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

Margita Lacova
Renata Gasparova
Dusan Loos
Tibor Liptay
2 and
Nada Pronayova
Department of Organic Chemistry, Faculty of Natural Sciences, Comenius University, Mlynska dolina CH-2, SK-842 15 Bratislava, Slovak Republic
Central Laboratories, Faculty of Chemical Technology, Slovak University of Technology, SK-812 37 Bratislava, Slovak Republic
Authors to whom correspondence should be addressed.
Molecules 2000, 5(2), 167-178;
Submission received: 14 October 1999 / Published: 19 February 2000


Different types of 3-substituted 4H-4-oxobenzopyrans were prepared by microwave irradiation as well as by a classical method. The beneficial effect of microwave irradiation 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. Our results show that the effect of microwave irradiation on the reactions studied was a shortening of the reaction times and a smooth increase in the yields. The subsequent reactions of the product with some nucleophiles are discussed. The structure of the products was proven by elemental analysis, IR and NMR spectra.


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 Scheme 1 and Scheme 2. Details of the experimental results are listed in Table 1.

Results and Discussion

2-Acetamido-1-methyl-5-[(6-R-4-oxo-4H-benzopyran-3-yl)methylidene]-4,5-dihydroimidazol-4-ones 5a-5f were obtained by condensations of 1a-1f with creatinine 2 in acetic anhydride, both under microwave irradiation (A) and classical (B) conditions. Although the yields by both methods were almost the same (46-84%), the reactions in a microwave oven were considerably faster (Table 1). Imino derivatives 6a-6e (2-imino-1-methyl-5-[(6-R-4-oxo-4H-[1]-benzopyran-3-yl) methylidene]- imidazoli-din-4-ones) were obtained using dimethylsulfoxide as a solvent and boric acid as a catalyst by both methods A and B.
A convenient synthesis of carbamoic acid derivatives 7 (1-methyl-4-oxo-5-[(6-R-4-oxo-4H-[1]-benzopyran-3-yl)methylidene]-4,5-dihydroimidazol-2-carbamoic acids) was accomplished by reaction of creatinine with ethylchloroformate in N,N-dimethylformamide followed by the subsequent addition of aldehydes 1a-1e. The hydrolyzed products 7a-7e were obtained in 69-71% yields by both the classical and microwave irradiation condensation methods, even under anhydrous conditions. It is evident that compounds 7 resulted from the utilization of the water of condensation for the hydrolysis process. In the 1H NMR spectra of compounds 7 no signals for the ethyloxy group were observed (Table 2).
3-Formylchromone condensations with thiohydantoin 3 and 3-ethylrhodanine 4 were carried out in acetic anhydride in the presence of potassium acetate under both irradiation and classical conditions. The yields of 2-thioxo-5-[(6-R-4-oxo-4H-[1]-benzopyran-3-yl) methylidene]imidazolidin-4-ones 8a-8e and 2-thioxo-5-[(6-R-4-oxo-4H-benzopyran-3-yl)methylidene]thiazolidin-4-ones, 9a and 9b, respectively, were comparable by both methods.
Attempts to hydrolyze the condensation products with diluted mineral acids to prepare ring opened heterocycles were unsuccessful. The 5-(2-hydroxyphenyl)-4-(hydroxy-methylidene)-2-(1-methyl-guanidino)-2-pentenoic acid hydrolysis products (10) were obtained only by refluxing compounds 5 in concentrated hydrochloric acid. We propose the structure of compounds 10, which contain guanidinyl, carboxyl and enolic groups on the basis of 1H NMR, 13C NMR spectra and elemental analysis. Compounds 10 could be regarded as a mixtures of isomers with a very fast tautomeric equilibrium of both enolic and oxo groups. The assumption of this fast tautomeric equilibrium is supported by the data for the shift signals of C-9 in the 13C NMR spectra.
We next attempted to carry out Diels - Alder reactions with various dienophiles, using e.g. maleic anhydride, diethyl maleate and tetracyanoethylene, using both the classical and microwave irradiation procedures. Only heating and stirring a mixture of 5b in toluene with an excess of maleic anhydride at 40°C over 15 hr. was successful and the spiroheterocyclic adduct spiro[(1´-methyl-2´-imido-4´-oxo)-1´, 3´-diazolane-5´, 2-(7-methyl-9-oxo-2, 3, 4, 4a tetrahydroxantene)]-3, 4-dicarboxylic acid (11) was formed in 64% yield. The proposed structure was confirmed by 13C NMR. Similar Diels - Alder reactions were reported previously [18]. The use of microwave irradiation for the Diels - Alder experiments was unsuccessful.
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 1H NMR spectra at elevated temperatures (Table 2). The resonance signals and their multiplicity confirmed the proposed 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).



