EP0912538A1

EP0912538A1 - Process for preparing 2,3-dihydro-2-methyl-2-alkylbenzofuran derivatives

Info

Publication number: EP0912538A1
Application number: EP96918908A
Authority: EP
Inventors: Eung Kul Ryu; Kyoung Mahn Kim
Original assignee: Korea Research Institute of Chemical Technology KRICT
Current assignee: Korea Research Institute of Chemical Technology KRICT
Priority date: 1996-06-12
Filing date: 1996-06-12
Publication date: 1999-05-06
Also published as: CA2258131A1; CN1224423A; JP2000507600A; WO1997047615A1

Abstract

The present invention relates to process for preparing 2,3-dihydro-2-methyl-2-alkylbenzofuran derivatives of formula (I) useful as intermediate of agricultural chemicals and pharmaceutical products, wherein X is selected from the group consisting of hydrogen, halogen, hydroxy group, aldehyde group and C1-C6 alkyl group; and R is selected from the group consisting of C1-C6 alkyl group.

Description

PROCES S FOR PREPARING 2,3-DIHYDRO-2-METHYL-2- ALKYLBENZOFURAN DERIVATIVES

BACKGROUND OF THE INVENTION Technical Field

The present invention relates to process for preparing 2,3-dihydro-2- methyl-2-alkylbenzofuran derivatives of the formula(I) useful as intermediate of agricultural chemicals and pharmaceutical products.

wherein,

X is selected from the group consisting of hydrogen, halogen, hydroxy group, aldehyde group and C,~C₆ alkyl group ; and R is selected from the group consisting of C_]~C₆ alkyl group.

Description of the Related Art

2,3-Dihydro-2-methyl-2-alkylbenzofuran derivatives of the formula(I) were already known as intermediates of agricultural chemicals such as insecticides and pharmaceutical products. Among the compounds of the formula(I), 2,3-dihydro-2,2-dimethyl-7-hydroxybenzofuran, known as carbofuranphenol, was very useful intermediate of 2,3-dihydro-2,2-dimethyl- 7-hydroxybenzofuranyl methylcarbamate as an insecticide.

In addition, 2,3-dihydro-2,2-dimethylbenzofuranaldehyde derivatives were known as intermediate of pyrethroide derivatives which were known in the art as an insecticide[Japanese Patent No. 402,753 Al; European Patent unexamined publication No. 0473,041(1992) ; German Patent No.2108,932;

European Patent No. 0271,170]. A few conventional process for preparing carbofuranphenol was known in the art. For example it was prepared by alkylation of catechol and methallyl halide to 2-methallyloxyphenol which then was cyclized in the presence of a strong acid or Lewis acid at high temperature [U.S. Patent No.

5 4,380,654; Japanese Patent Kokai Soh 60-100,569; European Patent unexamined publication No. 115,837(1984); Japanese Patent Kokai Soh 58-174,375; Japanese Patent Kokai Pyung 5-835,180; Japanese Patent Kokai Pyung 5-839,679; Japanese Patent Kokai Soh 58-21,676]. Also carbofuranphenol was prepared by Claisen rearrangement of 2-methallyl oxyphenol which was cyclized in the i o presence of a strong acid or Lewis acid at high temperature (Japanese Patent Kokai Soh 62-178,580; Brazilian Patent Application No.8301,980; German Patent unexamined publication No.3,027,335(1981)].

The present invention is accomplished the new and easy process to prepare 2,3-dihydro-2-methyl-2-alkylbenzofuran derivatives, which is

15 characterized by the cyclization of 2-(β - alkylallyl)phenols and 2-(2-alkylpropenyl)phenols, prepared by Claisen rearrangement of (β - alkylallyl)oxybenzene.

SUMMARY OF THE INVENTION

20 The object of the present invention is to provide a new process for preparing 2,3-dihydro-2-methyl-2-alkylbenzofuran derivatives, which may be used for the intermediates of agricultural chemicals and pharmaceutical products such as 2,3-dihydro-2,2-dimethyl-7-hydroxybenzofuranyl methylcarbamate or pyrethroide as an insecticide.

25 It is to be understood that both the forgoing general description and the following detailed description are examplary and are intended to provide further explanation of the invention as claimed. DETAILED DESCRIPTION OF THE INVENTION

The present invention is a process for preparing the compounds of the formula(I), which is characterized by the Claisen rearrangement of (β -alkylallyl)oxybenzene derivatives of the formula(II) to give stereoisomers of the formula (III-l) and (III-2), and then cyclization of formula(III-l) and (III-2) in the presence of a catalytic amount of iodine and an inert organic solvent at room temperature,

ι o wherein, X and R are respectively defined as described above.

In the process according to the present inventon, Claisen rearrangement of (β -alkylallyl)oxybenzene derivatives of the formula(II) may be carried out in high boiling solvent or in the absence of solvent at a temperature ranged from 180 TJ to 250 t, preferably at a temperature ranged from 210 "C to 220

15 "c . Suitably preferred solvents are N,N-dimethylaniline, or dodecane etc..

