The overall goal of this protocol is to synthesize novel ortho-trifluoromethoxylated anilines with the discovery and development of new drugs, agrochemicals, and functional materials. This method can help to answer key questions in the field of foreign chemistry such as how incorporation of trifluoromethoxy group into a molecule effects its physical, chemical, and biological properties. The main advantage of this technique that our method uses easy-to-handle reagents.

It's amendable to gram-scale synthesized and it has broad substrate scope and high tolerance of functional groups. For the reduction of methyl 4-nitrobenzoate, add 5.00 grams of methyl 4-nitrobenzoate, 159 milligrams of 5%Rhodium on carbon, and a magnetic stir-bar into an oven-dried 250 milliliter two-neck round-bottom flask. Connect one neck of the flask to a nitrogen-vacuum manifold and cap the other neck with a septum.

Perform three vacuum-refill cycles to replace the air in the flask with nitrogen gas, then add 138 milliliters of anhydrous tetrahydrofuran to the reaction flask using an airtight syringe. Cool and stir the reaction mixture at zero degrees Celsius for 15 minutes. Next, add 1.47 milliliters of hydrazine monohydrate drop-wise to the reaction mixture at zero degrees Celsius using an airtight syringe.

At this point, Rhodium on carbon will start aggregation to form larger particles. Monitor the reaction using thin-layer chromatography or TLC. Use a mixture of hexane and ethyl acetate as an element to develop the TLC.

When methyl 4-nitrobenzoate is completely consumed, filter the reaction mixture through a short pad of Celite in a 60 milliliter frit Buchner funnel using vacuum filtration. Wash the filter with 20 milliliters of ethyl acetate three times. Concentrate the filtrate in vacuo using a rotary evaporator to afford the crude methyl 4-hydroxyamino benzoate which is used directly without further purification.

To perform acetyl protection of methyl 4-hydroxyamino benzoate, add 2.55 grams of sodium bicarbonate, all the crude methyl 4-hydroxyamino benzoate obtained in the previous step, and a stir-bar into an oven-dried 500 milliliter two-neck round-bottom flask. Cap one neck with a septum, and connect another neck to a nitrogen-vacuum manifold. Perform three vacuum-refill cycles to replace the air in the flask with nitrogen gas.

Add 138 milliliters of anhydrous diethyl ether to the reaction flask using an airtight syringe. Cool and stir the reaction mixture at zero degrees Celsius for 15 minutes. Prepare a solution of 2.17 milliliters of acetyl chloride and 138 milliliters of anhydrous diethyl ether.

Add the solution to the reaction mixture at zero degrees Celsius using a syringe pump at a rate of 10.0 milliliters per hour. At the end of the addition, filter the reaction mixture through a short pad of Celite in a 16 milliliter frit Buchner funnel using vacuum filtration. After washing the filter with 20 milliliters of ethyl acetate three times, concentrate the filtrate in vacuo using a rotary evaporator.

Purify the crude product with flash-column chromatography eluting with a mixture of hexane and ethyl acetate to afford 5.31 grams of methyl 4-hydroxy acetamido benzoate as a light yellow solid. Add 2.00 grams of methyl 4-hydroxy acetamido benzoate, 311 milligrams of cesium carbonate 3.63 grams of Togni reagent II, and a magnetic stir-bar into an oven-dried 250 milliliter round-bottom flask inside a glove box. This reaction can also be performed using Schlenk techniques outside the glove box, then add 95.6 milliliters of dried and degassed chloroform to the reaction flask.

Cap the flask with a septum and stir the reaction mixture at 23 degrees Celsius under nitrogen atmosphere either inside or outside the glove box for 16 hours. Filter the reaction mixture through a filter funnel to remove any solid residue before concentrating the filtrate in vacuo using a rotary evaporator. Next, purify the crude product using flash-column chromatography eluting with a mixture of hexane and dichloromethane to afford 2.51 grams of methyl 4-trifluoromethoxy acetamido benzoate To synthesize the final product at 2.51 grams of methyl 4-trifluoromethoxy acetamido benzoate, a magnetic stir-bar, and 9.05 milliliters of anhydrous nitromethane into a 15 milliliter pressure vessel.

Cap the vessel with a screw cap, stir the reaction mixture at 120 degree Celsius behind the safety shield for 20 hours. After cooling the reaction mixture to room temperature, transfer to a 100 milliliter round-bottom flask. Concentrate the reaction mixture in vacuo using a rotary evaporator.

Purify the crude product with flash-column chromatography eluding with a mixture of hexanes and ethyl acetate to afford 2.13 grams of methyl 4-acetamido 3-trifluoromethoxy benzoate. Characterize all the new compounds by proton-carbon-13 nuclear magnetic resonance or NMR spectroscopy and high-resolution mass spectroscopy. Use fluorine-19 NMR spectroscopy to characterize compounds containing fluorine atoms.

Representative results of Togni reagent II mediated intermolecular trifluoromethoxylation of arenes are shown here. This protocol is general and applicable to a wide array of aromatic compounds. The reaction tolerates a broad spectrum of functional groups.

In addition, high levels of ortho over para selectivity are observed, for example, substrates, 3f, 3k, and 3l. In the presence of two non-identical ortho positions, low levels of Regio-control are obtained as in substrates, 3d.3e. 3k, and 3m.

Furthermore, the reaction temperature for the trifluoromethoxy migration step depends on the electronic nature of the arenes. Generally, more electron-deficient arenes require higher reaction temperature. After its development, this technique paved the way for researchers in the field of chemistry and biology to explore trifluoromethoxylated arenes, and the discovery, and the development of new technique molecules.