BAXENDALE Research Group

201 Discovery of a potent dual inhibitor of aromatase and aldosterone synthase.

Tinivella, A.; Banchi, M.; Gambacorta, G.; Borghi, F.; Orlandi, P.; Baxendale, I. R; Di Paolo, A.; Bocci, G.; Pinzi, L.; Rastelli, G. ACS Pharmacol. Transl. Sci. 2023, 6, 1870-1883.

Estrogen deficiency derived from inhibition of estrogen biosynthesis is a typical condition of postmenopausal women and breast cancer (BCs) patients undergoing antihormone therapy. The ensuing increase in aldosterone levels is considered to be the major cause for cardiovascular diseases (CVDs) affecting these patients. Since estrogen biosynthesis is regulated by aromatase (CYP19A1), and aldosterone biosynthesis is modulated by aldosterone synthase (CYP11B2), a dual inhibitor would allow the treatment of BC while reducing the cardiovascular risks typical of these patients. Moreover, this strategy would help overcome some of the disadvantages often observed in single-target or combination therapies.

200 Spectroscopic dataset of Hedione’s derivatives gathered during process development.

Sharley, J. S.; Gambacorta, G.; Pérez, A. M. C.; Ferri, E. E.; Miranda, A. F.; Quesada, J. S.; Baxendale, I. R. Data in Brief 2023, 46, 108801(1)-108801(24).

The dataset of spectroscopic analysis performed on starting materials, intermediates, and products relating to the synthesis of Hedione are hereby presented. The data were acquired in Durham university during the period between October 2020 and September 2021 for the development of a preparative method to Dehydrohedione. The latter is a key intermediate for the synthesis of cis- Hedione, an important fragrance ingredient. Proton, Carbon-13, and Fluorine-19 Nu- clear magnetic resonance of the compounds were recorded employing a Varian 600 MHz, and a Bruker Avance-400 instrument. The IR spectra were recorded in a Perkin Elmer Spectrum Two UATR Two FT-IR and the accurate mass employing a Waters QtoF premier as mass spectrometer.

199 In situ facile one-step solvothermal synthesizing hexagonal ammonium tungsten bronze (NH4)0.33WO3 to tap NIR light absorption ability by controlling crystallinity.

Ceramics International 2023, 49, 11589-11599.

Tungsten bronze (TB) has potentially high visible light transparency and excellent near-infrared (NIR) shielding ability. To fully dig out the concealed optical properties of TB with specific chemical components, in this work, hexagonal ammonium tungsten bronze (h-ATB) (NH4)0.33WO3 was fabricated by a one-step solvothermal reaction. Through X-ray diffractometer (XRD), scanning electron microscope (SEM), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), and ultraviolet–visible–near infrared (UV–vis–NIR) spectroscopy to characterize h-ATB, which unraveled that controlling crystallinity could adjust the optical property of h-ATB. In particular, when the crystallinity of the h-ATB is over 95%, it exhibits the attractive NIR light shielding capability, which is in line with the predicted optical property via the first principle calculation based on density functional theory (DFT). Given the result, this work can provide a feasible research idea to explore the hidden optical properties of TB.

198 Continuous-Flow Hofmann Rearrangement Using Trichloroisocyanuric Acid for the Preparation of 2-Benzoxazolinone.

Gambacorta, G.; Baxendale, I. R. Org. Process Res. Dev. 2022, 26, 422-430.

A continuous-flow preparation of 2-benzoxazolinone via the Hofmann rearrangement of salicylamide has been implemented employing trichloroisocyanuric acid as the stable and atom-economic chlorinating agent. The system was optimized to avoid solid accumulation and allow the preparation of hundreds of grams of the pure desired material over a working day. Furthermore, a trichloroisocyanuric acid (TCCA)-based chlorination of 2-benzoxazolone to the corresponding 5-chloro derivative was also carried out under batch conditions.

197 6-Chloro-3H-benzo[d][1,2,3]dithiazol-2-ium Chloride.

Nicholls, A. J.; Baxendale, I. R. Molbank 2022, 2022, M1339-1-M1339-8.

This short note describes the synthesis of an amorphous benzo[1,2,3]dithiazole chloride salt (commonly known as a “Herz salt”) by use of the Herz reaction. Hetero- and homolytic transformations of this species to a variety of useful adducts in medicinal and materials chemistry are well established, although there are limited examples of isolation in the literature, and characterisation data is even harder find. While several studies have confirmed the structure of the benzodithiazole ring beyond doubt, (having generated suitably crystalline salts with large counterions for XRD-analysis), there remains value in understanding and optimising the synthesis of the simple, amorphous polymorphs. For the first time, MS data is provided for this compound and a new mechanism of its formation is proposed based upon new experimental observations and data.

196 Identification of potential biological targets of oxindole scaffolds via in silico repositioning strategies.

Tinivella, A.; Pinzi, L.; Gambacorta, G.; Baxendale, I. R. Rastelli, G. F1000Research 2022, 22, 1-16.

Drug repurposing is an alternative strategy to traditional drug discovery that aims at predicting new uses for already existing drugs or clinical candidates. Drug repurposing has many advantages over traditional drug development, such as reduced attrition rates, time and costs. This is especially the case considering that most drugs investigated for repurposing have already been assessed for their safety in clinical trials. Repurposing campaigns can also be designed for libraries of already synthesized molecules at different levels of biological experimentation, from null to in vitro and in vivo. Such an extension of the “repurposing” concept is expected to provide significant advantages for the identification of novel drugs, as the synthetic accessibility of the desired compounds is often one of the limiting factors in the traditional drug discovery pipeline.

