Ethyl nicotinate

Ethyl nicotiiiate may be prepared either by direct esterification of the acid with ethanol and sulphuric acid, followed by pouring into water and rendering ammoiilacal or by interaction of the acid with thionyl chloride, followed by reaction of nlcotiiiyl chloride hydrochloride with ethanol and subsequent neutralisation. 

Method 1. Reflux a mixture of pure nicotinic acid (Section V,22), 84 g. (105 ml.) of absolute ethanol and 90 g. (50 ml.) of concentrated sulphuric acid in a flask for 4 hours 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 solution with five 25 ml. portions of ether, dry the combined ethereal extracts with anhydrous magnesium sulphate, remove the ether and distil under reduced pressure. The ethyl nicotinate passes over at 117-118°/ 6 mm. the yield is 34 g. The b.p. under normal pressure is 222-224°. 

Ethyl nicotinate upon treatment with concentrated ammonia solution yields nicotinamide, which gives p-cyanopjTidine upon heating with phosphoric oxide  

Nicotinamide. Place 50 g. of pure ethyl nicotinate (Section V,23) in a. 350 ml. bolt-head flask and add 75 ml. of concentrated aqueous ammonia saturated at 0 . Keep the flask loosely stoppered for 18 hours, after wliich time the lower layer generally dissolves on shaking. Saturate the solution with ammonia and allow it to stand for a further 4 hours. Repeat the saturation with ammonia crystals of the amide commerce to appear in the solution. Evaporate to dr mess in a dish on the steam bath and dry at 120°. The yield of nicotuiamide, m.p. 130°, is usuallj quantitative. 

Uramil (aminobarbituric acid) (III) may be prepared by the oxidation of barbituric acid (I) to nitrobarbituric acid (II), followed by reduction of the latter  

P-Cyanopyridine. Mix 25 g. of powdered nicotinamide with 30 g. of phosphoric oxide in a 150 ml. distilling flask by shaking. Immerse the flask in an oil bath and arrange for distillation under a pressure of about 30 mm. Raise the temperature of the oil bath rapidly to 300°, then remove the oil bath and continue the heating with a free flame as long as a distillate is obtained. The nitrile crystallises on cooling to a snow-white solid. Redistil the solid at atmospheric pressure practically all of it passes over at 201° and crystallises completely on cooling. The yield of (3-cyanopyridine, m.p. 49°, is 20 g. 

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Chapter V. Quinaldine (V,2) 2-methyl-, 2 5-dimethyl- and 2-acetyl-thiophene (V,8-V,10) 2 5-dimethyl and 2 4-dimethyl-dicarbethoxy-p3nrole (V,12-V,13) 2-amino- and 2 4 dimethyl-thiazole (V,15-V,16) 3 5-dimethyl-pyrazole (V,17) 4-ethylp3rridine (from pyridine) (V,19) n-amyl-pyridines from picolines) (V,28) picolinic, nicotinic and isonicotinic acid (V,21-V,22) (ethyl nicotinate and p-cyanop3n idine (V,23-V,24) uramil (V,25) 4-methyl-(coumarin (V,28) 2-hyi-oxylepidine (V,29). 

Reaction of -picoline over degassed Raney nickel was found to give 5,5 -dimethyl-2,2 -bipyridine (5), the structure of which was established by its synthesis from 2-bromo-5-methylpyridine. Oxidation of this dimethyl-2,2 -bipyridine, and similar oxidation of the diethyl-2,2 -bipyridine derived from 3-ethylpyridinc, gave the corresponding dicarboxylic acid and the same acid was produced by the action of degassed Raney nickel on sodium nicotinate (in water) or on ethyl nicotinate. These transformations established the 5,5 -substitution pattern for three 2,2 -bipyridines derived from 3-substituted pyridines but such evidence is not available for the biaryls... 

Relatively few pyridines with substituents other than alkyl groups have so far been examined, and with some of these the reaction has been carried out only in the presence of added solvent. A comparison of the reactivities of these pyridines is therefore difficult. It has, however, been established that the presence of benzoyl groups in the 3- and 4-positions causes a very marked drop in the yields of the corresponding 2,2 -bipyridines. The 3- and 4-benzylpyridines were found to be more reactive but even in the absence of solvent, and in vacuo, 4-benzylpyridine gave only about one-third of the yield of the 2,2 -bipyridine compared with pyridine itself. Ethyl nicotinate in the absence of solvent and under vacuum -- gave a similar yield of biaryl but 4-phenylpyridine was found to be less reactive. 

A palladium-catalyzed aerobic oxidative annulation of indoles, in the presence of ethyl nicotinate, has been disclosed.137,13711 The stereochemical outcome of this reaction indicates that an initial C-H functionalization at C(2) of the indole, followed by yvv/-carbopa 11 adation and ry -/ -H-elimination, operates (Equation (163)).137 This process has also been employed for the synthesis of benzofuran analogs.1373... 

NMR spectrum showing the presence of a 3-substituted pyridine with four nonequivalent methylene units in the substituent, and by its conversion to 2,3-bi-pyridyl with chloranil (26). Its synthesis was made by condensation of A -ben-zoylpiperidone (258) with ethyl nicotinate (259) followed by heating with concentrated hydrochloric acid, resulting in hydrolysis, decarboxylation, and ring closure (Scheme 18) 401). Application of the Mundy A-acyllactam rearrangement to A-nicotinoylpiperidone (261) has also led to a synthesis of anaba-seine (8) (Scheme 18) 402). 

By using an olefin embedded into the parent molecule Stoltz developed the oxidative annulation of indoles. The optimal catalyst consisted of palladium acetate and ethyl nicotinate, and molecular oxygen was used as the oxidant in the process. The reaction proceeded equally well irrespective of the attachment point of the alkyl chain bearing the pendant olefin bond on the five membered ring, and the formation of five and six membered rings were both effective (6.95.),127... 

In 1979, Ferles and Silhankva showed that ethyl nicotinate was converted into the self condensation product 4-(2-carboethoxypyridyl)-3-... 

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