Pyridine-3-carboxylates, condensed

Esters of pyridine-carboxylic acids react normally with compounds containing activated methylene groups. The reactions are valuable, for example as routes to acylpyridines. The ethoxide-catalysed condensation of ethyl pyridine carboxylates with ethyl acetate has often been described early work suggested that esters of nicotinic acid gave lower yields than their isomers, but this is not so . Many esters other than ethyl acetate have been used and a number of substituted pyridine esters > Condensations with picolines to give desoxypyridoins are of practical value (p. 380). 

The formation scheme of furfural is speculated as shown in Figure 3. An aldehyde group of furfural reacted with an amino group of lysine to form an imine. The double bond was migrated to form Amadori type compound, which was hydrolyzed to form alpha-keto carboxylic acid. The formed keto carboxylic acid reacted with an intra-molecular amino group to form tetrahydro-pyridine carboxylic acid or reacted with another furfural by aldol condensation, from which furpipate was formed by dehydration of 2 molecules of water. Another possible scheme is that lysine was converted to tetrahydropyridine carboxylic acid, which reacted with furfural to form furpipate. 

Pyridine, 4-methoxy-3-styryl-photoelectron spectroscopy, 2, 137 Pyridine, 2-methyI-alkylation, 2, 176 amination, 2, 233, 236 carboxylation, 2, 53 chlorination, 2, 201, 331 Claisen condensation, 2, 51 methiodide... 

Such an easy isomerization of acetylenylbenzoic acid amides implies the formation of a five-membered nonaromatic ring condensed with the pyrazole ring. However, the pyrazole analog of o-iodobenzamide (amide of 4-iodo-l-methylpyrazole-3-carboxylic acid) formed under heating with CuC=CPh in pyridine for 9 h only the disubstituted acetylene in 71 % yield is identical in all respects to the compound obtained from the corresponding acid by successive action of SOCI2 and NH3 (90IZV2089) (Scheme 126). 

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)... 

It is worth noting that the Ullmann-Goldberg condensation of aryl halides with phenols and anilines worked efficiently in the presence of copper in water.50 For example, the coupling of 2-chlorobenzoic acid with 4-chlorophenol (K2C03/pyridine/copper powder) gave 2-(4-chlorophenoxy)carboxylic acid (Eq. 6.23).51 The Cu(I)-catalyzed transformation of 2-bromobenzoic acid into salicylic acid has also been studied in aqueous media (Eq. 6.24).52... 

The ring closure of aminomethylenemalonates (278) in Dowtherm A at 240°C for 0.5 hr under nitrogen afforded the corresponding condensed pyridine-3-carboxylates (678, X as in 278) (86EUP168350 87USP4647566). 

The acetic anhydride-induced cyclodehydration of the symmetrical diamide 411, derived from the tetrahydro-benzothiophene / -amino ester 410 and diethyl malonate, afforded the thieno[2,3-r7 [h3]oxazine derivative 413 rather than the expected bis-oxazine 412 (Scheme 78). The reaction probably takes place through sequential cyclizations, in which the pyridine ring of 413 is produced by condensation of the exocyclic double bond of the enamine tautomeric form of the 1,3-oxazine moiety and the mixed anhydride formed by the carboxylic group and acetic anhydride <2003PS245>. 

Aminothiophene, readily available from methyl 3-aminothiophene-2-carboxylate, undergoes a condensation reaction with compound 92, followed by heating at elevated temperatures in Dowtherm , to produce pyridone product (Equation 28). The pyridone can be converted into a thieno[3,2- ]pyridine derivative in a few straightforward steps <2004BML21>. 

Imidazo[4,5- ]pyridines can be synthesized by a large number of routes, from which condensation of the appropriate carboxylic acid or acid chloride with the corresponding diaminopyridine, sometimes requiring cyclization of the intermediate amide with strong acid, appears to be the most widely used method <1996CHEC-II(7)283>. A recent example has been reported for the synthesis of pyridoimidazole C-nucleosides, and although the yield in this particular case was low, no epimerization at the C-1 stereocenter was observed (Equation 29) <2003TL5807>. 

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