Nitration Using Fuming HNO₃ in Sulfolane: Synthesis of 6-Nitrovanillin in Flow Mode

Abstract

We report herein an improved synthesis of 6-nitrovanillin, an important building block used in pharmaceuticals and agrochemicals. The key step in this sequence is the nitration of O-Bn vanillin, which was carried out using fuming HNO 3 . Sulfolane emerged as the solvent of choice for this transformation due to its high stability toward strongly acidic and oxidizing conditions. The specific hazards of this reaction were studied, and the nitration was efficiently and safely conducted leveraging flow conditions.

Applications of Flow Chemistry in the Pharmaceutical Industry—Highlights of the Recent Patent Literature

“…This byproduct was noted in a nitration flow process of O -benzylvanillin in fuming nitric acid/sulfuric acid/sulfolane. In that example, the main product was the 6-nitro isomer, with none of the 2-nitro isomer reported, showing that the change in electronics in going from the OAc group to the OBn group completely alters the regiochemistry of the nitration …”

“…In that example, the main product was the 6-nitro isomer, with none of the 2-nitro isomer reported, showing that the change in electronics in going from the OAc group to the OBn group completely alters the regiochemistry of the nitration. 29 Nitration for Metronidazole. Metronidazole is an antibiotic that has been in use since the 1960s and is on WHO Model List of Essential Medicines.…”

Semisynthesis and biological evaluation of amidochelocardin derivatives as broad-spectrum antibiotics

“…Finally, CDCHD was also subjected to nitration using fuming nitric acid in sulfolane at 0 °C. [23] The desired molecule 16 was obtained in a poor yield of 4%. In spite of several attempts to reduce 16, we could not isolate the respective 7-amino analog.…”

Synthesis of 5-nitrovanillin in low temperature as cyanide anion sensor

“…Mondal et al, Used yttrium nitrate, Y(NO3)3.6H2O, in glacial acetic acid solvent as an intermediate medium for phenol nitration at room temperature. Nitration of vanillin at position 6 was carried out by Yadav et al, Through acetyl vanillin intermediates using DCM, acetic anhydride, and dry pyridine [7,8]; and Rakshit et al, [9] carried out the nitration of vanillin via the o-Bn-vanillin intermediate. 5-nitrovanilin compounds can also be synthesized in cold conditions using HNO3 and acetic acid [10].…”