Ring transformation of chromone-3-carboxylic acid under nucleophilic conditions

The effect of sodium hydroxide solution on chromone-3-carboxylic acid ( 1 ) afforded ω -formyl- 2-hydroxyacetophenone ( 2 ) and 1-(3-chromonyl)-2-(2-hydroxybenzoyl)ethene ( 3 ). The reactivity of carboxylic acid 1 towards primary and secondary amines, hydrazines, cyanoacetohydrazide, cyanoacetamide and malononitrile in different media led to interestingly ring transformation via γ -pyrone and carboxylic group. Structures of the products have been established on the basis of elemental analysis and spectral data.


Results and Discussion
The effect of one molar aqueous sodium hydroxide solution on 2-methylchromone-3-carboxylic acid was studied previously by Klutchko 9 where no reaction or rearrangement took place at 20 ºC but on warming degradation of chromone ring was observed and salicylic acid was obtained.Herein, chromone-3-carboxylic acid (1) in the presence of sodium hydroxide solution undergoes different reactions depending on the concentration of sodium hydroxide and reaction conditions.Thus, treatment of 1 with 0.025 M sodium hydroxide solution in refluxing ethanol afforded ωformyl-2-hydroxyacetophenone (2), while when the reaction carried out using 0.05 M aqueous sodium hydroxide solution at 70 ºC, 1-(3-chromonyl)-2-(2-hydroxybenzoyl)ethene (3) was obtained (Scheme 1).Compounds 2 and 3 were found to be identical with an authentic samples prepared according to Schönberg 14 and Prakash, 15 respectively.This rearrangement was explained through opening of the pyrone ring by sodium hydroxide solution followed by decarboxylation producing ω-formyl-2-hydroxyacetophenone (2) which underwent self condensation 16 in aqueous sodium hydroxide solution to produce the dimeric product 3 (Scheme 1).Both compounds 2 and 3 gave red color with ferric chloride solution.The IR spectra showed characteristic absorption bands at 3421 (OH) and 3449 (OH) cm -1 for compounds 2 and 3, respectively. 1H NMR spectrum of compound 3 displayed characteristic signals at 9.05 (H-2 of chromone ring) and 12.35 (OH proton exchangeable with D 2 O) ppm.Also, for the olefinic protons only the down field doublet is visible; β to the carbonyl group, while the signal of the other one is overlapped by the complex multiplet of the signals of the 1,2-disubstituted rings in the range 6.99-8.20 ppm.The mass spectrum of compound 3 exhibited the molecular ion peak at m/z 292 (22 %) and its base peak at m/z 171.
It is well known that the pyrone ring in chromone 18 can be easily opened under the influence of primary and secondary amines with the formation of enaminones with a 2-hydroxyphenyl substituent at the carbonyl group.Surprisingly, the same products were obtained when chromone-3-carboxylic acid (1) was allowed to react with primary and secondary amines in ethanol, where the enaminones 5a-h were obtained (Scheme 2).The melting points of these products are sharply identical with those obtained previously by Krzysztof. 18 withdrawing carboxylic group in 2-unsubstituted-chromone-3-carboxylic acid (1) enhances the electrophilicity of C-2 atom of the pyrone ring.Thus, the suggested route for the formation of enaminones 5a-h involves nucleophilic attack of primary or secondary amino group at C-2 of compound 1 with concomitant opening of the pyrone ring followed by decarboxylation (Scheme 2).Structures of compounds 5a-h were also confirmed by cyclization with 50 % HCl, where unsubstituted chromone (6) was obtained with mp 59 ºC (lit. 1459 ºC).No reactions took place when tertiary amines were allowed to react with compound 1.According to these results, chromone-3-carboxylic acid (1) can be used for identification of primary and secondary amines as ω-formyl-2-hydroxyacetophenone and unsubstituted chromone. 18On the other hand, when carboxylic acid 1 was allowed to react with primary amines such as aniline and n-propylamine in glacial acetic acid, 3-(phenyl/n-propyl)aminomethylenechroman-2,4-dione (7a,b) were isolated as stereoisomeric (Z and E) mixtures (Scheme 2).The Z:E ratio of compound 7a was found to be 3:4, respectively.The Z:E ratio was determined from studies of the 1 H NMR spectrum.The relatively higher deshielding effect on the β-H which is cis to the cyclic ester (lactone) function of an α,β-unsaturated ester compared to that of an α,β-unsaturated ketone helps to distinguish the Z and E isomers.The 1 H NMR spectrum of compound 7a revealed the presence of two doublets at 13.47 and 11.83 ppm assigned to NH protons in both Z and E isomers, respectively.The high δ values are attributed to the intramolecular hydrogen bond in both isomers.Also, the spectrum exhibited two doublets at 8.92 and 8.89 ppm for the exocyclic =CH protons in E and Z isomers, respectively.The two doublets at 13.47 and 11.85 ppm were disappeared by shaking with D 2 O with concomitant collapsing of the two doublets at 8.92 and 8.89 ppm to singlets.The melting point of compound 7a was found to be identical with the earlier reported. 