Dealkylation of tertiary amines with

Unsymmetrical secondary aliphatic amines have been prepared by reaction of alkyl halides with benzylidene amines and subsequent hydrolysis 814 by reaction of alkyl halides with alkyl amines 5 by reduction of amine-aldehyde adducts 8-8 and by dealkylation of tertiary amines with dibenzoyl peroxide. ... 

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. 

Dealkylation of tertiary amines with dibenzoyl peroxide, 44, 74 Decarboxylation, intermolecular, of isocyanates to carbodiimides, 43,32 Decker synthesis of amines, 44, 7t, 75 Dehalogenation of l,l,2-trichloro-2,3,3-trifluorocydobutane, 42,45 Dehydration, of formamides with phosphorus oxychloride to isocy-anides, 41, 13, 101 of 4- 2-hydroxyethyl)piperidine to quinuclidine, 44, 90 Dehydrohalogenation of 2-chloroallyl-amines to propargylamines, 44,55 Delepine reaction, to prepare 2-bromo-allylamine, 43, 6 Deoxyanisoin, 40,16 Deoxybenzoin, 40, IT Deoxypiperoin, 40, IT Deaylamine, 41, 8T... 

The activation of C—H bonds in tertiary amines is a reasonably well understood reaction. It has its origins in the dealkylation chemistry reported by dePaolini in 1932 and the mechanistic explanation put forth by Homer et al. It is similar to the oxidative dealkylation of tertiary amines with peroxides catalyzed by peroxidases and P450 enzymes. 

The second type of oxidative biotransformation comprises dealkylations. In the case of primary or secondary amines, dealkylation of an alkyl group starts at the carbon adjacent to the nitrogen in the case of tertiary amines, with hydroxylation of the nitrogen (e.g lidocaine). The intermediary products are labile and break up into the dealkylated amine and aldehyde of the alkyl group removed. 0-dealkylation... 

Oxidative deamination basically resembles the dealkylation of tertiary amines, beginning with the formation of a hydroxylamine that then decomposes into ammonia and the corresponding aldehyde. The latter is partly reduced to an alcohol and partly oxidized to a carboxylic acid. 

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). 

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). 

Hamilton GL, Backes BJ (2006) Dealkylative functionalization of tertiary amines with electron deficient heteroaryl chlorides. Tetrahedron Lett 47 2229-2231... 

Protection.—Amines have been protected by conversion into their 9-anthrylmethyl carbamates. These carbamates are readily prepared, are stable to acids and bases, and furthermore are easily deblocked by treatment with the sodium salt of methyl mercaptan (Scheme 5). The merits of vinyl chloroformate have been explored for amino protection in peptide synthesis and for the selective dealkylation of tertiary amines. ... 

In addition to epoxidation, Tabushi s system also catalyzes aromatic and aliphatic hydroxylation, as well as dealkylation of tertiary amines [81], i.e. all of the important types of reactions that are catalyzed by cytochrome P-450. A practical disadvantage of this artificial P-450 catalytic system is that the active oxometal species is to a considerable extent (typically 80-90%) consumed for water production via interaction with the reducing agent Pt/H. ... 

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]. 

The dealkylative functionalization of tertiary amines 23 with electron deficient heteroaryl chlorides including triazinyl chloride 24 has been published <06TL2229>. Efficient and practical reaction conditions were determinated for a range of substrates. 

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. 

Elguero and Espada29S have used this dealkylation reaction with quaternary salts of heterocyclic compounds. Another application is the preparation of tertiary amines functionalized in the <5 position.296 In these reactions, the ammonium salt 196 is both the catalyst and the reagent. 

Cleavage of tertiary amines.1 Tertiary aliphatic and alicyclic amines can be dealkylated by reaction with phenyl chloroformate in methylene chloride at 10-40°... 

Dealkylation of a tertiary amine was firstly reported by Olofson et al. [5]. In this reaction, Ratz et al. reported the effective use of Proton Sponge (1) for carbamate formation [6]. Thus, the reaction of the tertiary amine with 2,2,2-trichloroethyl chlor-oformate (ACE-Cl) and Proton Sponge (1), and subsequent hydrolysis of the resulting carbamate with sodium hydroxide (NaOH) gave amine in 75% yield without loss of optical purity (Scheme 8.2). 

Dealkylation of Amines. Treatment of a secondary or tertiary amine with diethyl azodicarboxylate in nonpolar solvents followed by acidic hydrolysis leads to the formation of mon-odealkylated amines. The mechanism of this reaction is believed to involve the formation of a triaza adduct (by Michael addition) followed by a two-step ylide rearrangement yielding an alkyl-substituted hydrazocarboxylate. Research on unsymmetrically substituted amines suggests that benzyl groups are more easily removed than alkyl groups methyl groups are the hardest to remove except in cyclic amines like iV-methylpiperidine (eq 3). The Al-dealkylation of imines has also been reported. ... 

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. ... 

Although dealkylation using haloformates has been used with tertiary amines to provide intermediate carbamates, in the case of aromatic amines the reaction requires a large excess of the chloroformate, high temperatures, and long reaction times. For example, see a) J. P. Bachelet, P. Caubere, 7. Org. Chem. 1982, 47, 234 b) R. A. Olofson, D. E. Abbott, 7. Org. Chem. 1984, 49, 2795 c) R. A. Olofson, Pure Appl. Chem. 1988, 60,1715. 

The reaction of tertiary aromatic amines with butyl nitrite has been investigated in detail. The main products arise from 7V-dealkylation/7V-nitrosation, e.g. equation 91270. 

Reaction of 9-chloroacridine with aryl sulfonyl hydrazides results in aminodechlo-rination to give the corresponding A-acridinylbenzenesulfonyl hydrazides kinetic studies in methanol and DMSO have been reported.44 Reaction of electron-deficient heteroaryl chlorides with tertiary amines may proceed by quaternization and dealkylation, as shown in Scheme 3. These reactions occur under mild conditions, e.g. acetonitrile solvent at room temperature, and in THF may be accelerated by the addition of lithium chloride.45... 

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