7th International Electronic Conference on Synthetic Organic Chemistry (ECSOC-7), http://www.mdpi.net/ecsoc-7, 1-30 November 2003

---

[A034]

3-Formylchromones III. ^♠

Synthetic, Kinetic and Theoretical Study of Novel Solvatochromic System

of 2-[(4H-4-Oxo-benzopyran-3-yl)ethenyl]benzothiazolium Salts

Pavol Kois ¹*, Dusan Loos¹, Jan Lac ², Anton Gaplovsky ³, Mario Klestinec¹ and Margita Lacova ¹*

¹Department of Organic Chemistry and ²Institute of Chemistry, Faculty of Natural Sciences, Comenius University, SK-842 15 Bratislava, Slovakia, ³European Media Laboratory, Villa-Bosch, Schloss-Wolfsbrunnenweg 33, D-69118, Heidelberg, Germany,

*Corresponding authors: [email protected], [email protected] Tel. +421 2 60296-338 or -341

^♠Previous part 3-Formylchromones II - see ECSOC-7

---

Abstract: Synthesis of novel 2-(4H-4-oxo-benzopyran-3-yl)benzothiazolium salts is presented by fast and one-pot condensation of 3-formylchromones with 3-benzyl-2-methylbenzothiazolium (or benzoxazolium) bromides, using classical conditions or microwave irradiation. The product of solvolysis of 2-(4H-4-oxo-benzopyran-3-yl)benzothiazolium salts was identified. The microwave irradiation showed a beneficial effect on these reactions, especially in improving overall yields and purity of products. Prepared compounds were identified by elemental analysis and by ¹H NMR spectra.

The color changes of prepared salts after interaction with water, DMF, DMSO, methanol and CHCl₃ were measured by UV and fluorescence spectral kinetic methods.

Quantum-chemical AM1 method was used to study all structural parameters, to perform full geometry optimization, to calculate heats of formation and charge densities.

Keywords: Chromone, 3-Formylchromone, Benzoxazolium salt, Microwave synthesis, AM1 Quantum-chemical method, , Aldol reaction, Kinetic

Introduction

This work is aimed at the preparation of chromones bonding benzothiazolium or benzoxazolium groups at C-3 position of chromone ring. As a substituents these azole salts have strong electron withdrawal properties. Generally, C-3 modified chromones are useful reactive agents. They are acceptors of nucleophiles and they can rearrange under mild conditions^1-4. It is obvious these salts have versatile synthetic utility in the field of new heterocycles.

In our earlier papers we described the condensations of 3-formyl-chromones with various heterocyclic components with active methyl- or methylene- groups as creatinine⁵, rhodanine⁵, benzothiazoles⁶, furopyroles⁷, butanolides⁸. None of these chromone derivatives showed any solvato-chromic effect. Later we studied the photochemical behavior, photochromism and thermo-chromism of carboxyimide derivatives of chromone by UV and fluorescent spectral methods⁹.

Benzothiazole salts are known as antihelmintic¹⁰, antineoplastic¹¹, and antimicrobial^12,13 agents. It is worth mentioning that the activity of various chromone salts on photosynthetic electron transport in spinach chloroplast we also reported^{14, 15}.

The main goal of this work was a synthetic study of chromone salts 3 and 4 by classical method and by microwave-irradiation, and then the study of sensitivity of these compounds to water by kinetic and theoretical methods.

Results and Discussion

Synthetic study

Scheme 1. R = H, Cl, Br, CH₃, NO₂

X = S, O

We report here on the fast, facile and one-pot synthesis of 2-[(4H-4-oxobenzopyran-3-yl)ethenyl]benzothiazolium (or benzoxazolium) salts by condensation of three starting compounds: 3-formylchromones, 2-methylbenzothiazole and benzylbromide in solvents CH₃NO₂, CH₃CN, CHCl₃ or (CH₃ CO)₂O.

Experimental results showed that N-substituted 2-methylbenzothiazolium salt 2 as a starting material was more convenient component for the condensation than 2-methylbenzoazoles⁶ in the classical as well as microwave-assisted aldol synthesis.

