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

Lacova, Margita; Loos, Dusan; Furdik, Mikulas; Matulova, Maria; El-Shaaer, Hafez M.

doi:10.3390/30600149

Open AccessArticle

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

by

Margita Lacova

^1,*,

Dusan Loos

¹,

Mikulas Furdik

¹,

Maria Matulova

² and

Hafez M. El-Shaaer

³

¹

Department of Organic Chemistry, Faculty of Natural Sciences, Comenius University, SK-84215 Bratislava, Slovak Republic

²

Slovak Academy of Sciences, 842 38 Bratislava, Slovak Republic

³

Department of Chemistry, Faculty of Education,Ain Shams University, Roxy, Cairo, Egypt

^*

Author to whom correspondence should be addressed.

Molecules 1998, 3(6), 149-158; https://doi.org/10.3390/30600149

Submission received: 27 January 1998 / Accepted: 14 April 1998 / Published: 15 May 1998

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Abstract

:

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

Keywords:

3-Formylchromones; Vilsmeier - Haack reaction; 2-oxobenzopyrane; imines; enamines; AM1 calculations

Introduction

This work was done in connection with our study of synthetic, theoretical, spectral [1,2,3,4,5] 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. 3-formylchromones containing the condensed 2-oxopyran ring 5a - 5e and difficultly accessible aldehydes with non - protected hydroxy groups at the benzene ring 3a - 3c.

Results and Discussion

In the first part of the work the preparation of 7-hydroxy-, 6-n-hexyl-7-hydroxy- and 7, 8-dihydroxy-3-formylchromones 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 interme-diates. The new 2, 4-dihydroxy-5-hexylacetophenone 1c was prepared by acetylation in acetic acid and ZnCl₂ 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 3-formylchromones 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 5d₁ from 2-oxo-2H-6-acetyl-5,7-dihydroxy-4-methylbenzopyran 4d . However, only one product was isolated from the reaction mixture. The ¹H NMR spectra confirmed the structure of 5d. The signal of the proton of the hydroxy group was a singlet and a coupled constant ⁴J 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, 4-dihydroxyacetophenone 1a by the Pechmann reaction in the presence of POCl₃.

6-Acetyl-5-hydroxy-4-methyl coumarin 4c was also prepared from compound 1a by Pechmann reaction in the presence of AlCl₃. 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 ¹H 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 γ-pyrone ring, the aldehyde groups and the α-pyrone ring, respectively (Table 2).

The structure of the prepared compounds was also confirmed by ¹H 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 ¹H NMR spectral data.

The condensation reactions of the aldehydes 3a - 3c and 5a - 5e were carried out with 2-hydroxyaniline, 2,4-dinitrophenylhydrazine, 2-benzothiazolylhydrazine and ethyl acetoacetate. 2,4-Dinitrophenylhydrazones and 2-benzothiazolylhydrazones 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 2-hydroxyaniline 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 CH₃COOK as catalyst.

The starting compounds 1, and 3-formylchromone derivatives 3a - 3c, 5a - 5e were studied by the semi-empirical 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 ¹H NMR spectra, the results of theoretical calculation of both isomers of aldehydes 5d and 5d₁ (Scheme 2) shows that the isomer 5d is about 4.5 kJ/mol more stable than the isomer 5d₁.

Table 1. Elemental analysis data of prepared compounds.

