Organic Chemistry Portal
Organic Chemistry Highlights

Monday, January 12, 2015
Douglass F. Taber
University of Delaware

Developments in Flow Chemistry

Klavs S. Jensen of MIT showed (Angew. Chem. Int. Ed. 2014, 53, 470. DOI: 10.1002/anie.201306468) that "batch" kinetics could be developed in flow by online IR analysis and continuous control. Professor Jensen also demonstrated (Org. Process Res. Dev. 2014, 18, 402. DOI: 10.1021/op400294z) the continuous flow production of an active pharmaceutical product, the direct renin inhibitor aliskiren, over two steps and two crystallizations, starting from two advanced intermediates. Michael Werner and Rainer E. Martin of Hoffmann-La Roche AG Basel combined (Angew. Chem. Int. Ed. 2014, 53, 1704. DOI: 10.1002/anie.201309301) flow synthesis with a flow-based bioassay to develop structure-activity relationships for a series of β-secretase inhibitors.

Carlos Mateos of Lilly S. A. and C. Oliver Kappe of the University of Graz used (J. Org. Chem. 2014, 79, 223. DOI: 10.1021/jo402409k) flow photolysis to promote the bromination of 1 to 2. Alessandro Palmieri of the University of Camerino and Stefano Protti of the University of Pavia added (Adv. Synth. Catal. 2014, 356, 753. DOI: 10.1002/adsc.201300859) the aldehyde 3 to the acceptor 4 to give, after in-flow reduction, the lactone 5. Peter H. Seeberger of the Max Planck Institute Mühlenberg showed (Org. Lett. 2014, 16, 1794. DOI: 10.1021/ol500530q) that the tumbling action of flow photolysis made the production of 7 by the unlinking of 6 from the polymer bead particularly efficient.

Enzymes can also be used under flow conditions. Jörg Pietruszka of the Heinrich-Heine-Universität Düsseldorf employed (Adv. Synth. Catal. 2014, 356, 1007. DOI: 10.1002/adsc.201300990) commercial laccase to prepare 10 by coupling 8 with 9.

Gas-liquid mixing under flow conditions can also be effective. Núria López of ICIQ Catalonia and Javier Pérez-Ramírez of ETH Zürich developed (Chem. Eur J. 2014, 20, 5926. DOI: 10.1002/chem.201304795) conditions for the selective semihydrogenation of an alkyne 11 to the cis alkene 12. Jun-ichi Yoshida of Kyoto University trapped (Chem. Eur J. 2014, 20, 7931. DOI: 10.1002/chem.201402520) the intermediate organolithium from 13 with CO2 to give a carboxylate that was carried on to the purifiable O-Su ester 14, ready for further coupling. Timothy F. Jamison, also of MIT, prepared (Angew. Chem. Int. Ed. 2014, 53, 3353. DOI: 10.1002/anie.201310572) the amino phenol by adding the chloromagnesium amide from 16 to the intermediate benzyne, then oxidizing the product with air. Professor Kappe used (J. Org. Chem. 2014, 79, 1555. DOI: 10.1021/jo402849z) in situ generated diazomethane to convert the acid 18 to the chloroketone 19.

Thomas Wirth of Cardiff University combined (Synlett 2014, 25, 871. DOI: 10.1055/s-0033-1340835) the diazo ester 21 generated in flow, with the aldehyde 20 to give an intermediate that was transformed in a third flow step into into the β-keto ester 22. Michael A. McGuire of GlaxoSmithKline and Michael G. Organ of York University found (Chem. Eur. J. 2014, 20, 6603. DOI: 10.1002/chem.201402092) that the diazonium salt could be generated from 23 and in situ coupled with 24 under Pd catalysis to give the ester 25. André B. Charette of the Université de Montréal effected (Synlett 2014, 25, 1409. DOI: 10.1055/s-0033-1338634) hydrolysis of the iodide 26 to the phenol, and then in a subsequent flow step benzylation of the phenoxide, leading to 27. Anastatios Polyzos of CSIRO and David W. Lupton of Monash University reduced the acid chloride 28 to the aldehyde 30 (ACS Catal. 2014, 4, 2070. DOI: 10.1021/cs5004917) by first forming the thioester with the mercaptan 29. Oliver Trapp of the Ruprecht-Karls-Universität Heidelberg cyclized (Adv. Synth. Catal. 2014, 356, 2081. DOI: 10.1002/adsc.201301182) 31 to 32 using an improved immobilized Grubbs Ru catalyst.

One of the great advantages of flow synthesis is the ease with which electrochemical transformations can be included. This is illustrated by the reductive cyclization of 33 to 34, reported (Tetrahedron Lett. 2014, 55, 1299. DOI: 10.1016/j.tetlet.2013.12.104) by Mitsuhiro Okimoto of the Kitami Institute of Technology.

D. F. Taber, Org. Chem. Highlights 2015, January 12.