The reaction products prepared by Claisen rearrangement, which are 2-(β -alkylallyl)phenol derivatives having the formula(III-l ) and 2-(alkylpropenyl)phenol derivatives having the formula(III-2) can occur in any of the possible stereoisomeric configuration. The stereoisomers may be used as the mixtures of stereoisomers or may be used respectively as essentially pure stereoisomer to afford the compound of the formula(I). The

5 stereoisomers of the formular (III-l) and (III-2) can be separated using generally known methods, and were identified by nuclear magnetic resonance spectra, infrared spectra, and mass spectra.

A pure stereoismer or the mixtures of them were cyclized in the presence of a catalytic amount of iodine in an inert organic solvent at room t o temperature for ranging from 30 minutes to 4 hours to obtain the compounds of formula(I). In the cyclization, the amount of iodine as catalyst is preferably 0.1 ~ 1 equimolar quantity, more preferably 0.2 equimolar quantity to the compound of the formula(III-l) and /or (III-2). The preferred solvents are hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride,

15 toluene, xylene etc..

The main feature of process according to the present invention is not caused iodocyclization by reacting iodine with 2-methallyl phenol or 2- iosobutenyl phenolfTetrahedron, Vol. 46, pp. 3321 ~ 3408(1990)]. And the compounds of the formula(I) are obtained quantitatively in mild condition.

20 The present invention may be illustrated as the following examples.

These examples are for illustrative purposes and are not intended to limit the scopes of the invention. EXAMPLE 1 A. 2-Methallyloxyphenol

25 To a mixture of catechol(22 g, 0.2 mol) in acetone(120 ml) and

N,N-dimethylformamide(30 ml), were added anhydrous potassium carbonate(14 g, 0.1 mol) and methallyl chloride(20 ml, 0.2 mol) with stirring. The reaction mixture was heated at reflux for 18 hours. The reaction mixture was cooled to room temperature and filtered, and the filtrate was concentrated. The residue was dissolved in 2N hydrochloric acid(100 ml), and extracted sequentially with hexane(50 ml x 3 ) and ethyl acetate(50 ml x 3). The organic layer was washed with 20% aqueous sodium hydroxide (50 ml x

5 3), acidified with cone, hydrochloric acid, and extracted with hexane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure to provide a crude product, which was purified using silicagel column chromatography to provide 17.8 g of 2- methal ly loxyphenol .

I o b.p. : 78 ~ 80 "C / 0.05 torr

Η NMR(CDC1,) : δ 1.8(s, 3H), 4.46(s, 2H), 4.95(s, 1H), 5.05(s, 1H), 5.68(br,

1H), 6.76 ~ 6.95(m, 4H). B. 2-Methallyl catachol and 2-isobutenyl catechol

A mixture of 2-methallyloxyphenol(15.94 g) and N,N-dimethyl aniline(

15 30 g) was heated at 200 "C for 1 hour and cooled to room temperature. The reaction mixture was added 2N hydrochloric acid(100 ml), and extracted sequentially with hexane and ethyl acetate(50 ml x 4). The resulting organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was distilled under

20 high vaccum to provide 11.6 g of a mixture of 2-methallyl catachol and 2- isobutenyl catechol(3 : 1 molar ratio) as a yellow oil. Yield(mixture) : 73 % b.p.(mixture) : 104 12 / 0.05 torr 2-methallyl catachol :

25 ^JH NMR(CDC1,) : δ 1.7(s, 3H), 3.35(s, 2H), 4.85(dd, 2H), 5.7(br, 2H), 6.76(m,

3H). 2-isobutenyl catechol : 'H NMR(CDCL,) : δ 1.68(s, 3H), 1.90(s, 3H), 4.72(dd, 2H), 5.7(br, 2H), 6.76(m, 3H). C. 2,3-Dihydro-2,2-dimethyl-7-hydroxybenzofuran

To a mixture of 2-methallyl catachol and 2-isobutenyl catechol(3 : 1 molar ratio, 7.75 g) in carbon tetrachloride(50 ml), was added iodine^, 2.4 g,

5 0.2 eq.) and stirred at room temperature for 30 minutes. The reaction mixture was diluted with 5% aqueous Na₂S₂0₃ solution until the dark color turned to clear. The resulting organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified using silicagel column chromatography i o to provide 6.5 g of 2,3-dihydro-2,2-dimethyl-7-hydroxybenzofuran. Yield : 84% b.p. : 84 ~ 85 tϊ / 0.002 torr

Η NMR(CDCL,) : δ 1.45(s, 3H), 3.0(s, 2H), 5.42(s, 1H), 5.7(br, 2H), 6.7(m, 3H). EXAMPLE 2

1 5 A. 4-Methallyloxybenzaldehyde

To a mixture of 4-hydroxybenzaldehyde(61 ml, 0.5 mol) in acetone( 150 ml) and N,N-dimethylformamide(25 ml), were added anhydrous potassium carbonate(51 g) and methallyl chloride(63 ml, 0.75 mol) with stirring. The reaction mixture was heated at reflux for 18 hours. The reaction mixture

20 was cooled to room temperature and filtered, and the filtrate was concentrated. The residue was dissolved in ethyl ether(100 ml ), and washed sequentially with water, 20% aqueous sodium hydroxide and brine. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified using

25 silicagel column chromatography to provide 76.5 g of a colorless 4-methallyl oxybenzaldehyde. Yield : 86.8 % b.p. : 95 t: / 0.001 torr Η NMR(CDC1₃) : δ 1.80(s, 3H), 4.45(s, 2H), 4.98(dd, IH), 5.15(dd, IH), 6.70(d,

IH), 7.50(dd, 2H), 9.7(s, IH).