**Table 1.** Elemental analysis data of prepared compounds.
Compound	Formula	W_i (calc.) %			M.p. (°C)
	M_r	W_i (found) %
		C	H	N
1c	C₁₄H₂₀O₃	71.18	8.51		75-77
	236.2	71.13	8.47
3a	C₁₀H₆O₄	63.14	3.17		268-270
	190.2	63.31	3.1
3b	C₁₀H₆O₅	58.3	2.91		264-266
	206.2	58.26	2.98
3c	C₁₆H₁₈	70.07	6.57		233-234
	274.2	70.01	6.6
5a	C₁₄H₈O₅	65.62	3.13		310-312
	256.2	65.33	3.12
5b	C₁₄H₈O₅	65.62	3.13		255-260
	256.2	65.48	3.01
5c	C₁₄H₈O	65.62	6.57		233-234
	256.2	65.32	3.07
5d	C₁₄H₈O₆	61.79	2.94		273-274
	272.2	61.62	2.99
5e	C₁₄H₈O₆	61.79	2.94		291-293
	272.2	61.77	2.92
7a	C₁₇H₁₁N₃O₃S	60.53	3.26	12.46	248-250
	337.3	60.37	3.25	12.27
7b	C₂₃H₂₃N₃O₃S	65.6	5.46	9.97	219-220
	421.4	65.35	5.33	9.54
7c	C₁₇H₁₁N₃O₄S	57.79	3.12	11.9	259-261
	403.3	57.48	3.11	11.76
7d	C₂₁H₁₃N₃O₄S	62.5	3.24	10.41	253-255
	403.3	62.37	3.23	10.29
7e	C₂₁H₁₃N₃O₅S	60.13	3.12	10.01	325-8
	419.3	60.22	3.19	9.71
7f	C₂₁H₁₃N₃O₄S	62.5	3.24	10.41	240-242
	403.3	62.38	3.2	10.39
7g	C₁₆H₁₀O₇N₄	51.9	2.72	15.13	297-9
	378.3	51.62	2.76	14.89	decomp.
7h	C₂₂H₂₂O₇N₄	58.15	4.88	12.33	296-8
	454.4	57.86	4.84	12.09	decomp.
7i	C₁₆H₁₀O₈N₄	49.75	2.61	14.5	173-6
	386.3	49.36	2.66	14.28	decomp.
7j	C₂₀H₁₂O₈N₄	55.05	2.77	12.84	289-94
	436.3	54.89	2.77	12.75
7k	C₂₀H₁₂O₉N₄	53.11	2.67	12.38	300-2
	452.3	52.84	2.8	12.06	decomp.
8a	C₂₂H₁₉NO₆	67.18	4.83	3.56	275-6
	393.4	66.89	4.59	3.12
8b	C₂₂H₁₉NO₇	64.55	4.65	3.42	259-60
	409.4	64.36	4	3.3
9a	C₂₆H₂₀N₂O₆	68.42	4.39	6.13	180-5
	456.4	68.22	4.51	6.02
9b	C₂₆H₂₀N₂O₆	66.1	4.24	5.92	158-62
	472.4	66.05	4.24	5.74
9c	C₂₆H₂₀N₂O₆	68.42	4.39	6.13	188-90
	456.4	68.51	4.37	6.19

Table 2. IR - spectral data (in cm⁻¹).

**Table 2.** IR - spectral data (in cm⁻¹).
Compound		CH=O		ν_s(NO₂)	ν_as(NO₂)
3a	1620	1695	-	-	-
3b	1630	1682	-	-	-
3c	1630	1696	-	-	-
5a	1657	1700	1726	-	-
5b	1655	1693	1748	-	-
5c	1637	1693	1700	-	-
5d	1640	1702	1734	-	-
5e	1640	1704	1724	-	-
7a	1634	-	-	-	-
7b	1630	-	-	-	-
7d	1630	-	1720	-	-
7g	1640	-	-	1318	1580
7h	1612	-	-	1350	1580
7i	1610	-	-	1345	1580
7j	1640	-	1722	1345	1580
7k	1606	-	1748	1310	1580
8a	1642	-	1718	-	-
8b	1642	-	1708	-	-
9a	1648	-	1700	-	-

^a For numbering of carbon atoms see Scheme 2.

Scheme 1.

Scheme 2.

Table 3. ¹H NMR - spectral data.

