Nicotinic acids, methyl-, reaction with

Derivatives of pyridine-3,5-dicarboxylic acid have been shown to undergo reaction with lithium aluminum hydride by attack on the pyridine ring to form 1,4-dihydropyridines.57,58 Presumably the decrease in electron-density at the ring carbon atoms due to these substituents causes the ring to be extremely susceptible to hydride attack. Similar results were obtained with 3,5-dicyanopyridine derivatives. Methyl nicotinate, however, underwent reaction with LAH with exclusive reduction of the ester function.57 Recently the 3,5-dicyanopyridines have been reported to give mixtures of 1,2- and 1,4-dihydropyridines on reduction with LAH or sodium boro-hydride.20 ... 

As aforementioned, some natural products have the bipyridine unit in their structure. Therefore, we also tried to make an intermediate which could be utilized for the preparation of the natural products. Scheme 3.10 shows two examples. 2,3-Bipyridine (sla) was prepared by the coupling reaction of P6 with 5-bromo-nicotinic acid methyl ester in the presence of Pd(PPh3)4 in THF at refluxing temperature affording the coupling product in 64% isolated yield (route A, Scheme 3.10). Under similar conditions, 2,2 -bipyridine (sib) was achieved in moderate yield (65%) by Pd(0)-catalyzed cross-coupling reaction of PI (route B, Scheme 3.10). As depicted in Scheme 3.10, further manipulation of sla and sib would result in the formation of many natural products. 

Route A utilizes the easily available 2-mercaptonicotinic acid as starting material. First, the nicotinic acid is esterified with acidic methanol to afford methyl 2-mercaptonicotinate, which is oxidized chlorine in aqueous acetic acid, followed amination with tert-butylamine, to give methyl 2-t-butylaminosulfonylnicotinate. This, in turn, is subjected to reaction with N,N-dimethylaminodimethylaluminum to afford a nicotinamide, which is finally converted to the target intermediate by de-butylation using tri-fluoroacetic acid. 

In the case of nicotinamide, the color yield is often low. This problem can be circumvented by either hydrolysis to nicotinic acid or by conversion of the amide to a fluorescent compound. Treatment of nicotinamide with methyl iodide yields the quaternary ammonium salt, /V-methyl nicotinamide (5). Reaction of this compound with acetophenone yields a fluorescent adduct (49). Other carbonyl compounds have also been used (50—54). 

For more specific analysis, chromatographic methods have been developed. Using reverse-phase columns and uv detection, hplc methods have been appHed to the analysis of nicotinic acid and nicotinamide in biological fluids such as blood and urine and in foods such as coffee and meat. Derivatization techniques have also been employed to improve sensitivity (55). For example, the reaction of nicotinic amide with DCCI (AT-dicyclohexyl-0-methoxycoumarin-4-yl)methyl isourea to yield the fluorescent coumarin ester has been reported (56). After separation on a reversed-phase column, detection limits of 10 pmol for nicotinic acid have been reported (57). 

Condensation of ethyl acetoacetate with phenyl hydrazine gives the pyrazolone, 58. Methylation by means of methyl iodide affords the prototype of this series, antipyrine (59). Reaction of that compound with nitrous acid gives the product of substitution at the only available position, the nitroso derivative (60) reduction affords another antiinflammatory agent, aminopyrine (61). Reductive alkylation of 61 with acetone in the presence of hydrogen and platinum gives isopyrine (62). Acylation of 61 with the acid chloride from nicotinic acid affords nifenazone (63). Acylation of 61 with 2-chloropropionyl chloride gives the amide, 64 displacement of the halogen with dimethylamine leads to aminopropylon (65). ... 

Nicotine Nicotine, l-methyl-2-(3-piridyl)pirrolidine (13.1.27), is an alkaloid that is isolated from the plant Nicotiana (Nicotiana tabacum, Nicotiam rustica, and others) and can be synthesized in varions ways [33-36]. In particular, it is proposed to proceed from nicotinic acid ethyl ester, which is condensed with iV-methylpyrrolidone, giving l-methyl-2-nicotinoyl pyrrolidone-2 (13.1.23). Acidic hydrolysis of this compound leads to an opening of the pyrrolidine ring giving the intermediate (13.1.24), which under the reaction conditions is decarboxylated to the /-aminoketone (13.1.25). The carbonyl group is reduced to an alcohol and the resnlting prodnct (13.1.26) undergoes dehydration to nicotine (13.1.27). 

