Uses
4-(Trifluoromethyl)-N-methylaniline is used in the synthesis of Tasquinimod (T007820), an orally active antiangiogenic agent which may inhibit HDAC4 signalling. This affects cancer cell survival thus making this compound and anti-cancer agent.
Synthesis
GENERAL PROCEDURE: The selective N-monomethylation reaction was carried out in a Vapourtec E-Series continuous flow system equipped with a high temperature tubular reactor (10 mL, stainless steel, 0.03 inch ID, Figure 2) and a membrane back pressure regulator (Zaiput). In an oven, stock solutions of p-trifluoromethylaniline (20 mmol, 1.0 eq, 2M), dimethyl carbonate (DMC, 5.05 mL, 60 mmol, 3.0 eq, 6M), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 4.47 mL, 30 mmol, 1.5 eq, 3M) were prepared in dry 10 mL volumetric flask using N-methylpyrrolidone (NMP) as solvent. The solution was transferred to a threaded vial with a septum cap and the reagent was pumped directly from the vial. After the high-temperature coil reactor was heated to 250 °C, the reactant solution was pumped into the system using a peristaltic pump (Vapourtec V-3) at a flow rate of 0.277 mL/min (residence time 12 min). The solutions were mixed through a cross-mixer (0.4-inch ID) and into a high-temperature coil reactor. After flowing through the reactor, the reactants are cooled through a small section of stainless steel tubing and subsequently exit the system through a back pressure regulator (Note: PFA fittings should not be used at the outlet as they can deform at high temperatures and cause the system to leak. This system utilizes stainless steel connectors and tubing (12 inches)). The flow system was equilibrated for 18 minutes and the product stream was collected for 5 minutes (corresponding to 2.77 mmol p-trifluoromethylaniline). The crude product was dissolved in ethyl acetate and washed with brine. The combined organic layers were dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage 25g Ultra-sil, eluent 3-15% ethyl acetate in hexane solution) to afford the target product 4-trifluoromethyl-N-methylaniline.
References
[1] Tetrahedron, 2018, vol. 74, # 25, p. 3124 - 3128
