Amide formation application

Ragnarsson U, Grehn L. Novel amine chemistry based on DMAP-catalysed acylation. Acc. Chem. Res. 1998 31 494-501. Meshram HM, Reddy GS, Reddy MM, Yadav JS. Zinc mediated facile amide formation application to alkyl, aryl, heterocycle, carbohydrate and amino acids. Tetrahedron Lett. 1998 39 4103-4106. 

Many examples of retention of activity in the face of replacement of benzene by thiophene have been noted so far. Application of this stratagem to a clozapine-like antipsychotic constitutes yet another example where activity is retained. The seven-membered ring of the compound in question is established by intramolecular amide formation on intermediate 102. Treatment of amide 103 with N-methylpiperazine in the presence of titanium tetrachloride affords flumezapine (104) [20]. 

Since then, catalytic antibodies which catalyze different chemical reactions have been described. The reactions range from ester or carbonate hydrolysis to carbon-carbon bond forming reactions, bimolecular amide formation or peptide bond cleavage, so the application of catalytic antibodies to general synthetic organic chemistry seems to be very promising [22]. 

It has been reported that Horeau s method can be applied to micromolar quantities of secondary alcohols, if the enantiomeric composition of the remaining 2-phenylbutanoic anhydride is determined by means of gas chromatography. To the acylation mixture an optically active amine [(+)-(R)-l-phenylethanamine] is added which reacts rapidly with the excess of 2-phenylbutanoic anhydride. The resulting diastereomeric amides are then characterized by GLC. The amine salts of 2-phenylbutanoic acid do not interfere. Success is dependent upon rapid amide formation (without significant resolution of the anhydride by the amine)236. The application of this method to (+)-(A/)-binaphthol (9) is shown237. 

The entire process is catalytic the only by-product is water. More than 80% of the process solvent (toluene) can be recovered. The efficiency of amide bond formation is thus hindered by the widespread use of reagents with poor atom economy. The development of reagents with lower mass intensity (MI) factors or catalytic methods such as the exciting application of boric acid or its derivatives to catalyze amide formation in an eco-friendly manner would certainly transform the environmental profile of many processes. 

Kiso, Y. Yajima, H. Amide-Formation, Deprotection, and Disulfide Formation in Peptide Synthesis in Peptides Synthesis, Structures, and Applications, Gutte, B., Ed. Academic Press New York, 1995 pp 40-93. 

Other Preparative Reactions. Polyamidation has been an active area of research for many years, and numerous methods have been developed for polyamide formation. The synthesis of polyamides has been extensively reviewed (54). In addition, many of the methods used to prepare simple amides are applicable to polyamides (55,56). Polyamides of aromatic diamines and aliphatic diacids can also be made by the reaction of the corresponding aromatic diisocyanate and diacids (57). 

Efforts have also been made to improve the methodology used to prepare various mixed donor macrocycles especially applicable to binding transition metal cations <2006POL599>. Various approaches were tried including amide formation followed by reduction (see Figure 4). Activated leaving groups such as tosylate were employed and... 

Conditions for the efficient use of Fmoc-protected amino acid chlorides in stepwise peptide synthesis have been delineated. The acid chlorides are reasonably stable solids that are readily aminolyzed if a base is added to neutralize the hydrogen chloride liberated in the reaction. They form the corresponding oxazol-5(4//)-ones and undergo stereomutation if left in the presence of tertiary amines, however, amide formation without stereomutation can be obtained under appropriate conditions. The acid chlorides are advantageously applied to acylate weak nucleophiles and sterically hindered amino components, but their application may be limited by the lack of stability of tert-butyl-type side-chain protecting groups toward conditions of acid chloride preparation. 

Heterocycles. While several reports deal with formation of furan derivatives by reaction of 2-diazo-l,3-cyclohexanediones and alkynes which are substituted with electron-withdrawing or electron-donating groups, an a-pyridone synthesis based on an analogous reaction of Af-(a-diazoacyl)amides is applicable to the elaboration of the indolizidine skeleton, and accordingly, a synthesis of ipalbidine. ... 

The hydrolysis of nitriles to amides is applicable to C-cyanoglycosides. As shown in Scheme 2.2.19, BeMiller, et al.,14 utilized titanium tetrachloride in acetic acid to effect the conversion of a peracetylated C-cyanogalactoside to its corresponding primary amide. This transformation was effected in an 80% yield. Furthermore, base hydrolysis of the nitrile provides a clean conversion to the carboxylic acid.15 Thus through the methods already mentioned, extensions with standard organic techniques allow the formation of a wide variety of useful functional groups. 

Recently, many new coupling agents have been used to improve the yields of amide formation from acids and amines. However, these coupling agents are expensive and only a few of them have found application in macrocyclic chemistry. For example, diphenylphosphenyl azide was used to prepare a macrocyclic diamide with higher yields than other methods (Qian et al., 1990). 

In contrast to the intermolecular Hantzsch reaction, which has been widely used, intramolecular examples have been scarce in the literature. Recently, an elegant Hantzsch macrocylization has been applied to the synthesis of IB-01211. ° Application of the Holzapfel-Meyers-Nicolaou modification to a-bromoketone-thioamide 27 brings about intramolecular thiazole formation with concomitant dehydration of the primary alcohol to give IB-01211 in moderate yield. This reaction is remarkable, especially considering the fact that the macrocyclization through amide formation at either bond a or b fails to produce any cyclized product. 

The industrial application of catalytic direct amide formation is still little explored and the eurrent proeesses are still unoptimised. Moreover, due to the high tolerance to water, aeids or bases, boron-based catalysts could be considered one of the most potentially interesting areas of research in the arena of direct amidation used in pharmaceuticals and fine chemicals. Clear steps have been followed so far by the scientific community in this direction for amide transformation, especially with boron-based eatalysts, and a renaissance in this area has already been triggered. 

As a further application of the reaction, the conversion of an endocyclic double bond to an c.xo-methylene is possible[382]. The epoxidation of an cWo-alkene followed by diethylaluminum amide-mediated isomerization affords the allylic alcohol 583 with an exo double bond[383]. The hydroxy group is eliminated selectively by Pd-catalyzed hydrogenolysis after converting it into allylic formate, yielding the c.ro-methylene compound 584. The conversion of carvone (585) into l,3-disiloxy-4-methylenecyclohexane (586) is an example[382]. 

Ring expansion of haloalkyloxiranes provides a simple two-step procedure for the preparation of azetidin-3-ols (Section 5.09.2.3.2(f)) which can be extended to include 3-substituted ethers and O-esters (79CRV331 p. 341). The availability of 3-hydroxyazetidines provides access to a variety of 3-substituted azetidines, including halogeno, amino and alkylthio derivatives, by further substitution reactions (Section 5.09.2.2.4). Photolysis of phenylacylamines has also found application in the formation of azetidin-3-ols (33). Not surprisingly, few 2-0-substituted azetidines are known. The 2-methoxyazetidine (57) has been produced by an internal displacement, where the internal amide ion is generated by nucleophilic addition to an imine. 

This is a very general and mild method for the preparation of amides, applicable to large structural variations in both the acid and the amine. A variety of chloro-formates can be employed, but isobutyl chloroformate is used most often. The solvent is not critical, but generally, THE is used. 

The reaction of carboxylic acids, aldehydes or ketones with hydrazoic acid in the presence of a strong acid is known as the Schmidt reaction A common application is the conversion of a carboxylic acid 1 into an amine 2 with concomitant chain degradation by one carbon atom. The reaction of hydrazoic acid with a ketone 3 does not lead to chain degradation, but rather to formation of an amide 4 by formal insertion of an NH-group. 

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