195 Tracking on crystallization process of doped metal oxide IATO to optimize solvothermal conditions.

Hu, T.; Ian R. Baxendale, I. R.; Su, Y.; Li, F.; Duan, S.; Zhang, Y.; Fan, H. Applied Physics A 2022, 128, 1-8.

XRD (X-ray diffraction) pattern analysis can estimate approximate preparation condition values based on nanomaterials formation; however, these initial values can be further refined without additional experiments by combining DSC (Differential Scanning Calorimetry) curves with thermodynamic equations to track crystallinity and crystallization rate of nanomaterials, which effectively improves the speed of preparation scheme. In this study, XRD pattern analysis from the comparative experimental results revealed that the optimum preparing solvothermal conditions on the IATO (tin-doped indium oxide) are at 200 °C for 24 h with 20 vol% 1-butanol; however, these conditions can be further optimized as 160 °C for 20 h with 5 vol% 1-butanol by simulating the growth process of nanomaterials in accordance to combine DSC curves with thermodynamic equations.

194 Development of α,7α-Dihydroxy-6α-ethyl-24-nor-5b-Cholan-23-Sulfate Sodium Salt (INT-767): Process Optimization, Synthesis and Characterization of Metabolites.

Cerra, B.; Venturoni, F.; Souma, M.; Ceccarelli, G.; Lozza, A. M.; Passeri, D.; De Franco, F.; Baxendale, I. R.; Pellicciari, R.; Macchiarulo, A.; Gioiello, A. Euro. J. Med. Chem. 2022, 242, 114652(1)-114652(15).

Estrogen deficiency derived from inhibition of estrogen biosynthesis is a typical condition of postmenopausal women and breast cancer (BCs) patients undergoing antihormone therapy. The ensuing increase in aldosterone levels is considered to be the major cause for cardiovascular diseases (CVDs) affecting these patients. Since estrogen biosynthesis is regulated by aromatase (CYP19A1), and aldosterone biosynthesis is modulated by aldosterone synthase (CYP11B2), a dual inhibitor would allow the treatment of BC while reducing the cardiovascular risks typical of these patients. Moreover, this strategy would help overcome some of the disadvantages often observed in single-target or combination therapies. Following an in-depth analysis of a library of synthesized benzylimidazole derivatives, compound X21 was found to be a potent and selective dual inhibitor of aromatase and aldosterone synthase, with IC50 values of 2.3 and 29 nM, respectively. Remarkably, the compound showed high selectivity with respect to 11β-hydroxylase (CYP11B1), as well as CYP3A4 and CYP1A2. When tested in cells, X21 showed potent antiproliferative activity against BC cell lines, particularly against the ER+ MCF-7 cells (IC50 of 0.26 ± 0.03 μM at 72 h), and a remarkable pro-apoptotic effect. In addition, the compound significantly inhibited mTOR phosphorylation at its IC50 concentration, thereby negatively modulating the PI3K/Akt/mTOR axis, which represents an escape for the dependency from ER signaling in BC cells. The compound was further investigated for cytotoxicity on normal cells and potential cardiotoxicity against hERG and Nav1.5 ion channels, demonstrating a safe biological profile. Overall, these assays demonstrated that the compound is potent and safe, thus constituting an excellent candidate for further evaluation.

193 A Simple One-Pot Oxidation Protocol for the Synthesis of Dehydrohedione from Hedione.

Sharley, J. S.; Gambacorta, G.; Collado Pérezb, A. M.; Ferri, E. E.; Miranda, A. F.; Fernández, I. F.; Quesada, J. S.; Baxendale, I. R. Tetrahedron 2022, 126, 133068(1)-133068(11).

A new method of oxidising Hedione 1 to dehydrohedione 2, a highly valuable target in the flavour and fragrance industry, was developed based on α-chlorination-elimination. The spontaneous elimination of the α-chloro intermediate 5 in methanol was unprecedented and allowed for the oxidation, typically performed in multiple steps/reactions, to be carried out in one-pot and one/two steps depending on the chlorinating agent used. A flow process for the reaction with sulfuryl chloride was also devised which allowed for steady, safe ejection of SO2 gas from the reaction medium.

192 Further Investigations into Imine-Mediated Formation of Allylic Nitro Compounds.

Sharley, J. S.; Gambacorta, G.; Collado Pérez, A. M.; Ferri, E. E.; Miranda, A. F.; Quesada, J. S.; Baxendale, I. R. Tetrahedron 2022, 126, 133058(1)-133058(14).

Nitro alkanes are valuable starting materials for functionalisation via their corresponding anions as well as their transformation into other important groups such as ketones via the Nef reaction. Herein, we report a process development study for the construction of a series of cyclic allylic nitro compounds that features a greener solvent and a lower cost, more robust catalyst than previously reported. The process was developed to target the selective synthesis of an important fragrance intermediate, namely, α-dehydroherbac. Process scoping and optimisation involved solvent & catalyst screening along with a basic kinetic investigation to evaluate critical reaction parameters (concentration and reagents ratio). The final optimised conditions were further demonstrated via synthesis of a small collection of additional derivatives to demonstrate scope and utility.

191 A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries.

Gambacorta, G.; Sharley, J. S.; Baxendale, I. R. Beilstein J. Org. Chem. 2021, 17, 1181-1312.

