set-up could becontinuously run for periods up to 36 h at temperatures of100–120◦C in order to prepare 120–350 g batches of the bulkintermediates in high yields and excellent purities.

The design and evaluation of novel microwave reactor inserts isa valuable method of utilizing existing batch based processingcapabilities as offered by commercial microwave units andadapting them to enable a more facile scale up. Conventionallythe direct scale up of a microwave reactions has been problematic.Typical operating frequency of most commercial microwave


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Step 1: Loading

Step 2: Reaction

Scheme 4. Automated peptide synthesis in flow.

Scheme 5. Flow microwave aromatization reactions using a glass insert reactor.


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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 microwaveirradiation.

Scheme 7. Dimerization of pyrazoles and reaction with nitriles undermicrowave irradiation.

reactors (2.45 GHz) means they have a restricted penetrationdepth of only a few centimetres into the reaction media.Consequently the heating effect will decrease exponentially fromthe surface to the inner region of a large reactor leading to non-homogeneous heating. This intrinsic complication has tended toprevent the direct scaling of microwave reactors past a couple oflitres inhibiting their use for the production of larger quantitiesof material. Alternatively exploring the use of continuousflow microwave processing avoids such considerations. Ourinvestigations have led us to construct a number of differentreactor designs which make use of existing microwave reactors toestablish flow through microwave experiments. As an illistrationtwo basic channel designs are shown in Figure 7.99 These consistof a simple recessed baffled core (with an alternating stepwiseinclination) and a classical helical coil unit (easily prepared fromTeflon rods using standard machine cutting techniques). Thesecomponents were then placed into a simple straight glass cylindercapped with Teflon end pieces which allowed connects to beestablished to the flow stream whilst also securing the device inthe microwave camber.

By adopting these reactor configurations a series of differentchemistries have been successfully processed with regard toscaling the reactions over time and in quantity of materialgenerated. For example, the Hantzsch reaction between3-nitrobenzaldehyde and ethyl 3-oxobutanoate in the presence ofammonium acetate and catalyzed by phenyl boronic acid (5 mol%)was preformed. The reactor was operated continuously for 48 hprocessing a total of 576 mL of reaction solution with a residencetime of 12.5 min equating to 349 g of isolated product (followingcrystallization) (Scheme 8). This gives a good indication of the levelof enhanced processing that could be achieved using such simpleset-ups.

A simple glass column or coil containing an immobilized reagentcan also be utilized to conduct heterogeneous flow catalysis undermicrowave irradiation. Reactions with metal-tethered catalysts,e.g. polyurea microencapsulated palladium species (PdEnCat) are agood example, whereby microwave heating activates the encasedpalladium species (Figure 8).100

The microencapsulated catalyst can be packed into a simpledesign U-tube reactor for easy alignment in the microwavecavity. Often with microwave heating accurate and consistenttemperature measurement is difficult to achieve therefore to assistin calibrating the system a modified reactor was commissionedthat allowed the insertion of a fibre optic probe into the flowstream permitting more detailed thermal readings to be taken(Figure 9). However, it should be noted that this reference pointstill only supplies a bulk solution value which can be significantlydifferent 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 ofthe PdEnCat catalyst we were able to generate a flow systemfor the rapid assembly of biaryl units via the Suzuki reaction(Figure 10).113,114 A basic set-up delivered ethanolic solutions ofthe aryl bromide, boronic acid and tetra-butylammonium acetateas the base to mix prior to passage through the catalyst bed. A finalscavenging step with a polymer-supported sulfonic acid facilitatedthe clean-up of the reaction stream upon exiting the reactor.

This approach gave products which were generally of ahigher purity than those generated through the analogousbatch 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 concentrationwas extremely high. Thus the desired cross-coupling was able totake place, but the short time frame involved avoids decompositionand prevents many side reactions from occurring.


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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 thesame catalyst bed could be used to generate multiple productsin a serial fashion. Aliquots of the paired starting materials wereintroduced in succession to the reactor interspersed by a washingstage to ensure complete elution of the product before the nextpair of substrates was coupled (Figure 11). The yields of theproducts obtained were consistent with those isolated from batchprocessing and following solvent evaporation gave the desiredmaterial directly in high purity. It was also shown that more efficientuse of the catalysts could be achieved when larger quantities ofthe substrates were processed through the catalyst bed. In batchmost reactions required between 3–5 mol% of catalyst to ensurecomplete conversion of the starting materials. Alternatively, inflow, the reactor could be maintained under steady state operationresulting in greater catalyst utilization pertaining to an effectivecatalyst concentration of only 0.2 mol% (Figure 12). This conceptof increased efficiency with continued use is a significant benefitof applying immobilized catalysts under flow conditions.

Reactive intermediates in multi-step chemicaltransformationsThe generation and in situ telescoping of reactive or unstableintermediates directly into a secondary transformation is one ofthe major processing advantages of flow chemistry. The capacityto constantly produce a manageable quantity of a hazardouschemical entity which remains contained within the reactor forthe duration of it existence offers may safety and handling benefits.Several groups have demonstrated specific advantages in terms ofsuperior overall isolated yields, enhanced purities, increased safetywindows and shortened overall reaction times by integrating an

initial generation step with a subsequent reaction.115–118 Webelieve 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 ofthese processes from our laboratory which involve this concept ofdirect in-line clean-up are illustrated below.

Curtius rearrangementThe Curtius rearrangement transforms carboxylic acids or acidchlorides to the corresponding isocyanate functionality. Thereaction proceeds via an intermediate acyl azide which undergoesrearrangement to give a reactive isocyanate which can in turn beintercepted by a nucleophile to give a modifed product. We have

employed a Merrifield type azide ion-exchange monolith119–125 tofacilitate this transformation generating reactive acyl azides fromvarious acid chlorides which then undergo Curtius rearrangementsto give a variety of aryl isocyanates in a subsequent heated coilreactor (Scheme 9).126

Alternatively for larger-scale applications the reactive acyl azidecould be generated using diphenylphosporyl azide (DPPA) directlyfrom carboxylic acids.127 In this protocol a solution of the carboxylicacid with triethylamine plus a suitable nucleophile was loaded asone reaction stream which was then combined with a secondstream containing diphenylphosphoryl azide (DPPA) (Scheme 10).In practice an excess of the carboxylic acid was used to ensurecomplete consumption of the DPPA reagent. On mixing of thestreams, an acyl azide was generated which on heating in aconvection flow coil (CFC) produced the isocyanate which wasquenched immediately with the in situ resident nucleophileto give the desired products. A mixed acid/base scavengerwork-up was then used to remove the base, excess carboxylicacid and by-products. For nitrogen-containing heterocycliccarboxylic acid starting materials it was found necessary touse a catch-and-release protocol128,129 to afford the purifiedproducts.

