A Simple One-Pot Synthesis of 2,6-Disubstituted 4-(Polyfluoroalkyl)pyridines and -pyrimidines by Reaction of 2-Polyfluoroalkylchromones with Aromatic Methyl Ketimines and Amidines

Abstract

The reaction of 2-polyfluoroalkylchromones with ketimines, derived from aromatic methyl ketones and isopropylamine, gives 2,6-diaryl-4-polyfluoroalkylpyridines in moderate to low yields. Benzamidine and guanidine also react with 2-polyfluoroalkylchromones to afford the corresponding 2,6-disubstituted 4-polyfluoroalkylpyrimidines.Much attention has been given to the chemistry of R F -containing N-heterocycles, because they find wide use in various areas of industry, medicine, and agriculture due to their unique physical properties, chemical reactivity, and biological activity. 1,2 In connection with this, remarkable progress has been made in the development of new and efficient methods for the synthesis of polyfluoroalkylated pyridine and pyrimidine derivatives using fluorinated building blocks.2,6-Diaryl-4-(trifluoromethyl)pyridines have recently been synthesized by the reaction of enamines, prepared from substituted acetophenones and morpholine, with trifluoromethylated b-diketones in the presence of ammonium acetate. 3a The condensation of CF 3 -containing a,bunsaturated ketones and b-diketones with primary amines, such as b-aminocrotononitrile and ethyl b-aminocrotonates, affords 2-and 4-trifluoromethylpyridines. 3b,c These compounds were also obtained from the reaction of trifluoromethylated a,b-unsaturated ketones and b-diketones with N-silyl-1-azaallyl anions 3d and by Hantzsch's dihydropyridine synthesis. 3e,f 2,6-Disubstituted 4-(polyfluoroalkyl)pirimidines were obtained by reactions of amidines with R F -substituted alkyl ketones, 4a a,b-unsaturated ketones, 4b b-diketones, 4c b-alkoxy-4d-f and b-aminovinyl ketones, 4g,h N-aryl acetylenic imines, 4i iodoalkenes, 4j and 3-hetarylchromones. 4k In addition, fluoroalkyl pyrimidines have been synthesized from one-pot reactions of a-fluoroalkyl carbonyl compounds, orthoesters and ammonium carbonate. 4l The condensation of fluoro-containing nitriles with methyl ketimines 4m and enamines 4n provides a simple route to pyrimidines with two polyfluoroalkyl groups.

Synthesis and Transformation of Halochromones

“…During the last decade Sosnovskikh [128,[194][195][196][197][198][199][200][201] and his group continued to devote great attention to the chemistry of 2-(polyhaloalkyl)chromones (2-R F -chromones) 185, particularly 2-(polyfluoromethyl)chromones (2-CF 3 -chromones) [52]. Some of their possible reactions are depicted in (Scheme 60): the reaction with ketimines leading to compounds 186-189 [194,196,198]; with acetophenones in the presence of lithium diisopropylamide to give 2-aroylmethyl-2-R F -chromanones 190 [197]; and a novel annulation reaction with salicylaldehydes in the presence of piperidine that constituted a direct route to chromeno [2,3-b]chromen-11-ones 191 by a tandem intermolecular oxa-Michael addition and subsequent intramolecular Mannich condensation [195].…”

“…Some of their possible reactions are depicted in (Scheme 60): the reaction with ketimines leading to compounds 186-189 [194,196,198]; with acetophenones in the presence of lithium diisopropylamide to give 2-aroylmethyl-2-R F -chromanones 190 [197]; and a novel annulation reaction with salicylaldehydes in the presence of piperidine that constituted a direct route to chromeno [2,3-b]chromen-11-ones 191 by a tandem intermolecular oxa-Michael addition and subsequent intramolecular Mannich condensation [195].…”

One‐Pot Domino Synthesis of Polyfunctionalized Benzophenones, Dihydroxanthones, and m‐Terphenyls from 2‐(Polyfluoroalkyl)chromones

“…we reported that 2-(trifluoromethyl)chromones serve as 1,3dielectrophilic units to afford trifluoromethylated pyrazoles, isoxazoles, dihydrothienocoumarins, [8] pyridines, pyrimidines, [9] benzenes, [10] and benzo[c]coumarins [11] upon treatment with 1,2-and 1,3-dinucleophiles such as hydrazines, hydroxylamine, ethyl mercaptoacetate, amidines, methyl ketimines, and ethyl cyanoacetate, respectively. The last domino reaction involves ethyl cyanoacetate, which behaves as a synthetic equivalent of 1,3-dicyanoacetone with two nucleophilic centers.…”

“…1 H NMR (400 MHz, CDCl 3 ): δ = 1.12 (t, J = 7.3 Hz,9 H, 3ϫ Me), 2.84 (q, ) ppm.19 F NMR (376 MHz, CDCl 3 ): δ = 103.4 (s, CF 3 ) ppm. 127-128°C (dec.), yellow powder.…”

A Novel and Simple Synthesis of Substituted Anilines by Reaction of 2-Polyfluoroalkylchromones with (Isopropylidene)isopropylamine

“…We recently reported 1,2 that aromatic methyl ketimines, capable of reacting with electrophilic substrates as 1,3-C,N-dinucleophiles through their enamine tautomeric form, underwent conjugate addition to 2-polyfluoroalkylchromones 1. This reaction can be followed by the pyrone ring opening and intramolecular cyclization at the keto group to give 2,6-diaryl-4-(polyfluoroalkyl)pyridines in moderate yields.…”