Synthesis and Reactions of New 4-Oxo-4H-benzopyran-3-carboxaldehydes Containing Hydroxy Groups or 2-Oxopyran Cycles

The synthesis of eight hydroxy- and 2-oxopyranochromone-3-carboxaldehydes 3, 5 and their reactions with 2-hydroxyaniline, 2,4-dinitrophenylhydrazine and 2-benzothiazolylhydrazine were investigated. Products were confirmed by IR, NMR spectral and elemental analysis data. The semi-empirical AM1 quantum-chemical method has been used to study optimal geometries and heats of formation of synthesized 3-formylchromones.


Introduction
This work was done in connection with our study of synthetic, theoretical, spectral [1 -5] and biological [6,7] properties of 3-formylchromone derivatives.In the course of biological investigation of 3-formylchromone derivatives we found a hereditary bleaching effect on the plastid system of Euglena gracilis [7] and antimycobacterial activity similar to effect of isonicotin acid hydrazide (INH) [5,7].Due to their biological activity are chromone derivatives are a subject of considerable pharmaceutical and chemical interest.The natural chromones of the abundant flavonoid family contain prevailingly one or several hydroxyl groups which can be free or protected.3-Formylchromones are also attractive syntons for preparative organic chemistry due to a behaviour similar to α,β-unsaturated aldehydes [8,9].Therefore our attention was aimed at the investigation of favourable conditions for the preparation of two biologically interesting groups of aldehydes e.g.3formylchromones containing the condensed 2-oxopyran ring 5a -5e and difficultly accessible aldehydes with nonprotected hydroxy groups at the benzene ring 3a -3c.

