Batch and Flow Electrochemical Synthesis of Allyl Sulfones via Sulfonation of Allyl Trifluoroborates: A Robust, Regioselective, and Scalable Approach

This work describes the electrochemical synthesis of allyl sulfones via sulfonation of allyl trifluoroborates. The process involves a radical addition to the alkene followed by the elimination of the trifluoroborate...


General methods and commercial starting materials
Starting materials and solvents for the reactions were acquired from commercial sources (Acros Organics, Aldrich Chemical Co., Alfa Aesar, TCI Chemicals, Fluorochem and/or BLDpharm) unless otherwise specified.For thin layer chromatography (TLC), silica gel plates with fluorescence indicator 254 nm were used and compounds were visualized by irradiation with UV light and/or by treatment with a solution of potassium permanganate in water followed by heating.Flash column chromatography was performed using Geduran® Silica Gel 60 (0.040-0.063 nm).
Cyclohexane and diethyl ether for flash column chromatography were acquired from commercial sources and were used without previous purification.NMR spectra were acquired on a Bruker Avance 300 MHz spectrometer, running at 300 and 75 MHz for 1 H and 13 C, respectively.Chemical shifts (δ) are reported in ppm relative to residual solvent signals (CDCl3, 7.26 ppm for 1 H-NMR; 77.2 ppm for 13 C-NMR). 13C-NMR was acquired on a broad band decoupled mode.The following abbreviations are used to describe peak patterns when appropriate: s (singlet), bs (broad singlet), d (doublet), bd (broad doublet), t (triplet), q (quartet), p (pentet), h (heptet), m (multiplet), dd (doublet of doublets), ddd (doublet of doublets of doublets), dt (double of triplets), ddt (doublet of doublets of triplets), tt (triplet of triplets).
Electrospray ionization has been used for measuring the exact mass (indicated for each case):

HRMS (ESI) (Electrospray ionization mass spectroscopy) was acquired with an Agilent
Technologies 6120 Quadrupole LC/MS.In this technique, MassWorks software ver.4.0.0.0 (Cerno Bioscience) was used for the formula identification.MassWorks is a MS calibration software which calibrates for isotope profile as well as for mass accuracy, allowing highly accurate comparisons between calibrated and theoretical spectra. 1 All the electrodes and equipment (ElectraSyn 2.0) used for the batch electrochemical experiments were acquired from IKA.

General procedure A1: Synthesis sodium sulfinates 1n-o
Starting materials 1a-m were acquired from commercial sources.Sodium sulfinates 1n and 1o were prepared following a procedure described in the literature and spectra data are consistent with those reported. 2

General procedure A2: Synthesis of potassium allyltrifluoroborate salts
Starting material 2a was acquired from commercial sources.Potassium allyltrifluoroborate salts 2b-g were prepared following a modified procedure described in the literature: 3 To a solution of the corresponding allylboronic acid pinacol ester (1.0 equiv.) in methanol (2 mL/mmol) and acetonitrile (2 mL/mmol) was added a solution of KF (4.0 equiv.) in water (0.1 mL/mmol) and the mixture was stirred until complete dissolution.Then, L-(+)-tartaric acid (2.05 equiv.) in tetrahydrofuran (1.5 mL/mmol of allylboronic acid pinacol ester) was added dropwise and the resulting mixture was stirred for 1 hour at 40ºC.The reaction was cooled to room temperature and acetonitrile (5 mL/mmol of allylboronic acid pinacol ester) was added and stirred for 5 min.
Then, solids were filtered, and the solution was concentrated to dryness.Pentane was added to the oily mixture, and it was stirred and sonicated until the precipitation of the corresponding potassium allyltrifluoroborate salt 2. The salt was filtered and washed with pentane to give pure product 2. Spectra data of starting materials 2b-g are consistent with those reported in the literature. 3

General procedure B1: Electrochemical synthesis of allylsulfones
Sodium sulfinate 1 (0.1 mmol) and potassium allyltrifluoroborate 2 (0.25 mmol) were added to a 5 mL ElectraSyn vial.Acetonitrile (1.5 mL) and distilled water (1.5 mL) were added to the vial and it was stirred until solids were dissolved.Then, carbon graphite electrodes were fitted in the cap of the vial and it was closed.The reaction was set at constant current (2.5 mA) for 3 hours.
After that time, the solution was transfer to a round bottom flask, electrodes and vial were rinsed with dichloromethane and then concentrated to dryness.Diethyl ether was added to the flask in order to dissolve the product and then the mixture was filtered and concentrated under reduce pressure.The residue was purified by manual flash column chromatography using the eluents indicated in each case to give final product 3.

