Alkylation of Hydroxamic Acids

As already mentioned N-hydroxy- ec-amino acids (118) may also be obtained by addition of the N-substituted hydroxylamine to a double bond (149). 

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Dioxazines are prepared by di-O-alkylation of hydroxamic acids (Scheme 52) using 1,2-dihalides or 1,2-dimesylates (7UOC284,75NKKI041). 

Acid-catalyzed dehydration of A-(2-hydroxyethyl)-A-acylhydrazines 674 is a general route to 4,5-dihydro-l,3,-4-oxadiazines 675 (Scheme 292) <1964JOC668>. 4,2-Dioxazines 678 are prepared by di-O-alkylation of hydroxamic acids using 1,2-dihalides or 1,2-dimesylates 676 (Scheme 293) <1971JOC284>. 

The principal routes to heterocycles of this type are (i) di-O-alkylation of hydroxamic acids with... 

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). 

In the latest of a series of papers Miller and coworkers 202) described the alkylation of hydroxamic acids (263) with alcohol (262) under Mitsunobu conditions 197). In this manner, starting from glutamic acid they obtained several derivatives of N -hydroxyornithine (264-269) which were used subsequently in the synthesis of rhodotorulic acid 202) (Scheme 53). 

A general synthetic method for acyclic a-alkoxynitrones (196) involves the alkylation with triflates of hydroxamic acids (195) in neutral conditions (Scheme 2.69) (352). Similarly, the synthesis of cyclic methoxynitrone of pyrrolines (197) has been carried out (353). 

The presence in the heterocycle of additional basic centers or those open to alkylation can lead to a change in reaction directions. It essentially limits the application of this method in the formation of a-methoxy nitrones. In such cases, it is reasonable to use diazomethane and, depending on the structure of hydroxamic acid (198-201) the yields of a-methoxy nitrones (197), (202-204) can rise from 17% up to 62% (Scheme 2.70) (353). 

Scheme 22 Synthesis of N-alkyl urea hydroxamic acids as PDF inhibitors...

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]. 

Reduction of hydroxamic acids. Buffered TiC lj can reduce simple hydroxamic acids (equation I). Yields are high when R1 is an alkyl group when it is hydrogen, aldehydes are obtained as by-products. The reagent also reduces substituted N-hydroxy-2-azetidinones to /Mactams (equation 11). 

Hackbarth, C.J. et al. 2002. V-alkyl urea hydroxamic acids as a new class of peptide deformylase inhibitors with antibacterial activity. Antimicrob. Agents Chemother. 46, 2752-2764. 

The lactim/lactam tautomerism of hydroxamic acids and their O-alkyl and O-acyl derivatives has also been studied [146], Hydroxamic acids exist in the solid state and in polar solvents as the lactam tautomer only, whereas in nonpolar solvents the hydroximic tautomer is also present. Further analogous solvent-dependent lactim/lactam equilibria have been observed for certain Schiff bases (prepared from anilines and 2(4)-hydroxybenzaldehyde [256] or 2-hydroxynaphthaldehyde [257]), for 3-hydroxypyrazole [258], and for 3-methyl-l-phenylpyrazolin-5-one [259]. 

Luzyanin, K. V., Kukushkin, V. Y., Haukka, M., Frausto da Silva, J. J. R., Pombeiro, A. J. L. The metalla-Pinner reaction between Pt(IV)-bound nitriles and alkylated oxamic and oximic forms of hydroxamic acids. Dalton Transactions 2004, 2728-2732. 

Fig. 4a. Pathways of hydroxamic acid syntheses of siderophores containing Ns-hydroxyornithine building blocks, a) Starts with e-nitro-L-norvaline. Schemes b) and c) start with ornithine derivatives protected at N5 with CBZ (benzyloxycarbonyl) and Tos (toluenesulfonate), BZL (benzyl), respectively Fig. 4b. Scheme of the synthesis of aerobactin. Protected g-hydroxynorleucine 1 (P = BOC,P = CH3) is transformed into the protected hydroxamic acid 2. Deprotection of the a-NH2 grqup enables alkylation of the o-substituted hydroxamate to give compound 3...

For this reason, we consider it hardly possible to cite all of the publications. Let us focus only on the following examples. Hydroxamic acids have already been for a long time subject of the classical analytical chemistry. In [71], the possibility of using these compounds in flotation of rare-earth minerals is shown. It has been concluded that on a mineral surface cerium chelates are formed. Besides, chemisorption is accompanied by a physical multilayer adsorption of hydroxamic acid derivatives formed by reaction with cations in the water phase. A number of chelate-forming compounds including hydroxamic acids has been tested in flotation of niobium ores [72]. The best results are obtained when using alkyl phosphonic acids. Chemisorption mechanism and the structure of the surface compounds are established by spectroscopic methods. 

Feringa and coworkers reported a copper-catalyzed O-arylation of dialkyl phosphonates and phosphoramidates with diaryliodonium triflates and 2,6-di-ferf-butylpyridine (DTBP), giving easy access to mixed alkyl aryl phosphonates via elimination of one of the alkyl groups as the alkyl triflate prior to arylation (Scheme 10a) [133]. Aryl(mesityl)iodonium salts reacted in a chemoselective way. Copper-catalyzed arylations of hydroxamic acids [134] and carboxylic acids [135] have also been reported, the latter utilizing thiophosphoramides as cooperative catalysts to allow arylation at room temperature. Onomura s group discovered a Cu-catalyzed monoarylation of vicinal diols in toluene at 100 °C. Only traces of product were obtained with alcohols lacking the vicinal hydroxyl group [136]. 

Compounds such as IV, VI, and X are esters of hydroxamic acids and in the case of structure IV are named alkyl hydroxamates. 

To synthesize the monoxacetam stmctures (Fig. 6), alkylation of A/-protected 1-hydroxyazetidinones (46) with the appropriate haloacetic acid derivatives provided (47). Alternatively, (47) could be prepared from the acycHc hydroxamate ester (48). Deprotection of (47) furnished the zwitterionic intermediate (49) [90849-16-4] CgH2QN204, which subsequendy underwent acylation using the C-3 aminothiazole oxime side chain to afford SQ 82,291 (45) also known as oximonam (37). 

Because of the great range of structures containing cyclic hydroxamic acid functions it is difficult to give a concise summary of the available synthetic methods. Nevertheless, the vast majority of published syntheses depend on condensation reactions involving only familiar processes of acylation or alkylation of hydroxylamine derivatives. The principles of such syntheses are outlined in a number of typical examples in Section III, A but no attempt has been made to cover all reported cases. 

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. 

Cyclic hydroxamic acids and V-hydroxyimides are sufficiently acidic to be (9-methylated with diazomethane, although caution is necessary because complex secondary reactions may occur. N-Hydroxyisatin (105) reacted with diazomethane in acetone to give the products of ring expansion and further methylation (131, R = H or CH3). The benzalphthalimidine system (132) could not be methylated satisfactorily with diazomethane, but the V-methoxy compound was readil3 obtained by alkylation with methyl iodide and potassium carbonate in acetone. In the pyridine series, 1-benzyl-oxy and l-allyloxy-2-pyridones were formed by thermal isomeriza-tion of the corresponding 2-alkyloxypyridine V-oxides at 100°. 

There has as yet been no systematic work on the mass spectra of cyclic hydroxamic acids, but from the limited information available the direct loss of 0 or OH from the molecular ion is to be expected. The fragmentation behavior of the 0-alkyl derivatives is rather unpredictable, although again processes involving fission of the N—0 bond are generally important. Table II shows the prominent first-generation fragment ions from a few hydroxamic acids and their ethers. 

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