RU2159239C2 - Method of preparing 3-(alpha-methoxy)methylenebenzofurans - Google Patents

Abstract

FIELD: organic synthesis. SUBSTANCE: invention provides method of preparing compounds of general formula II (presented in description), wherein R¹, R², R³ and R⁴, independently from each other, are hydrogen, halogen, C1-C4-alkyl, C1-C4-alkoxy, acetoxy, or acyl. For that, compounds of formula XIV with R¹, R², R³ and R⁴ defined above are brought into interaction with trimethyl orthoformate. Resulting benzofuran compounds are useful as intermediates in synthesis of agrochemical products. EFFECT: increased resource of agrochemical products. 3 cl, 7 ex

Description

 This invention relates to a method for producing 3- (α-methoxy) methylenebenzofuranones, which are intermediates in the process of preparing phenoxypyrimidine compounds useful as intermediates for fungicides.

 It is known that 3- (α-methoxy) methylenebenzofuran-2 (3H) -one can be obtained by methylation of 3-formylbenzofuran-2 (3H) -one or diazomethane or methanol sulfuric acid (JA Elix and BA Ferguson, Australian Journal of Chemistry 26/5 / 1079-91 (1973)).

 Attempts to formyl benzofuran-2 (3H) -one have been reported to be unsuccessful (A. D. Haimon and C. P. Hutchinson Journal of Organic Chemistry 40/24 3474-3480 (1975)).

According to the present invention, there is provided a process for the preparation of 3- (α-methoxy) methylenebenzofuranones having the general formula (II) in which R ¹ , R ² , R ³ and R ⁴ independently represent hydrogen, halogen, C _1-4 alkyl, C _{1- 4} alkoxy, acetoxy or acyl; comprising the reaction of a compound of formula (XIV), wherein R ¹ , R ² , R ³ and R ⁴ are as defined above, with trimethyl orthoformate.

According to the invention, a compound of formula (II) is prepared by reacting a compound of formula (XIV) with trimethyl orthoformate in a suitable solvent (for example, trimethyl orthoformate or in an inert solvent such as a hydrocarbon solvent, for example toluene), at a suitable pressure, preferably in the range of 1-5 atm usually at atmospheric pressure and at a suitable temperature (preferably in the range of 20-180 ^° C, suitably 90-130 ^° C (for example, 95-110 ^° C). It is preferred that the acid anhydride (preferably alk anhydride of ananoic acid (e.g., acetic anhydride or isobutyric anhydride)) was used in this reaction with trimethyl orthoformate, and in this case, a suitable solvent may be acid anhydride, trimethyl orthoformate, or a mixture of these two and / or an inert solvent, such as a hydrocarbon solvent, e.g. toluene.

 As noted above, the compounds of formula (II) are intermediates for phenoxypyrimidine compounds.

For example, compound (II) by reaction with a compound of formula ROCH ₃ in which R is a metal; and subsequent reaction of the obtained product with a compound of formula (III) in which Z ¹ and Z ² represent halogen atoms, give compounds of formula (I) in which R ¹ , R ² , R ³ and R ⁴ have the above meanings, Z ¹ represents a halogen atom and W represents a group (CH ₃ ) ₂ CH • CH — CO ₂ CH ₃ or CH ₃ O • CH = CCO ₂ CH ₃ .

 The following examples illustrate the method of the present invention, as well as the preparation of compounds of formula (I) from the products of this method. All reactions are carried out in a nitrogen atmosphere.

 Where shown, NMR data are sampled and no attempt is made to list each signal. The following abbreviations are used in the examples: mp. = melting point, br.s = wide singlet, s. = singlet, gx = gas chromatography, d = doublet, m = multiplet, t = triplet, MS = mass spectrum.

Example 1
This example illustrates the preparation of 3- (α-methoxy) methylenebenzofuran-2 (3H) -one.

Benzofuran-2 (3H) -one (10.2 g), acetic anhydride (30 cm ³ ) and trimethylorthoformate (12.1 g) were stirred at 100-105 ^o C for 12 hours. During this time, liquids with a low boiling point were collected using Dean-Stark apparatus.

