DOI: 10.1002/cssc.201100262 Organocatalyzed Epoxidation of Alkenes in Continuous Flow using a Multi- Jet Oscillating Disk Reactor Raffaele Spaccini, [a, c] Lucia Liguori, [b] Carlo Punta, [c] and Hans-RenØ Bjørsvik* [a, b] Several epoxidation reactions and methods have been report- ed in the literature, [1] and the majority of these are based on transition metal catalysis. Examples include the Mukaiyama ep- oxidation, [2, 3] Sharpless epoxidation, [4] and Jacobsen–Katsuki epoxidation. [5] 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 phar- maceuticals, nutraceuticals, or other food and feed additives: the need for an extensive purification of the synthesized target product. Guidelines from The European Medicines Agency [6] state that the oral permitted exposure to, for example, palladi- um and nickel in pharmaceutical ingredients should be < 2.6 mg Pd kg 1 day 1 and 20 mg Ni kg 1 day, 1 respectively. Devel- oping protocols that meet these requirements can be a chal- lenging task, but this can usually be solved by means of classi- cal purification methods. These often involve several consecu- tive purification steps and/or a combination of several meth- ods. A new, emerging technology known as organic solvent nanofiltration can also be applied, [7] without the need of sever- al repeating steps. However, processing in this manner increas- es costs and decreases throughput and yield. Competitive or- ganic 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 pro- cess. The epoxidation of alkenes via aerobic oxidation with an al- dehyde as a co-reagent has been reported by Kaneda and col- laborators, [8a] Lassila and collaborators, [8b] and Beak and Jar- boe. [8c] The Shi epoxidation gives access to epoxides starting from various alkenes using a fructose-derived organocatalyst with Oxone as the terminal oxidant. [9] Minisci and co-workers disclosed an organocatalyzed epoxidation (Scheme 1) in which olefins 1 are treated with acetaldehyde 2 under an oxygen at- mosphere in the presence of N-hydroxyphthalimide (NHPI) 3 as catalyst, to obtain epoxides 4 in good to excellent yields. [10] 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 acy- clic 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 disadvant- age 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 continu- ous-flow conditions by means of a new technology: the multi- jet oscillating disk (MJOD) reactor. [11a] During recent years, we have in our laboratories at the University of Bergen and at Fluens Synthesis designed, manufactured, developed, and in- vestigated an approach for flow organic synthesis that has re- sulted in this novel reactor platform. A detailed account of the MJOD reactor technology was recently disclosed by us, [11b] 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 dis- closed herein is given in Figure 2. The right-hand side of Figure 1 shows a transparent top-down view of the input sec- tion, 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 ad- vantageous reactor net volume versus the heating/cooling sur- face ratio of the reactor tube, an exceptionally good heat transfer capacity is achieved. A variable-frequency and varia- ble-amplitude oscillator is used for the vertical “piston move- ment” 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 con- trol 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 AllØgaten 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. [10] Special Issue: Flow Chemistry ChemSusChem 2012, 5, 261 – 265  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 261