An Efficient Synthesis of 1-Alkyl-2-phenyl-4-quinolones from 2-Halobenzoic Acids

Yoon Ju Song, Jin Sun Choi, Jae In Lee
2013 Bulletin of the Korean Chemical Society (Print)  
1-Methyl-2-phenyl-4-quinolones are naturally occurring alkaloids isolated from the leaves and stems of the plant family Rutaceae. 1 They have drawn considerable interest because of their potent pharmacological activities that include antifungal 1a and antitumor activity, 2 inhibition of acetylcholinesterase (AChE), 3 and antimutagenic effect. 4 Several methods have been developed to synthesize 1alkyl-2-phenyl-4-quinolones from 2'-substituted acetophenones, anilines, and 2-halobenzoyl chlorides
more » ... s starting materials. 5 The reaction of N-methylisatoic anhydride with the lithium enolate of an 4'-methoxyacetophenone afforded the 1-methyl-2-phenyl-4-quinolone in a short sequence, but the yield was low. 6 N-(2-Acetylphenyl)benzamides, prepared by Friedel-Crafts acylation of N-phenyl benzamides with acetyl chloride 7 or benzoylation of 2'-aminoacetophenones with benzoyl chlorides, 8 were cyclized with potassium tbutoxide to yield 2-aryl-4-quinolones, which were further alkylated with alkyl iodides to give 1-alkyl-2-aryl-4-quinolones. However, acylation was accompanied by formation of the regioisomer and alkylation yielded a mixture of Nalkylquinolones as the main products together with 4alkoxyquinolines as minor products. On the other hand, Nmethylated (2-acetylphenyl)benzamides, prepared from 2'-(N-methylamino)acetophenones and benzoyl chlorides, could be cyclized with sodium hydride in DMF to afford the 1-methyl-2-phenyl-4-quinolones in moderate yields. 9 2'-(N-Alkylamino)chalcones, prepared by aldol condensation of 2'-aminoacetophenones and benzaldehydes followed by N-alkylation with alkyl halides, upon treatment with polystyrene-supported selenenyl bromide in the presence of ZnCl 2 afforded 2,3-dihydro-3-polystyrene-supported selenenyl-4-quinolones. These compounds were subsequently oxidized with H 2 O 2 and eliminated to give 1-alkyl-2-phenyl-4-quinolones. 10 Palladium-catalyzed carbonylative coupling of 2-iodo-N-ethylaniline with phenylacetylene occurred smoothly to give a mixture of the corresponding enamine and the desired cyclic quinolone. Further cyclization of the enamine intermediate with sodium hydride in refluxing THF led to 1-ethyl-2-phenyl-4-quinolone. 11 Palladium-catalyzed tandem amination of 2-bromoalkynones, obtained by Sonogashira cross-coupling of arylacetylenes and 2-bromobenzoyl chlorides, with arylamines in refluxing dioxane was effective for the synthesis of 1-aryl-2-phenyl-4-quinolones. 12 Similarly, treatment of 2-halophenyl alkynones with aryl-amines afforded the corresponding 3-(N-arylamino) α,βunsaturated ketones by conjugate addition. These compounds were then cyclized with K 2 CO 3 in refluxing DMF for 52 h 13 or K 2 CO 3 /CuI and DMEDA as a ligand in DMSO 14 to give 1-phenyl-2-aryl-4-quinolones, but the scope of the synthesis of 1-alkyl-2-phenyl-4-quinolones was not fully investigated. Although several methods to synthesize 1-alkyl-2-phenyl-4-quinolones have been reported, they often suffer from harsh reaction conditions, multiple steps, and low yields. As part of an extension of our studies on azaflavonoids as potential drug candidates, 15 we report that novel 1-alkyl-2phenyl-4-quinolones can be efficiently synthesized in high overall yields from 2-halobenzoic acids under relatively mild conditions. 2-Halobenzoyl chlorides (2) were efficiently prepared by treating 2-halobenzoic acids (1) with oxalyl chloride in the presence of pyridine in dichloromethane between 0 o C and 25 o C (Scheme 1). After stirring overnight, dichloromethane was evaporated, the residue was dissolved in anhydrous THF, and pyridinium hydrochloride was removed by filtration. The condensed residue was purified by vacuum distillation to give 2 (R 1 =H, R 2 =H, X=Br; 87%, R 1 =Cl, R 2 =H, X=Br; 97%, R 1 =Me, R 2 =H, X=Br; 93%, R 1 =OMe, R 2 =H, X=F; 75%, R 1 =H, R 2 =OMe, X=F; 91%). Novel 4,6-pyrimidyl di(2-halobenzoates) (3) were prepared by acylation of 2 equiv of 2 with 4,6-dihydroxypyrimidine in the presence of 2 equiv of triethylamine in dichloromethane at 25 o C according to our previous similar method. 16 After evaporating dichloromethane, the mixture was dissolved in anhydrous THF, and triethylamine hydrochloride was removed by filtration. The condensed residue was purified by short-pathway silica gel (Davisil ® , pH = 7) column chromatography or recrystallization from 75% EtOAc/n-hexane to give 3 (R 1 =H, R 2 =H, X=Br; 87%, R 1 =Cl, R 2 =H, X=Br; 85%, R 1 =Me, R 2 =H, X=Br; 94%, R 1 =OMe, R 2 =H, X=F; 87%, R 1 =H, R 2 =OMe, X=F; 93%). Successful synthesis of 1-(2-halophenyl)-3-(hetero)aryl-2propyn-1-ones (5) was accomplished by reacting 1 equiv of 3 with 2 equiv of (hetero)arylethynylmagnesium bromide. The addition of 2 equiv of (hetero)arylethynylmagnesium bromide, generated from (hetero)arylacetylene and EtMgBr in THF for 0.5 h at 0 o C, to a solution of 1 equiv of 3 in THF at 0 o C led to the formation of a precipitate. The intermediate was hydrolyzed with saturated NH 4 Cl solution to give 5
doi:10.5012/bkcs.2013.34.10.3117 fatcat:swtuku5jbjbtxpfnzdsodx4d4m