Organic Chemistry Portal
Organic Chemistry Highlights

Monday, September 22, 2014
Douglass F. Taber
University of Delaware

Flow Chemistry: The Direct Production of Drug Metabolites

Several overviews of flow chemistry appeared recently. Katherine S. Elvira and Andrew J. deMello of ETH Zürich wrote (Nature Chem. 2013, 5, 905. DOI: 10.1038/nchem.1753) on microfluidic reactor technology. D. Tyler McQuade of Florida State University and the Max Planck Institute Mühlenberg reviewed (J. Org. Chem. 2013, 78, 6384. DOI: 10.1021/jo400583m) applications and equipment. Jun-ichi Yoshida of Kyoto University focused (Chem. Commun. 2013, 49, 9896. DOI: 10.1039/C3CC44709J) on transformations that cannot be effected under batch conditions. Detlev Belder of the Universität Leipzig reported (Chem. Commun. 2013, 49, 11644. DOI: 10.1039/C3CC46548A) flow reactions coupled to subsequent micropreparative separations. Leroy Cronin of the University of Glasgow described (Chem. Sci. 2013, 4, 3099. DOI: 10.1039/C3SC51253C) combining 3D printing of an apparatus and liquid handling for convenient chemical synthesis and purification.

Many of the reactions of organic synthesis have now been adapted to flow conditions. We will highlight those transformations that incorporate particularly useful features. One of those is convenient handling of gaseous reagents. C. Oliver Kappe of the Karl-Franzens-University Graz generated (Angew. Chem. Int. Ed. 2013, 52, 10241. DOI: 10.1002/anie.201303528) diimide in situ to reduce 1 to 2. David J. Cole-Hamilton immobilized (Angew. Chem. Int. Ed. 2013, 52, 9805. DOI: 10.1002/anie.201302718) Ru DuPHOS on a heteropoly acid support, allowing the flow hydrogenation of neat 3 to 4 in high ee. Steven V. Ley of the University of Cambridge added (Org. Process Res. Dev. 2013, 17, 1183. DOI: 10.1021/op400152r) ammonia to 5 to give the thiourea 6. Alain Favre-Réguillon of the Conservatoire National des Arts et Métiers used (Org. Lett. 2013, 15, 5978. DOI: 10.1021/ol401273k) oxygen to directly oxidize the aldehyde 7 to the carboxylic acid 8.

Professor Kappe showed (J. Org. Chem. 2013, 78, 10567. DOI: 10.1021/jo401945r) that supercritical acetonitrile directly converted an acid 9 to the nitrile 10. Hisao Yoshida of Nagoya University added (Chem. Commun. 2013, 49, 3793. DOI: 10.1039/C3CC41068D) acetonitrile to nitrobenzene 11 to give the para isomer 12 with high regioselectively. Kristin E. Price of Pfizer, Inc. Groton coupled (Org. Lett. 2013, 15, 4342. DOI: 10.1021/ol4018134) 13 to 14 with very low loading of the Pd catalyst. Andrew Livingston of Imperial College demonstrated (Org. Process Res. Dev. 2013, 17, 967. DOI: 10.1021/op400073p) the utility of nanofiltration under flow conditions to minimize Pd levels in a Heck product. Andreas Kirschning reported (Angew. Chem. Int. Ed. 2013, 52, 9813. DOI: 10.1002/anie.201302239) on high frequency inductive coupling for the flow thermal rearrangement of 16 to 17.

Rapid heating was also the key to the Kondrat’eva assembly of the pyridine 20 from 18 and cyclopentene 19 reported (Org. Lett. 2013, 15, 3550. DOI: 10.1021/ol4013525) by Robert Britton of Simon Fraser University and Rainer E. Martin of Roche Basel. A flow technique allowed (Org. Process Res. Dev. 2013, 17, 1137. DOI: 10.1021/op400050n) Kai Guo of the Nanjing University of Technology to optimize the preparation and separation of epoxidized soybean oil, represented here by linoleic acid 21. Maurizio Benaglia and Alessandra Puglisi of the Università degli Studi di Milano passed (Org. Lett. 2013, 15, 3590. DOI: 10.1021/ol401390z) 23 and 24 through a column packed with an organocatalyst to give 25 in substantial ee. Srinivas Gangula employed (Org. Process Res. Dev. 2013, 17, 1272. DOI: 10.1021/op300325f) a flow technique to optimize the two step coupling of 26 with 27 followed by oxidation to give 28.

Gregory P. Roth of the Sanford-Burnham Medical Research Institute took advantage (ACS Med. Chem. Lett. 2013, 4, 1119. DOI: 10.1021/ml400316p) of the ease with which electrolysis is carried out under flow conditions to oxidize Diclofenac 29 to its metabolites. With added NaHSO3, the product was the phenol 30. When glutathione was added after the oxidation, the product was the adduct 31.

D. F. Taber, Org. Chem. Highlights 2014, September 22.