Carboxylic acids 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.). 

In 2000, an efficient three-step procedure for the synthesis of 5-substituted 3-isoxazolols (without formation of undesired 5-isoxazolone byproduct) was published. The method uses an activated carboxylic acid derivative to acylate Meldrum s acid, which is treated with A,0-bis(ten-butoxycarbonyl)hydroxylamine to provide the N,0-di-Boc-protected P-keto hydroxamic acids 14. Cyclization to the corresponding 5-substituted 3-isoxazolols 15 occurs upon treatment with hydrochloric acid in 76-99% yield. 

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>. 

B. Synthesis of Hydroxamic Acids from Carboxylic Acids. 188... 

The A-hydroxycarboxamide group is a key fragment of many siderophores so that a convenient synthesis of this group is crucial for further progress. A variety of methods have been attempted for the preparation of hydroxamic acids starting from carboxylic acids. Although some of these methods are quite efficient for the preparation of substituted hydroxamic acids, the preparation of the parent compound is still a problem and yields are often moderately unacceptable, in part due to the low solubility of the parent hydroxylamine hydrochloride in organic solvents. 

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. 

In 2001, De Luca and GiacomeUi " reported a new simple and high-yielding one-flask synthesis of Weinreb amides from carboxylic acids and A-protected amino acids that uses different 1,3,5-triazine derivatives (such as 236) as the coupling agents (Scheme 104). The method allows the preparation of Weinreb amides 237 and hydroxamates as O-benzyl and 0-silyl hydroxamates that can be easily transformed into hydroxamic acids. 

A variety of Af-methoxy-A-methylamides were thus prepared from commercially available carboxylic acids and amino acids. This methodology is applicable to the synthesis of other O-alkylhydroxamates and also to the preparation of 0-silyl hydroxamates. 

Selection of appropriate hydroxamic esters and carboxylic acid salts has enabled synthesis of a wide range of A-acyloxy-Af-alkoxyamides in which and can be alkyl or aryl but, to date, only aUcoxyl or arylalkoxyl groups have been present at R". ... 

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. 

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. 

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. 

Elshani, S. Du. H. Laintz, K.E. Natale, N.R. Wai, C.M. Elkarim, N.S.A. Bartsch, R.A. Lariat ether carboxylic acids, O-benzylhydroxamates and hydroxamic acids with fluorinated substituents Synthesis, metal ion complexation and solubility in supercritical carbon dioxide. Tetrahedron 2000. 56. 4651-4657. 

Alkylation of hydroxamic acids as a method of co-N-hydroxyamino acids (2) synthesis was introduced by Maurer and Miller 196), When N- r -butoxycarbonyl-6-hydroxynorleucine benzylhydroxamate (248) or a homologue was treated with triphenylphosphine and diethylazodi-carboxylate (DEAD) under Mitsunobu conditions 197), intramolecular alkylation took place leading to N-hydroxylactams (249) or (250) as well as lesser amounts of hydroximates Z-(251) and -(252) (Scheme 50). The products were separated and distinguished by NMR spectrometry 196,198,199). Derivatives of the seven-membered N-hydroxylactam (253) were applied for the total synthesis of mycobactin S2 (254) 199) (Scheme 51). 

The synthesis of 0-methyl hydroxamates has been accomplished starting from carboxylic acids (Schane 3.76 and Example 3.11) [81]. The multistep process was carried out under mild conditions and afforded outstanding yields of the desired hydroxamate (up to 96%). A related report outUned the conversion of unactivated aniUnes into amides under continuous flow conditions (Scheme 3.77) [82]. The reactions were quite fast and only required a 2min residence time. 

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