Nicotinic acid decarboxylation

Chandler JLR, Gholson RK (1972) Nicotinic acid decarboxylation in tobacco roots. Phytochemistry 11 239-242... 

Oxidation. The synthesis of quinolinic acid and its subsequent decarboxylation to nicotinic acid [59-67-6] (7) has been accompHshed direcdy in 79% yield using a nitric—sulfuric acid mixture above 220°C (25). A wide variety of oxidants have been used in the preparation of quinoline N-oxide. This substrate has proved to be useful in the preparation of 2-chloroquinoline [612-62-4] and 4-chloroquinoline [611 -35-8] using sulfuryl chloride (26). The oxidized nitrogen is readily reduced with DMSO (27) (see Amine oxides). 

Pyridine 210 is oxidized by 20% nitric acid at the acetyl group to 2-methyl-5-pyridinecarboxylic acid, while its ozonation gives cinchomeronic acid [pyridine-2,5-dicarboxylic acid (215)] (75DIS) which is decarboxylated (200°C, 2 h) to nicotinic acid 216 in 97% yield (75DIS). 

Nicotinic acid and related compounds react with l-chloro-2,4-dinitrobenzene in the manner of the cyanogen bromide reaction to yield derivative I, which possibly also decarboxylates at elevated temperature. In alkaline medium this derivative first adds an hydroxyl ion and then undergoes ring opening to yield the colored derivative II. 

Vitamin Ba (pyridoxine, pyridoxal, pyridoxamine) like nicotinic acid is a pyridine derivative. Its phosphorylated form is the coenzyme in enzymes that decarboxylate amino acids, e.g., tyrosine, arginine, glycine, glutamic acid, and dihydroxyphenylalanine. Vitamin B participates as coenzyme in various transaminations. It also functions in the conversion of tryptophan to nicotinic acid and amide. It is generally concerned with protein metabolism, e.g., the vitamin B8 requirement is increased in rats during increased protein intake. Vitamin B6 is also involved in the formation of unsaturated fatty acids. 

The B-group vitamin, nicotinic acid (259), was irradiated with low-intensity light at 254 nm. In aqueous solution without buffer, the bi-aryl (260) was obtained, presumably via decarboxylation to give the pyridyl anion which would attack position 6 of nicotinic acid. In aqueous acid, the substrate was photo-hydroxylated to give 2-hydroxynicotinic acid (40%). Clearly, only the cationic form was sufficiently activated for position 2 to be attacked by the solvent. Nicotinamide under the same conditions was also converted to the 2-hydroxy derivative, but the reaction was slower [161]. 

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). 

Nicotinic acid forms some piperidine as well as nipecotic acid when it is reduced with hydrogen over ruthenium, rhodium or platinum oxide presumably decarboxylation involves the intermediate 3,6-dihydro compound (265), which behaves like a j8-keto acid (Scheme 189). 

The synthesis of quinolinic acid and its subsequent decarboxylation to nicotinic acid has been accomplished directly in 79% yield using a nitric-sulfuric acid mixture above 220°C. A wide variety of oxidants have been used in the preparation of quinoline iV-oxice. 

This reaction is a good example of the interrelationship of vitamin B coenzymes. Four vitamin coenzymes are necessary for this one reaction (1) thiamine (in TPP) for decarboxylation (2) nicotinic acid in nicotinamide adenine dinucleotide (NAD) (3) riboflavin in flavin adenine dinucleotide (FAD) and (4) pantothenic acid in coenzyme A (CoA) for activation of die acetate fragment. 

Several of the B vitamins function as coenzymes or as precursors of coenzymes some of these have been mentioned previously. Nicotinamide adenine dinucleotide (NAD) which, in conjunction with the enzyme alcohol dehydrogenase, oxidizes ethanol to ethanal (Section 15-6C), also is the oxidant in the citric acid cycle (Section 20-10B). The precursor to NAD is the B vitamin, niacin or nicotinic acid (Section 23-2). Riboflavin (vitamin B2) is a precursor of flavin adenine nucleotide FAD, a coenzyme in redox processes rather like NAD (Section 15-6C). Another example of a coenzyme is pyri-doxal (vitamin B6), mentioned in connection with the deamination and decarboxylation of amino acids (Section 25-5C). Yet another is coenzyme A (CoASH), which is essential for metabolism and biosynthesis (Sections 18-8F, 20-10B, and 30-5A). 

