Group Publications
 
166. Diastereoselective Synthesis and Diversification of Highly Functionalized Cyclopentanones.
Baumann, M.; Baxendale, I. R. Synthesis 2017, xx, xx-xx. DOI link: 10.1055/s-0036-1591745

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An efficient entry into highly substituted cyclopentanones is presented based on functionalizing cyclopentenones by means of an aza-Michael reaction with different aniline nucleophiles. The excellent diastereoselectivity of this process is ascribed to H-bonding between a tertiary alcohol and the incoming nucleophiles. Additionally, the functionalization of the parent cyclopentenones via the Baylis–Hillman reaction is demonstrated. Together, these transformations showcase the elaboration of a simple precursor by installation of versatile functionalities at either the ?- or ?-position of the embedded enone and thus represent valuable methods for the construction of diversely functionalized cyclopentanones.
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165. A concise flow synthesis of indole-3 carboxylic ester and its derivatisation to an auxin mimic.
Baumann, M.; Baxendale, I. R.; Deplante, F. Beilstein J. Org. Chem. 2017, 13, 2549-2560. DOI link: 10.3762/bjoc.13.251

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An assembled suite of flow-based transformations have been used to rapidly scale-up the production of a novel auxin mimic-based herbicide which was required for preliminary field trials. The overall synthetic approach and optimisation studies are described along with a full description of the final reactor configurations employed for the synthesis as well as the downstream processing of the reaction streams.
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164. Flow-Assisted Synthesis: A Key Fragment of SR 142948A.
Kitching, M. O.; Dixon, O. E.; Baumann, M.; Baxendale, I. R. Euro. J. Org. Chem. 2017, 44, 6540-6553. DOI link: 10.1002/ejoc.201700904

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We report a series of multi-step flow operations to deliver an advanced hydrazine intermediate used in the assembly of the neurotensin modulator SR 142948A. Several new reactor configurations have enabled chemical transformations that would be otherwise difficult or dangerous to perform at scale. Overall the flow approach has allowed the preparation of kilogram quantities of the required hydrazine through a short and efficient route.
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163. A Continuous Flow Method for the Desulfurization of Substituted Thioimidazoles Applied to the Synthesis of New Etomidate Derivatives.
Baumann, M.; Baxendale, I. R. Euro. J. Org. Chem. 2017, 44, 6518-6524. DOI link: 10.1002/ejoc.201700833

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A simple yet robust flow set-up for the efficient desulfurization of a series of thioimidazoles is presented generating the corresponding imidazole derivatives in high yields. The strategic choice of peristaltic over piston pumps allowed reliable delivery of the heterogeneous stream of thioimidazole substrate into a T-piece where it reacted with NaNO2 in the presence of acetic acid. This approach enabled the controlled and safe formation of the reactive nitrosonium species without uncontrolled exposure to hazardous nitrous oxide by-products as observed in related batch protocols. The value of the resulting imidazole products was further demonstrated by their conversion into various esters representing new derivatives of the known analgesic etomidate via an efficient one pot Corey-Gilman-Ganem oxidation procedure.
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162. Sustainable Flow Synthesis of a Versatile Cyclopentenone Building Block.
Baumann, M.; Baxendale, I. R.; Filipponi, P.; Hu, T. Org. Proc. Res. Dev. 2017, 21, 2052-2059. DOI link: 10.1021/acs.oprd.7b00328

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A flow based multistep processing sequence to reliably provide the delivery of a highly functional cyclopentenone is described. The exemplification of employing solid dosing of reagents and in-line aqueous extraction has enabled an integrated workflow in a highly automated reactor setup.
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161. Purification of poly(acrylic acid) using a membrane ultra-filtration unit in flow.
Brocken, L.; Price, P. D.; Whittaker, J.; Baxendale, I. R. React. Chem. Eng. 2017, 2, 656-661. DOI link: 10.1039/c7re00080d

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We have developed methodology to synthesise aqueous soluble polymers such as poly(acrylic acid) in flow, enabling access to a variety of molecular weights. However, full conversion was hard to achieve without increasing the dispersity and therefore purification was necessary. In this work we demonstrate that flow polymerisation can be directly coupled with purification to furnish a purified polymer sample in under one hour.
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160. Continuous flow synthesis of poly(acrylic acid) via free radical polymerisation.
Brocken, L.; Price, P. D.; Whittaker, J.; Baxendale, I. R. React. Chem. Eng. 2017, 2, 662-668. DOI link: 10.1039/c7re00063d

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The free radical polymerisation of aqueous solutions of acrylic acid (1) has been studied using a continuous flow reactor to quickly screen reaction parameters such as temperature, residence time, monomer- and initiator concentration. The experimental data sets produced established a theoretical basis for conducting scale up processes to efficiently produce larger quantities of poly?acrylic acid) delivered with good control over the molecular weight and dispersity.
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159. Rac-20,3a,6,6,60,60-Hexamethyl-3a,3b,6,7-tetrahydrospiro-[ benzo[2,3]cyclopropa[1,2-c]pyrazole- 1,10-cyclo-hepta[2,4]diene].
Baumann, M.; Lapraille, S.; Baxendale, I. R. Molbank 2017, , M948-M948. DOI link: 10.3390/M948

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This note describes a novel reaction cascade in which a tosylhydrazone derivative of eucarvone undergoes a non-classical dimerization process under basic conditions. The key step in this sequence is a dipolar cycloaddition between a diazo species and a transient cyclopropene. A proposed mechanism for this sequence is presented that is supported by single crystal X-ray analysis of the resulting dimer. We believe this unique transformation is of note as it highlights a neat and efficient entry to complex polycyclic architectures containing an embedded pyrazoline moiety.
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158. Ethyl 5-(4-Bromophenyl)-4-methyl-1H-pyrrole-2- carboxylate.
Baumman, M.; Baxendale, I. R. Molbank 2017, , M951-M951. DOI link: 10.3390/M951

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This note describes a sequence converting an oxime-substituted pyrrolidine into a trisubstituted pyrrole structure. The synthetic route is based on a double chlorination of the pyrrolidine substrate followed by the base induced formation of both an imine and a nitrile oxide functionality. The latter reacts with an immobilized thiourea to yield an isothiocyanate which upon elimination generates the final pyrrole in an unprecedented cascade of events.
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157. Adjust band gap of IATO nanoparticles to obtain desirable optical property by one-step hydrothermal oxidation.
Hu, T.; Su, Y.; Baxendale, I. R.; Tan, J.; Tang, H.; Xiao, L.; Zheng, F.; Ning, P. Curr. Appl. Phys. 2017, 1, 584-591. DOI link: 10.1016/j.cap.2017.01.011

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Antimony-tin-doped indium oxide (IATO) as transparent conducting oxide (TCO) exhibits significant optical property on blocking UV and Infrared(IR) for wavelengths less ?400 nm and over ?1400 nm as well as appropriate transmissivity on visible wavelength in our work that can be as an optional idea optical material applying in shielding film or nanocomposite to achieve desired optical application. We have successfully developed an optimal synthesis system which allows for a single hydrothermal oxidation directly synthesizing IATO nanoparticles without high-temperature calcination. These nanoparticles show superior size, crystallinity, agglomeration and are free of intermediates In(OH)3 and InOOH. We also have demonstrated they give scope to desired optical property as a result of an altered IATO band gap energy. We highlight this approach due to the shortened preparation time, the reduced energy consumption and decreased chemical usage which dramatically saves on production costs and protects environment.
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156. A continuous flow synthesis and derivatization of 1,2,4-thiadiazoles.
Baumann, M.; Baxendale, I. R. Biorg. Med. Chem. 2017, 25, 6218-6223. DOI link: 10.1016/j.bmc.2017.01.022

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A continuous flow process is presented that enables the efficient synthesis and derivatization of 1,2,4-thiadiazole heterocycles. Special attention was given to the safe handling of the versatile yet hazardous trichloromethane sulfenylchloride reagent including its in-line quenching in order to eliminate malodourous and corrosive by-products. Based on this flow method gram quantities of 5-chloro-3-phenyl-1,2,4-thiadiazole were safely prepared allowing for further elaboration of this valuable building block by reaction with different nitrogen-, sulfur- and oxygen-based nucleophiles. This synthetic approach was subsequently applied to generate a series of bromophenyl-5-chloro-1,2,4-thiadiazoles providing a valuable entry towards further structural diversification on this important heterocyclic scaffold.
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155. Diastereoselective Trifluoroacetylation of Highly Substituted Pyrrolidines by a Dakin–West Process.
Bammann, M.; Baxendale, I. R. J. Org. Chem. 2016, 81, 11898-11908. DOI link: 10.1021/acs.joc.6b02346

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A robust approach allowing for the efficient trifluoroacetylation of a series of highly substituted pyrrolidines in a diastereoselective manner is reported. The transformation is based on a Dakin–West reaction of advanced pyrrolidine 2-carboxylic acid derivatives that can be assembled stereoselectively in four synthetic steps. Importantly, this work demonstrates how the introduction of lateral substituents on the pyrrolidine scaffold enables the generation of the desired trifluoroacetylation products, which was not possible previously due to the exclusive formation of trifluoromethylated oxazoles (vide infra). In the course of this work we succeeded for the first time in isolating and characterizing (HRMS, IR, 1H, 13C and 19F NMR, X-ray) different intermediates of the Dakin–West reaction allowing us to probe its mechanism.
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154. Catalytic Chan—Lam coupling using a ‘tube-in-tube’ reactor to deliver molecular oxygen as an oxidant.
Mallia, C. J.; Burton, P. M.; Smith, A. M. R.; Walter, G. C.; Baxendale, I. R. Beilstein J. Org. Chem. 2016, 12, 1598-1607. DOI link: 10.3762/bjoc.12.156

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A flow system to perform Chan–Lam coupling reactions of various amines and arylboronic acids has been realised employing molecular oxygen as an oxidant for the re-oxidation of the copper catalyst enabling a catalytic process. A tube-in-tube gas reactor has been used to simplify the delivery of the oxygen accelerating the optimisation phase and allowing easy access to elevated pressures. A small exemplification library of heteroaromatic products has been prepared and the process has been shown to be robust over extended reaction times.
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153. Flow carbonylation of sterically hindered ortho-substituted iodoarenes.
Mallia, C. J.; Walter, G. C.; Baxendale, I. R. Beilstein J. Org. Chem. 2016, 12, 1503-1511. DOI link: 10.3762/bjoc.12.147

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The flow synthesis of ortho-substituted carboxylic acids, using carbon monoxide gas, has been studied for a number of substrates. The optimised conditions make use of a simple catalyst system compromising of triphenylphosphine as the ligand and palladium acetate as the pre-catalyst. Carbon monoxide was introduced via a reverse ‘tube-in-tube’ flow reactor at elevated pressures to give yields of carboxylated products that are much higher than those obtained under normal batch conditions.
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152. Exploring Flow Procedures for Diazonium Formation.
Hu, T.; Baxendale, I. R.; Baumann, M. Molecules 2016, 21, 918-941. DOI link: 10.3390/molecules21070918

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The synthesis of diazonium salts is historically an important transformation extensively utilized in dye manufacture. However the highly reactive nature of the diazonium functionality has additionally led to the development of many new reactions including several carbon-carbon bond forming processes. It is therefore highly desirable to determine optimum conditions for the formation of diazonium compounds utilizing the latest processing tools such as flow chemistry to take advantage of the increased safety and continuous manufacturing capabilities. Herein we report a series of flow-based procedures to prepare diazonium salts for subsequent in-situ consumption.
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151. α,β-Unsaturated Ketones via Copper(II) Bromide Mediated Oxidation.
Sharley, J. S.; Pérez, A. M. C.; Ferri, E. E.; Miranda, A. F.; Baxendale, I. R. Tetrahedron 2016, 72, 2947-2954. DOI link: 10.1016/j.tet.2016.04.011

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A protocol for effecting a rapid Saegusa-type oxidation of enol acetates is reported. This new method relies on the in-situ elimination of an α-bromo intermediate to generate α,β-unsaturated ketones using copper(II) bromide. The methodology developed was applied to a range of substrates including a cyclohexanone, which could be directly converted to the corresponding phenol derivative. A catalytic system in which a non-masked ketone was successfully oxidised using substoichiometric CuBr2 was also developed as a proof of principle.
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150. The Generation of a Library of Bromodomain Containing Protein Modulators Expedited by Continuous Flow Synthesis.
Filipponi, P.; Baxendale, I. R. Euro. J. Org. Chem. 2016, 11, 2000-2012. DOI link: 10.1002/ejoc.201600222

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A continuous flow process delivering key building-blocks for a series of BCP modulator libraries is reported. A dynamically mixed flow reactor has emerged as a pivotal technology in both synthetic and isolation phases enabling the processing of slurries and suspension whilst maintaining high productivity and reliability. Indeed, a key requirement of the synthesis is the rapid, large scale delivery of target compounds for progression into different lead optimization series. Accordingly, the common intermediates are employed herein to build a pyridazone based library (36 compounds) addressed at improving the lead potency and selectivity while further exploring the SAR of a new BCPs modulator family.
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149. Development of the industrial synthesis of vitamin A.
Parker, G. L.; Smith, L. K.; Baxendale, I. R. Tetrahedron 2016, 72, 1645-1652. DOI link: 10.1016/j.tet.2016.02.029

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The advances made in chemistry during the last 70 years are excellently illustrated by the development of the industrial synthesis of vitamin A, a diterpene crucial in preventing premature death and visual problems. Arens and van Dorp published the first route in 1946, and critical contributions have been made by a number of scientists since, benefitting from fruitful collaborations between industry and academia. However, these improvements have been mostly incremental, and the work has been performed by a limited number of companies; as yet, there is still no ‘ideal’ synthesis of vitamin A.
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148. Continuous photochemistry: the flow synthesis of ibuprofen via a photo-Favorskii rearrangement.
Baumann, M.; Baxendale, I. R. React. Chem. Eng. 2016, 1, 147-150. DOI link: 10.1039/C5RE00037H

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A new enabling technology for performing photochemical reactions in a continuous fashion is presented. This photo-reactor is compatible with existing flow systems and can be furthermore linked to a photo-spectrometer in order to allow for real time analysis of photochemical reactions. In this communication we wish to report the profiling of this system and its application to the continuous synthesis of ibuprofen based on a photo-Favorskii rearrangement reaction of a readily available α-chloropropiophenone precursor.
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147. Online quantitative mass spectrometry for the rapid adaptive optimisation of automated flow reactors.
Holmes, N.; Akien, G. R.; Savage, R. J. D.; Stanetty, C.; Baxendale, I. R.; Blacker, A. J.; Taylor, B. A.; Woodward, R. L.; Meadows, R. E.; Bourne, R. A. React. Chem. Eng. 2016, 1, 96-100. DOI link: 10.1039/C5RE00083A

