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Electrochemical Nozaki-Hiyama-Kishi Coupling: Scope, Applications, and Mechanism

Yang Gao, David E. Hill, Wei Hao, Brendon J. McNicholas, Julien C. Vantourout, Ryan G. Hadt, Sarah E. Reisman*, Donna G. Blackmond* and Phil S. Baran*

*Caltech, Pasadena, California 91125; Scripps Research, 10550 N. Torrey Pines R., La Jolla, California 92037, United States, Email: reismancaltech.edu, blackmonscripps.edu, pbaranscripps.edu

Y. Gao, D. E. Hill, W. Hao, B. J. McNicholas, J. C. Vantourout, R. G. Hadt, S. E. Reisman, D. G. Blackmond, P. S. Baran, J. Am. Chem. Soc., 2021, 143, 9478-9488.

DOI: 10.1021/jacs.1c03007 (free Supporting Information)


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Abstract

A carefully optimized electroreductive procedure enables a more sustainable Nozaki-Hiyama-Kishi coupling, even in an asymmetric fashion on highly complex medicinally relevant systems. Redox-active esters can be used as substrates in a decarboxylative Nozaki-Hiyama-Kishi coupling with low loadings of Cr when conventional chemical techniques fail.

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proposed mechanism



Preparation of CrCl2 solution in DMF (0.08 M):

A screw-capped culture tube was charged with CrCl2 (30 mg, 0.24 mmol) in the glovebox. The tube was removed from the glovebox and placed under an argon balloon, whereupon degassed DMF (3 mL) was added via a syringe. The resulting mixture was sonicated until a homogeneous green solution was obtained.

Procedure for the electrochemical Nozaki-Hiyama-Kishi reaction:

An ElectroSyn vial (5 mL) with a magnetic stir bar was charged with NiCl2·glyme (0.9 mg, 0.004 mmol, 2 mol%), 2,9-dibutyl-1,10-phenanthroline (1.8 mg, 0.006 mmol, 3 mol%), aldehyde (0.2 mmol, 1.0 equiv), alkenyl bromide (0.4 mmol, 2.0 equiv), Cp2ZrCl2 (29 mg, 0.1 mmol, 0.5 equiv), and TBAB (0.1 M, 80 mg). The ElectroSyn vial cap equipped with anode (aluminum) and cathode (nickel foam) was inserted into the mixture. The vial was then evacuated, and backfilled with an argon balloon for three cycles. [Note: volatile aldehyde and alkenyl bromide should be added after this step.] CrCl2 solution in DMF (0.5 mL, 0.04 mmol, 20 mol%) and additional DMF (2.0 mL) were added to the vial via syringe. The ElectraSyn was set up as follows: New exp. > Constant voltage > 2 V > No ref. electrode > Total charge > 0.2 mmol, 4 F/mol > No alternating polarity > Start. After the reaction stopped, the EletraSyn vial cap was removed and electrodes were rinsed with EtOAc. Water was added, and the resulting mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography or preparative thin-layer chromatography to furnish the desired product.


Key Words

Nozaki-Hiyama-Kishi coupling, electrochemistry, chromium(II)


ID: J48-Y2021