Inductively heated steel reactors continuously perform organic transformations in water under high temperature conditions, utilizing the unique physiochemical properties of water at subcritical conditions. We demonstrated the power of this set-up in the continuous synthesis of the atypical antipsychotic drug iloperidone, in which we performed four out of five steps under aqueous conditions.

Automation steht wieder auf der Tagesordnung! Der erste automatisierte, iterative C-C-Kupplungsprozess nutzt die beiden Gesichter von MIDA-Boronaten. Es werden die Möglichkeiten und Herausforderungen offenbart, wie iterative Synthesen mit komplexen, bifunktionalisierten Bausteinen unter Nutzung von „Liquid-Handling”︁-Systemen sogar Naturstoffsynhesen möglich machen.

More than five decades ago Bruce Merrifield introduced the idea of automation to organic chemistry through the use of solid supports as an enabling technology that facilitates synthesis as well as work-up. The age of combinatorial chemistry popularized solid-phase-assisted synthesis, but also paved the way for new enabling technologies and technical devices such as liquid-handling systems, radiofrequency tags, as well as microwave and inductive heating (Scheme 1). Nonconventional solvents such as ionic liquids, perfluorinated solvents, as well as supercritical fluidic conditions are other options to simplify organic synthesis and work-up procedures. Multistep continuous synthesis and microreactor design coupled with online monitoring are the latest trends in automation. In addition to enabling technologies and technical devices, the automation of multistep processes is closely linked with certain methods and chemical concepts such as multicatalysis, multicomponent and domino reactions, and iterative processes (Scheme 1). Modularity and iteration are also common structural as well as processing concepts found in nature, as manifested in polypeptides, oligonucleotides, and oligosaccharides as well as in secondary metabolites such as terpenes and polyketides. Iterative multistep processes are known in organic synthesis because it provides complexity in a modular fashion from simple precursors. Peptide and nucleic acid syntheses are the most prominent examples, but in other synthetic arenas iteration is still in its infancy. The research groups of Aggarwal and Burke both disclosed impressive new iterative processes in which C¢C coupling reactions play a key role. AggarwalÏs iterative approach is based on the homologation of boronic esters 5 in the reaction with lithiated benzoates 6. After a Matteson-type rearrangement, boronate 7 is formed, which is used in the next iterative process. This iterative homologation can provide complex methylbranched alkyl chains in high yield after nine iterative loops with minimal purification (Scheme 2). BurkeÏs concept utilizes bifunctional MIDA boronates (MIDA = N-methyliminodiacetic acid) 1, and importantly the automation of this chemistry was demonstrated for the first time using liquid-handling systems as technical devices. Boronates 1 lack the necessary reactivity under common transition-metal cross-coupling conditions. However, their hidden reactivity can be unleashed under basic hydrolytic conditions, which forms the more reactive boronic acids 3. The cross-coupling reaction with bifunctional MIDA boronates yields new extended adducts n + i 2, again containing the MIDA boronate moiety, and the iterative loop is closed after the new MIDA boronate is submitted to the initial hydrolytic conditions (Scheme 1). To automate this iterative process, a technically simple set up based on liquid-handling concepts was developed that relates to solid-phase peptide synthesis. It comprises deprotection (D), coupling (C), and purification (P) units (Figure 1). Three syringe pumps deliver solvents, solutions, and reaction mixtures. The deprotection unit D is responsible for activation of the MIDA boronate terminus of the starting building block as well as the products obtained after each iterative cycle. The coupling module C is a cartridge that contains all the reagents necessary for the cross-coupling reactions such as the extender building block that contains halide and MIDA boronate termini, the catalysts, and other agents if required. The purification module D consists of a precipitation cartridge for the separation of salts from the reaction mixture and a silica gel plug for purification through a “catch and release” mechanism. The “primary” syringe pump plays a key role in that it controls operations in all three modules D, C, and P by injecting and withdrawing reaction mixtures or washing solvents in and out of the cartridges at different stages of the process. A second pump, called the “wet” pump is only responsible for hydrolysis of the MIDA boronates, and a third pump, called the “auxiliary” pump, is involved in the purification of the cross-coupling product 2. In the following, the whole process, the role of the pumps, and the function of the modules are described in detail. First, hydrolytic cleavage of the MIDA boronate 1 (lacking the halide terminus) is achieved by the action of two pumps. The “primary” pump adds THF and the “wet” pump adds water to the deprotection vessel, which is charged with the starting MIDA boronate and NaOH. The hydrolysis is terminated by the addition of phosphate buffer (pH 6) or a saturated solution of ammonium chloride using the “wet” pump. The “primary” pump adds diethyl ether, and mixing is achieved by pulses of nitrogen gas bubbles. The aqueous phase now [*] J. Hartwig, Prof. Dr. A. Kirschning Institut fír Organische Chemie und Biomolekulares Wirkstoffzentrum (BMWZ), Leibniz Universit•t Hannover Schneiderberg 1B, 30167 Hannover (Germany) E-mail: andreas.kirschning@oci.uni-hannover.de . Angewandte Highlights

Highly functionalized α‐dibromoketones are formed from the corresponding esters in a flow reactor.

