Pyridine methyl isonicotinate

Kosower and Teuerstein showed that o-xylylene bis-pyridinyl and 1,8-biphenyl-ene bis-pyridinyl diradicals could be photolyzed in low quantum yields at 400 nm to yield the corresponding pyridine (methyl isonicotinate) and either a carbomethoxy-azaanthracene or 1,8-dimethylbiphenylene (Eqs. 22). 

Likewise, pyridines such as methyl isonicotinate 1999 or quinolines are readily oxidized by BTSP 1949 in the presence of HOReOs in CH2CI2 to give, after 6 h at 24°C, 98% yield of, e.g., methyl isonicotinate N-oxide 2000 [174] (Scheme 12.49). The oxidation of diphenylsulfide with BTSP 1949 and triphenylphosphine dichloride in acetonitrile results, after 60 h at room temperature, in only 12% diphenyl sulfoxide 2001 and 88% recovered diphenyl sulfide [175] (Scheme 12.49), whereas thianthrene 5-oxide 2002 is oxidized by the peroxy-Mo complex 2003 to give 58% of a mixture of 2004 to 2007 in which the trans 5,10-thioxide 2005 predominates [176] (Scheme 12.50). 

Synthesis of Pyridine-V-Oxides. Methyl isonicotinate was oxidized by (TMSO)2 in the presence of CHsReOs, or other inorganic rhenium derivatives such as ReOs, Re20v and HOReOs, to the V-oxide in high yield (95-98% isolated yields). With ReCls or NaOReOs as catalyst, only trace amounts of oxidation products were obtained (eq 10). The importance of a trace amount of water in this oxidation process was confirmed when the reaction was retarded by the presence of molecular sieves. The optimal water content was found to be between a trace and 15 mol %, with higher proportions leading to lower conversion. A commercial 65-70% solution of perrhenic acid in water was found to be a convenient source of both Re and water. 

Chapter V. Quinaldine (V,2) 2-methyl-, 2 5-dimethyl- and 2-acetyl-thiophene (V,8-V,10) 2 5-dimethyl and 2 4-dimethyl-dicarbethoxy-p3nrole (V,12-V,13) 2-amino- and 2 4 dimethyl-thiazole (V,15-V,16) 3 5-dimethyl-pyrazole (V,17) 4-ethylp3rridine (from pyridine) (V,19) n-amyl-pyridines from picolines) (V,28) picolinic, nicotinic and isonicotinic acid (V,21-V,22) (ethyl nicotinate and p-cyanop3n idine (V,23-V,24) uramil (V,25) 4-methyl-(coumarin (V,28) 2-hyi-oxylepidine (V,29). 

The pyridine-N-oxide 245 was converted into the cyanopyridine 246 and its isomer (Scheme 80). Grignard reaction, Fischer s indole synthesis, and N-protection gave a pyridinyl indole 247. Selenium dioxide selectively oxidized the methyl group to give the isonicotinic acid. The synthesis of Flavocarpine (244) was finally accomplished by a set of standard reactions as outlined in Scheme 80 (87TL5259). 

A thioamide of isonicotinic acid has also shown tuberculostatic activity in the clinic. The additional substitution on the pyridine ring precludes its preparation from simple starting materials. Reaction of ethyl methyl ketone with ethyl oxalate leads to the ester-diketone, 12 (shown as its enol). Condensation of this with cyanoacetamide gives the substituted pyridone, 13, which contains both the ethyl and carboxyl groups in the desired position. The nitrile group is then excised by means of decarboxylative hydrolysis. Treatment of the pyridone (14) with phosphorus oxychloride converts that compound (after exposure to ethanol to take the acid chloride to the ester) to the chloro-pyridine, 15. The halogen is then removed by catalytic reduction (16). The ester at the 4 position is converted to the desired functionality by successive conversion to the amide (17), dehydration to the nitrile (18), and finally addition of hydrogen sulfide. There is thus obtained ethionamide (19)... 

Isonicotinic acid hydrazide (isoniazid 275), a drug used in treating tuberculosis269, has been 1 -labelled264 by introduction of a [nC]cyano group at the 2-position of the pyridine ring of l-methoxy-4-methoxcarbonyl pyridinium methyl sulphate and subsequent treatment of the 1 -labelled methyl ester 276 with hydrazine hydrate. The reaction has been carried out on a solid support (silica gel) to yield methyl 2[11C]cyano-isonicotinate in 32.4+12% (EOB) yield. 275 was obtained in 10% (EOB), radiochemical... 

