Substitution hydroxamic acids

Abstract. The direct scale-up of a solid-phase synthesis has been demonstrated with 4-(2-amino-6-phenylpyrimidin-4-yl)benzamide and an arylsulfonamido-substituted hydroxamic acid derivative as examples. These compounds were obtained through combinatorial chemistry and solution-phase synthesis was used in parallel to provide a comparison. By applying highly loaded polystyrene-derived resins as the solid support, a good ratio between the product and the starting resin is achieved. We have demonstrated that the synthesis can be scaled up directly on the solid support, successfully providing the desired compounds easily and quickly in sufficient quantities for early development demands. 

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. 

Breitenstein W, Hayakawa K, Iwasaki G, Kanazawa T, Kasaoka T, Koizumi S, Matsunaga S, Nakajima M, Sakaki J (2001) Preparation of arylsulfonamido-substituted hydroxamic acid derivatives as MMP2 inhibitors. Int Pat Appl... 

FIGURE 2.11 Structures and nomenclature of compounds that serve as auxiliary nucleophiles. Generation of activated esters. Substituted hydroxamic acids are sometimes added to carbodi-imides or other reactions to improve the efficiency of couplings. The additive suppresses side reactions by converting activated species into activated esters (see Section 2.10) before they have time to undergo secondary reactions, p(Me2SO) HOBt 9.30, HOAt 8.70. 

An appraisal has been made of the available kinetic data on the acid hydrolyses of hydroxyamic acids. For A-substituted hydroxamic acids both A-2 and A-1 paths are recognized, but for primary hydroxamic acids there is evidence only for the A-2... 

Other 0-aUcylation methods are exploited less frequently. 0-Allylation of Af-substituted hydroxamic acids of type 25 with allyl carbonates such as 26 and related compounds has been achieved through palladium catalyzed addition-elimination (equation 16). 

K. 0-Linked Polymer-bound A-Substituted Hydroxamic Acids. 214... 

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. 

The preparation of A-phenyl-substituted hydroxamic acids 125 in the reaction of formaldehyde with nitrosobenzene to give 124 is strongly catalyzed by Fe + ions, which stabilize the transition states 126 and 127 for the rate-controlling proton transfer from the carbon atom of nitrosocarbinolic cation intermediate 125 leading to the product 128 (Scheme 62) . 

O-linked polymer-bound Af-substituted hydroxylamines are prepared by reduction of resin-bound oximes with borane-pyridine complex in the presence of dichloroacetic acid (Scheme 94). Other reducing systems commonly used for imine or oxime reduction are ineffective, including borane-pyridine in the presence of acetic acid. Subsequently, the A-substituted products are acylated and cleaved from the resin to afford Af-substituted hydroxamic acids 220. ... 

A formal synthesis of ( )-Eseroline (69) via a 3-aza-4-oxa-Cope rearrangement was reported. An iV-aryl A-hydroxycarbamate was reacted with 2-phenylsulfanylpropanoic acid to yield the O-acylhydroxamic acid derivative 65, R = H that rearranged in the presence of potassium bis(trimethylsilyl)amide. The [3,3] and [3,5] rearrangement products, respectively 66 and 67, were formed (equation 22). If the para-substituted hydroxamic acid 65, R = OCOBu-t is used, no [3,5] rearrangement product is observed and the [3,3] rearrangement product 68 is the only product formed (equation 23). The authors proposed two parallel mechanisms, a concerted pathway and an ionic mechanism by an ion-pair recombination. 

Amide formation from carboxylic acids 480 with O-subsituted hydroxylamine hydrochlorides also proceeds in the presence of DCC to give the substituted hydroxamic acid 481 in 91 % yield.451... 

The fourth related rearrangement reaction is the Lossen reaction, which generally occurs by base treatment of 0-substituted hydroxamic acids which possess electron-withdrawing functions at the oxygen atom (e.g. O-acylhydroxamic acids), giving amines via isocyanates (equation 6). Preliminary 0-activation (e.g. O-acylation) of hydroxamic acids is essential for a smooth rearrangement, otherwise it will not occur, ilie Lossen reaction is not as useful as the other three rearrangements since hydroxamic acids are not readily available. 

Stability constants for the complexation of Cd by edta (H L) to yield [Cd(HL)] and [CdL] have been determined, as well as data on the complexation of zinc with propylenediaminetetra-acetic acid, zinc and cadmium with trans-1,2-cyclohexanediaminetetra-acetic acid, ° and mercury with diamino derivatives of succinic and malonic acids. Substituted hydroxamic acids have also been used as chelates in the complexation of zinc and cadmium. ... 

Supplementary information concerning the 1,4-cycloaddition of nitrosoben-zene to A -(ethoxycarbonyI)azepine is now available. A new adduct (27) has been reported. Decomposition" of the known adduct (28) in the presence of alkenes leads to the formation of A-substituted hydroxamic acids in high yield. The procedure gives an effective method of allylic amidation. 

Substituted hydroxamic acids successfully cyclize to form 3-lactams as long as EtsN is present (eq 19). In the absence of the base, complex mixtures are formed. Unsubstituted amides can be converted into nitriles via dehydration (eq 20). This is the reagent of choice for the transformation of the amide to the nitrile in eq 21. ... 

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