Hydroxylamines, addition with carboxylic esters

Hydroxylamine is acylated by carboxylic esters, giving hydroxamic acids. The reaction often occurs in a few hours at room temperature if the components are mixed in alcoholic solution, preferably with addition of an equivalent of an alkoxide. In the latter case the hydroxamic acids are obtained as salts, but are easily liberated therefrom. 

Isoniazide, the hydrazide of pyridine-4-carboxylic acid, is still, well over half a century after its discovery, one of the mainstays for the treatment of tuberculosis. Widespread use led to the serendipitous discovery of its antidepressant activity. This latter activity is retained when pyridine is replaced by isoxazole. The requisite ester (45-4) is obtained in a single step by condensation of the diketo ester (45-1), obtained by aldol condensation of acetone with diethyl oxalate, with hydroxylamine. One explanation of the outcome of the reaction assumes the hrst step to consist of conjugate addition-elimination of hydroxylamine to the enolized diketone to afford (45-2) an intermediate probably in equilibrium with the enol form (45-3). An ester-amide interchange of the product with hydrazine then affords the corresponding hydrazide (45-5) reductive alkylation with benzaldehyde completes the synthesis of isocarboxazid (45-6) [47]. 

In an early report on peptide hydroxamic acids as metalloprotease inhibitors, the peptide acid (Z-Gly-L-Leu-OH) was converted into the V-hydroxysuccinimide ester using DCC, which was subsequently reacted with hydroxylamineJ10 More reactive condensing reagents such as BOP can form the hydroxamic acid directly from the carboxylic acid and hydroxylamine via an intermediate HOBt ester. A number of hydroxamic acids has been synthesized by the treatment of the corresponding methyl esters with hydroxylamine in the presence of KOH 122 this reaction requires careful choice of reagent concentrations and ratios. In addition, the precursor carboxylic acid is treated with diazomethane to make the methyl ester. The use of diazomethane makes the procedure hazardous, but should be useful in special cases that require a better cost performance. 

To a solution of isopropyl ester of 6-formyl-5-methoxycarbonyl-2-methyl-4-(3-nitrophenyl)-l,4-dihydropyridine- 3-carboxylic acid (4.5 g) in acetic acid (35 ml) were added hydroxylamine hydrochloride (0.97 g) and sodium acetate (1.43 g), and the mixture was stirred at ambient temperature for 2.5 hours. After acetic anhydride (4.14 g) was added to this reaction mixture, the mixture was stirred at ambient temperature for 1.5 hours and at 95-100°C for additional 4 hours. The acetic acid and the excess of acetic anhydride were removed in vacuum, followed by adding water to the residue and it was neutralized with a saturated aqueous solution of sodium bicarbonate. This aqueous suspension was extracted twice with ethyl acetate, and the combined extract was washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to give a reddish-brown oil (4.88 g), which was chromatographed over silica gel (150 g) with a mixture of... 

In the synthesis of hydroxamic acid 19a, having a free quaternary amino group (see Scheme 4.4), the intermediate sulfone 21 was synthesized by Pd-catalyzed reaction of phenol with p-bromo derivative 20 [24], Lithiation of 20, followed by nucleophilic addition to the A-Cbz imine of trifluoropyruvate 22 [25] afforded the a-CF3 a-amino acid derivative 23 in fair yields. Basic hydrolysis of the ester function gave the carboxylic acid 24, which was submitted to condensation with ()-15 n-hydroxylamine, affording hydroxamate 25. The subsequent hydrogenolysis of 25 afforded the target molecule 19a. 

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