Due to their intrinsic physical properties, which includes being able to perform as volatile liquids at room and biological temperatures, fragrance ingredients/intermediates make ideal candidates for continuous-flow manufacturing. This review highlights the potential crossover between a multibillion dollar industry and the flourishing sub-field of flow chemistry evolving within the discipline of organic synthesis. This is illustrated through selected examples of industrially important transformations specific to the fragrances and flavours industry and by highlighting the advantages of conducting these transformations by using a flow approach. This review is designed to be a compendium of techniques and apparatus already published in the chemical and engineering literature which would constitute a known solution or inspiration for commonly encountered procedures in the manufacture of fragrance and flavour chemicals.

190 Benzo[1,2,3]dithiazole Compounds: A History of Synthesis and Their Renewed Applicability in Materials and Synthetic Chemistry, Originating from the Herz Reaction.

A. J. Nicholls; I. R. Baxendale Reactions 2021, 2, 175-208.

The benzo[1,2,3]dithiazole is a unique heteroaromatic functionality whose conjugated profile instils some fascinating electronic properties. This has been historically recognized in the design and manufacture of organic dyes early last century. Although, with the benefit of increased diagnostic techniques and improved understanding, these structures are attracting greater attention in additional research settings, including applications as organic radicals and semiconductors. In addition, the benzodithiazole functionality has been shown to be a valuable synthetic intermediate in the preparation of a variety of other privileged aromatic and heteroaromatic targets, many of which are important APIs. In this review, the authors aim to critically analyse the potential applicability of these compounds to the fields of not only small-scale laboratory synthetic and medicinal chemistry but also commercial-scale processes and increasingly materials chemistry.

189 Synthesis of 7-Chloroquinoline Derivatives Using Mixed Lithium-Magnesium Reagents.

Murie, V. E.; Nicolino, P. V.; dos Santos, T.; Gambacorta, G.; R. H. V. Nishimura, R. H. V., Perovani, I. S.; Furtado, L. C.; Costa-Lotufo, L. V.; de Oliveira, A. M.; Vessecchi, R.; Baxendale, I. R.; Clososki, G. C. J. Org. Chem. 2021, 86, 13402-13419.

We have prepared a library of functionalized quinolines through the magnesiation of 7-chloroquinolines under mild conditions, employing both batch and continuous flow conditions. The preparation involved the generation of mixed lithium-magnesium intermediates, which were reacted with different electrophiles. Mixed lithium-zinc reagents allowed the synthesis of halogenated and arylated derivatives. Some of the synthesized 4-carbinol quinolines have shown interesting antiproliferative properties, their hydroxyl group being a suitable amino group bioisostere. We also report a two-step approach for optically active derivatives.

188 Protein domain-based prediction of drug/ compound-target interactions and experimental validation on LIM kinases.

Doğan, T.; Akhan, Güzelcan E.; Baumann, M.; Koyas, A.; Atas, H.; Baxendale, I. R; Martin, M.; Cetin-Atalay, R. PLoS Comput. Biol. 2021, 17(11), e1009171-1-34.

Predictive approaches such as virtual screening have been used in drug discovery with the objective of reducing developmental time and costs. Current machine learning and networkbased approaches have issues related to generalization, usability, or model interpretability, especially due to the complexity of target proteins’ structure/function, and bias in system training datasets. Here, we propose a new method “DRUIDom” (DRUg Interacting Domain prediction) to identify bio-interactions between drug candidate compounds and targets by utilizing the domain modularity of proteins, to overcome problems associated with current approaches. DRUIDom is composed of two methodological steps. First, ligands/compounds are statistically mapped to structural domains of their target proteins, with the aim of identifying their interactions. As such, other proteins containing the same mapped domain or domain pair become new candidate targets for the corresponding compounds. Next, a million- scale dataset of small molecule compounds, including those mapped to domains in the previous step, are clustered based on their molecular similarities, and their domain associations are propagated to other compounds within the same clusters. Experimentally verified bioactivity data points, obtained from public databases, are meticulously filtered to construct datasets of active/interacting and inactive/non-interacting drug/compound-target pairs (~2.9M data points), and used as training data for calculating parameters of compound-domain mappings, which led to 27,032 high-confidence associations between 250 domains and 8,165 compounds, and a finalized output of ~5 million new compound-protein interactions. DRUIDom is experimentally validated by syntheses and bioactivity analyses of compounds predicted to target LIM-kinase proteins, which play critical roles in the regulation of cell motility, cell cycle progression, and differentiation through actin filament dynamics. We showed that LIMK-inhibitor-2 and its derivatives significantly block the cancer cell migration through inhibition of LIMK phosphorylation and the downstream protein cofilin. One of the derivative compounds (LIMKi-2d) was identified as a promising candidate due to its action on resistant Mahlavu liver cancer cells. The results demonstrated that DRUIDom can be exploited to identify drug candidate compounds for intended targets and to predict new target proteins based on the defined compound-domain relationships. Datasets, results, and the source code of DRUIDom are available.

187 4,4’-(Pyridin-4-ylmethylene)dibenzonitrile.

Lancaster, B. M. J.; Nicholls, A. J.; Baxendale, I. R. Molbank 2021, 2021, M1302-1-M1302-5.

methylpyridine, following deprotonation with LDA, twice acts as a carbon nucleophile in an unusual SNAr process, to form a novel triarylmethane structure. A proposed mechanism for this sequence is presented that is supported by single crystal X-ray analysis of the resulting product. We believe this unique transformation is of note as it highlights a neat and efficient entry as a single step to complex triarylmethane architectures containing both substituted phenyl and pyridyl aromatics.

