Picolinic acid, decarboxylation

Decarboxylation of crystalline isoxazole-3-carboxylic acids appears to proceed by another mechanism,probably with formation of a zwitterion (159) which reacts as in the case of picolinic acid de-... 

Photodecomposition products included acidic compounds and five methylated derivatives (Plimmer, 1970). When picloram in an aqueous solution (25 °C) was exposed by a high intensity monochromatic UV lamp, dechlorination occurred yielding 4-amino-3,5-dichloro-6-hydroxy-picolinic acid which underwent decarboxylation to give 4-amino-3,5-dichloropyridin-2-ol. In addition, decarboxylation of picloram yielded 2,3,5-trichloro-4-pyridylamine which may undergo dechlorination yielding 4-amino-3,5-dichloro-6-hydroxypicolinic acid (Burkhard and Guth, 1979). 

Bipyridine was first prepared in 1888 by the dry distillation of the copper salt of picolinic acid. This method and modifications give low yields of 2,2 -bipyridine. Another old method Involves oxidation of 1,10-phenanthrbline (28) to 2,2 -bipyridine-3,3 -dicarboxylic acid (29) by alkaline permanganate, followed by decarboxylation. This... 

Results. The experimental 15N isotope effect at N1 for the decarboxylation of OMP in ODCase (Scheme 1) was measured by Cleland et al. to be 1.0068.66 Comparison of this normal isotope effect with IEs measured for the model compounds picolinic acid (17) and A-methyl picolinic acid (18) led Cleland and coworkers to conclude that the normal IE observed for OMP decarboxylation is indicative of the lack of a bond order change at Nl. This conclusion was based on the following reasoning. The IE for the decarboxylation of picolinic acid (17) is 0.9955 this inverse value is due to the change in bond order incurred when the proton shifts from the carboxylate group to the N in order to effect decarboxylation (equation 2) the N is ternary in the reactant, but becomes quaternary in the intermediate, which results in the inverse IE. The decarboxylation of A-methyl picolinic acid (18) involves no such bond order change (equation 3), and the observed normal IE of 1.0053 reflects this. 

Phillips and Lee calculated the 15N isotope effect for the decarboxylation of 1-methyl orotate (lb) via 2-protonation (4b) and via 4-protonation (6b). They found that in both cases, the calculated isotope effect is normal 1.0043 for 2-protonation, and 1.0054 for 4-protonation. An examination of the optimized structures showed clearly that very little bond order change occurs at Nl, regardless of which oxygen is protonated. Phillips and Lee also benchmarked their calculations by computing the IEs for protonation of pyridine and for decarboxylation of picolinic acid (17) and A-methyl picolinic acid (18) the results of these calculations are in agreement with the experimental values mentioned above. Therefore, Philips and Lee asserted that... 

In most of their reactions, the pyridine- and azinecarboxylic acids and their derivatives behave as any other acid (cf. Scheme 86). However, some acid chlorides can be obtained only as hydrochlorides, and we must also consider decarboxylation. Esterification of pyridine carboxylic acids can be usefully achieved via in situ generation of the acid fluoride. For example, treatment of picolinic acid with a stoichiometric amount of N,N,N,A-tetramethylfluoroformami-dinium hexafluorophosphate (TFFH) in dichloromethane and triethylamine leads to generation of the acid fluoride, which reacts with (3-methyloxetan-3-yl)methanol to give the corresponding ester in 95% yield <2004S2485>. 

An interesting class of elusive neutral species is heterocyclic ylids, as represented by the so-called Hammick intermediate that was postulated 65 years ago to explain the accelerated decarboxylation of 2-picolinic acid [146, 147]. An analogous dissociation takes place in ionized 2-picolinic acid in the gas-phase and was employed to generate the pyridine ion isomer 35+ (Scheme 13) [148]. Collisional neutralization of 35+ with A/,AT-dimethylaniline produced neutral ylid 35, which can also be represented as a singlet a-carbene (Scheme 13). Ylid 35 showed a survivor ion in the +NR+ mass spectrum, which was further char-... 

One should be very careful in dealing with data on the ionization equilibrium and rates of decarboxylation of pyridinecarboxylic acids (71JOC454 72JOC3938), since these acids may exist in zwitterionic forms and, for picolinic acids, with intramolecular H-bonds. It is precisely the latter that can account for the essential difference of the p values for ionization of 5-substituted... 

It is possible that quinolinic acid might be decarboxylated to picolinic (pyridine-2-carboxylic) acid as well as to nicotinic (pyridine-3-carboxylic) acid. Such may be the origin of the homarine (picolinic acid betaine) widely occurring in marine organisms (e.g., 423). 

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... 

An extensive study of the decarboxylation of picolinic acid in twelve polar solvents has been concluded. Thirty-two sets of activation parameters were obtained. The data favor the uncharged molecule (X-144) over the zwitterion (X-145) as the entity involved in the formation of the transition state. 

The kinetic isotope effect in the decarboxylation of picolinic acid (X-144) was measured in a variety of solvents. The observed effects are related to hydrogen bonding. ... 

