Pyridine-3-hydroxamic acid

Pyridine-3-hydroxamic acid (nicotinohydroxamic acid) (CgH502N2) (Other references in Vol.5, p.464)... 

Krogsgaard-Larsen and co-workers have protected the P-keto functionality as a ketal as a modification to the traditional conditions so attack of hydroxylamine is directed towards the ester. They prepared hydroxamic acid 10 from ester 9 then cyclized with sulfuric acid to isoxazole 11, in route to 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), a selective GABAa receptor agonist studied clinically for insomnia. 

Cyclic hydroxamic acids and V-hydroxyimides are sufficiently acidic to be (9-methylated with diazomethane, although caution is necessary because complex secondary reactions may occur. N-Hydroxyisatin (105) reacted with diazomethane in acetone to give the products of ring expansion and further methylation (131, R = H or CH3). The benzalphthalimidine system (132) could not be methylated satisfactorily with diazomethane, but the V-methoxy compound was readil3 obtained by alkylation with methyl iodide and potassium carbonate in acetone. In the pyridine series, 1-benzyl-oxy and l-allyloxy-2-pyridones were formed by thermal isomeriza-tion of the corresponding 2-alkyloxypyridine V-oxides at 100°. 

JMJD2 demethylases are inhibited by analogues of the cofactor 2-OG that include N-oxalylamino acids, pyridine dicarboxylates, and related bipyridyl derivatives. Other chemotypes that are also presumed to bind to the active-site Fe(II) include catechols, hydroxamic acids (including the clinically used HD AC inhibitor SAHA/Vorinostat), and tricarboxylic acid cycle intermediates, such as succinate and fumarate [59,62]. 

O-linked polymer-bound Af-substituted hydroxylamines are prepared by reduction of resin-bound oximes with borane-pyridine complex in the presence of dichloroacetic acid (Scheme 94). Other reducing systems commonly used for imine or oxime reduction are ineffective, including borane-pyridine in the presence of acetic acid. Subsequently, the A-substituted products are acylated and cleaved from the resin to afford Af-substituted hydroxamic acids 220. ... 

The low value for oS30 undoubtedly arises from intramolecular hydrogen bonding stabilizing the neutral form of the acid (4), a circumstance also occurring in the pyridine-2-carboxylic and -2-hydroxamic acids as well as 2-hydroxypyridine. 

Chlorination of aldoximes. NCS converts aryl aldoximes to hydroxamic acid chlorides without significant chlorination of the aryl group. This reaction has been used for a novel synthesis of nitrile oxides. Thus reaction of salicylaldoxime (1) with NCS followed by dehydrochlorination with pyridine generates a nitrile oxide, which is trapped by styrene to give the isoxazoline 2. The N-O bond can be cleaved by catalytic hydrogenation to 3, which is converted into the chalcone 4 on elimination of water. This product can be converted by classical methods to the flavanone 5 and the flavone 6. An analogous route can be used to synthesize 2-... 

An antibiotic active against Mycobacterium phlei, S. aureus and other bacterial strains has been isolated from a Streptomyces sp. and named actinonin. It is obtained as fine, white needles or colorless rods from ethanol-ether, m. p. 148-149° (uncorr.). Soluble in water, alcohols, and pyridine stable in cold dilute alkali and acid. C19H35O5N3. Actinonin is apparently a primary hydroxamic acid (49, 93). 

Clauson-Kaas and co-workers333 have carried out a different pyridine synthesis with acylfurans. 2-Acetylfuran (54) is first converted into the ketal (55). After electrolysis to 56, the pyridine-A-oxide (57) is formed via acid-catalyzed ring opening and treatment with hydroxylamine. A tautomeric pyridone form (58) (hydroxamic acid) has also been proposed334 ... 

The enhanced reactivity of zwitterionic nucleophiles, as mentioned above, can be applied to the bifiinctional system. The hydroxamic acid group was introduced by partial quatemization into poly-l-vin d-2-ediylimidazole 25 and poly-4-tdnyl-pyridine 26 (109). The pK value of the hydroxamic acid unit is 8.0 0.2 in toth cases, vdiUi is lower by 1 to 2 pK unit than those of ordinary hydroxamic adds. 

N-oxidation can occur in a number of ways to give either hydroxylamines from primary and secondary amines [Eqs. (11) and (12)], hydroxamic acids from amides, or N-oxides from tertiary amines [Eq. (13)]. The enzyme systems involved are either cytochrome P450 or a flavoprotein oxygenase. Hydroxylamines may be further oxidized to a nitro compound via a nitroso intermediate [Eq. (11)]. Oximes can be formed by rearrangement of the nitroso intermediate or N-hydroxylation of an imine, that could in turn be derived by dehydration of a hydroxylamine [Eq. (11)]. N-Oxides may be formed from both tertiary arylamines and alkylamines and from nitrogen in heterocyclic aromatic systems, such as a pyridine ring. 

The 4-pyridinecarboxylic acids [440, 441], 2-carboxythiazoles [445] and 2-carboxyi-midazoles [436, 446], and their esters amides, and thiamides [392, 447-450] are reduced in this way. The corresponding hydrazides [451] and hydroxamic acids [51] are reduced to the amides in the first step and then further reduced. When the activating group in pyridine is in the 3-position the reduction may take place in the nucleus, depending on pH. 

Synthesis. The synthesis of these new compounds are shown in Schemes 4-8. Condensation of -chloropivaloy1 chloride with tri-methylsilyl chloride-treated benzylhydroxylamine in methylene chloride in the presence of pyridine gave a hydroxamic acid derivative 9 in good yield. It is important to block the hydroxyl group of the hydroxylamine to ensure the desired N-acylation otherwise, a stable mixture of 40 60 N- and O-acylated products (9, 10) will be obtained. This isomeric mixture is not only difficult to separate but also reduces the efficiency of the synthesis. 

Differently cross-linked poly(methyl methacrylate) (PMMA) (137) has been employed for the synthesis of supported hydroxamic acids 138 after treatment with hydroxylamine, and reacted with acyl chlorides in the presence of pyridine to give the supported hydroxamic acid esters 139, which are suitable as solid acyl transfer reagents when reacting with alkyl and aryl amines (Scheme 7.42) [143]. 

Known examples are the partial Hofmann degradation of pyridine-2,3-dicarbox-amides,134 the Lossen degradation of pyridine-2,3-bis(hydroxamic) acid,135 this giving both possible products, i.e. 3-hydroxypyrido[2,3-(/]pyrimidine-2,4(l//,3//)-dione and 3-hydroxy-pyrido[3,2-d]pyrimidine-2,4(l//,3//)-dione as a 5 1 mixture, and the conversion of a primary carboxamide function into an intermediate isocyanate in the 2-position by oxidation with lead(IV) acetate.136... 

An example is the partial Lossen degradation of pyridine-3,4-bis(hydroxamic) acid, this giving both possible products, i.e. pyrido[4,3-[Pg.204]

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