186 Radical Polymerisation under Flow Conditions in Flow Chemistry: Integrated Approaches for Practical Applications

Brocken, L.; Baxendale. I. R.

Book edited by S. V Luis, E. Garcia-Verdugo

Published by: RSC - Green Chemistry Series. 2020, Chapter 7, pages: 217-256. ISBN: 978-1-78801-498-4.

Polymers are an important class of compounds used in many commercial products; for example, in the aerospace and automotive industries functioning as low weight construction parts and seals, through into the packaging of food and drink and even as aqueous soluble polymers, which are found in numerous detergents and other cleaning products. Significant research has, therefore, been invested towards the design and synthesis of new polymers using a variety of polymerisation techniques to deliver specifically tailored structures with refined macromolecular structures including tailoring parameters such as molecular weight, polydispersity and tacticity. One interesting approach, which has started to demonstrate value in the synthesis of polymers, is the conducting of polymerisation processes in a dynamic continuous flow scenario. Flow polymerisation has been shown to facilitate access to new polymers which cannot be synthesised or would be difficult to prepare under conventional batch conditions through improved control over the various reaction parameters. In this chapter, a brief selective overview is given of the various syntheses of polymers and polymeric particles that have been reported in the literature via flow processes to date.

185 Ionic Polymerisation and New Approaches to Polymerisation under Flow Conditions in Flow Chemistry: Integrated Approaches for Practical Applications - Green Chemistry Series

Brocken, L.; Baxendale. I. R.

Book edited by S. V Luis, E. Garcia-Verdugo

Published by: RSC - Green Chemistry Series. 2020, Chapter 8, pages: 257-315. ISBN: 978-1-78801-498-4.

Although ionic polymerisations are a valuable methodology historically they are less widely used because they are considered capricious, requiring significantly more optimisation due to their sensitivity to the specific reaction and processing conditions. Increasingly though flow processing regimes are being successfully implemented to allow better control over reaction parameters and facilitate a more consistent processing environment; this has also shown promising results for challenging reactions such as ionic polymerisation. Furthermore, as flow chemistry is becoming more widely implemented additional and complementary processing tools such as photochemical, supported reagents and enzymatic based plug-in reactors are being evaluated for their ability to expand the range of polymers on offer. Supplementing this era of advanced and accelerated synthesis is an explosion in direct integrated analysis routines and the development of smart selfoptimising platforms capable of self-sustained assembly of new polymers. Whilst the machines have been taking over the physical synthesis, chemists have been starting to think beyond simply the isolated stage of polymer synthesis, considering options to create more encompassing work-flows. The next generations of polymer synthesis will encompass all aspects of synthesis, purification and final analysis as a single unified sequence. These new polymer products will ultimately be used for new applications such as light-emitting diodes and in photovoltaics.

184 A One-Pot Divergent Sequence to Pyrazole and Quinoline Derivatives.

Gambacorta, G.; Apperley, D. C.; Baxendale, I. R. Molecules 2020, 25, 2160-2160(14).

The hydroxy-pyrazole and 3-hydroxy oxindole motifs have been utilised in several pharma and agrochemical leads but are distinctly underrepresented in the scientific literature due to the limited routes of preparation. We have developed a one-pot procedure for their synthesis starting from simple isatins. The method employs cheap and easy-to-handle building blocks and allows easy isolation.

183 Rearrangement of 3-Hydroxyazetidines into 2-Oxazolines.

Ruggeri, M.; Dombrowski, A. W.; Djuric, S. W.; Baxendale, I. R. J. Org. Chem. 2020, 85, 7276-7286.

A novel rearrangement sequence of 3-hydroxyazetidines via a Ritter initiated cascade provides highly substituted 2-oxazolines in high yields. The reaction conditions and substrate scope of the transformation have been studied demonstrating the generality of the process. The derived products can also be functionalized in order to undergo further intramolecular cyclization leading to a new class of macrocycle. The final cyclization step was shown to be a transformation amenable to continuous flow processing allowing for a dramatic reduction in the reaction time and simple scale-up.

182 Straight forward and versatile differentiation of the L-glycero and D-glycero-D-manno heptose scaffold.

Suster, C.; Baxendale, I. R.; Mihovilovic, M. D.; Stanetty, C. Front. Chem. 2020, 8, 1-7.

Bacterial lipopolysaccharides (LPS) are important bio-medical structures, playing a major role in the interaction with human immune systems. Their core regions, containing multiple units of L-glycero-D-manno heptoses (L,D-heptose), are highly conserved structurally (with O3 and O7 glycosidic bonds), making them an epitope of high interest for the potential development of new antibiotics and vaccines. Research in this field has always been restricted by the limited availability of the parent L,D-heptose as well as its biochemical epimeric precursor D-glycero-D-manno heptose (D,D-heptose). This problem of availability has recently been solved by us, through a rapid and efficient practical synthesis of L,D-manno-heptose peracetate demonstrated at scale. Herein we report an optimized, technically simple and versatile synthetic strategy for the differentiation of both the L-glycero and D-glycero-D-manno heptose scaffold. Our approach is based on an orthoester methodology for the differentiation of all three positions of the sugar core using a O6,O7-tetraisopropyl disiloxyl (TIPDS) protecting group for the exocyclic positions. Furthermore, the regioselective opening towards 7-OH acceptors (6O-FTIPDS ethers) differentiates the exocyclic diol which has been demonstrated with a broader set of substrates and for both manno-heptoses for the first time.

