Pyridine reaction with amide anion

Tertiary benzylic nitriles are useful synthetic intermediates, and have been used for the preparation of amidines, lactones, primary amines, pyridines, aldehydes, carboxylic acids, and esters. The general synthetic pathway to this class of compounds relies on the displacement of an activated benzylic alcohol or benzylic halide with a cyanide source followed by double alkylation under basic conditions. For instance, 2-(2-methoxyphenyl)-2-methylpropionitrile has been prepared by methylation of (2-methoxyphenyl)acetonitrile using sodium amide and iodomethane. In the course of the preparation of a drug candidate, the submitters discovered that the nucleophilic aromatic substitution of aryl fluorides with the anion of a secondary nitrile is an effective method for the preparation of these compounds. The reaction was studied using isobutyronitrile and 2-fluoroanisole. The submitters first showed that KHMDS was the superior base for the process when carried out in either THF or toluene (Table I). For example, they found that the preparation of 2-(2-methoxyphenyl)-2-methylpropionitrile could be accomplished h... 

The reaction of arylacetamides with ethyl phenylpropiolate gives 4,5-diaryl-l,5-dihydro-2//,67/-pyridine-2,6-diones (197). - It has been suggested that the pyridinediones in these reactions are formed through the initial addition of either the amide anion (195) or the carbanion (196), generated under basic conditions, to ethyl phenylpropiolate (Scheme 30). 

One of the first compounds to be introduced to the clinic, aztreonam (40-9), has been produced by total synthesis. Constmction of the chiral azetidone starts with amide formation of L-threonine (40-1) via its acid chloride treatment with ammonia leads to the corresponding amide (40-2). The primary amino group in that product is then protected as its carbobenzyloxy derivative (40-3). Reaction of that product with methanesulfonyl chloride affords the mesylate (40-4). Treatment of that intermediate with the pyridine sulfur trioxide complex leads to the formation of the A -sulfonated amide (40-5). Potassium bicarbonate is sufficiently basic to ionize the very acidic proton on the amide the resulting anion then displaces the adjacent mesylate to form the desired azetidone the product is isolated as its tetrabutyl ammonium salt (40-6). Catalytic hydrogenation over palladium removes the carbobenzyloxy protecting group to afford the free primary amine (40-7). The... 

Similar to that of pyridine, the Chichibabin amination on quinoline and isoquinoline proceeds with alkali metal amides in liquid ammonia. In accordance to that, the reaction of quinoline with liquid ammonia initially forms a complex, which allows amide anion to add to the heterocyclic core of quinoline and isoquinoline bicycle, obtaining 2- or 4-aminoquinolines and 1-aminoisoquinolines, respectively, in good yields. ... 

Methyl 2-trifluoromethyl-2-siloxycyclopropanecarboxylate was found to undergo successive smooth deprotonation with lithium di-isopropyl amide and reaction with carbon disulfide and methyl iodide to afford a dihydrothiophene derivative most likely via ring-expansion of the anionic intermediate by a [1,3] sigmatropic rearrangement (14JOC4492).The dide-hydrothiophene derivative was then converted to the corresponding 5-trifluoromethylthiophene by treatment with phosphoryl chloride in refluxing pyridine. An example of this reaction is shown below. 

Syntheses of the formamidine AdNHCH=NAd from 1-aminoadamantane hydrochloride (AdNH2,HCl) by reaction with s-triazene in pyridine and of the amide from p-(2-furyl)acrylie acid chloride and AdNH2 have been recorded the amide has antiviral activityReaction of 3-methylpentadienyl anion with adamantanone affords (668 75%) as the exclusive product the anion is a convenient reagent for the introduction of a 1,3-diene unit of the above type, and applications to terpene synthesis are discussed." Thermolyses of esters of P-hydroxyalkyltrimethylsilanes,... 

A different route has to be used to synthesize 5-alkyluridines (Scheme 10) because introduction of an electron-donating alkyl group at the C-S position of 27 decreases the acidity of H-S. Thus, while 30 can be prepared in high yield by methylation of the amide a-anion, its reaction with the PhSeCl-pyridine complex only resulted in complete tecoveiy... 

In conclusion, structures containing polyiodide anions, with cationic aromatic ligands as counter parts of formulae [(L)(HL+)] (I ) are known to be synthesized by the treatment of the appropriate amide with HI [26-28], In contrast, the complexes with PYOH, in the present case, were formed by the direct reaction of 2-hydroxypyridine with di-iodine in a molar ratio of 2 1 and 1 2. This is a redox reaction, where 2-hydroxy-pyridine firstly is oxidized to pyridinone-2 radical cation. In the case of 2-hydroxy-pyridine however, peroxide structures are not formed like disulphides in the case of PYSH. Polyiodide anions are simultaneously produced in this case This should be a consequence of redox differences between -SH and OH groups and may be proven a useful pathway for the synthesis of polyiodide materials. 

In a related vein, one of the benzene rings in dibenzepin (36-7) can be replaced by pyridine. In a one-pot reaction, condensation of the 2-chloronicotinic acid (43-2) with ortho-phenylenediamine (43-1) leads to the lactam (43-3). The order in which the two steps, aromatic displacement and amide formation, take place has not been elucidated. Simple alkylation of the anion from the product with 3-chloro-2-(AA -drmethylamino)propane (43-4) affords the antidepressant agent propizepine (43-5) [43]. 

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