Fluorination reactionsFluorine is often added to drug molecules to improve binding orprovide greater metabolic stability. However, its introduction canbe difficult due to the hazards associated with the fluorinatingreagents. Using a flow microreactor system with immobilizedin-line purification means many of these hazards are eliminatedowing to the contained environment and the robustness of thescavenging protocols.130


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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 PdEncatpacked reactor. (c) Side arm inlet reactor with Fibre optic probe insert for more accurate temperature measurement.

Figure 10. Flow microwave Suzuki reactions.


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Figure 11. Sequential processing of Suzuki coupling partners using a singlecatalyst cartridge in flow.

Trifluoromethylation of aldehydes has been demonstrated usingTMS-CF3 (Ruppert’s reagent) as a source of nucleophilic ‘CF3’.131 Inparticular, a fluoride monolith provided a versatile source of fluo-ride anions (Scheme 11). The reaction stream was purified using asolid supported aldehyde to trap any unreacted Ruppert’s reagent,while an acid resin acid deprotects the initially formed intermedi-ate silylated product. Finally, an immobilized hydrazine sequestersany unreacted aldehyde delivering a purified reaction stream.

Other flow methods for the introduction of fluorine involvethe use of commercially available fluorinating agents such as1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (Selectfluor) and diethylamino sulfurtrifluoride(DAST). The safe work-up of these reactions is particularlyimportant but can again be achieved by the application ofimmobilized reagents. The α-fluorination of an activated ketonecan be conducted using Selectfluor while similarly a fluoro-Ritterreaction with olefinic substrates can be realized in the same reactorset-up.132

In the first reaction, a stream of the activated carbonylwas combined with a corresponding stream of Selectfluor andheated (100–120◦C) (Scheme 12). The product stream thenwas purified using a combination of an’ immobilized sulfonicacid and dimethylamine resins to scavenge excess reagents and

Figure 12. Scaled-up processing of Suzuki reactions in flow using PdEnCatcatalyst.

by-products. This process afforded the desired products in highyield and excellent purity.

The same reactor arrangement was also used for several fluoro-Ritter reactions whereby an alkene starting material in the presenceof wet acetic acid (<5% mol water) reacts with acetonitrile tofurnish a monofluorinated product (Scheme 13).

DAST (diethylaminosulfur trifluoride) is another useful reagentfor substituting fluorine for an alcohol or a carbonyl functionality(aldehyde or activated ketone) yielding the corresponding monoor di-fluorinated products (Scheme 14).130,132 In the process excessDAST along with liberated HF were scavenged using a calciumcarbonate quench immediately followed by a silica gel plug totrap inorganic salts. Although this scavenging procedure producesquantities of carbon dioxide this is easily managed using thecontinuous flow system thus avoiding pressure build-up. Whileyields were affected by the electronics of the carbonyl moiety, thereaction was found to be tolerant of a wide range of functionalgroups, e.g. epoxides, alkenes, acetals, amines, esters, amides andvarious heterocycles creating a very useful protocol.

DAST has also found application in the cyclodehydrationof β-hydroxy amines which are efficiently converted to thecorresponding oxazolines in excellent yields (Scheme 15).130,132

This has also allowed for the construction of a number of chiralPyBOX ligands in flow.133,134

Flow synthesis of novel chemical building blocksAccess to a wide array of chemical building blocks is anessential perquisite for many medicinal chemistry synthesisprogrammes. These compounds can be simple core templatesenabling rapid chemical decoration in initial hit finding screens ormore specially tailored structures designed to enhance a certainphysical characteristic or present a particular functional pattern


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Scheme 9. Synthesis of acyl azides using a monolith reactor.

in later stage compound development. Their availability and costultimately determines the scope of their usage, consequentlymore automated ways of preparing these materials on demandis particularly important. The next sections highlight some of theflow chemistry methods that can be employed to generate specificclasses of useful building blocks.

Ynones and pyrazoles as primary building blocksThe flow synthesis of ynones facilitated by in-line purificationfurnishes reactive building blocks for further transformation tonumerous heterocyclic scaffolds.135 The attractive feature of thisprocess is the ability to split the product stream and divert thesetowards different product outcomes by varying the subsequentcoupling agents. Using palladium catalysis an acid chloride andacetylene can undergo a Sonogashira coupling to yield variousynones (Scheme 16). The acid chloride and acetylene are combinedin flow with a stream containing a catalytic amount of Pd(OAc)2

and Hunig’s base. The reaction was then heated at 100◦C for 30min and the reactor output purified by passage through a series offour solid reagents and scavengers. First, a polyol resin is used toremove excess acid chloride, then a column of CaCO3 to trap HCl

formed during the reaction and to deprotonate any ammoniumsalts. The resultant tertiary amine base (iPr2NEt, Hunig’s base)was next trapped on a sulfonic acid resin and finally a columnof immobilized thiourea removes palladium contamination. Theynone products were thus obtained in high yield (41–95%) andpurity following removal of the solvent.

The ynones can be further elaborated by combination withan additional input stream containing a nucleophile such as ahydrazine or guanidine derivative. By uniting the flow streams andheating the resultant mixture the corresponding heterocycles canbe prepared as a single linked flow sequence (Scheme 17). In thisway, a collection of pyrimidines, pyrazoles, oximes, guanidines andflavones have been obtained.

