Amide formation, from a carboxylic acid

Amide formation, from a carboxylic acid and urea, 37, 50 from 2-amino-5-nitroanisole and ethyl benzoylacetate, 37, 4 from aniline and ethyl benzoylacetate, 37, 3... 

Although there are several reports in the literature on boron-mediated amide formations, the boron reagents had to be used in stoichiometric amounts.1-4-5-6-7-8-9 Recently, Yamamoto et al. presented the first truly catalytic method allowing for a direct amide formation from free carboxylic acids and amines as the reaction partners.10-1112 Best results were obtained by using phenylboronic acids bearing electron withdrawing substituents in the meta- and/or para-positions such as 3,4,5-trifluorophenylboronic acid or 3,5-bis(trifluoromethyl)boronic acid as the catalysts. 

Amides. Amides can be prepared in one step from a carboxylic acid and an amine by reaction with 1 (1 equiv.) and triethylamine (2 equiv.) in CH2C12 at 25°. Presumably a mixed anhydride is first formed, which reacts subsequently with the amine. A variation involves conversion of the carboxylic acid into the carboxylic anhydride by reaction with 1 (0.5 equiv.) and triethylamine subsequent addition of the amine results in the formation of the amide. Yields are generally greater than... 

Amides.1 Tetrachlorosilane has been used as a coupling reagent for the formation of an amide from a carboxylic acid and an amine. Pyridine is used as solvent. Aromatic amines react at room temperature, but aliphatic amines require a reflux temperature for satisfactory yields. The reported yields are 25-90%. One advantage of this procedure is that the other product formed is silica, which is insoluble in all common solvents. 

The process of protein synthesis in the cell mimics amide formation in the laboratory it involves acyl group transfer. There are several important differences between the chemistry in the laboratory and the chemistry in the cell. During protein synthesis, the aminoacyl group of the amino acid is transferred, rather than the acyl group of a carboxylic acid. In addition, the aminoacyl group is not transferred from a carboxylic acid derivative it is transferred from a special carrier molecule called a transfer RNA (tRNA). When the aminoacyl group is covalently bonded to a tRNA, the resulting structure is called an aminoacyl tRNA ... 

An amide is produced in a reaction called amidation, in which a carboxylic acid reacts with ammonia or a primary or secondary amine. An —OH group is removed from the carboxylic acid and an —H is removed from ammonia or an amine to form water. The remaining part of the carboxylic acid and ammonia or amine molecule join to form an amide, much like the formation of an ester. Because a hydrogen atom must be removed from ammonia or an amine, only primary and secondary amines undergo amidation. 

In 2007, Milstein reported an approach for the transition metal catalysed intermolecular formation of amides from alcohols and amines in the absence of a hydrogen acceptor (Scheme 12.19). In contrast with conventional amide synthesis from activated carboxylic acid derivatives which produces chemical waste, this environmentally benign approach produces hydrogen gas as the only byproduct. The catalyst used for this reaction is a dearomatised Ru(PNN)pincer complex which serves as a bifunctional catalyst. The ligands, as well as the metal centre, play a role in bond making or bond breaking steps of the catalytic cycle. 

In his cephalosporin synthesis methyl levulinate was condensed with cysteine in acidic medium to give a bicyclic thiazolidine. One may rationalize the regioselective formation of this bicycle with the assumption that in the acidic reaction mixture the tMoI group is the only nucleophile present, which can add to the ketone. Intramolecular amide formation from the methyl ester and acid-catalyzed dehydration would then lead to the thiazolidine and y-lactam rings. The stereochemistry at the carboxylic acid a-... 

The ketocarbene 4 that is generated by loss of Na from the a-diazo ketone, and that has an electron-sextet, rearranges to the more stable ketene 2 by a nucleophilic 1,2-shift of substituent R. The ketene thus formed corresponds to the isocyanate product of the related Curtius reaction. The ketene can further react with nucleophilic agents, that add to the C=0-double bond. For example by reaction with water a carboxylic acid 3 is formed, while from reaction with an alcohol R -OH an ester 5 is obtained directly. The reaction with ammonia or an amine R -NHa leads to formation of a carboxylic amide 6 or 7 ... 

The mechanism of amide formation is a source of insight into the properties of carboxylic acids and amines. Initially, we might expect an amine to act as a base and simply accept a proton from the carboxylic acid. Indeed, that does happen, and a quaternary ammonium salt is formed when the reagents are mixed in the absence of a solvent. For example,... 

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]. 

The problem in the above example is to perform an enantiocontrolled electrophilic substitution in the a-position of a carboxylic acid derivative 1. To this end, chiral auxiliary 2, readily available in both (R) and (5) form from phenylalanine, is attached to the acid chloride 1 by amide formation. The amide 3 is converted into the (T )-enolatc 4, with the chelate ring forming... 

For a review of amide formation from carboxylic acids, see Beckwith, in Zabicky, Ref. 555. pp, 105-109. " See, for example, Bladd-Font Tetrahedron Lett. 1988, 21, 2443. 

This postulated sequence of events may leave you wondering why the enzyme speeds up the hydrolysis, especially because the sequence proceeds through an energetically unfavorable reaction, the formation of a carboxylic anhydride from an amide and a carboxylic acid ... 

Possibly the most important condensation reaction is that between a carboxylic acid and an amine to give an amide. A great many methods are known by which this formal dehydration process may be carried out, almost all of which involve the two step sequence (i) activation of CO2H COX, where X is a leaving group and (ii) aminolysis of RCOX. Japanese workers have recently advocated the use of 2,2-dichloro-5-(2-phenylethyl)-4-trimethylsilyl-3-furanone (1, "DPTF") for carboxyl activation, and its use for peptide formation is illustrated by the representative conversion 2 —> 3. The byproduct formed from DPTF in these reactions is 5-(2-phenylethyl)-4-trimethylsilylfuran-2,3-dione. 

The reaction under consideration is typified by the formation of saturated carboxylic acids from olefins, carbon monoxide, and water. Other compounds have been used in place of olefins (alkyl halides, alcohols), and besides water, a variety of compounds containing active hydrogen may be employed. Thus, alcohols, thiols, amines, and acids give rise to esters, thio-esters, amides, and acid anhydrides, respectively (15). If the olefin and the active hydrogen are part of the same molecule, three or four atoms apart, cyclizations may occur to produce lactones, lactams, imides, etc. The cyclizations are formally equivalent to carbonylations, however, and will be considered later. 

This synthesis also gives a small glimpse at the chemistry of heterocyclic compounds. Most active compounds in today s pharmaceuticals or agrochemicals include heterocycles, as well as most vitamins and natural products. The chemistry of heterocycles is thus very important and lectures or textbooks should be consulted.6 Formation of amide bonds also plays a large role in this problem. It was demonstrated that the strong amide bond can be formed from an amine and a carboxylic acid only after the acid has been activated. This can be done by transformation into the carboxylic halide or imidazolide or by application of an activating agent developed for peptide synthesis. 

The synthesis of amides directly from carboxylic acids is not easy because the reaction of an amine with a carboxylic acid is a typical acid-base reaction resulting in the formation of a salt (Following fig.). Some salts can be converted to an amide by heating strongly to expel water. 

NH3 or RNH2 or R2NH Amide formation from carboxylic acid derivatives (mild) or from carboxylic acids (A technical synthesis of nylon-6,6) transamidation [capro-lactame —> nylon-6 (perlon)] Peptide synthesis (Section 6.4.3)... 

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