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An automated continuous reactor for the synthesis of organic compounds, which uses online mass spectrometry (MS) for reaction monitoring and product quantification, is presented. Quantitative and rapid MS monitoring was developed and calibrated using HPLC. The amidation of methyl nicotinate with aqueous MeNH2 was optimised using design of experiments and a self-optimisation algorithm approach to produce >93% yield.
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146. Continuous Flow Synthesis of 2H-Azirines and their Diastereoselective Transformation to Aziridines.
Baumann, M.; Baxendale, I. R. SynLett 2016, 27, 159-163. DOI link: 10.1055/s-0035-1560391

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Using continuous-flow techniques, a small collection of 2H-azirines was prepared from oxime precursors via mesylation and base-promoted cyclisation. The 2H-azirines were either isolated after in-line purification or derivatised into a selection of 2-substituted aziridines through a telescoped reaction sequence involving nitrile, trifluoromethyl, or hydride nucleophilic addition. Importantly, these 2-substituted aziridines were produced with high cis diastereoselectivity providing access to small chiral heterocyclic entities that hold promise for medicinal chemistry programs because of their druglike features.
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145. Batch and Flow Synthesis of Pyrrolo[1,2-a]-quinolines via an Allene-Based Reaction Cascade.
Baumann, M.; Baxendale, I. R. J. Org. Chem. 2015, 80, 10806-10816. DOI link: 10.1021/acs.joc.5b01982

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An efficient reaction cascade delivering a series of pyrrolo[1,2-a]quinolines bearing phosphonate or phosphine oxide moieties is presented. This sequence exploits the in situ transformation of propargylic alcohols into transient allenes by means of a strategic [2,3]-sigmatropic rearrangement followed by trapping of the resulting allenes by an adjacent pyrrole ring. Furthermore, the initial small scale batch process was successfully translated into a continuous flow process allowing efficient preparation of selected pyrrolo[1,2-a]quinolines on multigram scale without any safety concerns due to the reaction's inherent exothermic profile.
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144. Synthesis of 1,3,6-Trisubstituted Azulenes.
Leino, T. O.; Baumann, M.; Yli-Kauhaluoma, J. Baxendale, I. R.; Wallén, E. A. A. J. Org. Chem. 2015, 80, 11513-11520. DOI link: 10.1021/acs.joc.5b02271

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We have developed a short, general synthetic route to 1,3,6-trisubstituted azulenes. The key intermediate, 6-methylazulene, was synthesized from readily available and inexpensive starting materials in 63% yield over two steps. The methyl group of 6-methylazulene was then used as a synthetic handle to introduce different substituents at the 6-position via two different methods. Subsequently, the 1- and 3-positions were substituted with additional functional handles, such as formyl, chloromethylketone, and iodide. The efficiency of the synthetic route was demonstrated by preparing a collection of three different products with the best demonstrated yield 33% over seven steps.
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143. Controlled Flow Precipitation as a Valuable Tool for Synthesis.
Filipponi, P.; Gioiello, A.; Baxendale, I. R. Org. Process Res. Dev. 2016, 20, 371-375. DOI link: 10.1021/acs.oprd.5b00331

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In most standard flow process, the formation of solids represents a major problem often leading to obstruction of the flow device and reactor shutdown. However, many reactions produce solid products, and therefore finding ways to process these materials is an important area of research. In this article we demonstrate how a dynamically agitated flow reactor can be a powerful tool to facilitate workup and processing of biphasic solid-liquid flow streams at scale.
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142. Total syntheses of natural products containing spirocarbocycles.
Smith, L. K.; Baxendale, I. R. Org. Biomol. Chem. 2015, 13, 9907 -9933. DOI link: 10.1039/C5OB01524c

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The structures of natural products from a variety of sources contain spirocycles, two rings that share a common atom. The spiro motif is finding increasing inclusion in drug candidates, and as a structural component in several promising classes of chiral ligands used in asymmetric synthesis. Total syntheses of products containing all-carbon spirocycles feature several common methods of ring closure which we examine in this review.
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141. A Short Multistep Flow Synthesis of a Potential Spirocyclic Fragrance Component.
Baxendale, I. R. Chem. Eng. Technol. 2015, 38, 1713-1716. DOI link: 10.1002/ceat.201500255

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The search for novel chemical architectures displaying improved biological properties is a never-ending synthetic challenge. In this context many new test structures are often conceived by selecting and replicating specific design elements from naturally occurring molecules and displaying them in an alternative format by way of a new chemical assembly. Constructing these newly designed compounds can be a timely and expensive process especially when a large quantity of the target material is required for physiochemical and property testing. To permit easier scale-up and safer working practice, many chemical researchers are employing flow chemistry approaches to aid in their synthesis challenges. The preparation of a key spirocyclic lactone using flow-based reaction processing techniques is reported.
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140. The Use of Gases in Flow Synthesis.
Mallia, C. J.; Baxendale, I. R. Org. Process Res. Dev. 2016, 20, 327-360. DOI link: 10.1021/acs.oprd.5b00222

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This review will highlight the potential benefits that can be leveraged by using flow chemistry to allow gases to be used in research in a safer and more efficient way. An overview of the different approaches used to introduce gases into flow reactors is presented along with a synopsis of the different gaseous reactions classes already successfully translated into flow.
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139. The synthesis of active pharmaceutical ingredients (APIs)using continuous flow chemistry.
Baumann, M.; Baxendale, I. R. Beilstein J. Org. Chem. 2015, 11, 1194-1219. DOI link: 10.3762/bjoc.11.134

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The implementation of continuous flow processing as a key enabling technology has transformed the way we conduct chemistry and has expanded our synthetic capabilities. As a result many new preparative routes have been designed towards commercially relevant drug compounds achieving more efficient and reproducible manufacture. This review article aims to illustrate the holistic systems approach and diverse applications of flow chemistry to the preparation of pharmaceutically active molecules, demonstrating the value of this strategy towards every aspect ranging from synthesis, in-line analysis and purification to final formulation and tableting. Although this review will primarily concentrate on large scale continuous processing, additional selected syntheses using micro or meso-scaled flow reactors will be exemplified for key transformations and process control. It is hoped that the reader will gain an appreciation of the innovative technology and transformational nature that flow chemistry can leverage to an overall process.
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138. Ethyl 2-hydroxy-2-phenyl-2-(thiazol-2-yl)acetate.
Mallia, C. J.; Englert, L.; Walter, G. C.; Baxendale, I. R. Molbank 2015, 2015(1), M857-M857. DOI link: 10.3390/M857

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This short note describes the synthesis of the title compound through spontaneous aerobic oxidation of ethyl 2-phenyl-2-(thiazol-2-yl)acetate. Due to the prevalence of such functional motifs in biologically active substances, we believe the oxidation encountered, highlights an important degradation pathway worthy of note.
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137. Thiazole Formation Through a Modified Gewald Reaction.
Mallia, C. J.; Englert, L.; Walter, G. C.; Baxendale, I. R. Beilstein J. Org. Chem. 2015, 11, 875-883. DOI link: 10.3762/bjoc.11.98

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The synthesis of thiazoles and thiophenes starting from nitriles, through a modified Gewald reaction has been studied for a number of different substrates. 1,4-dithiane-2,5-diol was used as the aldehyde precursor to give either 2-substituted thiazoles or 2-substituted aminothiophenes depending on the substitution of the ?-carbon to the cyano group.
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136. Large-Scale Synthesis of Crystalline 1,2,3,4,6,7-Hexa-O-acetyl-L-glycero-α-D-manno-heptopyranose.
Stanetty, C.; Baxendale, I. R. Eur. J. Org. Chem. 2015, 12, 2718-2726. DOI link: 10.1002/ejoc.201500024

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The higher-carbon sugar L-glycero-D-manno-heptose is a major constituent of the inner core region of the lipopolysaccharide (LPS) of many Gram-negative bacteria. All preparative routes used to date require multiple steps, and scalability has been rarely addressed. Here a highly practical synthesis of crystalline 1,2,3,4,6,7-hexa-O-acetyl-L-glycero-α-D-manno-heptopyranose by a simple four-step sequence starting from L-lyxose is disclosed. Only two recrystallisations are required and the process was demonstrated on a >100 mmol scale, yielding 41 g of the target compound.
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135. Syn-Ethyl 1-hydroxy-7-methoxy-2,3-dihydro-1H-pyrrolo[3,4-b]quinolone-3-carboxylate HCl Salt.
Baumann, M.; Baxendale, I. R. Molbank 2015, 1, M846-M846. DOI link: 10.3390/M846

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This short note describes a one-step synthesis of the title compound from commercially available starting materials and reports its full spectroscopic characterization data.
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134. Flow synthesis of ethyl isocyanoacetate enabling the telescoped synthesis of 1,2,4-triazoles and pyrrolo-[1,2-c]pyrimidines.
Baumann, M.; Rodriguez Garcia, A. M.; Baxendale, I. R. Org. Biomol. Chem. 2015, 13, 4231-4239. DOI link: 10.1039/c5ob00245a

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The efficient flow synthesis of important heterocyclic building blocks based on the 1,2,4-triazole and pyrrolo[1,2-c]pyrimidine scaffold has been achieved. Crucially, a telescoped continuous flow process was developed based on the reaction of N-formylglycine with triphosgene to deliver a stream of ethyl isocyanoacetate in situ, which subsequently yielded the desired heterocyclic entities in a telescoped reaction. Additionally, the functionalisation of the pyrrolo[1,2-c]pyrimidine core via subsequent SEAr reactions was studied revealing insight into a 'halogen dance' phenomenon associated with these medicinally relevant architectures.
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133. Boehmeriasin A as new lead compound for the inhibition of topoisomerases and SIRT2.
Christodoulou, M. S.; Calogero, F.; Baumann, M.; García-Argáez, A. N.; Pieraccini, S.; Sironi, M.; Dapiaggi, F.; Bucci, R.; Broggini, G.; Gazzola, S.; Liekens, S.; Silvani, A.; Lahtela-Kakkonen, M.; Martinet, N.; Nonel-Canals, A.; Santamaría-Navarroh, E.; Baxendale, I. R.; Via, L. D.; Passarell, D. Euro. J. Med. Chem. 2015, 92, 766-775. DOI link: 10.1016/j.ejmech.2015.01.038

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Two synthetic approaches to boehmeriasin A are described. A gram scale racemic preparation is accompanied by an efficient preparation of both the pure enantiomers using the conformationally stable 2-piperidin-2-yl acetaldehyde as starting material. The anti-proliferative activity in three cancer cell lines(CEM, HeLa and L1210) and two endothelial cell lines (HMEC-1, BAEC) indicates promising activity at the nanomolar range. Topoisomerases and SIRT2 are identified as biological targets and the experimental data has been supported by docking studies.
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132. A monolith immobilised iridium Cp* catalyst for hydrogen transfer reactions under flow conditions.
Rojo, M. V.; Guetzoyan, L.; Baxendale, I. R. Org. Biomol. Chem. 2015, 13, 1768-1777. DOI link: 10.1039/c4ob02376e

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An immobilised iridium hydrogen transfer catalyst has been developed for use in flow based processing by incorporation of a ligand into a porous polymeric monolithic flow reactor. The monolithic construct has been used for several redox reductions demonstrating excellent recyclability, good turnover numbers and high chemical stability giving negligible metal leaching over extended periods of use.
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131. Achieving Continuous Manufacturing: Technologies and Approaches for Synthesis, Workup, and Isolation of Drug Substance.
Baxendale, I. R.; Braatz, R. D.; Hodnett, B. K.; Jensen, K. F.; Johnson, M. D.; Sharratt, P.; Sherlock J.-P.; Florence, A. J. J. Pharm. Sci. 2015, 104, 781-791. DOI link: 10.1002/jps.24252

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This whitepaper highlights current challenges and opportunities associated with continuous synthesis, workup, and crystallization of active pharmaceutical ingredients (drug substances). We describe the technologies and requirements at each stage and emphasize the different considerations for developing continuous processes compared with batch. In addition to the specific sequence of operations required to deliver the necessary chemical and physical transformations for continuous drug substance manufacture, consideration is also given to how adoption of continuous technologies may impact different manufacturing stages in development from discovery, process development, through scale-up and into full scale production. The impact of continuous manufacture on drug substance quality and the associated challenges for control and for process safety are also emphasized. In addition to the technology and operational considerations necessary for the adoption of continuous manufacturing (CM), this whitepaper also addresses the cultural, as well as skills and training, challenges that will need to be met by support from organizations in order to accommodate the new work flows.
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130. Back Pressure Regulation of Slurry Forming Reactions in Continuous Flow.
Deadman, B. J.; Ley, S. V.; Browne, D. L.; Baxendale, I. R. Chem. Eng. Tech. 2015, 38, 259-264. DOI link: 10.1002/ceat.201400445

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The handling of solid components in flow chemical processes is still a significant challenge. Current devices for regulating back pressure in laboratory-scale flow chemistry experiments are vulnerable to blockage by solid particulates. A simple device is presented herein for generating back pressure in continuous flow processes that produce chemical slurries. The prototype was constructed from commercially available components and accommodated the use of superheated reaction conditions generated in an agitating cell reactor used to produce a suspended precipitate product.
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129. Sustainable Synthesis of Thioimidazoles via Carbohydrate-Based Multicomponent Reactions.
Baumann M.; Baxendale, I. R. Org. Lett. 2014, 16, 6076-6079. DOI link: 10.1021/ol502845h

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The synthesis of diversely functionalized thioimidazoles through a modern variant of the Marckwald reaction is presented. This new protocol utilizes unprotected carbohydrates as well as simple amine salts as sustainable and biorenewable starting materials. Importantly it was discovered that a bifurcated reaction pathway results from using aldoses and ketoses respectively, yielding distinct reaction products in a highly selective manner.
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128. Synthesis of Riboflavines, Quinoxalinones and Benzodiazepines through Chemoselective Flow Based Hydrogenations.
Baumann M.; Baxendale, I. R.; Hornung, C. H.; Ley, S. V.; Rojo, M. V.; Roper, K. A. Molecules 2014, 19, 9736-9759. DOI link: 10.3390/molecules19079736