The reaction mixture was allowed to cool and concentrated under reduced pressure (using a water bath temperature of 60 ^° C.) to give a brown solid. This substance was dissolved in dichloromethane (100 cm ³ ), and this solution was washed with water (2 x 50 cm ³ ) and concentrated under reduced pressure (using a water bath temperature of 60 ^° C.) to give a crude product (13.5 g). Some of this crude product was added to the crude product from similar experiments, and all of the crude product was taken up in methanol and treated with activated carbon. After that, the methanol solution was heated under reflux for 30 minutes, cooled to below 10 ^° C, filtered, and the residue was washed with cold methanol. The residue was dried at 50 ^° C. in vacuo to give an off-white solid with a melting point of 102-103 ^o C.

The product from a similar experiment gave the following physical data:
¹ H NMR (CDCl ₃ , 250 MHz); δ 7.6 (1H, s.), 7.6-7.1 (4H, m.), 4.15 (3H, s.) ppm.

¹³ C NMR (CDCl ₃ , 62.9 MHz); δ 169.9, 160.1, 152.0, 128.3, 123.9, 123.0, 122.8, 110.4, 103.9, 63.9 ppm.

 MS: molecular ion m / z 176.

Example 2
This example illustrates the preparation of compound (I) in which R ¹ , R ² , R ³ and R ⁴ are all hydrogen, Z ¹ is chloro, and W is (CH ₃ O) ₂ CHCHCO ₂ CH ₃ .

(α-Methoxy) methylenebenzofuran-2 (3H) -one (8.8 g) was dissolved in tetrahydrofuran (100 ml). Sodium methylate (2.7 g) and methanol (1.6 g) were added to this solution. After addition, the reaction mixture turned red and exomerism occurred (reaction mixture from 20 ^° C. reached 45 ^° C.). The reaction mixture was cooled to 20 ^° C., stirred for 15 minutes, 4,6-dichloropyrimidine (7.45 g) was added, and the mixture was stirred for 22 hours. The reaction mixture was then filtered and the residue was washed with dichloromethane (50 ml). The filtrate and washings were combined and evaporated under reduced pressure using a water bath temperature of 30 ^° C., leaving an orange oil. The oil was dissolved in dichloromethane (200 ml), to which water (100 ml) was added. The mixture was shaken, the aqueous layer was neutralized with concentrated hydrochloric acid, and the organic layer was separated and evaporated under reduced pressure (using a temperature of a water bath of 50 ^° C.), leaving a viscous, cloudy orange oil (15.66 g). Proton NMR showed that this substance mainly comprised a compound of formula (I) in which Z ¹ represents chlorine, W represents (CH ₃ O) ₂ CHCHCO ₂ CH ₃ , X represents oxygen, and R ¹ , R ² , R ³ and R ⁴ represent hydrogen.

The product from a similar experiment showed the following physical data:
¹ H NMR (CDCl ₃ ): δ 8.6 (1H, s), 7.7-7.1 (4H, m), 6.9 (1H, s), 5.0 (1H, d), 4.2 (1H, d) , 3.55 (3H, s.), 3.4 (3H, s.), 3.2 (3H, s.) Ppm.

¹³ C NMR (CDCl ₃ ): δ 170.8, 170.4, 162.0, 158.4, 150.2, 130.0, 129.1, 126.7, 122.4, 107.9, 104.8, 55.5, 53.6, 52.2, 48.0 ppm.

Example 3
This example illustrates the preparation of an (E) isomer of a compound of formula (I) in which R ¹ , R ² , R ³ and R ⁴ are all hydrogen, Z ¹ is chloro, and W is CH ₃ O • CH = CCO ₂ CH ₃ .

Sodium methylate (2.84 g) was suspended in methyl acetate (30 ml) and methanol (1.6 g), and the suspension was cooled to 0-5 ^° C. To the suspension, (α-methoxy) methylenebenzofuran-2 (3H) - was added in portions over 1 min. he (8.8 g) to maintain the temperature below 20 ^o C. The reaction mixture was allowed to warm to room temperature, and 4,6-dichloropyrimidine (7.45 g) was added. The reaction mixture was stirred at 20-25 ^° C. for 19 hours (approximately). The reaction mixture was cooled to 0-5 ^° C, and additional charges of sodium methylate (1.0 g), methanol (0.56 g) and 4,6-dichloropyrimidine (2.61 g) were added to it. The reaction mixture was stirred at room temperature for 23 hours.

