Esters, ammonolysis

In the first steps, ester condensation to diketo acid, preparadon of oxime and cyclization are completed under standard conditions. Ester ammonolysis is followed by Hofmann rearrangement of amide to heterocyclic amine. Sulfonation of amine under Schotten-Baumann conditions, in a water-organic solvent mixmre, is based on an interesting trick hydroxide is added at a controlled rate to scavenge the hydrochloric acid formed in sulfonation and to maintain the neutral pH of the aqueous solution of heterocyclic amine as a stronger nucleophile than water, avoiding the hydrolysis of sulfonyl chloride ... 

The amide can be prepared classically from the acid chloride or by ammonolysis of the ester, prepared directly by cyclization (15, 75, 78-80). 

Aqueous ammonia and acryUc esters give tertiary amino esters, which form the corresponding amide upon ammonolysis (34). Modem methods of molecular quantum modelling have been appHed to the reaction pathway and energetics for several nucleophiles in these Michael additions (35,36). 

Reduction. Hydrogenation of dimethyl adipate over Raney-promoted copper chromite at 200°C and 10 MPa produces 1,6-hexanediol [629-11-8], an important chemical intermediate (32). Promoted cobalt catalysts (33) and nickel catalysts (34) are examples of other patented processes for this reaction. An eadier process, which is no longer in use, for the manufacture of the 1,6-hexanediamine from adipic acid involved hydrogenation of the acid (as its ester) to the diol, followed by ammonolysis to the diamine (35). 

In general, the reactions of the perfluoro acids are similar to those of the hydrocarbon acids. Salts are formed with the ease expected of strong acids. The metal salts are all water soluble and much more soluble in organic solvents than the salts of the corresponding hydrocarbon acids. Esterification takes place readily with primary and secondary alcohols. Acid anhydrides can be prepared by distillation of the acids from phosphoms pentoxide. The amides are readily prepared by the ammonolysis of the acid haUdes, anhydrides, or esters and can be dehydrated to the corresponding nitriles (31). 

Ammonolysis or aminolysis of an ester can be used to make the respective amide or N-substituted amide. 

Ammonolysis and Aminolysis. Esters and ammonia react to form amides and alcohols ... 

It is, chemically, a point of weakness, being susceptible to hydrolysis, ammonolysis and ester interchange, the first two reactions leading to chain scission. In some cases the reactivity is influenced by the nature of the adjacent groupings. 

Sheldon et al. have reported the DKR of phenylglycine esters via lipase-catalyzed ammonolysis [53]. Racemization was carried out by an aldehyde, such as salicyalde-hyde or pyridoxal, under basic conditions. The major problem they found was the racemization by these aldehydes of the final products. However, when performing the DKR at low temperatures (—20 °C) the substrate was racemized much faster than the product, and DKR was feasible yielding the product in good yield and high enantiomeric excess (Figure 4.27). 

An efficient biocatalytic method for the production of amides in multigrara scale has been developed for the synthesis of a pyrrole-amide, which is an intermediate for the synthesis of the dipeptidyl peptidase IV that regulates plasma levels of the insulinotropic proglucagon. CALB catalyzes the ammonolysis of the ester with ammonium carbamate as source of ammonia (Scheme 7.8) [22]. The use of ascarite and calcium chloride as adsorbents for carbon dioxide and ethanol by-products. 

The enzymatic resolution of esters via aminolysis or ammonolysis processes represents an efficient alternative to the resolution of substrates by transesterification... 

Azetidine ring is an important structure because it is present in many compounds of pharmaceutical interest however, its manipulation must be done very carefully owing to the reactivity of these heterocycles of small size. An interesting application of the use ofbiocatalytic processes is the resolution of azetidine esters (Scheme 7.11). The procedure to choose for the resolution of these compounds is the enzymatic ammonolysis of the corresponding N-substituted azetidines [26]. 

A derivative of the anti-inflammatory ibuprofen, the corresponding (S)-2-chloroethyl ester, has been obtained vhth 96% ee by CALB-catalyzed ammonolysis of the... 

Scheme 7.12 Resolution of an ibuprofen ester derivative by enzymatic ammonolysis.

The strategy described here explains the different possibilities of enzymatic ammonolysis and aminolysis reaction for resolution of esters or preparation of enantiomerically pure amides, which are important synthons in organic chemistry. This methodology has been also applied for the synthesis of pyrrolidinol derivatives that can be prepared via enzymatic ammonolysis of a polyfunctional ester, such as ethyl ( )-4-chloro-3-hydroxybutanoate [30]. In addition, it is possible in the resolution of chiral axe instead of a stereogenic carbon atom. An interesting enzymatic aminolysis of this class of reaction has been recently reported by Aoyagi et al. [31[. The side chain of binaphthyl moiety plays an important role in the enantiodis-crimination of the process (Scheme 7.14). 

Here, we have selected a few representative examples of the enzymatic resolution of esters by aminolysis or ammonolysis reactions. On the other hand, the enzymatic acylation of racemic amines is also of great utility for the preparation of optically pure... 

Scheme 7.14 Resolution of a binaphthyl ester by an ammonolysis reaction.

The degree of ammonolysis Ra shows the percentage of the reacted ester groups converted into amides ones. 

Influence of the Monovalent Ions. The addition of ammonium salts retard the course of the deesterification by changing the reaction rate of hydrolysis and ammonolysis. By increasing the concentration of the ions the conversion of the ester groups is reduced from 83.3 % for 0,01 M to 62.8 % for 0.2 M (without added salt this value is 84.05 %), and the ratio hydrolysis ammonolysis is changed correspondingly from 53.8 76.2 to 37.3 62.7 (without added salt this ratio is 57.6 42.4). 

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