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Robust chemical routes towards valuable bioactive entities such as riboflavines, quinoxalinones and benzodiazepines are described. These make use of modern flow hydrogenation protocols enabling the chemoselective reduction of nitro group containing building blocks in order to rapidly generate the desired amine intermediates in situ. In order to exploit the benefits of continuous processing the individual steps were transformed into a telescoped flow process delivering selected benzodiazepine products on scales of 50 mmol and 120 mmol respectively.
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127. An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles.
Baumann, M.; Baxendale, I. R. Beilstein J. Org. Chem. 2013, 9, 2265-2319. DOI link: 10.3762/bjoc.9.265

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This review which is the second in this series summarises the most common synthetic routes as applied to the preparation of many modern pharmaceutical compounds categorised as containing a six-membered heterocyclic ring. The reported examples are based on the top retailing drug molecules combining synthetic information from both scientific journals and the wider patent literature. It is hoped that this compilation, in combination with the previously published review on five-membered rings, will form a comprehensive foundation and reference source for individuals interested in medicinal, synthetic and preparative chemistry.
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126. The Development and Application of Supported Reagents for Multi-step Organic Synthesis in Supported catalysts and their applications
Baxendale, I. R.; Ley, S. V.
Book edited by D. C. Sherrington and K. P. Kybett
Published by: The Royal Society of Chemistry. 2001, Chapter 2, pages: 9-18. ISBN: 0-85404-880-4.
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125. Development of New Synthetic Tools for the Preparation of Biologically Active Molecules in Chemical Probes in Biology (NATO Science series)
Ley, S. V.; Baxendale, I. R.; Grice, P.
Book edited by M. Schneider
Published by: Kluwer Academic Publishers, Netherlands. 2003, Series Volume 129, pages: 235-244. ISBN: 978-1-4020-1770-4.
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The synthesis of organic compounds, especially biologically active molecules, is a very complex task involving many important decision making steps. These decisions are especially important at the synthesis planning stage where issues of regio-, chemo- and stereo-control and the knowledge of mechanisms and functional group compatibility are paramount. Furthermore, if the plan uses more creative and innovative approaches rather than a more logistic and strategic approach even more careful understanding and preparation is required. Even given a workable plan there are several further phases where key decisions need to be made. For example the selection of the reaction conditions to effect a specific transformation involves specific knowledge or extensive optimisation of a vast range of reagents, safety factors, solvents and temperatures that can be quite a phenomenal exercise. This part of the process also makes use of considerable operator experience especially when scale and cost issues are important.
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124. Supported Reagents and Scavengers in Multi-Step Organic Synthesis in Polymeric Materials in Organic Synthesis and Catalysis
Baxendale, I.R.; Storer, R.I.; Ley, S.V.
Book edited by M. R. Buchmeiser
Published by: VCH Berlin. 2003, Chapter 2, pages: 53-136. ISBN: 3-527-30630-7.
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123. Polymer Supported Hydroxide in Electronic Encylopaedia of Reagents for Organic Synthesis
Ley, S. V.; Baxendale, I. R.; Lee, A-L.
Book edited by L. A. Paquette
Published by: J. Wiley. 2003, Electronic, pages: E1-E2. ISBN: 9780470842898.
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122. Integrated Microwave Assisted Synthesis and Solid-Supported Reagents in Microwave-Assisted Organic Synthesis
Baxendale, I. R.; Lee, A.-L. Ley, S. V.
Book edited by J. P. Tierney and P. Lidstrom
Published by: Blackwells. 2005, Chapter 6, pages: 133-174. ISBN: 978-1-4051-1560-5.
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121. Evolution or Revolution: The Challenge to the Modern Medicinal Chemist in The Chemical Theatre of Biological Systems (Proceedings of the Beilstein-Institut Workshop, May 24th-28th 2004, Bozen)
Ley, S. V.; I.R. Baxendale, I. R.; Myers, R. M.
Book edited by M. G. Hicks and C. Kettner
Published by: Logos Verlag Berlin GmbH Italy.. 2005, Chapter 1, pages: 1-31. ISBN: 3-8325-1019-2.
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120. Polymer-Supported Regents, Scavengers and Catch-and-Release Techniques for Chemical Synthesis in Comprehensive Medicinal Chemistry II
Ley, S. V.; Baxendale, I. R.; Myers, R. M.
Book edited by J. Taylor and D. Triggle
Published by: Elsevier, Oxford. 2006, Volume 3, Drug Discovery Technologies, pages: 791-839. ISBN: 0-08-044513-6.
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119. The Use of Polymer Supported Reagents and Scavengers in the Synthesis of Natural Products in Combinatorial Synthesis of Natural Product-Based Libraries
Ley, S. V.; Baxendale, I. R.; Myers, R. M.
Book edited by A. M. Boldi
Published by: CRC Press – Taylor Francis,. 2006, Chapter 6, pages: 131-163. ISBN: 0-8493-4000-4.
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118. Natural Products as an Inspiration for the Discovery of New High Throughput Chemical Synthesis Tools in In Drug Discovery & Development
Ley, S. V.; Baxendale, I. R.; Longbottom D. A.; Myers, R. M.
Book edited by M. S. Chorghade
Published by: John Wiley & Sons. 2007, Chapter 2, pages: 51-91. ISBN: 978-0471-39847-9.
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The natural world inspires us all; from artist and philosopher to biologist and chemist alike. In our quest for new knowledge, the exquisite and varied architectures of natural products provide a rich pallet for discovery. Whether these are used to probe biological mechanisms, or to provide the basis for pharmaceutical drug discovery, natural products continue to command attention. For many of these reasons synthesis chemists are drawn to these structures as testing grounds for synthetic strategies and for the development of new methods. But we are also drawn to advance the art of molecular assembly of some of nature’s most enigmatic creations. However, more is accessible to the synthesis chemists’ skills, they can modify natural materials to probe structure activity profiles; they can provide fragment molecules or related structural scaffolds through library generation. Only the synthesis chemist can go beyond the molecule, contemplating macromolecular assemblies and creating unnatural arrangements with awe-inspiring levels of molecular diversity, limited only by their imaginations.
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117. Solid-Supported Reagents in Multi-Step Flow Synthesis in New Avenues to Efficient Chemical Synthesis: Emerging Technologies (Ernst Schering Foundation Symposium Proceedings 2006-3.)
Baxendale, I. R.; Ley, S. V.
Book edited by P. H. Seeberger and T. Blume
Published by: Springer-Verlag Berlin Heidelberg. 2007, Chapter 9, pages: 151-187. ISBN: 978-3-540-70848-3.
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The frequently overlooked benefits that considerably simplify and enrich our standard of living are most often hinged upon 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 pivotally involved science. Furthermore, the quality and quantity of our food supply relies heavily upon synthesised products, as do almost all aspects of our modern society ranging from paints, pigments and dyestuffs to plastics, polymers and other man-made materials. However, the demands being made on chemists are changing at an unprecedented pace and synthesis, or molecular assembly, must continue to evolve in response to the new challenges and opportunities that arise. Responding to this need for improved productivity and efficiency chemists have started to explore new approaches to compound synthesis. Flow-based synthesis incorporating solid supported reagents and scavengers has emerged as a powerful way of manipulating chemical entities and is envisaged to become a core laboratory technology of the future.
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116. Organic Chemistry in Microreactors; Heterogenous Reactions in Microreactors in Organic Chemistry and Catalysis
Baxendale, I. R.; Hayward, J. J.; Lanners, S.; Ley, S. V.; Smith, C. D.
Book edited by T. Wirth
Published by: John Wiley & Sons. 2008, Chapter 4.2, pages: 84-121. ISBN: 978-3-527-31869-8.
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Modern organic synthesis is undergoing a period of rapid change due to the many demands challenging it today. The need for greater speed in the discovery process requires high?throughput methods and inevitably more advanced automation. However, safety factors, sustainable procedures and costs are all key issues which must be considered. This is especially true if we wish to retain all the required levels of synthetic flexibility necessary to assemble the vast range of products and materials that are needed, and at the same time be able to stimulate further innovation and invention.
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115. The Evolution of Immobilized Reagents and their Application in Flow Chemistry for the Synthesis of Natural Products and Pharmaceutical Compounds in Modern Tools for the Synthesis of Complex Bioactive Molecules
Myers, R. M.; Roper, K. A.; Baxendale, I. R.; Ley, S. V.
Book edited by J. Cossy and S. Arseniyadis
Published by: Wiley-VCH. 2012, Chapter 11, pages: 359-394. ISBN: 978-0-470-61618-5.
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Underpinning a healthy drug discovery and development programme is the ability to prepare large numbers of structurally diverse molecules. Developing innovative practical chemical techniques to achieve this goal has therefore become essential. Indeed, the incorporation of new technologies for chemical synthesis is now commonplace and encompasses automation, informatics and robotic approaches, along with the use of immobilized reagents and catch-and-release strategies together with microfluidic flow reactors and focussed microwave techniques.
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114. Molybdenum(II)-catalysed allylic substitution.
Malkov, A. V.; Baxendale, I. R.; Mansfield, D. J.; Kocovsky, P. Tetrahedron Lett. 1997, 38, 4895-4898. DOI link: 10.1016/S0040-4039(97)01052-6

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The new Mo(II) triflate complex 5 has been found to catalyze the C?C bond forming allylic substitution with silyl enol ethers derived from ?-dicarbonyls (e.g., 6 + 12 ? 14) and from simple ketones (e.g., 6 + 13 ? 16) as nucleophiles.
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113. Molybdenum(II)-catalysed allylation of electron rich aromatics and heteroaromatics.
Davis, S. L.; Mitchell, W. C.; Malkov, A. V.; Baxendale, I. R.; Mansfield, D. J.; Kocovsky, P. J. Org. Chem. 1999, 64, 2751-2764. DOI link: 10.1021/jo982178y

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The stable, readily available molybdenum(II) complexes [Mo(CO)4Br2]2 (B) and Mo(CO)3(MeCN)2(SnCl3)Cl (C) have been found to catalyze C?C bond-forming allylic substitution with electron-rich aromatics (e.g., 15 + PhOMe ? 62) and heteroaromatics (e.g., 15 + 36 ? 88) as nucleophiles under mild conditions (room temperature, 30 min?3 h). Remarkable is the para-selectivity for anisole, whereas phenol tends to favour ortho-substitution in certain instances. Mechanistic and stereochemical experiments are indicative of Lewis-acid catalysis rather than a metal template-controlled process.
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112. Molybdenum(II)- and tungsten(II)-catalysed allylic substitution.
Malkov, A. V.; Baxendale, I. R.; Dvorak, D.; Mansfield, D. J.; Kocovsky, P. J. Org. Chem. 1999, 64, 2737-2750. DOI link: 10.1021/jo9821776

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The molybdenum(II) complexes Mo(CO)5(OTf)2 (7a), [Mo(CO)4Br2]2 (8a), their tungsten(II) congeners 7b and 8b, and bimetallic complex Mo(CO)3(MeCN)2(SnCl3)Cl (9a) have been found to catalyze the C?C bond-forming allylic substitution with silyl enol ethers derived from ?-dicarbonyls (e.g., 16 + 30 ? 46) or from simple ketones (e.g., 16 + 32 ? 50), aldehydes, and esters as nucleophiles under mild conditions (room temperature, 1?2 h). Methanol, as a prototype oxygen nucleophile, reacts in a similar fashion (e.g., 16 + MeOH ? 43). Mechanistic and stereochemical experiments are indicative of Lewis-acid catalysis rather than a metal template-controlled process.
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111. Multi-step organic synthesis using solid-supported reagents and scavengers: a new paradigm in chemical library generation.
Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.; Leach, A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.; Storer, R. Ian; Talyor, S. J. J. Chem. Soc., Perkin Trans. 1 2000, (23), 3815-4196. DOI link: 10.1039/b006588i

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The use of polymer-supported reagents and scavengers provides an attractive and practical method for the clean and efficient preparation of novel chemical libraries with potential application in the pharmaceutical or agrochemical industries. These methods can be extended in a multi-step fashion to provide access to more complex structures, including biologically active natural products. In this review, an extensive listing of known supported reagents, catalysts and scavenging agents has been included as an aid in the future design of synthesis programmes.
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110. Polymer-Supported Reagents for Multi-Step Organic Synthesis: Application to the Synthesis of Sildenafil..
Baxendale, I. R.; Ley, S. V. Bioorg. Med. Chem. Lett. 2000, 10, 1983-1986. DOI link: 10.1016/S0960-894X(00)00383-8

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Sildenafil 1 (Viagra™), a well known and commercially important pharmaceutical drug, has been prepared using polymer-supported reagents in a multi-step, convergent process resulting in a clean and efficient preparation without the need for conventional purification methods.
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109. The Clean and Efficient Synthesis of Azo-Dyes Using Polymer-Supported Reagents..
Caldarelli, M.; Baxendale, I. R.; Ley, S. V. Green Chem. 2000, 2, 43-45. DOI link: 10.1039/b000816h

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The recent technological advancements in polymer-supported reactions have led to the propagation of combinatorial chemistry as a method for the rapid and efficient preparation of novel functionalised molecules. An interesting and fast growing branch of this area is polymer-supported reagents. Here we describe the principles of generating diazonium salts and their coupling using polymer-supported reagents and sequestrating agents, to form azo dyes in a clean manner.
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108. Synthesis of new chiral 2,2 '-bipyridyl-type ligands, their coordination to molybdenum(0), copper(II), and palladium(II), and application in asymmetric allylic substitution, allylic oxidation, and cyclopropanation..
Malkov, A. V.; Baxendale, I. R.; Bella, M.; Langer, V.; Fawcett, J.; Russell, D. R.; Mansfield, D. J.; Valko, M.; Kocovsky, P. Organometallics 2001, 20, 673-690. DOI link: 10.1021/om000850n

