0-Methyl hydroxamates

Cleavage of N-0 bonds. 0-Methyl hydroxamates are reduced to primary amides in ethanol. Hydroxylamines are transformed into secondary amines or imines. ... 

Further studies by Yu and coworkers [62] were devoted to the search for more efficient directing groups. Thus, simple benzoic acids could be ortho-methylated with methylboronic acid in 63-75% yield. Subsequently, a broader scope and milder conditions were found for the alkylation of the more challenging C(sp )-H bonds [63] by using 0-methyl hydroxamic adds, which are stronger directing groups than carboxyUc adds and easily functionalizable (Scheme 19.41) [64]. 

SCHEME 3.76 Synthesis of 0-methyl hydroxamates from benzoic acid derivatives [81]. 

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. 

Annulation reactions between unactivated alkynes and a range of heteroatom-containing substrates have facilitated the preparation of a host of heterocycles. For example, the preparation of isoquinolones was achieved through a rhodium-catalyzed annulation of internal acetylenes with 0-methyl hydroxamates (Scheme 3.78 and Example 3.12) [81]. The reaction conditions were quite mild, and most reactions were complete within 16 h. The overall process was redox neutral and used a catalytic amount of cesium acetate to promote the reaction. Additionally, the process was not appreciably sensitive to the electronic composition of the 0-methyl hydroxamates. One of the more attractive aspects of this chemistry was the observation that the rhodium-catalyzed reaction... 

P,y-Diamino analogues 49 of statine are prepared stereoselectively starting from the O-methyl hydroxamate derivative of N-protected statine. The reaction sequence involves the formation of a p-lactam intermediate obtained by internal cyclization under Mitsunobu conditions.184 Alternatively, direct amination of either a p-oxo ester 31 followed by reduction of the resulting enamine 50, 85 or by reduction of the corresponding ,p-unsaturated ester, 88 gives an enantiomeric mixture of the corresponding unprotected p-amine, which is protected by a carbamate prior to chromatographic separation (Scheme 20). 

The benzylation of both activated and deactivated arenes has been achieved using the boron trifluoride activation of A -methyl hydroxamate leaving groups to liberate the reactive benzyl cations. Elimination of p-toluenesulfinic acid from a-amidosulfones under the influence of tris(pentafluorophenyl)borane gives acyl iminium ions, which may attack activated arenes to yield p-tolylsulfone derivatives (12), as indicated in Scheme 1 (where Cbz represents the fV-benzyloxycarbonyl leaving group). Elimination... 

Scheme 19.41 C(sp )-H alkylation with boronic acids directed by O-methyl hydroxamic acids.

C(sp ]-H Alkylation with Boronic Acids Directed by O-Methyl Hydroxamic Acids... 

As a follow-up work, Yu et al. succeeded to develop O-methyl hydroxamic acids-directed P-C(sp )-H arylation with aryl boronic acids imder mild reaction conditions in 2008 (Scheme 1.6) [23]. Remarkably, they identified that air could be employed as a sustainable external oxidant to replace silver salts (Scheme 1.6b). Since the O-methyl hydroxamic acids are readily to undergo a series of organic transformations, this protocol provides a facile access to a class of bioactive target molecules. 

SCHEME 3.79 Metal-free amiulation reactions between O-methyl hydroxamates and internal aUcynes [83]. 

Benzoic acids are convenient entry points for this chemistry as they can be converted in a one-pot reaction into an O-methyl hydroxamates [81] This reaction has been developed using rhodium complexes as catalysts and O-methyl hydroxamates as the substrates along with an internal alkyne [81]... 

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. 

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°. 

Metal alkoxides undergo alkoxide exchange with alcoholic compounds such as alcohols, hydro-xamic acids, and alkyl hydroperoxides. Alkyl hydroperoxides themselves do not epoxidize olefins. However, hydroperoxides coordinated to a metal ion are activated by coordination of the distal oxygen (O2) and undergo epoxidation (Scheme 1). When the olefin is an allylic alcohol, both hydroperoxide and olefin are coordinated to the metal ion and the epoxidation occurs swiftly in an intramolecular manner.22 Thus, the epoxidation of an allylic alcohol proceeds selectively in the presence of an isolated olefin.23,24 In this metal-mediated epoxidation of allylic alcohols, some alkoxide(s) (—OR) do not participate in the epoxidation. Therefore, if such bystander alkoxide(s) are replaced with optically active ones, the epoxidation is expected to be enantioselective. Indeed, Yamada et al.25 and Sharp less et al.26 independently reported the epoxidation of allylic alcohols using Mo02(acac)2 modified with V-methyl-ephedrine and VO (acac)2 modified with an optically active hydroxamic acid as the catalyst, respectively, albeit with modest enantioselectivity. 

Prepare a 1M solution of hydroxylamine in coupling buffer sufficient to again treat the slide. The pH of the coupling buffer should be adjusted to pH 10 after dissolving the hydroxylamine into it. Expose the slide to the hydroxylamine solution in the same manner as the crosslinker treatment. The hydroxylamine will react with the methyl ester groups on the salicylic acids and form hydroxamate functionalities suitable for conjugation with the P(D)BA-modified protein from above. 

Namely, the reaction of 2-thioxothiazolidin-4-one N-hexanoic acid (116) with 2,5-dimethyl-l-phenylpyrrol-3-carboxaldehyde (117) in methanol under the catalytic action of ethylenediamine diacetate (EDDA) yields 5-[(2,5-dimethyl-l-phenylpyrrol-3-yl)methylidene]-2-thioxothiazolidin-4-one N-hexanoic acid (118) in 79% yield. The hydroxamate derivative of 118 is prepared by reacting this compound with 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine followed by treatment with p-toluenesulfonic acid in methanol to afford compound 121 in 60% yield. Esterification of compound 118 is carried out by using methyl iodide in acetonitrile in the presence of sodium carbonate to give compound 120. The 5-(cyclohexyl)methylidene analogue (119) is obtained in 42% yield by direct reaction of compound 116 with cyclohexanecar-boxaldehyde in methanol under the catalytic action of EDDA. 

The discovery of oxazoline hydroxamates as potential inhibitors of LpxC was the result of high-throughput screening of large libraries of compounds at the Merck Research Laboratories in collaboration with the Department of Biochemistry, Duke University Medical Center [95]. The lead compound, L-573,655, was a racemic mixture of 4-carbohydroxamido-2-phenyl-2-oxazoline, which had been previously made by Stammer et al. [96] as a precursor in the chemical synthesis of cyclosporine. Namely, (R,S)-serine methyl ester hydrochloride (149) is converted into (R,S)-4-carbomethoxy-2-phenyl-2-oxazoline (150) via treatment with ethyl benzimidate using the Elliot procedure [97]. Treatment of this ester with one equivalent each of hydroxylamine and sodium methoxide in methanol at room temperature affords the desired (R,S)-4-carbohydroxamido-2-phenyl-2-oxazoline (151), as depicted in Scheme 30. 

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. 

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