Amines, tertiary demethylation

Potassium ferricyanide [potassium hexacyanoferrate(lll)], K3Fe-(CN), in the presence of a base, dehydrogenates hydroaromatic compounds to aromatic compounds [919] and can cause dehydrogenative cy-clizations [920]. The reagent is used for the conversion of acid hydrazides into aldehydes [921], of sterically hindered phenols into phenoxy radicals [922, 923], and of primary amines into nitriles [924], Tertiary amines are demethylated to secondary amines [925, 926]. 

N-Demethylation of tertiary amines. Tertiary amines are converted into N-demethyl-N-nitrosamines (40-80% yield) by treatment with AgN02 (4-8 molar eq.) in DMF (70°, 2-24 hr.). N-Nitrosamines are readily hydrolyzed to secondary amines by acid. ... 

The formation of N-oxides of tertiary amines and demethylation of secondary amines are biochemical processes which may also be involved in detoxification. In the case of A, iV-dimethylaniline, the N-oxide is considered to be the possible intermediate in its NADPH- and oxygen-dependent oxidative demethylation. The formation of this A -oxide appears to be catalyzed via a flavoprotein oxidase (509). Tertiary amine A -oxides, thus formed, are often excreted in urine. In the case of A -methyl-4-aminoazobenzene (MAB), demethylation to 4-aminoazoben-zene (AB) appears to occur via a cytochrome P-450 mediated oxidation. Since an A -methyl substituent is regarded as essential for carcinogenic activity among derivatives of AB, this oxidative demethylation would be a specific mode of detoxifying this carcinogenic aromatic amine. 

Desipramine [50-47-5] (35) and nortriptyline [72-69-5] (36) are demethylated derivatives and principal metaboHtes of (32) and (33), respectively. Both compounds possess less sedative and stronger psychomotor effects than the tertiary amine counterparts, probably because tricycHcs containing secondary amine groups generally show greater selectivity for inhibiting the reuptake of norepinephrine compared with the reuptake of serotonin. Protriptyline [438-60-8] (37), a stmctural isomer of nortriptyline, is another important secondary amine that displays a similar clinical profile. 

In this series, too, replacement of the N-methyl by a group such as cyclopropylmethyl leads to a compound with reduced abuse potential by virtue of mixed agonist-antagonist action. To accomplish this, reduction of 24 followed by reaction with tertiary butylmagnesium chloride gives the tertiary carbinol 27. The N-methyl group is then removed by the classic von Braun procedure. Thus, reaction with cyanogen bromide leads to the N-cyano derivative (28) hydrolysis affords the secondary amine 29. (One of the more efficient demethylation procedures, such as reaction with ethyl chloroformate would presumably be used today.) Acylation with cyclopropylcarbonyl chloride then leads to the amide 30. Reduction with lithium aluminum hydride (31) followed by demethylation of the phenolic ether affords buprenorphine (32).9... 

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). 

The photooxidation of tertiary methylamines sensitized by electron acceptors such as 9,10-dicyanoanthracene in the presence of lithium perchlorate results in demethylation thus tropinone yields nortropinone257. Photoinduced cyanation of tertiary amines with oxygen, a sensitizer and trimethylsilyl cyanide results in a-cyano nitriles (equation 88)258. 

The cyclic metabolite 11.169 was also a substrate in further biotransformations, being (V-demethylated to the corresponding endocyclic imine, and oxidized to phenolic metabolites. Very little if any of the secondary amine metabolite (11.168) appeared to undergo direct (V-demethylation to the primary amine, in contrast to many other tertiary amines, presumably due to very rapid cyclization of the secondary amine facilitated by steric and electronic factors. The possibility for the iminium cation (11.169 H+) to become deprotonated (a reaction impossible for the iminium 11.166 in Fig. 11.20) should also drive the cyclization reaction. 

Sensitivities of 1 ng can be achieved by demethylation of the quarternary amines to tertiary amine analogs and analysis with FID detection (Tsai, 2000). However, the lack of volatility of these compounds makes them difficult to analyze satisfactorily with GC. Most work since the last edition of the Handbook of Neurochemistry on these compounds has utilized HPLC because these substances can be analyzed without demethylating or derivatizing (Tsai, 2000). 

A different mode of reaction, however, is observed in photoreductions of nitroaromatics by aromatic tertiary amines. Irradiation of benzene solutions of N-methylated anilines and either m-chloronitrobenzene or 1-nitronaphthalene results in oxidative demethylation of the amines accompanied with reduction of the nitro compound to the corresponding arylamine 49). The authors suggest that hydrogen abstraction from the methyl group takes place as the primary chemical event. 

Highly efficient and stereoselective addition of tertiary amines to electron-deficient alkenes is used by Pete et al. for the synthesis of necine bases [26,27], The photoinduced electron transfer of tertiary amines like Af-methylpyrrolidine to aromatic ketone sensitizers yield regiospecifically only one of the possible radical species which then adds diastereospecifically to (5I )-5-menthyloxy-2-(5//)-furanone as an electron-poor alkene. For the synthesis of pyrrazolidine alkaloids in approximately 30% overall yield, the group uses a second PET step for the oxidative demethylation of the pyrrolidine. The resulting secondary amine react spontaneously to the lactam by intramolecular aminolysis of the lactone (Scheme 20) [26,27]. 