Products were characterized by elemental analyses (Table 1), NMR spectra (Table 2) and IR spectra (Table 3 and Table 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). 1H and 13C NMR spectra were measured on a 300 MHz spectrometer VARIAN GEMINI 200 in deuterated DMSO at 50-80°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 3-ethylrhodanine 4) ( 2.87 mmol) in dry acetic anhydride (2 cm3) 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 6a6e

Method A

A mixture of 6-R-3-formylchromone 1 (2.87 mmol), creatinine 2 (2.87 mmol), a catalytic amount of H3BO3 (20 mg) in 1cm3 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 1cm3 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 cm3 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 dimethyl-formamide ( 1 cm3) 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 hydro-chloride acid was heated at 90-100°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
13C NMR spectral data for compound 10e [δ(ppm); DMSO - d6, 300 MHz]

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 cm3) was heated at 40°C for 15 h. The solid adduct after cooling was filtered off, washed with 10 cm3 of toluene and dried. The product was suspended in 30 cm3 water was then stirred at 40°C for 3 h. The solid acid was removed by suction and recrystallized from ethanol. Yield 64%.
13C NMR spectral data for compound 11 [δ(ppm); DMSO - d6, 300 MHz]

Analytical Data

References and Notes

  1. Stankovicova, H.; Fabian, W. M.; Lacova, M. Molecules 1996, 1, 223.
  2. Stankovicova, H.; Gasparova, R.; Lacova, M.; Chovancova, J. Collect. Czech. Chem. Commun. 1997, 62, 781.
  3. Lacova, M.; Stankovicova, H.; Odlerova, Z. Il Pharmaco 1995, 50, 885.
  4. El-Shaaer, H.M.; Perjessy, A.; Zahradnik, P.; Lacova, M.; Matulova, M. Monatsh. Chem 1993, 124, 539.
  5. Lacova, M.; El-Shaaer, H.M.; Loos, D.; Matulova, M.; Chovancova, J.; FurdIk, M. Molecules 1998, 3, 120.
  6. Gasparova, R.; Lacova, M.; El-Shaaer, H.M.; Odlerova, Z. Il Pharmaco 1997, 52, 251.
  7. Lacova, M.; Chovancova, J.; Veverkova, J.; Toma, S. Tetrahedron 1996, 52, 14995.
  8. Nohara, A.; Sugihara, H.; Ukawa, K. Japan. Kokai Tokyo Koho 1978, 78, 111,070. ; Chem. Abstr. 1979, 90, 54828z.
  9. Klutchko, S.; Kaminski, D.; Von Strandtmann, M. U.S. Patent 4,008,252, 1977. ; Chem. Abstr. 1977, 87, 5808a.
  10. Lacova, M.; El-Shaaer, H. M.; Odlerova, Z.; Furdik, M. Chem. Papers 1994, 48, 344.
  11. Deulofeu, V.; Guerrero, T. J. Org. Synth. Coll. 1955, 3, 586.