General procedure B2: Electro-flow synthesis of allylsulfones
Sodium sulfinate 1 (0.1 mmol) and potassium allyltrifluoroborate 2 (0.25 mmol) were added to a vial equipped with a septum.A 1:1 mixture of acetonitrile: water (4 mL) was added to the vial, and the solution was homogenised by sonication in an ultrasound bath.The above prepared solution is pumped through the system at 150 µL min -1 (4 minutes in the electrochemical cell, 17.3 minutes in all the system).Two carbon graphite foils were used as electrodes, a constant current of 2.5 mA (consisting with a potential close to 2.5 V) was applied to the reaction and after 3 hours recirculating ( ̴ 42 minutes in the electrochemical cell), the flow system was washed with a 1:1 mixture of acetonitrile: water (2 mL) and everything was collected in a 25 mL roundbottom flask.Solvents were removed under reduced pressure, then, the residue was dissolved in water (5 mL) and extracted with ethyl acetate (3 x 5 mL).Organic phase was collected and concentrated to dryness.The residue was purified by manual flash column chromatography using the eluents indicated in each case to give final product 3.
The reaction was scaled up to 1.0 mmol.Procedure B1 was followed using a 10 mL ElectraSyn vial as 4 mL of acetonitrile and 4 mL of distilled water were used as solvents.The reaction was carried out at 5 mA for 16 hours.After workup and purification as described above, 3a (62% yield) was obtained as a colourless oil that solidifies upon time.
The reaction was carried out under electro-flow conditions.Procedure B2 was followed.After workup and purification as described above, 3a (92% yield) was obtained as a colourless oil.Spectra data are consistent with those reported in the literature. 5
The reaction was carried out under electro-flow conditions.Procedure B2 was followed.After workup and purification as described above, 3e (56% yield) was obtained as a colourless oil.Spectra data are consistent with those reported in the literature. 4
The reaction was carried out under electro-flow conditions.Procedure B2 was followed.After workup and purification as described above, 3f (59% yield) was obtained as a colourless oil.
The reaction was carried out under electro-flow conditions.Procedure B2 was followed.After workup and purification as described above, 3j (43% yield) was obtained as a colourless oil.
The reaction was carried out under electro-flow conditions.Procedure B2 was followed.After workup and purification as described above, 3l (35% yield) was obtained as a colourless oil.Spectra data are consistent with those reported in the literature. 8
Spectra data are consistent with those reported in the literature. 9
The reaction was carried out under electro-flow conditions.Procedure B2 was followed.After workup and purification as described above, 3o (28% yield) was obtained as a white solid.Spectra data are consistent with those reported in the literature. 10
The reaction was scaled up to 1.0 mmol.Modified procedure B1 was followed using a 10 mL ElectraSyn vial as 6.7 mL of acetonitrile and 1.3 mL of distilled water were used as solvents.Ni foam was used as counterelectrode and the reaction was carried out at 5 mA during 16 hours.
After workup and purification as described above, 3q (71% yield) was obtained as a colourless oil that solidifies upon time.
The reaction was carried out under electro-flow conditions.Procedure B2 was followed.After workup and purification as described above, 3q (65% yield) was obtained as a colourless oil.

Discarted mechanism
If a radical-radical recombination mechanism (Scheme S1) is taking place due to the oxidation of both substrates (sodium sulfinates (1) and potassium allyltrifluoroborate salts (2)) at the anode, the reactivity through the most stabilized position of the allylic radical intermediate should be observed experimentally.However, only formation of product 3q was observed when substrate 2c was subjected to the standard reaction condition.The same observation was achieved in the case of substrate 2g, product 3u was obtained in 30% yield as sole product.Scheme S1.Radical-radical recombination mechanism.

Cyclic Voltammetry
CVs were performed under nitrogen atmosphere at room temperature, using 0.25 M tetrabutylammonium hexafluorophosphate (TBAPF6) as electrolyte solution in acetonitrile (CH3CN) or dimethylformamide (DMF).Measurements were carried out by using a commercially available IKA Electrasyn 2.0 Package.A standard IKA three-electrode vial was used as well as the commercially available IKA CV Package.Potentials were referred to Ag/AgCl, KCl 3.0 M reference electrode in water, and measured potentials were calibrated using an internal Fc/Fc+ standard.The working electrode used to perform the experiments was a glassy carbon electrode.The counterelectrode consisted of a Pt electrode.CVs are consistent with those reported in the literature. 16

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Vapourtec Setup The electrochemical-flow experiments were carried out using a commercially available Vapourtec Ion Electrochemical Reactor and Controller on an E-series Vapourtec equipment.The system (Figure S1), consist of a pump, an electrochemical reactor, and a 20 psi Back Pressure Regulator (BPR: 20 psi) at its ending which was connected to the reaction vial for its recirculation.Materials (Figure S2): the electrodes used were Graphite (Flexible Graphite Plain obtained from Vapourtec Ltd.) and Graphite (Flexible Graphite with 3 holes obtained from Vapourtec Ltd.).The electrodes (5 x 5 cm 2 ) are separated by a 0.5 mm membrane with a channel volume of 0.6 mL and an exposed electrode surface area of 12 cm 2 (each electrode).A 2 mm electrode spacer was used between the side of the carrier with 2 fluid hole and the plain electrode.

Figure S3 .
Figure S3.CV of sodium sulfinate (1a) (blue).It was measured in DMF (0.25 M TBAPF6) at 100 mV/s using glassy carbon electrode as WE, Ag/AgCl as RE and Pt as CE.

Figure
Figure S4.CV of potassium allyltrifluoroborate (2a) (orange).It was measured in CH3CN (0.25 M TBAPF6) at 100 mV/s using glassy carbon electrode as WE, Ag/AgCl as RE and Pt as CE.