Hydroxyamide

Industrial Synthetic Improvements. One significant modification of the Stembach process is the result of work by Sumitomo chemists in 1975, in which the optical resolution—reduction sequence is replaced with a more efficient asymmetric conversion of the meso-cyc. 02Lcid (13) to the optically pure i7-lactone (17) (Fig. 3) (25). The cycloacid is reacted with the optically active dihydroxyamine [2964-48-9] (23) to quantitatively yield the chiral imide [85317-83-5] (24). Diastereoselective reduction of the pro-R-carbonyl using sodium borohydride affords the optically pure hydroxyamide [85317-84-6] (25) after recrystaUization. Acid hydrolysis of the amide then yields the desired i7-lactone (17). A similar approach uses chiral alcohols to form diastereomic half-esters stereoselectivity. These are reduced and direedy converted to i7-lactone (26). In both approaches, the desired diastereomeric half-amide or half-ester is formed in excess, thus avoiding the cosdy resolution step required in the Stembach synthesis. 

Polyfunctional 2-hydtoxyalk5iamides can serve as cross-linkers for carboxyHc acid-terrninated polyester or acryHc resins (65). The hydroxyl group is activated by the neighboring amide linkage (66). SoHd grades of hydroxyamides are finding use as cross-linkers for powder coatings (67). 

Oxazole synthesis tram aldehydes and a-hydroxyamides or cyanohydnns. 

Synthesis, reactions, and metal-chelating properties of functionalized heterocycles possessing N-hydroxyamide moiety 97YGK524. 

By transformation of modified PAN fibres of type 2 into iV-hydroxyamide derivatives of type 3 (Scheme 1), it is possible to form intermolecular chelate bonds by interaction with Fe+3 ... 

A major limitation still remained in this methodology cychzation of hydroxyamides substituted a to the hydroxy group could not be achieved except when the substituent was a mere methyl group, as anything bulkier would prevent the tosylation step, hi this case, using microwave irradiation to force the reaction (Scheme 16) did not prove sufficient, and even after prolonged microwave irradiation at 150 °C no trace of the desired material could be observed. 

A further modification of the same reaction pattern has been described [83] starting from the /f-hydroxyamide 128 that cycUzed in the presence of DIG and Cu(OTf)2 under microwave irradiation at 100-175 °C within 5-15 min to give compound 129 (Scheme 45). 

Whereas cycHzation of the cu-keto-co -hydroxyamide 1466 in boihng toluene or xylene in the presence of camphorsulfonic acid (CSA) results in decomposition of the starting material 1466, heating of 1466 with excess TMSOTf 20 and N-methyl-morphoHne in 1,2-dichloroethane affords 46% of the desired cycHzation product 1467 [30] (Scheme 9.16). The close relationship of product 1467 to d -oxazolines suggests that reaction of carboxylic acids 11 with free (or C-substituted) ethanola-mines 1468 and HMDS 2/TCS 14 might lead analogously, via the silylated intermediates 1469, to d -oxazolines 1470 and HMDSO 7. As demonstrated in the somewhat related cyclization of 1466 to 1467, combination of TMSOTf 20 with N-... 

Lithium enolates of carboxylic acids such as phenylacetic acid or of amides such as N-methyl-N-phenylvaleric acid amide 1974 are oxidized by BTSP 1949 to a-hydroxy acids, which are isolated after esterification, e.g., to 1973, or to a-hydroxyamides such as 1975 [155] (Scheme 12.43) (cf. also the formation of 3-hydroxybutyrolactam 1962). 

The pyruvaldehyde and phenylglyoxal adducts (19) with trimethyl phosphite reacted with isocyanates to give the carbamoyl-1,3,2-dioxa-phospholens (20), probably as shown. These, with hydrogen chloride, gave phosphate esters of )3-keto-a-hydroxyamides. 

In addition, a fluid loss additive for oil-based drilling fluids, which consists of fatty acid compounds and lignite or humic acid, an oil-soluble or oil-dispersible amine or amine salt with phosphorie acid, or an aliphatic amide or hydroxyamide [392], has been described. 

Boronic acid derivatives are able to form ring structures with other molecules having neighboring functional groups consisting of 1,2- or 1,3-diols, 1,2- or 1,3-hydroxy acids, 1,2- or 1,3-hydroxylamines, 1-2- or 1,3-hydroxyamide, 1,2- or 1,3-hydroxyoxime, as well as various... 

On reaction with hydroxylamine in the presence of appropriate bases, such derivatives of D-glucofuranurono-6,3-lactones as 25, 26, and 33 form114 N-hydroxyamides. On the other hand, when treated with hydroxylamine without base catalysis, compound 4 yields115 aWeJjt/do-D-glucurono-6,3-lactone oxime. 

TV-Acyl indoles derived from amides have been employed for the conversion of lactones into protected hydroxyacids. Thus, (chloromethyl)alumi-num 2-(2-propenyl)anilide reacts (120) with 1,4- and 1,5-lactones, as for example per-O-terZ-butyldimethylsilyl-D-ribono-1,4-lactone (104), to afford hydroxyamides. After protection of the free hydroxyl group, these amides were converted by ozonolysis into TV-acyl indoles, 105, which were readily saponified to the acid 106. 

The procedure was proved to be general for the preparation of protected hydroxy acids from lactones (121). This apparently trivial process is often difficult to carry out, as the attempted derivatization of y or J-hydroxyacids frequently results in relactonization rather than hydroxyl protection. The method was applied to several aldonolactones to produce the corresponding intermediate hydroxyamides. Protection using [(2-trimethylsilyl)-ethoxy]methyl chloride, methoxymethyl chloride, ter/-butylchlorodimeth-ylsilane, or zm-butylchlorodiphenylsilane followed by ozonolysis gave the protected N-(y- or <5-hydroxyacyl)indole derivatives. Mild saponification gave indole and the acetal- or silyl-protected hydroxy acids. 