Diagnostics integrated with flow processesOwing to the dynamic environment of a flow process it ispossible to effect rapid changes in reaction parameters leadingto immediate downstream changes in the reaction conditions.Therefore utilizing real-time analysis of the flow stream it ispossible to harvest large amounts of data regarding multiple


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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 adjustablewavelength photodiode detectors (or similar spectrometers)placed as in-line analysis cells. Other diagnostic devices can be usedto report on reaction progress, e.g. impedance measurements,Raman spectroscopy, near or React IR, fluorescence measurementsand various bioassays. Alternatively, or in addition, automatedsampling techniques can be used to divert aliquots of reactionmedia into auxiliary monitoring equipment allowing LCMS orGCMS to be assimilated into the system.

Butane-2,3-diacetal protected diols synthesisReact IR flow cells can be easily integrated to analyse flow streamsin real time including monitoring for the presence of importanttransient or reactive intermediates (Scheme 18).139,140 We haveused such a system to help evolve a flow route to variousbutane-2,3-diacetals (BDAs) which are key building block in manynatural product syntheses. The flow approach allowed the BDAunits 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 amixed stream of dimethyl-L-tartrate and trimethyl orthoformateand 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 anintermediate orthoester which was observed using the ReactIRflow cell and was identified as an important reactive species inthe diol protection. The processed product stream was finallypurified using an immobilized benzylamine scavenger to removeany remaining butanedione and CSA catalyst which could againbe confirmed using the React IR flow cell. A periodate resin wasthen employed to perform a rapid glycol cleavage of the residualtartrate ester to generate a volatile by-products that could be easilyremoved. This enabled the generation of multi-gram quantitiesof the BDA protected adduct in a very reproducible fashion. Onlyevaporation of volatiles was required in order to isolate the productin a crystalline form.

This BDA-protected tartrate was further used as a startingmaterial in a two-step transformation first to furnish theunsaturated system by treatment with a strong base in thepresence of iodine (Scheme 19). To clean up the reaction stream itwas quenched with simultaneous removal of the diisopropylamine(HNiPr2) by elution through a sulfonic acid resin whilst the excessiodine was scavenged using a thiosulfate resin. Finally, a shortplug of silica gel was used to remove the inorganic salts. Nextthe selective hydrogenation of the alkene was achieved at scaleusing the H-cube Midi system (from ThalesNano) yielding the


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Scheme 11. Synthesis of trifluoromethylated alcohols using a fluoride monolith.

Scheme 12. Electrophilic fluorine reactions with Selectfluor.

NHAc

FNHAc

F

F

OHF

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.


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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 BrBr

O

PhF

96%

NN

Cl

F

F

N N

Cl

FF

N

N

F F

O

O

F

F

F

F

O2N

N

O

Cl

F

FF

F

86% 87% 89% 96%

75% 75%83%

NH

O

F FN N

O O

O

O

CN F

F71%

94%

R H/R

O

Aldehydes/KetonesN

F

F

50%

Alcohols

R OH

Scheme 14. Synthesis of mono or di-fluorinated products using DAST.

N

Cl

O

NN

ORR

R = Ph 95%R = iPr 92%R = tBu 90%

N

OBr

N

O

O

MeO 91%O

NHHO

R

DehydrationO

NF

ON

ClF

87%

MeO

MeO

N

O O

O

90%

Scheme 15. Synthesis of oxazolines using DAST.

corresponding meso reduced form in quantitative conversionusing a Rh on alumina catalyst.

A more challenging sequence was also investigated involvingthe generation of a BDA protected glyceraldehyde from thecorresponding mannitol starting material (Scheme 20). When asmall excess of butadione was used with gentle heating of thereaction stream (40◦C) an optimum yield of the desired productwas obtained. Applying the ReactIR system the procedure wasquickly optimized to reduced the propensity for the formation of

the tris-protected by-product. A column of benzylamine resin wasused in-line at the end of the reactor to scavenge excess reagentsgenerating a clean flow stream.

From this protected material the half-aldehyde fragment wasreadily obtained by oxidative cleavage of the diol unit using a resinbound periodate oxidant (Scheme 21). Similarly, the analogousmethyl ester could also be formed (via additional oxidation ofthe intermediate aldehyde) using an immobilized pyridiniumperbromide resin.


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Scheme 16. Synthesis of ynones.

Scheme 17. Synthesis of pyrazoles and pyrimidines.

In a final sequence a BDA protected glycolate, anotheruseful building block, was synthesized using related procedures(Scheme 22).141,142 Applying similar conditions to those usedfor the tartrate protection reaction above, enantiomericly purechloropropanediol was converted to the bis-acetal in 95% yieldwithout racemization. Indeed, this conversion proceeded soefficiently that it was not necessary to incorporate the previouslyused periodate cleavage protocol to remove unreacted diol (cf .Scheme 18). The resulting chloride substituted product was thentreated with a strong base to effect elimination furnishing the exo-alkene, the product stream being in this case collected into waterand extracted in a typical batch fashion. Interestingly, the newflow procedure consistently produced high quality product, in an

improved ratio of 24:1, exo:endo, compared with variable ratios ofbetween 15:1 and 5:1 in batch. The final double bond cleavageemployed a combination of Osmium EnCat and sodium perioidatewith N-methyl morpholine as a solution-phase reoxidant to givethe corresponding lactone. Clean-up of the reaction stream wasaffected by passage through a sulfonic acid resin to scavengethe morpholine then an immobilized thiourea to scavenge anyleached osmium. Isolation of the pure lactone product involvedonly solvent evaporation.

3-Nitropyrrolidine building blocksA functionalized heterocycle that is becoming increasinglycommon in medicinal chemistry projects is the 3-nitropyrrolidine.


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MeO2C CO2MeOH

OH

O

O

OO

OMe

OMe

MeO2CMeO2C

CH(OMe)3

MeO

MeO

MeOMeO

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 dipolarstructure from N-(methoxymethyl)-N-(trimethylsilyl)benzylamine

which will undergo cycloaddition with an alkene.143–145 Underflow conditions a stream of the nitroalkene with TFA canbe combined with a second stream containing the couplingpartner (Scheme 23).146,147 The united flow stream is then heatedto facilitate the reaction and purified by scavenging with abenzylamine resin and a short plug of silica gel thereby removingany unreacted nitroalkene and releasing the product from itsinitially formed TFA salt. Optimization studies revealed thatnitropyrrolidines could also be obtained under milder conditions

when a fluoride monolith was used to generate the dipolecomponent. Here the starting materials flowed through a heatedfluoride monolith prior to scavenging with a benzylamine resin toafford pure products in high yields.

