Very Important Publication DOI: 10.1002/adsc.201501023 Development of a Continuous-Flow Microreactor for Asymmetric Sulfoxidation Using a Biomimetic Manganese Catalyst Wen Dai, +a Yuan Mi, +a Ying Lv, a Bo Chen, a Guosong Li, a Guangwen Chen, a, * and Shuang Gao a, * a Dalian Institute of Chemical Physics, the Chinese Academy of Sciences and Dalian National Laboratory for Clean Energy, Dalian 116023, People)s Republic of China Fax: (+ 86)-411-8437-9248 or (+ 86)-411-84379327; phone: (+ 86)-411-8437-9248 or (+ 86)-411-84379031; e-mail: gwchen@dicp.ac.cn or sgao@dicp.ac.cn + These authors contributed equally to this work. Received: November 7, 2015; Revised: November 25, 2015; Published online: January 22, 2016 Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201501023. Abstract: Asymmetric sulfoxidation catalyzed by a biomimetic manganese complex under continu- ous-flow microreactor is described. The reaction is conducted in microreactor, it can rapidly (< 4 min) oxidize a wide scope of sulfides with high yield (up to 91%) and excellent enantioselectivity (up to 99% ee), and allows shorter reaction times, easier scale-up and lower catalyst loadings than its batch- wise counterpart. Additionally, a convenient num- bering-up strategy for the scale-up of asymmetric sulfoxidation has been developed which enables a direct scaling of the reaction to 5 g affording the corresponding sulfoxides within 20 min. Keywords: asymmetric sulfoxidation; biomimetic process; continuous flow conditions; microreactor; porphyrin-inspired catalyst Optically active sulfoxides are extremely useful and versatile building blocks, chiral auxiliaries and orga- nocatalysts in organic synthesis. [1] They have also been extensively applied in the manufacture of phar- maceuticals such as modafinil and esomeprazole. [2] In view of the importance of optically pure sulfoxides, intensive effort has been devoted to expand the meth- ods towards sulfoxides with high enantiomeric purity. [3] Among the available approaches, it is widely appreciated that the asymmetric sulfoxidation is the most straightforward and reliable route. Nevertheless, despite the general success story of this approach, some problems such as long reaction times, high cata- lyst loading and/or difficult scale-up still remain that can rarely be addressed by conventional batch ap- proaches. Consequently, the pursuit of new methods for the synthesis of enantiopure sulfoxides is desira- ble. Over the past decade, interest has grown in contin- uous-flow microreactors due to their potential in ac- celerating reactions, facilitating scale-up and allowing safe handling of hazardous reactions. [4] Owing to these attributes, the microreactors are becoming an ideal alternative to traditional batch reactors for syn- thetic chemistry and have been applied to many stan- dard transformations in organic synthesis. However, only a few examples on homogeneous enantioselec- tive catalysis performed in microreactors have been described to date. [4a–d,o,5] In addition, we recently de- veloped a new type of porphyrin-inspired N 4 ligands which fulfilled the structural requirements of the por- phyrin ligand in some way. [6] The biomimetic ligands possessing excellent tolerance have been successfully applied in the asymmetric sulfoxidation. [6e,f] With this background in mind, it was envisioned that we could develop an asymmetric sulfoxidation method conduct- ed in continuous-flow microreactor exploiting the por- phyrin-inspired manganese catalyst which could allow shorter reaction times, easier scale-up and lower cata- lyst loading than its batchwise counterpart (Scheme 1). Herein we present the, to the best of our knowledge, first example of homogeneous asymmetric sulfoxidation conducted in a microreactor which can rapidly (< 4 min) oxidize a wide range of sulfides with low catalyst loading (0.35 mol%) using environmen- tally friendly hydrogen peroxide which provides a val- uable approach to circumvent the known drawbacks of asymmetric sulfoxidation in traditional batch reac- tors. Moreover, direct scaling of the reaction to 5 g af- forded the corresponding sulfoxides in good yield and enantioselectivity within 20 min. Adv. Synth. Catal. 2016, 358, 667 – 671 # 2016 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim 667 UPDATES