Acid Cleavage of Esters, Amides and Nitriles

Esters, amides, and nitriles are not readily hydrolyzed under neutral conditions, but they are hydrolyzed by aqueous acid. 

Electrostatic potential map for dimethylacetamide shows negatively-charged regions (in red) and positively-charged regions (in blue). 

LUMO for protonated methyl acetate reveals likely site of attack by water. 

Two mechanisms for acid-catalyzed hydrolysis can be imagined depending on the initial site of protonation. One mechanism begins widi protonation at X this makes X a better leaving group. The alternative is protonation of the carbonyl oxygen. 

Examine electrostatic potential maps for methyl acetate (X=OMe), dimethylacetamide (X=NMe2), mdacetonitrile. What is die most electron-rich site in each molecule Does this site correspond to a bonding pair of electrons or a nonbonding pair of electrons Assuming that protonation occurs onto the most electron-rich site, where would you expect each molecule to protonate  

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Addition of the alcohol 42 to a solution of BF3 Et20/TMSCN in DCM provided the nitrile 43 in 83% yield. Hydrolysis of nitrile 43 then furnished amide 44 in 85% yield. Demethylation of the methoxyindole 44 with BBra in DCM provided the hydroxyindole 45 in 80% yield. This was followed by alkylation of 45 with the bromide 46 under phase transfer conditions to provide the phosphonate ester 47 and subsequent cleavage of the methyl ester by TMS-I furnished trimethylsilyl phosphonic acid 48, which upon alcoholic workup afforded LY311727. 

If care is taken to avoid ring cleavage, 5-aryl-l,3,4-oxadiazole-2-carboxylic acids will undergo typical reactions such as the formation of acid chlorides, amides and esters. Decarboxylation may occur on heating, for example with 5-amino-l,3,4-oxadiazole-2-carboxylic acids (77JHC1385), and an amide has been dehydrated to a nitrile (78GEP2808842). 

There are many methods for the cleavage of 4,5-dihydrooxazoles once they have served their purpose. An effective method for hydrolyzing them back to carboxylic acids employs trifluoro-methanesulfonic anhydride <92SC13>. Intermediate ring-opened esters (100) are A(-methylated, then saponified to the acids (Scheme 34). The oxazoles may also be converted into aldehydes or nitriles. In a one-pot, two-step procedure, 4,5-dihydrooxazoles are transformed into alcohols (101) <93TIj4893>. Chloromethyl methyl ether converts the dihydrooxazoles into ring-opened amides in the first step, and these are reduced with diisobutylaluminum hydride (Scheme 35). 

Substituted derivatives of type (105) have been reported to undergo cleavage in the presence of acid to yield the acetic acid derivative (106 Scheme 48) (65AHC(5)119). The nitrile functions of the isomeric compounds (107) and (108) have been converted into the corresponding amides, carboxylic acids and methyl esters in the usual fashion (81JOC771). 

In the course of these reactions, P450 3A4 catalyzes examples of some atypical reactions " including desaturation , oxidative carboxylic acid ester cleavage , and oxidation of a nitrile to an amide . An unexpected reaction encountered in this laboratory was the oxidation of alkylphenyl ether non-ionic detergents, which have been commonly used in enzyme purifications and also have some medical and industrial applications . Methylene hydroxylations yield hemiacetals, which break down to shorten the chains . 

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