A-dealkylation reactions

Benzodiazepines undergo extensive and complex metabolism. They are excreted mainly in the urine, largely in the form of several metabolites. Biotransformation processes include mainly hydroxylation and A-dealkylation reactions, whereas the end-products include both free and conjugated compounds (116). Chlordiazepoxide, for example, is metabolized to oxazepam and other metabolites and, depending on its dosage, urine may contain significant concentrations of oxazepam (117). 

An example of a tertiary amine dealkylation via oxidative degradation is seen with diphenoxylate hydrochloride (Fig. 32). An example of a secondary amine dealkylation via oxidative degradation, the API brinzola-mide undergoes a dealkylation reaction converting the secondary amine to a primary amine in the presence of heat, light (neutral pH), and peroxide... 

Support for a nitrogen radical cation mechanism in P450-catalyzed A-dealkylation reactions... 

Figure 6.13. Probes designed to investigate whether a nitrogen radical cation is involved in P450-catalyzed A -dealkylation reactions.

As described in the preceding section, some A-dealkylation reactions may arise, at least in part, from an SET process in which an electron is initially removed from the nitrogen atom and therefore can be formally viewed as heteioatom... 

Okazaki O, Guengerich FP (1993) Evidence for specilic base catalysis in A-dealkylation reactions catalyzed by cytochrome P450 and chloroperoxi-dase. Diffeiences in rates of deprotonation of amin-ium radicals as an explanation for high kinetic hydrogen isotope effects observed with peroxidases. J Biol Chem 268 1546 1552... 

A dealkylation reaction can be defined as the removal of an alkyl group, and its subsequent replacement by hydrogen, or the removal of an alkyl group from an ammonium salt with the formation of an amine, e.g. 

The molecular weight of PPP obtained by the polymerization of deuteriated benzene (C Dg) was lower than that of PPP prepared from normal benzene (CgHg) [3,15]. This last result was interpreted as an additional proof of the stair-step mechanism, which implies that polyphenylene is obtained from (12) which rearranges into PPP by successive steps corresponding either to proton loss (13) or to a dealkylation reaction (14), according to the pathway in Scheme 6.5. 

Shannon and Bruice found a P-450 model system for A-dealkylation reactions by employing A,A-dimethylaniline A/ -oxide (Scheme 11 A) [228]. In the presence of 2,4,6-tri-tert-butylphenol as an active species trap, dimethylaniline is formed in quantitative yield [231]. Miyata et al. also reported similar deoxygenation reactions by Fe (TPP) [241]. When a variety of alkenes and cyclohexane were present, competitive oxidation of... 

FIGURE 57.7 Aging of the DFP phosphorylated NTE protein. The aging process is a dealkylation reaction. In the case of AChE, the alkyl group is released to the medium as the corresponding alcohol. This represents the case of NTE with DFP in which the isopropyl group remains attached to the protein and is released to the medium only after an alkaline treatment. The nature of the "Z" site remains unknown. 

Reductive [ CJmethylation procedures have found broad application in the rapid labeling of investigational drug substances for in vitro studies where metabolism does not occur, in early exploratory in vivo investigations in drug research and development, and in peptide and protein mapping. However, because A -dealkylation reactions are common metabolic events, compounds labeled by Af-[ C]methylation are usually not suitable for registration studies. 

Deall lation. Chloroformates such as vinyl chloroformates (40) are used to dealkylate tertiary amines. Chloroformates are superior to the typical Von Braun reagent, cyanogen bromide, because of increased selectivity producing cleaner products. Other chloroformates such as aHyl, methyl, phenyl, and trichloroethyl have also been used in dealkylation reactions. Although the dealkylation reaction using chloroformates is mostiy carried out on tertiary amines, dealkylation of oxygen or sulfur centers, ie, ethers or thioethers, can also be achieved. a-Chloroethyl chloroformate [50893-53-3] (ACE-Cl) (41,42) is superior to all previously used chloroformates for the dealkylation reaction. ACE-Cl has the advantage that the conditions requked for ACE... 

In an attempt to study the behavior and chemistry of coal in ionic liquids, 1,2-diphenylethane was chosen as a model compound and its reaction in acidic pyri-dinium chloroaluminate(III) melts ([PyHjCl/AlCb was investigated [69]. At 40 °C, 1,2-diphenylethane undergoes a series of alkylation and dealkylation reactions to give a mixture of products. Some of the products are shown in Scheme 5.1-40. Newman also investigated the reactions of 1,2-diphenylethane with acylating agents such as acetyl chloride or acetic anhydride in the pyridinium ionic liquid [70] and with alcohols such as isopropanol [71]. 

