5-Nitrovanillin

5-Nitrovanillin (4-hydroxy-3-methoxy-5-nitrobenzaldehyde) is a derivative of vanillin in which the hydrogen ortho- to the hydroxy group is substituted by a nitro group. Because it contains many reactive functional groups – in addition to the nitro group, a hydroxyl group, a methoxy group and an aldehyde group are present – 5-nitrovanillin is suitable as a starting material for the synthesis of phenethylamines, for coenzyme Q and for the inhibitors of catechol-O-methyltransferase (COMT inhibitors) that are effective against Parkinson's disease.

Properties
5-Nitrovanillin is a yellow crystalline solid with a characteristic odor. It is sparingly soluble in water, readily soluble in alkali solutions on heating and in methanol. When recrystallized from acetic acid, the substance precipitates as pale yellow plate-like crystals, and from ethanol as needle-like crystals.

Preparation
5-Nitrovanillin is obtained upon nitration of vanillin with concentrated nitric acid in glacial acetic acid with a 75% yield.



With acetyl nitrate as the nitrating agent, yields of up to 88% are obtained in the presence of silica gel.

Uses
5-Nitrovanillin was patented as a yellow hair dye in combination with other nitrobenzene dyes for consistent blonde to brown shades.

Because of the low solubility of 5-nitrovanillin in water, the potassium salt, which is readily soluble in water, is used for methylation. It is reacted with dimethyl sulfate to form 3,4-dimethoxy-5-nitrobenzaldehyde (5-nitroveratraldehyde) in 91% yield.



In early work on psychoactive phenethylamines, 3,4-dimethoxy-5-nitrobenzaldehyde was condensed with nitromethane in a Knoevenagel reaction to give the corresponding nitrostyrene, which is reduced electrochemically to yield the corresponding β-phenylethylamine.



An important intermediate for the chemical synthesis of coenzyme Q is 2,3-dimethoxy-5-methyl-1,4-benzoquinone, which is accessible in a four-step synthesis from 5-nitrovanillin via 3,4-dimethoxy-5-nitrobenzaldehyde. Demethylation of 5-nitrovanillin by ether cleavage using hydrobromic acid or using lithium hydroxide and thiophenol in NMP leads to 3,4-dihydroxy-5-nitrobenzaldehyde (DHNB), which is being discussed as an active ingredient for the treatment of hyperuricemia and gout.



3,4-Dihydroxy-5-nitrobenzaldehyde (DHNB) has gained greater importance as a precursor for the synthesis of the COMT inhibitor entacapone for the treatment of Parkinson's disease. A more recent patent application describes a synthetic route for the active ingredient opicapone, which has been approved in the EU since 2016, in which 5-nitrovanilline is initially reacted directly with hydroxylamine hydrochloride in DMSO to form the corresponding nitrile.



The nitrile obtained reacts with a hydroxamic acid chloride to give a 3,5-disubstituted 1,2,4-oxadiazole as a further intermediate.



With hydrazides, the aldehyde 5-nitrovanillin forms hydrazones that can be cyclized with Chloramine-T to give substituted 1,3,4-oxadiazoles.