Ring Transformation of Chromone-3-Carboxamide under Nucleophilic Conditions

A reatividade química de cromona-3-carboxamida foi estudada para uma série nucleófilos de carbono e de nitrogênio. O tratamento da carboxamida com algumas aminas primárias forneceu cromona-2,4-dionas. A condensação da carboxamida com hidrato de hidrazina, fenilihidrazina e hidrocloridrato de hidroxilamina forneceu cromenopirazóis e cromeno isoxazol, respectivamente. A reação da carboxamida com cloridrato de guanidina, cianoguanidina e tioureia resultou na transformação do anel, produzindo cromenopiridinas. O comportamento químico da carboxamida também foi estudado para etilenodiamina, o-fenilenodiamina, 2-aminofenol e 2-aminotiophenol. Uma variedade de produtos foi isolada a partir da reação de carboxamidas com alguns nucleófilos de carbono.


Introduction
3-Substituted chromones are very active substrates toward nucleophilic reagents, due to the availability of different electron deficient centers.The diversity of properties of these compounds is due to the fact that they are highly reactive geminally activated push-pull alkenes (α,β-unsaturated ketones) with a good leaving group at the β-carbon atom, whose role is played by the phenolate anion.][3][4] Chromone-3-carbonitriles on treatment with carbon nucleophiles produced chromeno [2,3-b]pyridines. 5 variety of products was obtained from reactions of chromone-3-carboxylic acid with nucleophilic reagents. 6urthermore, the heating of chromone-3-carboxylate with concentrated ammonium hydroxide leads to 3-formimidoyl-4-hydroxycoumarin. 7Primary and secondary amines reacted with 3-bromochromone to yield ring contraction products and 3-aminochromones. 8,9The work on the chemistry of chromone-3-carboxamide is rare, 10 thus as an extension of the work directed to study the chemical behavior of 3-substituted chromones under nucleophilic conditions, the present investigation describes the chemical reactivity of chromone-3-carboxamide (1) towards a variety of nucleophilic reagents.