The microwave irradiation of the reaction mixture for 8-10 min gave yields about 10-30 % higher with cleaner product in comparison with classical conditions (3-4 hours, 90-100 ºC). The products are pale yellow solids with high melting points, rather insoluble in common solvents. Their color is sensitive to water – yellow color can change to red, violet or brown. The rate of color changes is so rapid, that this method can be used for determination of water content in some solvents. Our explanation of the mechanism of nucleophilic reaction at C-2 of compounds 3 in the presence of traces of water in solvent is illustrated on Schemes 1 and 2

Reaction of 3 with water ends in the compounds 4 or 5. The detailed investigation of reaction mixture by TLC, ¹H NMR and UV spectroscopy excluded the presence of compounds 5, but all experimental results confirmed the presence of compound 4c. This compound was prepared as a stable molecule after addition of water to acetonitrile solution of 3 and then irradiation by microwave.

Scheme 2. R = H, Cl, Br, CH₃, NO₂

X = S, O

Kinetic study

The solvatation ability of prepared salts 3 is related to their polarity and can play important role in the color changes. These salts absorb UV-light in the range 200–420 nm in anhydrous solvents. Absorption maximum is red shifted with increasing polarity of solvent (Fig.1).

DMF l¹_max=386 nm, l²_max=490 nm;

DMSO l¹_max=386 nm, l²_max=498 nm;

CHCl₃ l_max=396 nm

This absorption corresponds to p, p*band, which overlaps n, p* band.

After addition of small amount of water to the methanol solution of this compound there appears a new long-wave absorption band in a visible region (Fig.2 and Fig.4). The intensity of new band is proportional to water concentration in solution. At the same time the intensity of bands in the range of l= 390 nm are proportionally going down (Fig.2 and Fig.3).

The kinetic study revealed a rapid chemical equilibrium between compounds 3 and their water adducts 4 in methanol solution. It showed a marked linear dependence of changes on the square of water concentrations of compounds 4 and their adducts (Fig.3 and Fig.5).

Fig.1.: Absorbance of 2-Benzyl-2-[2-(chromon-3-yl) ethenyl]benzothiazolium bromide in

1. DMF l¹_max=386 nm, l²_max=490 nm

2. DMSO l¹_max=386 nm, l²_max=498 nm,

3. CHCl₃ l_max=396 nm

Fig.2.: Absorbance of 3-benzyl-2-[2-(chromon-3-yl)ethenyl] benzothiazolium bromide in methanol

after gradual addition of water (0.044, 0.088, 0.133, 0.177, 0.222, 0.266, 0.311, 0.355, 0.400 mol.dm^-3)

Band at λ_max. = 378 nm is decreasing

Band at λ_max. = 502 nm is increasing

Fig.3.: The dependence of concentration changes of benzothiazole derivatives 3 and 4 on square of water concentration in methanolic solution of samples.

Fig.4: Fluorescencent spectra

Effect of water concentration in methanol solution of 3-benzyl-2-[2-(chromone-3-yl)ethenyl]benzothiazolium bromide on the gradual decrease of emission band l_exc =380nm and simultaneous increasing of emission band at l_max =540nm

(water concentration - 0.044, 0.088, 0.133, 0.177, 0.222, 0.266, 0.311, 0.355, 0.400 mol.dm^-3)

Fig.5: Fluorescencent spectra

Effect of water concentration in methanol solution of 3-benzyl-2-[2-(chromone-3-yl)ethenyl] benzothiazolium bromide. The gradual increasing of fluorescent emission at band l_exc =540 nm (water concentration - 0.044, 0.088, 0.133, 0.177, 0.222, 0.266, 0.311, 0.355, 0.400 mol.dm^-3)

Theoretical study

The optimal structures and quantum chemical parameters of starting compounds and products 1-5 were calculeted by the AM1 method¹⁶ with standard parametrization and full optimization of all geometrical parameters. Schemes 1 and 2 comprise our proposal of possible mechanism of water addition on compounds 3.

From calculated values of heat of formation of compounds 3 is evident, that reaction with benzothiazole salts is energetically preferable to benzoxazole salts. The electronwithdraving substituent in benzothiazole derivatives decreases the reaction ability, on the contrary the reaction ability in the benzoxazole derivatives is increasing.

