N-Dealkylation of Tertiary Amines

In a well-estabhshed protocol, the above reaction is very useful for the preparation of the free secondary amines. Several available chloroformates are traditional reagents for the N-dealkylation of tertiary amines by cleavage of the intermediate carbamates [134]. 

The reaction between phosgene itself and triethylamine has been reported to give diethylcarbamoyl chloride [133], but, surprisingly enough, when tribenzyl-amine was used, no C-N bond-breaking was observed, and no carbamoyl chloride was formed. Instead, tribenzylamine 1762 reacts smoothly with one-third of an equivalent of triphosgene in dichloromethane to give, very selectively, the expected carbamoyl chloride 1763 (71% conversion) [135]. 

The reaction most probably proceeds according to the mechanism described for chloroformates 1764. Indeed, an equimolar amount of benzyl chloride along with the carbamoyl chloride 170 has been isolated in all reported reactions. 

The results in Table 4.49 also show that the method is compatible with various functional groups (ketone, ester, amide, unsaturation). However, the presence of a phenyl group on the nitrogen atom seems to prevent the reaction from occurring since, in this particular case, the starting material is entirely recovered. Interest- 

General procedure. Carbamoyl chlorides 170 from tertiary benzylamines 1759 [135] A solution of the benzylamine 1759 (1 equiv.) in dichloromethane (0.3 m) is added to a solution of triphosgene (0.33 equiv.) in dichloromethane (0.1 m) at 0 °C under inert atmosphere. The mixture is then allotved to tvarm to room temperature and is stirred until no further change is seen by TLC. The reaction mixture is then concentrated under reduced pressure and purified by fiash chromatography. 

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A new and interesting chioroformate reagent, a-chloroethyl chioroformate, was recently introduced for selective N-dealkylation of tertiary amines (106). When it was applied to the demethylation of 3a-acetoxytropane (2), the corresponding nor salt (198) was obtained in 97% yield (Scheme 20). 

Olofson, R.A., Schnur, R.C., Bunes, L., Pepe, J.P. Selective N-dealkylation of tertiary amines with vinyl chloroformate - an improved synthesis of naloxone, Tetrahedron Lett. 1977, 1567-1571. 

Olofson and coworkers also introduced vinyl chloroformate as a reagent for the N-dealkylation of tertiary amines (Ref. 157,158,159). Compared with commonly utilized reagents in N-dealkylation procedures, the use of VOC-CI leads to significantly improved yields under milder conditions combined with greater discrimination between alkyl groups in unsymmetrical amines. The procedure is illustrated by the selective N-deethylation of N-ethyl piperidine to afford piperidine.HCI in 90% yield (Ref. 159) as depicted in scheme 107. 

Besides its interest for the synthesis of 1-chloroethyl carbamates from tertiary amines and the N-dealkylation of tertiary amines, this result is also quite unexpected. With most chloroformates other than vinyl chloroformate (VOC-CI), for example EtOCOCI, CI3CH2OCOCI, Ph-CH2OCOCI, the cationic intermediate analogous to (II) fragments to alkyl chloride, carbon dioxide and (I). 

Olofson and Martz have developed numerous applications of ACE-CI to the N-dealkylation of significant tertiary amines, especially in the field of analgesics and narcotic antagonists alkaloids, for example in a brilliant synthesis of Nalbuphine from Oxycodone in 69 % overall yield (Ref. 191). The scope and limitations of ACE-CI as a new reagent for the selective, high-yield N-dealkylation of tertiary amines will be examined in section 4-5 of voi. 2. 

Some examples of 1-chloroalkyl carbamates obtained through N-dealkylation of tertiary amines are gathered in table 3-21 (Ref. 127, 193). 

The use of vinyl chloroformate 2 for N-dealkylation of tertiary amines, protection of amino groups, protection of hydroxyl groups formation of 2-ketoimidazoles. Synthesis of vinyl carbonates by means of fluoro or chloroformates (see 1st edition). 

N-dealkylation occurs whether nitrogen has the form of amine (secondary or tertiary), amide, or sulphonamide. Recently, it has been appreciated that the N-dealkylation of tertiary amines by microsomal enzymes occurs in two distinct steps which have different kinetics. In neral. removal of the first alkyl group takes place much more readily than removal of the second. Accordingly, administration of the tertiary amines imipramine or amitriptyline to animals results in the accumulation of the monodemethylated metabolites (desmethylimipramine and nortriptyline) in brain and other tissues. A significant portion of the psychophamtacologic effects elicited by the parent compounds appear to be mediated by the monomethyl metabolites. 

An example of N-dealkylation of an amine adjacent to a tertiary carbon can be found in the metabolism of synthetic opiod, alfentanil. The CYP3A4-catalyzed oxidation of the opiod alfentanil follows two major pathways (119) N-dealkylation to form no-ralfentanil and cleavage of the spiro center to generate N-phenylproprionamidc. Moreover,... 