A combination of mutasynthesis, precursor-directed biosynthesis and semisynthesis provides access to new ansamitocin derivatives including new nanostructured particle-drug conjugates. These conjugates are based on the toxin ansamitocin and superparamagnetic iron oxide-silica core shell particles. New ansamitocin derivatives that are functionalized either with alkynyl- or azido groups in the ester side chain at C-3 are attached to nanostructured iron oxide core-silica shell particles. Upon exposure to an oscillating electromagnetic field these conjugates heat up and the ansamitocin derivatives are released by a retro-Diels-Alder reaction. For example, one ansamitocin derivative exerts strong antiproliferative activity against various cancer cell lines in the lower nanomolar range while the corresponding nanostructured particle-drug conjugate is not toxic. Therefore, these new conjugates can serve as dormant toxins that can be employed simultaneously in hyperthermia and chemotherapy when external inductive heating is applied.

Continuous flow chemistry as a process intensification tool is well known. However, its ability to enable chemists to perform reactions which are not possible in batch is less well studied or understood. Here we present an example, where a new reactivity pattern and extended reaction scope has been achieved by transferring a reaction from batch mode to flow. This new reactivity can be explained by suppressing back mixing and precise control of temperature in a flow reactor set up.

A continuous flow protocol for the oxidation of allylic and benzylic alcohols to aldehydes and ketones, respectively, using oxygen gas or atmospheric air is reported. The key features of this work are gold nanoparticles that are attached to the surface of nanostructured core shell particles composed of an Fe3O4-containing core and a silica shell. These nanostructured particles exert superparamagnetic properties and thus inductively heat up in an external oscillating electromagnetic field, conditions under which the gold catalyst is able to perform these oxidation reactions.

