Hydroxamic chlorides, reaction with

The reaction with hydroxamic acid chlorides has been extensively used recently by Italian chemists to synthesize di- and poly-isoxa-zolyls, as exemplified by 5-substituted 3,3 -diisoxazolyIs (29). °... 

Nowadays, the most economical way of preparing hydroxamic acid derivatives is the reaction of hydroxylamine with acid chlorides or esters . Unfortunately, the preparation of acid chlorides is often tedious. In addition, it is very difficult to avoid further acylation during the reaction with hydroxylamine. 

BrOP). These active esters react smoothly with amines at room temperature (reaction 9).42 Similarly, supported oximino esters 2743 and hydroxamic esters 2844 undergo facile acyl transfer reactions with amines at room temperature (reaction 10). The spent activating agent can be regenerated many times (by acylation with the appropriate acid chloride) without appreciable loss in activity. 

Benzonitrile oxide (C in Figure 15.44) is an isolable 1,3-dipole. It can be generated from benzaldoxime and anNaOH/Cl2 solution. Under these reaction conditions the oxime/nitroso anion (A B) is initially formed and chlorine disproportionates into Cl—O and chloride. An SN reaction of the negatively charged C atom of the anion A B at the Cl atom of Cl— O or of Cl—O—H affords the oc-chlorinated nitroso compound E, which tautomerizes to the hydroxamic acid chloride D. From that species, the nitrile oxide C is generated via a base mediated 1,3-elimination. Isoxazoles are formed in the reactions of C with alkynes (Figure 15.44), while isoxazolines would be formed in its reactions with alkenes. 

By retro synthetic analysis collagenase inhibitor RO0319790 (1) can be assembled from two chiral building blocks, (R) -succinate 2 and (S)-tert-leucine N-methyla-mide 13. As the latter can be prepared from commercially available (S)-tert-leucine 8 our work concentrated in particular on the construction of the first building block 2. In order to assemble the carbon skeleton of 2 in the most efficient way, extremely cheap maleic anhydride 4 was converted in a known ene reaction with isobutylene to provide the cyclic anhydride 6. Hydrogenation of the double bond followed by the addition of EtOH/p-TsOH yielded the racemic diethyl ester substrate 9 for the enzyme reaction. The enzymatic monohydrolysis of 9 afforded the monoacid (R)-2a. (R)-2 a was coupled via its acid chloride with leucine amide 13 to ester 14, which finally was converted into the hydroxamic acid 1. 

A test for sulphonic acids is based on conversion to the sulphonyl chloride and then reaction with hydroxylamine. The reaction product can be converted with a drop of acetaldehyde to a hydroxamic acid which is detected in the classical way through the brown-violet colour with a drop of a Fe3+ reagent264. 

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. 

This test identifies the presence of esters, and if the test is negative the assumption is made that a polyether is present. The test is based on the reaction of the ester with hydroxylamine, with the formation of the hydroxamic salt and the subsequent reaction with acidic ferric chloride to give a complex salt possessing an intense violet or purple colour. 

The degradation of glucosinolates by ammonia in aqueous methanol has been investigated with simple hydroxamic acid derivatives (21) as model substrates. Nitriles or hydroxynitriles and thioglucose and its dimer, bis-(D-glucopyranosyl)disulphide, were the major products. In a similar study, use was made of the [4, 5 - H] labelled derivative (22), prepared by reaction of the chloride (23) with 1-thioglucose 2,3,4,6-tetraacetate and subsequent deacetylation. ... 

If the copper was immersed in a sodium chloride solution with or without benzo-hydroxamic acid (BHA) derivatives, a thick layer was formed on the metal surface, which consisted of copper oxide, chloride, and the inhibitor molecule. The results revealed that the curve representing the aggressive solution showed two semi-circles which characterize the anodic reaction involving mass transfer through the copper oxide layer. The semi-circle at a higher frequency is due to the modulation for cop-per(I)chloride adsorbed at the electrode, while the low frequency part represents the diffusion process at the electrode due... 

Nucleophilic Reactions. M,C)-Bis(trimethylsilyl)hydroxyl-amine is a protected, lipophilic form of hydroxylamine. It reacts with a variety of electrophiles predominantly by attack on the nitrogen nucleophilic center. Reaction with acid chlorides (1 equiv) in the presence of triethylamine gives M<9-bis(trimethylsilyl)-hydroxamic acids by iV-acylation. A related reagent, tris(tri-methylsilyl)hydroxylamine, gives the same product in high yields, also by iV-acylation. Hydrolysis gives the free hydroxamic acids, whereas thermal fragmentation affords isocyanates (eq 1). ... 

Acid anhydrides and chlorides react with hydroxylamine in the same way as esters, with the formation of hydroxamic acids. The color reaction and paper chromatographic analysis can be carried out as described on p. 262 for esters. The reaction conditions can be adjusted so that anhydrides can be detected or identified in the presence of esters. However, acid chlorides react under both sets of conditions (53, 54). 

Sulfonic acids can be converted on reaction with thionyl chloride to corresponding chlorides, which on reaction with hydroxylamine change to sulfonyl-hydroxamic acids. These acids react in an alkaline medium with acetaldehyde with the formation of acetohydroxamic acids and sulfinic acids. Both products give colors with ferric chloride the first red, the second red-orange. 

The experimental conditions for the syntheses starting from acid chlorides of hydroxamic acids and from nitrile oxides are somewhat different. In the former case the other component of the reaction is organometallic, usually an organomagnesium derivative of an acetylene or, less frequently, a sodium enolate of a /8-diketone. Nitrile oxides condense directly with unsaturated compounds. 

As second example for the scale-up of solid-phase reactions directly on solid support, we chose an arylsulfonamido-substituted hydroxamic acid derivative stemming from the matrix metalloproteinase inhibitor library (MMP) of our research colleagues (Breitenstein et al. 2001). In this case, there was already a solution-phase synthesis available for comparison (see Scheme 4). The synthesis starts with the inline formation of a benzaldehyde 18 with the glycine methyl ester, which is then reduced to the benzylamine 20 using sodium borohydride in methanol/ THF (2 1). The sulfonamide formation is carried out in dioxane/H20 (2 1) with triethylamine as the base and after neutralisation and evaporation the product 21 can be crystallised from tert. butylmethyl ether. After deprotection with LiOH, the acid is activated by treatment with oxalyl chloride and finally converted into the hyroxamic acid 23 in 33.7% yield overall. 

Although the simplest route to prepare hydroxamic acid derivatives remains the reaction of hydroxylamine with acid chlorides, this last method cannot be apphed to all Af-protected-a-amino acids. The synthesis of Fmoc-protected amino acid hydroxamates represents the only exception to this rule . In fact, Fmoc-amino acid hydroxamates 98 can be synthesized by the acylation of hydroxylamine using Fmoc-amino acid chlorides 97 in the presence of MgO (Scheme 52). The route is simple, efficient, and affords good yields of products. 

An alternative approach applicable both to the synthesis of racemic aspergillic acid428 and neoaspergillic acid is illustrated by the synthesis (Scheme 50) of neoaspergillic acid (8).429 The initial reaction of dl-leucine anhydride (235) with phosphoryl chloride produces, in addition to the required monochloro compound (236), some dichloro compound (237), and flavacol (4). Reaction of the latter compound with a mixture of phosphoryl chloride and phosphorus pentachloride yields further 2-chloro-3,6-diisobutylpyrazine (236). The remaining steps of the synthesis involve reactions discussed previously in this review, with the exception that the hydroxamic function is protected by diazomethane methylation and finally regenerated by ethanolic hydriodic acid treatment.429... 

---