Temperature‐Controlled Mechanochemistry for the Nickel‐Catalyzed Suzuki–Miyaura‐Type Coupling of Aryl Sulfamates via Ball Milling and Twin‐Screw Extrusion.

The nickel catalyzed Suzuki–Miyaura‐type coupling of aryl sulfamates and boronic acid derivatives enabled by temperature‐controlled mechanochemistry via the development of a programmable PID‐controlled jar heater is reported. This base‐metal‐catalyzed, solvent‐free, all‐under‐air protocol was also scaled 200‐fold using twin‐screw extrusion technology affording decagram quantities of material.


General Experimental
All chemicals were obtained from commercially available sources and used without additional purification unless stated otherwise.
Ball milling was carried out on a Retsch MM 400 Mixer mill and an IST500. Stainless steel milling jars and stainless-steel grinding balls were used unless stated otherwise.
Thin layer chromatography (TLC) was carried out on Merck TLC 60Å silica gel sheets and visualised using ultraviolet light of wavelength 254 nm.
Flash column chromatography (FFC) was performed using Merck/Sigma Aldrich silica gel (40-60 Å) as the stationary phase. High resolution mass spectral (HRMS) data were obtained on a Micromass Q-TOF Premier Tandem Mass Spectrometer coupled to nano acquilty LC. Spectra were obtained using electrospray (ES) Infrared spectra were recorded on an Agilent Cary 630 FTIR spectrometer.
Melting points were measured on a Stuart SMP10 melting point apparatus.

Equipment used
Mixer Mills: Mechanochemical reactions were conducted using a Retsch MM400 mixer mill and an IST500 high-energy mixer mill at the frequency denoted where relevant (below see www.retsch.com and www.insolidotech.org for more details)

Monitoring reaction temperatures
The temperature of the milled reactions (both when ran at room temperature and at elevated temperatures were monitored over time using a Lascar Electronics Data Logger (lascarelectronics.com) attached to a RS Pro Type K Thermocouple. The thermocouple was attached to the jars using electrical tape and remained fastened throughout milling. Temperature values were obtained every 1 second over the course of a milling period. These temperature values were verified through use of an IR thermometer (Testo 830-T1) on the outside of the milling jar and also of an opened milling jar just after reaction finished.
Darker lines in graph below shows a 25 second moving average for clarity. Original values are shown in pastel colours.

Figure S1: Temperature monitoring studies using different sized jars
Heating profiles -Heat-Gun vs. Jar Heaters. To the relevant stainless steel milling jar was added a 3 g stainless steel ball, 1-naphthyl dimethylsulfamate (0.5 mmol), 4-fluorophenyl boronic acid (0.75 mmol), NiCl2(PPh3)2 (10 mol%), sodium chloride (2 mass equiv.), hexanol (0.122 µL/mg) and tripotassium phosphate (1.5 mmol). Using either the heat-gun set-up or the jar heater set-up, the jar was then milled at 30 Hz for 30 minutes and the temperature monitored over time. As the jar heater can overshoot -manual oversight of the temperature by stopping the temperature increase about 5 degrees below the target and then pressing heat again -can lead to a more accurate reaction profile (shown in blue). This latter process was used throughout the subsequent reaction development. Darker lines in the graph below shows a 25 second moving average for clarity. Original values are shown in pastel colours.    30 ml → 15 ml jar is 0.5, 3 g ball to 1.5 g ball however we only have 1 g and 2 g milling balls so both were used for comparison S19

Variable temperature experiments using HP2
Starting with electron rich 4-methoxyphenyl boronic acid (2c), a steady increase was observed culminating in highest yields at 130 °C. It should be noted that (along with 2b and 2d) no reaction occurred without the addition of heat, at either 30 mins or 4-hour reaction time. The well-studied electron neutral 4-fluorophenyl boronic acid (2a) showed excellent reactivity at all studied temperatures with those between 90 °C and 120 °C resulting in the greatest yields. Interestingly in this case, further heating to 130 °C resulted in a decreased yield of 85%. Proceeding to electron poor boronic acids bearing CO2Et (2d) and CF3 (2e) similar good reactivity was observed throughout the temperature range, with optimal points at 120 °C and 100 °C respectively.
Scheme S1: Temperature variations using a variety of electronically-diverse boronic acid species including control experiments at room temperature The consistent drop in yield at 110 °C across this study is suggested to be linked to a phase change in the sulfamate starting material which has a melting point of. 71-74 °C. The use of 110 °C goes through a mid point temperature of 68 °C (for 10 minutes during HP2) whereas the alternative temperatures (higher than this) result in a mid point above or below this. To assess this finding the 110 °C reaction was conducted again for 1ag and 2d with a mid point of 73 °C. In so doing, the yield moderately increased from 65% to 75% demonstrating the importance of the phase change.