Using the H-Cube flow hydrogenator (ThalesNano) selectivereduction of the nitro group to the amine while retaining thebenzyl group could be performed using a Raney nickel catalyst.This selective reduction ultimately enabled libraries of derivativesto be rapidly assembled for biological testing (Figure 13).148

Alternatively both the nitro reduction and benzyl deprotectioncould be achieved simultaneously when a Pd/C catalyst systemwas employed.

Scheme 20. Flow synthesis of BDA protected glyceraldehyde.


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Scheme 21. BDA protected glyceraldehyde aldehyde or ester.

Scheme 22. Synthesis of BDA protected glycolate.

Scheme 23. Synthesis of 3-nitropyrrolidines from the nitroalkene.


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Figure 13. A small sample set of pyrrolidine templates prepared in flow.

Triazoles1,4-disubstituted triazole formation by copper(I) mediated [3+2]Huisgen cycloadditions of an organic azide with a terminalacetylene is of much current interest, with applications in manydifferent areas from cell biology to materials science. Our grouphas used a series of immobilized reagent to prepare the triazolesproducts in flow (Scheme 24).149 The cycloaddition was catalysedusing Amberlyst 21 (a benzylic dimethyl amine functionalizedresin) preloaded with copper(I) iodide with the flow stream beingdirected through a cartridge of QP-TU (a thiourea metal scavenger)to remove any leached copper residues. Finally, an immobilizedtriphenylphosphine equivalent, PS-PPh2, was used to scavengeexcess organic azide. This system afforded the desired compoundsin high purity without the need for chromatography and with noGlaser homo-coupled acetylene products being observed.

Although this type of ‘Click chemistry’ is synthetically veryvaluable it is restricted by the commercial availability of thestarting materials. In addition the azide and acetylene couplingcomponents have associated safety considerations regarding theirsynthesis and use especially at scale. Consequently it would bepreferable to generate such species in situ and immediate usethem without isolation. We therefore devised a set of protocolsthat allow the preparation of the individual units that can bereadily telescoped into our previously described cycloadditionsflow sequence as as shown in scheme 24.

Azide formationWe modified a set of batch conditions developed by Moses andcoworkers150 as a convenient starting point for the developmentof a flow process for aryl azides (Scheme 25). However, inthis transformation the resulting azide products are potentiallycontaminated with unreacted trimethylsilyl azide and anilinestarting materials both of which are toxic. The trimethylsilylazide can also be readily hydrolysed to toxic, volatile and highlyexplosive hydrazoic acid. Thus, contamination with unreactedstarting 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 scavengingprotocol was developed to purify in-line the azide product streamusing readily available and inexpensive scavenger resins. As shownin Scheme 25, following azide synthesis, the reaction streampasses through a scavenging column containing PS-sulfonic acid,followed by PS-dimethylamine. The PS-sulfonic acid traps anyunreacted aniline (red band) while at the same time convertingany remaining trimethylsilyl azide to hydrazoic acid, which is inturn 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 additionaltransformations for example a Staudinger aza-Wittig reactionemploying a monolithic triphenylphosphine reagent or cycload-ditions reactions to form 5-amino-4-cyano-1,2,3-triazoles.151,152

Acetylene formationThe Seyferth–Gilbert homologation of an aldehyde usingthe Bestmann–Ohira reagent has been successfully run ina flow microreactor leading to the formation of acetylenes(Scheme 26).153 The aldehyde starting material along with theBestmann–Ohira reagent were combined with a secondary streamof potassium tert-butoxide and introduced to a heated flowcoil. The reaction stream was first scavenged with immobilizedbenzylamine to remove excess aldehyde, then a sulfonic acidresin to both remove excess base and protonate any phosphoricresidues. Finally, a dimethylamine resin was employed to removeacidic impurities. The acetylene could then be collected in highyield. A small modification to the sequence was necessary fornitrogen-containing starting materials where the sulfonic acidresin was substituted for an alumina packed cartridge to avoidcapture of the newly formed product.

Demonstrating the full utility of working in a multi-step regimethe Bestmann–Ohira reagent was further used in the directtransformation of an alcohol through to the correspondingtriazoles in a single continuous sequence (Scheme 27). The


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Scheme 24. Copper catalysed [3+2] Huisgen cycloadditions.

Scheme 25. Formation of aryl azides in flow.

benzyl alcohol starting material was first selectively oxidizedupon passage through a column of immobilized TEMPO, with theresulting aldehyde reacting with the Bestmann–Ohira reagentunder subsequently established basic conditions. The freshlygenerated acetylene was immediately coupled with the in situazide (Cu catalysed) and progressed through the previouslydescribed train of scavenger and reaction cartridges to finallyafford the triazole in high purity and 55% isolated yield aftercrystallization.

Target orientated synthesisAs has been aptly demonstrated flow chemistry is ideally suitedto the rapid production of small building blocks enhancing thediversity of available structures by making use of the improvedsafety profile and extended processing windows inherent with

the contained reactor design. The inclusion of high levels ofautomation and an improved safety profile also allow the optionof preforming several traditionally ‘forbidden chemistries’ furtherexpanding the chemical repertoire available to the operator.However, this is only a small component part of the widertask of a synthesis chemist who must also assemble thesemolecular fragments into more elaborate constructs. Here again,flow chemistry can be used to assist in the multi-step assemblyprocess. Indeed, it is often more apparent what the true processingpotential of flow chemistry provides when viewed in the contextof a target driven synthesis.

