3-Pyridinecarboxylates, synthesis

Synthesis of acylpyridines, pyridinecarboxylic acids and their derivatives 98KGS1013. 

The base-catalyzed Michael addition of 2-chlorocyanoacetate to a,p-unsaturated ketones or aldehydes affords 5-oxopentenenitrile derivatives. In the presence of anhydrous HCl, these compounds cyclize to yield 2-chloro-3-pyridinecarboxylates. The process is highly regiospecific and usefiil in the synthesis of 2,Xdisubstituted pyridines <95T(51)13177>. 

The cycloadducts formed from the Diels-Alder reaction of 3-amino-5-chloro-2(17/)-pyrazinones with methyl acrylate in toluene are subject to two alternative modes of ring transformation yielding either methyl 6-cyano-l,2-dihydro-2-oxo-4-pyridinecarboxylates or the corresponding 3-amino-6-cyano-l,2,5,6-tetrahydro-2-oxo-4-pyridinecarboxylates. From the latter compounds, 3-amino-2-pyridones can be generated through subsequent loss of HCN <96 JOC(61)304>. Synthesis of 3-spirocyclopropane-4-pyridone and furo[2,3-c]pyridine derivatives can be achieved by the thermal rearrangement of nitrone and nitrile oxide cycloadducts of bicyclopropylidene <96JCX (61)1665>. 

Similar ring systems were prepared <97JHC1693> by Coppo and Fawzi from the reaction of substituted ethyl 5-[methyl(methylsulfonyl)amino]-l 7/-pyrazole-4-carboxylates 119 with sodium hydride. This gave the 7-substitued 1,7-dihydro-l-methylpyrazolo[3,4-c][l, 2]thiazin-4(37/)-one 2,2-dioxides 120 in fair to good yield (Scheme 30). They also extended this synthesis by treating methyl 2-[methyl(methylsulfonyl)amino]-6-(trifluoromethyl)-3-pyridinecarboxylate 121 with sodium hydride in dimethylformamide to yield l-methyl-7-(trifhioromethyl)-l//-pyrido[2,3-c][l,2]thiazin-4(3//)-one 2,2-dioxide 122 in 79% yield (Scheme 31) <98JHC499>. 

The Balz-Schiemann synthesis can be applied not only to substituted anilines but also to aminobiphcnyls1,131 or amino-substituted fused polyaromatic compounds, such as naphthalene,1114,119,129 anthracene,136 phenanthrene,1135 acenaphthene,133 fluorene,1,131,134 benzanthracene,130 136 pyrene,136 chrysene,136 fluoranthene,131 fluorenone,1,131 anthra-quinone,1,137,139,140 benzanthrone,1,117,118 phenanthraquinone,138 or xanthone.132 Fluorinated pyridines,1,141"146 methylpyridincs,126,147 149 pyridinecarboxylic acids,150 quinolines,1,151 isoquinolines,152 quinazolone,1 thiazoles,153,154 isothiazoles,156 benzothiazoles,157 thiadiazoles,155 and thiophenes154 can also be obtained from the corresponding aminated heterocycles. Modified Balz-Schiemann methods are recommended for amino nitrogen-containing heterocycles, the diazonium salts of which are rather water-soluble and unstable (a violent explosion was reported for pyridine-3-diazonium tetrafluoroborate).159 These new techniques have also been specially adapted for pyrazol-, imidazol-, or triazolamines which fail to react under classical conditions.158... 

Spanish workers have recently described a rapid method for the construction of pyridoacridines which could be of value for the synthesis of a range of cytotoxic pyridoacridine alkaloids. Thus, treatment of MEM-protected 4-quinolone 1 with 3 equivalents of LDA in THF, first at -78°C then with stirring at room temperature, followed by addition of 1 equivalent of methyl 3-formyl-2-pyridinecarboxylate gave, after quench with aqueous ammonium chloride and chromatography, a mixture of the tetracycles 2 (15%) and 3 (20%). Oxidation of either 2 or 3, or a mixture of 2... 

The appropriateness of using of microwave-assisted organic synthesis to obtain pyridinecarboxylic acids and pyrimidinecarboxylic acids was also described in [202]. The application of microwave irradiation reduces significantly the reaction time from 2 h to 10 min, increases yields of the target compounds and also allows high-boiling and hard-to-remove solvents (DMF and acetic acid) to be replaced by ethanol. 