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A series of chiral bipyridine-type ligands 5?12 has been synthesized via a de novo construction of the pyridine nucleus. The chiral moieties of the ligands originate from the monoterpene realm, namely, pinocarvone (13 ? 6, 7, and 9), myrtenal (18 ? 5), nopinone (21 ? 8 and 10), and menthone (28 ? 11 and 12); the first three precursors can be obtained in one step from ?- and ?-pinene, respectively. Complexes of these ligands with molybdenum(0) (38?40) and copper(II) (41) have been characterized by single-crystal X-ray crystallography. While complex 38 exhibits polymorphism (monoclinic and tetragonal forms crystallize from the same batch), 41 is characterized by a tetrahedrally distorted geometry of the metal coordination. The Mo and Pd complexes exhibit modest asymmetric induction in allylic substitution (43 ? 44), and the Cu(I) counterpart of 41, derived from 10 (PINDY) and Cu(OTf)2, shows promising enantioselectivity (49?75% ee) and reaction rate (?30 min at room temperature) in allylic oxidation of cyclic olefins (47 ? 48). The Cu(I) complex of 11 (MINDY) proved effective in cyclopropanation (49 ? 50) with up to 72% ee.
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107. Molybdenum(0) and tungsten(0) catalysts with enhanced reactivity for allylic substitution: regioselectivity and solvent effects..
Malkov, A. V.; Baxendale, I. R.; Mansfield, D. J.; Kocovsky, P. J. Chem. Soc. Perkin Trans. 1 2001, (10), 1234-1240. DOI link: 10.1039/b100903f

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The binuclear Mo(II) and W(II) complexes 28a,b and 29a,b have been developed as pre-catalysts for allylic substitution with ?-dicarbonyl nucleophiles. These complexes are reduced in situ to Mo(0) and W(0) catalytic species 30a,b and 31a,b by excess of NaH, employed to generate sodiomalonate nucleophiles, or by DIBAL-H. 1,3-Dioxolane and 1,4-dioxane, when used as solvents, substantially accelerate the reaction. These new catalysts exhibit “traditional” Mo regiochemistry, i.e., the nucleophilic attack occurring preferentially at the more substituted carbon (5 ? 9; 37 ? 38), unless an additional factor, such as further coordination to another moiety of the allylic electrophile takes part (41), as in the case of the geranyl-type substrates (32 or 33 ? 36).
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106. A concise synthesis of the natural product carpanone using solid-supported reagents and scavengers..
Baxendale, I. R.; Lee, A.-L.; Ley, S. V. Synlett 2001, (9), 1482-1484. DOI link: 10.1055/s-2001-16783

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Polymer-supported reagents have been applied to the synthesis of the natural product carpanone resulting in a clean and efficient synthesis without the requirement for conventional purification techniques.
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105. Synthesis of nornicotine, nicotine and other functionalised derivatives using solid-supported reagents and scavengers..
Baxendale, I. R.; Brusotti, G.; Matsuoka, M.; Ley, S. V. J. Chem. Soc. Perkin Trans. 1 2002, NA, 143-154. DOI link: 10.1039/b109482n

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The sequential use of solid-supported reagents and scavengers has led to an efficient synthesis of the natural products nornicotine 1, nicotine 2 and further fuctionalised derivatives. Also reported is a diastereoselective route to both enantiomers of nicotine 2.
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104. A polymer-supported iridium catalyst for the stereoselective isomerisation of double bonds..
Baxendale, I. R.; Lee, A.-L.; Ley, S. V. Synlett 2002, (3), 516-518. DOI link: 10.1055/s-2002-20483

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A polymer-supported iridium catalyst has been prepared and used in the isomerisation of the double bonds in aryl allylic derivatives with excellent trans selectivity and without the need for conventional work-up procedures.
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103. A clean conversion of aldehydes to nitriles using a solid-supported hydrazine..
Baxendale, I. R.; Ley, S. V.; Sneddon, H. F. Synlett 2002, (5), 775-777. DOI link: 10.1055/s-2002-25333

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A polymer-supported hydrazine reagent has been applied to the conversion of a range of aldehydes to nitriles, providing a clean and efficient route to more diverse building blocks for combinatorial chemistry programmes.
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102. Total synthesis of the amaryllidaceae alkaloid (+)-plicamine and its unnatural enantiomer by using solid-supported reagents and scavengers in a multistep sequence of reactions..
Baxendale, I. R.; Ley S. V.; Piutti, C. Angew. Chem. Int. Ed. 2002, 41, 2194-2197. DOI link: 10.1002/1521-3773(20020617)41:12<2194::AID-ANIE2194>3.0.CO;2-4

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A sequence of polymer-supported reagents and scavengers was used to promote the synthetic transformations in the first total synthesis of (+)-plicamine (1), a member of the amaryllidaceae alkaloid family, starting from L-4-hydroxyphenylglycine.
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101. Total synthesis of the amaryllidaceae alkaloid (+)-plicamine using solid-supported reagents..
Baxendale, I. R.; Ley, S. V.; Nesi, M.; Piutti, C. Tetrahedron 2002, 58, 6285-6304. DOI link: 10.1016/S0040-4020(02)00628-2

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In this report we describe in full the total synthesis of the amaryllidaceae alkaloid (+)-plicamine 1 including a model compound study. In both cases the compounds were prepared using solid-supported reagents and scavengers in multi-step sequences of reactions to give materials which required no conventional purification but could be carried on to the next synthetic step.
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100. Solid-supported reagents for multi-step organic synthesis: preparation and application..
Ley, S. V.; Baxendale, I. R.; Brusotti, G.; Caldarelli, M.; Massi, A.; Nesi, M. Farmaco 2002, 57, 321-330. DOI link: 10.1016/S0014-827X(02)01210-7

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Since the early days of combinatorial chemistry solid-phase organic synthesis has been the method of choice for the production of large libraries. Solution-phase synthesis is again gaining importance especially for the synthesis of parallel arrays of smaller, focussed libraries containing single compounds with high degrees of purity. In the field of solution-phase library generation, the use of solid-supported reagents, catalysts and scavengers is emerging as a leading strategy, combining the advantages of both solid-phase organic synthesis (e.g. allowing the employment of an excess of reagent without the need for additional purification steps) and solution-phase chemistry (e.g. the ease of monitoring the progress of the reactions by applying LC-MS, TLC or standard NMR techniques). An account of some of the most recent advances in this area of research will be presented.
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99. A concise synthesis of carpanone using solid-supported reagents and scavengers..
Baxendale, I. R.; Lee, A-L.; Ley, S. V. J. Chem. Soc. Perkin Trans. 1 2002, 16, 1850-1857. DOI link: 10.1039/b203388g

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Polymer-supported reagents have been applied to the synthesis of the natural product carpanone resulting in a clean and efficient synthesis without the requirement for conventional purification techniques. A new polymer-supported transition metal isomerisation catalyst is also reported.
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98. Application of polymer-supported enzymes and reagents in the synthesis of gamma-aminobutyric acid (GABA) analogues..
Baxendale, I. R.; Ernst, M.; Krahnert, W. R.; Ley, S. V. Synlett 2002, (10), 1641-1644. DOI link: 10.1055/s-2002-34249

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Polymer-supported pig liver esterase was used for the resolution of meso-diesters. The enzyme can be recovered quantitatively from the reaction mixture by filtration and reused without significant loss of activity. Further transformation of the resulting enantiomerically enriched carboxylic acids through the application of polymer-supported reagents and scavengers provides a number of GABA-analogues.
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97. New tools and concepts for modern organic synthesis..
Ley, S. V.; Baxendale, I. R. Nat. Rev. Drug Discovery 2002, 1, 573-586. DOI link: 10.1038/nrd871

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The increasing need to efficiently assemble small molecules as potential modulators of therapeutic targets that are emerging from genomics and proteomics is driving the development of novel technologies for small-molecule synthesis. Here, we describe some of the general applications and approaches to synthesis using one such technology — solid-supported reagents — that has been shown to significantly improve productivity in the generation of combinatorial libraries and complex target molecules.
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96. Organic synthesis in a changing world..
Ley, S. V.; Baxendale, I. R. Chem. Rec. 2002, 2, 377-388. DOI link: 10.1002/tcr.10033

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This article is based on a lecture presented to the Chemical Society of Japan at Wasada University on March 27, 2002, by Professor Steven V. Ley. The lecture, “Organic Synthesis in a Changing World,” was a comprehensive account of the ongoing research efforts of professor Ley's group in the development and application of solid-supported reagents and scavengers for use in organic synthesis.
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95. Synthesis of Trifluoromethyl Ketones Using Polymer-Supported Reagents..
Baxendale, I. R.; Ley, S. V.; Nesi, M.; Lumeras, W. Comb. Chem. & High Throughput Screening 2002, 5, 197-199. DOI link: 10.2174/1386207024607220

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A two step synthesis of trifluoromethyl ketones from aldehydes is reported. A combination of polymer-supported reagents and sequestering agents were employed to effect the transformation without the need for chromatographic purification.
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94. Enantioselective synthesis of the tetrahydrobenzylisoquinoline alkaloid (-)-norarmepavine using polymer supported reagents..
Baxendale, I. R.; Davidson, T. D.; Ley, S. V.; Perni, R. H. Heterocyles 2003, 60, 2707-2715. DOI link: 10.3987/COM-03-9892

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We describe, in full, the enantioselective synthesis of the tetrahydrobenzylisoquinoline alkaloid (-)-norarmepavine (1) in 77% e.e. This compound was prepared using solid-supported reagents and scavengers in multi-step sequences of reactions to give materials that required no conventional purification at the individual steps.
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93. Microwave assisted Leimgruber-Batcho reaction for the preparation of indoles, azaindoles and pyrroylquinolines..
Siu, J.; Baxendale, I. R.; Ley, S. V. Org. Biomol. Chem. 2004, 2, 160-167. DOI link: 10.1039/B313012F

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The development of enhanced conditions for Lewis acid catalysed Leimgruber–Batcho indole synthesis using microwave acceleration is described.
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92. Multi-step application of immobilized reagents and scavengers: A total synthesis of epothilone C..
Storer, R. I.; Takemoto, T.; Jackson, P.S.; Brown, D. S.; Baxendale, I. R.; Ley, S. V. Chem. Euro. J. 2004, 10, 2529-2547. DOI link: 10.1002/chem.200305669

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The total synthesis of the cytotoxic antitumour natural product epothilone C has provided a stage for the exploitation and further development of immobilized reagent methods. A stereoselective convergent synthetic strategy was applied, incorporating polymer-supported reagents, catalysts, scavengers and catch-and-release techniques to avoid frequent aqueous work-up and chromatographic purification.
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91. Microwave-Enhanced Palladium-Catalysed Reactions.
Baxendale, I. R.; Pitts, M. R. Innovations in Pharmaceutical Technology 2005, 18, 86-90. DOI link:

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Microencapsulated palladium has been shown to be compatible with microwave heating, offering benefits such as increased yields, higher purities and simple work-up procedures, and permitting access to many previously unattainable molecular assemblies.
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90. Synthesis of Alkaloid Natural Products using Supported Reagents and Scavengers.
Baxendale, I. R.; Ley, I. R. Curr. Org. Chem. 2005, 9, 1521-1534. DOI link: 10.2174/138527205774370513

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Supported reagents and scavengers have become key tools for the synthesis of biologically important molecular entities. The complexity of the target molecules attainable and the synthetic flexibility afforded by these systems now rivals any solution phase approach whilst offering the added advantage of rapid purification and work-up. This short review highlights the application of these immobilized reagents to the preparation of alkaloid natural products.
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89. Formation of 4-Aminopyrimidines via the Trimerization of Nitriles using Focused Microwave Heating..
Baxendale, I. R.; Ley, S. V. J. Comb. Chem. 2005, 7, 483-489. DOI link: 10.1021/cc049826d

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A series of substituted aliphatic nitriles have been trimerized to their corresponding pyrimidine structures under solvent-free conditions in the presence of catalytic quantities of potassium tert-butoxide using a focused microwave reactor. Multigram quantities of the corresponding 4-aminopyrimidines have been prepared in high yields and purity following a simple and scaleable protocol.
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88. A Phase-Switch Purification Approach for the Expedient Removal of Tagged Reagents and Scavengers Following their Application in Synthesis..
Siu, J.; Baxendale, I. R.; Lewthwaite, R. A.; Ley, S. V. Org. Biomol. Chem. 2005, 3, 3140-3160. DOI link: 10.1039/b503778f

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In this paper we wish to report on a variety of expedient chemical transformations and purifications achieved via a generic ‘catch and release’ methodology, based on a synthetically inert bipyridyl chelating tag that can be selectively captured with a resin-bound copper(II) species. Utilising this approach we are able to derive many of the same benefits associated with both solid phase synthesis and supported reagent methods.
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87. Synthesis of the Alkaloid Natural Products (+)-Plicane and (–)-Obliquine using Polymer-Supported Reagents and Scavengers.
Baxendale, I. R.; Ley, S. V. Ind. & Eng. Chem. Res. 2005, 44, 8588-8592. DOI link: 10.1021/ie048822i

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Two new naturally occurring amaryllidaceae alkaloids have been synthesized, using a divergent approach facilitated by the use of polymer-supported reagents and scavengers.
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86. The Rapid Preparation of 5-Substituted-2-Aminosulfonamide-1,3,4-oxadiazoles Using Polymer-Supported Reagents and Scavengers.
Baxendale, I. R.; Ley, S. V.; Martinelli, M. Tetrahedron 2005, 61, 5323-5349. DOI link: 10.1016/j.tet.2005.03.062

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Herein, we report on the preparation of a library of 5-substituted-2-amino-1,3,4-oxadiazoles and the corresponding thiadiazole analogues. Presented is a one-pot preparation of the 2-aminosulfonylated analogues through a three component coupling of an acylhydrazine, an isocyanate and sulfonyl chloride promoted by a polymer-supported phosphazine base under microwave dielectric heating. Also described is the optimization process and details pertaining to the elucidation of the reaction products.
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85. Non-Metal Catalysed Intramolecular Alkyne Cyclotrimerization Reactions Promoted by Focussed Microwave Heating in Batch and Flow Modes..
Baxendale, I. R.; Ley, S. V.; Saaby, S. Org. Biomol. Chem. 2005, 3, 3365-3368. DOI link: 10.1039/b509540a

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A number of oligomeric alkynes underwent [2 + 2 + 2] intramolecular trimerization to afford arenes under metal-free conditions using focussed microwave heating.
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84. Fully Automated Continuous Flow Synthesis of 4,5-Disubstituted Oxazoles.
Baumann, M.; Baxendale, I. R.; Ley, S. V.; Smith, C. D.; Tranmer, G. K. Org. Lett. 2006, 8, 5231-5234. DOI link: 10.1021/ol061975c

