4-Cyanobenzyl bromide is an important intermediate for pharmaceutical production. It can be used for the synthesis of a series of piperidine-linked aromatic diimidazolines, which have been synthesized as conformationally restricted congeners of the anti-Pneumocystis carinii (PCP) drug, Pentamidine. 4-(Bromomethyl)benzonitrile may be used in the synthesis of ligands containing a chelating pyrazolyl-pyridine group with a pendant aromatic nitrile.

Sythesis of 4-cyanobenzyl bromide from 4-cyanotoluene

Benzoic acid compounds and benzaldehyde compounds are widely used in the fields of medicine, agricultural chemicals, and material science. These compounds (like 4-Cyanobenzyl bromide) are generally synthesized by oxidizing a toluene compound. For example, in the reaction of oxidizing a toluene compound to obtain a benzoic acid compound, a method of using a heavy metal oxidizing agent containing manganese or chromium has long been known. However, heavy metal oxides are harmful and have a large environmental load, and are not suitable for mass synthesis. Therefore, in industrial production, instead of using heavy metal oxidizing agents, a method of oxidizing a toluene compound or the like with air at high temperature and pressure and a method of chlorinating and hydrolyzing have been proposed. However, such methods also have problems such as the toxicity of the reagent, the environmental load, and the danger of the process. In order to address the above problems, a method of performing the above oxidation reaction more safely and with a smaller environmental load has been proposed. For example, it has been proposed to use bromine compounds such as hydrobromic acid (HBr), potassium bromide (KBr), and carbon tetrabromide (CBr４) together with hydrogen peroxide, oxone, oxygen, and the like under light irradiation to cause an oxidation reaction of toluene compounds and xylene compounds. The method enables production of 4-cyanobenzyl bromide simply and cost-effectively with high yield and purity.[1]

1.76 g (15 mmol) of 4-cyanotoluene and 60 ml of trifluoromethylbenzene (hereinafter referred to as BTF) as a solvent were placed in a 200 ml four-neck flask containing a stirrer. Then, 3.73 ml of 48% HBr aqueous solution (33 mmol as HBr), 6.67 g of NaOCl-pentahydrate crystals (40.5 mmol as NaOCl) and 21 mL of water were placed in the flask. The flask was immersed in an ice bath (0°C), the flask was replaced with nitrogen, and the solution in the flask was irradiated with light for 4 hours under a nitrogen atmosphere (absence of oxygen) while stirring. The light irradiation was performed by placing a blue LED light source (wattage: 10 W, wavelength: 454 nm) at a distance of 5 cm from the flask. A few drops of sodium sulfite aqueous solution were dropped into the flask to remove the color of bromine in the solution, and then sodium bicarbonate water and ethyl acetate were placed in the flask and shaken to separate the aqueous phase and the organic phase. This operation dissolves NaCl in the solution into the aqueous phase, and NaCl is removed. The organic phase obtained was then washed with saturated saline, and the washed organic phase was then dried with sodium sulfate. The sodium sulfate was filtered off, and the dried organic phase was concentrated under reduced pressure to obtain 3.63 g (crude yield: 88%) of 4-cyanobenzyl bromide as a yellow solid (photoreaction product).

As a result of GC-MS measurement, this solid contained 4.5% 4-bromomethylbenzonitrile, 90.8% 4-Cyanobenzyl bromide, and 2.3% 4-tribromomethylbenzonitrile (also referred to as 4-Cyanobenzyl bromide with a GC purity of 90.8%). The above "crude yield" refers to the yield (the percentage of the molar amount (M2) of the dibromomethyl body relative to the molar amount (M1) of the toluene compound (starting material) ((M2/M1) x 100)) assuming that all of the solid is a dibromomethyl body, and the same applies in the following explanation. The content ratios of the monobromo, dibromo, and tribromo compounds in the photoreaction products are area percentages obtained from the results of GC-MS measurement, and the same applies to the following explanations. GC-MS of 4-Cyanobenzyl bromide: m/z = 277 (M+4; relative intensity 0.60%), 275 (M+2; relative intensity 1.16%), 273 (M＋ ; relative intensity 0.60%), 196 (M-Br+2, 94%), 194 (M-Br, 100%), 115 (M-2Br, 48%), 114 (M-CHBr２ , 23%).

References

[1]IHARANIKKEI CHEMICAL INDUSTRY - JP2024/58196, 2024, A