Stamicarbon217> claims the use of anion exchange membranes in divided cells for the electrochemical oxidation of alkylpyridines to the corresponding pyridinecarboxylic acids. Finally, Takeda 218) has used the principle of paired synthesis in a divided cell for the simultaneous generation of synthetic intermediates. 

Such a synthesis is evident in the Dieckmann cyclization981 of ethyl 3-[2-(ethoxycarbonyl)acetamido]-2-pyridinecarboxylate (15) (prepared in situ) to give... 

Iqbal N, Akula MR, Vo D et al (1998) Synthesis, rotamer orientation, and calcium channel modulation activities of alkyl and 2-phenethyl 1, 4-dihydro-2, 6-dlmethyl-3-nltro-4-(3- or 6-substltuted-2-pyrldyl)-5-pyridinecarboxylates. J Med Chem 41 1827-1837 LI RWS, Tse CM, Man RYK et al (2007) Inhibition of human equilibrative nucleoside transporters by dihydropyridine-type calcium channel antagonists. Eur J Pharmacol 568 75-82 Cosconatl S, Marlnelli L, Lavecchia A et al (2007) Characterizing the 1,4-dlhydropyrldlnes... 

Within the total synthesis of the antitumor antibiotics streptonigrin and lavendamycin, steiically hindered polyfunctional pyridinecarboxylic acids (87-89) have been conveniently converted to their corresponding amines by treatment with DPPA-triethylamine in refluxing benzene for 1-2S h, followed by a brief reflux after addition of water. 

Sanchez. J.P.. Mich, T.E. and Huang, G.G.. An efficient synthesis of 6-formyl-l,2-dihydro-2-oxo-3-pyridinecarboxylic acid and some carbonyl derivatives of it and its 6-acetyl homologue, J. Heterocyd. Chem.. 31. 297, 1994. 

Pyrido[4,3-ii]pyrimidin-5(6//)-one (64) was prepared, along with the expected ethyl 4-oxo-l,4-dihydro-3-pyridinecarboxylate (65), by reaction of a )S-ketoester with 1,3,5-triazine and sodium ethoxide in ethanol (Equation (4)) <80JHC359>. This reaction was extended to the synthesis of the... 

Stereoselective Michael addition of cuprates on the didehydropiperidinecarboxylate is part of a synthesis of indolizidines <97T9553>. The reactions and stereoselectivity of attack of nucleophiles on 2-cyano-l,4,5,6-tetrahydro-l-pyridinecarboxylic acids is reported <97M1061>. 

Synthesis of Pyridinecarboxylic Acids Containing Sulfur Substituents... 

Pyridinecarboxylic adds are useful and important intermediates in pharmaceutical syntheses. Although the synthesis of these carboxylic adds by the aerobic oxidation of alkylpyridines is straightforward, the oxidation is usually difficult to carry out selectively owing to their low reactivities [52,56). Pyridinecarboxylic acids are readily prepared by the oxidation of alkylpyridines with nitric add or by the hydrolysis of pyridinecarboxamides derived from pyridinecarbonitrile [57]. According to the... 

The tetrahydroquinolylimidazolinone 4 (AC 263,754) was also found to be an active herbicide. It was anticipated that fusion of a heterocycle such as a pyran to pyridylimidazolinone 1 might also afford interesting herbicidal activity. With this background in mind, investigations directed toward the synthesis of isomeric pyranopyridine analogs were undertaken. This paper will focus on the synthesis and herbicidal activity of imidazolinyldihydropyrano[2,3-b]pyridinecarboxylic acid 5 and its derivatives. However, for comparison of the herbicidal activity, the other pyranopyridylimidazolinones such as 6, 7, and 8 will also be included. The syntheses of these compounds (i.e. 6, 7, and 8) have been reported elsewhere (8). 

Kametani, T., S. Tanaka, and A. Kozuka Syntheses of Streptonigrin and Related Compounds. X. A Synthesis of Methyl 3-Acetamido-l,2-dihydro-4-(2,3,4-trimethoxy-phenyl)-5-methyl-2-oxo-6-pyridinecarboxylate. Yakugaku Zasshi 91, 1068 (1971). 

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