Carboxylic esters, acylation with ammonia

In the second major method of peptide synthesis the carboxyl group is activated by converting it to an active ester, usually a p-nitrophenyl ester. Recall from Section 20.12 that esters react with ammonia and amines to give fflnides. p-Nitrophenyl esters are much more reactive than methyl and ethyl esters in these reactions because p-nitrophenoxide is a better (less basic) leaving group than methoxide and ethoxide. Simply allowing the active ester and a C-protected amino acid to stand in a suitable solvent is sufficient to bring about peptide bond formation by nucleophilic acyl substitution. 

The resistance of the furoxan ring to chemical attack allows derivatives to be prepared via the reactions of the substituents (Section 4.22.3.4). Carboxylic acids are available by permanganate oxidation of methyl derivatives or by hydrolysis of the corresponding esters reaction with ammonia affords carboxamides. Acylfuroxans provide a source of hydroxyalkyl compounds by reduction, and oximes, for example, via nucleophilic addition. Acylation and oxidation of aminofuroxans allows the amide and nitro derivatives to be prepared. Nucleophilic displacements of nitro substituents can take place, but can be somewhat hazardous on account of the explosive nature of these compounds. Alkoxy derivatives are formed with sodium alkoxide, while reaction with thiolate anions yields sulfides, from which sulfones can be synthesized by peracid oxidation. Nitrofuroxans have also been reduced to... 

Due to the extremely low nucleophilicity of the imino group, 187,188 acylation of thiazolidine-4-carboxylic acid (11) is not a trivial procedure. In fact, N-protected Thz derivatives can be prepared by standard procedures, but strong acylating conditions are required. The related N-Boc derivative is obtained only by prolonged reaction times with Boc-N3 U2,189 or with Boc20. 113 For preparation of the N-Z derivative, silylation of Thz with, for example, chlorotrimethylsilane is recommended prior to the reaction benzyl chloroformate. 200 Due to the stability of thiazolidine-4-carboxylic acid to acids its methyl ester is obtained by HC1 catalyzed reaction with methanol, 190 whereas the amide is formed by reacting Thz N-carboxyanhydride with ammonia.1 89 Derivatives of thiazolidine-4-carboxylic acid are listed in Table 8. 

Acylation of nitrogen compounds by carboxylic esters. The action of carboxylic esters on ammonia or primary or secondary amines generally leads to carboxamides under relatively mild conditions, and the analogous treatment of carboxylic esters with hydrazine and hydroxylamine provides the most important methods of preparing simple carboxhydrazides and carbohydrox-amic acids. 

Shin, C., K. Nanjo, M. Kato, and J. Yoshimura a,P Unsaturated Carboxylic Acid Derivatives. IX. The Cyclization of a-(N-Acyl-hydroxyamino) Acid Esters with Ammonia or Hydroxylamine. Bull. Chem. Soc. Japan 48, 2584 (1975). 

The chromatographic behavior of choline and its esters has been studied by Whittaker and Wijesundera (98-100). The esters were detected on the paper by treatment with alkaline hydroxylamine and then with ethereal ferric chloride which is specific for carboxylic esters and certain other acyl derivatives. The lower limit of sensitivity was 0.6-2 ftg. A table of the B/ values of choline and many of its esters with various solvents was given and it was observed that the same values were obtained whether the esters were developed alone or in a mixture. Increasing the water content of the solvent increased the B/ values but reduced separation. Solvents with ammonia tended to destroy the esters which are alkali labile. 

Reactions, not being accompanied by the displacement of fluorine atoms are also important for functionalization of fluorinated quinolines. For instance, 6-substituted 5,7,8-trifluoroquinolines 148-153 were obtained from 6-trifluoro-methyl-5,7,8-trifluoroquinoline 147 (Scheme 67) through hydrolysis of the CF3 group in quinoline 147 followed by decarboxylation of 5,7,8-trifluoroquinoline-6-carboxylic acid 148 on heating in DMF [6]. From the acid 148 obtained is the acyl chloride 150, which gives with methanol the methyl ester 151 and with ammonia - the amide of... 

Amides can be obtained from acyl halides, carboxylic anhydrides, or esters with amines or ammonia. The mechanisms of these reactions are very similar to the corresponding reactions of alcohols ... 

Conventionally the acyl derivatives of acyloins and benzoins may readily be obtained by reaction with acid anhydrides. The acyloin esters can more conveniently be prepared by allowing the corresponding a-bromo ketones and the sodium or potassium salts of the appropriate carboxylic acid to react, either in ethanol or in the acid to be esterified. The esters may not necessarily be isolated, and the oxazoles are obtained directly by adding the ammonium salt to, or passing ammonia through, the mixture, which is then boiled.84 The reaction then becomes useful for the preparation of oxazoles (53) from a-bromo ketones and carboxylic acids.84 121... 

Water, alcohols, ammonia, or amines are the nucleophiles that are usually employed in reactions with acyl chlorides. The products of these reactions are carboxylic acids, esters, or carboxamides according to the following reactions. 

So far we have shown you conjugate additions mainly of a,P-unsaturated aldehydes and unsaturated a,P-ketones. You won t be at all surprised to learn, however, that unsaturated acids, esters, amides, and nitriles—in fact all carboxylic acid derivatives—can also take part in conjugate addition reactions. Two examples, an amide and an ester, are shown on the right below. But notice how the selectivity of these reactions depends on the structure of the unsaturated compound compare the way butyllithium adds to this a,P-unsaturated aldehyde and a,P-unsaturated amide. Both additions are irreversible, and BuLi attacks the reactive carbonyl group of the aldehyde, but prefers conjugate addition to the less reactive amide. Similarly, ammonia reacts with this acyl chloride to give an amide product that derives from direct... 

Amides can be prepared in a variety of ways, starting with acyl chlorides, acid anhydrides, esters, carboxylic acids, and carboxylate salts. All of these methods involve nucleophilic addition—elimination reactions by ammonia or an amine at an acyl carbon. As we might expect, acid chlorides are the most reactive and carboxylate anions are the least. 

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