Alkylpyridines 1-oxides

A rearrangement of alkylpyridine-1-oxides that is related was also investigated. Ethyl 2-methylnicotinate-l-oxide (X-229) afforded an oil on treatment with acetic anhydride, which, after acid hydrolysis, yielded the... 

Nitrosation of 2- and 4-alkylpyridines, their quaternary salts and N-oxides, can be effected with an alkyl nitrite and sodamide in liquid ammonia the product is an oxime (Scheme 54) (69AP494, 65YZ451). 

Pyridinecarboxylic acids also result from the oxidation of alkylpyridines with potassium permanganate (55OS(3)740), nitric acid, and chromium trioxide in sulfuric acid (Scheme 60) (71S31). Alkylquinolines can be oxidized at the side chain with potassium dichromate and sulfuric acid. 

In the absence of the strong acid a different course ensues. The acetate ion attacks the A-acyloxypyridinium cation (127) at the a-position and elimination of acetic acid gives the product, 2-acetoxypyridine (128 Scheme 116) (65T1971,63JA958). The course of the reaction under these conditions with 2- and 4-alkylpyridine A-oxides has been discussed earlier (Section 2.06.3.1). 

The above reactions have been illustrated for 2- and 4-alkylpyridines. They generally fail if no heteroatom is a or 7, as in 3-alkylpyridines and 5-alkylpyrimidines. a- and [3-Alkyl groups in pyridine A-oxides are somewhat more reactive than those on the corresponding pyridines. In addition to the reactions already mentioned, 2-picoline 1-oxide undergoes Claisen condensation with ethyl oxalate to yield the pyruvic ester (630) (for the conversion of alkyl substituents in A-oxides into CH,OAc groups see Section 3.2.3.12.5.iv). 

A 1,3-dipolar cycloaddition of indanoneenamines and nitrilimines produces the indeno[2,1 -cjpyrazole (52).135 The yields of such cyclization reactions are high (60-80%). Reactions of A-alkylpyridine-3-ylides with picryl chloride involving cyclization give a mixture of pseudoazulenes 35 and 36.103 An additional preparation of pyrindine 26 is from 1,2- and 1,4-oxides of azonine.55... 

The greatest amount of work has been done on the oxidation of alkylpyridines and pyridine itself. However, this reported synthesis technology was neither modern nor necessarily optimum. 

Very little work has been done on selectivity in anodic reactions of pyridines. Selective methoxylation and acetoxylation are known for al-kylbenzenes, but such reactions have not been reported for alkylpyridines. Also, reports on the oxidation of pyridines having aldehyde, ketone, halogen, hydroxyalkyl, or aminoalkyl functionalities are sparse. 

Anodic oxidation of alkylpyridines to pyridinecarboxylic acids is an old but viable synthetic procedure, usually giving the desired product in reasonable yield. In contrast to catalytic air oxidation, which works best for making... 

Isocinchomeronic (135) and lutidinic (136) acids have also been prepared by similar methods.203-205 One of the earliest attempts to oxidize alkylpyridines... 

A recent patent describes selective oxidations on certain alkylpyridines.206 For instance, oxidation of the isomeric ethylpyridines gave the isomeric acetylpyridines (137) in reasonable yields (Scheme 45). The carboxylic acid was always a co-product. Certain of the dimethylpyridines (138,20) were oxidized... 

Alkylpyridines.3 Highly selective alkylation of pyridine at C4 is possible by quatemization with this triflate followed by reaction with a Grignard reagent. Substitution occurs with almost complete regiospecificity ( > 99%) to give 4-alkyl-l, 4-dihydropyridines, which are oxidized by oxygen to 4-substituted pyridines (equation 1). 

Alkylpyridines. RLi and RMgX both add selectively to pyridines to form 1,2-dihydro-2-alkylpyridines. A number of organometallic reagents add to N-ethoxycar-bonylpyridinium chloride (1) to give a mixture of 1,4- and 1,2-dihydropyridine derivatives (equation I). The most efficient and also selective reactions are shown by n-BuCu and n-BuCu BF3. The products are oxidized to the desired 4-alkylpyridines in 40 70% yield when stirred undcra stream of oxygen.17... 

Stamicarbon217> claims the use of anion exchange membranes in divided cells for the electrochemical oxidation of alkylpyridines to the corresponding pyridinecarboxylic acids. Finally, Takeda 218) has used the principle of paired synthesis in a divided cell for the simultaneous generation of synthetic intermediates. 

Under dioxygen-deficient conditions, pyridinium cations can compete with dioxygen in capturing alkyl radicals (Scheme 3). The resulting alkylpyridinium radical cations rapidly rearomatize by means of Fe(III)-induced oxidation to afford alkylpyridines and replenish the pool of Fe(II) sites. Other potential traps of alkyl radicals are Fe(III)—Cl moieties, which are known to effect oxidative chlorination (Eq. 8). 

R)-l-(3-pyridyl)propan-l-ol in 70% yield and greater than 99% ee (Equation 33). 2-Alkylpyridines undergo some ring hydroxylation and this mode of oxidation predominates with 4-alkylpyridines. 

As mentioned before, alkyl radicals and acyl radicals have a nucleophilic character therefore, radical alkylation and acylation of aromatics shows the opposite reactivity and selectivity to polar alkylation and acylation with the Friedel-Crafts reaction. Thus, alkyl radicals and acyl radicals do not react with anisole, but may react with pyridine. Eq. 5.1 shows the reaction of an alkyl radical with y-picoline (1). The nucleophilic alkyl radical reacts at the 2-position of y-picoline (1), where electron density is lower than that of the 3-position. So, 2-alkyl-4-methylpyridine (2) is obtained with complete regioselectivity. When pyridine is used instead of y-picoline, a mixture of 2-alkylpyridine and 4-alkylpyridine is obtained. Generally, radical alkylation or radical acylation onto aromatics is not a radical chain reaction, since it is just a substitution reaction of a hydrogen atom of aromatics by an alkyl radical or an acyl radical through the addition-elimination reaction. Therefore, the intermediate adduct radical (a complex) must be rearomatized to form a product and a hydrogen atom (or H+ and e ). Thus, this type of reactions proceeds effectively under oxidative conditions [1-6]. 

Selenium dioxide oxidizes CH3 to CHO (662 663) and this differentiates 2- and 4-methyls from 3-methyl, e.g., Scheme 85 <2003SC475>. Conversion of 2- and 3-alkylpyridines into chiral hydroxyalkyl derivatives can be achieved with the enzyme toluene dioxygenase from the mutant soil bacterium Pseudomonas putida in high ee <2002TA2201>. 

Characterization of Vanadium Oxide Catalysts in Relation to Activities and Selectivities for Oxidation and Ammoxidation of Alkylpyridines... 

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