One-pot multistep mechanochemical synthesis of fluorinated pyrazolones

Solventless mechanochemical synthesis represents a technique with improved sustainability metrics compared to solvent-based processes. Herein, we describe a methodical process to run one solventless reaction directly into another through multistep mechanochemistry, effectively amplifying the solvent savings. The approach has to consider the solid form of the materials and compatibility of any auxiliary used. This has culminated in the development of a two-step, one-jar protocol for heterocycle formation and subsequent fluorination that has been successfully applied across a range of substrates, resulting in 12 difluorinated pyrazolones in moderate to excellent yields.


S2
General methods 1 H, 19 F and 13 C NMR spectra were obtained on Bruker 400 Ultrashield TM and Bruker Ascend TM 500 MHz spectrometers with chloroform-d as deuterated solvent. The obtained chemical shifts; δ, are reported in ppm and are referenced to the residual solvent signal.
Spin-spin coupling constants; J, are given in Hz.
High resolution mass spectral (HRMS) data were obtained on a Thermo Scientific LTQ Orbitrap XL by the EPSRC UK National Mass Spectrometry Facility at Swansea University or on a Waters MALDI-TOF mx in Cardiff University.
Infrared spectra were recorded on a Shimadzu IR-Affinity-1S FTIR spectrometer.
Melting points were measured using a Gallenkamp apparatus and are reported uncorrected.
The ball mill used was a Retsch MM 400 mixer mill. Unless otherwise stated, mechanochemical reactions were performed in 10 mL stainless steel jars with one stainless steel ball of mass 4 g.
All chemicals were obtained from commercial sources and used without further purification unless stated otherwise. Dry THF was obtained from a solvent purification system.

Synthesis of β-ketoesters
General procedure (GP1) Following a literature procedure 1 : to a suspension of NaH (1.2 g, 30 mmol, 60% in mineral oil) in dry THF (10 mL) was added diethyl carbonate (4.85 mL, 40 mmol) in oven-dried glassware under N 2 . A solution of the corresponding ketone (10 mmol) in dry THF (5 mL) was added slowly and the reaction mixture heated under reflux for 6 hours. The reaction mixture was quenched with glacial acetic acid (1 mL) and HCl (10%, 20 mL). The aqueous phase was extracted with ethyl acetate (3 × 10 mL) and the combined organic phase washed with saturated sodium hydrogen carbonate (10 mL), water (10 mL) and brine (10 mL). The combined organic phase was dried (MgSO 4 ), filtered and the solvent removed under reduced pressure to yield the crude product. This was purified by flash column chromatography on silica gel (gradient elution EtOAc in petroleum ether (0-25%)). To a 10 mL stainless steel milling jar was added the β-ketoester (1 mmol), the hydrazine (1 mmol), sodium chloride (six times the total mass of reagents) and glacial acetic acid (30 μL, 0.5 mmol). The ball was added and the mixture milled at 30 Hz for 40 minutes.

Ethyl 3-oxo-3-(p-tolyl)propanoate
Following this initial grinding period, Selectfluor (0.708 g, 2 mmol) and sodium carbonate (0.133 g, 1.25 mmol) were added to the reaction mixture. The jar was hand sealed and milled for a further 60 minutes at 30 Hz (Scheme S1). The resulting powder was transferred into a flask, washing the residue with dichloromethane (approximately 40 mL).
The insoluble material was removed by filtration. The solvent was removed under reduced pressure to yield the crude product. This was purified by flash column chromatography on silica gel (gradient elution EtOAc (0-5%) in petroleum ether).

General Procedure 3 (GP3)
Diethyl ether (10 mL) and sodium hydroxide solution (10 mL, 0.5 M) were added to the hydrazine hydrochloride (2 mmol) and shaken until dissolved. The layers were separated and the aqueous layer further extracted with diethyl ether (2 × 10 mL). The organic phase was dried (MgSO 4 ), filtered and the solvent removed to yield the hydrazine. To a 10 mL stainless steel milling jar was added ethyl benzoylacetate (0.192 g, 1 mmol), the hydrazine (1 mmol), sodium chloride (six times the total mass of reagents) and glacial acetic acid (30 μL, 0.5 mmol). The ball was added and the mixture milled at 30 Hz for 40 minutes.
Following this intial grinding period, Selectfluor (0.708 g, 2 mmol) and sodium carbonate (0.133 g, 1.25 mmol) were directly added to the reaction mixture. The jar was hand sealed and milled for a further 60 minutes at 30 Hz. The resulting powder was transferred into a flask, washing the residue with dichloromethane (about 40 mL). The insoluble material was removed by filtration. The solvent was removed under reduced pressure to yield the crude product. This was purified by flash column chromatography on silica gel (gradient elution EtOAc (0-5%) in petroleum ether).