The enzyme is the principal participant in N-demethylation reactions where the substrate is a tertiary amine. The list of substrates includes erythromycin, ethylmor-phine, lidocaine, diltiazem, tamoxifen, toremifene, verapamil, cocaine, amiodarone, alfentanil and terfenadine. Carbon atoms in the allylic and benzylic positions, such as those present in quinidine, steroids and cyclosporin A, are also particularly prone to oxidation by CYP3A4, a range of substrates is illustrated in Figure 7.10. 

A2 Tertiary amine TCAs, duloxetine, theophylline, phenacetin, TCAs (demethylation), clozapine, diazepam, caffeine Fluvoxamine, fluoxetine, moclobemide, ramelteon Tobacco, omeprazole... 

FIGURE 24.4 Postulated pathway for P450-catalyzed tertiary amine /V-dcalkylation (shown for iV-demethylation of iV,iV-dimethylamine). (From FP Guengerich, CFI Yun, TL Macdonald. J Biol Chem 271 27321-27329, 1996. With permission.)... 

Demethylation of, POCH3. Phosphate and phosphonate esters are partially dealkylated by tertiary amines. r-Butylamine is superior Tor this cleavage, and it is very selective. Only O—Cl I3 bonds are affected ethyl esters are stable to the amine for several weeks. A benzyl group can be cleaved under forcing conditions.1 [Examples ... 

POLONOVSKI REACTION. Demethylation of tertiary (or Heterocyclic) amine A-oxides on treatment with acetyl chloride or acetic anhydride 1o give A-acylated secondary amines and formaldehyde, along with (9-acylated aminophenols as a result of a side reaction. 

The Ru(II)/ROOH system can also be used to oxidize tertiary amines. The intermediate iminium ion is formed, as described earlier for secondary amines, and can be trapped by nucleophiles. Thus, the ruthenium-catalysed oxidation of tertiary amines with hydrogen peroxide in methanol can be performed to give the corresponding a-methoxyamines with high efficiency as illustrated in Fig. 24 [ 137]. Another example is the selective demethylation of tertiary amines in methanol with a combination of Ru(II) and H202, followed by hydrolysis of the intermediate a-methoxylated amines. For example, the methoxylation of N,N-dimethyl-p-toluidine followed by treatment with 2 N HC1 solution gave N-methyl-p-toluidine in 75% yield (Eq. 35) [137]. 

Similarly, for tertiary amines a distinction can be made between oxometal and peroxometal pathways. Cytochrome P450 monooxygenases catalyze the oxidative N-demethylation of amines in which the active oxidant is a high-valent oxoiron species. This reaction can be mimicked with some oxometal complexes (Ruv=0), while oxidation via peroxometal complexes results in oxidation of the N atom (Fig. 4.93 a and b) [261]. A combination of MTO/hydrogen peroxide can... 

Demethylation of 1-methyl-3-piperideines may be accomplished with the use of the von Braun cyanogen bromide procedure.60,128 A certain drawback of this method consists in loss of half of the tertiary amine in formation of a quaternary salt (e.g., 146), in addition to the required 1-cyano derivative (e.g., 147), which is then hydrolyzed to the required secondary amine. 3-Piperideine was obtained by this procedure in the form of a stable free base.128... 

Generation of benzomorphan secondary amines, for conversion to appropriate N-substituted derivatives, usually requires N-demethylation of the corresponding tertiary amine. This may be effected by the von Braun reaction with cyanogen bromide or by the use of alkyl-, halogenated alkyl-, and arylchloroformates or diethylazodicarboxylate. Methods for N-demethylation in the series have been summarized by Rice.(62) Removal of an N-benzyl substituent affords an alternative path to norbenzomorphans and is exemplified by Michne and co-workers(63) and Kametani and Aoyama.(s4)... 

Following rapid absorption, TCAs are strongly bound to plasma albumin (90-95% at therapeutic plasma concentrations). Inactivation occurs via CYP isoenzymes by the demethylation of tertiary TCAs to secondary amine metabolites, and then glucuronidation and excretion in the urine. 

Note that amitriptyline, imipramine, and other tertiary amines give rise to the corresponding demethylated metabolites in urine samples. Measurement of plasma concentrations of tiiese (hugs is rarely necessary and should only be cMried out by specific gas chromatographic procedures. 

Selective oxidative demethylation of tertiary methyl amines is one of the specific and important functions of cytochrome P-450. Novel cytochrome P-450-type oxidation behavior with tertiary amines has been found in the catalytic systems of low-valent ruthenium complexes with peroxides. These systems exhibit specific reactivity toward oxidations of nitrogen compounds such as amines and amides, differing from that with RUO4. It was discovered in 1988 that low-valent ruthenium complex-catalyzed oxidation of tertiary methylamines 53 with f-BuOOH gives the corresponding a-(f-butyldioxy)alkylamines 54 efficiently (Eq. 3.70) [130]. The hemiaminal type 54 product has a similar structure to a-hydroxymethylamine intermediate derived from the oxidation with cytochrome P-450. 

The oxidation of N-methylamines provides various useful methods for organic synthesis. Selective demethylation of tertiary methylamines can be carried out by the ruthenium-catalyzed oxidation and subsequent hydrolysis (Eq. 3.71). This is the first synthetically practical method for the N-demethylation of tertiary amines. The methyl group is removed chemoselectively in the presence of various alkyl groups. 

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