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A multipurpose mesofluidic flow reactor capable of producing gram quantities of material has been developed as an automated synthesis platform for the rapid on-demand synthesis of key building blocks and small exploratory libraries. The reactor is configured to provide the maximum flexibility for screening of reaction parameters that incorporate on-chip mixing and columns of solid supported reagents to expedite the chemical syntheses.
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83. A flow reactor process for the synthesis of peptides utilizing immobilized reagents, scavengers and catch and release protocols..
Baxendale, I. R.; Ley, S. V.; Smith, C. D.; Tranmer, G. K. Chem. Commun. 2006, NA, 4835-4837. DOI link: 10.1039/b612197g

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A general flow process for the multi-step assembly of peptides has been developed and this procedure has been used to successfully construct a series of Boc, Cbz and Fmoc N-protected dipeptides in excellent yields and purities, including an extension of the method to enable the preparation of a tripeptide derivative.
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82. Microwave Flow Chemistry: The Next Evolutionary Step in Synthetic Chemistry.
Baxendale, I. R.; Pitts, M. R. Chimica Oggi, Chemistry Today 2006, 24, 41-45. DOI link:

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Microwave assisted chemistry is an increasingly important tool in the medicinal chemist’s quest to speed up drug development. With the development of commercial focussed-microwave reactors, reactions can be carried out safely and reproducibly at a useful laboratory scale. Attention is now turning to the scale up of these processes with chemists increasingly investigating continuous flow applications. This review intends to highlight the significant benefits in terms of efficiency and control that flow-based microwave applications offer modern organic synthesis.
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81. Microwave Assisted Suzuki Coupling Reactions using an Encapsulated Palladium Catalyst for Batch and Continuous Flow Transformations..
Baxendale, I. R.; Deeley, J.; Griffiths-Jones, C. M.; Ley, S. V.; Saaby, S.; Tranmer, G. K. Eur. J. Chem. 2006, 12, 4407-4416. DOI link: 10.1002/chem.200501400

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This article describes the design, optimisation and development of a Suzuki cross-coupling protocol mediated by an efficient palladium-encapsulated catalyst (Pd EnCatTM) under microwave irradiation. The methodology has been used in both batch mode for classical library preparation and in continuous-flow applications furnishing multigram quantities of material. Described is a method that uses direct focused microwave heating whilst applying an external cooling source. This enables a lower than normal bulk temperature to be maintained throughout the reaction period leading to significant improvements in the overall yield and purity of the reaction products. Additional aspects of this novel heating protocol are discussed in relation to the prolonged lifetime and enhanced reactivity of the immobilised catalyst system.
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80. A flow process for the multi-step synthesis of the alkaloid natural product oxomaritidine..
Baxendale, I. R.; Deeley, J.; Griffiths-Jones, C. M.; Ley, S. V.; Saaby, S.; Tranmer, G. K. Chem. Commun. 2006, 24, 2566-2568. DOI link: 10.1039/b600382f

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A flow process for the multi-step synthesis of the alkaloid natural product (±)-oxomaritidine is described, mediated through the use of microfluidic pumping systems that progress material through various packed columns containing immobilized reagents, catalysts, scavengers or catch and release agents; our route involves the combination of seven separate synthetic steps linked into one continuous sequence utilizing flow chemistry.
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79. Preparation of the Neolignan Natural Product Grossamide by a Continuous Flow Process..
Baxendale, I. R.; Griffiths-Jones, C. M.; Ley, S. V.; Saaby, S.; Tranmer, G. K. Synlett 2006, (3), 427-430. DOI link: 10.1055/S-2006-926244

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This article describes the first enantioselective total synthesis of 2-aryl-2,3-dihydro-3-benzofurancarboxyamide neolignan, grossamide (1) using a fully automated and scalable flow reactor.
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78. A Microcapillary Flow Disc (MFD) Reactor for Organic Synthesis.
Hornung, C. H.; Mackley, M. R.; Baxendale, I. R.; Ley, S. V. Org. Proc. Res. Dev. 2007, 11, 399-405. DOI link: 10.1021/op700015f

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This paper reports proof of concept, development, and trials for a novel plastic microcapillary flow disc (MFD) reactor. The MFD was constructed from a flexible, plastic microcapillary film (MCF), comprising parallel capillary channels with diameters in the range of 80?250 ?m. MCFs were wound into spirals and heat treated to form solid discs, which were then capable of carrying out continuous flow reactions at elevated temperatures and pressures and with a controlled residence time. Three reaction schemes were conducted in the system, namely the synthesis of oxazoles, the formation of an allyl-ether, and a Diels?Alder reaction. Reaction scales of up to four kilograms per day could be achieved. The potential benefits of the MFD technology are compared against those of other reactor geometries including both conventional lab-scale and other microscale devices.
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77. Microwave Reactions under Continuous Flow Conditions..
Baxendale, I. R.; Hayward, J. J.; Ley. S. V. Combinatorial Chemistry & High Throughput Screening 2007, 10, 802-836. DOI link: 10.2174/138620707783220374

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Microwave chemistry has already impacted significantly on the everyday synthesis of organic molecules. The adoption and integration of this liberating technology has permitted a resurrection of many synthetic transformations that were previously considered too extreme in their conditions (temperatures, pressures, reaction times) to be synthetically useful. Furthermore, whole arrays of additional chemical transformations have been devised under microwave heating that allow access to more diverse chemical architectures via more expedient routes. Continuous flow processing of chemical intermediates taking advantage of the unique heating mechanism and characteristics of microwave irradiation will certainly be the next evolutionary step forward in this area. The synergistic combination afforded by the simultaneous application of these two core processing tools will enhance still further the synthetic capabilities of tomorrows chemists. This short review aims to highlight the current developments and future potential offered by continuous flow microwave mediated synthesis.
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76. Batch and Flow Mode Focused Microwave Synthesis of 5-Amino-4-cyanopyrazoles and their Further Conversion to 4-amino-pyrazolopyrimidines..
Smith, C. J.; Iglesias-Sigüenza, J.; Baxendale, I. R.; Ley, S. V. Org. Biomol. Chem. 2007, 5, 2758-2761. DOI link: 10.1039/b709043a

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A new approach to the synthesis of 5-amino-4-cyanopyrazoles has been developed, utilising a novel flow microwave device. These products are then converted by a batch mode microwave process to structurally more complex dimeric and ‘mixed’ pyrazolopyrimidine structures.
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75. Pharmaceutical Strategy and Innovation: An Academics Perspective.
Baxendale, I. R.; Hayward, J. J.; Ley, S. V.; Tranmer, G. K. MedChemMed 2007, 2, 768-788. DOI link: 10.1002/cmdc.200700008

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The pharmaceutical industry is under increasing pressure on many fronts, from investors requiring larger returns to consumer groups and health authorities demanding cheaper and safer drugs. It is also feeling additional pressure from the infringement upon its profit margins by generic drug producers. Many companies are aggressively pursuing outsourcing contracts in an attempt to counter many of the financial pressures and streamline their operations. At the same time, the productivity of the pharmaceutical industry at its science base is being questioned in terms of the number of products and the timeframes required for each company to deliver them to market. This has generated uncertainties regarding the current corporate strategies that have been adopted and the levels of innovation being demonstrated. In this essay we discuss these topics in the context of the global pharmaceutical market, investigating the basis for many of these issues and highlighting the hurdles the industry needs to overcome, especially as they relate to the chemical sciences.
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74. [3 + 2] Cycloaddition of Acetylenes with Azides to give 1,4-Disubstituted 1,2,3-Triazoles in a Modular Flow Reactor.
Smith, C. D.; Baxendale, I. R.; Lanners, S.; Hayward, J. J.; Smith S. C.; Ley, S. V. Org. Biomol. Chem. 2007, 5, 1559-1561. DOI link: 10.1039/b702995k

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The cycloaddition of acetylenes with azides to give the corresponding 1,4-disubstituted 1,2,3-triazoles is reported using immobilised reagents and scavengers in pre-packed glass tubes in a modular flow reactor.
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73. Tagged Phosphine Reagents to Assist Reaction Work-up by Phase-Switched Scavenging Using a Modular Flow Reactor Process.
Smith, C. D.; Baxendale, I. R.; Tranmer, G. K.; Baumann, M.; Smith, S. C.; Russell A. Lewthwaite, R. A.; Ley, S. V. Org. Biomol. Chem. 2007, 5, 1562-1568. DOI link: 10.1039/b703033a

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The use of three orthogonally tagged phosphine reagents to assist chemical work-up via phase-switch scavenging in conjunction with a modular flow reactor is described. These techniques (acidic, basic and Click chemistry) are used to prepare various amides and tri-substituted guanidines from in situ generated iminophosphoranes.
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72. The Use of diethylaminosulfurtrifluoride (DAST) for Fluorination in a Continuous Flow Microreactor.
Baumann, M.; Baxendale, I. R.; Ley, S. V. Synlett 2008, (14), 2111-2114. DOI link: 10.1055/s-2008-1078026

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The convenient and safe use of diethylaminosulfur tri­fluoride as a fluorinating agent in a continuous-flow microreactor is described using an in-line purification method to obtain clean reaction products.
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71. The application of focused microwave irradiation coupled with freeze drying to investigate the reaction of MgO and Al2O3 slurries in the formation of layered double hydroxides.
Mitchell, S.; Baxendale, I. R.; Jones, W. Green. Chem. 2008, 10, 629-634. DOI link: 10.1039/b801365a

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Focused microwave irradiation (MI) and freeze drying (FD) techniques have been used to study the generation of layered double hydroxides prepared from MgO–Al2O3–H2O systems. Reactions were undertaken at temperatures of between 100 and 180 °C in order to study the formation of the 3R1 and 3R2 polytypes, respectively. MI was found to enhance the rate of formation of both polytypes. FD provided an effective means of quenching the reaction, enabling effective ex situ analysis at intermediate stages. The phase selectivity of the reaction was shown to vary with temperature, promoting the formation of an impurity Mg(OH)2 at elevated temperatures.
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70. A Bifurcated Pathway to Thiazoles and Imidazoles Using a Modular Flow Microreactor..
Baxendale, I. R.; Smith, C. D.; Voica, F.; Tamborini, L.; Ley, S. V. J. Comb. Chem. 2008, 10, 851-857. DOI link: 10.1021/cc800070a

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A scalable method for the preparation of 4,5-disubstituted thiazoles and imidazoles as distinct regioisomeric products using a modular flow microreactor has been devised. The process makes use of microfluidic reaction chips and packed immobilized-reagent columns to effect bifurcation of the reaction pathway.
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69. A New Focused Microwave Approach to Amino-Substituted Pyrroloisoquinolines and Pyrroloquinolines via a Sequential Multi-component Coupling Process.
Hopkin, M. D.; Baxendale, I. R.; Ley, S. V. Synthesis 2008, (11), 1688-1702. DOI link: 10.1055/s-2008-1067048

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A multi-component reaction has been developed allowing direct access to pyrroloisoquinolines and pyrroloquinolines with new, electron-rich substitution patterns. The synthesised amino-substituted heterocyclic compounds and intermediates involved in their formation represent novel compounds. Focused microwave irradiation was used extensively to allow simple access to a wide temperature range using low boiling point solvents.
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68. Azide Monoliths as Convenient Flow Reactors for Efficient Curtius Rearrangement Reactions.
Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N.; Smith, C. D. Org. Biomol. Chem. 2008, 6, 1587-1593. DOI link: 10.1039/b801634h

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The preparation and use of an azide-containing monolithic reactor is described for use in a flow chemistry device and in particular for conducting Curtius rearrangement reactions via acid chloride inputs.
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67. A Modular Flow Reactor for Performing Curtius Rearrangements as a Continuous Flow Process.
Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N.; Smith, C. D.; Tierney, J. P. Org. Biomol. Chem. 2008, 6, 1577-1586. DOI link: 10.1039/b801631n

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The use of a mesofluidic flow reactor is described for performing Curtius rearrangement reactions of carboxylic acids in the presence of diphenylphosphoryl azide and trapping of the intermediate isocyanates with various nucleophiles.
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66. The Changing Face of Organic Synthesis.
Ley, S. V.; Baxendale, I. R. Chimia 2008, 62, 162-168. DOI link: 10.2533/chimia.2008.162

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The article describes the content of the Paul Karrer Lecture given at the University of Zürich on the 20th of June 2007 by Professor Steven V. Ley. The lecture illustrates the work underway within the Chemistry Department at Cambridge to develop microreactors for flow chemistry applications. These modular, small footprint devices are capable of preparing a wide range of compounds including natural products in up to seven synthesis steps. Products can generally be obtained in high yield and purity without conventional work-up methods using a variety of reaction mixer chips and pre-packed flow tubes of immobilised reagents and scavengers.
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65. A Base-catalysed One-pot Three-component Coupling Reaction Leading to Nitrosubstituted Pyrroles.
Baxendale, I. R.; Buckle, C. D.; Ley,S. V.; Tamborini, L. Synthesis 2009, (9), 1485-1493. DOI link: 10.1055/s-0028-1087991

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Tosyl isocyanide and ethyl chloroformate react with nitrostyrenes to afford nitro-substituted pyrroles in good yield when a catch-and-release protocol was employed as a purification strategy.
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64. New Tools for Molecule Makers: Emerging Technologies..
Ley, S. V.; Baxendale, I. R. Beilstein J. Org. Chem. 2009, NA, 65-85. DOI link: www.beilstein-institut.de/Bozen2008/Proceedings/Ley/Ley.pdf

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If one reflects for a moment about the current practices used by a skilled synthesis chemist, we must be impressed by the sheer complexity of what can be achieved. Moreover, the impact on society is staggering, given the array of healing drugs, compounds that protect and guarantee our food supply to the colours and materials of our modern society. All the sciences benefit to some degree from our ability to assemble novel molecular architectures that display function and beneficial properties. The synthesis chemist’s ability to understand and create these selective features at a molecular level from simple building blocks is truly awe-inspiring; especially given that a combination of only a small selection of nine different elements of the periodic table and a molecular weight limit of 500 Daltons can, in principle, generate a difficult to comprehend number of 1063 different molecules! Despite the obvious achievements of chemical synthesis, it is not without its problems. These relate to its current sustainability as a discipline, where we see issues of poor atom and step economy.
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63. A microfluidic flow chemistry platform for organic synthesis: the Hofmann rearrangement..
Palmieri, A.; Ley, S. V.; Hammond, K.; Polyzos, A.; Baxendale, I. R. Tetrahedron Lett. 2009, 50, 3287-3289. DOI link: 10.1016/j.tetlet.2009.02.059

