Esters hydroxamic acid synthesis

Classical reactions involving nucleophiles such as saponification ("OH as the nucleophile), aminolysis (with amines also ammonia in ammonolysis reactions), transesterification (alkoxides, "OR) and others (hydrazinolysis, hydroxamic acid synthesis, etc.) have been adapted to solid phane and used to obtain, for instance, carboxylic acids, amides and esters. Internal or intramolecular nucleophilic attack has been employed to obtain cyclic products such as lactones, lactams (including cyclic peptides) and a great variety of heterocycles (hydantoins, diketopiperazines, benzodiazepinones, etc.). 

Clark, A.J., Al-Faiyz, Y.S.S., Patel, D. and Broadhurst, M.J. (2001) Rearrangement of unactivated A-alkyl-O-benzoyl hydroxamic acid derivatives with phosphazene bases. Tetrahedron Letters, 42, 2007-2009 Clark, A.J., Patel, D. and Broadhurst, M.J. (2003) Base-mediated reaction of A-alkyl-O-acyl hydroxamic acids synthesis of 3-oxo-2,3-dihydro-4-isoxazole carboxylic ester derivatives. Tetrahedron Letters, 44, 7763-7765. 

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). 

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... 

Polymer-bound 1-hydroxybenzotriazole 1008 reacts with carboxylic acids in the presence of 1,3-diisopropylcarbo-diimide (1,3-DIC) and DMAP to produce esters 1009. Treated with hydroxylamine, esters 1009 are converted to hydroxamic acids 1010 (Scheme 167) <20030BC850>. Starting 1-hydroxybenzotriazole 1008 is recycled in the process and can be used for other syntheses. This method is well suited for automated synthesis of a library of hydroxamic acids. In similar applications of polymer-supported 1-hydroxybenzotriazole 1008, a wide variety of amides is synthesized <1997JOC2594, 2002JC0576>. 

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. 

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... 

TR Govindachari, S Rajappa, AS Akerkar, VS Iyer. Hydroxamic acids and their derivatives IV. Further studies on the use of esters of pivalohydroxamic acid for peptide synthesis. Tetrahedron 23, 4811, 1967. 

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). 

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>. 

Stereospecific synthesis of succinyl derivatives is now commonly carried out as shown in Scheme 7. The tert-butyl ester of the succinyl amino acid methylamides 16 was treated with TFA to deprotect the carboxy group, which was then activated by isobutyl chloroformate and reacted with H2NOTMS.[18] The OTMS protection was removed during the isolation and purification of the hydroxamic acid 17. 

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. 

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. 

Differently cross-linked poly(methyl methacrylate) (PMMA) (137) has been employed for the synthesis of supported hydroxamic acids 138 after treatment with hydroxylamine, and reacted with acyl chlorides in the presence of pyridine to give the supported hydroxamic acid esters 139, which are suitable as solid acyl transfer reagents when reacting with alkyl and aryl amines (Scheme 7.42) [143]. 

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