Imines, acid/base hydrolysis

Acid/base stress testing is performed to force the degradation of a drug substance to its primary degradation products by exposure to acidic and basic conditions over time. Functional groups likely to introduce acid/base hydrolysis are amides (lactams), esters (lactones), carbamates, imides, imines, alcohols (epimerization for chiral centers), and aryl amines. 

The methyl group of TNT will condense with aldehydes in a similar way to other substrates containing acidic protons. TNT (1) reacts exothermically with benzaldehyde in alkaline solution to form 2,4,6-trinitrostilbene (140). 2,4,6-Trinitrobenzaldehyde (142) is synthesized from the base hydrolysis of the imine (141) formed from the condensation of TNT (1) with /t-nitroso-N,N-dimethylaniline. ... 

A general methodology for the construction of quaternary carbon atoms at the carbonyl carbon of ketones has been successfully exploited for the facile synthesis of ( )-lycoramine (299) (Scheme 30) (165). Thus, the O-allylated o-vanillin 322 was allowed to react with vinyl magnesium bromide followed by Jones oxidation, and the acid-catalyzed addition of benzyl IV-methylcarbamate to the intermediate a,(3-unsaturated ketone furnished 323. Wadsworth-Emmons olefination of 323 with the anion derived from diethyl[(benzylideneami-no)methyl]phosphonate (BAMP) provided the 2-azadiene 324. The subsequent regioselective addition of n-butyllithium to 324 delivered a metalloenamine that suffered alkylation with 2-(2-bromoethyl)-2-methyl-l,3-dioxolane to give, after acid-catalyzed hydrolysis of the imine and ketal moieties, the 8-keto aldehyde 325. Base-catalyzed cycloaldolization and dehydration of 325 then provided the 4,4-disubstituted cyclohexenone 326. The entire sequence of reactions involved in the conversion of 323 to 326 proceeded in very good overall yield and in one pot. 

A kinetic study of the hydrolysis of JV-salicylideneaniline (113) in the presence and absence of cobalt(II), nickel(II), copper(II) and zinc(II), using 10% ethanol-water as solvent, has been carried out by Dash and Nanda. The (1 1) Schiff base-metal complexes (ML ) were found to undergo acid-catalyzed hydrolysis at rates decreasing with the thermodynamic stabilities of the complexes, the most thermodynamically stable complexes undergoing the slowest rate of hydrolysis. More recent measurements using high copper(II) to ligand ratios have indicated that the copper(II)-imine is quite stable to hydrolysis at pH 5. 

As with hemiacetal- and acetal-forming reactions, imine formation is reversible acid-catalyzed hydrolysis of an imine gives a 1° amine and an aldehyde or a ketone. When one equivalent of acid is used, the 1° amine, a weak base, is converted to an ammonium salt. 

Besides the synthetic aspects of the preparation of (functional) poly(2-oxazoline)s, it is noteworthy to mention that poly(2-oxazoHne)s are weU-known precursors for the preparation of linear poly(ethylene imine)s upon hydrolysis under either alkaline [147] or acidic [148] conditions (Scheme 6.21). Detailed kinetic investigations on the acidic deacetylation of poly(2-oxazoline)s have revealed that both partial and full deacetylation can be achieved by varying the stoichiometry between the acid and the cleavable groups [149]. Furthermore, partial cleavage of the side chains can be controlled by selective acidic hydrolysis based on the easier hydrolysis of poly(2-ethyl-2-oxazoline) compared to poly(2-[4-tert-butylphenyl]-2-oxazoline) [150]. 

Comforth has reviewed literature reports and independently studied the special cases of reaction of 1 with salicylaldehyde and with 2-acetoxybenzaldehyde. Coumarins (10) are afforded in the condensation of 1 with salicylaldehyde or its imine, whereas when 2-acetoxybenzaldehyde is used, acetoxy oxazolone 12 is the major product. The initial aldol condensation product between the oxazolone and 2-acetoxybenzaldehyde is the 4-(a-hydroxybenzyl)oxazolone 11, in which base-catalyzed intramolecular transacetylation is envisioned. The product 9 (R = Ac) can either be acetylated on the phenolic hydroxy group, before or after loss of acetic acid, to yield the oxazolone 12, or it can rearrange, by a second intramolecular process catalyzed by base and acid, to the hydrocoumarin, which loses acetic acid to yield 10. When salicylaldehyde is the starting material, aldol intermediate 9 (R = H) can rearrange directly to a hydrocoumarin. Comforth also accessed pure 4-(2 -hydroxyphenylmethylene)-2-phenyloxazol-5(4//)-one (13) through hydrolysis of 12 with 88% sulfuric acid. 

Compounds containing carbon-nitrogen double bonds can be hydrolyzed to the corresponding aldehydes or ketones. For imines (W = R or H) the hydrolysis is easy and can be carried out with water. When W = H, the imine is seldom stable enough for isolation, and hydrolysis usually occurs in situ, without isolation. The hydrolysis of Schiff bases (W = Ar) is more difficult and requires acid or basic catalysis. Oximes (W = OH), arylhydrazones (W = NHAr), and, most easily, semicarbazones (W = NHCONH2) can also be hydrolyzed. Often a reactive aldehyde (e.g., formaldehyde) is added to combine with the liberated amine. 

Aminocarbazoles are typical aromatic amines 3-aminocarbazoles, which are the most studied, form Schiff bases with aromatic aldehydes, and ketones. Use was made of such a benzaldehyde imine by methyla-tion with dimethyl sulfate and then by hydrolysis with acid to produce the mono-N-methylated amine. The dimethylated material was obtained via the trimethylammonium iodide, which gave 3-dimethylaminocarbazole on... 

As early as the 1960s, some syntheses based on the addition of nucleophilic reagents (vinyl magnesium bromide, HCN, isonitrile) on A-acyl trifluoroacetaldi-mines (fluoral imine) have appeared. The acidic function is further introduced by an appropriate oxidation or hydrolysis. These approaches have allowed preparation of higher fluoroalkylated homologues of trifluoroalanine and of nonracemic trifluor-oalanines (vide infra). However, preparation of the acyl imine of fluoral is rather... 

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