Quinolinic acid (133) was prepared by methods similar to those described for the monocarboxylic acids.182,183,189-191,196-202 In many cases the resulting diacid was decarboxylated to nicotinic acid (126). Quinoline (130) was simultaneously oxidized to the diacid (133) and reduced to tetrahy-droquinoline (134) in one of the rare reports of paired synthesis of pyridine compounds (Scheme 44).189 An attempt was made to delineate some of the electrode processes for the diacid (133).200... 

In the formation of nicotine, a pyrrolidine ring derived from ornithine, most likely as the /V-methyl-A1 -pyrrolinium cation (see Figure 6.2) is attached to the pyridine ring of nicotinic acid, displacing the carboxyl during the sequence (Figure 6.31). A dihydronicotinic acid intermediate is likely to be involved allowing decarboxylation to the enamine 1,2-dihydropyridine. 

Pyridine, treated with iodine in the vapor phase, gave only poor yields of 3,5-di- and penta-iodopyridines (57JCS387). Decarboxylative iodination of the mercury(II) salt of nicotinic acid gave a 44% yield of 3-iodopyridine (83JOC3297). 

Decarboxylations occurred also in the LukeS reduction of the methyl betaines of picolinic and nicotinic acids. Thus, both homarine (87) and trigonelline (88) afforded a mixture of l-methyl-3-piperideine and 1-methylpiperidine.91... 

Nicotine biosynthesis also involves the incorporation of nicotinic acid (Fig. 2.2) (Robins et al., 1987), and the availability of this moiety can be as important in nicotine accumulation as that of the putrescine-derived portion. However, the enz)une responsible for the condensation of N-methylpyrrolinium with decarboxylated nicotinic acid, nicotine s)mthase (Friesen and Leete, 1990), was measured at only a very low level of activity, quite inadequate to account for the rates of nicotine accumulation observed in cultures. The molecular analysis of low-nicotine mutants of N. tabacum suggested the presence of regulatory genes (Me 1 and Me 2) governing the expression of nicotine bios)mthesis (Hibi et al, 1994). 

The B group vitamins, thiamine and riboflavin, are destroyed on irradiation in dilute aqueous solutions. Riboflavin is reduced in air-free solutions to a semiqui-none form. Nicotinic acid is decarboxylated on irradiation in air-saturated aqueous solutions. 

That worked rather well Though reduction is needed to get the enamine, the final product must The same reduction of pyridinium be oxidized back to a pyridine again so there is no overall oxidation or reduction. Let s try adding s lts to tetrahydropyridines with a the same enamine to nicotinic acid as an electrophile. Now we need decarboxylation of both rings, oxidation of the left-hand ring, and reduction of the right-hand ring, all easily achieved with imines or enamines. 

Catalyst inhibition by carbon monoxide and carbon dioxide can be a problem in the hydrogenation of some compounds since decarbonylation or decarboxylation can take place during the hydrogenation of some functional groups. Palladium is a good decarbonylation catalyst for aldehydes 02-104 decarboxylation can accompany the hydrogenation of some acids, particularly nicotinic acid. O ... 

The hydrogenation of 2- and 4-pyridinecarboxylic acids proceeded best in water over a platinum catalyst at room temperature and 3-4 atmospheres of hydrogen. Nicotinic acid (3-pyridinecarboxylic acid) was, however, decarboxylated under these conditions. 25 This compound, as well as the pyridine alkanoic acids (except 2-pyridine acetic acid which is easily decarboxylated), was hydrogenated at room temperature and 3-4 atmospheres of hydrogen over a rhodium catalyst in water to which had been added a slight excess of ammonium hydroxide. Product isolation merely involved the removal... 

