3-picoline direct oxidation

The N-oxide function has proved useful for the activation of the pyridine ring, directed toward both nucleophilic and electrophilic attack (see Amine oxides). However, pyridine N-oxides have not been used widely ia iadustrial practice, because reactions involving them almost iavariably produce at least some isomeric by-products, a dding to the cost of purification of the desired isomer. Frequently, attack takes place first at the O-substituent, with subsequent rearrangement iato the ring. For example, 3-picoline N-oxide [1003-73-2] (40) reacts with acetic anhydride to give a mixture of pyridone products ia equal amounts, 5-methyl-2-pyridone [1003-68-5] and 3-methyl-2-pyridone [1003-56-1] (11). 

A new route to prepare nicotinic acid starts from 2-methylglutaronitrile, a major side-product in the adiponitrile process and, as such, a readily available starting-material. It is easily hydrogenated to 2-methylpentanediamine, which is then condensed to methyl piperidine and dehydrogenated to 3-picoline. The gas-phase ammoxidation of the latter to cyanopyridine is followed by hydrolysis to either nicotinamide or nicotinic acid (Scheme 20.4). The cyanopyridine route for the production of nicotinic acid has the advantage of a significantly better selectivity with respect to the direct oxidation route from 3-picoline owing to the easy decar-... 

Since no other materials are involved in the direct oxidation than picoline, water and air or oxygen, any pollutants arising must be by-products of the reaction. It therefore follows that the higher the selectivity the fewer the potential pollutants and the smaller the waste streams. In the direct-oxidation process, the major side-reaction is... 

Picoline-l-oxide was converted to the Af-methor -4-picoIinium iodide (X-207) by treatment with methyl iodide. The latter was treated with cyanide to yield 2-cyano-4-picoline (X-208, X = CN) which was hydrolyzed to the acid (X-208, X = CO2H) with dflute hydrochloric acid. The nitrile (X-208, X = CN) was converted to the 1-oxide (X-209, X = CN), which could also be hydrolyzed to the corresponding acid (X-209, X = CO2H). The same A -oxide add (X-209, X = CO2 H) could be obtained directly by Af-oxidation of the add (X-208, X = C02H). ... 

An economically advantaged alternative to 3-picoline is 2-methyl-5-ethyl pyridine (MEP), which is a less expensive and more readily available feedstock. MEP is thus a preferred starting material for producing nicotinic acid whether by a direct oxidation or ammoxidation route. For direct conversion of MEP to nicotinonitrile, an added requirement of the catalyst and process is the dealkylation that must occur concurrently with the selective ammoxidation reaction. 

Quinoline directs alkoxylation and phenoxylation of tethered arenes. The 8-aminoquinoline directs the copper oxidation of the sp C-H bond (Scheme 76) (130L5842). A number of alcohols are tolerated, including both aliphatic (6 examples 39-85%) and aromatic alcohols (9 examples, 59-88%).The aryl amides can also have a range of functional groups including cyano, nitro, alkoxy, and alkyl groups. Picolinic acid derivatives also direct oxidative formation of the ether. 

A convenient process involving direct oxidation of P-picoline has been developed for the synthesis of nicotinic acid. ... 

Na-dichromate dihydrate added portionwise with stirring at 20-30° during ca. 0.5 hr. to a soln. of 3-picoline-4-sulfonic acid 1-oxide in coned. H2SO4, and allowed to react for 12 hrs. at the same temp. 3-carboxypyridine-4-sulfonic acid 1-oxide. Y 50-60%. - Direct oxidation of 3-picoline-4-sulfonic acid instead of its N-oxide gave poor results. J. Delarge, Farmaco, Ed. Sci. 22, 99 (1967). 

Although an inherently more efficient process, the direct chemical oxidation of 3-methylpyridine does not have the same commercial significance as the oxidation of 2-methyl-5-ethylpyridine. Liquid-phase oxidation procedures are typically used (5). A Japanese patent describes a procedure that uses no solvent and avoids the use of acetic acid (6). In this procedure, 3-methylpyridine is combined with cobalt acetate, manganese acetate and aqueous hydrobromic acid in an autoclave. The mixture is pressurized to 101.3 kPa (100 atm) with air and allowed to react at 210°C. At a 32% conversion of the picoline, 19% of the acid was obtained. Electrochemical methods have also been described (7). 

Picolinic acid has been generally prepared by the permanganate oxidation of a-picoline and isolated through the copper salt.1-2 3-4 5 In one instance,6 it was isolated directly as in the present procedure. It has recently been secured by the hydrolysis of w-trichloropicoline.7... 

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. 

Skolmeistere et al.136 studied the oxidation of 2-methylpyridine and pyridine-2-carboxaldehyde on a V-Mo oxide catalyst and observe that the main products formed in the second case are high-molecular condensation products and that a small amount of 2-picolinic acid is formed directly from the first compound. 

Fischer attempted the bromination of apoharmine in dilute sulfuric acid at room temperature and obtained a tetrabromo compound, which he did not characterize further. Treatment of l-benzoyl-2,5-dimethyl-4-azaindole with bromine in acetic acid at 25° gave the 3-bromo-l-benzoyl compound in 60% yield. On oxidation with permanganate it gave the same picolinic acid obtained before. Alkaline hydrolysis gave 3-bromo-2,5-dimethyl-4-azaindole (90%), also obtained by direct bromination of 2,5-dimethyl-4-azaindole in 60 % yield. 

Alkylpyridines undergo reactions analogous to benzene such as side-chain halogenation and oxidative functionalization (cf. p 291). In addition, C-H bonds directly attached to the heterocycle display a kinetic acidity which is greater by a factor of > 10 compared to the corresponding benzene derivatives. This is more pronounced in the 2- and 4-positions than in the 3-position. H/D-Exchange experiments of 2-, 3- and 4-picoline with a relative exchange rate of 130 1 1810 (MeOD/MeONa at 20°C, cf toluene 10" ) demonstrate this point. 

The transformation from arenes into phenol acetates can be achieved with hypervalent iodine compounds (such as phenyliodonium acetate, PhI(OAc)2), with chromates, or under aerobic conditions. Ligands, like picolinic acids, stabilize the intermediate palladium(IV) salts. In the presence of Lewis acids or silver salts, biaryl formation takes place. The influence of different directing groups has recently been reviewed. For example, diaryl sulfones or sulfoxides having at least one heteroaryl attached can be oxidized to the corresponding aryl acetates (Scheme 5-194, Experimental Procedure below). ... 

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