Hydroxamic acid preparation

Table 3 Tripeptide Hydroxamic Acids Prepared with a Modified Wang Resin 50 ...

Phosphorus analogs of hydroxamic acids, prepared fromphos-phinic chlorides and Ai,0-bis(trimethylsilyl)hydroxylamine, tend to be unstable. The stable O-sulfonyl derivatives of the phos-phinoylhydroxylamines undergo base-induced, Lossen-type rearrangement to phosphonamidates by aryl group migration from P to N (eq 4). ... 

The hydrogenolysis of hydroxamic acids (22) and hydra2ides (23) has also been used to synthesi2e amides. One of the earliest methods for the preparation of amides consists of treating acid chlorides with dry ammonia or an amine (24). 

Ring substituents show enhanced reactivity towards nucleophilic substitution, relative to the unoxidized systems, with substituents a to the fV-oxide showing greater reactivity than those in the /3-position. In the case of quinoxalines and phenazines the degree of labilization of a given substituent is dependent on whether the intermediate addition complex is stabilized by mesomeric interactions and this is easily predicted from valence bond considerations. 2-Chloropyrazine 1-oxide is readily converted into 2-hydroxypyrazine 1-oxide (l-hydroxy-2(l//)-pyrazinone) (55) on treatment with dilute aqueous sodium hydroxide (63G339), whereas both 2,3-dichloropyrazine and 3-chloropyrazine 1-oxide are stable under these conditions. This reaction is of particular importance in the preparation of pyrazine-based hydroxamic acids which have antibiotic properties. 

Earlier reported syntheses have been shown to give isoxazolin-5-ones. Other isoxazolin-3-ones have been prepared by the reaction of methylacetoacetic esters and hydroxylamine. An additional synthesis was reported by the action at 0°C of hydroxylamine on ethyl -benzoylpropionate to produce an insoluble hydroxamic acid which cyclized on acid treatment. The hydroxamic acid acetal was similarly transformed into the isoxazolin-3-one (Scheme 149) (71BSF3664, 70BSF1978). 

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. 

Only one cyclic hydroxamic acid which contains the pyrido[2,3-d]-pyrimidine ring system has been reported.This is 2-methyl-3-hydroxypyrido[2,3-d]pyrimidin-4(3i/)-one (21) which was prepared by the action of acetic anhydride on 2-aminonieotinhydroxamic acid (20) or from ethyl 2-aeetamidonicotinate (22) and hydroxylamine. In view of the known antibacterial activity of certain cyclic hydroxamic acids further work on these compounds would be of interest. 

The cyclic hydroxamic acid (104) obtained by this route had previously been prepared by the two methods illustrated. These exemplify well the variants possible within route (ii). 

This type of synthesis has been used extensively in the preparation of hydroxamic acids resembling aspergillic acid. a-Aminohj droxamic acids react with a-dicarbonyl compounds to yield pyrazine hydroxamic acids (18). Glyoxal and diacetyl react readily, but poor... 

Quinazoline hydroxamic acids (26) can be prepared by acylation of an o-aminobenzohydroxamic acid (25). An alternative procedure... 

Shaw and McDowellhave prepared imidazolone derivatives by cyclization of a-acylamino amides. In a variation of this reaction the azlactone (30) was gradually converted to the hydroxamic acid (31) by methanolic hydroxylamine. Sodium methoxide and hydroxylamine readily gave the acyclic hydroxamic acid (32) which could be cyclized to 31 by dilute acid. Benzyloxyurea has been used in the sjrnthesis of pyrimidine hydroxamic acids (33) by reaction with /S-diketones followed by catalytic hydrogenation of the benzyl group. Protection... 

By this method, Chauveau and Mathis have prepared cyclic hydroxamic acids (41) containing a sulfur atom in the ring. The acyclic precursors (40) were formed by alkylation of a thiol anion. 

During a study of azonitrones (70), Forrester and Thomson showed that reaction with toluene-p-sulfinic acid resulted in nitrogen evolution and formation of the hydroxamic acid (66) together with the pyrrolidone (71) and the amidine (72). These workers suggested the following reaction course. Although the yield of hydroxamic acid was high, the method is not likely to be of preparative value. 

Several reactions are particularly applicable to the synthesis of cyclic hydroxamic acids as they involve some kind of ring expansion. Some are quite general reactions which are of high preparative utility, whereas others exist as fairly isolated examples which have not as yet been generalized. 

The method which has been of most preparative value is that established by Panizzi el and Di Maio and Tardella. Benzene-sulfonhydroxamic acid (74), known as Piloty s acid, reacts with a cyclic ketone (73) in alkaline media at 0 , to produce the ring-expanded hydroxamic acids (75 and 76) in approximately equal yield. 

Alicyclic hydroxamic acids undergo several specific oxidative cleavage reactions which may be of diagnostic or preparative value. In the pyrrolidine series compounds of type 66 have been oxidized with sodium hypobromite or with periodates to give y-nitroso acids (113). Ozonolysis gives the corresponding y-nitro acids. The related cyclic aldonitrone.s are also oxidized by periodate to nitroso acids, presumably via the hydroxamic acids.This periodate fission was used in the complex degradation of J -nitrones derived from aconitine. 

A mixture of 3-hydroxy-4-phenylfurazan and 1,2,4-oxadiazole 243 was prepared from a-phenyl-a-hydroximino hydroxamic acid by acylation and subsequent treatment with 15% aqueous NaOH (Scheme 164) (25G201). The reaction of tetraacetate 244 with sodium acetate hydrate in glacial acetic acid at 70°C gives 3,4-dihydroxyfurazan (9%) (92URP1752734). a-Hydroximino ester 245 reacts with hydroxylamine to form furazan 246 in 25% yield (Scheme 164) (79JHC689). 

