Effect of Microwave Irradiation on the Condensation of 6-Substituted 3-Formylchromones with Some Five-membered Heterocyclic Compounds

Central Laboratories, Faculty of Chemical Technology, Slovak University of Technology, SK-812 37Bratislava, Slovak RepublicReceived: 14 November 1999 / Accepted: 31 December 1999 / Published: 19 February 2000Abstract: Different types of 3-substituted 4H-4-oxobenzopyrans were prepared by micro-wave irradiation as well as by a classical method. The beneficial effect of microwave irra-diation on the aldol condensation of 3-formylchromones with 2-imino-1-methyl-imidazolidine-4-one (creatinine), 2-thioxoimidazolidine-4-one (thiohydantoin) and 2-ethyl-2-thioxothiazolidin-4-one (3-ethylrhodanine) in different reaction media is described. Ourresults show that the effect of microwave irradiation on the reactions studied was a shorten-ing of the reaction times and a smooth increase in the yields. The subsequent reactions ofthe product with some nucleophiles are discussed. The structure of the products was provenby elemental analysis, IR and NMR spectra.Keywords: Creatinine, thiohydantoin, rhodanine, carbamoic acids, guanidine derivatives,Diels - Alder reaction, IR,


Introduction
This study is a continuation of our earlier publications [1][2][3][4][5][6][7], in which we described the theoretical, spectral and biological properties of newly synthesized chromone and chromanone derivatives.The aim of this work was the preparation of some new five-membered nitrogen heterocyclic derivatives of chromone as potentially useful intermediates for synthesis.
3-Formylchromones 1 were chosen as being synthetically versatile molecules with a reactive carbonyl group.They have considerable significance for their biological activities [8][9][10] and for their reactivity towards nucleophiles which allows the synthesis of a wide variety of heterocycles.A study of the influence of microwave irradiation on the condensation reactions was the next goal of this paper.Five-membered ring heterocycles 2-4 are known as precursors of α-amino acids and they can be condensed easily with aldehydes.It is known that condensations of creatinine with aldehydes [11,12] as well as the Gränacher synthesis [13] with rhodanine under classical conditions take several hours at high temperatures (160-180°C).
As we have shown before [14], microwave irradiation is a suitable method for shortening the duration of condensation reactions.Condensations of creatinine [15] and thiohydantoin [16] with aromatic aldehydes without a solvent under microwave irradiation and giving good yields of products were described by Villemin and al.The starting 3-formylchromones used in this work are accessible via Vilsmeier-double formylation of appropriate o-hydroxyacetophenones [17].Commercially available nitrogen heterocycles were used for the reactions.The reactions are outlined in Schemes 1 and 2. Details of the experimental results are listed in Table 1.
All condensation products are stable solid compounds, rather insoluble in common solvents, with high melting points.Because of their poor solubility in DMSO we had to measure their 1 H NMR spectra at elevated temperatures (Table 2).The resonance signals and their multiplicity confirmed the pro-posed structures.The infrared spectra of the prepared compounds 5-9 showed strong absorption bands of the C=O stretching vibrations in two very well distinguished regions 1645 -1668 cm -1 and 1688 -1745 cm -1 (Table 3).The absorption bands in the lower region of the spectra belong to the ν(C=O) of the γ-pyrone ring.The higher region was attributed to the azole heterocyclic part of the prepared compounds.Compounds 10 lacked the ν(C=O) band at 1640 -1660 cm -1 .Strong bands around 1740 cm -1 confirmed the presence of unsaturated aldehyde groups (Table 4).

General
Products were characterized by elemental analyses (Table 1), NMR spectra (Table 2) and IR spectra (Tables 3-4).The melting points were determined on a Kofler block and are uncorrected.Infrared spectra of nujol suspensions were recorded in 400 -4000 cm -1 region on a Specord IR 75 spectrometer (Zeiss Jena). 1 H and 13 C NMR spectra were measured on a 300 MHz spectrometer VARIAN GEMINI 200 in deuterated DMSO at 50-80 O C. All microwave assisted reactions were carried out in a Lavis -1000 multi Quant microwave oven.The apparatus was adapted for laboratory applications with magnetic stirring and an external reflux condenser.

Synthesis of 5a-5f , 8a-8e and 9a, 9b
Method A A mixture of 6-R-3-formylchromones 1a-1f (2.87 mmol), creatinine 2 (or thiohydantoin 3 or 3ethylrhodanine 4) ( 2.87 mmol) in dry acetic anhydride (2 cm 3 ) in the presence of freshly fused potassium acetate was stirred and irradiated in a microwave oven for the time given in Table 1.The solid was filtered off.The products were recrystallized from dioxane or toluene.

Method B
A mixture of the same composition as in method A was heated at 110-120°C for the time given in Table 1.Isolation of products was accomplished as described in method A.

Synthesis of 6a-6e
Method A A mixture of 6-R-3-formylchromone 1 (2.87 mmol), creatinine 2 (2.87 mmol), a catalytic amount of H 3 BO 3 (20 mg) in 1cm 3 of dry dimethyl sulfoxide was stirred and irradiated at 270 W in a microwave oven.The solid product was filtered off and recrystallized from dioxane or toluene.

Method B
A mixture of the same composition as in method A was heated in 1cm 3 of dry dimethyl sulfoxide at 120°C over 3 h.The solid product was filtered off and recrystallized from dioxane.

Synthesis of 7a, 7b
Method A Creatinine 2 (2.87 mmol) was dissolved in 1 cm 3 of dry dimethylformamide and then ethyl chloroformate was added to the solution.The mixture was stirred and irradiated in a microwave oven at 270 W. The solid product was filtered off and recrystallized from dioxane or toluene.

Method B
The mixture of creatinine 2 ( 2.87 mmol) and ethyl chloroformate ( 3.0 mmol ) in dry dimethylformamide ( 1 cm 3 ) was stirred at room temperature for 3h and then 6-R-3-formylchromone 1 ( 2.87 mmol) was added to the mixture and heated at 90°C for 6 h.The isolation of products was the same as described above.

Acid hydrolysis of compounds 5a, 5e and 5f
The solution of 0.3 g (1 mmol) creatinine derivative 5a (or 5e, 5f) in 10 ml of concentrated hydrochloride acid was heated at 90-100 o C for 4 h.After cooling the resulting white crystals were filtered off, washed with cold water and recrystallized from dioxane.Thus prepared were compounds 10a, 10e and 10f 13

Diels -Alder reaction of compound 5b with maleic anhydride (11)
The mixture of 1g (2.51 mmol) of compound 5b and 0.52 g (5.02 mmol) of maleic anhydride in toluene (30 cm 3 ) was heated at 40 o C for 15 h.The solid adduct after cooling was filtered off, washed with 10 cm 3 of toluene and dried.The product was suspended in 30 cm 3 water was then stirred at 40 o C for 3 h.The solid acid was removed by suction and recrystallized from ethanol.Yield 64%.The upper yield and reaction time (t r ) data are given for the condensation in microwave oven, the lower data for the classic condensation.

Table 1 .
Characterization of the prepared compounds. a

Table 2 .
1H NMR spectra data of prepared compounds.

Table 4 .
IR spectral data of synthesized compounds 10 and 11.