Amide , amines from hydrolysis

The aqueous phase from the petroleum ether extraction contains the amine from hydrolysis of the amide. This may be identified by neutralizing the aqueous phase with alkali and analyzing by GC. 

The reaction is applicable to the preparation of amines from amides of aliphatic aromatic, aryl-aliphatic and heterocyclic acids. A further example is given in Section IV,170 in connexion with the preparation of anthranilic acid from phthal-imide. It may be mentioned that for aliphatic monoamides containing more than eight carbon atoms aqueous alkaline hypohalite gives poor yields of the amines. Good results are obtained by treatment of the amide (C > 8) in methanol with sodium methoxide and bromine, followed by hydrolysis of the resulting N-alkyl methyl carbamate ... 

In these papers, the carboxylic acid to be protected was a stable, unsubstituted compound. Harsh conditions were acceptable for both formation and cleavage of the amide. Typically, a simple secondary amide is very difficult to cleave. As the pKa of the conjugate acid of an amide decreases, the rate of hydrolysis of amides derived from these amines increases. The dimethylamide of a cephalosporin was prepared as follows using 2,2 -dipyridyl disulfide. ... 

Another alternative for preparing a primary amine from an alkyl halide is the Gabriel amine synthesis, which uses a phthalimide alkylation. An imide (—CONHCO—) is similar to a /3-keto ester in that the acidic N-H hydrogen is flanked by two carbonyl groups. Thus, imides are deprotonated by such bases as KOH, and the resultant anions are readily alkylated in a reaction similar to the acetoacetic ester synthesis (Section 22.7). Basic hydrolysis of the N-alkylated imide then yields a primary amine product. The imide hydrolysis step is analogous to the hydrolysis of an amide (Section 21.7). 

This conclusion has been drawn by Moffatt and Khorana,2 based on limited data. A subsequent, more detailed study [R. K. Ledneva, N. N. Preobrazhenskaya, Z. A. Shabarova, and M. A. Prokof ev, Molek. Biologiya, 5, 264 (1971)] clearly shows an unexpected decrease in the rate of the acid hydrolysis of the phosphor-amidates derived from strong amines. If a similar order of reactivities exists for the pyrophosphate synthesis, the phosphomorpholidate derivative seems close to being the most active. 

The success of the Gabriel synthesis depends on N-alkylation being favored over O-alkylation and SN2 being favored over E2. Polar, aprotic solvents such as methylsulfinylmethane, (CH3)2SO, are useful for the Gabriel synthesis. Hydrolysis of the alkylation product often is difficult and amide interchange (analogous to ester interchange, Section 18-7A) with hydrazine can be an effective way to free the amine from the imide. 

Analogous to the use of chiral enoates (see previous section), a, -unsaturated carboxylic amides, prepared from chiral amines, may be utilized in asymmetric 1,4-additions. When Grignard reagents are added to unsaturated amides (21), derived from (-)-ephedrine (20),25 highly optically active fi-sub-stituted alkanoic acids (22 R and R = alkyl or phenyl) are obtained in a variety of cases, after hydrolysis of the initially formed adducts (Scheme 7). This method was used for the synthesis of the antibiotic (-) malyngolide and its stereoisomers.26 Recrystallization of the intermediate (saturated) amide was necess-... 

It should be noted that amines may be formed by hydrolysis of amides arising from the intramolecular Beckmann rearrangement of ketoximes (p. 1047) this rearrangement is a further example of the migration of a nucleophilic carbon species from a carbon to an electron-deficient nitrogen. 

The conversion of ketones to amides by the Schmidt reaction has been mentioned elsewhere (method 362). Since the hydrolysis of the amides so obtained proceeds readily, the two steps provide a convenient synthesis of amines from ketones. The yields are often higher than those obtained from the Beckmann rearrangement with subsequent hydrolysis (method... 

Nitriles are usually prepared either by reacting the corresponding halide or diazonium salts with a cyanide salt or by dehydrating an amide. Hence, possible contaminants are the respective halide or alcohol (from hydrolysis), phenolic compounds, amines or amides. Small quantities of phenols can be removed by chromatography on alumina. More commonly, purification of liquid nitriles or solutions of solid nitriles in a solvent such as diethyl ether is by shaking with dilute aqueous sodium hydroxide, followed by washing successively with water, dilute acid... 

Amide formation and hydrolysis is of course also catalysed by enzymes and the recent report that the penicillin acylase from Alcaligenes faecalis catalyses an efficient kinetic resolution of racemic primary amines is very promising. A typical case is our old friend a-methylbenzylamine 57 (see chapter 22). One equivalent of an acyl donor 58 is needed and nearly 50% of the amide 59 can be isolated in excellent ee. The E value is 350 for this amine.20... 

Lithium enolates of propionamides of chiral amines undergo stereoselective 1,4-addition reactions to a,P-unsaturaled esters. The highest selectivities are obtained with C2-symmetric amides derived from 1.65 (R = CH OCH QMie) bearing a substituent that is capable of metal chelation (Figure 7.61). After hydrolysis, diacid 7.95 is obtained with a good selectivity [161]. Some nonracemic natural... 

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