Hans-René Bjørsvik

Organocatalyzed Epoxidation of Alkenes in Continuous Flow using a Multi-Jet Oscillating Disk Reactor

Several epoxidation reactions and methods have been reported in the literature, and the majority of these are based on transition metal catalysis. Examples include the Mukaiyama epoxidation, 3] Sharpless epoxidation, and Jacobsen–Katsuki epoxidation. Even though such transition metal-catalyzed processes offer several advantages, a serious disadvantage exists if the epoxide is to be used in the preparation of pharmaceuticals, nutraceuticals, or other food and feed additives: the need for an extensive purification of the synthesized target product. Guidelines from The European Medicines Agency state that the oral permitted exposure to, for example, palladium and nickel in pharmaceutical ingredients should be <2.6 mgPd kg 1 day 1 and 20 mg Ni kg 1 day, 1 respectively. Developing protocols that meet these requirements can be a challenging task, but this can usually be solved by means of classical purification methods. These often involve several consecutive purification steps and/or a combination of several methods. A new, emerging technology known as organic solvent nanofiltration can also be applied, without the need of several repeating steps. However, processing in this manner increases costs and decreases throughput and yield. Competitive organic processes that do not require the use of any transition metals in order to operate exist, but from an industrial point of view these also suffer from a drawback, namely the need for long reactor residence times to reach suitable product yields. This of course limits the efficiency and throughput of the process. The epoxidation of alkenes via aerobic oxidation with an aldehyde as a co-reagent has been reported by Kaneda and collaborators, Lassila and collaborators, and Beak and Jarboe. The Shi epoxidation gives access to epoxides starting from various alkenes using a fructose-derived organocatalyst with Oxone as the terminal oxidant. Minisci and co-workers disclosed an organocatalyzed epoxidation (Scheme 1) in which olefins 1 are treated with acetaldehyde 2 under an oxygen atmosphere in the presence of N-hydroxyphthalimide (NHPI) 3 as catalyst, to obtain epoxides 4 in good to excellent yields. The Minisci epoxidation was demonstrated to operate superbly with a-olefins and cyclic olefins, producing the corresponding epoxides in excellent yields and selectivities, while internal acyclic olefins were proven to be unreactive. Even though the Minisci epoxidation can be said to be a green and economical process, it also suffers from a disadvantage from an industrial point of view: its low relative efficiency owing to long batch reactor residence times (24–48 h). To overcome this major drawback, we initialized a project for technology transfer, development, and optimization to realize an aerobic epoxidation catalyzed by NHPI (3) under continuous-flow conditions by means of a new technology: the multijet oscillating disk (MJOD) reactor. During recent years, we have in our laboratories at the University of Bergen and at Fluens Synthesis designed, manufactured, developed, and investigated an approach for flow organic synthesis that has resulted in this novel reactor platform. A detailed account of the MJOD reactor technology was recently disclosed by us, but a short description of the MJOD reactor technology follows here. A 3D drawing of the MJOD reactor that includes the input section, reactor body, output section, and oscillator section is shown in Figure 1. A process flowchart for the experiments disclosed herein is given in Figure 2. The right-hand side of Figure 1 shows a transparent top-down view of the input section, together with a small section of the reactor zone. The MJOD unit is placed in the center of the reactor tube. The outer shell of the reactor body forms a ring-shaped room that encapsulates the whole length of the reactor tube. This room is used for circulating a heating or cooling fluid. Due to the advantageous reactor net volume versus the heating/cooling surface ratio of the reactor tube, an exceptionally good heat transfer capacity is achieved. A variable-frequency and variable-amplitude oscillator is used for the vertical “piston movement” of the MJOD unit. An electric motor connected to a cam mechanism is used to power the up–down movement of the MJOD assembly. In addition, the cam assembly provides control of the amplitude by linear translation of the cam assembly to a predefined position (i.e. , the distance to the motor shaft). Frequencies in the range of f = 1–10 Hz and amplitudes in the range of A = 0.5–15 mm can be achieved by adjusting the motor speed and the cam assembly. Various types of feeding [a] Dr. R. Spaccini, Prof. Dr. H.-R. Bjørsvik Department of Chemistry University of Bergen All gaten 41, 5007 Bergen (Norway) Fax: (+ 47) 55 58 94 90 E-mail : hans.bjorsvik@kj.uib.no [b] Dr. L. Liguori, Prof. Dr. H.-R. Bjørsvik Fluens Synthesis Thormøhlensgate 55, 5008 Bergen (Norway) [c] Dr. R. Spaccini, Dr. C. Punta Dipartimento di Chimica, Materiali e Ingegneria Chimica, “Giulio Natta” Politecnico di Milano Via Mancinelli 7, 20131 Milano (Italy) Scheme 1. The Minisci epoxidation process.

Separation of reaction product and palladium catalyst after a Heck coupling reaction by means of organic solvent nanofiltration.

Organic solvent nanofiltration (OSN) is a recently commercialized technology, which we have used to develop a method for the separation of a target product and the Pd catalyst from a Heck coupling postreaction mixture. The experimental setup included commercially available polyimide copolymer membranes with molecular weight cut-off (MWCO) values in the range of 150-300 Da, acetone as the solvent, and a working pressure (N(2)) of 3 MPa. The investigation of the membranes revealed that a membrane with a MWCO of 200 Da provided quantitative retention of the Pd catalyst and quantitative recovery of the target product by means of a cross-flow dia-nanofiltration procedure.

