Dealkylation pyridines

Microwave chemistry has been found to be a useful method for accelerating reactions or catalyzing reactions that are difficult to carry out by other methods. A modification of the Hantzsch method to directly obtain pyridines has been communicated. A dry medium using ammonium nitrate bentonitic clay system with microwave irradiation affords pyridines 96 in a single pot within 5 minutes. When the pyridine is not the major product (> 75% yield), the dealkylated pyridine 97 becomes an... 

Secondary alkyl groups or benzyl groups may be cleaved from certain compounds during reactions in which radicals are formed as intermediates. This can, for instance, happen during the oxidation of 4-benzyl or 4-isopropyl dihydropyridines, which usually yields the dealkylated pyridines (Scheme 3.5). Similarly, if a strained bond connects two electron-withdrawing groups, this bond might be cleaved by SET-mediated reduction (second reaction, Scheme 3.5) [15]. 

Delgado et al. (1991) reported oxidation of several Hantzsch 4-alky 1-1,4-dihy-dropyridines to the corresponding aromatic systems. An unexpected mixture of 4-alkyl pyridines and/or dealkylated pyridines was formed. 

Scheme 14). The reaction of 72 with pyridine causes the dealkylation both at the methoxy group and at the metal leading to 77 and to the organic products shown in Scheme 15. 

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. 

Investigation of the in vitro metabolism of delavirdine is accomplished using mouse, rat, dog, monkey, rabbit, and human liver microsomes. The primary metabolite observed is the A-dealkylated delavirdine 26. Another primary metabohte observed is the hydroxy-lation of the pyridine ring at C-6 (compound 27). The primary metabolism is by CYP3A4 and also CYP2D6. Delavirdine reduces the activity of CYP3A4, thereby inhibiting its own metabolism. 

Reactions involving sulfur-linked substituents have been exclusively dealkylations of S-alkyl substituents to yield a thiocarbonyl group. Debenzyl-ations under mild conditions with aluminum chloride in benzene were mentioned earlier (Section IV,A,2,a). Pyridine demethylates salts 137 selectively to give 175. ° ... 

The concave acids 38 and the esters 39 could be interconverted. Reaction of the acids 38 with diazomethane led to the methyl esters 39. 8 2 dealkylation of the esters 39 by lithium iodide in pyridine gave the acids 38 [27]. 

Quaternization of molecules containing alkoxy and thioalkoxy substituents can be complicated by dealkylation of the substituent. Such side reactions are especially facile in molecules that give rise to a carbonyl or thiocarbonyl group following dealkylation. The reaction between a 2-substituted pyridine and Mel is illustrative [Eq. (16)]. This sequence is reversible and can be used to advantage to compare the enthalpies of unquaternized starting material and product.137,138... 

If the heterocyclic base contains several pyridine-type nitrogens select can also be observed. Indeno[l,2-b]quinoxalines, for example, are quaternized at the N-10 atom.110 The alkylation of heterocycles conta one pyrrole-type nitrogen and several pyridine-type nitrogens is appar selective (e.g., indolo[2,3-b]quinoxaline).201 The yields of quaternary however, are extremely low,201 even if phenacyl halides or a-halo ester used.207 Perhaps the resultant quaternary salts are dealkylated.200,207... 

It is also important to mention the use of the reactivation of the acetylcholinesterase by pyridine-2-aldoxime methochloride to discriminate between the toxin and potential insecticides [96]. Once phos-phorylated, the active site serine of the enzyme can be reactivated by powerful nucleophilic agents such as oximes. However, this reactivation is not possible if attempted too late due to the stable adduct formed by the dealkylation (aging) of the inhibitor s remaining group. When acetylcholinesterase is inhibited by anatoxin-a(s), it shows immediately the characteristics of an aged enzyme and cannot be reactivated. In this way, it is possible to distinguish between the inhibition caused by anatoxin-a(s) and the one provoked by other insecticides. 

Concentration of active sites increases with the S/V-factor, all other parameters being equal. As a consequence, the target product yield also increases. Therefore, all following experiments were implemented in a reactor filled with quartz granules [95], A temperature increase above 640 °C abruptly reduces 4-VP yield and the process selectivity, and increases the amounts of side products (pyridine, in particular), which indicates that under definite conditions in the presence of hydrogen peroxide alkylpyridine dealkylation reaction may be implemented. 

A mechanistic study by Deady and Korytsky, which showed that dealkylation is exactly the reverse of the alkylation reaction (79TL451), implies, according to the principle of microscopic reversibility, that the amount of strain in the TS for quaternization is two-thirds of that in the final quaternary salt, in close agreement with the early estimate by Brown. The ratio of substituent steric effects is 3/1 for disubstituted pyridines in methylation vs. demethylation. Because of smaller sensitivity to steric effects in thiazoles, steric acceleration in the reverse reaction is small (76AJC1745 79BSF(2)484). 

After isolation, the isomerization proceeds with a measurable rate, but dealkylation leading to the pyridine competes with isomerization and it is still a matter of speculation whether the observed isomerization occurs with or without (rotation) bond breaking. Examples of analogous hindered rotations in the benzene series have been reviewed (84ACR154). 

Formyl-l,2,3,3-tetramethylindoline (29) was converted to various 5-([3-heterocyclylvinyl) indolines (30) via condensation with heterocyclic quaternary salts and subsequent N-dealkylation by triphenylphosphine. The resultant indolines were oxidized with mercuric acetate to the 5-substituted Fischer s bases (31, R = benzoxazol-2-yl quinolin-2-yl quinolin-4-yl pyridin-4-yl 1,3,3-trimethylindo-len-2-yl). These were used as intermediates for cyanine dyes their conversion to spiropyrans was not recorded. 41... 

---