Hydroxamic Acids and Hydrazides

Hydrazine can readily be linked to acid-labile benzyl alcohol resins either as /V-ben-zylhydrazine (Entry 7, Table 3.17) or as carbamate (Entries 8 and 9, Table 3.17). The 

Hydroxamic acids and hydrazides can also be prepared by nucleophilic cleavage of resin-bound esters, activated amides, or thiol esters [359] with hydroxylamine and 

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Figure 3.22. Strategies for the solid-phase preparation of hydroxamic acids and hydrazides. X leaving group, Y NH, O.

Seifier, S., P. M. Gallup, S. Michaels and E. Meilman Analysis of hydroxamic acids and hydrazides preparation and properties of dinitrophenyl derivatives of hydroxamic acids, oximes, hydrazides and hydrazones. J. Biol. Chem. 235, 2613 (1960). 

The hydrolysis of esters (and amides) by chymotrypsin satisfies these criteria. The hydrolysis of, say, acetyl-L-tryptophan p-i itrophenyl ester forms an acylen-/yme that reacts with various amines such as hydroxylamine, alaninamide, hydrazine, etc., and also with alcohols such as methanol, to give the hydroxamic acid, dipeptide, hydrazide, and methyl ester, respectively, of acetyl-L-tryptophan. The same acylenzyme is generated in the hydrolysis of the phenyl, methyl, ethyl, etc., esters of the amino acid (and also during the hydrolysis of amides). 

Amides, Imides, Hydrazides, Hydroxamic Acids, and Azides... 

Activation of Carboxylic Acids Synthesis of Acyl Imidazoles. iV,AA-Carbonyldiimidazole (1) converts carboxylic acids into the corresponding acylimidazoles (2) (eq 1). The method can be applied to a wide range of aliphatic, aromatic, and heterocyclic carboxylic acids, including some examples (such as formic acid and vitamin A acid) where acid chloride formation is difficult. The reactivity of (2) is similar to that of acid chlorides, but the former have the advantage that they are generally crystalline and easily handled. Isolation of (2) is sirr5>le, but often unnecessary further reaction with nucleophiles is usually performed in the same reaction vessel. Conversion of (2) into acid chlorides (via reaction with HCl), hydrazides, hydroxamic acids, and peroxy esters have all been described. Preparation of the more irr5)ortant carboxylic acid derivatives is described below. 

Method 6. Polymerization of Bis(hydroxamic acids) and Bis(hydrazides) WITH Metal Salts... 

As in 10-55 hydrazides and hydroxamic acids can be prepared from carboxylic esters, with hydrazine and hydroxylamine, respectively. Both hydrazine and hydroxylamine react more rapidly than ammonia or primary amines (the alpha effect, p. 445). Imidates, RC(=NH)OR, give amidines, RC(=NH)NH2. Lactones, when treated with ammonia or primary amines, give lactams. Lactams are also produced from y- and 5-amino esters in an internal example of this reaction. 

Researchers at Novartis, Senju and Hoffman-La Roche have reported structurally related bicyclic hydroxamic acids as potent PDF inhibitors [106-108]. In 2001, screening efforts at Hoffman-LaRoche identified hydrazide (28)... 

In the patent literature, Aventis has published a patent application covering hydroxamic acid containing macrocycles (39) with the same general template as the A-formyl-A-hydroxylamine macrocycles described above [114] and GlaxoSmithKline has published an application on macrocyclic PDF inhibitors containing a hydrazide scaffold (40) [115], No data has been published on these inhibitors to date. 

Much more important than these reactions, however, are the reactions of CDI and its analogues with carboxylic acids, leading to AAacylazoles, from which (by acyl transfer) esters, amides, peptides, hydrazides, hydroxamic acids, as well as anhydrides and various C-acylation products may be obtained. The potential of these and other reactions will be shown in the following chapters. In most of these reactions it is not necessary to isolate the intermediate AAacylazoles. Instead, in the normal procedure the appropriate nucleophile reactant (an alcohol in the ester synthesis, or an amino acid in the peptide synthesis) is added to a solution of an AAacylimidazole, formed by reaction of a carboxylic acid with CDI. Thus, CDI and its analogues offer an especially convenient vehicle for activation of... 

Table 13.10. Preparation of hydrazides and hydroxamic acid derivatives.

Many carbamoylpyrazines and related compounds such as IV-hydroxyamides (hydroxamic acids), hydrazides, cyanamides, guanidinocarbonyl-, guanidino-carbamoyl-, and ureidocarbonylpyrazines have been prepared from pyrazinecarboxylic esters. The amides were usually prepared with ammonia in methanol (or other alcohols) but also under other conditions. 

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. 

Oxidations of hydroxamic acids by periodate (assumed to involve a nitrosylacyl intermediate) and of hydrazides by potassium ferrocyanide, followed by quenching with amines, are of limited preparative value. 

Salts of thiols (170) oi of sulfinic acids (171) react like the alkoxides, giving 4-alkylthio- oi 4-alkylsulfono-suhstituted butyrates. Alkali cyanides give 4-cyanobutyrates (172), hydroxylamine gives a hydroxamic acid (173), and hydrazine a hydrazide (174). 

The imidazo[5,l -e]-l.2,3,5-Letrazine-8-carbonyl chloride 17 reacts preferentially with nucleophiles (Nu ) at the 8-carbonyl group rather then at the 4-oxo group, allowing the preparation of a wide range of ester, thioester, amide, hydroxamic acid, hydrazide, sulfoximide, azide, and diazoacetyl derivatives.42... 

The hydrogenolysis of hydroxamic acids (22) and hydrazides (23) has also been used to synthesize amides. One of the earHest methods for the preparation of amides consists of treating acid chlorides with dry ammonia or an amine (24). 

Hydrazinolysis provides access to hydrazides [20, 21], and the action of hydrox-ylamine results in the formation of hydroxamic acid derivatives [22]. However, both of the latter transformations have not been used extensively. 

TABLE XI-33. Pyridine Side-Chain Hydrazides, Hydroxamic Acids, Amidines, and Imides (Continued)... 

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