19,20In a similar manner, compound 7b exists in a stereoisomeric (Z and E) mixture in 2:3 ratio, respectively, (c.f.experimental).The reaction may be proceeds through ring opening followed by ring closure (RORC) between the phenolic hydroxyl and carboxylic acid functions without decarboxylation (Scheme 2).The above results confirm the loss of CO 2 molecule after opening of pyrone ring in ethanol but no decarboxylation occurred in acetic acid medium.Reaction of chromone-3-carboxylic acid (1) with cyanoacetohydrazide was studied in different media.Therefore, reaction of 1 with cyanoacetohydrazide in ethanol and acetic acid gave compounds 12 and 13, respectively.When the later reaction takes place in sodium ethoxide compound 14 was isolated, while the N-amino pyridine derivative 15 was not obtained (Scheme 4).Compounds 12-14 are produced in the course of the ring transformation because cyanoacetohydrazide thereby acts as an ambient nucleophile, that is, as both Nand Cnucleophile. 21 1H NMR measurements showed a stereoisomeric (Z and E) mixture in 2:3 ratio, respectively, of 2-cyano-N'-[3-(2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)]acetohydrazide (12).Its IR spectrum showed absorption bands at 3275, 3201 and 2262 cm -1 for OH, NH and C≡N groups, respectively.The 1 H NMR studies of chromeno[4,3-c]pyrazol-4(1H)-one (13) showed singlet signal at 9.12 ppm (H-3) and a broad signal exchangeable with D 2 O at 13.23 ppm (NH proton), while its IR spectrum showed characteristic absorption bands at 3217 and 1735 cm -1 for NH and (OC=O) groups, respectively.The C≡N group was disappeared in the spectrum due to loss of one molecule of cyanoacetic acid as seen in Scheme 4. 21 The 1 H NMR spectrum of 7hydroxy-3-(2-hydroxyphenyl)-1H-1,2-diazepine-6-carbonitrile ( 14) revealed three different broad signals exchangeable with D 2 O at 12.35, 12.95 and 13.34 ppm corresponding to one NH and two OH protons, while its IR spectrum showed a broad absorption band at 3243 cm -1 for NH and OH groups.Refluxing compound 12 in dimethylformamide afforded the well known 3-(2hydroxyphenyl)-1H-pyrazole (16). 22Compounds 13 and 16 were obtained authentically from the reaction of carboxylic acid 1 with hydrazine hydrate in acetic acid and ethanol, respectively (Scheme 4).Reaction of chromone-3-carboxylic acid (1) with some carbon nucleophiles was studied.Therefore, treatment of 1 with cyanoacetamide in ethanol containing few drops of triethylamine as catalyst afforded 6-(2-hydroxyphenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (17) (Scheme 5).The IR spectrum of compound 17 showed absorption bands at 3375 and 3172 cm -1 assigned to OH and NH groups, respectively.Its 1 H NMR spectrum revealed a broad signal exchangeable with D 2 O at 11.94 ppm for the NH and OH protons.On the other hand, reaction of 1 with malononitrile in ethanol containing few drops of triethylamine as catalyst afforded (4E)-2-amino-3-cyanobenzo[b]oxocin-6-one (18).The latter compound was obtained authentically from condensation reaction of compound 2 with malononitrile under the same conditions (Scheme 5).The other possible product 19 was excluded on the basis of the spectral data.Compound 18 gave no color with ferric chloride solution.The IR spectrum of compound 18 showed the presence of characteristic bands attributed to the amino group at 3443, 3326, 3212 cm -1 .Its 1 H NMR spectrum exhibited broad signal exchangeable with D 2 O at 8.75 ppm assigned to NH 2 protons, in addition to two doublets at 6.52 and 9.02 ppm with the same coupling constant (J = 12.8 Hz).The latter two signals are attributed to the two hydrogen atoms in the benzoxocin-2-one 18, that are trans as illustrated from their coupling constant (J = 12.8 Hz).The higher down field shift of the δ value of the H β to C=O (H-4 proton) attributed to the higher deshielding of this proton.Triethylamine was used as a catalyst for deprotonation of cyanoacetamide and malononitrile, while piperidine should be avoided because it reacts more rapidly as secondary amine with compound 1 producing compound 5g.

Conclusions
This work reports the chemical reactivity of chromone-3-carboxylic acid towards sodium hydroxide solution and a variety of nitrogen and carbon nucleophiles.The products obtained when the reaction took place in ethanol are similar to those obtained from ω-formyl-2hydroxyacetophenone, indicating loss of carbon dioxide during the course of reaction.

3 Scheme 2 . 1 Scheme 3 .
Scheme 2. Reaction of carboxylic acid 1 with a variety of amines in different media.

Scheme 4 .
Scheme 4. Reaction of carboxylic acid 1 with cyanoacetohydrazide in different media.