181 Photochemical Flow Oximation of Alkanes.

Griffiths,O. M.; Ruggeri, M.; Baxendale, I. R. Synlett 2020, 19, 1907-1912.

The nitrosation of several alkanes using tert-butyl nitrite has been performed in flow showing a remarkable reduction in the reaction time compared with batch processing. Due to the necessity for large excesses of the alkane component a continuous recycling process was devised for the preparation of larger quantities of material.

180 Synthesis of new derivatives of boehmeriasin A and their biological evaluation in liver cancer.

Güzelcan, E. A.; Baxendale, I. R.; Cetin-Atalay, R.; Baumann, M. Euro. J. Med. Chem. 2019, 166, 243-245.

Two series of boehmeriasin A analogs have been synthesized in short and high yielding processes providing derivatives differing either in the alkaloid's pentacyclic scaffold or its peripheral substitution pattern. These series have enabled, for the first time, comparative studies into key biological properties revealing a new lead compound with exceptionally high activity against liver cancer cell lines in the picomolar range for both well (Huh7, Hep3B and HepG2) and poorly (Mahlavu, FOCUS and SNU475) differentiated cells. The cell death was characterized as apoptosis by cytochrome-C release, PARP protein cleavage and SubG1 cell cycle arrest. Subsequent testing associated apoptosis via oxidative stress with in situ formation of reactive oxygen species(ROS) and altered phospho-protein levels. Compound 19 decreased Akt protein phosphorylation which is crucially involved in liver cancer tumorigenesis. Given its simple synthetic accessibility and intriguing biological properties this new lead compound could address unmet challenges within liver cancer therapy.

179 A solid-supported arylboronic acid catalyst for direct amidation.

Du, Y.; Barber, T.; Lim, S. E.; Baxendale, I. R.; Whiting, A. Chem. Commun. 2019, 55, 2916-2919.

A new catalyst has been prepared by co-polymerisation of styrene, DVB with 4-styreneboronic acid to derive a efficient heterogeneous direct amidation catalyst. The catalyst shows wide substrate applicability and higher levels of reactivity than the equivalent homogeneous phenylboronic acid, suggesting potential cooperative catalytic effects. The catalyst can be easily recovered and reused and is suitable for use in a packed bed flow reactor.

178 A Simple and Efficient Flow Preparation of Pyocyanin a Virulence Factor of Pseudomonas aeruginosa.

Mortzfeld, F. B.; Pietruszka, J.; Baxendale, I. R. Euro. J. Org. Chem. 2019, X, 5424-5433.

The synthesis of the naturally occurring toxin pyocyanin has been realized in a short 4 step sequence. The key photochemical reaction and isolation of the final product have been facilitated by the use of flow chemistry techniques and immobilised reagents. Using these procedures gram quantities of pyocyanin were easily prepared in high yield and purity.

177 Flow Hydrodediazotization of Aromatic Heterocycles.

Röder, L.; Nicholls, A. J.; Baxendale, I. R. Molecules 2019, 24(10), 1996-1996(18).

Continuous flow processing was applied for the rapid replacement of an aromatic amino group with a hydride. The approach was applied to a range of aromatic heterocycles, confirming the wide scope and substituent-tolerance of the processes. Flow equipment was utilized and the process optimised to overcome the problematically-unstable intermediates that have restricted yields in previous studies relying on batch procedures. Various common organic solvents were investigated as potential hydride sources. The approach has allowed key structures, such as amino-pyrazoles and aminopyridines, to be deaminated in good yield using a purely organic-soluble system.

176 Photochemical flow synthesis of 3-hydroxyazetidines.

Ruggeri, M.; Dombrowski, A. W.; Djuric, S. W.; Baxendale, I. R. ChemPhotoChem 2019, 3(12), 1212-1218.

A photo-flow Norrish-Yang cyclisation has been devised that delivers 3-hydroxyazetidines in good yields. The high reproducibility and short residence times of the flow process enables easy scaling of the transformation allowing access to these valuable chemical entities at synthetically useful multi-gram scales. A systematic exploration of the constituent structural components was undertaken allowing an understanding of the reactivity and functional group tolerance of the transformation.

175 The Synthesis and Utility of Metal-Nitrosophenolato Compounds—Highlighting the Baudisch Reaction.

Nicholls, A. J.; Thomas Barber, T.; Baxendale, I. R. Molecules 2019, 24(22), 4018-(1-32).

The syntheses of the title compounds demonstrate a privileged introduction of a nitroso (and a hydroxyl via the Baudisch reaction) group to an aromatic ring. These complexes first appeared in the literature as early as 1939, and a range of applications has subsequently been published. However, optimisations of the preparative sequences were not considered, and as such, the reactions have seldom been utilised in recent years; indeed, there remains confusion in the literature as to how such complexes form. In this review, we aim to demystify the misunderstanding surrounding these remarkable complexes and consider their renewed application in the 21st century.

174 Copper-Mediated Nitrosation: 2-Nitrosophenolato Complexes and Their Use in the Synthesis of Heterocycles.

Nicholls, A. J.; Batsanov, A. S.; Baxendale, I. R. Molecules 2019, 24(22), 4154-(1-19).