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We report on the use of commercially available chemical microreactors to effect the Hofmann rearrangement of aromatic amides to the corresponding carbamates.
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62. Continuous flow based catch and release protocol for the synthesis of a-Ketoesters.
Palmieri, A.; Ley, S. V.; Polyzos, A.; Ladlow, M.; Baxendale, I. R. Beilstein J. Org. Chem. 2009, 5(23), 1-17. DOI link: 10.3762/bjoc.5.23

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Using a combination of commercially available mesofluidic flow equipment and tubes packed with immobilised reagents and scavengers, a new synthesis of á-ketoesters is reported.
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61. Development of Fluorination Methods using Continuous-Flow Microreactors.
Baumann, M.; Baxendale, I. R.; Martin, L. J.; Ley, S. V. Tetrahedron 2009, 65, 6611-6625. DOI link: 10.1016/j.tet.2009.05.083

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The safe and reliable use of various fluorination methods including nucleophilic fluorination (DAST), trifluoromethylation (Ruppert's reagent) and electrophilic fluorination (Selectfluor®) in a continuous-flow microreactor is reported. Special attention was given to the use of in-line scavenging procedures in order to obtain clean products without the need for further purification.
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60. Multi-Step Synthesis using Modular Flow Reactors: Bestmann-Ohira Reagent for the Formation of Alkynes and Triazoles.
Baxendale, I. R.; Ley, S. V.; Mansfield, A. C.; Smith, C. D. Angew. Chem. Int. Ed. 2009, 48, 4017-4021. DOI link: 10.1002/anie.200900970

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Multistep in flow: The Seyferth–Gilbert reagent 1 has been applied in a flow system to rapidly synthesize terminal alkynes. The system has been further applied to synthesize triazole 3 from alcohol 2 in a three-step oxidation/homologation/copper(I)-catalyzed azide–alkyne cycloaddition sequence without isolation of intermediates.
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59. An efficient and transition metal free protocol for the transfer hydrogenation of ketones as a continuous flow process.
Sedelmeier, J.; Ley, S. V.; Baxendale, I. R. Green Chem. 2009, 11, 683-685. DOI link: 10.1039/b821752a

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We report the efficient reduction of a selection of ketones to the corresponding secondary alcohols using only catalytic amounts of LiOtBu in iPrOH facilitated by using a continuous flow reactor.
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58. Pd-EnCatTM TPP30 as a Catalyst for the Generation of Highly Functionalized Aryl- and Alkenyl-substituted Acetylenes via Microwave Assisted Sonogashira type Reactions.
Sedelmeier, J.; Ley, S. V.; Lange, H.; Baxendale, I. R. Eur. J. Org. Chem. 2009, (26), 4412-4420. DOI link: 10.1002/ejoc.200900344

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We report a rapid microwave-assisted Sonogashira cross-coupling of aryl iodides and bromides with terminal alkynes using Pd-EnCatTM TPP30. Both electron-rich and electron-deficient aryl halides reacted smoothly with a broad variety of terminal alkynes in MeCN at 100–120 °C. The coupling products were obtained in good to excellent yields and in high purity. This reaction can be performed under copper- and DMF-free conditions and does not require an inert atmosphere. Furthermore, the encapsulated catalyst can be recovered and recycled by a simple filtration of the reaction mixture. It can be reused in further reactions with only minor decrease in activity. Additionally, we were able to produce a variety of enyne derivatives under modified conditions employing the same Pd-EnCatTM source.
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57. Synthesis of Acetal Protected Building Blocks using Flow Chemistry and Flow I.R. Methods: Preparation of Butane-2,3-Diacetal Tartrates.
Carter, C. F.; Baxendale, I. R.; O’Brien, M.; Pavey, J. B. J.; Ley, S. V. Org. Biomol. Chem. 2009, 7, 4594-4597. DOI link: 10.1039/b917289k

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The syntheses of butane-2,3-diacetal protected tartrate derivatives are described using continuous flow processing techniques with in-line purification and I.R. analytical protocols.
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56. Multi-Step Synthesis by Using Modular Flow Reactors: The Preparation of Yne-ones and their use in Heterocycle Synthesis.
Baxendale, I. R.; Schou, S. C.; Sedelmeier, J.; Ley, S. V. Chem. Eur. J. 2010, 16, 89-94. DOI link: 10.1002/chem.200902906

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Multi-step in flow: The palladium-catalysed acylation of terminal alkynes for the synthesis of yneones as well as their further transformation to various heterocycles in a continuous-flow mode is presented. Furthermore, an extension of the simple flow configuration that allows for easy batch splitting and the generation of a heterocyclic library is described.
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55. Synthesis of 3-Nitropyrrolidines via Dipolar Cycloaddition Reactions using a Modular Flow Reactor.
Baumann, M; Baxendale, I. R.; Ley, S. V. Synlett 2010, (5), 749-752. DOI link: 10.1055/s-0029-1219344

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The generation and subsequent use of unstabilised azomethine ylides in dipolar cycloaddition reactions within a flow microreactor is demonstrated. The 3-nitropyrrolidines produced were furthermore subjected to chemoselective hydrogenation reactions using the H-Cube® system. To ensure product purities in excess of 90-95%, immobilised scavengers were successfully employed.
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54. A flow process using microreactors for the preparation of a quinolone derivative as a potent 5HT1B antagonist.
Qian, Z.; Baxendale, I. R.; Ley, S. V. Synlett 2010, (4), 505-508. DOI link: 10.1055/s-0029-1219358

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This article describes the continuous flow synthesis of ­6-methoxy-8-(4-methyl-1,4-diazepan-1-yl)-N-(4-morpholinophen-yl)-4-oxo-1,4-dihydroquinoline-2-carboxamide, a potent 5HT1B antagonist developed by AstraZeneca.
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53. The Application of Flow Microreactors to the Preparation of a Family of Casein Kinase I Inhibitors.
Venturoni, F.; Nikbin, N.; Ley S. V.; Baxendale, I. R. Org. Biomol. Chem. 2010, 8, 1798-1806. DOI link: 10.1039/b925327k

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In this article we demonstrate how a combination of enabling technologies such as flow synthesis, solid-supported reagents and scavenging resins utilised under fully automated software control can assist in typical medicinal chemistry programmes. In particular automated continuous flow methods have greatly assisted in the optimisation of reaction conditions and facilitated scale up operations involving hazardous chemical materials. Overall a collection of twenty diverse analogues of a casein kinase I inhibitor has been synthesised by changing three principle binding vectors.
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52. A multiple microcapillary reactor for organic synthesis.
Hornung, C. H.; Hallmark, B.; Baumann, M.; Baxendale, I. R.; Ley, S. V.; Hester, P.; Clayton, P.; Mackley, M. R. Ind. & Eng. Chem. Res. 2010, 49, 4576-4582. DOI link: 10.1021/ie901674h

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This paper presents process characteristics and proof of concept reactions for a newly developed microreactor system, termed the Cambridge Disc Microreactor (CDM), using plastic microcapillary flow discs (MFDs). These flat reactor discs were constructed from a flexible, temperature resilient, solvent resistant fluoropolymer microcapillary film (MCF) comprising 10 parallel capillary channels with mean hydraulic diameters typically between 150 and 400 ?m. The MFDs were heated inside the microreactor via conductive heat transfer from two heated surfaces, which were in contact with the flat outer surfaces of the disc. This allowed continuous flow processing of liquid phase reactions through the reactor at elevated temperatures and pressures at a precisely controlled residence time. The process characteristics of the reactor system were established experimentally by investigating the hydraulic response and the temperature profile or modelled analytically such that the residence time characteristics inside the device could be predicted. A series of organic chemical reactions, namely electrophilic fluorination and the formation of various mono- and bicyclic heteroaromatic compounds, were conducted in the system at temperatures between 110 and 120 °C.
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51. The Continuous Flow Synthesis of Butane-2,3-Diacetal Protected Building Blocks Using Microreactors.
Carter, C. C.; Lange, H.; Ley, S. V.; Baxendale, I. R. Org. Biomol. Chem. 2010, 8, 1588-1595. DOI link: 10.1039/b924309g

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The continuous flow synthesis of butane-2,3-diacetal protected derivatives has been achieved using commercially available flow chemistry microreactors in concert with solid supported reagents and scavengers to provide in-line purification systems. The BDA protected products are all obtained in superior yield to the corresponding batch processes.
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50. ReactIR Flow Cell: A New Analytical Tool for Continuous Flow Chemical Processing.
Carter, C. C.; Lange, H.; Ley, S. V.; Baxendale, I. R.; Wittkamp, B.; Goode J. G.; Gaunt N. L. Org. Process Res. Dev. 2010, 14, 393-402. DOI link: 10.1021/op900305v

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A newly developed ReactIR flow cell is reported as a convenient and versatile inline analytical tool for continuous flow chemical processing. The flow cell, operated with ATR technology, is attached directly into a reaction flow stream using standard OmniFit (HPLC) connections and can be used in combination with both meso- and microscale flow chemistry equipment. The iC IR analysis software (version 4.0) enables the monitoring of reagent consumption and product formation, aiding the rapid optimisation of procedures. Short-lived reactive intermediates can also be observed in situ, giving further mechanistic insight into complex transformations.
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49. Flow Ozonolysis Using a Semipermeable Teflon AF-2400 Membrane To Effect Gas-Liquid Contact.
O’Brien, M.; Baxendale, I. R.; Ley, S. V. Org. Lett. 2010, 12, 1596-1598. DOI link: 10.1021/ol100322t

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A flow-through chemistry apparatus has been developed which allows gases and liquids to contact via a semipermeable Teflon AF-2400 membrane. In this preliminary investigation, the concept was proven by application to the ozonolysis of a series of alkenes.
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48. A flow-based synthesis of Imatinib: the API of Gleevec.
Hopkin, M. D.; Baxendale, I. R.; Ley, S. V. Chem. Commun. 2010, 46, 2450-2452. DOI link: 10.1039/c001550d

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A concise, flow-based synthesis of Imatinib, a compound used for the treatment of chronic myeloid leukaemia, is described whereby all steps are conducted in tubular flow coils or cartridges packed with reagents or scavengers to effect clean product formation. An in-line solvent switching procedure was developed enabling the procedure to be performed with limited manual handling of intermediates.
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47. Enzymatic Oxidative Cyclisation Reactions Leading to Dibenzoazocanes.
Tozzi, F.; Ley, S. V.; Kitching, M. O.; Baxendale, I. R. Synlett 2010, (13), 1919-1922. DOI link: 10.1055/s-0030-1258486

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From simple N-isovanillyltyramine derivatives double oxidative biotransformations can be achieved using tyrosinase leading to the corresponding hydroxylated dibenzoazocanes.
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46. Preparation of arylsulfonyl chlorides by chlorosulfonylation of in-situ generated diazonium salts using a continuous flow reactor.
Laia Malet-Sanz, L.; Madrzak, J.; Ley, S. V.; Baxendale, I. R. Org. Biomol. Chem. 2010, 8, 5324-5332. DOI link: 10.1039/c0ob00450b

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A new flow procedure for the preparation of arylsulfonyl chlorides from aniline starting materials is described. The reaction conditions are mild, requiring no added acid and are amenable to continuous flow processing, in a safe, easily scalable and less labour intensive way than the corresponding batch method.
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45. Synthesis of Highly Substituted Nitropyrrolidines, Nitropyrrolizines and Nitropyrroles via Multicomponent-Multistep Sequences within a Flow Reactor.
Baumann, M.; Baxendale, I. R.; Kirschning, A.; Ley, S. V.; Wegner, J. Heterocycles 2010, 82, 1297-1316. DOI link: 10.3987/COM-10-S(E)77

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We expand upon recent results concerning dipolar cycloaddition reactions of unstabilized azomethine ylids with nitro alkenes to generate 3-nitropyrrolidines via a flow chemistry sequence. This new work describes the development of a three-component coupling reaction between glycine esters, aldehydes and nitro alkenes. In order to further demonstrate the utility of flow technology in concert with heterogeneous reagents and scavengers for complex reaction sequences an in-line oxidation resulting in the conversion of tetra-substituted pyrrolidines to their pyrrole congeners has been developed.
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44. KMnO4 Mediated Oxidation as a Continuous Flow Process.
Sedelmeier, J.; Ley, S. V.; Ian R. Baxendale, I. R.; Baumann, M. Org. Lett. 2010, 12, 3618-3621. DOI link: 10.1021/ol101345z

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An efficient and easily scalable transformation of alcohols and aldehydes to carboxylic acids and nitroalkane derivatives to the corresponding carbonyls and carboxylic acids using permanganate as the oxidant within a continuous flow reactor is reported. Notably, the generation and downstream processing of MnO2 slurries was not found to cause any blocking of the reactor when ultrasound pulses were applied to the flow system.
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43. A Palladium Wall Coated Microcapillary Reactor for Use in Continuous Flow Transfer Hydrogenation.
Hornung, C. H.; Hallmark, B.; Mackley, M. R.; Baxendale, I. R.; Ley, S. V. Adv. Synth. Catal. 2010, 352, 1736-1745. DOI link: 10.1002/adsc.201000139

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Herein we describe the preparation of a novel continuous flow multi-channel microreactor in which the internal surface has been functionalised with a palladium coating, enabling its use in catalytic heterogeneous liquid-phase reactions. Simple chemical deposition techniques were used to immobilise palladium(0) on the channel wall surface of a polymeric multi-capillary extrudate made from ethylenevinyl alcohol copolymer. The Pd coating of the microcapillaries has been characterised by mass spectrometry and light and electron microscopy. The functional activity of the catalytic Pd layer was tested in a series of transfer hydrogenation reactions using triethylsilane as the hydrogen source.
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42. A Continuous Flow Process Using 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 Selective D-opioid Receptor.
Qian, Z.; Baxendale, I. R.; Ley, S. V. Chem. Euro. J. 2010, 14, 12342-12348. DOI link: 10.1002/chem.201002147

