الفهرس | Only 14 pages are availabe for public view |
Abstract In the present study, we aimed to synthesize a variety of 3-substituted-6,8-dimethylchromones, and study their chemical transformations towards a diversity of nucleophilic reagents. Vilsmier Haack formylation of 3,5-dimethyl-2-hydroxy- acetophenone using dimethylformamide and phosphoryl chloride, yielded 6,8-dimethylchromone-3-carboxaldehyde (1) as previously reported. Treatment of carboxaldehyde 1 with hydroxylamine hydrochloride in aqueous ethanol produced the corresponding oxime 2, which upon dehydration using acetic anhydride gave 6,8-dimethylchromone-3-carbonitrile (3) (Scheme 1). Herein, treating carboxaldehyde 1 with N-bromosuccinamide (NBS) in carbon tetrachloride under irradiation using 200-W Tungsten lamp followed by quenching with water afforded 6,8-dimethylchromone-3-carboxylic acid (4), via non isolable intermediate A. Quenching the reaction medium in the previous reaction with aqueous ammonia, instead of water, produced 6,8-dimethylchromone-3-carboxamide (5) in moderate yield (Scheme 1). Carboxamide 5 was also synthesized in good yield from acidic hydrolysis of carbonitrile 3 using concentrated sulfuric acid (Scheme 1).Stirring carbonitrile 3 with 2M sodium hydroxide solution at 70 oC for 2 h gave 2-amino-6,8-dimethylchromone-3- carboxaldehyde (6), throughout ring opening following by ring closure (Scheme 1).Scheme1. Synthesis of 3-substituted-6,8-dimethylchromones. Next, condensation reaction of carboxaldehyde 1 with cyanoacetic acid in boiling pyridine furnished E-chromonyl acrylonitrile derivative 7, via condensation followed by decarboxylation under the reaction conditions (Scheme 1). The present research concises on studying the chemical transformations of the previously synthesized 3-substituted-6,8- dimethylchromones towards some nucleophilic reagents under different reaction conditions. Stirring carboxaldehyde 1 with phenylhydrazine, in ethanol, immediately. gave the corresponding hydrazone 8 in good yield (Scheme 2). Repeating the reaction of carboxaldehyde 1 with phenylhydrazine in 1:2 molar ratio, in ethanol under reflux, afforded pyrazole derivative 9, via the formation of hydrazone 8 followed by nucleophilic attack of another molecule of phenylhydrazine at C-2 position with γ-pyrone ring opening followed by intramolecular heterocyclization with the carbonyl group (Scheme 2).Scheme 2. Reaction of carboxaldehyde 1 with phenylhydrazine.After that, condensation of carboxaldehyde 1 with S-benzyl dithiocarbazate in ethanol under stirring condition afforded the corresponding hydrazone 10 (Scheme 3). Repeating the reaction in the presence of piperidine yielded piperidinylcarbonothioylpyrazole derivative 11, throughout nucleophilic substitution of SCH2Ph group with piperidinyl group (intermediate B) with γ- pyrone ring opening. Similarly, using morpholine, instead of piperidine, in the previous reaction yielded morpholinylcarbonothioylpyrazole derivative 12, via intermediate C (Scheme 3). Compounds 11 and 12 give dark green color with FeCl3 solution, indicating the presence of free phenolic OH groupScheme 3. Reaction of carboxaldehyde 1 with S-benzyl dithiocarbazate Then, stirring a hot solution of carboxaldehyde 1 with ophenylenediamine in ethanol produced orange crystals in high yield, immediately. Inspection the spectral data confirms the formation of addition product 13, throughout addition of amino group into the formyl group (1,2-addition) with addition of water molecule at C2-C3 double bond (1,2-addition) during the reaction (Scheme 4). Repeating the previous reaction under reflux for 2h. furnished the annulated