The relative rates of decarboxylation of picolinic acid (X-144), its Af-methyl homologue, homarine (X-147), and its A(-oxide (X-148) in ethylene glycol at 134° are 1 720 160. Homarine decarboxylates 10 times faster than the 3 osition isomer, trigonelline, and Af-methylisonicotinic acid. The... 

Decarboxylation of 3-hydroxyanthranilic acid in the presence of picolinic carboxylase leads to the formation of picolinic acid. The steps involved in this transformation are not clear, nor are the enzymes involved known. 

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. 

Picolinic Carboxylase. An enzyme in liver decarboxylates the original carboxyl group of 3-hydroxyanthranilic acid from the oxidation product. The product of the decarboxylation is picolinic acid. Picolinic carboxylase has no known cofactors. The mechanism of its action is thought to involve a temporary loss of the double bond during decarboxylation. This permits rotation of the amino group into a position favoring condensation to form the pyridine ring (XII). 

Mehler (69) has found that compound I can be decarboxylated to yield picolinic acid [reactions (Ilb) and (Illb), Fig. 2]. The formation of this pyridine derivative appears to take place in two steps with the formation of an open chain unsaturated aldehyde as an intermediate. Mehler s enzyme is specific with respect to the formation of picolinic acid and does not promote the conversion of compound I to nicotinic acid and does not decarboxylate quinolinic acid. Picolinic acid is not present in urine in large amounts following 3-hydroxyanthranilate injection (28). However, the glycine conjugate, picolinuric acid, appears to be excreted when the anthranilic acid is administered (70). 

There is no evidence at present for the conversion of compound I to nicotinic acid. The formation of the vitamin from hydroxyanthranilic acid, however, has been demonstrated in rat liver slices and homogenates (71,72). The mechanism by which nicotinic acid is formed is not clear at present, although it is possible that the open chain saturated aldehyde shown in reactions (Ila) and (Ilia) in Fig. 2 may be an intermediate. The alpha decarboxylation and ring closure involved in the generation of nicotinic acid from compound I is not a spontaneous reaction and appears to be enzymic. Henderson (28) has pointed out that one of the reasons for the failure to observe nicotinic acid synthesis from compound I might be due to the competitive formation of quinolinic and picolinic acids. 

Picolinic acid 1-oxide gives 2-hydroxypyridine when heated with acetic anhydride, but decarboxylation is thought to precede hydroxylation" ... 

A kinetic study of the decarboxylation of picolinic acid, molten and in solution, showed decarboxylation to be easier in basic than in acid media, and the reaction was concluded to be of the 5e1 type ... 

Compound (27) may also be obtained dkecdy by oxidation of P-picoline (3) or by exhaustive oxidation of 5-ethyl-2-methylpyridine (7), followed by decarboxylation of the initially formed pyridine-2,5-dicarboxyhc acid [100-26-5] (28) (eq. 8) (30). 

Ethyl pyridine-2-acetate and ethyl 6-methylpyridine-2-acetate have previously been prepared by carboxylation of the lithio derivatives of a-picoline and lutidine, respectively. Use of ethyl carbonate to acylate the organometallic derivative avoids the intermediacy of the (unstable) carboxylic acid, and the yields are better. In the present procedure potassium amide is used as the metalating agent the submitters report that the same esters may be formed by metalation with sodium amide (43% yield) or with w-butyllithium (39% yield). The latter conditions also yield an appreciable amount of the acid (which decarboxylates). 

Myadera and Iwai (64CPB1338) have devised a convenient route to the bromide (139 R1 = R2 = R3 = H) starting with commercially available materials (Scheme 84). The anion formed from -y-butyrolactone by the action of sodium hydride was allowed to react with ethyl picolinate to yield the keto lactone (141) which, when heated with hydrobromic acid, undergoes decarboxylation as well as bromination, yielding the bromo ketone (139). Several substituted ethyl picolinates have been used successfully, and it has also been found that the anion of the keto lactone (141) may be alkylated. 

Condensation of y-picoline with mesoxalic ester yielded 4-(j8,j8-diethoxycarbonylvinyl)pyridine (35). The unsaturated ester (35) was hydrogenated with platinum catalyst to form 36 which was treated with bromine. 4-(j8-Bromo-j8,j8-diethoxycarbonylethyl)-piperidine (37) was obtained and was cyclized with pyridine to 2,2-die th 0 xycarbony 1 quinuclidine (38). Hydrolysis of 38 and partial decarboxylation gave quinuclidine-2-carboxylic acid (39). 

Tschitschibabin reaction,290 thus counteracting the example based on 3-hydroxypyridine. The second reaction to be discussed is that of 2-picoline with sodamide at a relatively high temperature, when 3,6-diamino-2-picoline (126) is one of the products isolated.293 If this is so, this represents another example of the type of orientation recently observed in the phenylation of pyridine with phenylcalcium iodide which gave some 2,5-diphenylpyridine.264 Alternatively, a 3,4-pyridyne intermediate (125) might perhaps actually be involved here. The evolution of hydrogen is not mentioned in this case. The decarboxylation of pyridine carboxylic acids under strongly basic conditions is unexceptional. 

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... 

---