  12. Coirnwaite, W. R.; Lazarus, S.; Snelling, R. H.; Denoon, C. E. J. Am. Chem. Soc. 1936, 58, 628.
  13. Fitton, A. O.; Frost, J. R.; Suschitsky, H.; Houghton, P. G. Synthesis 1977, 133.
  14. Gasparova, R.; Lacova, M. Collect. Czech. Chem. Commun. 1995, 60, 1178.
  15. Villemin, D.; Martin, B. Synth. Commun. 1995, 25, 3135.
  16. Villemin, D.; Ricard, M. Synth. Commun. 1987, 17, 283.
  17. Nohara, A.; Ishiguto, T.; Sanno, Y. Tetrahedron Lett. 1974, 13, 1183.
  18. Silva, A. M. S.; Silva, A. M. G.; Tome, A. C.; Cavaleiro, J. A. S. J. Org. Chem. 1999, 135.
  • Samples Availability: Available from the authors and MDPI.
Scheme 1.
Scheme 1.
Molecules 05 00167 sch001
Scheme 2.
Scheme 2.
Molecules 05 00167 sch002
Table 1. Characterization of the prepared compounds.
Table 1. Characterization of the prepared compounds.
Comp.RFormula Mrm.p. °Cwi (calcd)/ %
wI (found)/ %
Yield %tr min
5aHC16H13 N3 O4246 - 24861.734.2113.50753
311.29 61.314.1413.417160
5bCH3C17H15 N3O4277 - 27962.764.6512.92604
325.32 62.154.6612.5957120
5cClC16H12ClN3O4268 - 27055.583.5012.15762
345.74 55.583.5912.137260
5dBrC16H12BrN3O4270 - 27249.253.1010.77841
390.19 48.913.0210.54--
5eAcOC18H15N3O6259 - 26258.544.0911.38463
369.33 58.064.0711.284090
5fNO2C16H12N4O6285 - 28653.943.3915.72843
356.29 53.833.2915.43--
6aHC14H11N3O3250 - 25262.454.1215.61703
269.26 62.383.9615.72
6bCH3C15H13N3O3294 - 29763.604.6314.83673
283.28 63.244.6814.06
6cClC14H10ClN3O3356 - 36055.363.3213.83923
303.7 55.213.4913.22
6dBrC14H10BrN3O3276 - 27848.302.8912.07683
348.16 48.252.9612.44
6eNO2C14H10N4O5237 - 24053.513.2117.83983
314.26 52.942.9917.39
7aHC15H11N3O5253 - 25557.823.5113.41696
313.3 57.503.9013.08
7bClC15H10ClN3O5356 - 36054.343.7611.18714
375.76 54.693.2311.23
7cCH3C16H13N3O5299 - 30158.713.9712.84587
327.3 58.444.3012.75
392.2 46.282.3610.48
8aHC13H8N2O3S292 - 29557.352.9610.29798
272.3 56.982.9110.057260
8bCH3C14H10N2O3S315 - 31758.733.529.78706
286.3 58.503.529.046630
8cClC13H7ClN2O3S319 - 32150.912.309.13744
306.7 51.032.349.057130
351.2 44.532.027.168860
8eAcOC15H10N2O5S303 - 30554.543.058.486210
330.3 53.822.987.9959120
9aHC15H11NO3S2215 - 21756.773.494.41705
317.4 57.073.484.457460
9bClC15H10ClNO3S2231 - 23351.212.863.98675
351.8 50.962.823.796560
10aHC14H15N5O5325 - 32755.084.9513.76020
10eOHC14H15N3O6315 - 31752.334.7013.08020
11CH3C19H17N3O7221 - 22357.164.2510.51020 - 30
399.3 57.104.2210.418915 hr.
