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Regiodivergent Nucleophilic Fluorination under Hydrogen Bonding Catalysis: A Computational and Experimental Study

Matthew A. Horwitz*, Alexander B. Dürr*, Konstantinos Afratis, Zijun Chen, Julia Soika, Kirsten E. Christensen, Makoto Fushimi, Robert S. Paton* and Véronique Gouverneur*

*University of Oxford, Oxford OX1 3TA, U.K.; Colorado State University, Fort Collins, CO 80528, USA, Email: mah9122gmail.com, alexanderbdurr.chemistrygmail.com, robert.patoncolostate.edu, veronique.gouverneurchem.ox.ac.uk

M. A. Horwitz, A. B. Dürr, K. Afratis, Z. Chen, J. Soika, K. E. Christensen, M. Fushimi, R. S. Paton, V. Gouverneur, J. Am. Chem. Soc., 2023, 145, 9708-9717.

DOI: 10.1021/jacs.3c01303



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Abstract

The charge density of fluoride with a hydrogen-bond donor urea catalyst directly influences the kinetic regioselectivity in the fluorination of dissymmetric aziridinium salts with aryl and ester substituents. These findings offer a route to access enantioenriched fluoroamine regioisomers from a single chloroamine precursor.


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proposed reaction pathway



General Procedure for α-Fluorination with CsF

A 3.5 mL vial equipped with a stir bar was sequentially charged with the amino chloride substrate (0.25 mmol, 1.0 equiv.) and CsF (0.75 mmol, 3.0 equiv.) before adding MeCN (1.0 mL, 0.25 M). The reaction was placed in the center of a stir plate at a height of 2 cm and was stirred at 1200 rpm at 40 °C (in an oil bath) for 24 h. Et2O was used to flush the reaction through a short plug of silica gel and the filtrate was concentrated in vacuo. The crude material thusly obtained was purified using flash column chromatography.

General Procedure for β-Fluorination with KF under Hydrogen Bonding Phase Transfer Catalysis (HBPTC)

A 3.5 mL vial equipped with a stir bar was sequentially charged with the amino chloride substrate (0.25 mmol, 1.0 equiv.), Schreiner's urea (0.05 mmol, 20 mol %), and KF (5.0 equiv.) before adding 1,2-difluorobenzene (1.0 mL, 0.25M). The reaction was placed in the center of a stir plate at a height of 2 cm and was stirred at 1200 rpm at the temperature listed in an oil bath for 24 h. Et2O was used to flush the reaction through a short plug of silica gel and the filtrate was concentrated in vacuo. The crude material thusly obtained was purified using flash column chromatography. Note: In some cases, removal of the catalyst from the desired β-fluorinated product proved challenging. In these instances, the following procedure was applied. By complexing the residual catalyst with the acetate anion, chromatographic separation between the residual catalyst and the desired product improved.

Catalyst removal procedure (optional): After flushing the reaction through a silica plug, the crude reaction mixture was concentrated as above. The crude residue was dissolved in a small amount of DCM (~2 mL) and tetrabutylammonium acetate (0.5 equiv., 37.7 mg) was added. After stirring for 30 minutes at room temperature, the crude reaction mixture was concentrated once again and purified by flash column chromatography.


Key Words

1,2-fluoroamines, α-fluorocarboxylic acids, β-fluorocarboxylic acids, organocatalysis


ID: J48-Y2023