Monodealkylation

On reaction with triflic anhydride, the mono oxides of 2,2 -bis(alkylthio)biphenyl are converted into a dithiadication (48) which spontaneously monodealkylates to give a thiasulfonium salt (49) <96TL667>. 

N - Benzyl- N -p icolinoylpiperazine (EGYT-475, 4.88), a compound with potential antidepressant activity, underwent similar hydrolysis. After intravenous administration, picolinic acid (4.89) was one of its major urinary metabolites in rats the other product, A-benzylpiperazine (4.90) was also detected, but at much lower levels, since it was further transformed by A-de-benzylation [55], Since the products of direct hydrolysis of these cyclic tertiary amides (i.e., the corresponding secondary amines) were found at substantial levels, it appears that oxidative A-monodealkylation is not an essential step for hydrolysis in these compounds, in contrast to the findings for A,A-diethylbenzamide. This contradicts the hypothesis [52] (see above) that the steric bulk of the tertiary amide group impedes direct hydrolysis. Here, although the degree of steric bulk is at least comparable, direct hydrolysis clearly takes place. 

Plant. In tolerant plants, atrazine is readily transformed to hydroxyatrazine which may degrade via dealkylation of the side chains and subsequent hydrolysis of the amino groups with some evolution of carbon dioxide (Castelfranco et al, 1961 Roth and Knuesli, 1961 Humburg et al, 1989). In corn juice, atrazine was converted to hydroxyatrazine (Montgomery and Freed, 1964). In both roots and shoots of young bean plants, atrazine underwent monodealkylation forming 2-chloro-4-amino-6-isopropylamino-s-triazine. This metabolite is less phytotoxic than atrazine (Shimabukuro, 1967). 

The strong Lewis acid niobium(V) pentachloride has been found to be an effective reagent for the monodealkylation of diethers with two alkyl-aryl linkages.128... 

A study was designed to define the relative rates of dealkylation of selected triazine herbicides and two monodealkylated triazine degradation products in the unsaturated zone and in surface runoff. Atrazine and propazine degrade to DEA by deethylation and deisopropylation, respectively. Similarly, atrazine and simazine can both dealkylate to DIA by removal of an isopropyl and ethyl side chain, respectively (Figure 30.12). Differences in the concentration of the dealkylated degradation product from the two different sources should indicate any preferential removal of ethyl versus isopropyl side chain. Furthermore, because monodealkylated DEA and DIA have different side chains remaining, their relative rate of removal should provide additional information on the liability of the ethyl side chain versus an isopropyl side chain. 

This study showed that under field conditions, the removal of an ethyl side chain from atrazine occurred more readily than the removal of an isopropyl side chain. Furthermore, deethylation rates of atrazine and simazine were comparable, and approximately two to three times more rapid than the rates of deisopropylation from atrazine and propazine, regardless of parent triazine. Continued dealkylation of the monodealkylated degradation products at 1 m in the unsaturated zone also shows a preferential removal of ethyl side chains over isopropyl side chains. Therefore, the small concentrations of DIA commonly reported in the environment do not result purely from a smaller production of the degradation product, but from a rapid removal once produced. This substantial turnover rate or flux of DIA in the environment is evidence for the presence of a didealkylated degradation product in the unsaturated zone (Mills and Thurman, 1994 Thurman et al., 1994). 

Maturano, M. D., Bongibault, V., Klaebe, A., and Fournier, D. (1997) A chemical model for the enzymic monodealkylation of (methyl and ethyl) parathion by glutathione-S-transferase, Tetrahedron 53, 17241-... 

Dealkylation of phosphonates. Vigorous acid treatment is usually required for this reaction. To circumvent this difficulty, both bromo- and chloro-trimethylsilane have been used with limited success. lodotrimethylsilane is more selective the parent phosphonic acids can be obtained under very mild conditions without modification of a variety of other functional groups. However, monodealkylation is not practical with this reagent. Aryl esters are not cleaved hence selective dealkylation of alkyl aryl esters of phosphonic acids may be possible. 