The formation of a trinicotinate was reported.2409 The best method of preparing this starch derivative involved reacting nicotinoyl chloride hydrochloride and starch in boiling pyridine.2410 Starch isonicotinates and 4-(sulfinylamino)benzoates were subsequently prepared. Starch isonicotinate was further cationized by treating it in nitromethane solution with methyl 2-(chloroacetyl)lactate or benzoylhydrazide A-chloroacetate and l-[2-(chloroacetoxy)propanoyl]-3-methylpyrazole.2411... 

Pyridine derivatives are precursors of many chemical products of medicinal, agricultural, and industrial importance. Pyridine itself is used not only as a solvent, but also as a starting material for pharmaceuticals, herbicides, insecticides, and fungicides. a-Picoline is a precursor for 2-vinylpyridine which is used in the production of an adhesive for textile tire cord. The major use of y-picoline is in the production of isonicotinic hydrazide, an antituberculosis agent. / -Picoline and 2-methyl-5-ethylpyridine are important intermediates in the production of two members of the vitamin B family, nicotinamide, and nicotinic acid (also known as vitamin B3). All this shows there is a substantial need for the production of picolines. The following text describes a novel route to a-picoline which might in the future lead to new processes. 

Homologues of Pyridine.—Many homologues of pyridine have been obtained from bone-oil and coal-tar or by syntheses from other compounds. The methyl derivatives of pyridine are called picoUneSy the dimethyl derivatives are called lutidines, and the trimethyl derivatives are called collidines. As in the case of toluene and the xylenes, the side-chains are converted into carboxyl groups by oxidation. The a, /S, and 7 mono-carboxylic acids of pyridine are called picolinic acid, nicotinic acid, and isonicotinic acid, respectively. 

Green RW and Tong HK, The constitution of the pyridine monocarboxylic acids in their isoelectric forms, JACS, 78,4896-4900 (1956). Used a glass electrode standardized with phflialate solution (pH = 4.00) and the Guntelberg equation to correct for I. Estimated the microconstants from spectrophotometric data on the acid and its methyl ester pJ A, 2.11 pK, 3.13 pJ o 4.77 pKo, 3.75 where the subscripts represent the following equilibria A, diprotonated to zwitterion B, diprotonated to neutral C, zwitterion to fully deprotonated D, neutral to fully deprotonated. Also reported the corresponding data for picolinic and isonicotinic acids. 

Methyl 2-aminoisonicotinate in anhydrous pyridine reacts with p-nitroben-zenesulfonyl chloride to give methyl 2-(p-nitrobenzenesulfonamido)isonicotinate... 

Derivatives of pyridine carboxylic acids form 1 1 complexes with Eu + in strongly acidic conditions. Whereas the complexes with nicotinic and picolinic acids are stable with respect to further reaction, isonicotinic acid and its Af-methyl derivative undergo reduction with an Eu + substrate stoicheiometry of 2 1. 

The reduction of pyridine-carboxylic acids has been mentioned already (pp. 258, 263), and it has been seen that electrolytic reduction or reduction with zinc and acetic acid can give methyl- or hydroxymethylpyridines. Whilst the electrolytic reduction of benzoic acid to benzyl alcohol is well known, benzene-carboxylic acids are generally not so readily reduced as the pyridine-carboxylic acids. Two other additional cases might be quoted. A dichloropyridine-carboxylic acid has been reduced by phosphorus and hydriodic acid to a dichloromethylpyridine , and 2,6-dichloropyridine-4-carboxylic acid with zinc and acetic acid gives 2,6-dichloro-4-hydroxy-methylpyridine . Isonicotinic acid is reduced to the alcohol by tin and hydrochloric acid . 

The amides and hydrazides of pyridine-carboxylic acids arc of some importance, though their chemistry is not marked by unusual properties. Nicotinamide is, of course, an important compound, and isonicotinic acid hydrazide (isoniazid) is an antitubercular drug. Substituted derivatives are used as antidepressants. In general, however, these compounds show normal chemical behaviour. The amides undergo hydrolysis, dehydration and Hofmann bromination without difficulty. Their reduction has been much studied as a route to pyridine aldehydes. The Sonn-Muller reduction is not very satisfactory in this series, but the McFadyen-Stevens reaction is useful . Nicotinic acid diethylamide gives only poor yields of the aldehyde upon reduction with lithium aluminium hydride, but yields from the methyl-phenylamide are high. Most satisfactory is the reduction of nicotinic acid dimethylamide with lithium diethoxyaluminium hydride . 

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