Nitropyridines in Organic Synthesis. 2.5-Disubstituted Pyridine Compounds

Abstract

The goal of this project was to explore how 5-nitropyridine-2-sulfonic acid (18) and its potassium salt (18a) could be utilised as starting materials for 2,5- substituted pyridines. Compounds 18/18a were prepared by oxidation of 5- hydroxy-aminopyridine-2-sulfonic acid (9).

Compound 9 was synthesised in 74% yield from a reaction between 3- nitropyridine (6) and sodium sulfite, via the intermediate 5-(N-sulfohydroxyamino) pyridine-2-sulfonic acid (8).

Compound 9 was reduced to 5-aminopyridine-2-sulfonic acid (16) in a 46% yield, but attempts to substitute the sulfo group of 9 with nucleophiles were unsuccessful. It was therefore decided to oxidise the hydroxylamine group to a nitro group, giving compound 18. The electron withdrawing nitro group make the sulfo group of 18 more susceptible to nucleophilic substitutions than that of hyroxylamine 9.

A wide range of oxidising agents were tried to achieve this oxidation. It was shown that the reaction might be performed selectively by SPB in acetic acid, NaOCl in water or KMnO4 in water. The crude products proved difficult to purify due to inorganic impurities, but substitution of the sulfo group in 18 with methanol yielded 2-methoxy-5-nitropyridine (30) in 44, 42 and 57% overall yield from 9, respectively for the three methods. In addition to give the best yield, the oxidation with KMnO4 also gave the purest product (based on melting points). This made KMnO4 the preferred oxidising agent for the oxidation of 9 to 18.

The use of sodium acetate as an internal standard in 1H NMR spectroscopy was shown to be a suitable method to determine the amount of inorganic impurities in the crude products. By this method the purity of the potassium salt of 5- nitropyridine-2-sulfonic acid (18a) was estimated to be in the range 40-50 wt%, and the purity of 5-nitropyridine-2-sulfonic acid (18) was in the range 60-70 wt%.

The yields of 18a and 18 from 9 calculated on this basis, were between 50-60% after work-up.

The sulfo groups of 5-nitropyridine-2-sulfonic acid (18) and its potassium salt 18a were readily replaced by oxygen, nitrogen and halogen nucleophiles as shown in the schemes below.

No reactions were observed when 18a and 18 were reacted with phenols or aniline.

2-Chloro-5-nitropyridine (25) was formed in 87% yield from reaction of 18a with PCl5. No reactions were observed when 18a was treated with PBr3 and PBr5, nor with potassium chloride, bromide or iodide.

Potassium 5-nitropyridine-2-sulfonate (18a) was also reacted with carbon nucleophiles. A vicarious nucleophilic substitution (VNS) reaction between 18a and methyl chloroacetate (55) gave potassium 4-methoxycarbomethyl-5- nitropyridine-2-sulfonate (58) in 43% yield. Compound 58 was then used as substrate in nucleophilic aromatic substitution reactions with methoxide ions, ammonia and n-butylamine, as shown in the scheme below.