4-Alkylated Silver–N-Heterocyclic Carbene (NHC) Complexes with Cytotoxic Effects in Leukemia Cells

Computational chemistry has shown that backbone‐alkylated imidazoles ought to be efficient ligands for transition metal catalysts with improved carbene‐to‐metal donation. In this work, such alkylated imidazoles were synthesized and complexed with silver(I) by means of an eight/nine‐step synthetic pathway we devised to access a new class of biologically active silver complexes. The synthesis involves selective iodination of the imidazole backbone, followed by Sonogashira coupling to replace the backbone iodine. The installed alkyne moiety is then subjected to reductive hydrogenation with Pearlman’s catalyst. The imidazole N1 atom is arylated by the palladium‐catalyzed Buchwald N‐arylation method. The imidazole N3 position was then methylated with methyl iodine, whereupon the synthesis was terminated by complexation of the imidazolium salt with silver(I) oxide. The synthetic pathway provided an overall yield of ≈20 %. The resulting complexes were tested in vitro against HL60 and MOLM‐13 leukemic cells, two human‐derived cell lines that model acute myeloid leukemia. The most active compounds exhibiting low IC50 values of 14 and 27 μM, against HL60 and MOLM‐13 cells, respectively. The imidazole side chain was found to be essential for high cytotoxicity, as the imidazole complex bearing a C7 side chain at the 4‐position was four‐ to sixfold more potent than the corresponding imidazole elaborated with a methyl group.

Carboxylic acids from methyl aryl ketones by means of a new composite aerobic oxidation process

A new aerobic oxidation method for conversion of methyl aryl ketones to the corresponding benzoic acids is presented. The method is cheap and environmentally friendly, which also makes it suitable for large scale industrial use. The method affords a yield of >75% with an almost 100% selectivity. Experiments have shown that the process operates following two mechanistic pathways, namely by base-catalysed autoxidation and by single electron transfer processes.

Chapter 2 – Synthesis of Imidazole Alkaloids Originated in Marine Sponges

Abstract A number of secondary metabolites resembling a polysubstituted 2-aminoimidazole scaffold are found in a variety of marine sponges. Due to the diversity in the biological activity with drug-like properties, several research groups have designed and developed strategies and syntheses leading to these marine alkaloids. This report constitutes a summary of the literature during the period 1990 to the mid 2012 that presents syntheses belonging to seven different classes of marine alkaloids based on the imidazole scaffold, namely, preclathridines A–C, clathridines A–C, isonaamines A–E, isonaamidines A–E, naamines A–G, naamidines A–I, and pyronaamidines.

New free-radical chain processes involving substitution of vinyl and aryl chlorides by alkanes, alkenes, esters and ethers

Abstract New free-radical substitutions of vinyl and aryl chlorides by alkanes, alkenes, ethers and esters are described. The free-radical chains are rationalized on the basis of the known kinetics of the elementary steps involved.

Continuous flow synthesis of the iodination agent 1,3-diiodo-5,5-dimethyl-imidazolidine-2,4-dione telescoped with semi-continuous product isolation

A batch synthesis to the iodinating agent 1,3-diiodo-5,5-dimethyl-imidazolidine-2,4-dione (DIH) was devised and developed. This batch process was then up-scaled (10×) and optimized by means of statistical experimental design and multivariate regression. The optimized batch procedure was then transferred and adapted for continuous flow synthesis using a multi-jet oscillating disk (MJOD) continuous flow reactor platform to provide a flow process that allowed a throughput of 47 g h−1 with a residence time of 9 min. A semi-continuous work-up step based on vacuum filtration was established and successfully telescoped to be an integrated part of the flow process. An 8 h test run using the optimized flow synthesis in combination with the semi-continuous filtration step afforded 375 g (≈90% isolated yield) of the pure title compound that was collected from 14 filtration batches of 25–27 g each.

Continuous flow synthesis concatenated with continuous flow liquid–liquid extraction for work-up and purification: selective mono- and di-iodination of the imidazole backbone

Flow processes for mono- and di-iodination of the imidazole backbone were devised, developed, and implemented on the multi-jet oscillating disk (MJOD) flow reactor platform. The flow processes were based on batch protocols previously developed in our research group and involved N,N′-1,3-diiodo-5,5-dimethylhydantoin as the iodination reagent. The flow processes demanded short reactor residence times, and afforded the mono- or di-iodinated imidazoles at a high mass × time yield [g min−1]. The continuous flow processes leading to 4(5)-iodo-1H-imidazole HCl salt was concatenated with a continuous flow work-up section that was assembled by a series of hold-up tanks and two additional MJOD flow reactors that both were utilized as liquid–liquid extractors. The overall mass throughput allowed a production of 4(5)-iodo-1H-imidazole HCl salt at a capacity of 95 g day−1. The continuous flow reaction unit utilized for the preparation of 4,5-diiodo-1H-imidazole was concatenated with a double set of hold-up tanks/stirred tank-batch reactors and semi-continuous vacuum filtration units for the isolation of precipitated/crystallized 4,5-diiodo-1H-imidazole at a production capacity of 295 g day−1.

A bromine-catalysed free-radical oxidation of acetamides from primary and secondary alkylamines by H2O2

New procedures based on the oxidation by bromine-catalysed hydrogen peroxide in a two-phase system provide simple and cheap transformations of alkylamines to carbonyl derivatives (aldehydes, ketones, carboxylic acid, imides, lactams) through the corresponding acetamides.

A NEW DIRECT HOMOLYTIC IODINATION REACTION OF ALKANES BY PERFLUOROALKYL IODIDES

A new method for the direct free-radical chain iodination of alkanes by perfluoroalkyl iodides is described.