According to the difference of heat of formation the preferred reaction of compounds 3 hydratation is (b) to compound 4c, in comparison to step (a) to compound 4a. It means that opening of chromone ring occurs. Substituents in the position 6 of chromone system and heteroatoms in benzoazole ring have influence on corresponding reaction rates (Table 1).

According to heat of formation is clear that benzoxazole derivatives should react better than benzotiazole derivatives. Similar effect has also the substituent with electronwithdrawing character in position 6 (compound 3), which decreases bond order O₁-C₂, very significantly especially in the case of benzoxazole derivatives. The energy for the formation of compounds 4c is 240 kJ larger than for compound 4a.

Geometry optimization for compound 4a allways resulted in compound 5 as is clear from calculated bond orders and charge densities, as well as corresponding bond lengths. Otimization of compounds 4b geometry (#18 in Table 1) was successful only for structure R=H. Substituents on 4b, (Cl or NO₂) decreased very significantly bond order O₁-C₂ . For this reason the opened structure of 4b is more stable and preferred.

For dehydrobromination reaction of 4c series, the difference of heat of formation (200 kJ.mol^-1) prefers the formation of compounds 4a (5), in contrast to 4d.

Table 1.

Thermodynamic parameters for salts 3 and chromones 4, 5

No.	Comp.	R	X	Q(O1)	Q(C2)	P(O1-C2)	DHf(kJ/mol)
01	1	H	-	-	-	-	-222.064
02	1	Cl	-	-	-	-	-251.087
03	1	NO2	-	-	-	-	-199.735
04	2	-	S	-	-	-	919.719
05	2	-	O	-	-	-	842.723
06	3	H	S	-0.098	0.126	1.1595	825.553
07	3	Cl	S	-0.097	0.125	1.1550	805.084
08	3	NO2	S	-0.099	0.115	1.1300	869.326
09	3	H	O	-0.093	0.147	1.1801	910.755
10	3	Cl	O	-0.092	0.146	1.1153	889.816
11	3	NO2	O	-0.094	0.138	1.1502	952.376
12	4a (5)	H	S	-0.226	0.201	0.9190	45.364
13	4a (5)	Cl	S	-0.223	0.202	0.9150	17.576
14	4a (5)	NO2	S	-0.218	0.205	0.9003	59.210
15	4a (5)	H	O	-0.226	0.202	0.9178	-50.091
16	4a (5)	Cl	O	-0.224	0.203	0.9139	-77.950
17	4a (5)	NO2	O	-0.218	0.205	0.8992	-36.467
18	4b	H	S	-0.335	0.268	0.0043	184.822
19	4c	H	S	-0.274	0.139	0.0007	668.171
20	4c	Cl	S	-0.269	0.135	0.0006	645.764
21	4c	NO2	S	-0.224	0.132	0.0002	683.537
22	4c	H	O	-0.277	0.157	0.0009	584.293
23	4c	Cl	O	-0.223	0.156	0.0006	562.384
24	4c	NO2	O	-0.223	0.151	0.0002	603.804
25	4d	H	S	-0.556	0.119	0.0003	269.320
26	4d	Cl	S	-0.540	0.124	0.0002	226.933
27	4d	NO2	S	-0.494	0.137	0.0001	226.837
28	4d	H	O	-0.560	0.131	0.0003	175.866
29	4d	Cl	O	-0.545	0.136	0.0003	134.145
30	4d	NO2	O	-0.499	0.149	0.0002	135.623

Experimental part

General

Melting points (uncorrected) of synthesized compounds were measured on a Kofler heated block. All compounds were analyzed for C, H, N, S. The results obtained were within ±0.4% of theoretical values. ¹H NMR spectra (in d-scale, ppm) were recorded on the VARIAN GEMIN 2000, 300MHz spectrometer in DMSO-d6. For some compounds, TESLA BS487 (80MHz) instrument using saturated solutions of the compounds in CF₃COOH-d was used. UV VIS spectra were obtained in 1cm thick cell using the HP Diod Array 8254 spectrophotometer, fluorescence spectra using the spectrofluorimeter Hitachi F-2000. Kinetic experiments were measured until the limiting equilibrium concentration was reached.