The reaction mixture was then filtered, and the residue was washed with methyl acetate (2x20 ml). The filtrate and washings were combined and evaporated under reduced pressure (using a water bath temperature of 60 ^° C. and for a period of time long enough to remove volatile pyrimidine residues), giving a viscous, cloudy red oil (17.02 g).

This oil was then heated at 160 ^° C. at 20 mm Hg for 1 hour using a Kugelor apparatus. After this period of time, potassium bisulfate (0.16 g) was added to the oil, and the oil was stored at 160 ^° C. at 20 mmHg. Art. for 2 hours. The oil was cooled, dissolved in dichloromethane (100 ml), and this solution was washed with water (100 ml) containing 36% hydrochloric acid (1 cm ³ ). The organic layer was separated and evaporated under reduced pressure (using a water bath temperature of 30 ^° C.), leaving an oil. This oil was heated at 180 ^° C. at 20 mmHg. within 3 hours

Example 4
This example illustrates an alternative preparation of the (E) -isomer of the compound of general formula (I) in which R ¹ , R ² , R ³ and R ⁴ are all hydrogen; Z ¹ represents chlorine and W represents CH ₃ O • CH = CCO ₂ CH ₃ .

Sodium methylate (6.25 g, 0.11 mol), methyl acetate (100 ml) and methanol (3.52 g, 0.11 mol) were charged into a 250 ml flask under a nitrogen atmosphere and cooled to 0-5 ^o C. 3- (α -methoxy) methylenebenzofuran-2 (3H) -one (21.12 g, 0.12 mol) while maintaining the temperature below 10 ^o C, and upon completion of the addition, the reaction mixture was allowed to warm to room temperature.

Then, 4,6-dichloropyrimidine (15.05 g, 0.10 mol) was added to the reaction mixture, and the reaction mixture was stirred overnight (approximately 20 hours) at 20-25 ^° C and then left to stand over the weekend.

The reaction mixture was evaporated on a rotary evaporator at 40 ^o C, giving a red oil. Red oil was dissolved in toluene (200 ml) and filtered through activated carbon, with the charcoal being washed with additional toluene (50 ml). The toluene solution and the washings were combined, washed with water (200 ml) and evaporated on a rotary evaporator at 60 ^o C, giving a viscous red oil (33.15 g).

A certain amount of viscous oil (23.15 g) was heated with potassium bisulfate (0.14 g) at 120-130 ^o C at 12 mm Hg for 1 h. This mixture was cooled to 80 ^o C and dissolved in toluene (150 ml). The toluene solution was washed with water (150 ml), and then evaporated on a rotary evaporator at 75 ^o C, giving a crude product (20.51 g).

Crystallization of the crude product from isopropyl acetate (25 ml) afforded the target compound (10.6 g, mp 104-106 ^° C).

¹ H NMR (CDCl ₃ , 250 MHz): δ 8.6 (1H, s), 7.5 (1H, s), 7.5-7.1 (4H, m), 3.8 (1H, s), 3.7 (3H, s.), 3.6 (3H, s.) mln.

Example 5
This example illustrates the preparation of a compound of formula (I) in which R ¹ , R ² , R ³ and R ⁴ are all hydrogen, Z ¹ is chloro, and W is CH ₃ O • CH = CCO ₂ CH ₃ .

Sodium methylate (2.97 g, 0.055 mol) and acetonitrile (19.60 g) were charged into the flask at ambient temperature, and (α-methoxy) methylenebenzofuran-2- (3H) -one (11.40 g, 0.065 mol) was added over 2 min. causing an increase in the temperature of the reaction mixture to about 40 ^° C. The reaction mixture was cooled to ambient temperature and 4,6-dichloropyrimidine (7.45 g, 0.05 mol) was added, giving a red-brown solution, which was heated at 60 ^° C. for 6.25 hours. The solvent was distilled off at 60 ^° C./15 mm Hg. Art. giving a red semi-solid product (21.85 g). Gas chromatographic analysis of the product showed a target product with a concentration of about 55% and a compound of formula (I) (in which X represents oxygen, R ¹ , R ² , R ³ and R ⁴ all represent hydrogen, Z ¹ represents chlorine and W represents ( CH ₃ O) ₂ CHCHCO ₂ CH ₃ ) with a concentration of about 2.5%.

