Hydroxamic acids, from esters

Very recently, Mordini and coworkers" have overcome the problems associated with the long reaction times that are normally required for the synthesis of hydroxamic acids from esters by performing these transformations under MW irradiation. The protective groups are also well tolerated under these reaction conditions, though a partial deprotection of the feri-butoxycarbonyl (Boc) group was observed in the reaction with Boc-proline ester. Amidic bonds and ketals also survive without any detectable decomposition. All the reactions go to completion in about six minutes, except in the case of the conversion of Boc-protected phenylalanine methyl ester, which required longer reaction times (12 min). 

Although several routes have been published for the preparation of hydroxamic acids on solid phase, these generally involve the preparation of a special linker to which hydrox-ylamine is attached. Dankwardt s approach obviates the need for special linkers or protecting groups, by displacing the desired hydroxamic acid from the resin directly using hydroxylamine, as illustrated in Scheme 86. CarboxyUc-acid-ester-linked, polymer-supported, Cbz-protected amino acids 195 (formed from 194) were displaced from the resin with aqueous hydroxylamine to provide the corresponding hydroxamic acids 196. 

The aglucone HDMBOA has been reported as present in com whorl surface waxes [64]. A structural assignment was given, however, some doubt remained, at least in the purity of the sample described. We followed two pathways for the preparation of the hydroxamic acid methyl esters HDMBOA and 2-hydroxy-4-methoxy-2/f-l,4-benzoxazin-3(4/i -one [120] from their precursors DIMBOA and DIBOA, respectively (Fig. (12)). Whereas an independent synthesis for the latter compound has been reported in a patent [110] a synthesis of HDMBOA has not been described yet. 

Cyclic hydroxamic acids from nitrocarboxylic acid esters O... 

RgureS. Generation of a peptidyl hydroxamic acid from a succinimide ester. 

Hydroxamic acids from carboxylic acid esters COOR CONHOH... 

Imidazoles from purines o-Aminocarboxylic acid amides from pyrimidine ring Carboxylic acid amides from hydroxamic acid benzyl esters... 

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. 

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). 

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. 

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... 

However, the switchover from an A2 to an A1 hydrolysis is a very common mechanistic pathway in strong acid media, probably more common than the pure A2 mechanism. Excess acidity analyses have shown that thioacetic acid, several thiobenzoic acids, and many thiolbenzoate and thionbenzoate esters show this sort of mechanism switch.179 Acylals and thioacylals also show this behavior,116 with thioacylals using two water molecules and acylals one. Many hydroxamic acids react this way,127,216 as do esters of various types,41,217,218 episulfoxides219 and aryloxatriazoles.220 Acylhydrazines can also show a mechanism switch of this sort, although with these substrates the situation is somewhat more complex.221... 

Although the synthesis of 3-isoxazolols from P-keto esters and hydroxylamine suffers from the formation of 5-isoxazolones as major products, treatment of acyl chlorides with Meldrum s acid 4 followed by aminolysis gave rise to p-keto hydroxamic acids 6 that cyclised to the corresponding 5-substituted 3-isoxazolols 7 without formation of any byproduct <00JOC1003>. Cyclisation of N-substituted salicylhydroxamic acids 9 under... 

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. 

Scheme 3 outlines synthetic strategies for the introduction of a range of substituents on the amide, alkoxyl and acyloxyl side chains. Hydroxamic esters 23 are readily synthesised from potassium salts of hydroxamic acids 21 according to Cooley et al.7 8 9 or by condensation of the corresponding acid chloride 24 with an alkoxyamine. 

In 1983, Prasad et al.12 first reported the condensation of chloromethyl polystyrene with /V-hydroxyphthalimide to give the ester, hydrazinolysis of which yielded the desired resin-bound hydroxylamine. However, the sole purpose of this reagent was to react with, and hence extract ketones from, a complex steroidal mixture, and its use for the solid-phase synthesis of hydroxamic acids was not explored. Recently, the exploitation of the above solid-phase approach for the synthesis of hydroxamic acids was independently reported by three groups,7-9 all of which differ only in the method for the initial anchoring of TV-hydroxyphtha-limide to an 4-alkoxybenzyl alcohol functionalized polystyrene or trityl chloride polystyrene. Subsequent /V-deprotection was... 