The 3-formylchromones 1 were prepared by Vilsmeier double formylation of appropriate 2-hydroxyacetophenones¹⁷. The preparation of benzothiazolium salts by classical procedures was carried out as described in detail elsewhere⁵.

All microwave assisted reactions were carried out in a Lavis–1000 multiQuant microwave oven. The apparatus was equipped with magnetic stirring and an external reflux condenser to suit the laboratory applications.

3-Benzyl-2-methylbenzothiazolium bromide 2

A stirred mixture of 2-methylbenzothiazole (0.5 g, 3.35 mmol) and benzylbromide (0.573 g, 3.35 mmol) in anhydrous nitromethane (2 ml), or acetonitrile (2 ml) was irradiated for 20 minutes at 270 W in microwave oven. Pale-green precipitate was diluted by acetone, filtered off and dried. Yields were about 55 % (acetonitrile) 70 % (nitromethane), m.p. 241 - 243 °C. The product was identical to that prepared by classical method^5,6 as evidenced by ¹H NMR.

3-Benzyl-2-[(6-R-chromon-3-yl)ethenyl]benzothiazolium bromides 3

Method A (by irradiation).

A stirred mixture of 3-benzyl-2-methylbenzothiazolium bromide (1 mmol) and 3-formylchromone derivative (1 mmol) in 2 ml anhydrous nitromethane was irradiated at 270 W for 2-8 minutes. Solid products were filtered off, washed with warm acetone and crystallized from acetonitrile.

Method B (one - pot - reaction, by irradiation).

A stirred mixture of benzylbromide (1 mmol), 2-methylbenzothiazole (1 mmol) and appropriate 3-formylchromone derivative (1 mmol) in anhydrous nitromethane (2 ml) was irradiated at 270 W for 2-8 minutes. The isolation of products was the same as for method A. Yields were in the range 84-89%.

Method C (classical conditions).

The same mixture as in method A was refluxed for 6 hours in argon atmosphere. The crystals were filtered off and recrystallized from acetonitrile. Yields were about 50-60 %.

Benzoxazole derivative 3g was also prepared by the method B.

Table 2.

Reaction time, yields and melting points of chromones 3a - *3g (microwave irradiation)

compounds	3a	3b	3c	3d	3e	3f	*3g
reaction time [min.]	10	8	6	7	4.5	6	2.5
yields [%]	75.9	68.2	76	81	81	79	54
melting point ^o[C]	215-217	171-173	242-245	253-256	294-297	255-258	221-223

*benzoxazole derivative

Table 3.

Analytical characteristics of chromones 3

Comp.		Formula Mr	Elemental analysis (calc. / found)
			%C	%H	%N	%S	%Br
3a	H	C25H18BrNO2S 476.4	63.03 63.21	3.81 3.86	2.94 2.82	6.73 6.35	16.77 17.06
3b	CH3	C26H20BrNO2S 490.4	63.89 63.68	4.11 4.32	2.86 2.73	6.54 6.38	16.30 16.58
3c	Cl	C25H17BrClNO2S 510.8	58.78 58.25	3.35 3.42	2.74 2.61	6. 28 6.06	15.64 15.21
3d	Br	C25H17Br2NO2S 555.3	54.08 53.84	3.09 3.12	2.52 2.47	5.77 5.68	28.78 29.12
3e	NO2	C25H17BrN2O4S 521.4	57.59 57.32	3.28 3.35	5.37 5.14	6.15 5.95	15.33 14.82
3f	CH3	C26H19BrClNO2S 524.8	59.50 59.30	3.65 3.57	2.67 2.76	6.11 5.89	15.22 15.84
*3g	H	C25H18BrNO3 460.3	65.23 64.94	3.94 3.82	3.04 3.04		17.36 17.56

*Benzoxazole derivative

Preparation of compound 4

The mixture as above (method A) was irradiated at 270 W for 10 minutes. Then water was added (2 mmol) and the irradiation was prolonged for another 20 minutes. After cooling, the red crystals were filtered off and washed with warm acetone. The yield of compound 4(R=H) with m.p. 220-223 °C was 60 %.