The crude product crystallized using isopropyl acetate, giving the target compound as a solid product (mp. 103-105 ^° C), which was pure by gas chromatography analysis.

The solid product showed the following physical data:
¹ H NMR (CDCl ₃ , 250 MHz): δ 8.6 (1H, s.), 7.5 (1H, s.), 7.2-7.5 (4H, m.), 6.8 (1H, s.), 3.7 (3H, s.), 3.6 (3H, s.) ppm.

¹³ C NMR (CDCl ₃ , 62.9 MHz): δ 170.3, 167.2, 161.8, 160.6, 158.5, 149.9, 132.8, 129.2, 126.1, 125.9, 121.9, 107.2, 106.9, 61.9, 51.5, ppm. Mass spectroscopy showed a molecular ion at m / z 320.

Example 6
This example illustrates the preparation of 3- (α-methoxy) methylene) -5-chloro-benzofuran-2 (3H) -one.

5-Chloro-benzofuran-2 (3H) -one (4 g, 0.02 M), acetic anhydride (16.7 g, 0.16 M) and trimethylorthoformate (4.24 g, 0.04 M) were heated to 100 ^o C for 2 hours. After that the reaction mixture was cooled to 20 ^o C, and then concentrated under reduced pressure (water bath at 70 ^o C), giving the crude product as a dark red resin (3.7 g).

 The resin was dissolved in hot methanol (5 ml), and the resulting solution was allowed to cool. A solid crystallized from this solution.

The above procedure for dissolving the crude product in hot methanol and then collecting the crystalline product was repeated twice, giving the target compound as a tan solid (0.3 g) with a melting point of 128-130 ^o C.

¹ H NMR (CDCl ₃ , 250 MHz): δ 7.6 (1H, s.), 7.6-7.0 (3H, m.), 4.2 (3H, s.) Ppm.

Example 7
This example illustrates the preparation of 3- ((α-methoxy) methylene) - 5-acetoxy-benzofuran-2 (3H) -one.

Acetic anhydride (25 ml) and 5-hydroxy-benzofuran-2 (3H) -one (1 g, 0.0067 M) were stirred at room temperature under a nitrogen atmosphere for 10 min. After this, trimethylorthoformate (1.06 g, 0.01 M) was added, and the resulting reaction mixture was heated at 100 ^° C (± 5 ^° C) for 12 hours. The reaction mixture was then allowed to cool to room temperature, and a pink solid was isolated from the mixture.

The reaction mixture was concentrated under reduced pressure (water bath at 70 ^° C.) to give a residue comprising a pink solid. The pink solid was dissolved in dichloromethane (50 ml), and the resulting solution was washed with cold water (50 ml). The organic layer was then concentrated under reduced pressure (water bath at 70 ^o C), giving the target compound in the form of pink needle-shaped crystals (1.15 g) with a melting point of 206-210 ^o C.

¹ H NMR (CDCl ₃ , 250 MHz): δ 7.6 (1H, s.), 7.4-6.9 (3H, m.), 4.2 (3H, s.), 2.3 (3H, s.) Ppm.

¹³ C NMR (CDCl ₃ , 100.6 MHz /: δ 169.8, 169.5, 160.7, 149.0. 146.6, 123.2, 121.0, 116.3, 110.6, 103.4, 63.8, 21.1 ppm.

 Chemical formulas are given at the end of the description.

Claims (3)

1. The method of obtaining 3- (α-methoxy) methylenebenzofuranones of the formula II

in which R ¹ , R ² , R ³ and R ⁴ independently represent hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy, acetoxy or acyl,
characterized in that the compound of formula XIV

in which R ¹ , R ² , R ³ and R ⁴ have the meanings defined above,
subjected to reaction with trimethylorthoformate.  2. The method according to p. 1, characterized in that the process is carried out in the presence of acid anhydride. 3. The method according to p. 1 or 2, characterized in that R ¹ , R ² , R ³ and R ⁴ all represent hydrogen.

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