In contrast, liquidiliquid phase-transfer catalysis is virtually ineffective for the conversion of a-bromoacetamides into aziridones (a-lactams). Maximum yields of only 17-23% have been reported [31, 32], using tetra-n-butylammonium hydrogen sulphate or benzyltriethylammonium bromide over a reaction time of 4-6 days. It is significant that a solidiliquid two-phase system, using solid potassium hydroxide in the presence of 18-crown-6 produces the aziridones in 50-94% yield [33], but there are no reports of the corresponding quaternary ammonium ion catalysed reaction. Under the liquidiliquid two-phase conditions, the major product of the reaction is the piperazine-2,5-dione, resulting from dimerization of the bromoacetamide [34, 38]. However, only moderate yields are isolated and a polymer-supported catalyst appears to provide the best results [34, 38], Significant side reactions result from nucleophilic displacement by the aqueous base to produce hydroxyamides and ethers. 

SYNTHESIS OF AN a-HYDROXYAMIDE N.N-DIETHYL-2-HYDROXY-4-PHENYLBUTANAMIDE. GENERATION OF N,N-DIETHYLCARBAMOYLLITHIUM VIA LITHIUM-TELLURIUM EXCHANGE AND ITS REACTION WITH 3-PHENYLPROPANAL (Benzenebutanamide, N,N-dlethyl-a-hydroxy-)... 

Tab. 5.4 Cyclodehydration of hydroxyamides and thioamides with polymeric Burgess reagent 26.

At the two lower concentrations, the orange color of methyl orange was confined to the top of the GPG spin column and with increasing concentrations the orange color moved down the column towards the top of the spin column frit, consistent with the ESI-MS intensity observations. Similar dose response titration studies have been reported with stronger binders, e.g., matrix metalloproteinase-1 (MMP-1) protein with a substituted hydroxyamide WY252 with an IC50 of 9.9 pM (see Fig. 2.7) [15]. 

Chiral butenolides are valuable synthons towards y-butyrolactone natural products [37] and have also been successfully applied to the synthesis of paraconic acids. The lactone 91, readily available from the hydroxyamide (rac)-90 by enzymatic resolution [38] followed by iodolactonization, proved to be an especially versatile key intermediate. Copper(I)-catalyzed cross coupling reactions with Grignard reagents allowed the direct introduction of alkyl side chains, as depicted in 92a and 92b (Scheme 13) [39, 40]. Further... 

Not only cyanide but also an isocyanide behaves as a nucleophile to attack a carbonyl compound or an imine that is prepared in situ from an carbonyl compound. " In these reactions, an isocyanide is a synthetic equivalent to an aminocarbonyl anion. Asymmetric version of this reaction appeared in 2003. Using a combination of Lewis acid SiCU and a Lewis base chiral bisphosphora-mide, the corresponding a-hydroxyamide is obtained in 96% yield with >98% ee (Scheme 4.23). 

Mai, A., Massa, S., Pezzi, R., Simeoni, S., Rotili, D., Nebbioso, A. etal. (2005) Class 11 (lla)-selective histone deacetylase inhibitors. 1. Synthesis and biological evaluation of novel (aryloxopropenyl) pyrrolyl hydroxyamides. Journal of Medicinal Chemistry, 48, 3344-3353. 

Aromatic or conjugated aldehydes react in excellent yields, whereas the reaction with aliphatic aldehydes requires longer times and leads to A-hydroxyamides in lower, althongh satisfactory, yield. When both aldehyde and ketone gronps are present on the same... 

For hydroxamic acids, it is generally assumed that it is the Af-hydroxyamide/keto form, as opposed to the hydroximic/hydroxyoxime form, that predominates in acid medium, the environment usually required for most precipitates or colors to form . It is in general unknown what is the stoichiometry and structure of most metal hydroxamate complexes in solution. Nevertheless, the reaction of the majority of hydroxamic acids with metal ions can be written schematically as shown in equation 2. 

Pantothenic acid (8.48), a hydroxyamide, occurs mainly in liver, yeast, vegetables, and milk, but also in just about every other food source, as its name implies [pantos (Greek) = everywhere]. It is part of coenzyme A, the acyl-transporting enzyme of the Krebs cycle and lipid syntheses, as well as a constituent of the acyl carrier protein in the fatty-acid synthase enzyme complex. 

Reaction with ammonia and primary and secondary amines can also give two types of products, 0-hydroxyamides or amino acids (equation 49). The amide is obtained from the reaction of 0-propiolactone with ammonia in water, while the amino acid is obtained from the reaction in acetonitrile, both in good yield. 0-Lactones react very generally with both aliphatic and aromatic amines, but the type of product does not correlate with polarity of solvent or basicity of amine. Fortunately, conditions can usually be found for the formation of the desired product. 

The reaction of several a-amino acid esters with 0-lactones in chloroform solution gave hydroxyamide esters (equation 50), said to be useful fungicides (74JAP(K)74127918>. Enamines derived from cyclohexanone react smoothly with 0-propiolactone to give 3-(2-cyclo-hexanonyl)propionamides in reasonable yields (equation 51). No acylation of the enamine is observed. This reaction has been used as a key step in a new synthesis of 8-aza steroids (75JOC50). Cyclohexanone imines react in the same manner, except that the expected initial product cyclizes to give bicyclic lactams and enaminones (equation 52) (80T3047). 

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