الفهرس 
Synthesis of 2-aminochromone-3-carboxaldehydesOnly 14 pages are availabe for public view
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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.