Organic Chemistry Portal
Organic Chemistry Highlights

Monday, March 25, 2013
Tristan H. Lambert
Columbia University

Flow Chemistry

Although photocatalytic chemistry has been the subject of intense interest recently, the rate of these reactions is often slow due to the limited penetration of light into typical reaction media. Peter H. Seeberger at the Max-Planck Institute for Colloids and Surfaces in Potsdam and the Free University of Berlin showed (Chem. Sci. 2012, 3, 1612. DOI: 10.1039/C2SC01016J) that Ru(bpy)32+ catalyzed reactions such as the reduction of azide 1 to 2 can be achieved in as little as 1 min residence time using continuous flow, as opposed to the 2 h batch reaction time previously reported. The benefits of flow on a number of strategic photocatalytic reactions, including the coupling of 3 and 4 to produce 5, was also demonstrated (Angew. Chem. Int. Ed. 2012, 51, 4144. DOI: 10.1002/anie.201200961) by Corey R. J. Stephenson at Boston University and Timothy F. Jamison at MIT. In this case, a reaction throughput of 0.914 mmol/h compares favorably with 0.327 mmol/h for the batch reaction.

Prof. Seeberger has also reported (Angew. Chem. Int. Ed. 2012, 51, 1706. DOI: 10.1002/anie.201107446) a continuous-flow synthesis of Artemisinin 7, a highly effective antimalarial drug, starting from dihydroartemisinic acid 6. The conversion occurs by a sequence of photochemical oxidation with singlet oxygen, acidic Hock cleavage of the O-O bond, and oxidation with triplet oxygen, a process calculated to be capable of furnishing up to 200 g/day per reactor. A scalable intramolecular [2+2] photocycloaddition of 8 to produce 9 was reported (Tetrahedron Lett. 2012, 53, 1363. DOI: 10.1016/j.tetlet.2012.01.010) by Matthias Nettekoven of Hoffman-La Roche in Basel, Switzerland.

Stephen L. Buchwald at MIT developed (Angew. Chem. Int. Ed. 2012, 51, 5355. DOI: 10.1002/anie.201202221) a flow process for the enantioselective β-arylation of ketones that involved lithiation of aryl bromide 10, borylation, and rhodium-catalyzed conjugate addition to cycloheptenone. For continuous flow production of enantioenriched alcohols like 14, Miquel A. Pericás of the Institute of Chemical Research of Catalonia developed (Org. Lett. 2012, 14, 1816. DOI: 10.1021/ol300415f) the robust polystyrene-supported aminoalcohol 13 for diethylzinc addition to aldehydes.

Prof. Jamison found (Org. Lett. 2012, 14, 568. DOI: 10.1021/ol2031872) that flow chemistry provides a convenient and reliable solution to the reduction of esters to aldehydes with DIBALH (e.g. 15 to 16) that occurs rapidly and without the usual problem of overreduction. Prof. Jamison leveraged (Org. Lett. 2012, 14, 2465. DOI: 10.1021/ol300722e) this system for a telescoped reduction-olefination sequence, which allowed for the rapid conversion of 17 to 18 in a single flow operation.

The problems associated with the generation of diazomethane on a large scale make the prospect of continuous-flow generation of this reagent particularly attractive. Michele Maggini at the University of Padova in Italy and Pierre Woehl, now at Merck Millipore, developed (Org. Process Res. Dev. 2012, 16, 1146. DOI: 10.1021/op200110a) such a process, which allows for the production of up to 19 mol/day of diazomethane from N-methyl-N-nitrosourea 19. A synthesis of hydrazine 21 by reduction of in situ generated diazonium salts was achieved (Tetrahedron 2011, 67, 10296. DOI: 10.1016/j.tet.2011.09.146) by Duncan L. Browne at the University of Cambridge using microfluidic chip technology.

One significant advantage of flow techniques is that they can allow for the generation and use of otherwise unstable species that would be difficult or impossible to handle in batch reactions. Jun-ichi Yoshida at Kyoto University found (Tetrahedron Lett. 2012, 53, 1397. DOI: 10.1016/j.tetlet.2012.01.019) that N-tosylaziridine 22 could be lithiated and reacted with methyl iodide to produce the tricyclic 23. The flow reactions could be run as high as 0°C while batch reactions required much lower temperatures (-78 °C).

Finally, C. Oliver Kappe at the University of Graz in Austria conducted (J. Org. Chem. 2012, 77, 2463. DOI: 10.1021/jo3001645) the flash flow pyrolysis of 24 to produce 25 in a high temperature, high flow reactor. The use of flow for reactions traditionally accomplished by flash vacuum pyrolysis should prove to be significantly more scalable.

T. H. Lambert, Org. Chem. Highlights 2013, March 25.