Preparation of casein kinase inhibitorsAs an illustration a four-step flow assisted synthesis of a series ofcasein inhibitors has been described.154 The route was developed


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N

OMe

Cl

H

78%

N

NH

Cl

64%

NH

Me

71%

H

H

H

NO2

H

Br Ph

H

H

MeO2C

H

NO284%

79%

>90% 77%

65%

Cl

O

O

81%

82%73%

HF3C

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 theimidazopyridazine core, in total a collection of 20 analogues wererapidly assembled. The sequence necessitated the developmentof a continuous flow method to safely scale up an organometallicreaction conducted at low temperature (Scheme 28). To provisionthe reactor a dual loop filling system was devized that enableda constant supply of a butyllithium solution (or LiHMDS) to thereaction stream. By using a simple valve selection system onesample loop could be filled while the second fed the reactor. A

rapid exchange between the two loops permitted an essentiallyseamless feed of the organometallic solution.

In the second step an immobilized perbromide was usedto enable mono-bromination through controlled contact timeof the solution passing through the polymeric packed bedreactor (Scheme 29). The resulting mono-bromo intermediatewas immediately subjected to a high temperature condensationreaction with 6-chloro-3-pyridazinamine to furnish the bicyclicimidazopyridazine core. Finally, a liquid handler was used to


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Scheme 28. Organolithium deprotonation in flow.

automate sequential compound generation through an SNArreaction to give amine diversified imidazopyridazine derivatives(Figure 14).

The ability to access low temperature domains for chemicalprocessing is a vital prerequisite for many selective chemicaltransformations. As well as impacting upon selectivity it canalso influence the stability of many chemical reagents such asorganometallic reagents and facilitates control of reaction ratesreducing the propensity for uncontrolled run away reactions.This therefore becomes particularly important when consideringprocess development routes and scaled manufacture wherecryogenic temperatures also become expensive and challengingengineering problems. It has therefore been of significant generalinterest to the chemical community that as a consequence oftheir high surface to volume ratios many microreactor systems

display excellent heat transfer charactoristics.155–158 This oftenmeans a greater stability in reaction temperature especially whenmixing reactive reagents. As a consequence many reactions canbe effectively conducted at higher temperatures than wouldbe possible under the corresponding classical batch set-ups (alower temperature is often used in batch to compensate for theformation of hot-spots, mixing fluctuations and inherent reactorgradients – cooling from the outside of the reactor towards thecentre). Because of the high surface to volume ratio encounteredin many flow systems (coil and chip reactors) cooling is veryefficient. We have evaluated the potential of scaling processesunder reduced temperatures for example the formation of theversatile coupling components aryl boronic acids (Scheme 30).159

Two independent flow streams were pre-cooled in a short lengthof tubing prior to being combined and reacted at −60◦C. Thehalogenated aromatic underwent lithium halogen exchange andthen rapidly quenched upon the pinicol boranate ester in situ. Thenewly formed ate species was decomposed under acid conditionsusing an in-line sulfonic acid quench. To conveniently establishthe 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 andstable temperature, there is no need to supply coolant or dosethe device with liquid nitrogen or dry ice and so maintenanceand user involvement is minimal. Consequently we were able togenerate libraries of boronic acid components and also conductscaled experiments by simply running the reactor for a longerperiod of time.

Target orientated synthesis of a 5HT1B antagonistA seven-step batch synthesis of the potent 5HT1B antagonistdeveloped by AstraZeneca160 was previously described in anoverall yield of 7%. This synthesis consequently became abenchmark for the evaluation of the potential benefits of usingflow chemistry for target development (Figure 16).

Our flow synthesis of this pharmaceutical was instigated bycombining streams of 3-fluoro-4-nitroanisole and piperizine at135◦C to promote the SNAr. The exiting reaction was scavengedwith a benzylamine resin to remove the liberated hydrofluoric acidprior to its transmission to a continuous flow hydrogenation.161 Theoutflow containing the aniline intermediate was scavenged witha thiourea resin to ensure complete removal of any potentiallyleached palladium species (Scheme 31). Following a solventswitch, from ethanol to toluene, the flow stream containingthe newly formed aniline was combined with a solution ofdimethyl acetylenedicarboxylate and heated. An in-line scavengefor residual dicarboxylate and the use of anhydrous potassiumcarbonate to remove traces of water allowed the stream to betelescoped into a high temperature cyclo-condensation reaction.An in-line BPR operating at 250 psi was fitted to the system tomaintain the system pressure under these superheated conditions.The output stream from the stainless steel reactor coil was rapidlycooled to ambient temperature and mixed with a third inputflow of THF/H2O. The combined flow stream was then progressedthrough a column containing an ion exchange hydroxide resinwhich promoted ester hydrolysis and simultaneous capture of theresulting carboxylic acid on the basic resin. The final step involved


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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) andHOBt (hydroxybenzotriazole) through the column containing theimmobilized carboxylate intermediate. This resulted in activationof the carboxylate by formation of the active ester thereby releasingit from the resin. The flow stream containing the HOBt-activated

ester was directed to merge with an additional stream of4-morpholinoaniline leading to amide coupling. Purification of thereaction stream was achieved using a ‘catch-and-release’ strategywith a sulfonic acid containing column. This resulted in trappingof the product which was washed and subsequently releasedby eluting with methanolic ammonia. The final solution wasconcentrated and the crude inhibitor isolated by recrystallization


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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 treblingthat of the original batch process.

δ-opioid receptor agonistThe use of a React IR flow cell to evaluate reaction progressiongreatly 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 theGrignard reagent, diisopropylmagnesium bromide, was used asa 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 aBoc-protected piperidinone. The resulting tertiary alcohol wasquenched and scavenged by passage through a sulfonic acid con-taining cartridge, with any residual piperidinone being removedvia a hydrazine functional resin. The React IR cell was positionedin the flow path at the end of this series to determine the disper-sion and effective concentration of the passing alcohol productstream. This enabled the controlled and automatically regulatedintroduction of a solution of Burgess’ reagent to meet the alcoholinducing the dehydration at an elevated temperature. The finalstage of the process involved a ‘catch-and-release’ purification ona additional column of sulfonic acid resin which at 60◦C also pro-moted the cleavage of the Boc-protecting group. The release stepwas conducted with a solution of ammonia in methanol allowingthe isolation of the target molecule in an impressive 35% overallyield and in high purity.

