Organic Chemistry Portal
Organic Chemistry Highlights

Monday, March 28, 2016
Douglass F. Taber
University of Delaware

Flow Methods in Organic Synthesis

Steven V. Ley of the University of Cambridge described (Angew. Chem. Int. Ed. 2015, 54, 144. DOI: 10.1002/anie.201409356) a systems approach toward an intelligent and self-controlling platform for integrated continuous reaction sequences. Klavs F. Jensen of MIT reported (Chem. Commun. 2015, 51, 8916. DOI: 10.1039/C5CC02051D) an oscillatory three-phase flow reactor for studies of bi-phasic catalytic reactions, and D. Belder of the Universität Leipzig discussed (Chem. Commun. 2015, 51, 8588. DOI: 10.1039/C4CC09595B) on-chip monitoring of chemical syntheses in microdroplets with surface-enhanced Raman spectroscopy.

Shu Kobayashi of the University of Tokyo prepared (Nature 2015, 520, 329. DOI: 10.1038/nature14343) 3 by flowing 1 and 2 together through a silica-supported amine with added CaCl2. Huw M. L. Davies of Emory University and Christopher W. Jones of Georgia Tech assembled (Angew. Chem. Int. Ed. 2015, 54, 6470. DOI: 10.1002/anie.201500841) 6 by flowing 4 and 5 through a supported Rh catalyst.

Photolysis is readily applied in flow. Akichika Itoh of Gifu Pharmaceutical University showed (Synlett 2015, 26, 412. DOI: 10.1055/s-0034-1379698) that O2, a potentially dangerous oxidant in batch applications, could be used for the controlled oxidation of 7 to 8. Miguel A. Garcia-Garibay of UCLA effected (J. Am. Chem. Soc. 2015, 137, 1679. DOI: 10.1021/ja512524j) photolysis of 9 in the solid state, leading to 10 in high ee.

Renzo Luisi of the University of Bari generated (Adv. Synth. Catal. 2015, 357, 21. DOI: 10.1002/adsc.201400747) the unstable chloromethyllithium from 12, adding it in flow to 11 to prepare 13. Jun-ichi Yoshida of Kyoto University deprotonated (Chem. Lett. 2015, 44, 214. DOI: 10.1246/cl.140980) 15 in flow, adding the resulting anion to 14 to give 16. Thomas Wirth of Cardiff University purified (Chem. Eur. J. 2015, 21, 7016. DOI: 10.1002/chem.201500416) the diazo ester prepared from 17 by liquid-liquid extraction in flow, then coupled it in flow with 18 to make 19. Christopher J. Moody of the University of Nottingham developed (Chem. Eur. J. 2015, 21, 4576. DOI: 10.1002/chem.201500118) a solid phase reagent for oxidizing the hydrazone 20 to the diazo ester, then coupled it with 21, leading to 22. Beate Koksch of the Freie Universität Berlin and Peter H. Seeberger of the Max-Planck Institute for Colloids and Surfaces in Potsdam oxidized (Eur. J. Org. Chem. 2015, 3036. DOI: 10.1002/ejoc.201500300) the fluorinated amine 23, added cyanide, and hydrolyzed the product to the amino acid 24, all in flow. Richard J. Whitby of the University of Southampton generated (Eur. J. Org. Chem. 2015, 1491. DOI: 10.1002/ejoc.201403603) the ketene from 25 by pyrolysis in flow in the presence of the amine 26, leading to 27.

Jörg Sedelmeier of Novartis Basel assembled (Org. Process Res. Dev. 2015, 19, 551. DOI: 10.1021/acs.oprd.5b00058) the oral antidiabetic DPP-4 inhibitor Vildagliptin (32) over three steps in flow. The proline amide 28 was acylated with the acid chloride 29 to give 30, that was dehydrated with the Vilsmeier reagent, then coupled with 31 to give 32.

Timothy F. Jamison of MIT prepared (Angew. Chem. Int. Ed. 2015, 54, 983. DOI: 10.1002/anie.201409093) Ibuprofen 36 over three steps in flow. Isobutylbenzene 33 was acylated with the acid chloride 34 to give 35. Oxidation with I-Cl led to the methyl ester, that was saponified in flow to 36. The dwell time in the reactor was just three minutes.

D. F. Taber, Org. Chem. Highlights 2016, March 28.