Disopyramide is metabolized to nordisopyramide (monodealkylated) by the action of CyP 2D6 nordisopyramide has antiarrhythmic activity approximately 25% that of disopyramide. Under normal circumstances, nordisopyramide accumulates to concentrations ranging from 0.2 to l.Opg/mL, and the compound does not accumulate out of proportion to disopyramide in situations of reduced hepatic or renal function. Therefore little additional therapeutic information is gained by monitoring nordisopyramide. 

Savignac, P, and Lavielle, G., Monodealkylation of phosphoric and phosphonic esters by thiolates and thiophenates. Bull. Soc. Chim. Fr., 1506, 1974. 

Krawczyk, H., A convenient route for monodealkylation of diethyl phosphonates, Synth. Commun., 27, 3151, 1997. 

Sodium thiolates and thiophenates in EtOH at reflux and alkali halides at room temperature (for Lil, Nal, or Kt) or on heating (for LiCl, LiBr, NaBr, or KBr) induce monodealkylation of diethyl l-(ethoxycarbonyl)methylphosphonate. 

The ageing process consists of the monodealkylation of the AChE-nerve agent complex. The loss of an alkyl group produces a conformational change that results in the formation of a very stable agent-enzyme complex which is then resistant to spontaneous hydrolysis and reactivation by oximes. The rate of ageing is dependent... 

By contrast, 2,3,4-tris(2-ethylhexyloxy)benzaldehyde in 1,2-dichloroethane was monodealkylated selectively at the 2-position by the dropwise addition over 30 mins, of titanium tetrachloride at 8-12°C with continued stirring for a further 30 mins, and then at ambient temperature for 2 hours prior to quenching with dilute hydrochloric acid to afford 2-hydroxy-3,4-bis(2-ethylhexyloxy)benzaldehyde in 73% yield (ref.24). 

Phosphite or pyrophosphite esters undergo dealkylation by protonic acids with decreasing ease in the series hydrogen halide, carboxylic acid, alcohol, or phenol. The carboxylic acid reaction (18,31,171), which stops at monodealkylation, has been utilized (141) for the synthesis of aryl esters of amino acid derivatives. 

Rapid monodealkylation was observed during A"-Fmoc deprotection of methyl- and benzyl-protected phosphates by the customary piperidine-DMF solution treatment [103,108]. Although this side reaction does not seem to compromise peptide purity, it could be decreased but not completely suppressed by employing the nonnucleophilic base 1,8-diazabicy-... 

Oximes, which are valuable intermediates for the conversion of oxoalkyl phosphonic diesters into those of aminoalkylphosphonic acids (Chapter 4, Section IV.C. 1. d), are also readily available, although it is necessary to prepare them with some care. Nevertheless, the feature of interest here is their ready degradability, particularly under aqueous conditions, and which has been intensively investigated by Breuer and coworkers. The necessity for care in the preparation of oximes of acylphosphonic diesters, is illustrated by the synthesis of dimethyl [a-(hydroxyimino)benzyl]phosphonate this compound exists in the thermodynamically more stable ( ) form which, under the influence of acid is converted into the less stable (Z) form, and both forms have been separately characterized by X-ray crystallography. The geometric isomers of the oxime differ in their behaviour under basic conditions with NaOH-MeOH, the ( ) form undergoes monodealkylation, whereas the (Z) isomer decomposes to dimethyl phosphate and benzonitrile. In aqueous solution, ( )-[a-(hydroxyimino)benzyl]phosphonic acid also decomposes into benzonitrile together with phosphoric acid, in a manner which is pH dependent, and consistent with a dissociative mechanism that involves the early formation of monomeric metaphosphate. ... 

The 2-oxoazetidine-l-phosphonic acids (22) have been prepared by monodealkylation of the corresponding dialkyl esters with thiourea. The acid (22 R = R = H) was obtained, as its monoanilinium salt, by reaction of its bis-(trimethylsilyl) ester with aniline in ether. ... 

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