A simple protocol yielding ortho-substituted nitrosophenols from phenols is demonstrated, in the form of copper(II) bis(nitrosophenolato) complexes. The developed methodology was applied to a range of substrates, confirming the role of the copper in both the formation and protection of the challenging 1, 2-substitution pattern. Using polymer supported thiourea, the Cu could be stripped from the complexes and thus enabled the isolation or identification of the uncoordinated ligands and their decomposition products, in yields generally low in line with the intrinsic high reactivity of 2-nitrosophenols. The product complexes are useful intermediates as demonstrated in revisiting a formal [4 + 2] cycloaddition with dimethylacetylene dicarboxylate to synthesise bicyclic products in variable yields, revealing the product has a novel structure different from those previously reported in the literature.

173 The Design and Preparation of Transparent Hybrid Composite Thin Films with Excellent Optical Properties and Improved Thermal Insulation by Optimized Combination of Nanomaterials.

Hu, T.; Su, Y.; Baxendale, I. R.; Zhang, Y.; Zhu, J. Journal of Electronic Materials 2019, 49(3), 1808-1818.

For a single nano-optical material, it is difficult to possess high transmittance and adequately filter ultraviolet (UV) and infrared radiation (IR) simultaneously. Consequently, hybrid nano-optical materials comprising components of appropriate proportions for superimposing serviceable optical property are required. The design, optimization and processing of new composite blends with an aim to creating defect free thin films is far from a trivial endeavor. In this report, optimum composition and optical properties of hybrid nano-optical material has been determined and improved by crossover matching experiments and ball milling, respectively. Film preparation has been optimized to reduce defects expressed as cracks, tiny bubbles, strips, groove points, corrugation, and formation of acicular fibers by regulating proportion of polyvinyl butyral colloid and dry film processes. Two ameliorative processing conditions are exemplified where the resultant composite films possessed 86% maximum transmittance in the visible range and 90% and 50% blocking rate with respect to the IR and UV bands.

172 Diastereoselective Synthesis and Diversification of Highly Functionalized Cyclopentanones.

Baumann, M.; Baxendale, I. R. Synthesis 2018, 50(4), 753-759.

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 α- or β-position of the embedded enone and thus represent valuable methods for the construction of diversely functionalized cyclopentanones.

171 The Indium and Zinc Mediated Acyloxyallylation of Protected and Unprotected Aldotetroses - Revealing a Pronounced Diastereodivergence and a Fundamental Difference in the Performance of the Mediating Metal.

Draskovits, M.; Stanetty, C.; Baxendale, I. R.; Mihovilovic, M. D. J. Org. Chem. 2018, 83, 2647-2659.

The acyloxyallylation of unprotected aldoses was first demonstrated more than a decade ago as a potentially elegant two-carbon homologation of reducing sugars (upon ozonolysis), however, its application in real case syntheses remained scarce. Following up on such a successful show-case and to answer several pending questions about this attractive transformation, we engaged in an in depth methodological re-investigation. The epimeric tetroses L-erythrose and D-threose in unprotected and protected form were successfully applied to the indium and also zinc mediated acyloxyallylation, the latter being a first for an unprotected sugar. The investigation largely benefited from the choice of these more exotic starting materials as it allowed unambiguous identification/quantification of the hexose-products which are available as authentic reference materials.

170 Flow Chemistry Approaches Applied to the Synthesis of Saturated Heterocycles in Flow Chemistry for the Synthesis of Heterocycles

Baumann, M.; Baxendale, I. R.

Book edited by Sharma, U. K.; Van der Eycken, E. V.

Published by: Springer. 2018, , pages: 187-236. ISBN: 978-3-319-94328-2.

Continuous flow processing approaches are having a significant impact on the way we devise and perform chemical synthesis. Flow chemistry has repeatedly demonstrated numerous improvements with respect to synthesis efficiency, process safety and ease of reaction scale-up. In recent years flow chemistry has been applied with remarkable success to the generation of valuable target structures across a range of industries from basic bulk chemical manufacture and materials development to flavors, food and cosmetic applications. However, due to its earlier implementation it has found so far many more advocates in areas of medicinal and agrochemical research and manufacture. In this review article, we summarize the key developments that continuous flow synthesis has had in the area of saturated heterocycles, specifically focusing on approaches that generate these important entities from acyclic precursors.

169 Flow synthesis of coumalic acid and its derivatization.

Smith, L. K.; Baxendale, I. R. React. Chem. Eng. 2018, 3, 722-732.

Coumalic acid is a valuable platform compound which can be prepared from malic acid, a biorenewable feedstock readily derived from the fermentation of glucose. Current batch procedures to synthesise coumalic acid have several drawbacks, which we address with the aid of tubular flow systems and a simple heated rotating flow reactor. The prepared coumalate derivatives can be further used in inverse electron demand Diels–Alder reactions to synthesise compounds with many applications including molecular electronics, with the added advantage of providing metal-free preparations.

168 A Robust and Scalable Continuous Flow Process for Glycerol Carbonate.

Mileghem, S. V.; De Borggraeve, W. M.; Baxendale, I. R. Chem. Eng. Tech. 2018, 41(10), 2014-2023.

We report a robust continuous flow procedure for the synthesis of glycerol carbonate (2‐GLC) from green reagents glycerol and dimethyl carbonate (DMC), mediated by an inexpensive polymer‐supported base catalyst using methanol as co‐solvent. High conversion and selectivity were obtained, while residence times were typically shorter than 10 minutes.

167 Methyl glycosides via Fischer glycosylation: translation from batch microwave to continuous flow processing.

Aronow, J.; Stanetty, C.; Baxendale, I. R.; Mihovilovic, M. D. Monatshefte für Chemie 2018, 150, 11-19.