Imatinib (Gleevec)The synthesis of the tyrosine kinase inhibitor Gleevec, a treatmentfor chronic myeloid leukaemia and gastrointestinal stromaltumours, proved an interesting test of the capabilities of flow


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Scheme 31. Flow synthesis of 5HT1B antagonist.

chemistry since all the previous batch syntheses involved thegeneration of very insoluble intermediates.163,164 This is an issuewhich is often raised as a significant hurdle for the wider adoptionof flow processing. Nevertheless, a flow synthesis was realizedthrough a reverse coupling strategy to that employed in the batchroute.165,166

Following Scheme 33, solutions of the appropriate acid chlorideand aniline coupling partner were united prior to entering a flowcoil generating the corresponding amide. The product stream wascollected using an automated fraction collector (triggered by aUV detector) after its passage through an in-line acid and basescavenger sequence. The product aliquot was collected into anincubated vial which already contained a known concentration ofN-methylpiperazine in DMF. A nitrogen gas purge was then usedto evaporate the volatile DCM solvent producing a homogeneousDMF mixture of known relative stoichiometry ready for the nexttransformation. Both the collection and reintroduction of thereaction solution into the system was automated via the useof an autosampler. Passage of the reaction mixture through aheated column containing calcium carbonate, as a basic media,promoted the substitution of the benzylic chloride. An immobilizedisocyanate species placed in-line ensured complete removal of anyexcess N-methylpiperazine allowing the product to be efficientlycaught onto a column of silica-supported sulfonic acid. Afterwashing, the product was released from the silica support byelution with a solution of DBU (the base for the next step). Thesolution 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 catalystsystem was found to be the ligand stabilized BrettPhos Pd pre-catalyst. It was further discovered that the introduction of anadditional water stream input just prior to the reactor exit aideddissolution of precipitate salts ensuring easy separation at the endof the sequence. The organic output was concentrated in vacuoand directly loaded onto a silica samplet cartridge for automatedflash chromatography to give imatinib in 32% yield and greaterthan 95% purity.

Using the same sequence but modifying the various inputs alsoallowed the generation of several derivatives (Figure 17). Runningthe reactor set-up in a fully automated mode allowed a newcompound to be generated on average every 8 hours.

GrossamideAs an example of using directed feedback routines to optimizeand facilitate the synthesis of new materials the assembly ofthe natural product grossamide is a key defining synthesis(Scheme 34).167 A number of important techniques and procedureswere brought together in this work that have been significant ininfluencing many recent multi-step syntheses: (a) both the input ofstarting materials and the product elution were controlled usingliquid handlers; (b) throughout the optimization process, thereactions were monitored using in-line LC-MS analysis enablingflow rates and stoicheiometries of reagents to be changed inorder to deliver the product in maximum yield and purity; and


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Scheme 32. Preparation of a δ-opioid receptor agonist.

Scheme 33. Flow synthesis of the tyrosine kinase inhibitor Gleevec.


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Figure 17. Gleevec derivatives formed using the automated flow reactor.

(c) the system employed a number of automated exchangeablereagent columns, and an in-line UV detector was used to monitorthe flow stream’s progress. This enabled many valve switchingoperations to be performed automatically under computercontrol.

For the initial amide bond forming reaction we built uponour previous work constructing peptides in flow (Scheme 4).87

In this case (Scheme 34) the desired amide was synthesizedby coupling tyramine and ferulic acid using the immobilizedHOBt protocol previously described. Following elution fromthe sulfonic acid scavenging column the product stream wasdiluted (3:1) with a second input solution containing a hydrogenperoxide–urea complex and sodium dihydrogen phosphate buffer(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 dimerizationand intramolecular cyclization to yield grossamide. This compactsynthesis demonstrates many advantages of drawing togetherenabling technologies such as automation, immobilized reagents,enzymatic reagents and flow chemistry to generate complexchemical structures.

One major advantage of flow chemistry and the level ofautomation that is involved is that once a synthetic sequencehas been worked out and implemented, it is relatively trivial toperform the same reaction again. Indeed, many of the operationalparameters can be simply reloaded into the software fromthe original run providing duplicate reaction conditions. Wehave used this approach to repeatedly prepare quantities ofvarious coumarin-8-carbaldehydes as selective IRE1-binders forinvestigations of mRNA splicing (Scheme 35).168 Having accessto freshly prepared material has been benifical for the biologicalwork as the aldehyde substrates tend to undergo auto oxidationupon storage. One particular route to these molecules is depictedin the scheme as shown below. The synthesis provides clean,easily isolated material (via filteration) which requires only dryingprior to use. Furthermore, the operation of the reactor can beperformed by numberous people and actually requires very littlechemical experience in order to conduct the repeat synthesis. Thissignificantly increases access times to these compounds whenscheduling time allocation in a busy synthesis laboratory.169,170

OxmaritadineA further convincing showcase for this mode of working is thetotal synthesis of the biologically interesting natural product

oxomaritidine which utilizes a combination of scavengers andfive different immobilized reagents to conduct each of the eightcontiguous steps of the sequence (Scheme 36).171

The initial step of the synthesis involved the transformationof 4-(2-bromoethyl)phenol to its corresponding azide whichwas achieved by the action of a packed bed azide exchangeresin. The output stream containing the organic azide wasthen directed into a second column containing an immobilizedphosphine species; this resulted in the formation of a solid-phase aza-Wittig intermediate. In a convergent sequence thealdehyde, 3,4-dimethoxybenzaldehyde, was prepared. For thisreaction a column of polymer-supported tetra-N-ethylammoniumperruthenate (PSP) was used to oxidize the prerequisite alcohol,and the aldehyde product stream was passed directly into thecolumn containing the aza-Wittig intermediate, reacting to yieldthe imine adduct. This imine-containing solution flowed on andwas next subjected to continuous flow hydrogenation using anH-Cube system, to yield the resultant secondary amine. A solventexchange was affected using a V-10 solvent evaporator and thecrude material re-dissolved in DCM for continued processing.The amine solution was next passed into a microfluidic reactionchip to combine with an additional stream of trifluoroaceticanhydride (TFAA) resulting in trifluoroacetylation of the amine.The reaction stream was directed through a column of polymer-supported (ditrifluoroacetoxyiodo)benzene (PS-PIFA) which actedto perform the phenolic oxidative coupling, generating theseven-membered spirodieneone. Finally, removal of the amideprotecting group was conducted with a column of hydroxideion-exchange resin, acting to facilitate deprotection of thesecondary amine which spontaneously undergoes cyclization togive oxomaritidine in 40% overall yield and 90% purity. Theentire route took only approximately 6 h of flow processing timewhich compares favourably with the batch run time of about4 days.

