Carbamates dealkylation

Alkyl esters are efficiently dealkylated to trimethylsilyl esters with high concentrations of iodotrimethylsilane either in chloroform or sulfolane solutions at 25-80° or without solvent at 100-110°.Hydrolysis of the trimethylsilyl esters serves to release the carboxylic acid. Amines may be recovered from O-methyl, O-ethyl, and O-benzyl carbamates after reaction with iodotrimethylsilane in chloroform or sulfolane at 50—60° and subsequent methanolysis. The conversion of dimethyl, diethyl, and ethylene acetals and ketals to the parent aldehydes and ketones under aprotic conditions has been accomplished with this reagent. The reactions of alcohols (or the corresponding trimethylsilyl ethers) and aldehydes with iodotrimethylsilane give alkyl iodides and a-iodosilyl ethers,respectively. lodomethyl methyl ether is obtained from cleavage of dimethoxymethane with iodotrimethylsilane. 

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. 

Phenylcarbamates, or carbanilates, generally exhibit low water solubilities, and thus they are almost immobile in soil systems. Chlorpropham and Propham are readily volatilized from soil systems, but Terbutol and Carbaryl (Fig. 10, Table 3) are not. Ester- and amide-hydrolysis, N-dealkylation and hydroxylation are among the chemical reactions that carbamates undergo. The N-methylcar-bamate insecticides (Fig. 10, Table 3) commonly used in soils are Carbaryl, Methiocarb,Aldicarb,and Carbofuran [74,173]. 

In contrast to the A-monosubstituted carbamates, the A,A-disubstituted analogues (8.124 and 8.125, R = R R"NCO R = Me or Et R" = Me, Et, i-Pr, etc.) proved very stable at pH 7.4 in both buffer and plasma, with less than 5% degradation in 4 d. In fact, these compounds were potent inhibitors of plasma cholinesterase (EC 3.1.1.8), with K values ranging from 600 to 3 nM. Although these carbamates were stable in plasma, they underwent rapid bioactivation in liver, as demonstrated with mouse and rat liver microsomes. For example, the A,A-dimethylcarbamate (8.124, R = Me2NCO) was bioactivated in rat liver microsomes with t1/2 of ca. 30 min. Two routes of bioactivation were postulated, namely direct carboxylesterase-catalyzed hydrolysis, and cytochrome P450 mediated A-dealkylation to a more labile A-monosubstituted carbamate. 

N-dealkylation results from an alkyl substitution on an aromatic molecule, which is one of the first places where microorganisms initiate catabolic transformation of atrazine, a xenobiotic molecule (Fig. 15.2). It is a typical example of a reaction leading to transformation of pesticides like phenyl ureas, acylanihdes, carbamates, s-tri-azines, and dinitranilines. The enzyme mediating the reaction is a mixed-function oxidase, requiring a reduced nicotinamide nucleotide as an H donor. 

The anodic oxidation of methyl N,/V-dialkylcarbamate in methanol, containing Et4NOTs, yielded three types of products a-methoxylated compounds, enamine-type products, and dealkylated carbamates.197 Methyl N-pyrrolidinylcarbamate (137), for example, gave on constant current oxidation... 

The condensation of an aldehyde, benzyl carbamate, and triphenyl phosphite, first described by Oleksyszyn et al., 25,26 affords a direct route to a-aminoalkylphosphonates 4 that are conveniently protected for subsequent reactions (Scheme 4). Since dealkylation of the quaternary phosphonium intermediate 3 is not possible in this case, formation of the pen-tavalent product 4 presumably involves activation of the solvent and formation of phenyl acetate. This method is useful for the synthesis of aliphatic and aromatic amino acid analogues. However, monomers with more elaborate side chains are often incompatible with the reaction conditions. The free amine can be liberated by treatment with HBr/AcOH or by hydrogenolysis after removal of the phenyl esters. The phosphonate moiety can be manipulated by ready exchange of the phenyl esters in alkaline MeOH and activation as described in Section 10.10.2.1.1. Related condensations with other trivalent phosphite derivatives have been reported. 27-30 ... 

Investigation of the metabolic fate of compounds 64b and 71b led to the following results After peroral administration of 71b in rats, about 90% of the ingested silicon could be detected in urine within 4 days. In the ethyl ether extract of the urine, no unchanged 71b could be found. In the ethyl acetate extract the dealkylation product 85 was detected (29% of ingested sila-carbamate 71b) ... 

Aliphatic amine R—NH2 CYP, FMO, MAO, UGT, SULT, MT, NAT, peroxidase N-Dealkylation, N-oxidation, deamination, N-glucuronidation, N-carbamoyl Carbamate V R-NH-C-O-R CYP, esterase... 

N-Dealkylation This is a common reaction in the metabolism of xenobiotics, including organophosphorus and carbamate insecticides. The reaction is believed to proceed by an unstable a-hydroxy intermediate that spontaneously releases an aldehyde in the case of the primary alkyl group. For example, the carbamate insecticide propoxur is N-demethylated to 2-isopropoxyphenyl carbamate via 2-iso-propoxyphenyl N-hydroxymethyl carbamate. Microsomal N-dealkylation results in detoxification (Figure 8.5). 

Selective phosphonate ester dealkylation. Alkyl phosphonate esters are selectively and nearly quantitatively cleaved by bromotrimethylsilane in the presence of alkyl carboxylate esters, carbamates, acetylenes, ketones, and halides. Alkyl iodides do not exchange under the reaction conditions. The resulting bis(trimethylsilyl) phosphonates are hydrolyzed in acetone by a small excess of water. 

Alkyl bromides. Alcohols are converted into bromides by reaction with bromotrimethylsilane (1.5-4 equiv.) in CHCI3 at 25-50° (equation I). The reaction occurs with inversion. Tertiary and benzylic alcohols react more rapidly than primary or secondary alcohols. Bromides are not formed under the same conditions from Irimethylsilyl ethers of alcohols. However, trimethyl orthoformate is converted into methyl formate, HC(OCH3)3 —s HCOOCH3. Unlike iodotrimethylsUane, the bromosilane does not dealkylate esters, ethers, or carbamates. 

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

However, vinyl chloroformate largely has been replaced for N-dealkylation by 1-chloroethyl chloroformate which shows similar dealkylation selectivities and equally easy replacement of N-alkyl by the carbamate group (see section 3-3). 

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). 

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

Martz, J.T. A synthesis and applications of a useful, new reagent for N-dealkylation. Some chemistry of alkenyl esters and carbamates Ph. D. Thesis, The Pennsylvania State University, 1982... 

Even N-dealkylation of aromatic amines occurs cleanly with ACE-CI as it is illustrated in a strigent test by the conversion of N,N-diethyl aniline to 1-chloroethyl N-methyl-N-phenyl carbamate in 87 % yield (Ref. 68). Caubere and Bachelet used this methodology while operating without a solvent for the demethylations as well as for the deethylations of dialkylamino benzofurans in good yields (Ref. 192). 

We first attempted to dealkylate the CPM group in naltrexone derivative 35 with 1-chloroethyl chloroformate (ACE-C1) under the original reaction conditions [33] however, the reaction hardly proceeded. After extensive investigation, we found that the piperidine ring of naltrexone derivative 35 could be cleaved with ACE-C1 (9 equiv.) in pyridine to give, surprisingly, oxazolidinone 36 in 60% yield concomitantly with the starting material 35. However, that reaction did not produce the objective carbamate derivative 37 (Scheme 15, condition (a) Fig. 9 shows the structure of compound 37). Therefore, we focused on the abnormal reaction that... 

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