Ethyl pyridine-3-carboxylate

Ethyl nicotinate (ethyl pyridine-3-carboxylate). Reflux a mixture of 37 g (0.3 mol) pure nicotinic acid (Expt 6.150), 92 g (115 ml, 2 mol) of absolute ethanol and 90 g (50 ml) of concentrated sulphuric acid on a steam bath. Cool the solution and pour it slowly and with stirring on to 200 g of crushed ice. Add sufficient ammonia solution to render the resulting solution strongly alkaline generally, some ester separates as an oil but most of it remains dissolved in the alkaline solution. Extract the mixture with five 25 ml portions... 

Among further specific methods, Newkome s group [99] has found that ethyl pyridin-3-carboxylate (534) underwent the dehydrogenative coupling at unhindered a-position to give the diethyl 2,2 -bipyridine-5,5 -dicarboxylate (535) in 35% yield, upon refluxing with 10% Pd-C under redueed pressure, Scheme 54. 

Scheme10.11 Partial hydrogenation of ethyl pyridine-3-carboxylate to vinylogous carbamate.

Kinetic data for the alkaline hydrolysis of ethyl pyridine-carboxylates and their 1-oxides are summarized in Table 6.4, All the esters of pyridine monocarboxylic acids and their oxides are hydrolysed with lower activation energies than that associated with ethyl benzoate. The oxide esters are hydrolysed about 1,000 times faster than ethyl benzoate but rather because of high logio A values than because of low activation energies. In these reactions the mechanism is probably Bac in such processes E is reduced by increased electron-attracting power in the group attached to the ethoxy-carbonyl group. The expected order as between 3- and 4-pyridyl is observed, but 2-pyridyl falls out of place, perhaps for steric reasons. Clearly, in the... 

Table 6.4. Alkaline Hydrolysis of Ethyl Pyridine-carboxylates and Pyridyl-acrylates" ...

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). 

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)... 

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). 

Chloro-2-aryl-2//-chromene-3-carbaldehydes, formed from the reaction of flav-4-ones with dimethylformamide (DMF)/POCl3, react with ethyl 3-aminocrotonate under Hantzsch conditions to give ethyl 2-methyl-5-aryl-5H-chromen[3,4-f]pyridine carboxylates in good yields <2001SC2589>. 

The cyclazine (Iv) was the only product isolated in poor yield from reaction of pyridine and methyl propiolate in acetonitrile. The indolizine derivative (35) may be an intermediate, since it was obtained from a similar reaction in ether.39 2-Acetylpyridine and ethyl pyridine-2-carboxylate reacted similarly.40... 

Refluxing 2-acetylpyridine (111) with MP gives a remarkable 29% yield of pyrrolo[2,1,5-< /]indolizine (112), which may be formed by the route (Scheme 5) outlined.296 Ethyl pyridine-2-carboxylate, presumably by a similar mechanism, yields a mixture of three pyrrolo[2,l,5-crf]-indolizines (113,114, and 115).296... 

Ethyl 5-cyano-2-(a-cyanoethoxycarbonylmethyl)-4-oxo-l,4-dihydro-3-pyridine-carboxylate (42) gave ethyl 3-cyano-7-hydroxy-4,5-dioxo-1,4,5,6-tetrahydro-l,6-naphthyridine-8-carboxylate (43) (Et3N, EtOH, reflux, 3 h 65%).698... 

If the coupling reaction of ethyl (4,6-diamino-3,5-dicyano-2-pyridyl)acetate with benzenediazonium chloride is performed in pyridine at 0°C, an oil results which, by refluxing in dimethylformamide, gives the cyclization product.64 In a one-pot reaction, 2-amino-3-benzoyl-5-cyano-4-phenylpyridine-6-acetonitrile, or the corresponding ethyl acetate, is coupled with benzenediazonium chloride in aqueous ethanolic sodium hydroxide, the mixture then left at room temperature to give 2-amino-3-benzoyl-5-imino-4,6-diphenyl-5,6-dihydropyrido[2,3-fi(]-pyridazine-8-carbonitrile (22a) or the ethyl 8-carboxylate 22b.65... 

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 ... 

In browsing through my notes I discovered that I had made another N-substitution product of DOM. Efforts to fuse free-base DOM with the ethyl cyclopropane carboxylate failed, but the reaction between it and the acid chloride in pyridine gave the corresponding amide, with a mp of 156-157 deg C from MeOH. Anal. (C16H23N03) C,H,N. This reduced smoothly to the corresponding amine,... 

Hofmaim degradations were carried out on 5pyridine carboxylic acids are treated with sodium azide in an oleum medium, a good yield (69%) of 3-aminopyridine and poorer yields (<30%) of 2- and 4-aminopyridine are realized. 3-Amino-5-nitropyridine is similarly prepared by the Schmidt reaction using 5-nitronicotinic and hydrazoic acid. ... 

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