3-picoline advantages

The use of picolinic and 6-methylpicolinic acids in a Mitsunobu reaction has been advocated because the resultant esters are readily cleaved by copper(II) (Scheme 22.6). The advantage is that ester cleavage occurs under neutral conditions, which minimizes the risk of elimination even with base-sensitive systems.9... 

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-... 

The advantages of the alternative picoline process are described above. It also illustrates that, in order to reduce the amount of waste produced in reaction, a starting material of the highest quality is desirable, since any by-products in the latter would have to be removed later in the process. 

This relatively simple compound 231 requires the 4-C1 picolinic acid chloride 227 easily made in high yield by the S0C12 reaction described earlier. This has the advantage of simultaneously turning the acid into the acid chloride. Formation of the amide 228 and then the diaryl ether is followed by coupling with an isocyanate 230 to make the unsymmetrical urea 231. This large scale synthesis is planned for manufacture.33... 

Cleavage of picolinic acid esters. One advantage of the Mitsunobu reaction protocol using picolinic acid as the nucleophile is that the configurationally inverted alcohols are readily recovered, that is, after treatment with Cu(OAc)2-MeOH. 

An acid-base reaction can be used to enhance separation by taking advantage of the difference in the pK values of the components to be separated (Duprat and Gau, 1991). For example, in the close boiling 3-/4-picolines mixture, addition of trifluoroacetic acid in stoichiometric deficiency results in preferential complexa-tion of 4-picoline with a selectivity of about 2 in formamide as the solvent. Because the pyridinium salts are nonvolatile, the vapor phase is enriched with respect to 3-picoline. A near complete separation can be expected by repetition of this enrichment by countercurrent staging. 3-Picoline will leave the column as the distillate at the top, and 4-picoline will leave as a liquid phase complex with the acid as the bottoms product. 4-Picoline can be regenerated from the complex by adding a stronger base. 

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. 

Amino-4-bromo-3-phenylisothiazole (96), obtained by bromination of (95) or directly from 3-phenyl-3-iminothiopropionamide (94), was deaminated to 3-phenyl-4-bromoisothiazole (97) and converted into the 4-cyano-analogue (98) by the action of cuprous cyanide in boiling picoline. Methylation of 3-phenyl-4-cyanoisothiazole (98) with butyl-lithium and methyl iodide gave low yields of the 5-methyl homologue (101) the alternative route (97) (102) (101) proved to be more advantageous. 

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... 

One system that takes advantage of both the chemical and thermal imidiza-tion is the gel casting of PMDA-ODA. This system starts as polyamic acid in NMP or DMAc to which is added /3-picoline and acetic anhydride. This mixture starts to imidize and forms a gel as it is coated onto a rotating heated drum. The swollen gel film has mechanical integrity that allows it to be stripped off the drum and gripped by a tenter frame. Final conversion and solvent removal is achieved thermally (infrared and convection) while the film is undergoing mechanical orientation (57). 

A decarboxylative approach to cross-coupling was explored with pico-linic acids (Scheme 38) (13T5732).The advantages of this approach are the stable and inexpensive starting materials when compared to organometallics and boronic acids. Under optimized conditions, a number of aryl bromides were coupled with picolinic acid. Lower yields were seen when the aryl bromides had electron-withdrawing groups (NO2 or CN).The yields were also moderate to poor when picolinic acid was coupled with 1- or 2-bro-monaphthalene or 2-bromopyridine. 2-Quinolinic acid coupled with bro-mobenzene in moderate yield. 

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