10: Extrusion protocols
The large-scale extrusion protocols were carried out using a Thermo Scientific TM Process 11 Twin-screw Extruder (TSE) with 7 controllable heating sections.

General Extrusion Procedure
To a large beaker was added 2-naphthalene sulfamate (1 equiv.), 4-fluorophenyl boronic acid (1.5 equiv.), NiCl2(PPh3)2 (10 mol%), sodium chloride (2 mass equiv.) and K3PO4 (3 equivs.). The mixture was mixed by hand using a spatula. The pre-mixed mixture was added to the volumetric hopper situated at the first port (Main Feed, Figure S2) with a feed rate of 2.52 gmin -1 -calibrated ex situ. Hexanol (0.1 volume equiv.) was added via syringe pump through the second port (Liquid feeding) at a rate of 0.103 mL min -1 The TSE was set at 50 rpm and each of the twin-screw extruder seven heating zones were heated to the correct temperature (2 x 25 °C, 2 x 63 °C, 3 x 100 °C).
The screw configuration was arranged as shown below in Figure S2. The reaction mixture came out of the twin-screw extruder and was collected in a beaker filled with water (≈40 mL) at 10-minute intervals. Each beaker was added to a separating funnel and ethyl acetate added. The reaction mixture was then washed with 1.1 M NaOH, water and brine, dried over magnesium sulfate and concentrated in vacuo to give the crude reaction mixture.
The resulting crude residue was purified by silica gel flash column chromatography using hexane to give the pure product unless stated otherwise.
Material started appearing at the end of the extruder after ~3 minutes and torque values between 1.8 and 3.2 Nm were maintained throughout the process.
*Sodium chloride and K3PO4 were both dried in 175 °C oven for approximately 3 hours prior to use *150g of NaCl was added at 140 minutes and the screw speed was increased from 50 rpm to 100 rpm at 150 minutes as torque values of over 4.0 Nm were recorded.
S27 Figure S4. Results from 100 mmol reaction Fractions from (ii) Steady state were combined and purified via silica gel column chromatography to give pure product 3a. (i) Initation and (ii) End were also combined together and purified via silica gel column chromatography. The two pots of material were combined together to give the overall isolated yield, 13.76 g (62%).
The reaction was washed with NaHSO4 and the aqueous layer extracted with DCM (3 x 25 mL). The combined organic layers were washed with brine (3 x 25 mL) and dried over magnesium sulfate. The solvent was evaporated to give the crude product.
The reaction was washed with NaHSO4 and the aqueous layer extracted with DCM (3 x 25 mL). The combined organic layers were washed with brine (3 x 25 mL) and dried over magnesium sulfate. The solvent was evaporated to give the crude product.
The crude product was purified by flash column chromatography to afford tert-Butyl This data is consistent with the literature. [2] S29