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This article describes the design, optimisation and development of a continuous flow synthesis of N,N-diethyl-4-(3-fluorophenylpiperidin-4-ylidenemethyl)benzamide, a potent ?-opioid receptor agonist developed by AstraZeneca. The process employs a sequence of flow-based microreactors, with integrated purification employing solid-supported reagents and in-line IR analytical protocols using a newly developed ReactIR flow cell. With this monitoring device, initiation of the fourth input flow stream can be precisely controlled during the synthesis.
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41. Microwave and flow syntheses of Pseudomonas quinolone signal (PQS) and analogues.
Hodgkinson, J.; Galloway, W.; Saraf, S.; Baxendale, I.R.; Ley, S. V.; Ladlow, M.; Welch, M.; Spring, D. Org. Biomol. Chem. 2011, 9, 57-61. DOI link: 10.1039/c0ob00652a

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Expedient syntheses of Pseudomonas quinolone signal (PQS) and related structural analogues using microwave and flow methods are reported.
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40. The Lab of the Future: The Importance of Remote Monitoring and Control.
Hopkin, M. D.; Baxendale, I. R.; Ley, S. V. Chemica Oggi, Chemistry Today 2011, 29(1), 28-32. DOI link:

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Chemical laboratories and the equipment within them have changed very little over the last two centuries. However, the introduction of enabling technologies and their impact on current working practices is starting to redefine the laboratory environment. In this article the application of remote control software applied to real applications of flow-based synthesis are demonstrated and related improvements in efficiency and safety discussed. We envisage that the integration of these techniques with potable devices such as mobile telephones will form part of the lab of the future.
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39. The Continuous Flow Synthesis of Carboxylic Acids using CO2 in a Tube-In-Tube Gas-Permeable Membrane Reactor.
Polyzos A.; O'Brien M.; Petersen T. P.; Baxendale I. R.; Ley S. V. Angew. Chem. Int. Ed. 2011, 49, 1190-1193. DOI link: 10.1002/anie.201006618

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Keep it simple: A gas-liquid flow reactor has been developed based on a gas permeable tube-in-tube configuration which effectively delivers gas to a liquid substrate stream in a safe, continuous fashion. A series of carboxylic acids were prepared from the reaction of CO2 with a range of Grignard reagents.
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38. Diastereoselective Chain Elongation Reactions Using Microreactors for Application in Complex Molecule Assembly.
Carter, C. F.; Lange, H.; Daiki Sakai, D.; Baxendale, I. R.; Ley, S. V. Chem. Eur. J. 2011, 17, 3398-3405. DOI link: 10.1002/chem.201003148

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Diastereoselective chain-elongation reactions are important transformations for the assembly of complex molecular structures, such as those present in polyketide natural products. Here we report new methods for performing crotylation reactions and homopropargylation reactions by using newly developed low-temperature flow-chemistry technology. In-line purification protocols are described, as well as the application of the crotylation protocol in an automated multi-step sequence.
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37. A fully automated, multistep flow synthesis of 5-amino-4-cyano-1,2,3-triazoles.
Smith, C. J.; Nikbin, N.; Ley, S. V.; Lange H.; Baxendale, I. R. Org. Biomol. Chem. 2011, 9, 1938-1947. DOI link: 10.1039/c0ob00815j

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Having demonstrated in the preceding publication the flow synthesis of aryl azides, we describe here a general protocol for the in-line purification of these versatile intermediates. As part of this investigation, we evaluated the use of ReactIR 45m as a tool for real-time detection of hazardous azide contaminants. This azide synthesis and purification process was then incorporated into a multistep flow sequence to generate a small collection of 5-amino-4-cyano-1,2,3-triazoles directly from aniline starting materials in a fully automated fashion.
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36. Flow synthesis of organic azides and the multistep synthesis of imines and amines using a new monolithic triphenylphosphine reagent.
Smith, C. J.; Nikbin, N.; Smith, C. D.; Ley, S. V.; Baxendale, I.R. Org. Biomol. Chem. 2011, 9, 1927-1937. DOI link: 10.1039/c0ob00813c

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Here we describe general flow processes for the synthesis of alkyl and aryl azides, and the development of a new monolithic triphenylphosphine reagent, which provides a convenient format for the use of this versatile reagent in flow. The utility of these new tools was demonstrated by their application to a flow Staudinger aza-Wittig reaction sequence. Finally, a multistep aza-Wittig, reduction and purification flow process was designed, allowing access to amine products in an automated fashion.
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35. Safe and Reliable Synthesis of Diazoketones and Quinoxalines in a Continuous Flow Reactor.
Martin, L. J.; Marzinzik, A. L.; Ley, S. V.; Baxendale, I. R. Org. Lett. 2011, 13, 320-323. DOI link: 10.1021/ol1027927

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A flow method for the synthesis of aliphatic and aromatic diazoketones from acyl chloride precursors has been developed and used to prepare quinoxalines in a multistep sequence without isolation of the potentially explosive diazoketone. The protocol showcases an efficient in-line purification using supported scavengers with time-saving and safety benefits and in particular a reduction in the operator's exposure to carcinogenic phenylenediamines.
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34. The Flow Synthesis of Heterocycles for Natural Product and Medicinal Chemistry Applications.
Baumann, M.; Baxendale, I. R.; Ley, S. V. Mol. Diversity 2011, 15, 615-630. DOI link: 10.1007/s11030-010-9282-1

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This article represents an overview of recent research from the Innovative Technology Centre in the field of flow chemistry which was presented at the FROST2 meeting in Budapest in October 2009. After a short introduction of this rapidly expanding field, we discuss some of our results with a main focus on the synthesis of heterocyclic compounds which we use in various natural product and medicinal chemistry programmes.
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33. A Breakthrough Method for the Accurate Addition of Reagents in Multi-step Segmented Flow Processing.
Lange, H.; Carter, C. F.; Hopkin, M. D.; Burke, A.; Goode, J. G; Baxendale, I. R.; Ley S. V. Chem. Sci. 2011, 2, 765-769. DOI link: 10.1039/c0sc00603c

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In order to use segmented chemical flow processing in more complex reaction sequences, a method has been developed to precisely control the addition of reagent streams during multi-step operations. Using in-line infra-red monitoring with a new LabVIEW software application, it is possible to control additional pumps to dispense further reagents in real time based upon the concentration of reaction intermediates. This enables precise mixing with perfect timing thus greatly increasing product quality and enabling segmented chemical flow processing to be used in extended reaction sequences.
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32. Hydrogenation in Flow: Homogeneous and Heterogeneous Catalysis Using Teflon AF-2400 to Effect Gas-Liquid Contact at Elevated Pressure.
O'Brien, M.; Taylor, N.; Polyzos, A.; Baxendale, I. R.; Ley, S. V. Chem. Sci. 2011, 2, 1250-1257. DOI link: 10.1039/c1sc00055a

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A Tube-in-Tube reactor/injector has been developed, based on a gas-permeable Teflon AF-2400 membrane, which allows both heterogeneous and homogeneous catalytic hydrogenation reactions to be efficiently carried out at elevated pressure in flow, thereby increasing the safety profile of these reactions. Measurements of the gas permeation through the tubing and uptake into solution, using both a burette method and a novel computer-assisted "bubble counting" technique, indicate that permeation/dissolution follows Henry's law and that saturation is achieved extremely rapidly. The same gas-permeable membrane has also been shown to efficiently effect removal of excess unreacted hydrogen, thus enabling further downstream reaction/processing.
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31. Oxidation Reactions in Segmented and Continuous Flow Chemical Processing Using an N-(tert-Butyl)phenylsulfinimidoyl Chloride Monolith.
Lange, H.; Capener, M. J.; Jones, A. X.; Smith, C. J.; Nikbin, N.; Baxendale, I. R.; Ley, S. V. Synlett 2011, (6), 869-873. DOI link: 10.1055/s-0030-1259923

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A supported version of N-(tert-butyl)phenylsulfinimidoyl chloride on a monolithic material is described, which can be incorporated into a flow chemical processing arrangement to oxidise a variety of substrates in both stoichiometric and catalytic processes to yield products in high yields and in high purity after in-line workup.
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30. An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals.
Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N. Beilstein J. Org. Chem. 2011, 7, 442-495. DOI link: 10.3762/bjoc.7.57

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This review presents a comprehensive overview on selected synthetic routes towards commercial drug compounds as published in both journal and patent literature. Owing to the vast number of potential structures, we have concentrated only on those drugs containing five-membered heterocycles and focused principally on the assembly of the heterocyclic core. In order to target the most representative chemical entities the examples discussed have been selected from the top 200 best selling drugs of recent years.
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29. Continuous Flow Processing of Slurries: Evaluation of an Agitated Cell Reactor.
Browne, D. L.; Deadman, B. J.; Ashe, R.; Baxendale, I. R.; Ley, S. V. Org. Process Res. Dev. 2011, 15, 693-697. DOI link: 10.1021/op2000223

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A general method for the continuous processing of suspensions and particulates is reported. A commercially available agitating cell reactor which uses a transverse mixing motion to maintain solids in suspension has been successfully applied to a salt-forming reaction. The flow device delivered 208 g of N-iodomorpholinium hydroiodide salt over a 9-h period (equating to 3.88 kg/week) under optimized conditions. The reactor is suitable for the medium-scale (5 kg) processing of solid-forming reactions and appears to offer the potential for a variety of more complex applications.
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28. Synthesis of a Drug-Like Focused Library of Trisubstituted Pyrrolidines Using Integrated Flow Chemistry and Batch Methods.
Baumann, M.; Baxendale, I. R.; Kuratli, C.; Ley, S. V.; Martin, R. E.; Schneider, J. ACS Comb. Sci. 2011, 13, 405-413. DOI link: 10.1021/co2000357

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A combination of flow and batch chemistries has been successfully applied to the assembly of a series of trisubstituted drug-like pyrrolidines. This study demonstrates the efficient preparation of a focused library of these pharmaceutically important structures using microreactor technologies, as well as classical parallel synthesis techniques, and thus exemplifies the impact of integrating innovative enabling tools within the drug discovery process.
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27. An Integrated Flow and Batch-based Approach for the Synthesis of O-Methyl Siphonazole.
Baumann, M.; Baxendale, I. R.; Brasholz, M.; Hayward, J. J.; Ley S. V.; Nikbin, N. Synlett 2011, (10), 1375-1380. DOI link: 10.1055/s-0030-1260573

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The bisoxazole containing natural product O-methyl siphonazole was assembled using a suite of microreactors via a flow-based approach in concert with traditional batch methods. The use of a toolbox of solid-supported scavengers and reagents to aid purification afforded the natural product in a total of nine steps.
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26. A New Enabling Technology for Convenient Laboratory Scale Continuous Flow Processing at Low Temperatures.
Browne, D. L.; Baumann, M.; Harji, B. H.; Baxendale, I. R.; Ley, S. V. Org. Lett. 2011, 13, 3312-3315. DOI link: 10.1021/ol2010006

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A new machine for conducting continuous flow processes at low temperatures on a laboratory scale is reported. The use of this cryogenic flow reactor has been demonstrated by the preparation of a variety of (hetero)aromatic boronic acids and esters via lithium halogen exchange chemistry. Furthermore, scale-up of the reaction conditions not only demonstrates the application of this device for the preparation of useful building blocks but also combines the ability to process n-butyllithium directly through pump heads attached to the unit.
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25. Teflon AF-2400 mediated gas-liquid contact in continuous flow methoxycarbonylations and in-line FTIR measurement of CO concentration..
Koos, P.; Gross, U.; Polyzos, A.; O'Brien, M.; Baxendale, I. R.; Ley, S. V. Org. Biomol. Chem. 2011, 9, 6903-6908. DOI link: 10.1039/c1ob06017a

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We report on the development of a continuous flow process for the palladium catalysed methoxycarbonylation of aryl, heteroaromatic and vinyl iodides and an aryl bromide using a Teflon AF-2400 based Tube-in-Tube reactor to mediate the selective permeation of carbon monoxide into solution at elevated pressures. The low volume of pressurised gas within the reactor (5.6 mL) offers the potential for an enhanced safety profile compared to batch processes. We also present preliminary results for the use of in situ FTIR to measure solution concentrations of carbon monoxide and demonstrate the use of a second reactor to effect the removal of carbon monoxide from the flow stream.
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24. The Continuous-Flow Synthesis of Styrenes using Ethylene in a Palladium Catalysed Heck Cross-Coupling Reaction.
Bourne, S. L.; Koos, P.; O'Brien,M.; Martin,B.; Schenkel, B.; Baxendale, I. R.; Ley, S. V. Synlett 2011, (18), 2643-2647. DOI link: 10.1055/s-0031-1289291

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We report a palladium-catalysed ethylene Heck reaction for the vinylation of aryl iodides using a tube-in-tube gas-liquid reactor. The flow process afforded various styrenes in short reaction times, employing moderate ethylene pressure.
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23. Syngas Mediated C-C Bond Formation in Flow: Selective Rhodium-Catalysed Hydroformylation of Styrenes.
Kasinathan, S.; Bourne,S. L.; Tolstoy, P.; Koos, P.; O'Brien, M.; Bates, R. W.; Baxendale, I. R.; Ley, S. V. Synlett 2011, (18), 2648-2651. DOI link: 10.1055/s-0031-1289292

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We report a continuous flow, rhodium-catalysed hydroformylation of various styrenes using a tube-in-tube gas-liquid reactor. The flow process afforded selectively branched aryl aldehydes in good yields.
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22. Piecing together the puzzle: understanding a mild, metal free reduction method for the large scale synthesis of hydrazines.
Browne, D. L.; Baxendale, I. R.; Ley, S. V. Tetrahedron 2011, 67, 10296-10303. DOI link: 10.1016/j.tet.2011.09.146

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A key intermediate for the synthesis of hydrazines via a mild, metal free reduction of diazonium salts has been isolated and characterized by X-ray analysis. The presence of this intermediate is general, as demonstrated by the preparation of a number of analogues. A discussion of the mechanism and potential benefits of such a process are also described.
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21. The application of a monolithic triphenylphosphine reagent for conducting Appel reactions in flow microreactors.
Roper, K. A.; Lange, H.; Polyzos, A.; Berry, M. B.; Baxendale, I. R.; Ley, S. V. Beilstein J. Org. Chem. 2011, 7, 1648-1655. DOI link: 10.3762/bjoc.7.194

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Herein we describe the application of a monolithic triphenylphosphine reagent to the Appel reaction in flow-chemistry processing, to generate various brominated products with high purity and in excellent yields, and with no requirement for further off-line purification.
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20. The Oxygen-Mediated Synthesis of 1,3-Butadiynes in Continuous Flow: Using Teflon AF-2400 to Effect Gas/Liquid Contact..
Petersen, T. P.; Polyzos, A.; O'Brien, M.; Ulven, T.; Baxendale, I. R.; Ley, S. V. ChemSusChem 2012, 5, 274-277. DOI link: 10.1002/cssc.201100339