CONCLUSIONAlthough flow chemistry has already proven itself as a valuable toolin manufacturing settings its adoption for small-scale laboratoryapplications or within research environments has until recentlyonly been via a small number of enthusiastic pioneers andinnovators. However, there is a rapidly expanding body of scientificevidence which continues to demonstrate the tremendousbenefits and enhanced processing capabilities inherent to the


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Scheme 34. Flow synthesis of Grossamide using in-line LC-MS monitoring.

Scheme 35. Synthetic flow route to coumarin-8-carbaldehyde.


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Scheme 36. The multi-step flow synthesis of oxomaritidine using solid-supported reagents.

bench chemist by embracing flow processing. Consequently, evenmany of the original sceptics are now exhorting the merits offlow synthesis. However, despite the growing acceptance andadoption of this technology it is certainly true there are still anumber of limitations that need to be overcome in order for itto be truly accepted as a mainstream chemistry technique. Forexample, one important pre-requisite in flow chemistry is thechoice of an effective solvent that avoids precipitation that canlead to blockages in the flow pathway. Although this is oftenover-emphasized as a critical issue (as it can be easily avoided)it does still require careful consideration as part of the synthesisplanning stage and so imparts certain restrictions. Furthermore,in many synthetic routes it is also essential to be able to modifyconcentrations or fully exchange solvents between steps, thereforeto harness the full benefits of continuous flow synthesis thisshould ideally be accomplished as part of an in-line telescopedsequence in a fully automated fashion. Without this facility tomake adjustments to the reaction solution the complex multi-stepsynthetic transformations which are currently regularly performedin batch will always remain difficult to translate to flow. Thereforea greater degree of development is urgently needed with regardto procedures and equipment for direct solvent exchange and in-line evaporation. In fact the whole area of downstream chemicalwork-up and purification is becoming an increasingly importantaspect of flow processing. Currently very few practical solutionsto continuous reaction quenching and aqueous extractions areavailable within research environments despite these already

existing for use at large scale (i.e. counter current extractionmethodologies). This is obviously limiting the scope and wideradoption of flow technologies.

Heavily linked to synthesis in the future will be a direct increasein the real time monitoring and analysis of each stage of thechemical process. Advances in the integration of diagnostic toolswill enable greater use of smart automated monitoring routinescapable of first harvesting comprehensive reaction data and theninterpreting the results to make informed decisions regarding theminor calibration and tailoring or full optimization of an operation.This work is currently a major research area which will rapidlyexpand 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 changingscale, allowing the reproducible production of varying quantitiesof final product for multiple applications in short time frames. Newflow platforms will be required to generate both large numbersof structural diversity products albeit in small quantities for high-throughput screens yet also simplify the operational up-scaling ofthe routes to furnish hundreds of grams to kilograms for early stagephysiochemical profiling and toxicology testing. Of additionalinterest will be the concept of ‘make and screen’ which attemptsto remove a traditional bottleneck in the discovery process by link-ing the synthesis component to rapid in-line biological evaluationor property determination. Indeed, the processing requirementsto only prepare and then evaluation a microgram or less of afinal material would considerably reduce cycle times, streamline


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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 experimentcould provide kinetics in terms of on- and off-rates directly yieldinga comparable measure of affinity and activity. Simultaneously inanother part of the system measurements of other physical char-acteristics such as pKa, log P or solubility could be taken by simplydiverting part of the synthesis product flow stream.

Many of the fundamental requirements in terms of informationretrieval and flexibility of synthetic implementation seem ideallysuited to a flow based approach to chemical synthesis. However,for this concept to be successfully realized the delivery ofclean material for testing is essential, and immobilizationtechniques – both in terms of synthetic reagents, and particularlyheterogeneous purification agents – will have a central role to play.

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142 Carter CF , Baxendale IR, Pavey JBJ and Ley SV, The continuous flowsynthesis of butane-2,3-diacetal protected building blocks usingmicroreactors. Org Biomol Chem 8:1588–1595 (2010).

143 Bigotti S, Malpezzi L, Molteni M, Mele A, Panzeri W andZanda M, Functionalized fluoroalkyl heterocycles by 1,3-dipolarcycloadditions with γ -fluoro-α-nitroalkenes. Tetrahedron Lett50:2540–2542 (2009).

144 Wright SW, Ammirati MJ, Andrews KM, Brodeur AM, DanleyDE, Doran SD, Lillquist JS, Liu S, McClure LD, McPherson RK,lson TV, Orena SJ, Parker JC, Rocke BN, Soeller WC, SogliaCB, Treadway JL, VanVolkenburg MA, Zhao Z and Cox ED,(3R,4S)-4-(2,4,5-Trifluorophenyl)-pyrrolidin-3-ylamine inhibitors ofdipeptidyl peptidase iv: synthesis, in vitro, in vivo, and X-ray crystallographic characterization. Bioorg Med Chem Lett 17:5638–5642 (2007).

145 Bucsh RA, Domagla JM, Laborde E and Sesnie JC, Synthesisand antimicrobial evaluation of a series of 7-[3-amino (oraminomethyl)-4-aryl (or cyclopropyl)-1-pyrrolidinyl]-4-quinoloneand −1,8-naphthyridone-3-carboxylic acids. J Med Chem36:4139–4151 (1993).

146 Baumann M, Baxendale IR and Ley SV, Synthesis of 3-nitropyrrolidinesvia dipolar cycloaddition reactions using a modular flow reactor.Synlett 5:749–752 (2010).