**Table 3.** ¹H NMR - spectral data.
compound	solvent	spectra δ (ppm)
1a	CDCl₃	12.52 (1H,s,OH), 7.42 (1H,s,H-6), 6.34 (1H,s,H-3), 1.65-0.87
		(13Hm)
3a	DMSO	10.11 (1H,s,CHO), 8.78 (1H,s,H-2), 7.99 (1H,d,H-5), 7.04-6.94
		(2H,t,H-6,8)
3b	DMSO	10.12 (1H,s,CHO), 8.77 (1H,s,H-2), 7.48 (1H,d,H-5), 7.00
		(1H,d,H-6)
3c	DMSO	10.12 (1H,s.CHO), 8.73 (1H,s,H-2), 7.79 (1H,s,H-5), 6.93
		(1H,s,H-8), 2.9 (2H,t), 1.30 (8H,m), 0.86 (3H,t)
4a	CDCl₃	7.68 (1H,d,H-5), 6.90 (1H,d,H-6), 6.12 (1H,s,H-3), 2.95
		(3H,s,CH CO), 2.41 (3H,s,CH ), 13.54 (1H,s,OH)
4b	CDCl₃	7.96 (1H,s,H-5), 6.84 (1H,s,H-8), 6.17 (1H,s,H-3), 2.70
		(3H,s,CH CO), 2.44 (3H,s,CH ), 12.61 (1H,s,OH)
4c	CDCl₃	7.85 (1H,d,H-7), 6.83 (1H,d,H-8), 6.13 (1H,s,H-3), 2.66
		(6H,s,CHCO), 14.07 (1H,s,OH)
4d	CDCl₃	6.26 (1H,s,H-3), 5.99 (1H,d,H-8), 2.68 (3H,s,CH CO), 2.51
		(3H,s,CH )
4e	CDCl₃	6.37 (1H,s,H-3), 5.94 (1H,s,H-6), 2.68 (3H,s,CH CO), 2.51
		(3H,s,CH )
5a^a	DMSO	10.12 (1H,s,CHO), 8.86 (1H,s,H-2), 8.18 (1H,d,H-10), 7.67
		(1H,d,H-9), 6.53 (1H,s,H-7)
5b^a	DMSO	10.12 (1H,s,CHO), 8.97 (1H,s,H-2), 8.39 (1H,s,H-5), 7.87
		(1H,s,H-10), 6.56 (1H,s,H-7), 2.54 (3H,s,CH )
5c^a	DMSO	10.14 (1H,s,CHO), 9.02 (1H,s,H-2), 8.31 (1H,d,H-5), 7.58
		(1H,d,H-6), 6.57 (1H,s,H-9), 2.74 (3H,s,CH )
5d^a	DMSO	10.05 (1H,s,CHO), 8.63 (1H,s,h-2), 8.12 (1H,s,H-10), 6.78
		(1H,s,H-7), 6.26 (1H,s,OH), 2.54 (3H,s,CH )
5e	DMSO	10.07 (1H,s,CHO), 9.06 (1H,s,H-2), 7.30 (1H,s,H-10), 6.31
		(1H,s,H-7), 2.62 (3H,s,CH )
6	CDCl₃	8.26 (2H,t,H-2,CH), 7.10-7.56 (3H,m,arom), 4.31 (2H,q,CH ),
6	CDCl₃	2.47 (3H,s,CH COO), 2.35 (3H,s,CH CO), 1.35 (3H,t,CH )

^a spectra were recorded on a Bruker AM 300

Scheme 3.

Experimental Section

General details

The synthesized compounds were characterized by melting points, elemental analysis, IR and ¹H 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 (300.13 MHz) spectrometers in deuterated DMSO and CHCl₃.

The synthesis of acetophenones 1a, 1b, 1d is described in papers [11,12,13] and the preparation of compounds 4a - 4e in papers [14,15,16].

2, 4-Dihydroxy-5-n-hexylacetophenone 1c

4-n-Hexyl-1, 3-dihydroxybenzene (30 g, 0.15 mol) was gradually added to a stirred and hot mixture (120 °C) of glacial acetic acid (45 ml) and anhydrous ZnCl₂ (44.6 g, 0.32 mol). The mixture was refluxed for 10 minutes. After cooling the mixture was diluted with HCl (120 ml, diluted 1 : 1) and was kept in refrigerator (12 hrs). The crystals were filtered off, washed with diluted HCl (1 : 3) and recrystallized from methanol. Yield 25 g (72 %)

3-Formylchromones 3, 5. General procedure

To the dry dimethylformamide (121 ml) in a three necked flask, POCl₃ (0.49 mol) was added slowly with intensive stirring at 50 °C. Heating and stirring was continued for 2 hrs at 45 - 55 °C. The solution of 2- hydroxyacetophenone (0.12 mol) in DMF (25 ml) was then slowly added under stirring at 50 °C. The stirring was continued for 2 hrs at 55 - 60 °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 %