aThe upper yield and reaction time (tr) data are given for the condensation in microwave oven, the lower data for the classic condensation.
Table 2. 1H NMR spectra data of prepared compounds.
Table 2. 1H NMR spectra data of prepared compounds.
CompoundSolvent1H NMR spectrum δ (ppm)
5aCDCl32.25 (s, 3H, CH3); 3.39 (s, 3H, CH3-N); 6.86 - 8.32 (m, 5H, H-Ar); 9.68 (s, 1H, H-2); 10.84 (s, 1H, NH).
5bDMSO-d62.50 (s, 3H, CH3); 2.54(s, 3H, CH3); 3.57(s, 3H, CH3-N); 6.56 (s, 1H, H-9); 7.60 - 7.70 (m, 5H, H-Ar); 7.97 (s, 1H, H-5); 9.56 (s, 1H, H-2).
5cDMSO-d62.76 (s, 3H, CH3); 3.52 (s, 3H, CH3-N); 6.72 (s, 1H, H-9); 8.02 (d, 1H, H-8, 3J=9Hz); 8.11 (d, 1H, H-7, 3J=9Hz); 8.32 (d, 1H, H-5, 4J=2Hz); 9.54 (s, 1H, H-2).
5dDMSO-d62.78 (s, 3H, CH3); 3.53 (s, 3H, CH3-N); 6.74 (s, 1H, H-9); 7.95 (d, 1H, H-8, 3J=9Hz); 8.24 (d, 1H. H-7, 3J=9Hz); 8.49 (d, 1H, H-5, 4J=1.8Hz), 9.55 (s, 1H, H-2).
5eDMSO-d62.13 (s, 3H, CH3O); 2.3 (s, 3H, CH3O); 3.45 (s, 3H, CH3-N); 6.47 (s, 1H, H-9); 7.6 - 7.85 (m, 3H, H-8, 7, 5); 9.30 (s, 1H, H-2); 11.41 (s (broad), 1H, N-H).
5fDMSO-d62.13 (s, 3H, CH3O); 3.21 (s, 3H, CH3-N); 6.43 (s, 1H, H-9); 8.00(s, 1H, H-8); 8.64 (s, 1H, H-7); 8.85 (s, 1H, H-7); 8.85 (s, 1H, H-5); 9.353 (s, 1H, H-2).
6aDMSO-d63.35 (s, 3H, CH3-N); 6.24 (s, 1H, H-9); 7.52 (dd, 1H, H- 7,3J=7.8Hz); 7.69 (dd, 1H, H-8, 3J=7.8Hz); 7.81 (dd, 1H, H-6, 3J=7.8Hz); 8.12 (dd, 1H, H-5, 3J=7.8Hz); 9.88 (s, 1H, H-2); 7.4 - 8.4 (broad, 1H, NH).
6bDMSO-d62.45 (s, 3H, CH3); 3.38 (s, 3H, CH3N); 6.25 (s, 1H, H-9); 7.60 - 7.95 (m, 3H, H-8, 7, 5); 9.86 (s, 1H, H-2); 7.4 - 8.4 (broad, 1H, NH).
7aDMSO-d63.39 (s, 3H, CH3CN); 6.19 (s, 1H, H-9); 7.53 (dd, 1H, H-6, 3J=7Hz); 7.69 (d, 1H, H-8, 3J=7Hz); 7.84 (dd, 1H, H-7, 3J=7Hz); 8.12 (d, 1H, H-5, 3J=7Hz); 9.8 (s, 1H, H-2).
7dDMSO-d63.39 (s, 3H, CH3CN); 6.19 (s, 1H, H-9); 7.70 (d, 1H, H-8, 3J=8Hz); 7.97 (dd, 1H, H-7, 3J=8Hz, 4J=2.2Hz); 8.17 (d, 1H, H-5, 4J=2.2Hz); 9.895 (s, 1H, H-2).
7eDMSO-d63.44 (s, 3H, CH3-N); 6.59 (s, 1H, H-9); 8.00 (d, 1H, H-8, 3J=9Hz); 8.61 (dd, 1H, H-7, 3J=9Hz, 4J=2.5Hz); 8.79 (d, 1H, H-5, 4J=2.54Hz); 9.395 (s, 1H, H-2); 9.64 (s( broad), 1H, NH).
8cDMSO-d66.36 (s, 1H, H - 9); 7.78 (d, 1H, H-8, 3J=10Hz); 7.87 (dd, 1H, H - 7, 3J=10Hz, 4J=2.2Hz); 8.23 (d, 1H, 4J=2.2Hz); 8.94 (s, 1H, H-5); 11.65 (s, 1H, NH); 12.46 (s, 1H, OH).
8dDMSO-d66.35 (s, 1H, H - 9); 7.74 (d, 1H, H-8, 3J=8.8Hz); 8.02 (dd, 1H, H - 7, 3J=8.8Hz, 4J=2.2Hz); 8.22 (d, 1H, 4J=2.2Hz); 8.92 (s, 1H, H-2);
