A fully recyclable heterogenized Cu catalyst for the general carbene transfer reaction in batch and flow

Carbene transfer reactions can be performed in batch and flow with a highly active, chemically stable heterogenized tris(triazolyl)methyl copper(i) catalyst.

6. Continuous flow production of a family of compounds resulting from carbene transfer reactions S7 7. 1 H NMR and 13 C NMR data for products 1-6 S8 8. 1 H NMR and 13 C NMR spectra for products 1-6 S11 9. GC chromatograms for products 1-6 S17

Synthesis of the polymer-supported copper complex PS-TTMCu(NCMe)PF 6 .
A mixture of PS-supported tris(triazolyl)methoxy ligand (300 mg, 1 equiv., f = 0.495 mmol·g -1 ) and [(CH 3 CN) 4 Cu]PF 6 (65 mg, 0.176 mmol, 1.20 equiv.) was stirred in 20 mL of dry dichloromethane for 16 h under nitrogen. After filtration, the solid was washed with dry dichloromethane (2 x 20 mL) and petroleum ether (2 x 20 mL) and dried under vacuum. No changes in color were observed in the isolated solid from that of the starting material. In the event that some greenish color was observed, this would be indicative of partial oxidation to Cu(II). This problem can be avoided by working under inert atmosphere.
In the case of the catalyst for continuous flow, the procedure for the formation of the Cu(I) complex was carried out inside a glovebox, with the resin sample loaded in the flow column. The column was then taken outside from the glovebox, and was shaken at room temperature under positive pressure of argon for 16 h.
The column was then connected to the flow instrument and was washed with dry dichloromethane (20 mL) with a flow rate of 500 µL/min prior to use.  The filtrate from the reaction mixture was analyzed by GC, identifying exclusively the product derived from ethanol functionalization 3 and some diethyl fumarate and maleate from the formal dimerization of the CHCO 2 Et units from EDA. The filtrate was taken to dryness, at 0º C to avoid evaporation of the product, and the residue was dissolved in CDCl 3 . and analyzed by NMR.
Average productivity in batch after 5 cycles : 6.3 mmol product ·mmol Cu -1 ·h -1 b) Preparative, large scale experiment: Dry and deoxygenated ethanol (30 mL) was added to a Schlenk flask containing freshly prepared PS-TTMCu(NCMe)PF 6 (600 mg, 0.234 mmol, recovered from the preparative experiment with aniline described below) under nitrogen atmosphere. EDA (4.5 mmol, 0.47 mL) was added in one portion and the mixture was stirred for 3 h at room temperature. The catalyst was separated by filtration, washed with CH 2 Cl 2 (2 x 30 mL), dried and stored for further use. The filtrate from the reaction mixture was analyzed by GC, showing exclusively the peak corresponding to 3 (>99% conversion and >99% selectivity).
Solvents were removed under reduced pressure (P = 150 mbar, 30 ºC) to a weight of 1.15 g. At this point, CH 2 Cl 2 (7 mL) was added, and the solvents (dichloromethane and residual ethanol) were removed under reduced pressure (P = 400 mbar, 30 ºC) to give pure 3 (0.58 g, 4.41 mmol, 98% isolated yield). Carbene insertion into C-H bonds of cyclohexane and tetrahydrofuran Following the above procedure, cyclohexane (3 mL) was reacted with EDA (0.75 mmol, 79 µL) in the presence of the solid catalyst (100 mg, 0.039 mmol) under nitrogen atmosphere. EDA was slowly added for 18 h (dissolved in cyclohexane). Identical protocol and amounts of reactants were employed in the case of tetrahydrofuran. Workup was similar to that described above, removal of volatiles being performed at room temperature.
3 mL of dry deoxygenated dichloromethane was added to a Schlenk containing the catalyst (100 mg, 0.039 mmol) under nitrogen atmosphere, followed by 3.75 mmol (0.42 mL) of 1-phenyl-1-propyne. A solution of 0.75 mmol (79 µL) of EDA in 10 mL of dichloromethane was slowly added over 6 hours. Workup was similar to that described above, removal of volatiles being performed at room temperature.

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Average productivity in batch after 5 cycles : 2.9 mmol product ·mmol Cu -1 ·h -1 Büchner ring expansion of benzene 3 mL of dry deoxygenated benzene was added to a Schlenk containing the catalyst (100 mg, 0.039 mmol) under nitrogen atmosphere. A solution of 0.75 mmol (79 µL) of EDA in 10 mL of benzene was slowly added for 6 h, before workup, that was similar to that described above, removal of volatiles being performed at room temperature.
Average productivity in batch after 5 cycles : 2.6 mmol product ·mmol Cu -1 ·h -1 Consecutive experiments with different substrates The above conditions were employed in a consecutive manner with the same initial loading of catalyst for an overall number of 12 experiments, two with each substrate (see Table 2 in the manuscript).

Continuous flow experiment with ethyl diazoacetate and ethanol
The column was assembled to the Asia120® flow chemistry system developed by Syrris as shown in Figure   S1. Deoxygenated dichloromethane was flushed by an Asian pump through the column at 500 µL·min -1 flow rate to swell the resin. After 30 min, the solvent channel was switched to the reagents and a solution of ethyl diazoacetate (11.2 mL, 106 mmol) and distilled ethanol (31 mL, 531 mmol) in deoxygenated dichloromethane (1400 mL) was pumped with a flow rate of 500 µL·min -1 through the system and the system was run for 48 h.
Periodically collected samples were analysed by gas chromatography to determine conversion of the final product. Samples were collected and solvent was removed under reduced pressure to give pure product 3 (12.6 g, 95.83 mmol, 89 % yield) as a brownish liquid.

Continuous flow production of a family of compounds resulting from carbene transfer reactions.
a) The column was filled with the catalyst as described above and assembled to an Asia120® flow chemistry system developed by Syrris ( Figure S1). Deoxygenated dichloromethane was first flushed through the column at 500 µL·min -1 flow rate to ensure that no unligated Cu(I) is available. After 30 min, the solvent was changed to dry tetrahydrofuran, which was pumped through the column at 500 µL·min       10  20  30  40  50  60  70  80  90  100  110  120  130  140  150  160  170  180  190  200 f1 (