Pharmaceutically important 3-substituted-[l,8]naphthyridine-2,4-diones have been prepared by the reaction of 2-methyl-477-pyrido[2,3-r/][3,l]oxazin-4-one with active methylene compounds (Scheme 66) <1997J(P1)1487, 2003JOC4567> and by the same group via an intramolecular azadiene-ketene electrocyclization reaction of amino-nicotinic acid derivatives in a related process <2001JOC4413>. 

Other reactions of pyridine nucleotides. Alkaline hexacyanoferrate (III) oxidizes NAD+ and NADP+ to 2-,4-, and 6-pyridones. The 6-pyridone of N-methyl-nicotinamide is a well-known excretion product of nicotinic acid in mammals. Reoxidation of NADH and NADPH to NAD+ and NADP+ can be accomplished with hexacyanoferrate (III), quinones, and riboflavin... 

The situation is simplified if the substituent is at a para position to the reaction site since in this case there are no conditions for realizing the indirect resonance effect. The substituent and the reaction site cannot be simultaneously directly conjugated with the nitrogen heteroatom of the azine ring and, as a rule, the reactivity parameters correlate well with the Hammett ffp values. Examples include (1) the ionization constants of 5-substituted picolinic (57) and 6-substituted nicotinic acids (59) (59NKZ1293) (2) the rates of alkaline hydrolysis of 5-substituted methyl picolinates (58) (70JCS(B) 1063) ... 

Radicals generated by irradiation of the esters of iV-hydroxy-2-thiopyri-done added efficiently to protonated pyridines. When ester 192, derived from adamantanoic acid, is irradiated with a tungsten lamp in the presence of pyridinium camphorsulfonate 193 in dichloromethane at room temperature, a smooth reaction occurs to give an 81% yield of the 6-substituted methyl nicotinate 194. The camphorsulfonate of pyridine itself affords approximately equal amounts of 2- and 4-substituted products (86TL1327). 

An early synthesis of the pyrido[2,3-J]pyridazine system starts from 2-acetyl nicotinic acid 52 a hot aqueous solution of this acid reacts with phenylhydrazine to give 8-methyl-6-phenylpyri-do[2,3-cf]pyridazin-5(67/)-one. Reaction with 4-nitrophenylhydrazine occurred similarly.53 Reactions of hydrazines with other 2-acyl-,54 2-aroylnicotinic acids,48,5S-15I-152 Gr 2-acetylnico-tinic acid A-oxide, e.g. to give 13,56 are known. 

Trier (101) extended his hypothetical suggestions to the formation of nicotine, again taking proline as the amino acid starting point. The only other reactant postulated was formaldehyde, which was supposed to give rise by Cannizzaro reaction to formic acid and methyl alcohol. Proline was supposed to be methylated by the alcohol, and reaction of a second proline molecule with formic acid was presumed to provide nicotinic acid. Nicotinic acid and methylproline were presumed to give nicotine and COi by oxidation. 

Nicotine.—Nicotine (33) is assembled in Nicotiana species from nicotinic acid (31) and N-methyl-A -pyrroline (32). Administration to Nicotiana plants of 5-fluoronicotinic acid and derivatives of (32) methylated at C-2 and C-3 has resulted in the formation in vivo of unnatural nicotine analogues.In contrast, 4-methylnicotinic acid has been found not to be transformed in vivo into 4-methylnicotine, presumably because this particular methyl group interferes sterically with the appropriate enzyme reactions involved in nicotine biosynthesis. ... 

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. 

This compound can be S5mthesized by passing ammonia gas into nicotinic acid or by treating it with molten urea > at 230°. The methyl or ethyl esters of nicotinic acid also undergo amidation upon reaction with ammonia in aqueous or alcoholic media . ... 

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