8eDMSO-d62.33 (s, 3H, CH3); 6.38 (s, 1H, H - 9); 7.60 (dd, 1H, H-7, 3J=9Hz, 4J=1.9Hz); 7.83 (d, 1H, H-8, 3J=9Hz); 7.88 (d, 1H, H-5, 4J=1.9Hz); 8.94 (s, 1H, H-2); 11.80 (s, 1H, NH); 12.45 (s, 1H, OH).
9bDMSO-d62.490 (t, 3H, CH3); 5.346 (q, 2H, CH2); 8.84 (s, 1h, H-2); 9.07 (d, 1H, H-8, 3J=9.1Hz); 9.072 (dd, 1H, H-7, 3J=9.1Hz, 4J=2Hz); 9.36 (d, 1H, H-5, 4J=2Hz); 10.27 (s, 1H, H-9).
10aDMSO-d66.27 (s, 1H, CH); 7.23 - 7.66 (m, H, Ar - H); 9.25 (s, 1H, CH); 10.26 (b., 6H, NH2, NH, OH).
10eDMSO-d63.38 (s, 3H, CH3); 6.70 (s, 1H, CH); 7.29 - 7.39 (dd, 1H, H-5, J=9Hz); 7.39 - 7.41 (d, 1H, H-3, J=3Hz); 7.57 - 7.60 (d, 1H, H-6, J=9Hz); 9.23 (s, 1H, CH); 10.28 (b., 7H, OH, NH, NH2).
10fDMSO-d63.68 (s, 3H, CH3); 7.95 - 8.81 (m, 3H, Ar-H); 9.32 (s, 1H, CH); 10.00 (b., 6H, OH, NH, NH2).
11DMSO-d62.46 (s, 3H, CH3); 2.48 (s, 3H, CH3); 4.71 (broad, 5H, NH amide, CO2H, CH); 6.23 - 6.56 (m, 4H, Ar-H, H-2); 7.64 (s, 1H, =CH); 9.47 (s, 1H, NH-imine).
Table 3. IR spectral data of synthesized compounds 5-9.
Table 3. IR spectral data of synthesized compounds 5-9.
ν (cm−1)
5a3078 - 3162173916501643
5b3070 - 3175174016501642
5c3075 - 3179173516591636
5d3075 - 3180172916581640
5e3081 - 3181173916521630, 1758
5f3080 - 3177174516601641
6a3070 - 318517201650
6b3095 - 318017201645
6c3070 - 317517351655
6d3090 - 318017211655
6e3094 - 318617191658
7a3080 - 3230171916571740
7b3075 - 3225172116581742
8a3038 - 318017401665
8b3086 - 318517391668
8c3070 - 319017421665
8d3060 - 318017361668
8e3078 - 3185174516631750
9a3069 - 311016881660
9b3060 - 311016881662
Table 4. IR spectral data of synthesized compounds 10 and 11.
Table 4. IR spectral data of synthesized compounds 10 and 11.
ν (cm−1)
aν(CO)pyr, bν(CO)het

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MDPI and ACS Style

Lacova, M.; Gasparova, R.; Loos, D.; Liptay, T.; Pronayova, N. Effect of Microwave Irradiation on the Condensation of 6-Substituted 3-Formylchromones with Some Five-membered Heterocyclic Compounds. Molecules 2000, 5, 167-178.

AMA Style

Lacova M, Gasparova R, Loos D, Liptay T, Pronayova N. Effect of Microwave Irradiation on the Condensation of 6-Substituted 3-Formylchromones with Some Five-membered Heterocyclic Compounds. Molecules. 2000; 5(2):167-178.

Chicago/Turabian Style

Lacova, Margita, Renata Gasparova, Dusan Loos, Tibor Liptay, and Nada Pronayova. 2000. "Effect of Microwave Irradiation on the Condensation of 6-Substituted 3-Formylchromones with Some Five-membered Heterocyclic Compounds" Molecules 5, no. 2: 167-178.

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