A continuous flow procedure for the synthesis of methyl glycosides (Fischer glycosylation) of various monosaccharides using a heterogenous catalyst has been developed. In-depth analysis of the isomeric composition was undertaken and high consistency with corresponding results observed under microwave heating was obtained. Even in cases where addition of water was needed to achieve homogeneity—a prerequisite for the flow experiments—no detrimental effect on the conversion was found. The scalability was demonstrated on a model case (mannose) and as part of the target-oriented synthesis of D-glycero-Dmanno heptose, both performed on multigram scale.

166 Unprecedented Alkene Transposition in Phthalate–Amino Acid Adducts.

Sahaa, I.; Baxendale, I. R.; Baumann, M. SynLett 2018, 29, 2648-2654.

A detailed account on the outcome of the thermal reaction between benzylidene phthalides and various amino acid derivatives is reported. It was discovered that the tricyclic pyrroles as previously described are not the products formed in these reactions. Instead under high-temperature conditions decarboxylated phthalamide adducts are formed within 5-10 minutes. Additionally, an unprecedented alkene transposition mechanism has been identified leading to the final products of these reactions.

165 A continuous flow synthesis and derivatization of 1,2,4-thiadiazoles.

Baumann, M.; Baxendale, I. R. Biorg. Med. Chem. 2017, 25, 6218-6223.

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.

164 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.

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.

163 Ethyl 5-(4-Bromophenyl)-4-methyl-1H-pyrrole-2- carboxylate.

Baumman, M.; Baxendale, I. R. Molbank 2017, , M951-M951.

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.

162 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.

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.

161 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.

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 polyIJacrylic acid) delivered with good control over the molecular weight and dispersity.

160 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.

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.

159 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.

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.

158 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.

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.

157 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.

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.

156 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.

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.

155 The Use of Gases in Flow Synthesis.

Mallia, C. J.; Baxendale, I. R. Org. Process Res. Dev. 2016, 20, 327-360.

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.

154 Controlled Flow Precipitation as a Valuable Tool for Synthesis.

Filipponi, P.; Gioiello, A.; Baxendale, I. R. Org. Process Res. Dev. 2016, 20, 371-375.

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.

153 Continuous Flow Synthesis of 2H-Azirines and their Diastereoselective Transformation to Aziridines.

Baumann, M.; Baxendale, I. R. SynLett 2016, 27, 159-163.

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.

152 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.

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.

151 Continuous photochemistry: the flow synthesis of ibuprofen via a photo-Favorskii rearrangement.

Baumann, M.; Baxendale, I. R. React. Chem. Eng. 2016, 1, 147-150.

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.

150 Development of the industrial synthesis of vitamin A.

Parker, G. L.; Smith, L. K.; Baxendale, I. R. Tetrahedron 2016, 72, 1645-1652.

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.

149 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.

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.

148 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.

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.

147 Exploring Flow Procedures for Diazonium Formation.

Hu, T.; Baxendale, I. R.; Baumann, M. Molecules 2016, 21, 918-941.

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.

146 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.

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.

145 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.

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.

144 Diastereoselective Trifluoroacetylation of Highly Substituted Pyrrolidines by a Dakin–West Process.

Bammann, M.; Baxendale, I. R. J. Org. Chem. 2016, 81, 11898-11908.

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.

143 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.

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.

142 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.

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.

141 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.

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.

140 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.

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.

139 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.

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.

138 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.

This short note describes a one-step synthesis of the title compound from commercially available starting materials and reports its full spectroscopic characterization data.

137 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.

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.

136 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.

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 α-carbon to the cyano group.

135 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.

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.

134 The synthesis of active pharmaceutical ingredients (APIs)using continuous flow chemistry.

Baumann, M.; Baxendale, I. R. Beilstein J. Org. Chem. 2015, 11, 1194-1219.

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.

133 A Short Multistep Flow Synthesis of a Potential Spirocyclic Fragrance Component.

Baxendale, I. R. Chem. Eng. Technol. 2015, 38, 1713-1716.

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.

132 Total syntheses of natural products containing spirocarbocycles.

Smith, L. K.; Baxendale, I. R. Org. Biomol. Chem. 2015, 13, 9907 -9933.

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.

131 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.

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.

130 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.

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.

129 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.

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.

128 Sustainable Synthesis of Thioimidazoles via Carbohydrate-Based Multicomponent Reactions.

Baumann M.; Baxendale, I. R. Org. Lett. 2014, 16, 6076-6079.

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.

127 The rapid generation of isothiocyanates in flow.

Baumann, M.; Baxendale, I. R. Beilstein J. Org. Chem. 2013, 9, 1613-1619.

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.

126 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.

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.

125 Flow chemistry approaches directed at improving chemical synthesis.

Baxendale, I. R.; Mallia, C. J.; Brocken, L. Green Process Synth. 2013, 2, 211-230.

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.

124 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.

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.

123 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.

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.

122 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.

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.

121 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.

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.

120 The integration of flow reactors into synthetic organic chemistry.

Baxendale, I. R. J. Chem. Technol. Biotechnol. 2013, 88, 519-552.

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.

119 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.

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).

118 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.

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.

117 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.

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).

116 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.

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.

115 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.

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.

114 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.

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.

113 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.

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.

112 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.

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).

111 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.

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.

110 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.

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 4μ8C) 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.

109 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.