benzochromenodiazepine derivative 14 as pale yellow crystals, via the formation of compound 13 followed by elimination of two molecules of water with subsequent dehydrogenation (Scheme 4). In this reaction, the orange crystals formed immediately was dissolved under reflux, indicating the formation of compound 14 throughout compound 13 (as isolable intermediate).Scheme 4. Reaction of carboxaldehyde 1 with o-phenylenediamine.Treatment of carboxaldehyde 1 with cyanoacetamide in boiling ethanol containing few drops of piperidine produced pyridine-3-carbonitrile derivative 15 in good yield (Scheme 5). Compound 15 gave red color with FeCl3 solution, indicating the presence of phenolic OH group and confirm the γ–pyrone ring opening.Scheme 5. Condensation of carboxaldehyde 1 with cyanoacetamide and malononitrile dimer. Condensation of carboxaldehyde1 with malononitrile dimer, (2-aminoprop-1-ene-1,1,3-tricarbonitrile), was studied in different solvent, the best yield and high purity was obtained in distilled water, producing the simple condensation product 16 (Scheme 5). Compound 16 gave no coloration with FeCl3 solution. On the other hand, when cyclohexane-1,3-dione was reacted with carboxaldehyde 1, in glacial acetic acid, furnished xanthenedione derivative 17, through reaction of two molecules of cyclohexane-1,3-dione with one molecule of aldehyde 1 (intermediate D) followed by cyclocondensation (Scheme 6).Scheme 6. Condensation of carboxaldehyde 1 with1,3- cyclohexanedione. Next, the chemical behavior of 6,8-dimethylchromone-3- carbonitrile (3) was studied towards some nucleophilic reagents under different reaction conditions. The reactivity of carbonitrile 3 was studied towards phenylhydrazine in different solvents namely ethanol, benzene and acetic acid. Thus, reaction of carbonitrile 3 with phenylhydrazine in boiling ethanol yielded aminopyrazole derivative 18, via nucleophilic attack of NH2 group at C-2 position with γ-pyrone ring opening, followed by cycloaddition of the another NH group onto the nitrile function (Scheme 7). Compound 18 gave dark red color with FeCl3 solution, indicating the presence of phenolic OH group. Repeating the reaction between carbonitrile 3 with phenylhydrazine in boiling benzene containing triethylamine (TEA) yielded hydrazone derivative 19. Meanwhile, treating carbonitrile 3 with phenylhydrazine in boiling acetic acid produced chromeno[4,3-c]pyrazole derivative 20 (Scheme 7).Scheme 7. Reaction of carbonitrile 3 with phenylhydrazine. In the same manner, the reactivity of carbonitrile 3 was studied towards S-benzyldithiocarbazate under different reaction conditions. Treatment of carbonitrile 3 with S-benzyldithio carbazate in boiling ethanol furnished pyrazole derivative 21 via intermediates E and F, respectively (Scheme 8). Carrying out the latter reaction in benzene as a non polar solvent containing TEA furnished hydrazone derivative 22 via intermediates E and G. Interestingly, boiling carbonitrile 3 with S-benzyldithiocarbazate in acetic acid afforded chromeno[4,3-c]pyrazol-4(1H)-one derivative 23, which obtained authentically from the reaction of carbonitrile 3 with hydrazine hydrate in boiling acetic acid (Scheme 8).Scheme 8. Reaction of carbonitrile 1 with S-benzyldithiocarbazate. Reaction of carbonitrile 3 with o-phenylenediamine in boiling DMF afforded benzochromenodiazepine derivative 14 (co-identical mp, mmp and spectral data with that prepared from the reaction of aldehyde 1 with the same reagent in boiling ethanol) (Scheme 9). After that, reaction of carbonitrile 3 with cyanoacetamide in boiling ethanol containing few drops of piperidine gave chromeno[2,3-b]pyridine 24 in good yield (Scheme 9).Scheme 9. Reaction of carbonitrile 1 with o-phenylenediamine and cyanoacetamide. Next, the present research aimed to study the chemical transformations of 6,8-dimethylchromone-3-carboxamide (5) towards the some nucleophilic reagents. Therefore, boiling carboxamide 5 with phenylhydrazine in DMF produced chromeno[4,3-c]pyrazole derivative 20, via nucleophilic attack of NH2 group at C-2 position with γ-pyrone ring opening, followed by lactonization and dehydration (Scheme 10). Meanwhile, treating carboxamide 5 with S-benzyldithiocarbazate in DMF under reflux afforded chromenopyrazole derivative 23 (Scheme 10) (co-identical spectral data with that from the reaction of carbonitrile 3 with the same reagent in acetic acid).Scheme 10. Conversion of carboxamide 5 into coumarines 20, 23, 25 and 26. Further, condensation of carboxamide 5 with ophenylenedimine in refluxing DMF afforded the chromane-2,4- dione derivative 25, as Z isomer (Scheme 10).Moreover, 4-hydroxyl-6,8-dimethyl-coumarin-3- carboxaldehyde (26) was efficiently synthesized from heating carboxamide 5 with 2M KOH solution for 10 min. This reaction resulted in conversion of chromone ring into coumarin ring, through ring opening followed by lactonization (Scheme 10). Moreover, treatment of carboxamide 5 with cyanoacetamide in sodium ethoxide under reflux produced the pyridine derivative 27. The reaction proceeds via deprotonation of cyanoacetamide followed by nucleophilic attack at C-2 position and γ-pyrone ring opening with concomitant cycloaddition as depicted in Scheme 11 Scheme 11. Reaction of carboxamide 5 with cyanoacetamide. Herein, the chemical transformation of carboxylic acid 4 and acrylonitrile 7 was concised towards cyanoacetamide. Therefore, treatment of carboxylic acid 4 with cyanoacetamide in ethanol containing few drops of triethylamine as a catalyst afforded 6-(2-hydroxy-3,5-dimethylphenyl)-2-oxo-1,2-dihydropyridine-3- carbonitrile (28) (Scheme 12).Scheme 12. Reaction of carboxylic acid 4 with cyanoacetamide. Finally, treatment of (2E)-3-(6,8-dimethylchromon-3-yl) acrylonitrile (7) with cyanoacetamide in boiling ethanol containing few drops of piperidine afforded 5-(cyanomethyl)-7,9-dimethyl-2- oxo-1,5-dihydro-2H-chromeno[4,3-b]pyridine-3-carbonitrile (29) as described in Scheme13.Scheme 13. Reaction of acrylonitrile 7 with cyanoacetamide. In Conclusion, a variety of 3-substituted 6,8- dimethylchromones were efficiently synthesized and found as a good precursors for the synthesis of different heterocyclic systems. 3-Substituted 6,8-dimethylchromones possess three electron deficient centers, C-2, C-4, and carbon atom of the functional group present at position 3. In all reactions of 3-substituted 6,8- dimethylchromones (except 3-formyl-6,8-dimethylchromone), with nucleophilic reagent, it was found that the nucleophile usually attack the chromone ring at C-2 position followed by different types of heterocyclization depending on the functional group present at C-3 position. In case of 3-formyl-6,8-dimethylchromone, the nucleophiles reacted with the aldehyde function with subsequent γ-pyrone ring opening leading to a diversity of nitrogen heterocyclic systems. Structures of the newly synthesized products have been deduced upon the help of elemental analyses and spectral data (IR, 1H NMR and mass spectra). The antimicrobial activity of the new products have been evaluated against the sensitive organisms Staphylococcus aureus (ATCC 25923) and Bacillus subtilis (ATCC 6635) as Gram positive bacteria, Escherichia coli (ATCC 25922) and Salmonella typhimurium (ATCC 14028) as Gram negative bacteria and Candida albicans as the fungus strain. |