The more activated the ester, the less stable is the compound. All the esters mentioned above can be used as shelf-stable reagents except benzotriazolyl esters, which decompose too readily. In addition to their use as activated forms of the A - a I ko x y ca r bo n y I am i n o acids, the esters derived from hydroxamic acids are implicated as intermediates in coupling reactions in which the A-hydroxy compounds have been added to promote efficient coupling between an acid and a primary or secondary amine (see Section 2.10). It is pertinent to mention that the O-acylisourea generated from carbodiimides (see Section 2.02) is an activated ester but one of nature different than those alluded to above. 

A group at Lilly reported that phenoxazine (89) is a potent inhibitor of cRBL (0.02 iM) [237]. Substitution at the 1-position by carboxylic acid, ester, or hydroxamic acid groups decreased potency 10- to 30-fold. Substitution at the 2-position was less destructive of inhibition as long as the substituent was lipophilic (ester, acrylate ester) carboxylate caused a 200-fold loss of potency. Activity in rat neutrophils has been disclosed for related structures in patents from Bayer [238]. The second aromatic ring is not required, as shown by the activity of series exemplified by (90)-(92) [239-242]. Antiasthmatic activity was indicated for these compounds, but few details were given. 

A patent from Ortho disclosed naphthoylvalerohydroxamic acids which inhibit 5-HETE release from RBL-1 cells (0.1 /rM) and also showed oral activity in RAA [292], The most potent compound (51 % at 50 mg/kg) was the A-isopropyl analogue (115). Although only the hydroxamic acids inhibited 5-LO activity, simple acids and esters showed comparable RAA activity, suggesting that the hydroxamic acids yielded an anti-inflammatory carboxylic acid metabolite. 

Ho and coworkers" have observed that the addition of small amounts of solid KCN (0.2 equivalents) can effectively accelerate the formation of hydroxamic acids 112 from methyl esters 111 (Scheme 58). The authors suggested that this reaction proceeds through an acylcyanide intermediate followed by nucleophilic substitution by 50% aqueous hydroxylamine at room temperature. The use and advantage of this methodology have been demonstrated for both solution-phase and solid-phase applications. 

The syntheses of the methyl esters 116-118 from 115 and hydroxamic acids 119-121 were carried out via a typical alkylation of the hydroxy function of methyl 4-hydroxyben-zoate 116 followed by either reaction with hydroxylamine to provide bishydroxamic acids 119-121 containing an alkyl spacer between two aromatic rings. 

In 2003, Devocelle and colleagues reported a convenient two-step procedure for the parallel synthesis of hydroxamic acids (or O-protected hydroxamic acids 207) from carboxylic acids and hydroxylamine. It involves the formation of a polymer-bound HOBt active ester 206 from 204 and the acid 205 and subsequent reaction with O-protected or free hydroxylamine (Scheme 89). The use of free hydroxylamine leads to increased yields while maintaining high purities. Recycling of the exhausted resin 204 to prodnce the same or a different hydroxamic acid has been achieved by a three-step protocol, which is easily amenable to automation and cost-economical. 

Opening of the dithiazole ring of the imidazolo[4,5-r7 [l,2,3]dithiazole 107 was employed as a key step in a multistep synthesis leading to hydroxamic acid derivatives 108 and 109 which are under investigation as matrix metalloproteinase inhibitors. Following initial reaction of 107 with NaOH treatment with 2-bromo-3-(4-chlorophenyl)propionic acid tert-butyl ester lead to the thioethers 108 from which 109 could be obtained (Scheme 10). <2000W0063197>. 

Product analyses showed that for all five esters, the OH - and buffer-dependent components generated the corresponding hydroxamic acids. The pH-independent reaction also led to the hydroxamic acid product for 39c and 39f, but 39a and 39e generated products that appeared to be derived from N—O bond heterolysis in the pH region dominated by (pH < 8). ... 

Since differences were often reported in product yields from photochemical and thermal reactions, it was not clear that the same intermediate was generated in both cases. This issue was complicated by the fact that the temperatures under whieh the two experiments were run were usually quite different. The acid-base chemistry of nitrenium ions was largely unexplored so it was not known under what conditions these species could be protonated or deprotonated. It had also not been demonstrated that nitrenium ions played any role in the biological activity of mutagenic and carcinogenic esters of N-arylhydroxylamines or hydroxamic acids, particularly in their reactions with the DNA bases. Over the next decade these issues would be resolved but many questions about nitrenium ion chemistry would remain unanswered. 

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