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.

108 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.

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.

107 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.

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.

106 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.

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.

105 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.

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.

104 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.

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.

103 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.

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.

102 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.

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.

101 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.

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.

100 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.

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.

99 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.

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.

98 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.

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.

97 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.

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.

96 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.

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.

95 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.

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.

94 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.

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.

93 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.

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.

92 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.

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.

91 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.

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.

90 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.

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.

89 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.

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.

88 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.

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.

87 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.

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.

86 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.

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.

85 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.

Expedient syntheses of Pseudomonas quinolone signal (PQS) and related structural analogues using microwave and flow methods are reported.

84 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.

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 δ-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.

83 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.

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.

82 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.

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.

81 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.

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.

80 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.

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.

79 Enzymatic Oxidative Cyclisation Reactions Leading to Dibenzoazocanes.

Tozzi, F.; Ley, S. V.; Kitching, M. O.; Baxendale, I. R. Synlett 2010, (13), 1919-1922.

From simple N-isovanillyltyramine derivatives double oxidative biotransformations can be achieved using tyrosinase leading to the corresponding hydroxylated dibenzoazocanes.

78 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.

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.

77 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.

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.

76 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.

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.

75 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.

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.

74 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.

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 μm. 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.

73 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.

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.

72 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.

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.

71 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.

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.

70 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.

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.

69 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.

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.

68 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.

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.

67 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.

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.

66 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.

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.

65 Development of Fluorination Methods using Continuous-Flow Microreactors.

Baumann, M.; Baxendale, I. R.; Martin, L. J.; Ley, S. V. Tetrahedron 2009, 65, 6611-6625.

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.

64 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.

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.

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.

We report on the use of commercially available chemical microreactors to effect the Hofmann rearrangement of aromatic amides to the corresponding carbamates.

62 New Tools for Molecule Makers: Emerging Technologies..

Ley, S. V.; Baxendale, I. R. Beilstein J. Org. Chem. 2009, NA, 65-85.

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.

61 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.

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.

60 The Changing Face of Organic Synthesis.

Ley, S. V.; Baxendale, I. R. Chimia 2008, 62, 162-168.

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.

59 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.

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.

58 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.

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.

57 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.

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.

56 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.

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.

55 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.

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.

54 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.

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.

53 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.

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.

52 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.

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.

51 [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.

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.

50 Pharmaceutical Strategy and Innovation: An Academics Perspective.

Baxendale, I. R.; Hayward, J. J.; Ley, S. V.; Tranmer, G. K. MedChemMed 2007, 2, 768-788.

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.

49 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.

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.

48 Microwave Reactions under Continuous Flow Conditions..

Baxendale, I. R.; Hayward, J. J.; Ley. S. V. Combinatorial Chemistry & High Throughput Screening 2007, 10, 802-836.

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.

47 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.

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 μm. 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.

46 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.

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.

45 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.

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.

44 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.

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.

43 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.

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.

42 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.

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.

41 Microwave Flow Chemistry: The Next Evolutionary Step in Synthetic Chemistry.

Baxendale, I. R.; Pitts, M. R. Chimica Oggi, Chemistry Today 2006, 24, 41-45.

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.

40 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.

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.

39 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.

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.

38 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.

37 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.

36 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.

A number of oligomeric alkynes underwent [2 + 2 + 2] intramolecular trimerization to afford arenes under metal-free conditions using focussed microwave heating.

35 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.

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.

34 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.

Two new naturally occurring amaryllidaceae alkaloids have been synthesized, using a divergent approach facilitated by the use of polymer-supported reagents and scavengers.

33 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.

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.

32 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.

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.

31 Synthesis of Alkaloid Natural Products using Supported Reagents and Scavengers.

Baxendale, I. R.; Ley, I. R. Curr. Org. Chem. 2005, 9, 1521-1534.

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.

30 Microwave-Enhanced Palladium-Catalysed Reactions.

Baxendale, I. R.; Pitts, M. R. Innovations in Pharmaceutical Technology 2005, 18, 86-90.

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.

29 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.

28 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.

27 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.

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.

26 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.

The development of enhanced conditions for Lewis acid catalysed Leimgruber–Batcho indole synthesis using microwave acceleration is described.

25 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.

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.

24 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.

23 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.

22 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.

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.

21 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.

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.

20 Organic synthesis in a changing world..

Ley, S. V.; Baxendale, I. R. Chem. Rec. 2002, 2, 377-388.

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.

19 New tools and concepts for modern organic synthesis..

Ley, S. V.; Baxendale, I. R. Nat. Rev. Drug Discovery 2002, 1, 573-586.

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.

18 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.

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.

17 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.

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.

16 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.

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.

15 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.

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.

14 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.

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.

13 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.

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.

12 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.

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.

11 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.

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.

10 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.

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.

9 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.

The binuclear Mo(II) and W(II) complexes 28a,b and 29a,b have been developed as pre-catalysts for allylic substitution with β-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).

8 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.

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 β- and α-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.

7 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.

6 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.

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.

5 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.

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.

4 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.

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.

3 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.

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 β-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.

2 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.

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.

1 Molybdenum(II)-catalysed allylic substitution.

Malkov, A. V.; Baxendale, I. R.; Mansfield, D. J.; Kocovsky, P. Tetrahedron Lett. 1997, 38, 4895-4898.

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 β-dicarbonyls (e.g., 6 + 12 → 14) and from simple ketones (e.g., 6 + 13 → 16) as nucleophiles.