Angewandte Chemie International EditionVolume 52, Issue 37 p. 9813-9817 Communication Heating under High-Frequency Inductive Conditions: Application to the Continuous Synthesis of the Neurolepticum Olanzapine (Zyprexa)† Jan Hartwig, Jan Hartwig Institut für Organische Chemie, Leibniz Universität Hannover, Schneiderberg 1B, 30167 Hannover (Germany)Search for more papers by this authorDr. Sascha Ceylan, Dr. Sascha Ceylan Institut für Organische Chemie, Leibniz Universität Hannover, Schneiderberg 1B, 30167 Hannover (Germany)Search for more papers by this authorLukas Kupracz, Lukas Kupracz Institut für Organische Chemie, Leibniz Universität Hannover, Schneiderberg 1B, 30167 Hannover (Germany)Search for more papers by this authorDr. Ludovic Coutable, Dr. Ludovic Coutable Institut für Organische Chemie, Leibniz Universität Hannover, Schneiderberg 1B, 30167 Hannover (Germany)Search for more papers by this authorProf. Dr. Andreas Kirschning, Corresponding Author Prof. Dr. Andreas Kirschning [email protected] Institut für Organische Chemie, Leibniz Universität Hannover, Schneiderberg 1B, 30167 Hannover (Germany)Institut für Organische Chemie, Leibniz Universität Hannover, Schneiderberg 1B, 30167 Hannover (Germany)Search for more papers by this author Jan Hartwig, Jan Hartwig Institut für Organische Chemie, Leibniz Universität Hannover, Schneiderberg 1B, 30167 Hannover (Germany)Search for more papers by this authorDr. Sascha Ceylan, Dr. Sascha Ceylan Institut für Organische Chemie, Leibniz Universität Hannover, Schneiderberg 1B, 30167 Hannover (Germany)Search for more papers by this authorLukas Kupracz, Lukas Kupracz Institut für Organische Chemie, Leibniz Universität Hannover, Schneiderberg 1B, 30167 Hannover (Germany)Search for more papers by this authorDr. Ludovic Coutable, Dr. Ludovic Coutable Institut für Organische Chemie, Leibniz Universität Hannover, Schneiderberg 1B, 30167 Hannover (Germany)Search for more papers by this authorProf. Dr. Andreas Kirschning, Corresponding Author Prof. Dr. Andreas Kirschning [email protected] Institut für Organische Chemie, Leibniz Universität Hannover, Schneiderberg 1B, 30167 Hannover (Germany)Institut für Organische Chemie, Leibniz Universität Hannover, Schneiderberg 1B, 30167 Hannover (Germany)Search for more papers by this author First published: 24 July 2013 https://doi.org/10.1002/anie.201302239Citations: 119 † This work was supported in part by the Fonds der Chemischen Industrie (PhD scholarship for J.H.) and by Henkel AG & Co. KGaA (Düsseldorf (Germany)). We thank H. Herzog and Prof. S. Katusic (EVONIK Industries AG, Essen (Germany)) for technical support and Dr. D. Candito for helpful discussions. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Graphical Abstract Hot chemistry! High-frequency inductive heating and flow chemistry are an ideal match for high-temperature synthesis. This is demonstrated in the multistep flow synthesis of the neurolepticum olanzapine (Zyprexa) that included three reactions with inductive heating and two purification steps conducted as continuous processes. Supporting Information As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Filename Description anie_201302239_sm_miscellaneous_information.pdf1.4 MB miscellaneous_information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. References 1A. Kirschning, W. Solodenko, K. Mennecke, Chem. Eur. J. 2006, 12, 5972–5990. 2Selected recent reviews on flow synthesis: 2aJ. Wegner, S. Ceylan, A. Kirschning, Adv. Synth. Catal. 2012, 354, 17–57; 2bR. Yuryev, S. Strompen, A. Liese, Beilstein J. Org. Chem. 2011, 7, 1449–1467; 2cJ. Wegner, S. Ceylan, A. Kirschning, Chem. Commun. 2011, 47, 4583–4592; 2dJ. P. McMullen, K. F. Jensen, Annu. Rev. Anal. Chem. 2010, 3, 19–42; 2eJ.-i. Yoshida, H. Kim, A. Nagaki, ChemSusChem 2011, 4, 331–340; 2fD. Webb, T. F. Jamison, Chem. Sci. 2010, 1, 675–680; 2gS. Marre, K. F. Jensen, Chem. Soc. Rev. 2010, 39, 1183–1202; 2hT. Illg, P. Löb, V. Hessel, Bioorg. Med. Chem. 2010, 18, 3707–3719; 2iJ.-i. Yoshida, Chem. Rec. 2010, 10, 332–341; 2jC. G. Frost, L. Mutton, Green Chem. 2010, 12, 1687–1703; 2kX. Y. Mak, P. Laurino, P. H. Seeberger, Beilstein J. Org. Chem. 2009, 5, 19. 3T. Razzaq, C. O. Kappe, Chem. Asian J. 2010, 5, 1274–1289. 4 4aM. Larhed, A. Hallberg, Drug Discovery Today 2001, 6, 406–416; 4bD. Bogdal, A. Loupy, Org. Process Res. Dev. 2008, 12, 710–722; 4cC. O. Kappe, Chem. Soc. Rev. 2008, 37, 1127–1139. 5 5aA. Schlange, A. R. dos Santos, U. Kunz, T. Turek, Beilstein J. Org. Chem. 2011, 7, 1412–1420; 5bU. Kunz, T. Turek, Beilstein J. Org. Chem. 2009, 5, 70. 6 6aL. Kupracz, J. Hartwig, J. Wegner, S. Ceylan, A. Kirschning, Beilstein J. Org. Chem. 2011, 7, 1441–1448; 6bS. Ceylan, L. Coutable, J. Wegner, A. Kirschning, Chem. Eur. J. 2011, 17, 1884–1893; 6cA. Kirschning, C. Friese, S. Ceylan, J. Wegner, Eur. J. Org. Chem. 2010, 4372–4375; 6dS. Ceylan, T. Klande, C. Vogt, C. Friese, A. Kirschning, Synlett 2010, 2009–2013; 6eS. Ceylan, C. Friese, Ch. Lammel, K. Mazac, A. Kirschning, Angew. Chem. 2008, 120, 9083–9086; Angew. Chem. Int. Ed. 2008, 47, 8950–8953. 7International Commission on Non-Ionizing Radiation Protection, Health Physics, 1998, 74, 494–522. 8Reviews: 8aA. Kirschning, L. Kupracz, J. Hartwig, Chem. Lett. 2012, 41, 562–570; 8bA.-H. Lu, E. L. Salabas, F. Schüth, Angew. Chem. 2007, 119, 1242–1266; Angew. Chem. Int. Ed. 2007, 46, 1222–1244; 8cY.-W. Jun, J.-S. Choi, J. Cheon, Chem. Commun. 2007, 1203–1214. 9A. Gagnoud, IEEE Trans. Magn. 2004, 40, 29–36. 10Olanzapine (Zyprexa) is used for the treatment of bipolar disorders and schizophrenia: N. Bhana, R. H. Foster, R. Olney, G. L. Plosker, Drugs 2001, 61, 111–161. 11The high-frequency inductor was obtained from Himmelwerk GmbH (Tübingen, Germany). 12MAGSILICA300 was obtained from EVONIK Industries AG (Essen, Germany). 13For details on the heating properties of steel beads of various size in an oscillating electromagnetic field see Ref. [6b] 14 14aJ. Gerlach, L. Peacock, Int. Clin. Psychopharmacol. 1995, 10, 39–48; 14bG. P. Reynolds, J. Psychopharmacol. 2004, 18, 340–345. 15Patent DE 25 52 403 C2 (published: 19.6.1986). 16 16aK. R. Hornberger, J. G. Badiang, J. M. Salovich, K. W. Kuntz, K. A. Emmitte, M. Cheung, Tetrahedron Lett. 2008, 49, 6348–6351; 16bK. A. Emmitte, G. M. Adjebang, C. W. Andrews, J. G. B. Alberti, R. Bambal, S. D. Chamberlain, R. G. Davis-Ward, H. D. Dickson, D. F. Hassler, K. R. Hornberger, J. R. Jackson, K. W. Kuntz, T. J. Lansing, R. A. Mook, Jr., K. E. Nailor, M. A. Pobanz, S. C. Smith, C. Sung, M. Cheung, Bioorg. Med. Chem. Lett. 2009, 19, 1694–1697. 17P. K. Mandal, J. S. McMurray, J. Org. Chem. 2007, 72, 6599–6601. 18Other materials, for example, Al2O3 and sulfur were less efficient. 19Two excellent examples of multistep flow synthesis of relevant drugs (Gleevec and Ibuprofen): 19aM. D. Hopkin, I. R. Baxendale, S. V. Ley, Chem. Commun. 2010, 46, 2450–2452; 19bA. R. Bogdan, S. L. Poe, D. C. Kubis, S. J. Broadwater, D. T. McQuade, Angew. Chem. 2009, 121, 8699–8702; Angew. Chem. Int. Ed. 2009, 48, 8547–8550. Citing Literature Volume52, Issue37September 9, 2013Pages 9813-9817 ReferencesRelatedInformation