2-Naphthyl diethylcarbamate (1ac)
Prepared according to modified literature. [2] To an oven dried round bottom flask equipped with a stirring bar, sodium hydride (60% parrafin oil) was added under argon. The flask was cooled to 0 °C and the alcohol (1 equiv.) in 1 M dry THF was added over 10 minutes. The reaction mixture was then stirred at rt. For 10 minutes. The reaction mixture was then cooled to 0 °C and Diethyl carbonyl chloride (1.2 equiv.) was added over 10 minutes. The reaction was left to stir overnight.
The reaction was quenched with water. Ether was added and the solution washed with 1.1 M NaOH (25 mL) and water (3 x 25 mL). The combined aqueous layers were then extracted with ether. The combined organic layers were washed with brine (3 x 25 mL) and dried over magnesium sulfate. The solvent was evaporated to give the crude product.
The crude product was purified by flash column chromatography to afford 2-Naphthyl diethylcarbamate ( This data is consistent with the literature. [2] 2-Naphthyl triflate (1ad) Prepared according to modified literature. [3] To round bottom flask equipped with a stirring bar, alcohol (1 equiv.), pyridine (1.2 equiv.) and dry DCM were added. The flask was cooled to 0 °C and Tf2O (1.5 equiv.) was added dropwise. The reaction was warmed to RT and left to stir overnight.
The reaction was saturated with NaHCO3 (25 mL). The aqueous phase was washed with DCM (3 x 25 mL) and dried over magnesium sulfate. The solvent was evaporated to give the crude product.
The crude product was purified by flash column chromatography to afford 2-Naphthyl triflate ( This data is consistent with the literature. [4] 2-Naphthyl tosylate (1ae) Prepared according to modified literature. [5] To round bottom flask equipped with a stirring bar, alcohol (1 equiv.), NEt3 (1.5 equiv.), DMAP (20 mol%) and DCM were added. The reaction was cooled to 0 °C and TsCl (1.2 equiv.) in DCM was added dropwise and left to stir for 2 hours.
The reaction was quenched with DCM (3 x 25 mL) and the combined organic layers washed with brine (3 x 25 mL) and dried over magnesium sulfate. The solvent was evaporated to give the crude product.

S30
The crude product was purified by flash column chromatography to afford 2-Naphthyl tosylate ( This data is consistent with the literature. [6] 2-Naphthyl mesylate (1af) Prepared according to modified literature. [7] To an oven dried round bottom flask equipped with a stirring bar, alcohol (1 equiv.), dry pyridine (5 equiv.) and dry DCM were added, and the flask was cooled to 0 °C. Methane sulfonyl chloride (1.2 equiv.) was added dropwise. The reaction was warmed to RT and left to stir overnight.
The reaction was quenched with water. The aqueous layer was washed with DCM (3 x 25 mL). The combined organic layers were washed with 15% HCl (25 mL), brine (3 x 25 mL) and then dried over magnesium sulfate. The solvent was evaporated to give the crude product. This data is consistent with the literature. [6] The reaction was cooled to rt. Ether was added and washed with 1.1 M NaOH (25 mL) and the layers separated. The aqueous layers were then extracted with ether (2 x 25 mL) followed by ethyl acetate (25 mL). The combined organic layers were with brine (2 x 25 mL) and dried over magnesium sulfate. The solvent was evaporated to give the crude product.
This was then purified by flash column chromatography to give the pure product.

3-hydroxylpyridyl dimethylsulfamate (1h)
Prepared according to general procedure B. This data is consistent with the literature. [11] 11.2. Synthesis of C-C coupled products

General Procedure C: Mechanochemical nickel-catalysed Suzuki-Miyaura cross coupling
To a 30 mL stainless steel milling jar was added a 3 g stainless steel ball, aryl dimethylsulfamate (0.5 mmol), boronic acid (0.75 mmol), NiCl2(PPh3)2 (10 mol%), sodium chloride (2 mass equiv.), hexanol (0.122 µL/mg) and tripotassium phosphate (1.5 mmol). A band heater encased the jar and milled at 30 Hz for 30 minutes. The first 10 minutes were conducted at rt. With the next 10 minutes heated to 63 °C and the remaining 10 minutes to 100 °C. After this time the milling was stopped, and jar allowed to cool to ~40 °C before further manipulation. The reaction mixture was removed from the jar into a conical flask with ethyl acetate (~30 mL) and water (~30 mL) *. The organic layer was washed with 1.1 M NaOH (25 mL), water (50 mL), brine (50 mL), dried over magnesium sulfate, and concentrated in vacuo to give the crude reaction mixture.** The resulting crude residue was purified by silica gel flash column chromatography using hexane/ ethyl acetate solvent system to give the pure product unless stated otherwise.
*a sonicator was used to break up any large pieces ** a dilute H2O2 solution (25 mL) was also used for boronic acids containing electron-donating groups to facilitate removal of PPh3 ligand, which could co-elute with C-C coupled products.