Step A. Synthesis of (E)-4-trifluoromethylcinnamic acid
1. In 30 mL of pyridine, 4-trifluoromethylbenzaldehyde (7.7 mL, 57.7 mmol), malonic acid (12.0 g, 115.4 mmol), and piperidine (0.567 μL, 5.75 mmol) were mixed, and the reaction was stirred for 18 hr at 70°C.
2. After completion of the reaction, the reaction solution was cooled to room temperature, water (300 mL) was added, and the pH was adjusted to 4 with concentrated hydrochloric acid (litmus paper test), and a precipitate was precipitated.
3. The solid product was collected by filtration and washed with water until the filtrate was neutral.
4. The solid product was dried under vacuum to obtain (E)-4-trifluoromethylcinnamic acid in white powder form (10a, 11.2 g, 90% yield).
1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.60 (bs, 1H), 7.92 (d, 2H, J = 8.2 Hz), 7.77 (d, 2H, J = 8.2 Hz), 7.66 (d, 1H, J = 16.0 Hz), 6.70 (d, 1H, J = 16.0 Hz).
Step B. Amplified synthesis of (E)-4-trifluoromethylcinnamic acid
1. In a 2L four-necked round-bottomed flask equipped with an air condenser, an argon inlet, a mechanical stirrer, a thermocouple, and a stopper, 4-trifluoromethylbenzaldehyde (250 g, 196.2 mL, 1.44 mol), malonic acid (302.6 g, 2.87 mol), and pyridine (750 mL) were added.
2. The reaction was initially exothermic to 38-40 °C and maintained for 30 min. Piperidine (14.202 mL, 143.58 mmol) was then added, again exothermic, and the temperature rose to 42 °C after about 10 min.
3. After stirring for 30 minutes, the reaction was heated to 60 °C for 18 hours (overnight).
4. Confirm completion of the reaction by TLC, cool to about 40 °C, slowly add water (2 L to prevent freezing of the reaction mixture), continue to cool to room temperature, and dilute to a total volume of 6 L with additional water.
5. Adjust pH to 2.0-3.0 with concentrated hydrochloric acid (~675-700mL), stir for 30 minutes, filter to collect white solid.
6. Wash the filter cake with water until the filtrate is neutral (pH ca. 5.5-6, water consumption ca. 2.5 L), air dry in a Brinell's funnel for 2 hr, then dry in a vacuum oven at 60 °C overnight to obtain (E)-4-trifluoromethylcinnamic acid in the form of a white solid (10a, 300.5 g, 96% yield).