The distribution of the radioactivity was as anticipated C-atoms 2, 15, and 17 were active whereas C-atoms 3, 4, 5, 12, 13, and 14 were not. Lysine-2-i4C was incorporated via a symmetric intermediate. The incorporation of doubly tagged a- N-Iysine-2-i4C into sparteine showed that the radioactivity of the was increased almost exactly by a factor of three over that of the ingested amino acid. A primary decarboxylation is therefore probable and 3 moles of lysine enter the molecule, the nitrogen being incorporated. This is strictly analogous to the incorporation of the amino acids into nicotinic acid. 

Freifelder found that pyridinecarboxylic acids can be hydrogenated smoothly over Rh-AljOa in ammonia solution. A particularly significant example is the hydrogenation of nicotinic acid to nipecotic acid, since this had not previously been accomplished without decarboxylation. 

It has been established independently and simultaneously in two laboratories that ornithine is the precursor of the pyrrolidine ring in nicotine (51, 52). Adult plants of N. rustica L. maintained 14 days in hydroponic solutions containing omithine-2-C are found to contain radioactive nicotine. After oxidation, carbon 2 of the pyrrolidine ring is isolated as nicotinic acid and carbons 3, 4, and 5 are isolated as barium carbonate. Nicotinic acid contains half the radioactivity and barium carbonate the other half. Decarboxylation of the nicotinic acid shows that the radioactivity is exclusively located in the carboxylic group. It is highly probable that the second half of the radioactivity is located on carbon 5, but the separation of this carbon from carbons 3 and 4 has not been effected (51, 52). 

Anabasine (3-pyridyl-2-piperidine) appears to be the sole constituent of N. glauca R. Grah., and this plant has been used for the study of the biogenesis of the alkaloid. Anabasine isolated from N. glauca cultured in hydroponic solution containing lysine-2-C hydrochloride is radioactive (53). The alkaloid when oxidized with nitric acid gives nicotinic acid which by decarboxylation yields pyridine and carbon dioxide isolated as barium carbonate. Whereas the activity of anabasine is... 

In the conversion of nicotinic acid Sorm reported considerable decarboxylation yielding only 50% of nipecotic acid along with piperidine. He postulates that the hydrogenation of nicotinic acid takes two paths ... 

He considers A a disguised form of a /9-aldehyde acid and as such readily loses carbon dioxide. When nicotinic acid was reduced in dilute hydrochloride acid only 10% of piperidine was obtained, indicating a small amount of decarboxylation. Decarboxylation has been observed during the hydrogenation of nicotinic acid in aqueous solution in the presence of ruthenium (8), rhodium (16), and platinum oxide (49). It has been... 

The most accepted biosynthetic pathways for piperidine is lysine via A -piperidine (3973, 17B05). Piperidine can also be formed through decarboxylation and dehydrogenation of nicotinic acid (17B37). 

Alkylpyridines can be oxidized to give pyridine carboxylic acids by a number of methods. For instance, nicotinic acid 114 is produced commercially by oxidation of 5-ethyl-2-methylpyridine 115 with HNO3, followed by selective thermal decarboxylation of the dicarboxylic acid 116 [60]. Selective side-chain oxidation is also possible, as shown in the examples 117 and 118 ... 

These compounds all closely resemble the corresponding benzene compounds in their reactivity because the carbonyl group cannot interact mesomerically with the ring nitrogen. The pyridine 2- (picolinic), 3- (nicotinic), and 4- (isonicotinic) acids exist almost entirely in their zwitterionic forms in aqueous solution they are slightly stronger acids than benzoic acid. Decarboxylation of picolinic acids is relatively easy and results in the transient formation of the same type of ylide which is responsible for specific proton a-exchange of pyridine in acid solution (see section 5.1.2. ). This transient ylide can be trapped by aromatic or aliphatic aldehydes in a reaction known as the Hammick reaction. As implied by this mechanism, quaternary salts of... 

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