As a result of our previous work on the scope and mechanism of tertiary amine nitrosation (X), we became interested in the behavior of N-alkylaziridines toward nitrous acid. Possible modes of reaction are illustrated in Scheme 1. The operation of either path A or C would be consistent with our previous studies of oxidative dealkylation of tertiary amines (1 ), while pathway B would be akin to the observed cheleotropic transformation of N-nitroso-aziridines (2). 

Secondary and Primary Amines. Secondary amines (cither patent compounds or metabolites) are susceptible to oxidative N-dealkylation. oxidative deamination, and N-oxi-dation reactions. - As in tertiary aminc.s. N-dealkylation of secondary amines proceeds by the carbinolamine path-... 

A study of the acetic anhydride induced rearrangement of the diazepam-N-4-oxide (24) to the acetyl compound (23, R = OCOMe) was made using highly enriched 0-labelled acetic anhydride as a model for the possible role of N-oxides as an enzymatic intermediate in microsomal oxidative dealkylation of tertiary amines. The results established that in the system examined, an intramolecular migration of oxygen from nitrogen to carbon can be effected via an activated A-acetoxyimmonium intermediate of type (23, R = OCOMe) [193, 194]. 

The chlorocarbonyl functionalized intermediates 1296 usually have limited stability. Under the reaction conditions, they are not isolable and easily eliminate carbon dioxide (in the case of 0-containing nucleophiles, e.g. alcohols or carboxylic acid substrates), or benzyl chloride (in the case of N-dealkylation of tertiary benzyl-amines). 

N-Dealkylation (N-debenzylation) of tertiary amines with phosgene or phosgene equivalents has also been employed by a recently disclosed process for the preparation of o-(chloromethyl)phenylacetic add derivatives, which are important intermediates for the preparation of microbiddes. o-Chloromethylphenylacetic acid derivatives 299 were prepared by reading the benzylamine 298 with an alkyl chlorofoimate or phosgene in the absence of water [228]. 

N-Dealkylation reactions are not restricted to tertiary amines. Secondary amines as well as primary amines can also be dealkylated although both types are less favored than tertiary amines. In the case of primary amines, the lone pair of electrons of the amino group can interact and complex with the Fe3+ of heme. Thus primary amines tend to be inhibitors of P450 activation and for that reason are generally poor substrates. Secondary amines have metabolic properties intermediary between those of tertiary amines and primary amines. They are less-effective inhibitors because of increased steric hindrance to complex formation but are also better substrates because they are less-effective inhibitors and thereby increase the effective concentration of enzyme. 

A similar mechanism was invoked by Ohshima and Kawabata (2) to account for their results in the nitrosation of tertiary amines and amine oxides. In applying these concepts to the nitrosative dealkylation of tetraalkyltetrazenes, Michejda al. 5) introduced an interesting variant by suggesting that immonium ions could be formed in two successive one-electron oxidation steps (for example by ferric ion oxidation of tertiary amine to the radical cation followed by radical abstraction of a hydrogen atom from the alpha position), rather than exclusively through the one-step removal of a hydride ion as nitroxyl. The resulting immonium ion was again considered to react directly with nitrite to produce the N-nitroso derivative. These reactions are summarized in Fig. 2b. 

Fig. S.7 Mechanistic pathways to the quasi-irreversible mechanism-based inactivation via P450-catalyzed MI-complex generation from amines. Pathway a entails P450-mediated sequential N-dealkylation of secondary and tertiary amines to the primary amine that is then oxidized to the hydroxylamine. The latter requires a further P450-mediated or autocatalytic oxidation to the nitroso...

Reductive C-N bond cleavage has been demonstrated in more complex systems using ethyl chloroformate as a solvent. Chlorination of corticosteroid cyclic ethers has been observed. Tertiary aliphatic and alicyclic amines can be dealkylated. Phenyl chloroformate, however, is usually regarded as the reagent of choice. In summary, deamination, demethylation, debenzylation, and deal-lylation of tertiary amines can all occur on treatment with ethyl chloroformate but the regioselectivities of these reactions are difficult to predict. ... 

Higher homologs of PEI can be obtained by cationic ring-opening polymerization of azetidine monomers21). Polymers of this kind can also be N-methylated as previously described in the case of PEI. The cationic polymerization of N-substituted azetidines may give rise to poly(tertiary amine)s. Linear poly(tertiary amine)s have been obtained by selective dealkylation of poly(quaternary ammonium salt)s22). 

A unique property of chloroformates is their ability to N-dealkylate tertiary amines to produce the carbamate of a corresponding secondary amine (Eq. 3)... 

Thus, only trace yields of alkylcarbamates are obtained and the tertiary amine primarily catalyzes the decarboxylation of the chloroformate. Phenyl chloroformate itself previously recommended for N-dealkylation (Ref. 190) afforded PhOC(=0)-piperidine in only 34% yield. 

A dimerisation reaction of N-methylanabasine (17) has been reported and a modification of the useful dealkylation reaction for tertiary amines has been used in a partial degradation (17) -> (18). The harsh conditions necessary for the von Braun reaction of heterocyclic benzamides with phosphorous penta-bromide has generally precluded its application to structural determination. It has now been found that carbonyl bromide is a useful reagent for this reaction... 

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