example, the 4-imidazolidinone 26 is a major in vivo metabolite of lidocaine (22) (Scheme 4). It can also be formed upon isolation of the N-deethyl metabolite of lidocaine (23), if a trace of acetaldehyde happens to be present in the extraction solvent51 (Scheme 4). A related example65 is the formation of the stable 3,3-diphenylpyrrolidine 29 that is generated by the intramolecular cyclization of N-desmethylmethadone (28), the major metabolite of methadone (27) (Scheme 5).
Since iminium ions are reactive electrophiles, it is not surprising that they have been associated with toxicity. An interesting example is provided by the psychotomimetic agent phencylclidine (30), whose use can lead to long-term psychoses. When phencyclidine is incubated with rabbit liver microsomes, a reactive intermediate is formed that can be trapped by the addition of cyanide ions (Scheme 6). The structure of the cyanide adduct (32) is consistent with being formed from reaction of cyanide with the phencyclidine iminium ion (31). Further NADPH-dependent metabolism of the iminium ion leads to the production of the conjugated pyridone 33, a reactive electrophile that is the likely species responsible for stable covalent binding with critical bio-macromolecules and toxicity (Scheme 6).68
Oxidative attack on a C-H bond of an alkyl group a to a nitrogen atom is not restricted to saturated aliphatic amines. In fact, X in an X-N-CH- structural subunit can be virtually any common atomic grouping that can be found in stable organic molecules. For example, a-carbon hydrogen atoms of N-alkyl-substituted aromatic cyclic amines (34),69 aryl amines (36),60 amides (38),70'71 amidines (41),72 and N-nitrosoalkylamines (43)73 (eqns -), are all subject to oxidative attack, carbinolamine formation, and, in most cases, release of an aldehyde or ketone, depending on the substitution pattern (1° or 2°) (eqns —) In some cases (e.g., N-alkyl aromatic cyclic amines), carbinolamines are stable enough to be isolated (e.g., 35) (eqn ).
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