Elemental analysis for C₂₅H₁₉NO₃S, M_r 413.5; (calc. 72.55 %C, 4.59%H, 3.38%N; found 72.42%C, 4,48%H, 3.21%N)

¹HNMR ( DMSO-6d) d(ppm) : 3.28s(1H, 4-OH); 6.0s,(2H, CH₂); 6.40s(1H,H-2); 7.30s(5H, H-Ph); 7.81 - 7.89m(4H, H-Btz.); 8.06d(1H, H-9, ³J=15Hz); 8.702 (d,1H, H-10, ³J=15Hz);

(CF₃COOH-d): 6.15 (s, 2H); 7.39 (s, 5H, H-Ph); 7.61 (t, 1H, H-5); 7.81 - 7.89 (m, 4H, H-Bt-het.); 8.06 (d, 1H, H-9, ³J=15Hz); 8.702 (d, 1H, H-10, ³J=15Hz); 8.19 (dd, 1H, H-6, ³J=8Hz, ⁴J=1.43Hz); 8.32 (d, 1H, H-8, ³J=8Hz); 8.50 (dd, 1h, H-7, ³J=8Hz, ⁴J=1.44Hz); 9.174 (s, 1H, H-2)

Table 4.

¹H NMR data of compounds 3

Comp.	^1H NMR ,d(ppm ) , DMSO-d6, 300 MHz, 100 ^oC
3a	6.15s,( 2H, CH2); 7.39s,( 5H, Ph); 7.71t,( 1H, ^3J=7.97Hz, ^3J=7.14Hz, H-8); 7.77d, (1H,^3J=8.24Hz, H-11); 7.81-7.89 m,(3H,H-5,6,7); 8.11d ( 1H,^3J=15.66Hz,H-10); 8.21d,( 1H,^3J=.7.69Hz ,H-13); 8.31d ( 1H,^3J=8.24Hz, H-12); 8.59d, ( 1H,^3J=7.69Hz, H-14); 8.69d ( 1H,^3J=15.66Hz,H-9); 9.17 s, (1H, H-2)
3b	2.47 (s, 3H, CH3); 6.15 (s, 2H, CH2); 7.40 s,(5H, Ph); 7.71-7.72m, (2H, H-8,11); 7.8-7.89m, (2H, H-7,14); );7.96 d,^4J=1.7Hz,H-5); 8.07d ( 1H,^3J=15.4Hz,H-10); 8.35d ( 1H,^3J=9.8Hz,H-12); 8.52d ( 1H,^3J=10Hz,H-11); 8.70d ( 1H,^3J=15.4Hz,H-9); 9.18s, ( 1H, ^3J=15.38 Hz, H-10)
**3c	6.11 (s, 2H, CH2); 7.307-7.505 (m, 5H, Ph); 7.761-8.326 (m, 8H, H-5,7,8,10 -14); 8.744 (s, 1H, H-10); 9.008 (d, ^3J=15.38 Hz, 1H, H-9)
3d	6.16 (s, 2H, CH2); 7.37-7.41 m,(5H, Ph); 7.79-7.88m, (3H, H-8,11,12); 8.01dd,(1H,^3J=7.2Hz ,^4J=2.Hz, H-7); 8.06d, ( 1H,^3J=15.6Hz,H-10); 8.24d,(1H,^4J=1.9Hz,H-5); 8.34d ( 1H,^3J=8Hz,H-13); 8.52d ( 1H,^3J=8Hz,H-14); 8.66d ( 1H,^3J=15.5Hz,H-9); 9.21s, ( 1H, H-2)
3e	6.21s,( 2H, CH2); 7.33-7.46 (m, 5H, Ph); 7.79-7.92 (m, 2H, H-12,13); 8.05d ( 1H,^3J=9.15Hz, H-8); 8.11 (d, 1H,^3J=.15Hz ,H-9); 8.37d ( 1H,^3J=8.24Hz, H-11); 8.59d, ( 1H,^3J=8.55Hz, H-14); 8.63dd ( 1H,^3J=9.15Hz,^4J= 2.9Hz,.H-7); 8.74 d ( 1H,^3J=.15Hz ,H-10); 8.8d ( 1H,^4J=.2.9Hz ,H-5); 9.36 s (1H, H-2)
3f	2.46 (s, 3H, CH3); 6.16 (s, 2H, CH2); 7.39 s,(5H, Ph); 7.79-7.89m, (2H, H-11,12); 7.91d, (1H,^4J=1.7Hz,H-7);7.94 d,(1H^4J=1.7Hz,H-5); 8.05d ( 1H,^3J=15.7Hz,H-10); 8.36d ( 1H,^3J=8.6Hz,H-13); 8.52d ( 1H,^3J=8.7Hz,H-14); 8.67d ( 1H,^3J=15.7Hz,H-9); 9.24s, ( 1H, H-2)
*3g	5.98m s,( 2H, CH2); 7.36-7.86m ( 5H, H-15 - 19); 7.73-7.86m, ( 4H, H-6,8,12,13); 7.89-7.97m, (1H, H-7); 8.06d,(1H,^3J 7.42Hz, H-14); 8.14d,(1H,^3J 7.44Hz, H-11); 8.22dd,(1H,^3J 7.92Hz,^4J=1.65Hz,H-5); 8.33d,(1H,^3J 15.65Hz, H-10); 8.52d,(1H,^3J 15.68Hz, H-9); 9.29s, 1H, H-2)

