2- Picoline reaction with acetic anhydride

Nitro-3-picoline, from 3-pic-oline-l-oxide, 3 hydrolysis of, 694 4-Nitro-2-picoline-l-oxide, effect of 4-nitro group, 719 reaction with acetic anhydride, 719... 

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). 

The Scholtz synthesis of indolizine (12CB734) is based on the reaction of 2-picoline with acetic anhydride (see Scheme 21 for a possible mechanism). The method is rarely used because of the poor yields often associated with it. 5-Methylindolizine (149 R = Me) has been obtained from lutidine in 5.4% yield together with 4.7% (148 R = Me). 

The original Scholtz synthesis of indolizine39 was based on the reaction of 2-picoline with acetic anhydride his intermediate picolide has been shown to be 1,3-diacetylindolizine.40... 

With alkyl groups in the 2- or 4-positions, however, the reaction may take a completely different course, resulting in side-chain oxidation. Thus, when 2-picoline A-oxide is heated with acetic anhydride, some 6-methyl-2-pyridone is indeed formed, but the main product is 2-pyridylmethyl acetate (172).397,400 4-Picoline A-oxide and acetic anhydride give 4-pyridylmethyl acetate (173) and... 

When water is chemically removed, a basic catalyst, such as triethyl-amine, pyridine, jS-picoline, or isoquinoUne, and acetic anhydride is added. Water produced in the imidization is chemically removed by the reaction with acid anhydride. However, this method, requires a process for purification of a reaction mixture to remove the residue, such as tertiary amines and acetic anhydrides, out of the system. 

Contrary to a previous report, the reaction of pyridine-l-oxide with acetic anhydride does not give exclusively 2-pyridone 2-aminopyridine and yV-(2-pyridyl)-2-pyridone (IX-23) are also formed. Similarly, 6-amino-3-picoline and 3-methyl-A -(5-methyl-2-pyridyl)-2-pyridone were isolated in the reaction of 3-picoline-l-oxide with acetic anhydride (see also Chapter IV). 

Electron-attracting substituents should assist this reaction. However, with acetic anhydride in acetonitrile, 2-picolinic acid 1-oxide gives mainly pyridine 1-oxide and carbon dioxide, whilst the same reaction carried out under ultra-violet irradiation proceeds similarly but with the formation of a little more 2-hydroxypyridine. The methyl esters of the pyridine-carboxylic acid 1-oxides behave normally, but there is no evidence that the methoxycarbonyl group promotes the reaction, and 2-cyanopyridine 1-oxide does not react with acetic anhydride . The results of a kinetic study of the rearrangement of pyridine 1-oxide in acetic anhydride exclude the intramolecular rearrangement of the free cation (113) and also a free radical process. There remain the two possibilities of nucleophilic substitution by reaction between... 

Picoline reacts with phthalic anhydride in the presence of zinc chloride or acetic anhydride to give pyrophthalone . Much work has been done on the structure of this compound . Perhaps the best formulationl is (30). Similar reactions occur with naphthalic and diphenic anhydride and in the cases of lutidines and collidines are assumed to occur at the 2-methyl group. Under similar conditions 2-picoline gives (31) with benzene-sulphonylbenzisothiazolone . 

In the Scholtz indolizine synthesis 2-picoline is heated with acetic anhydride, giving diacetylindolizine. The reaction has been represented as going by diacetylation of the methyl groups... 

The radical chain mechanism was considered because these reactions have induction periods and because styrene added to the reaction mixture is polymerized242. However, in the reaction of 2-picoline 1-oxide with acetic anhydride, whilst the formation of carbon dioxide and methane demonstrates the presence of free radicals, these are irrelevant to the main reaction, the addition of radical scavengers being without effect on the yield of 2-pyridylmethyl acetate. Further, conversion of 2-picoline 1-oxide by butyric anhydride into 2-pyridylmethyl butyrate is not influenced by the presence of acetate ions. These facts point to the intra-molecular production of radical or ion pairs in a solvent cage as the essential characteristic of the reaction243a. Similar experiments in which i 0-labelled acetic anhydride was used and the effect of solvents studied, point to the same conclusion and favour the formation of a radical pair in a solvent cage for the reaction both... 

Radical substitutions— The reactions of picoline 1-oxides with acetic anhydride may have radical character (p. 341). 

