0-Picoline preparation

Problem 20.32 From picolines prepare (a) the vitamin niacin (3-pyridinecarboxylic acid), (b) the antituberculosis drug isoniazide (4-pyridinecarboxylic acid hydrazide). 

If much liquid ammonia is lost during the preparation of the sodamide, the volume should be m e up to 500-600 ml. before adding the y picoline. 

Rcolinic acid Is readily prepared by the oxidation of a-picoline with potas-... 

A solution of sodamide in liquid ammonia (essentially the amide NHj ion) is a very powerful alkylation catalyst, enabling condensations to be carried out with ease and in good yield which are otherwise either impossible or proceed with difficulty and are accompanied by considerable by-products. Thus 3-alkylpjTidines, otherwise inaccessible, are easily prepared from 3-picoline (see 3-n-amylpyridine in Section V,20). Also benzyl cyanide (I) and cyclohexyX bromide give a- r/ohexylphenylacetonitrile (II) ... 

Another example illustrating the greater reactivity of organolithium compounds is the preparation of the otherwise difficultly accessible esters of 2-pyridyl-acetlc acid by the following series of reactions from a-picoline ... 

P-Picoline may serve as an important source of nicotinic acid [59-67-6] for dietary supplements. A variety of substituted pyridines may be prepared from acrolein (75—83). 

Trifluoromethylpyridine can be prepared ia 54% yield from picolinic acid and sulfur tetrafluoride—hydrogen fluoride (434). 2-Trifluoromethylpyridine is a weak base no hydrochloride salt is formed. However, 2-trifluoromethylpyridine 1-oxide [22253-71-0] (bp 132—133°C/2.7 kPa (20 mm Hg)) is prepared ia 81% yield usiag 30% hydrogen peroxide—acetic acid (438). 

Trifluoromethylpyridine can be prepared ia 25—65% yield from nicotinic acid and sulfur tetrafluoride (434,439). An alternative method is the passage of chlorine iato a mixture of ( -picoline and hydrogen fluoride ia an autoclave (190°C, 3 MPa) (440). 4-Trifluoromethylpyridine is prepared ia 57% yield from isonicotinic acid and sulfur tetrafluoride. 

The picolinamide is prepared in 95% yield from picolinic acid/DCC and an amino acid, and is hydrolyzed in 75% yield by aqueous Cu(OAc)2. ... 

Methylpyridine-l-oxide (3-picoline-l-oxide) may be prepared by a method similar to that employed for pyridine-1-oxide. To a mixture of 600-610 ml. of glacial acetic acid and... 

Marazano and co-workers have used the Zincke reaction extensively to prepare chiral templates for elaboration to substituted piperidine and tetrahydropyridine natural products and medicinal agents. For example, 3-picoline was converted to Zincke salt 40 by reaction with 2,4-dinitrochlorobenzene in refluxing acetone, and treatment with R- -)-phenylglycinol in refluxing n-butanol generated the chiral pyridinium 77. Reduction to... 

The formation of trace amounts of 2,2 -bipyridine following reaction between pyridine and ammonia in the presence of a variety of catalysts led Wibaut and Willink to develop a method for the preparation of 2,2 -bipyridine from pyridine under the influence of a nickel-alumina catalyst. Using a pyridine-to-catalyst ratio of 10 1, temperatures between 320° and 325°C, and pressures between 42 and 44 atm, 2,2 -bipyridine was formed in yields of 0.30-0.67 gm per gram of catalyst. This method w as later applied to -picoline, to quino-line, - and to some of its derivatives, ... 

A) Preparation of 1-Methyl-2-Picolinium Chloride 98 ml of cx-picoline is dissolved in 200 ml of methanol, cooled and 85 ml (at -68°C) of methyl chloride is added. The solution is charged to an autoclave, sealed and the nitrogen pressure of 300 psig is established. The mixture is heated at 120° to 130°C for 2 hours, cooled and opened. The resulting solution is then evaporated to dryness in vacuo, yielding a residue of 110 g. This residue is then dissolved in 50 ml of water and extracted with two 50 ml portions of ether. The aqueous phase is then diluted to 150 ml with water and an assay for ionic chloride is performed which indicates the presence of chloride ion equivalent to 721 mg/ml of 1-methyl-2-picolinium chloride. 

The three picolines react with alkyl halides in liquid ammonia solution in the presence of sodamide to yield the corresponding monoalkylpyridines. a-Picoline also reacts with alkyl chlorides in the presence of sodamide either alone or in the presence of xylene to give a fair yield of monoalkylpyridine CjH N.CHjR. With y-picoliue under similar experimental conditions disubstitution of the alkyl group (CjHjN.CHRj) occurs to an appreciable extent. The preparation of tile three n-amylpyridines is described the 3- and 4-compounds by the liquid ammonia - sodamide method and the 2-compound by the sodamide-3 ene procedure. 

Nicotinic acid is prepared in good yield by the oxidation of p picoline with potassium permanganate ... 

Preparation of ligand 31 Originally, chiral ligand 31 was prepared from (1R,2R)-1,2-diaminocydohexane 33 based on the racemic synthesis reported by Barnes et al. in 1978 [15], where picolinic acid 34 was activated with P(OPh)3 and then coupled with trans-l,2-diaminocyclohexane. The reported isolated yield in the case of racemate was only 47%. We optimized the preparation as shown in Scheme 2.8 [16]. Picolinic acid 34 was activated with CDI in THF. After confirmation of activation, chiral diamine 33 was added to the solution. When complete, the reaction was quenched via the addition of a small amount of water (to quench excess CDI). The reaction solvent was then switched from THF to EtOH, when the desired ligand 31 directly crystallized out. Ligand 31 was isolated in 87% yield by simple filtration of the reaction mixture in high purity. With a 22 litter flask, 1.25 kg of 31 was prepared in a single batch. 

To test this hypothesis, the picolinamide 22 was prepared using in situ activated picolinic acid (Scheme 8.12). The in situ activation of picohnic acid was used because picolinyl chloride (available commercially as the HC1 salt) is relatively expensive. The coupling reaction was not straightforward, and the best results were obtained by adding 1.4equiv of thionyl chloride to a solution of 1.4equiv of picolinic acid in acetonitrile, followed by addition of triethylamine. As soon as the addition of triethylamine was complete, aniline 5 was introduced immediately because the activated picolinic acid was unstable in the presence of triethylamine. 

A series of mixed-ligand thiosalicylato complexes of the type PtL(PPh3)Y2] (Y2 = thiosalicylate L = pyridine, 4-methylpyridine, picolinic acid hydrazide, imidazole) have been prepared by the reaction of [PtCl2(COD)] with PPh3, thiosalicylic acid, and A-donor ligand in MeOH solution.375 The X-ray structure of the pyridine derivative (162) was determined, the first example of where a platinum atom is coordinated to a N, O, P, and S donor atom set. 

The related aza analogue of this ring system, triazino[6,5-/][l,7]naph-thyridine 184 was prepared (86PHA284) by the cyclization of azauracilyl-picolinic acid 183 with ammonia in the presence of DCC. The starting material was prepared from 2-carboxy-3-pyridylglyoxylic acid thiosemi-carbazone 182. 

This procedure is based upon that of Ziegler.2 l-(a-Pyridyl)-2-propanol has also been prepared in poor yields (4-6 per cent) by heating a-picoline with aqueous acetaldehyde in sealed tubes.3-4... 

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