2.6- Dihydroxypyridine

The most demanding test of cesium carbonate as base was with 2,3-dihydroxypyridine (3-hydroxypyridone). The cesium salt was found to be fairly unstable, apparently oxidizing quite rapidly. Model reactions suggested that alkylation would occur 1,3 (N, 0) to give the substituted pyridone. Nevertheless, on the basis of UV and H-nmr analysis, the product of reaction between 2,3-dihydroxypyridine and tetraethylene glycol dibromide was assigned as the pyridocrown (23% yield, mp 77—78.5°) as shown in Eq. (3.60). 

The substance, C5H5O2N, which Adams et al. obtained by the pyrolysis of leucenol and tentatively suggested might be 2 5-dihydroxypyridine, later disproved by Adams and Govindachari, has been synthesised by Bickel and shown to be 3 4-dihydroxypyridine, and this has been confirmed by Adams, Jones and Johnson. ... 

Oxygen anion resonance. This means of stabilizing hydration depends on the resonance shown in 39b-c, which is akin to 2,4-dihydroxypyridine anion resonance. An example of its occurrence (e.g. 24) is mentioned in Section III,E, l,d. This resonance bears a close resemblance to the pteridine anion resonance shown in formula 21,... 

This replacement reaction has been reported to take place on treatment of 5-R-l,3-dimethyluracil derivatives (R = H, Me, CN, F, Br, Cl,) with of-substituted (R ) acetamides (R =C0NH2, CN, COMe, Ph) in basic medium. The reaction provides an easy entry to the synthesis of 3-R-5-R -2,6-dihydroxypyridines (Scheme 22). 

Figure 25 ORTEP diagram of Ph3Sn(IV)-dihydroxypyridine complex. ...

The dioxygenase that catalyzes the degradation of 2,5-dihydroxypyridine to maleamate and formate (Gauthier and Rittenberg 1971). 

Baitsch D, C Sandn, R Brandsch, GL Igloi (2001) Gene cluster on pAOl of Arthrobacter nicotinovorans involved in degradation of the plant alkaloid nicotine cloning, purification, and characterization of 2,6-dihydroxypyridine 3-hydrolase. J Bacterid 183 5262-5267. 

Gauthier JJ, SC Rittenberg (1971) The metabolism of nicotinic acid. I. Purification and properties of 2,5-dihydroxypyridine oxygenase from Pseudomonas putida N-9. J Biol Chem 246 3737-3742. 

Both 2-hydroxy- and 3-hydroxypyridine are hydroxylated to 2,5-dihydroxypyridine by strains of Achromobacter sp. (Houghton and Cain 1972). These metabolites are probably, however, formed by different reactions whereas 3-hydroxypyridine behaves as a true pyridine, addition of H2O across the Cg Nj bond would produce the 2,5-dihydroxy compound 2-hydroxypyridine is a cyclic amide and hydroxylation apparently occurs at the diagonal position. The degradation of 4-hydroxypyridine is also initiated by hydroxylation and is followed by dioxygenation before ring fission (Figure 10.12) (Watson et al. 1974). 

Pyridine-4-carboxylate is hydroxylated by Mycobacterium sp. strain INAl to 2,6-dihydroxypyridine-4-carboxylate. Two different hydroxylation enzymes were involved and were apparently Mo-dependent (Kretzer and Andreesen 1991). The formation of 2-ketoglutarate can, however, be rationalized equally as (3-oxidation to hexahydropyridine-2,3,6-trione-4-carboxy-CoA ester followed by hydrolysis. 

A diazodiphenoquinone is also produced as a chemical artifact (Knackmuss and Beckmann 1973). There are, however, a nnmber of unresolved features of the degradation, including the mechanisms for production of 2,6-dihydroxypyridine and oxidative fission of the pyridine ring. 

The degradation of 2,5-dihydroxypyridine has been examined using 02 and H2 0 (Gauthier and Rittenberg 1971), and was shown to involve the incorporation of both atoms of oxygen, one each into formate and maleamate. 

Holmes PE, SC Rittenberg, H-J Knackmuss (1972) The bacterial oxidation of nicotine. VIII. Synthesis of 2,3,6-trihydroxypyridine and accumulation and partial characterization of the product of 2,6-dihydroxypyridine oxidation. J Biol Chem 247 7628-7633. 

Houghton C, RB Cain (1972) Microbial metabolism of the pyridine ring. Formation of pyridinediols (dihydroxypyridines) as intermediates in the degradation of pyridine compounds by microorganisms. Biochem J 130 879-893. 

Watson GK, C Houghton, RB Cain (1974) Microbial metabolism of the pyridine ring. The hydroxylation of 4-hydroxypyridine to pyridine-3,4-diol (3,4-dihydroxypyridine) by 4-hydroxypyridine-3-hydroxylase. Biochem J 140 265-276. 

In an analogous reaction catalyzed by 2,5-dihydroxypyridine 5,6-dioxygenases from various strains (Scheme 3d), the hydrolysis products maleamate and formate were identified. The latter enzymes require Fe2+ and a thiol donor such as dithiothreitol, cysteine, or glutathion for activity. 

There has been considerable interest in hydroxy-3,3 -bipyridines and 3,3 -bipyridinones. Following from some very early work on the oxidation of citrazinic acid (2,6-dihydroxypyridine-4-carboxylic acid), which was considered to give some polyhydroxy-3,3 -bipyridines, it has been shown that the 3,3 -bipyridinone 59, a product of the hydrolysis of a natural blue pigment from Corynehacterium insidiosum, is obtained by oxidation of 2-hydroxy-5-aminopyridine (60) or 2,6-dihydroxypyridine-4-carboxylic acid 61) 80,83 similar oxidation of 2,6-dihydroxy-3-aminopyridine-4-carboxylic acid affords the natural product indigoidine (20). Numerous related oxidative condensations have been reported subsequently. Cyano-acetamide condensations analogous to those discussed in the synthesis of 2,3 -bipyridines afford, for example, the cyano-substituted 3,3 -bipyridinone 62 588 v, lereas condensation of 3-pyridylacetonitrile with ethyl phenyl-propiolate and ethanol affords compound 63. To complete the section on... 

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