Multi-faceted reactivity of N-fluorobenzenesulfonimide (NFSI) under mechanochemical conditions: fluorination, fluorodemethylation, sulfonylation, and amidation reactions

In the search for versatile reagents compatible with mechanochemical techniques, in this work we studied the reactivity of N-fluorobenzenesulfonimide (NFSI) by ball milling. We corroborated that, by mechanochemistry, NFSI can engage in a variety of reactions such as fluorinations, fluorodemethylations, sulfonylations, and amidations. In comparison to the protocols reported in solution, the mechanochemical reactions were accomplished in the absence of solvents, in short reaction times, and in yields comparable to or higher than their solvent-based counterparts.


Milling equipment
Mechanochemical reactions were carried out using mixer mills (InSolido

Nuclear magnetic resonance (NMR) spectroscopy
NMR spectra were recorded on a VNMRS 600 spectrometer. Proton and carbon chemical shifts are reported in parts per million and are calibrated using the residual non-deuterated solvent signal (CDCl 3 ) as an internal reference. Fluorine NMR spectra were recorded on a Bruker Avance III HD 600 MHz Ascend spectrometer.

Powder X-ray diffraction (PXRD)
PXRD patterns were collected on a PanAlytical Aeris diffractometer (CuK α radiation and Ni filter) in Bragg-Brentano geometry using a zero-background sample holder.

In-situ monitoring by Raman spectroscopy
Laboratory in-situ Raman monitoring was performed using portable Raman system with a PDLD (now Necsel) BlueBox laser source with the excitation wavelength of 785 nm equipped with B&W-Tek fiber optic Raman BAC102 probe and coupled with S5 one OceanOptics Maya2000Pro spectrometer (with resolutions of 1 cm −1 or 3.5 cm −1 ). The probe was positioned about 1 cm under a reaction vessel on a moving stand, and laser was focused 1 mm inside of the inner vessel wall. Timeresolved in-situ Raman spectra were collected in an automated fashion using an in-house code in MATLAB. Subtraction of vessel contribution to Raman spectra was described elsewhere [2].

Mechanochemical reaction of 1c with NFSI
A mixture of 1c (0.148 mmol) and NFSI (1.0-2.0 equiv) was milled in a 2 mL Eppendorf tube with four ZrO 2 milling balls (350 mg in total mass) at 25-30 Hz for 3 h (see Figure S1). Similar product distribution was obtained when a mixture of 1c (0.59 mol) and NFSI (1.0-2.0 equiv) was milled in a stainless steel milling jar (15 mL of internal volume) using one milling ball (4.0 g) of the same material. After the milling was halted, the crude reaction mixture was immediately analyzed by PXRD, IR and NMR. Isolation of 2c and 2c'' was carried out by column chromatography on silica gel using mixtures of n-hexane and ethyl acetate as eluent (40:1 v/v to pure ethyl acetate).

Mechanochemical reaction of 3 with NFSI
A mixture of 3 (0.734 mmol) and NFSI (1.0 equiv) was milled in a stainless steel milling jar (15 mL of internal volume) using one stainless steel milling ball (4.0 g) of the same material at 30 Hz for 3 h. Isolation of 4a, 4b, and 4d was carried out by column chromatography on silica gel using mixtures of n-hexane and ethyl acetate as eluent (20:1 to 1:1 v/v).

Mechanochemical reaction of 5 with NFSI
A mixture of 5 (0.367 mmol), NFSI (2.0 equiv), and K 2 CO 3 (10 mol %) was milled in a stainless steel milling jar (15 mL of internal volume) using one stainless steel milling S6 ball (4.0 g) of the same material at 30 Hz for 3 h. The milling process was carried out in the absence of external heating or thermally assisted at 40 °C and 60 °C ( Figure S2). Isolation of 6 was carried out by column chromatography on silica gel using mixtures of n-hexane and ethyl acetate as eluent (10:1 to 6:1 v/v).