As seen in many of the above examples, acetic anhydride and zinc chloride each make effective condensation catalysts for the free bases, presumably by efficient coordination with the ring nitrogen. The quaternary salts condense readily in the presence of piperidine. Potassium hydroxide, methoxide or piperidinium acetate are suitable for condensations with 2- and 4-methylpyridine AAoxides. For example, the Claisen condensation is effective with these Af-oxides using ethoxide catalyst (Scheme 45) but the reaction fails with the parent picolines unless activated by nitro substitution (69JHC775). 

The stilbazoles have been synthesized using three different routes, and these are now described briefly (Figs. 2 and 3). The first attempts involved reacting 4-alkoxybenzaldehyde with 4-picoline in acetic anhydride, which led to extremely poor yields of the stilbazoles after a week s work (2). This route was subsequently superseded by a Heck coupling method in which 4-vinylpyridine was reacted with 4-alkoxyiodobenzene in the presence of a palladium catalyst (2). The reaction worked very... 

An alternative means for effecting reaction at a side-chain depends on a prior electrophilic addition to the nitrogen this acidifies further the side-chain hydrogens, then deprotonation generates an enamine or an enamide, each being nucleophilic at the side-chain carbon the condensation of 4-picoline with benzal-dehyde using acetic anhydride illustrates this. 

Naphthoquinone[2,3 ]oxadiazine derivative 191 reacts with triethyl orthoformate in the presence of acetic anhydride to give compound 192. Further reaction with active methyl compounds (a-picoline, 7-picoline, quinaldine) affords the corresponding cyanine dyes 193 (Scheme 27) <1996IJH305>. 

Considerable attention has been devoted to the mechanisms of these reactions during the past decade and with only partial success. It should be emphasized that rearrangement to the nucleus at the 2- or 3-position or to the a-carbons of the side-chain on the 2- or 4-positions are different kinds of reactions. Studies with 0 labeled acetic anhydride show that rearrangement of 2-picoline-l-oxide is intramolecular and that equilibration of the two oxygens from the TV-acetyloxy group takes place. Although this suggests a radical pair ... 

Chemical imidization is not widely used because it employs additional reagents. However, it has the advantage of low temperature imidization and can he nsed to directly form fine polyimide molding powder (16,50). A t5 ical chemical imidization reaction employs a 20-30% solids polyamic acid in an amide solvent with a slight molar excess of acetic anhydride and a molar equivalent of a triamine (triethyl amine, pyridine, or -picoline) (51-54). The percent conversion for chemical imidization is a function of polyimide solnhiUty. If the polymer crystallizes and/or precipitates from the reaction medium, imidization will he incomplete (16,50). Those systems that remain soluble must imdergo thermal treatment to convert any isoimide, and remove residual solvent. The mechanistic routes of chemical imidization are shown in Figure 4, and involve the use of a triamine... 

Electrical conductivity of reaction mixtures and polymerization kinetics have been investigated for the pyridine- and picoline-initiated polymerization of MA. In acetic anhydride, it was found that the electrical conductivities of the polymerizing mixtures increased during the course of the reaction. Rates were examined at 25°C and found to increase with both monomer and pyridine concentration. Also, both the conductivity of the reaction mixtures and polymer conversion increased appreciably with increasing temperatures. An apparent overall activation energy was determined to be about 10 kcal/mol and the equation representing the overall rate was formulated as follows ... 

It has been reported that the best acidic conditions for stilbazole preparation require reaction of picoline with benzaldehyde (1 2 molar equivalents) in acetic anhydride (1 molar equivalent) and acetic acid (1 molar equivalent) with the exclusion of air, whilst in the best basic conditions picoline and benzaldehyde (1 4 molar equivalents) were heated with piperidine (0 2... 

Hydroxylation and substituted hydroxylation—Important reactions of this category, notably acetoxylation, occur with picoline oxides. In the parent example, 2-picoline 1-oxide is converted by boiling acetic anhydride into... 

Examination of the reactions of 4-picoline 1-oxide with labelled acetic anhydride and labelled butyric anhydride, both of which cause substitution at the methyl group and at C(3>, suggested three processes to be at work first, homolytic cleavage of the N—O bond in the anhydro base followed by radical recombination within a solvent cage second, similar cleavage followed by recombination after some radical transfer with solvent acid third, heterolytic cleavage of the N-O bond followed by nucleophilic attack of n-butyrate on the anhydro base. The relative importance of each of these three processes varies with the solvent used24i ... 

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