3-(4-Oxo-7-acetoxy-4H-1-benzopyran-3-yl)-2-(1- oxoethyl)-2-ethylpropenoate 6

A mixture of 7-hydroxy-3-formylchromone 3a (1 g, 5.3 mmol), ethyl acetoacetate (0.82 g, 6.3 mmol), acetic anhydride (4.32 g, 42 mmol) and K₂CO₃ (0.07 g, 0.53 mmol) was heated for 1 hr. After cooling, 30 ml diethylether was added and the ester was allowed to crystallize over 12 hours at room temperature. A yellow solid product was filtered off and recrystalized from ethanol. Yield 56 %.

2-Benzothiazolylhydrazone-3-formylchromone 7a - 7f, 2,4-dinitrophenylhydrazone-3-formylchromone 7g - 7k and 2-ethoxy-3-(2-hydroxyphenylaminomethylene)chroman-4-ones 8a, 8b

Ethanolic solutions of 3-formylchromone derivatives (1 mmol), and 2-benzotiazolhydrazine (or 2, 4-dinitrophenylhydrazine, or 2-hydroxyaniline) (1 mmol) and one crystral of p-toluenesulfonic acid were mixed together and stirred for 1 h, at 30 - 35 °C. The reaction mixture was then cooled to 10 °C. The yellow precipitate was filtered off and recrystallized from ethanol or a mixture DMSO - ethanol. Yields about 70 - 75 %.

2-(2-hydroxyphenylamino)-3-(2-hydroxyphenylaminometylene)chroman-4-ones 9a - 9c

The anhydrous chloroform solution (15 ml) of 3-formylchromone (1 mmol) and 2-hydroxyaniline (2 mmol) was stirred for 30 minutes at 50 °C. After cooling the mixture petroleum ether was added to form a precipitate. The product was filtered off. Toluene was used for recrystalization. Yields 50 - 58 %.

Acknowledgements

The authors would like to thank Dr. E. Greiplova for elemental analysis, Mgr. J. Prokes for ¹H NMR measurements (80 MHz), Dr. A. Perjessy for IR spectral measurements. Financial support for this research from the Slovak Agency (grant No. 1/5058/98) is gratefully acknowledged.

References

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Lacova, M.; Loos, D.; Furdik, M.; Matulova, M.; El-Shaaer, H.M. Synthesis and Reactions of New 4-Oxo-4H-benzopyran-3-carboxaldehydes Containing Hydroxy Groups or 2-Oxopyran Cycles. Molecules 1998, 3, 149-158. https://doi.org/10.3390/30600149

AMA Style

Lacova M, Loos D, Furdik M, Matulova M, El-Shaaer HM. Synthesis and Reactions of New 4-Oxo-4H-benzopyran-3-carboxaldehydes Containing Hydroxy Groups or 2-Oxopyran Cycles. Molecules. 1998; 3(6):149-158. https://doi.org/10.3390/30600149

Chicago/Turabian Style

Lacova, Margita, Dusan Loos, Mikulas Furdik, Maria Matulova, and Hafez M. El-Shaaer. 1998. "Synthesis and Reactions of New 4-Oxo-4H-benzopyran-3-carboxaldehydes Containing Hydroxy Groups or 2-Oxopyran Cycles" Molecules 3, no. 6: 149-158. https://doi.org/10.3390/30600149

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

Abstract

Introduction

Results and Discussion

Experimental Section

General details

2, 4-Dihydroxy-5-n-hexylacetophenone 1c

3-Formylchromones 3, 5. General procedure

3-(4-Oxo-7-acetoxy-4H-1-benzopyran-3-yl)-2-(1- oxoethyl)-2-ethylpropenoate 6

2-Benzothiazolylhydrazone-3-formylchromone 7a - 7f, 2,4-dinitrophenylhydrazone-3-formylchromone 7g - 7k and 2-ethoxy-3-(2-hydroxyphenylaminomethylene)chroman-4-ones 8a, 8b

2-(2-hydroxyphenylamino)-3-(2-hydroxyphenylaminometylene)chroman-4-ones 9a - 9c

Acknowledgements

References

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