Results and Discussion
In the first part of the work the preparation of 7hydroxy-, 6-n-hexyl-7-hydroxy-and 7, 8-dihydroxy-3formylchromones 3a -3e was studied.It has been found that their preparation using the Vilsmeier-Haack formylation of appropriate o-hydroxyacetphenones afforded very low yields (20 -30 %).Our efforts to prepare 5,7-dihydroxy-3-formylchromones by direct formylation of 2, 4, 6-trihydroxyacetphenone 1d were unsuccesfull.The reaction resulted in polymeric products in all experiments.It can be assumed that the hydroxy groups of compounds 1a -1d caused the lowering of the acetyl group acidity and preferably enables the formylation of the benzene ring and polycondensation of intermediates.The new 2, 4-dihydroxy-5-hexylacetophenone 1c was prepared by acetylation in acetic acid and ZnCl 2 at reflux in 56% yield.
In the second part of this work we developed the method of synthesis of a 3-formyl-chromone having a condensed 2-oxopyrane ring.The synthetic strategy of 3formylchromones 5a -5e had to be based on building up the 2-benzopyrone skeleton.The key -step in this synthesis was the preparation of a suitable acetyl derivative 4a -4d, from which the requested 3-formylchromones were obtained by Vilsmeier-Haack double formylation in 80 -90 % yields.The synthesis of 5a -5e is shown in Scheme 2.
The Vilsmeier-Haack formylation was used to afford two different aldehydes 5d and 5d 1 from 2-oxo-2H-6acetyl-5,7-dihydroxy-4-methylbenzopyran 4d.However, only one product was isolated from the reaction mixture.The 1 H NMR spectra confirmed the structure of 5d.The signal of the proton of the hydroxy group was a singlet and a coupled constant 4 J for a hydroxy group was absent.8-Acetyl-7-hydroxy-4-methylcoumarin 4a was prepared from 1,3-dihydroxybenzene in three reaction steps, namely by the Pechmann reaction, acetylation, and then by Fries rearrangement.All three reaction steps proceeded in high yields (84 -90 %).After recrystallisation of the Fries rearrangement product another isomer 4b (6 %) was isolated from the mother liquor.The product 4b (6-acetyl-7-hydroxycoumarin) was obtained directly as the main product from 2, 4dihydroxyacetophenone 1a by the Pechmann reaction in the presence of POCl 3 .
6-Acetyl-5-hydroxy-4-methyl coumarin 4c was also prepared from compound 1a by Pechmann reaction in the presence of AlCl 3 .2, 4, 6-Trihydroxyacetophenone 1d yielded a mixture of both isomers 4d and 4e by Pechmann reaction in a ratio 1 : 1.The pure products 4d were isolated by recrystallization from ethanol.Product 4e was soluble and was isolated after evaporation of the mother liquor.The preparation of compounds 5d and 5e from the parent phenol involved three steps.Two steps of the synthesis yielded about 80 -90 % of products.Only the second step, the product of the Pechmann reaction gave 40 -50 % yield.The elemental analysis data of the prepared compounds is listed in Table 1.
The assumed structures of the aldehydes 3, 5 and the compounds 4 were proved by infrared and 1 H NMR spectra.The infrared spectra of 3-formylchromones 3 showed two strong absorption bands of the C=O stretching vibrations belonging to the carbonyl group of γ-pyrone at 1620 cm -1 and to the aldehyde carbonyl group at 1695 cm -1 .
The C=O stretching vibrations of the carbonyl groups of 5 exhibited strong absorption bands in three very well distinguished regions: 1655 -1637 cm -1 , 1704 -1694 cm -1 and 1760 -1724 cm -1 belonging to the ν(C=O) of the γpyrone ring, the aldehyde groups and the α-pyrone ring, respectively (Table 2).
The structure of the prepared compounds was also confirmed by 1 H NMR spectra.The resonance signals and their multiplicity are given in Table 3.In this table also included are the chemical shifts for the acetyl derivatives 4a -4c, because these compounds were previously reported without 1 H NMR spectral data.The condensation reactions of the aldehydes 3a -3c and 5a -5e were carried out with 2-hydroxyaniline, 2,4dinitrophenylhydrazine, 2-benzothiazolylhydrazine and ethyl acetoacetate.2,4-Dinitrophenylhydrazones and 2benzothiazolylhydrazones 7a -7k were formed by refluxing the starting mixture in ethanol.The products appeared as coloured and slightly soluble compounds decomposing near their melting points.The reaction of 2hydroxyaniline with 3-formylchromones gives chromanones 8 or 9 using different reaction media (Scheme 3).In ethanol the adducts 8 were obtained, in diethylether the compounds 9 were formed with two molecules of 2-hydroxyaniline.The aldol condensation product 6 was obtained by heating the aldehyde 3a, and ethyl acetatoacetate with CH 3 COOK as catalyst.
The starting compounds 1, and 3-formylchromone derivatives 3a -3c, 5a -5e were studied by the semiempirical quantum chemical AM1 method [10].The full optimisation of the geometry of every structural parameter for several conformers was performed.Heats of formation were calculated for all s-cis and s-trans conformations.The s-cis conformations appeared to be energetically more favourable then the s-trans ones.The difference in the heats of formation is about 20 kJ mol -1 for acetophenones 1 and 22 -26 kJ mol -1 for 3-formylchromones 3, 5 .In accordance with the 1 H NMR spectra, the results of theoretical calculation of both isomers of aldehydes 5d and 5d 1 (Scheme 2) shows that the isomer 5d is about 4.5 kJ/mol more stable than the isomer 5d 1 .

General details
The synthesized compounds were characterized by melting points, elemental analysis, IR and 1 H NMR spectra.
The melting points were determined on a Boetius apparatus and are uncorrected.The IR spectra were taken on a Specord M-80 (Zeiss) spectrophotometer in a nujol suspension.
The NMR spectra were measured on a Tesla BS 487 (80 MHz) and Bruker AM 300 (300.13MHz) spectrometers in deuterated DMSO and CHCl 3 .

3-Formylchromones 3, 5. General procedure
To the dry dimethylformamide (121 ml) in a three necked flask, POCl 3 (0.49mol) was added slowly with intensive stirring at 50 o C. Heating and stirring was continued for 2 hrs at 45 -55 o C. The solution of 2hydroxyacetophenone (0.12 mol) in DMF (25 ml) was then slowly added under stirring at 50 o C. The stirring was continued for 2 hrs at 55 -60 o C.After cooling the mixture was kept over night at room temperature and diluted slowly by adding crushed ice (500 g) and stirred again for 6 hrs.The crystals were filtered off and recrystallized from alcohol.Yields of compounds 3 are 20 -30 %, of 5 are 80 -90 %

Table 1 .
Elemental analysis data of prepared compounds.__________________________________________________________________________________
a For numbering of carbon atoms see Scheme 2.O CHO O 3 1