Results and Discussion
Chromone-3-carboxamide has three electron deficient centers, C-2, C-4 as C=O and the amidic carbon at position 3.In continuation to our interest in the chemistry of chromone-3-carboxamide (1), 10 the present work aims to study the chemical reactivity of carboxamide 1 towards a variety of nitrogen and carbon nucleophiles.The treatment of carboxamide 1 with some primary aliphatic and aromatic amines namely; n-propylamine, benzylamine, p-bromoaniline and p-toluidine, in absolute ethanol resulted in ring transformation via γ-pyrone ring opening followed by lactonization with loss of ammonia to afford the corresponding chromane-2,4-diones 2-5 (Scheme 1).Compounds 2-4 were isolated as stereoisomeric mixtures of Z and E isomers, while compound 5 was isolated as a pure isomer (Z isomer).The ratio of Z:E isomers depends on the type of amine used.The Z:E ratios of compounds 2-4 were deduced from studies of their 1 H nuclear magnetic resonance (NMR) spectra.The relatively high deshielding effect on the β-hydrogen which is cis to the cyclic ester function of an α,β-unsaturated ester compared to that of an α,β-unsaturated ketone helped to distinguish the Z and E isomers.Also, the higher d values of NH in Z isomers as compared with that of E isomers help to differentiate between the Z and E isomers.The high d values are attributed to the intramolecular hydrogen bonds in both isomers.The two doublets assigned to the exocyclic CH protons, in E and Z isomers, are usually exchanged to singlets in the presence of D 2 O, with concomitant disappearance of the two signals assigned to the NH protons.On the other hand, the 1 H NMR spectrum of compound 5 showed one exchangeable signal at d 13.45 ppm corresponding to the NH proton.The high d value confirms the Z isomer for compound 5, in addition the spectrum also revealed characteristic singlet at d 2.33 attributed to the methyl protons.Moreover, the 13 C NMR spectrum of compound 5 showed characteristic signals at d 20.6 and 97.9 assigned to methyl carbon and C-3.
On the other hand, carboxamide 1 was allowed to react with some 1,3-binucleophiles.Thus, the condensation of carboxamide 1 with guanidine hydrochloride, cyanoguanidine and thiourea in ethanolic potassium hydroxide solution produced chromeno [4,3-d]pyrimidine derivatives 11-13, respectively (Scheme 4).The infrared (IR) spectra of compounds 11-13 showed characteristic absorption band in the range 1701-1734 cm -1 assigned to the O-C=O functions, the spectrum of compound 12 showed absorption band at 2259 cm -1 attributed to the nitrile function.respectively, which agree with the formula weights and support the structures.
Further, the chemical behavior of carboxamide 1 was studied towards o-phenylenedimine, 2-aminophenol and 2-aminothiophenol.Thus, the condensation of 1 with o-phenylenedimine and o-aminophenol in refluxing DMF afforded the chromane-2,4-dione derivatives 14 and 15, respectively, as Z isomers (Scheme 5).The 1 H NMR spectra of compounds 14 and 15 showed exchangeable doublets assigned to the NH protons at d 13.42 and 13.75 ppm, respectively, in addition to characteristic doublets exchanged to singlets in D 2 O at d 8.74 and 8.94 ppm, respectively, which were assigned to the exocyclic vinyl protons.The higher d values of the exocyclic vinyl protons and NH protons confirm the pure Z isomers for compounds 14 and 15.The structure of compound 14 was further deduced from its mass spectrum which revealed the molecular ion peak at m/z 280, agreeing with the formula weight 280.29.On the other hand, the treatment of carboxamide 1 with o-aminothiophenol in refluxing DMF achieved ring transformation producing benzothiazolylcoumarin derivative 17 via the non-isolable intermediate 16 as shown in Scheme 5.
Ethylenediamine showed different behavior when reacted with carboxamide 1 and produced the bis enaminone derivative 18 via the reaction of ethylenediamine with two equivalents of carboxamide 1 (Scheme 6).The mass spectrum of compound 18 showed the molecular ion peak at m/z 404 which agrees with the formula weight 404.38 and confirms the structure.
Also, the chemical reactivity of carboxamide 1 was studied towards a variety of carbon nucleophiles.Thus, the treatment of carboxamide 1 with malononitrile in ethanol containing few drops of piperidine afforded the pyridine derivative 19 as depicted in Scheme 7. The reaction proceeds via deprotonation of malononitrile followed by nucleophilic attack at C-2 position and γ-pyrone ring opening with concomitant cycloaddition.The IR spectrum In the same manner, the treatment of carboxamide 1 with cyanoacetamide under the same reaction conditions produced the pyridine derivative 20 (Scheme 8).Its 1 H NMR spectrum showed characteristic singlet at d 8.79 ppm due to the H-4 pyridine .
The reaction of carboxamide 1 with acetophenone in ethanolic potassium hydroxide solution gave the corresponding α,β-unsaturated ketone 21 (Scheme 9).The 1 H NMR spectrum of compound 21 showed two doublets at d 8.97 and 9.50 ppm assigned to the olefinic protons.Finally, the condensation of carboxamide 1 with thiobarbituric acid in ethanolic sodium ethoxide afforded pyrimidine derivative 22.Its 1 H NMR spectrum showed characteristic singlet due to the exocyclic vinyl proton at d 8.80 ppm, its mass spectrum showed the molecular ion peak at m/z 316 corresponding to the molecular formula (C 14 H 8 N 2 O 5 S) and confirms the structure.

Conclusion
In conclusion, chromone-3-carboxamide has three electron deficient centers, C-2, C-4 and the amidic carbon at position 3.The nucleophilic reagent usually attack at the C-2 position with γ-pyrone ring opening followed by further transformation during the course of the reaction producing a variety of products depending on the nucleophile used.

General
Melting points are uncorrected and were determined on a digital Stuart SMP3 apparatus.Infrared spectra were measured on FTIR Nicolet IS10 spectrophotometer (cm -1 ), using KBr disks. 1 H NMR spectra were measured on Gemini (200 MHz) and Mercury-300BB (300 MHz) spectrometers using DMSO-d 6 as a solvent and TMS (tetramethylsilane, d) as the internal standard.Mass spectra were obtained using GCMS qp 1000 ex Shimadzu instrument (70 eV).Elemental microanalyses were performed on a Perkin-Elmer CHN-2400 analyzer at the Chemical War Department, Ministry of Defense, Cairo, Egypt.General procedure for the reaction of chromone 3-carboxamide (1) with aliphatic and aromatic amines A mixture of carboxamide 1 (0.57 g, 3 mmol) and n-propylamine, benzylamine, p-bromoaniline and p-toluidine (3 mmol), in absolute ethanol (15 mL), was heated under reflux for 1 h.The crystalline products obtained after cooling were filtered off and recrystallized from ethanol to give compounds 2-5, respectively.A mixture of carboxamide 1 (0.57 g, 3 mmol) and hydrazine hydrate (0.15 mL, 3 mmol), in absolute ethanol (15 mL), was heated under reflux for 2 h.The white crystals obtained after cooling were filtered off and recrystallized from ethanol to give compound 6 as white crystals; mp 225-226 ºC (mp 226-227 ºC); 6 yield (0.31 g, 56%).
General procedure for the reaction of chromone-3 -c a r b ox a m i d e ( 1 ) g u a n i d i n e hy d r o c h l o r i d e , cyanoguanidine and thiourea