147 Baumann M, Baxendale IR, Wegner J, Kirschning A and Ley SV,Synthesis of highly substituted nitropyrrolidines, nitropyrrolizinesand nitropyrroles via multicomponent-multi-step sequenceswithin a flow reactor. Heterocycles 82:1297–1316 (2011).

148 Baumann M, Baxendale IR, Kuratli C, Ley SV, Martin RE and SchneiderJ, Synthesis of a drug-like focused library of trisubstitutedpyrrolidines using integrated flow chemistry and batch methods.ACS Comb Sci 13:405–413 (2011).

149 Smith CD, Baxendale IR, Lanners S, Hayward JJ, Smith SC and LeySV, [3 + 2] Cycloaddition of acetylenes with azides to give 1,4-disubstituted 1,2,3-triazoles in a modular flow reactor. Org BiomolChem 5:1559–1561 (2007).

150 Barral K, Moorhouse AD and Moses JE, Efficient conversion of aromaticamines into azides: a one-pot synthesis of triazole linkages. OrgLett 9:1809–1811 (2007).

151 Smith CJ, Nikbin N, Smith CD, Ley SV and Baxendale IR, Flow synthesisof organic azides and the multistep synthesis of imines and amines


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using a new monolithic triphenylphosphine reagent. Org BiomolChem 9:1927–1937 (2011).

152 Smith CJ, Nikbin N, Ley SV, Lange H and Baxendale IR, A fullyautomated, multistep flow synthesis of 5-amino-4-cyano-1,2,3-triazoles. Org Biomol Chem 9:1938–1947 (2011).

153 Baxendale IR, Ley SV, Mansfield AC and Smith CD, Multistepsynthesis using modular flow reactors: Bestmann-ohira reagentfor the formation of alkynes and triazoles. Angew Chem Int Ed48:4017–4021 (2009).

154 Venturoni F, Nikbin N, Ley SV and Baxendale IR, The application offlow microreactors to the preparation of a family of casein kinase Iinhibitors. Org Biomol Chem 8:1798–1806 (2010).

155 Cukalovic A, Monbaliu J-CMR and Stevens CV, Microreactortechnology as an efficient tool for multicomponent reactions.Top Heterocycl Chem 23:161–198 (2010).

156 Nagaki A, Moriwaki Y, Haraki S, Kenmoku A, Takabayashi N,Hayashi A and Yoshida J, Cross-coupling of aryllithiums with aryland vinyl halides in flow microreactors. Chem Asian J 7:1061–1068(2012).

157 Nagaki A, Takizawa E and Yoshida J, Generations and reactions ofN-t-butylsulfonyl-aziridinyllithiums using microreactors. Chem Lett38:1060–1061 (2009).

158 Ducry L and Roberge DM, Controlled autocatalytic nitration of phenolin a microreactor. Angew Chem Int Ed 44:7972–7975 (2005).

159 Browne DL, Baumann M, Harji BH, Baxendale IR and Ley SV, A newenabling technology for convenient laboratory scale continuousflow processing at low temperatures. Org Lett 13:3312–3315(2011).

160 Horchler CL, McCauley Jr. JP, Hall JE, Snyder DH, Moore WC, Hudzik TJand Chapdelaine MJ, Synthesis of novel quinolone and quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)amides: a late-stagediversification approach to potent 5HT1B antagonists. Bioorg MedChem 15:939–950 (2007).

161 Qian Z, Baxendale IR and Ley SV, A flow process using microreactorsfor the preparation of a quinolone derivative as a potent 5HT(1B)antagonist. Synlett 505–508 (2010).

162 Qian Z, Baxendale IR and Ley SV, A continuous flow processusing a sequence of microreactors with in-line IR analysis

for the preparation of N,N-diethyl-4-(3-fluorophenylpiperidin-4-ylidenemethyl)benzamide as a potent and highly selectiveδ-opioid receptor agonist. Chem Eur J 16:12342–12348 (2010).

163 Hopkin MD, Deadman B, Baxendale IR and Ley SV, The synthesis of Bcr-Abl inhibiting anticancer pharmaceutical agents Imatinib, Nilotiniband Dasatinib. Org Biomol Chem DOI 10.1039/C2OB27003J: (2012).Latest info required

164 Hopkin MD, Baxendale IR and Ley SV, A flow-based synthesisof imatinib: the API of Gleevec. Chem Commun 46:2450–2452(2010).

165 Hopkin MD, Baxendale IR, Deadman B and Ley SV, An expeditioussynthesis of Imatinib and analogues utilising flow chemistrymethods. Org Biomol Chem DOI: 10.1039/C2OB27002A (2012).Latest info required

166 Ingham RJ, Riva E, Nikbin N, Baxendale IR and Ley SV, A‘‘catch–react–release’’ method for the flow synthesis of 2-Aminopyrimidines and preparation of the Imatinib base. Org Lett14:3920–3923 (2012).

167 Baxendale IR, Griffiths-Jones CM, Ley SV and Tranmer GK, Preparationof the neolignan natural product grossamide by a continuous-flowprocess. Synlett 427–430 (2006).

168 Cross BCS, Bond PJ, Sadowski PG, Jha BK, Zak J, Goodman JM,Silverman RH, Neubert TA, Baxendale IR, Ron D and Harding HP, Themolecular basis for selective inhibition of unconventional mRNAsplicing by an IRE1-binding small molecule. PNAS 15:E869–E878(2012).

169 Zak J, Ron D, Riva E, Harding HP, Cross BCS and BaxendaleIR, Establishing a flow process to Coumarin-8-carbaldehydesas important synthetic scaffolds. Chem Euro J 32:9901–9910(2012).

170 Battilocchio C, Baxendale IR, Biava M, Kitching MO and Ley SV, Aflow-based synthesis of 2-Aminoadamantane-2-carboxylic acid.Org Process Res Dev 16:798–810 (2012).

171 Baxendale IR, Deeley J, Griffiths-Jones CM, Ley SV, SaabyS and Tranmer GK, A flow process for the multi-stepsynthesis of the alkaloid natural product oxomaritidine: a newparadigm for molecular assembly. Chem Commun 2566–2568(2006).
