Hydroxy amides formation

Interposition of a methylene group between the phenyl ring and the heterocycle leads to the benzyldiami nopyrimidines, a class of compounds notable for their antibacterial activity. Condensation of hydrocinnamate 54 with ethyl formate leads to the hydroxymethylene derivative 55. In this case, too, the heterocyclic ring is formed by reaction with guanidine. This sequence probably involves initial addition-elimination to the forniyl carbon to form 56 cyclization in this case involves simple amide formation. Tautomerization then affords the hydroxy derivative 57. This is converted to tetroxoprim (58) by first... 

The recombinantly expressed nitrilase from Pseudomonas fluorescens EBC 191 (PFNLase) was applied in a study aimed at understanding the selectivity for amide versus acid formation from a series of substituted 2-phenylacetonitriles, including a-methyl, a-chloro, a-hydroxy and a-acetoxy derivatives. Amide formation increased when the a-substituent was electron deficient and was also affected by chirality of the a- stereogenic center for example, 2-chloro-2-phenylacetonitrile afforded 89% amide while mandelonitrile afforded 11% amide from the (R)-enantiomer but 55% amide was formed from the (5)-enantiomer. Relative amounts of amide and carboxylic acid was also subject to pH and temperature effects [87,88]. 

Wuts and co-workers recently reported that the Vilsmeier reagent is superior to thionyl chloride for the cyclodehydration of primary and secondary p-hydroxy amides to prepare oxazolines, in particular, for oxazoline 18b, which is used in Taxol synthesis (Scheme 8.10). Some other examples are shown in Table 8.5 (Fig. 8.3). As expected, inversion of configuration at the alcohol bearing carbon atom is observed. Of the examples examined, serine afforded low yields due to the formation of dehydroalanine. The reaction is conveniently carried out in pyridine at room temperature. p-Chloro amides are also formed, which can be converted to the oxazoline with DBU, generally using the same mixture without isolation. The... 

Conversion of the hydroxyl group of a p-hydroxy amide to a mesylate, triilate, ° ° or an acetate ° ° followed by intramolecular displacement of the leaving group is a commonly employed strategy for oxazoline formation. Some examples from the recent literature are hsted in Table Oxazolines... 

Hydroxy amides undergo cyclodehydration to oxazolines under very mUd conditions with triphenylphosphine and carbon tetrachloride. Carbon tetrabromide can also be used. The formation of the corresponding p-chloro amide is generally not a significant problem. The major disadvantage is that removal of the byproduct triphenylphosphine oxide may be difficult at times. Representative examples are shown in Table 8.14 (Fig. 8.5).n4,i4o,i73-i8i... 

A method to prepare 2a based on the work of a related analog [4] was employed for the first mulh-kilogram campaign. In this approach, 2a was prepared from lactam 5, which is derived from an optically enriched P-hydroxy acid. This method requires introduction of the amino group as an 0-benzylhydroxylamine, which we hoped would sufficiently protect the amino group of 2b during amide formation with triazole 3. 

Details of the oxidation and rearrangement of tabersonine (126) to (+)-14,15-dehydrovincamine (127) and (+)-14,15-dehydro-16-cp/-vincamine (128), which were previously recorded only in the patent literature, have now been published.90 A minor product in this sequence of reactions was formulated as (129), since hydrogenation, hydrolysis, and decarboxylation afford a hydroxy-amide (130), which can be reduced to rhazinilam (131) (Scheme 18). The reaction of 14,15-dehydrovincamine (127) with iodine and potassium iodate results in the formation of a dehydro-derivative (not isolated), followed by closure of the tetrahydrofuran ring. The product is the iodo-compound (132), which, as an iodo-enamine, loses its iodine when treated with acid, with formation of the alkaloid criocerine (133).90... 

The oxyamination of C-2 C-3 and C-3-C-4 unsaturated sugars gave mixtures of regioisomeric hydroxy amides, i.e., 12, 13 and 14, 158s-91. The cis dihydroxylation was often a competitive reaction, especially for C-2-C-3 unsaturated sugars, e.g., formation of 1888-91. The products were generally separated by column chromatography. 