Toluene is dealkylated to benzene over a hydrogenation-dehydrogenation catalyst such as nickel. The hydrodealkylation is essentially a hydrocracking reaction favored at higher temperatures and pressures. The reaction occurs at approximately 700°C and 40 atmospheres. A high benzene yield of about 96% or more can be achieved ... 

During a study of these complexes, Treichel and Hess 145, 147) heated [Pt(PPh3)2(CNCH3)Cl]Cl, expecting to obtain Pt(PPh3)(CNCHj)Cl2 instead a novel dealkylation reaction occurred. This was extended to other related species [Eq. (36)]. Remarkably, very few examples of such reactions... 

Upon recrystallization, [Ni(tpzlmtacn)]2+ affords [Ni(L)(MeCN)]2+ (L = l,4-bis(pyrazol-l-ylmethyl)-l,4,7-triazacyclononane) via a N-dealkylation reaction and loss of a pendent arm.1420 More rational routes to Ni complexes of tacn ligands with only one or two pendent arms have been developed.1431,1432 In [Ni(L)(X) ]x (e.g., L= l-(3-aminopropyl)-l,4,7-triazacyclononane (n = 2) or l-(l-methylimidazol-2-ylmethyl)-l,4,7-triazacyclononane (n = 2) or l,4-bis(l-methyl-imidazol-2-ylmethyl)-l,4,7-triazacyclononane (n = 1), the coordination sphere is completed by additional ligands that bind either terminal (X = C1 , H20) or bridge two metal ions (X = N3 , OH, oxalate). The Ni11 complex of l,4-bis(2-pyridylmethyl)-l,4,7-triazacyclononane has been shown to be extremely inert to ligand dissociation in aqueous solution.1433 In (562), the tacn ligand provides a single bidentate arm.1434... 

We found that dichloro diorgano silanes are suitable reagents for the synthesis of diorgano bis(0-alkyl)phosphonates. A different reactivity of both chlorine atoms of the silanes is observed in the dealkylation reaction of dialkylphosphonates in contrast to Me3SiBr [2]. 

It should be noted that the preparation of complexes (RNC)AuCN can be carried out via very special routes. Thus AuCN reacts with Mel to give (MeNC)AuCN. This reaction involves an interesting A-alkylation of an Au(i)-bound cyanide group.219 Other (RNG)AuGN complexes were obtained from the reaction of K[AuC14] with the isocyanide in methanol. Examples are the compounds (L)Au2(CN)2 with L = l,8-diisocyano-/>-menthane or 2,5-diisocyano-2,5-dimethyl-hexane. The reactions proceed with a dealkylation of an isocyanide in the coordination sphere of a gold(m) center to produce free cyanide (Scheme 53).201... 

The product distribution determined for the reactions performed over a broad temperature range (from -176 to 199 °C) under microwave heating was always more or less different from that obtained by conventional method. Thus, a vigorous formation of isobutene under reflux using microwave heating indicates superheating of the catalyst to a higher temperature. This facilitates the dealkylation reaction, which is promoted by elevated temperature. 

Chau and coworkers133 investigated the bioaccumulation of alkyllead compounds from water and from contaminated sediments by freshwater mussels, Elliptio complanata. Higher levels of trimethyllead than triethyllead species were accumulated after the same exposure period. In vivo transformation of the trialkyllead species by a series of dealkylation reactions giving dialkyllead and inorganic lead(II) species appears to take place. Rates of accumulation are higher for the more contaminated sediments133. 

By analogy to N- and O-dealkylation reactions, one might expect esters and amides to be susceptible to P450-catalyzed oxidative attack at the a-carbon to oxygen (esters) or a to nitrogen (amides). This is indeed the case and was first established (132) by demonstration that the pyridine diester (Fig. 4.66) was oxidatively cleaved by rat-liver microsomes to yield the monoacid as shown. 

In Fig. 19(6) the formation of a hydrogen bond is envisaged followed by the attachment of the positive P atom to the negative site and elimination of HF (fig. 19 (c)). Reversal, when possible,3 is represented in fig. 19(d). The inhibitor is of course hydrolysed at the end of the reaction. It may well be that (i 0)2P0(0H) is not actually recoverable, but that the regeneration process involves, first of all, a dealkylation which then facilitates the removal of the phosphate moiety from the enzyme.4... 

Disproportionation. A chemical reaction in which a single compound serves as both an oxidizing and reducing agent such as the dealkylation of toluene to give benzene (the more reduced product) and xylene (the more oxidized product). 

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