Esters, carboxylic acid ammonolysis

Introduction. The general methods for the preparation of amides are (1) ammonolysis of esters, acyl halides, and anhydrides (2) the dehydration of the ammonium salts of carboxylic acids ... 

Classical reactions involving nucleophiles such as saponification ("OH as the nucleophile), aminolysis (with amines also ammonia in ammonolysis reactions), transesterification (alkoxides, "OR) and others (hydrazinolysis, hydroxamic acid synthesis, etc.) have been adapted to solid phane and used to obtain, for instance, carboxylic acids, amides and esters. Internal or intramolecular nucleophilic attack has been employed to obtain cyclic products such as lactones, lactams (including cyclic peptides) and a great variety of heterocycles (hydantoins, diketopiperazines, benzodiazepinones, etc.). 

Two different polyurethanes were used as starting materials a solid elastomer based on a trifunctional polyethertriol, 1,4-butanediol and methylenebis(phenyl isocyanate) and a flexible foam where the diol was replaced by water. The ammonolysis reactions were carried out at 139 °C and 140 atm for 120 min, and with a polyurethane/ammonia weight ratio of 1. Under these conditions the polyurethane conversion was practically total. The ammonolysis reaction transforms the CO group into urea and the ester groups and derivatives of carboxylic acids into amides, whereas ether and hydroxy groups are inert towards ammonia. Scheme 2.7 illustrates the stoichiometry proposed by the authors for the ammonolysis of the polyether urethane. 

Various methods have been used to cleave protected peptides from the resin, including hydrazinolysis, ammonolysis, or aminolysis using a suitable amino acid ester [48-52]. Probably the most useful procedure, however, is transesterification of the peptide-resin with hydroxypiperidine. This initially forms the hydroxypiperidine ester of the protected peptide, which, after treatment with zinc in HOAc, furnishes the corresponding free carboxylic acid. This method does not lead to epimerization at the C-terminal amino acid or to loss of acid-sensitive protecting groups. Cleavage yields are usually high. 

The synthesis of DPP-IV inhibitor Saxagliptin 5 also required (55)-5-amino-carbonyl-4,5-dihydro-lH-pyrrole-l-carboxylic acid, l-(l,l-dimethylethyl)ester 10 (Figure 16.3C). Direct chemical ammonolyses were hindered by the requirement for aggressive reaction conditions, which resulted in unacceptable levels of amide race-mization and side-product formation, while milder two-step hydrolysis-condensation protocols using coupling agents such as 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) [41] were compromised by reduced overall yields. To address this issue, a biocatalytic procedure was developed based on the Candida antartica lipase B (CALB)-mediated ammonolysis of (55)-4,5-dihydro-lH-pyrrole-l,5-dicarboxylic acid, l-(l,l-dimethylethyl)-5-ethyl ester 9 with ammonium carbamate to furnish 10 without racemization and with low levels of side-product formation. 

As we have seen, most reactions of carboxylic acids, esters, and related compounds involve, as the first step, nucleophilic attack on the carbonyl carbon atom. Examples are Fischer esterification, saponification and ammonolysis of esters, and the first stage of the reaction of esters with Grignard reagents or lithium aluminum hydride. All of these reactions can be summarized by a single mechanistic equation ... 

This result, is apparently, of a more or less general significance for the reactions of nucleophilic substitution at the carbonyl carbon. Thus, quantum chemical calculations predict appreciable acceleration of ammonolysis reactions of esters [93] and carboxylic acids [108] when an additional ammonia molecule takes part in their catalysis. The structure, found by a nonempirical calculation [109], of a transition state in the concerted reaction of formation of formaldehyde XXXVII in the reaction ... 

The relative stability of the oxiranes to bases at room temperature allows the selective ammonolysis of carboxylic ester groups with ammonia in methanol,49 and, conversely, free hydroxyl groups may be esterified with acid chlorides or anhydrides in pyridine without affecting the oxirane ring. Hydroxyl groups may also be converted into alkyl ethers by using either the Haworth50 or the Purdie-Irvine procedure.5152... 

Hydrolysis of carboxylic esters 0-17 Transetherification 0-18 Payne rearrangement 0-23 Transesterification 0-55 Ammonolysis of carboxylic esters 0-68 Cleavage of ethers with concentrated acids... 

In connection with different kinds of anchoring groups we should recall that numerous biologically active peptides have a carboxamide rather than a free carboxyl at their C-termini. As mentioned earlier, such peptide amides can be obtained by ammonolysis of the ester bond between peptide and polymer. A second possibility, to wit, acidolysis is equally useful and often practiced. In 1970 Pieta and Marshall constructed a new polymeric support in which the acid labile N—C bond in benzhydrylamine serves as the point of cleavage (Fig. 7). Of course, the bond s sensitivity to acids can be further increased by electron-releasing substituents such as methoxy groups. 

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