Pyridine carboxylic acids, decarboxylation

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. 

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>. 

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 ... 

The ready decarboxylation of pyridine-carboxylic acids was also early appreciated. Historically, the reaction played an important role in the orientation of quinoline, isoquinoline and the benzoquinolines . Decarboxylation occurs more readily than with benzene-carboxylic acids, and in the sequence 2 > 4 > 3 (see p. 367). The decarboxylation temperatures of solid pyridine-dicarboxylic acids depend roughly on their strengths as acids— the stronger the acid the lower the temperature . At 185 -190 , pyridine-2,3,4-tricarboxylic acid gives pyridine-3,4-dicarboxylic acid, which above... 

The introduction of vapour-phase oxidation of alkylpyridines over vanadium and molybdenum oxides in 1951 made pyridine aldehydes and dialdehydes technically available 2< 278d, With a deficiency of air, pyridoins result 4 > 278e, 294 with a sufficiency, aldehydes result (3-methyl groups are oxidized, but pyridine-3-aldehyde does not appear to have been made by this method 278e, 295) and with an excess, the carboxylic acids, including nicotinic acid, and pyridines are formed by decarboxylation , 296-7, Vapour-phase oxidation in presence of ammonia gives nitriles and pyridine-carboxylic acid amides278/, 296,... 

Other interactions of /3-lactams with electrophiles include the oxidative decarboxylation of the azetidin-2-one-4-carboxylic acid (85) on treatment with LTA and pyridine (81M867), and the reaction of the azetidin-2-one-4-sulfinic acid (86) with positive halogen reagents. This affords a mixture of cis- and trans-4-halogeno-/3-lactams (87), the latter undergoing cyclization to give the bicyclic /3-lactam (88) (8UOC3568). 

Treatment of alkyl 9-benzyloxycarbonyl-3-methyl-6-oxo-2/7,6//-pyr-ido[2,l-f ][l,3]thiazine-4-carboxylates with BBr3 in CH2CI2 at -70 °C for 0.5-1 h and at room temperature for 3h yielded 9-carboxyl derivatives. The decarboxylation of these acids was unsuccessful. Hydrolysis of diethyl cA-3,4-H-3,4-dihydro-3-methyl-6-oxo-2//,6//-pyrido[2,l-f ][l,3]thiazine-4,9-dicarboxylate in aqueous EtOH with KOH at room temperature for 3 days yielded 4-ethoxycarbonyl-3,4-dihydro-3-methyl-6-oxo-2//,6//-pyrido-[2,l-f ] [1,3]thiazine-9-carboxylic acid (00JCS(P1)4373). Alkyl 9-hydroxy-methyl-3-methyl-6-oxo-3,4-dihydro-2//,6//-pyrido[2,l-f ][l,3]thiazine-4-car-boxylates were O-acylated with AC2O and (PhC0)20 in pyridine at room temperature for 12-48h. 

Another example in which the free acid undergoes ready decarboxylation, but this time via a carbanion intermediate (50, actually an ylid), is pyridine-2-carboxylic acid (51), which is decarboxylated very much more readily that its 3- or 4-isomers ... 

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). 

Methyl-3,3 -bipyridine has been oxidized by permanganate to 3,3 -bi-pyridine-4-carboxylic acid. " 3,3 -Bipyridine carboxylic acids are easily decarboxylated and have been esterified and converted to amides, hydrazides, and acylazides. The Hofmann degradation, of the diamide of 3,3 -bipyridine-2,2 -dicarboxylic acid affords the expected 2,2 -diamino-3,3 -bipyridine, but some of the tricyclic system 108 is formed as well. A 2,2 -bis(acylazide) is converted to a similar tricyclic system with ethanol via the intermediate isocyanate, and several related reactions have been described. The simultaneous dehydration... 

Pyridine, pyrone and pyridone carboxylic acids undergo decarboxylation when heated, and the general order of reactivity is a > y > p. In pyridine, the carboxylic acids, as expected, exist mainly in the zwitterionic forms and decarboxylation of the a and y isomers under fairly mild conditions is a consequence of the relative stability of the ions of the type (48). 

In the pyrazolo [ 1,5-a]pyridine series, the reaction of hydrazine with the 2,3-dimethoxycarbonyl derivative afforded the corresponding 2-hydrazide, whereas saponification and decarboxylation gave the 3-carboxylic acid.169 Further, several 2-substituted 3-carboxamides, -hydrazides, and -carboxylic acids were obtained,169,239 using standard methods. Decarboxylation was also reported.169 A number of transformations of py razolo [3,4-h]pyridine... 

Alkyl radicals for such reactions are available from many sources such as acyl peroxides, alkyl hydroperoxides, particularly by the oxidative decarboxylation of carboxylic acids using peroxy-disulfate catalyzed by silver. Pyridine and various substituted pyridines have been alkylated in the 2-position in high yield by these methods. Quinoline similarly reacts in the 2-, isoquinoline in the 1-, and acridine in the 9-position. Pyrazine and quinoxaline also give high yields of 2-substituted alkyl derivatives <74AHC(16)123). 

In most of their reactions, the pyridine- and azine-carboxylic acids and their derivatives behave as expected (cf. Scheme 61). However, some acid chlorides can be obtained only as hydrochlorides, and we must also consider decarboxylation. 

Homophthalic acids are acylated by acid anhydrides in the presence of pyridine, producing 4-acylisochroman-l,3-diones (494) (80CB3927). Rearrangement to a 3-alkylisocoumarin-4-carboxylic acid (495) occurs in acid solution and may be accompanied by decarboxylation. 

Hydroxybenzo[6]thiophene has been isolated from coal tar.42 It may be prepared from 6-aminobenzo[fr]thiophene by standard procedures.241 6-Methoxybenzo[h]thiophene may be prepared by decarboxylation of the corresponding 2-carboxylic acid,341 and 6-ethoxybenzo[6]thiophene is obtained by reduction of 6-(ethoxy)-thioindoxyl (Section VI, 1,2). 6-Methoxy-5-methylbenzo[6]thiophene is obtained by cyclization of (3-methoxy-4-methylphenylthio)-acetaldehyde dimethyl acetal (Section IV,B).617 The product previously described542 as 6-hydroxy-3-phenylbenzo[6]thiophene has now been shown to be the 2-phenyl isomer.307 6-Methoxy-818 and 6-methoxy-5-methyl-benzo[6]thiophene617 are demethylated by pyridine hydrochloride. 

Benzo[6]thiophene carboxylic acids have been decarboxylated byT heating them with oxalic acid,254 by heating the ester with IN NaOH in dioxane,441 by heating the barium salt with barium hydroxide in vacuo,162, by heating them in quinoline with copper chromite347, 352.353 or> preferably, with copper,109 185 189,298 315 343 344 351 412 422, 638 an(j py heating them alone in quinoline54 or pyridine.114... 

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