Organic Chemistry Portal
Organic Chemistry Highlights

Monday, January 23, 2017
Douglass F. Taber
University of Delaware

Flow Methods in Organic Synthesis

Electrolysis is readily practiced in flow. Siegfried R. Waldvogel of University Mainz reduced (Org. Process Res. Dev. 2015, 19, 1428. DOI: 10.1021/acs.oprd.5b00272) the adduct 1 from dibromocarbene addition to the cyclopropane 2. Richard C. D. Brown of the University of Southampton oxidized (Org. Lett. 2015, 17, 3290. DOI: 10.1021/acs.orglett.5b01459) the aldehyde 3 in the presence of benzyl alcohol and a thiazolium catalyst to the ester 4. More recently, Professor Brown described (Org. Lett. 2016, 18, 1198. DOI: 10.1021/acs.orglett.6b00339) a similar oxidation in the presence of an amine to form the amide.

There are particular technical challenges to electrochemically-driven reactions. Professor Waldvogel (Org. Process Res. Dev. 2016, 20, 26. DOI: 10.1021/acs.oprd.5b00377), Robert A. Green of the University of Southampton (Org. Process Res. Dev. 2015, 19, 1424. DOI: 10.1021/acs.oprd.5b00260) and Craig E. Banks and Alan M. Jones of Manchester Metropolitan University (Tetrahedron Lett. 2015, 56, 6863. DOI: 10.1016/j.tetlet.2015.10.090) have addressed these in detail.

Photochemistry is also readily practiced in flow. Aaron B. Beeler of Boston University optimized (Angew. Chem. Int. Ed. 2015, 54, 11521. DOI: 10.1002/anie.201504454) the dimerization of 5 to cyclobutane 6. Stefano Protti and Maurizio Fagnoni of the University of Pavia activated (Adv. Synth. Catal. 2016, 358, 1164. DOI: 10.1002/adsc.201600019) the aryl chloride 7 to give an intermediate that coupled with the allyl silane 8 to give 9. Pengfei Li of Xi'an Jiaotong University used (Chem. Sci. 2016, 7, 3676. DOI: 10.1039/C5SC04521E) the same approach to borylate 10 to 11. Oscar de Frutos of Lilly S. A. and C. Oliver Kappe of the University of Graz oxidized (Chem. Eur. J. 2015, 21, 12894. DOI: 10.1002/chem.201502357) 13 to an intermediate that they then coupled with 12 under photochemical promotion to give 14.

Sulfonyl azides, useful for diazo transfer, are high energy materials. Stuart G. Collins and Anita R. Maguire demonstrated (Org. Biomol. Chem. 2016, 14, 3423. DOI: 10.1039/C6OB00246C) that a commercial sulfonyl chloride 15 could be converted in flow to the sulfonyl azide, that could then react with the keto ester 16 to give the diazo ketone 17. Steven V. Ley of the University of Cambridge oxidized (Nature Chem. 2016, 8, 360. DOI: 10.1038/nchem.2439) 18 to the corresponding aryl diazomethane, that was then coupled directly with the boronic acid 19 to give, after protection, the boronate 20. The authors also described several other applications of the initially formed boronic acids.

Immobilized enzymes work well in flow. László Poppe of the Budapest University of Technology and Economics coupled (Adv. Synth. Catal. 2016, 358, 1608. DOI: 10.1002/adsc.201500902) 21 with 22 under epimerizing conditions to give 23. Professor Ley used (Synlett 2016, 27, 262. DOI: 10.1055/s-0035-1560644) one enzyme to liberate HCN from 25, and another to add it to the aldehyde 24 to give, after protection, the ester 26.

Flow methods can be useful for handling delicate intermediates. The diazonium salt derived from 27 rapidly decomposes to the phenol. Weike Su of the Zhejian University of Technology was able in flow to couple (Org. Process Res. Dev. 2016, 20, 774. DOI: 10.1021/acs.oprd.6b00023) 27 with sodium thiomethoxide to give 28. Andreas Kirschning of Leibniz Universitat Hannover simplified (Chem. Eur. J. 2016, 22, 3044. DOI: 10.1002/chem.201504409) the purification of the product 31, from the coupling of 29 with 30, by flowing the reaction mixture onto silica gel. After an ethyl acetate wash to remove impurities, 31 was taken off with MeOH in CH2Cl2. Moist ethyl acetate (J. Org. Chem. 2010, 75, 5737. DOI: 10.1021/jo100890s) would probably have worked also.

The intermediate 34 is difficult to handle, as it spontaneously oxidizes to the indole. Andrew R. Bogdan of Abbvie showed (Org. Lett. 2016, 18, 1732. DOI: 10.1021/acs.orglett.6b00378) that in flow, the coupling of 32 with 33, high temperature deprotection to 34 and coupling with 35 led efficiently to 36.

D. F. Taber, Org. Chem. Highlights 2017, January 23.