*benzoxazole derivatives ** measured in CF₃COOH-d, 80 MHz

Conclusions

The novel solvatochromic systems was developed by condensation of 3-formylchromones with 3-benzyl-2-methylbenzothiazolium (or benzoxazolium) bromide. Synthesis by microwave irradiation is safer and at times more convenient alternative to classical method. . Kinetic measurements and theoretical calculations of hydration reaction demonstrated new and interesting properties of our chromone derivatives. Several questions remain to be answered with respect to the reactivity of chromone-heterocyclic conjugates. Among them is the question of the reactivity of chromone conjugates with various nucleophiles, e.g. amino compounds. These experiments are underway.

Acknowledgements: Financial support for this research by the Slovak Grant Agency is gratefully acknowledged, Grant No. 1/8207/01 and 1/0071/03

References

1. Sabitha,G., Aldrichimica Acta 1996, 29, 15.

2. Ghosh, C.K.; Bandyopadhyay Ch., J. Chem. Soc. Perkin Trans. 1, 1983, 1989.

3. Haas,G.; Stanton,J.,L.; Sprecher,A.; Wenk,P., J.Heterocyclic Chem. 1981, 18, 607.

4. Stankovicova, H.; Lacova;M., Gaplovsky, A.; Chovancova,J.; Pronayova,N., Tetrahedron 2001, 57, 3455.

5. Gasparova, R.; Lacova, M., Collect. Czech. Chem. Commun. 1995, 60, 1178.

6. Gasparova, R.; Lacova, M.; El-Shaaer, H.M.; Odlerova, Z., Il Farmaco 1997, 52, 251.

7. Krutosikova,A.; Lacova,M.; Dandarova, M.; Chovancova, J., ARKIVOC 2000, 2, 409.

8. Melikyan, G.,S.; Lacova, M.; Kralova, K.; El-Shaaer, H.,M.; Henselova, M.; Avetisyan, A., A., Chem. Papers 1993, 47, 388.

9. Gaplovsky, A.; Donovalova, J.; Lacova, M.; Mracnova, R.; El-Shaaer,H.,M., Journal of Photochemistry and Photobiology, A: Chemistry 2000, 136, 61.

10. Garmaise, D.L, Paris, G.Y., Komlossy, J., Chambers, C.H.: J. Med. Chem. 1968, 12, 30.

11. Krieg, M., Bilitz, J.M.: Biochem. Pharmacol. 1996, 51, 1461

12. Magdolen, P., Zahradnik, P., Foltinova, P.: Drug Res. 2000, 50(II), 1023

13. Buffa, R., Zahradnik, P., Foltinova, P.: Heterocyclic Commun. 2001, 7, 331

14. Kralova, K.; Sersen, F.; Lacova, M.; Stankovicova, H. Biol. Plant. 1996, 38, 397.

15. Kralova, K.; Sersen, F.; Gasparova R.; Lacova, M., Chem. Papers 1998, 52, 776.

16. AMPAC 6.7, 2001 Semichem, 7128 Summit, Shawnee, KS 66216

17. Nohara, A.; Ishiguto, T.; Sanno, Y., Tetrahedron 1974, 13, 1183.