Aldol Reactions. Pseudoephedrine amide enolates have been shown to undergo highly diastereoselective aldol addition reactions, providing enantiomerically enriched p-hydroxy acids, esters, ketones, and their derivatives (Table 11). The optimized procedure for the reaction requires enolization of the pseudoephedrine amide substrate with LDA followed by transmeta-lation with 2 equiv of ZrCp2Cl2 at —78°C and addition of the aldehyde electrophile at — 105°C. It is noteworthy that the reaction did not require the addition of lithium chloride to favor product formation as is necessary in many other pseudoephedrine amide enolate alkylation reactions. The stereochemistry of the alkylation is the same as that observed with alkyl halides and the formation of the 2, i-syn aldol adduct is favored. The tendency of zirconium enolates to form syn aldol products has been previously reported. The p-hydroxy amide products obtained can be readily transformed into the corresponding acids, esters, and ketones as reported with other alkylated pseudoephedrine amides. An asymmetric aldol reaction between an (S,S)-(+)-pseudoephe-drine-based arylacetamide and paraformaldehyde has been used to prepare enantiomerically pure isoflavanones. ... 

In the presence of weakly acidic additives, such as Ai-hydroxysuccinimide (HOSu),P l 1,2,3-benzotriazol-l-ol (HOBt),f l 3-hydroxy-l,2,3-benzotriazin-4(3//)-one (HODhbt),b l or 7-aza-l,2,3-benzotriazol-l-ol (HOAt),f l the O N acyl migration as well as racemization/ epimerization (vide infra) are largely prevented.f d Concurrently, conversion of the highly reactive O-acylisourea derivatives and symmetrical anhydrides into the related less reactive active esters 13 derived from these additives takes place which leads to still sufficiently activated species to allow rapid in situ amide formation. 

An alternative approach is to use the readily available P-hydroxy phenyl selenides as Ritter substrates. Amide formation occurs with retention of configuration, indicating that fission of the carbon-oxygen bond is assisted by the neighboring phenylseleno group (Scheme 61). Diphenyl diselenide and iodine react with 1,5-dienes to give carbocyclic products. Initial formation of the episelenonium ion is followed by intramolecular attack and subsequent Ritter reaction (Scheme 62). ... 

Thibault-Starzyk, F., Payen, R., Lavalley, J.-C. IR evidence of zeolitic hydroxy insertion in amide formation by the Ritter reaction. Chem. 

Addition of diethyl aluminum chloride at — 78 °C to a,/ -unsaturated oxazolidinone (154) affords an aluminum enolate that, on hydroxylation with (63a), gives the / -ethyl-a-hydroxy amide (155) with high anti selectivity (Equation (38)) <91AG(E)694>. Formation of the enolate of oxazoline thiol ester (156) under chelation (NaHMDS) and stereoelectronic (NaHMDS/HMPA) control gives the syn and anti alcohols (157), respectively, on hydroxylation with (63a) in good to excellent yield and better than 95% diastereoselectivity (Scheme 28) <93JOC6180>. A counterion dependent reversal in stereochemistry has also been reported for the hydroxylation of chiral amide enolates where the auxiliary was 2-pyrrolidinemethanol <85TL3539>. 

As the role of the common precursor 34 is critical, it has been synthesized in large scale by using an Evans syn aldol protocol [39], starting from the commercially available (i )-(-)-methyl 3-hydroxy-2-methyl propionate 1 . This compound was transformed in three steps to aldehyde 32 [40, 41] and used in an Evans aldol reaction with the dibutylboron enolate A. The Weinreb amide formation completed the construction of the common precursor 34 [42] (Scheme 7). From this precursor fragments C1-C8, C9-C14 and C15-C21 were synthesized (Scheme 8). 

The formation of the lactone (XIII) from the hydroxy-amide (XII) is free of strain and solvation effects and is, incidentally, a good model for the mechanism of hydrolysis of amides catalysed by chymotrypsin. The rate enhancement for this intramolecular reaction is 10 M and therefore agrees well with the theoretical prediction [40]. 

Scheldt and coworkers reported the addition of amide enolates to acylsilanes for generation of p-silylojq homoenolate equivalents 62, based on the fact that less electrophilic p-carbonyl groups disfavor the formation of cyclopropanolates 63 by internal carbanion attack (Scheme 6.30). Instead, the carbanion generated in situ can be trapped by allq l halides, aldehydes, ketones, and imines. The use of optically active amide enolates delivers p-hydroxy amides with high levels of diastereoselectivity. 

Most methods for the formation of oxazolines from B-hydroxy-amines and -acids call for vigorous conditions often leading to polymeric side-products. However Roush and Patel have found that treatment of the easily obtained hydroxy-amides (123) with... 

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