Heiße Chemie! Induktives Heizen unter Hochfrequenzbedingungen und Durchflusschemie sind eine ideale Kombination für Hochtemperatursynthesen. Dies konnte in der kontinuierlichen Mehrstufensynthese des Neuroleptikums Olanzapin (Zyprexa) gezeigt werden. Sie umfasst drei Reaktionen mit induktivem Heizen und zwei kontinuierlich betriebene Reinigungsoperationen.

Inductive heating has emerged as a new heating technique in the laboratory, particularly when combined with miniaturized flow reactor devices. Traditionally, inductive heating is found in industrial applications like the heating of large metallic objects such as in the bending of pipes, bonding and welding. New fields of application are the preparation of nanotubes as well as hyperthermia in the treatment of cancer. This account specifically addresses the use of heatable materials such as superparamagnetic iron oxide nanoparticles in many areas of organic synthesis and how this enabling technology compares to conventional as well as microwave heating.

AbstractAromatic heterocycles bearing a methyl group are applied as cross‐coupling partners in the reaction with cyclopentyl‐ or cyclohexyl‐derived mesityl esters.

We report the palladium-catalyzed asymmetric allylic alkylation (AAA) reaction of a variety of nitrogen-containing aromatic heterocycles, including pyrazine, pyrimidine, pyridazine, quinoxaline, and benzoimidazole derivatives. The mesityl ester, whose steric bulk prevents competitive deacylation of the electrophile from "hard" nucleophiles, is introduced as a new leaving group in allylic alkylation chemistry. In contrast to our previous studies of AAA reactions with pyridine-based substrates, no precomplexation with a Lewis acid is required before deprotonation with LiHMDS, underscoring the relative acidity of these electron-deficient nucleophiles.

The multistep flow synthesis of vinyl azides and their application in the synthesis of vinyltriazoles is reported. The synthesis relies on a stable polymer-bound equivalent of iodine azide that serves to carry out 1,2-functionalization of alkenes in a telescope flow protocol. The intermediate 2-iodo azides are subjected to a DBU-mediated polymer-supported elimination step yielding vinyl azides in good yield. The third step involves the formation of vinyl triazoles by a copper-catalyzed Huisgen-"click" cycloaddition. The required heat is generated by electromagnetic induction based on copper. Copper serves both as heatable as well as catalytically active packed-bed material inside the flow reactor.