The first synthesis of a 3,5-diarylisoxazole from aryl hydroxamic acid chlorides and sodium phenyl acetylides was that effected by Weygand and Bauer in 1927. Beginning in 1946, when Quilico and Speroni showed that acid chlorides of hydroxamic acids on treatment with alkalies readily yielded nitrile oxides,numerous isoxazole and especially A -isoxazoline derivatives have been prepared. 

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. 

When primary nitro compounds are treated with sulfuric acid without previous conversion to the conjugate bases, they give carboxylic acids. Hydroxamic acids are intermediates and can be isolated, so that this is also a method for preparing them. Both the Nef reaction and the hydroxamic acid process involve the aci form the difference in products arises from higher acidity, for example, a difference in sulfuric acid concentration from 2 to 15.5 M changes the product from the aldehyde to the hydroxamic acid. The mechanism of the hydroxamic acid reaction is not known with certainty, but if higher acidity is required, it may be that the protonated aci form of the nitro compound is further protonated. 

Hydroxamic acids can also be prepared from primary nitro compounds with SeOa and EtsN Sosnovsky, G. Krogh, J.A. Synthesis, 1980, 654. 

More recently, screening efforts at Novartis have identified a hydroxamic acid containing a benzothiazinone ring system (32) [108]. This inhibitor is very potent versus S. aureus Ni -PDF (<5nM) and displays good selectivity versus matrix metalloprotease-2 (MMP-2) and MMP-13. Unfortunately (32), and all other analogues prepared, such as carbon isosteres (33), sulfones (34), N-substituted analogues (35) and N-formyl-N-hydroxylamines (36), lacked appreciable antibacterial activity in spite of their potent enzyme inhibitory activity. Further studies performed by Novartis suggest that these molecules are unable to penetrate the outer cell membrane of E. coli, and may bind to the cell membrane of S. aureus [108]. 

Hydroxamic acids are an important class of compounds targeted as potential therapeutic agents. A-Fmoc-aminooxy-2-chlorotrityl polystyrene resin 61 allowed the synthesis and subsequent cleavage under mild conditions of both peptidyl and small molecule hydroxamic acids (Fig. 14) [70]. An alternative hydroxylamine linkage 62 was prepared from trityl chloride resin and tV-hydroxyphthalimide followed by treatment with hydrazine at room temperature (Scheme 30) [71]. A series of hydroxamic acids were prepared by the addition of substituted succinic anhydrides to the resin followed by coupling with a variety of amines, and cleavage with HCOOH-THF(l 3). 

An intramolecular hetero-Diels-Alder reaction of enantiomerically pure iV-acyl nitroso derivatives 78, prepared from hydroxamic acids 77 by oxidation on treatment with Pr4NI04 in an aqueous medium, afforded a mixture of diastereomeric pyrido[l,2-A][l,2]oxazin-8-ones 79 and 80 (Scheme 5) <1996J(P1)1113, 20000L2955,... 

Breitenstein W, Hayakawa K, Iwasaki G, Kanazawa T, Kasaoka T, Koizumi S, Matsunaga S, Nakajima M, Sakaki J (2001) Preparation of arylsulfonamido-substituted hydroxamic acid derivatives as MMP2 inhibitors. Int Pat Appl... 

Acyl nitroso compounds (3, Scheme 7.2) contain a nitroso group (-N=0) directly attached to a carbonyl carbon. Oxidation of an N-acyl hydroxylamine derivative provides the most direct method for the preparation of acyl C-nitroso compounds [10]. Treatment of hydroxamic acids, N-hydroxy carbamates or N-hydroxyureas with sodium periodate or tetra-alkyl ammonium periodate salts results in the formation of the corresponding acyl nitroso species (Scheme 7.2) [11-14]. Other oxidants including the Dess-Martin periodinane and both ruthenium (II) and iridium (I) based species efficiently convert N-acyl hydroxylamines to the corresponding acyl nitroso compounds [15-18]. The Swern oxidation also provides a useful alternative procedure for the oxidative preparation of acyl nitroso species [19]. Horseradish peroxidase (HRP) catalyzed oxidation of N-hydroxyurea with hydrogen peroxide forms an acyl nitroso species, which can be trapped with 1, 3-cyclohexanone, giving evidence of the formation of these species with enzymatic oxidants [20]. 

Bromolactamization (11, 76). This reaction can be used for stereoselective preparation of 3,4-disubstituted 3-lactams.1 Thus the P,-y-unsaturated hydroxamic acid 1, prepared in several steps from tiglic acid, on reaction with bromine and K2C03 in aqueous CH,CN cyclizes mainly to a rrans-p-lactam (2). In contrast, the protected a-amino-p,y-unsaturated hydroxamic acid 3, prepared in several steps from L-methionine, cyclizes on reaction with bromine mainly to a ris-p-lactam (4). 

TOA were determined, in the supernatant prepared as described by Hissett et al (25), by the method of Montgomery et al (26). The organic acids were esterified with acidified ethylene glycol. The esters were then reacted with hydroxylamine and the hydroxamic acids thus formed were converted to their ferric complexes and their concentrations were determined by optical density measurements at 500u. 

A very simple chiral Lewis acid, prepared by mixing optically pure BINOL with 3 equiv of Me3Al, catalyzes the [4+2] cycloaddition of A-hydroxy-A-phenylacry-lamine with cyclopentadiene at 0°C in high yield (>96%) and a fairly good level of enantioselectivity (91% ee). Facile conversion of the products to the corresponding alcohols or aldehydes makes the hydroxamic acid intermediates particularly useful (Scheme 12.14). ... 

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