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The gas is always greener: A continuous flow Glaser-Hay coupling reaction system, mediated by molecular oxygen, is developed based on a tube-in-tube gas/liquid reactor/injector. The system uses a semi-permeable Teflon AF-2400 membrane to effect rapid gas/liquid contact in flow, affording homogeneous solutions of oxygen. Measurements of out-gassing downstream of the back-pressure regulator indicate the onset of saturation is reached after about 16 seconds.
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19. Flow Assisted Scale-up of C2-symmetric Chiral PyBox-Ligands.
Battilocchio, C.; Baumann, M.; Baxendale, I. R.; Biava, M.; Kitching, M. O.; Ley, S. V.; Martin, R. E.; Ohnmacht, S. A.; Tappin, N. D. C. Synthesis 2012, (4), 635-647. DOI link: 10.1055/s-0031-1289676

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A series of PyBox ligands were prepared from commercially available chelidonic acid by a multistep flow sequence using mesoreactor technology. A chloro group introduced onto the ligand scaffold was subsequently exploited to give amine derivatives ready for immobilization through microencapsulation technologies.
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18. A Total Synthesis of Millingtonine A.
Wegner, J.; Ley, S. V.; Kirschning, A.; Hansen, A.-L.; Montenegro Garcia, J.; Baxendale, I. R. Org. Lett. 2012, 14, 696-699. DOI link: 10.1021/ol203158p

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A total synthesis of millingtonine A, a diglycosylated alkaloid, has been accomplished. Millingtonine A possesses a unique racemic tricyclic core structure not known from any other natural or synthetic source until now. The synthesis features a key bond-forming radical Ueno Stork cyclization to form the heterocyclic core.
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17. The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule.
Cross, B. C. S.; Bond, P. J.; Sadowski, P. G.; Jha, B. K.; Zak, J.; Goodman, J. M.; Silverman, R. H.; Neubert, T. A.; Baxendale, I. R.; Ron, D.; Harding, H. P. PNAS 2012, 15, E869-E878. DOI link: 10.1073/pnas.1115623109

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IRE1 couples endoplasmic reticulum unfolded protein load to RNA cleavage events that culminate in the sequence-specific splicing of the Xbp1 mRNA and in the regulated degradation of diverse membrane-bound mRNAs. We report on the identification of a small molecule inhibitor that attains its selectivity by forming an unusually stable Schiff base with lysine 907 in the IRE1 endonuclease domain, explained by solvent inaccessibility of the imine bond in the enzyme-inhibitor complex. The inhibitor (abbreviated 4?8C) blocks substrate access to the active site of IRE1 and selectively inactivates both Xbp1 splicing and IRE1-mediated mRNA degradation. Surprisingly, inhibition of IRE1 endonuclease activity does not sensitize cells to the consequences of acute endoplasmic reticulum stress, but rather interferes with the expansion of secretory capacity. Thus, the chemical reactivity and sterics of a unique residue in the endonuclease active site of IRE1 can be exploited by selective inhibitors to interfere with protein secretion in pathological settings.
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16. A Flow-Based Synthesis of 2-Aminoadamantane-2-carboxylic Acid.
Battilocchio, C.; Baxendale, I. R.; Biava, M.; Kitching, M. O.; Ley, S. V. Org. Process Res. Dev. 2012, 16, 798-810. DOI link: 10.1021/op300084z

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The development of a new, high-yielding, scalable and safe process for the preparation of 2-aminoadamantane-2-carboxylic acid (1) is described. This geminal, functionalized achiral amino acid has been reported to possess interesting biological activity as a transport mediator due to its unique physiochemical properties. We report herein on the use of various mesoreactor flow devices to expedite the lab-scale synthesis of this molecule by simplifying the processing requirements for use of several potentially hazardous reagent combinations and reaction conditions.
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15. A "Catch–React–Release" Method for the FlowSynthesis of 2-Aminopyrimidines and Preparation of the Imatinib Base.
Ingham, R. J.; Riva, E.; Nikbin, N.; Baxendale, I. R.; Ley, S. V. Org. Lett. 2012, 14, 3920-3923. DOI link: 10.1021/ol301673q

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The development of a monolith-supported synthetic procedure is reported, taking advantage of flow processing and the superior flow characteristics of monolithic reagents over gel-phase beads, to allow facile access to an important family of 2-aminopyrimidine derivatives. The process has been successfully applied to a key precursor on route to Imatinib (Ar = 3-pyridyl, R1 = 2-methyl-5-nitrobenzyl, R2 = H).
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14. Continuous flow reaction monitoring using an on-line miniature mass spectrometer.
Browne, D. L.; Wright, S.; Deadman, B.; Dunnage, S.; Baxendale, I. R.; Turner, R.; Ley, S. V. Rapid Commun. Mass Spectrom. 2012, 26, 1999-2010. DOI link: 10.1002/rcm.6312

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A recently developed miniature electrospray ionisation mass spectrometer has been coupled to a preparative flow chemistry system in order to monitor reactive intermediates and competing reaction paths, screen starting materials, and optimise reaction conditions. Although ideally suited to the application, mass spectrometers have rarely been used in this way, as traditional instruments are too bulky to be conveniently coupled to flow chemistry platforms.
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13. Establishing a flow process to coumarin-8-carbaldehydes as important synthetic scaffolds.
Zak, J.; Ron, D.; Riva, E.; Harding, H. P.; Cross, B. C. S.; Baxendale, I. R. Chem. Eur. J. 2012, 32, 9901-9910. DOI link: 10.1002/chem.201201039

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Despite their usefulness as fluorophores and synthetic precursors, efficient and reliable routes to coumarin-8-carbaldehydes are lacking. We describe here a high-yielding continuous flow synthesis that requires no manual intermediate purification or work-up, giving access to multigram quantities of the aldehyde product.
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12. Flow Microwave Technology and Microreactors in Synthesis.
Baxendale, I. R.; Hornung, C.; Ley, S. V.; Munõz Molina, J. de M.; Wikstrom, A. Aust. J. Chem. 2012, 66, 131-144. DOI link: 10.1071/CH12365

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A bespoke microwave reactor with a glass containment cell has been developed for performing continuous flow reactions under microwave heating. The prototype unit has been evaluated using a series of standard organic chemical transformations enabling scale-up of these chemical processes. As part of the development, a carbon-doped PTFE reactor insert was utilized to allow the heating of poorly absorbing reaction media, increasing the range of solvents and scope of reactions that can be performed in the device.
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11. Flow Chemistry Synthesis of Zolpidem, Alpidem and other GABAA Agonists and their Biological Evaluation through the use of In-line Frontal Affinity Chromatography.
Guetzoyan, L.; Nikbin, N.; Baxendale, I. R.; Ley S. V. Chem. Sci. 2013, 4, 764-769. DOI link: 10.1039/c2sc21850j

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The flow of information between chemical and biological research can present a bottleneck in pharmaceutical research. Tools that bridge these disciplines and aid information exchange have therefore clear value. Over the last few years, both synthetic chemistry and biological screening have benefited from automation, and a seamless chemistry–biology interface is now possible. We report here on the use of flow processes to perform synthesis and biological evaluation in an integrated manner. As proof of concept, a flow synthesis of a series of imidazo[1,2-a]pyridines, including zolpidem and alpidem, was developed and connected to a Frontal Affinity Chromatography screening assay to investigate their interaction with Human Serum Albumin (HSA).
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10. An Expeditious Synthesis of Imatinib and Analogues Utilising Flow Chemistry Methods.
Hopkin, M. D.; Baxendale, I. R.; Ley, S. V. Org. Biomol. Chem. 2013, 11, 1822-1839. DOI link: 10.1039/c2ob27002a

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A flow-based route to imatinib, the API of Gleevec, was developed and the general procedure then used to generate a number of analogues which were screened for biological activity against Abl1. The flow synthesis required minimal manual intervention and was achieved despite the poor solubility of many of the reaction components.
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9. The Synthesis of Bcr-Abl Inhibiting Anticancer Pharmaceutical Agents Imatinib, Nilotinib and Dasatinib.
Deadman, B. J. Hopkin, M. D.; Baxendale, I. R.; Ley, S. V. Org. Biomol. Chem. 2013, 11, 1766-1800. DOI link: 10.1039/c2ob27003j

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Imatinib (1), nilotinib (2) and dasatinib (3) are Bcr-Abl tyrosine kinase inhibitors approved for the treatment of chronic myelogenous leukemia (CML). This review collates information from the journal and patent literature to provide a comprehensive reference source of the different synthetic methods used to prepare the aforementioned active pharmaceutical ingredients (API's).
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8. The integration of flow reactors into synthetic organic chemistry.
Baxendale, I. R. J. Chem. Technol. Biotechnol. 2013, 88, 519-552. DOI link: 10.1002/jctb.4012

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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.
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7. Synthesis of (-)-Hennoxazole A: Integrating Batch and Flow Chemistry Methods.
Fernández, A.; Levine, Z. G.; Baumann, M.; Sulzer-Mossé, S.; Sparr, C.; Schläger, S.; Metzger, A.; Baxendale, I. R.; Ley, S. V. Synlett 2013, 24(4), 514-518. DOI link: 10.1055/s-0032-1318109

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A new total synthesis of (-)-hennoxazole A is reported. The synthetic approach is based on the preparation of three similarly sized fragments resulting in a fast and convergent assembly of the natural product. The three key reactions of the synthesis include a highly stereoselective 1,5-anti aldol coupling, a gold-catalyzed alkoxycyclization reaction, and a stereocontrolled diene cross-metathesis. The synthesis involves integrated batch and flow chemistry methods leading to the natural product in 16 steps longest linear sequence and 2.8% overall yield.
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6. A Machine-Assisted Flow Synthesis of SR48692: a Probe for the Investigation of Neurotensin Receptor-1.
Battilocchio, C.; Deadman, B. J.; Nikbin N.; Kitching, M. O.; Baxendale, I. R.; Ley, S. V. Chem. Eur. J. 2013, 19, 7917-7930. DOI link: 10.1002/chem.201300696

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Abstract:
Here we report the direct comparison of a conventional batch mode synthesis of Meclinertant (SR48692, 1), a neurotensin receptor-1 antagonist, with its machine-assisted flow chemistry alternative. By using these enabling tools, combined with solid-supported reagents and scavengers, many process advantages were observed. Care, however, must be taken not to convert these techniques into expensive solutions to problems that do not exist.
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5. The Synthesis of Neurotensin Antagonist SR 48692 for Prostate Cancer Research.
Baxendale, I. R.; Cheung, S.; Kitching, M. O.; Ley, S. V. Shearman, J. W. Bioorg. Med. Chem. 2013, 21, 4378-4387. DOI link: 10.1016/j.bmc.2013.04.075

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Abstract:
An improved synthesis of the molecule SR 48692 is presented and its use as a neurotensin antagonist biological probe for use in cancer research is described. The preparation includes an number of enhanced chemical conversions and strategies to overcome some of the limiting synthetic transformations in the original chemical route.
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4. Flow Synthesis and Bio-Pharmacological Studies of a P2X7 Antagonist that Shows Analgesic Activity.
Battilocchio, C.; Guetzoyan, L.; Cervetto, C.; Mannelli, L. D. C.; Daniela Frattaroli, D.; Baxendale, I. R.; Maura, G.; Sautebin, L.; Biava, M.; Ghelardini, C.; Marcoli, M.; Ley, S. V. A.C.S. Med. Chem. Lett. 2013, 4(8), 704-709. DOI link: 10.1021/ml400079h

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Abstract:
We report the biological evaluation of a class of adamantane derivatives, which were achieved via modified telescoped machine-assisted flow procedure. Among the series of compounds tested in this work, 5 demonstrated outstanding analgesic properties. This compound showed that its action was not mediated through direct interaction with opioid and/ or cannabinoid receptors. Moreover, it did not display any significant anti-inflammatory properties. Experiments carried out on rat cerebrocortical purified synaptosomes indicated that 5 inhibits the P2X7-evoked glutamate release, which may contribute to its antinociceptive properties. Nevertheless, further experiments are ongoing to characterize the pharmacological properties and mechanism of action of this molecule.
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3. Flow chemistry approaches directed at improving chemical synthesis.
Baxendale, I. R.; Millia, C. J.; Brocken, L. Green Process Synth. 2013, 2, 211-230. DOI link: 10.1515/gps-2013-0029

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Abstract:
Flow synthesis offers many advantages when applied to the processing of difficult or dangerous chemical transformations. Furthermore, continuous production allows for rapid scale up of reactions without significant redevelopment of the routes. Importantly, it can also provide a versatile platform from which to build integrated multi-step transformations, delivering more advanced chemical architectures. The construction of multi-purpose micro and meso flow systems, that utilize in-line purification and diagnostic capabilities, creates a scenario of seamless connectivity between sequential steps of a longer chemical sequence. In this mini perspective, we will discuss our experience of target orientated multi-step synthesis as presented at the recent inaugural meeting of LEGOMEDIC at Namar University, Belgium.
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2. Studies of a Diastereoselective Electrophilic Fluorination Reaction Employing a Cryo-Flow Reactor.
Nakayama, K.; Browne, D. L.; Baxendale, I. R.; Ley, S. V. Synlett 2013, 24(10), 1298-1302. DOI link: 10.1055/s-0033-1338455

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Abstract:
The application of meso-scale flow chemistry in research laboratories continues to increase. Here, we report on the use of a modular cryo-flow device as applied to a diastereoselective fluorination process. The reactor can be incorporated into existing flow chemistry setups to permit continuous processing at low temperatures without recourse to cryogenic consumables.
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1. The rapid generation of isothiocyanates in flow.
Baumann, M.; Baxendale, I. R. Beilstein J. Org. Chem. 2013, 9, 1613-1619. DOI link: 10.3762/bjoc.9.184

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Abstract:
Isothiocyanates are versatile starting materials for a wide range of chemical reactions. However, their high nucleophilic susceptibility means they are best prepared and used immediately. We report here on a flow platform for the fast and efficient formation of isothiocyanates by the direct conversion of easily prepared chloroximes. To expedite this chemistry a flow insert cartridge containing two immobilised reagents is used to affect the chemical transformation which typically eliminates the requirements for any conventional work-up or purification of the reaction stream.
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