B. 2-Methallylphenol-4-aldehyde and 2-isobutenylphenol-4-aldehyde The mixture of 4-methallyloxybenzaldehyde(57 g, 0.33 mol) and N,N-

5 dimethyl aniline(50 g) was heated at 210 'C for 1 hour with stirring and cooled to room temperature. The reaction mixture was diluted with hexane(50 ml), extracted with Claisen alkali(50 ml x 2), and washed with hexane. The alkali layer was cooled to 0 O, neutralized with cone, hydrochloric acid, and extracted with diethyl ether(30 ml x 3). The resulting organic layer was dried ι o over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified using silicagel column chromatography to provide 36 g of a mixture of 2-methallylphenol-4-aldehyde and 2-isobutenylρhenol-4-aldehyde as yellow oil. Yield(mixture) : 63 %

15 Η NMR(CDCi,) : δ 1.74(s, 3H), 3.38(s, 2H), 4.70(s, IH), 4.84(s, IH), 5.69(br,

IH), 6.70(d, IH), 7.50(dd, 2H), 9.7(s, IH).

C. 2,3-Dihydro-2,2-dimethylbenzofuran-5-aldehyde

To a solution of 27.5 g mixture of 2-methallylphenol-4-aldehyde and 2-isobutenylphenol-4-aldehyde in dichloromethane(160 ml), was added of

20 iodine(6.0 g, 0.2 eq.) and stirred at room temperature for 2 hours. The reaction mixture was diluted with 10% aqueous Na₂S₂0₃ solution. The resulting organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified using silicagel column chromatography to provide 20.3 g of 2,3-

25 dihydro-2,2-dimethylbenzofuran-5-aldehyde. Yield : 74 %

Η NMR(CDC-₃) : δ 1.48(s, 3H), 3.00(s, 2H), 6.70(d, IH), 7.50(dd, 2H), 9.7(s,

IH). EXAMPLE 3

A. 2-Methallyloxybenzaldehyde

To a mixture of salicyl aldehyde(36.6 g, 0.3 mol) in acetone(150 ml) and N,Λ/-dimethylformamide(25 ml), were added anhydrous potassium

5 carbonate(31 g, 0.2 mol) and methallyl chloride(44.4 ml, 0.45 mol) with stirring.

The reaction mixture was heated at reflux for 18 hours. The reaction mixture was cooled to room temperature and filtered, the filtrate was concentrated.

The residue was dissolved in ethyl ether(100 ml) and washed sequentially with 20% aqueous sodium hydroxide (50 ml x 3) and brine. The resulting i o organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was distilled under high vaccum to provide 47 g of 2-methallyloxybenzaldehyde as a pale yellow oil. Yield : 90 % b.p. : 84 T3 / 0.05 torr l b Η NMR(CDCl₃) : δ 1.8(s, 3H), 4.32(s, 2H), 4.97(d, IH), 6.7 ~ 7.2(m, 4H),

11.5(m, 4H).

B. 2-Methallylphenol-7-aldehyde

A mixture of 2-methallyloxybenzaldehyde(36.6 g) and N,N-dimethyl aniline(40 g) was heated at 170 ~ 175 "C for 1 hour with stirring and cooled to

20 room temperature. The reaction mixture was diluted with hexane(50 ml), extracted with Claisen alkali(25 ml x 3), and washed with hexane. The alkali layer was cooled to 0 "C, neutralized with cone, hydrochloric acid, and extracted with diethyl ether. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced

25 pressure. The residue was purified using silicagel column chromatography to provide 23.53 g of 2-methallylphenol-7-aldehyde as a yellow oil. Η NMR(CDC1₃) : δ 1.68(s, 3H), 3.31(s, 2H), 4.66(d, 2H), 5.6(br, IH), 6.5 ~

7.2(m, 3H), 9.62(s, IH). C. 2,3-Dihydro-2,2-dimethylbenzofuran-7-aldehyde

To a solution of 2-methallylphenol-7-aldehyde(7.04 g) in dichloromethane(60 ml), was added iodine(2.1 g, 0.2 eq.) and stirred at room temperature for 3 hours. The reaction mixture was diluted with 5% aqueous 5 Na₂S₂0₃. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified using silicagel column chromatography to provide 4.43 g of 2,3- dihydro-2,2-dimethylbenzofuran-7-aldehyde.

Yield : 63 % t o b.p. : 81 ~ 82 "C

Η NMR(CDC1₃) : δ 1.49(s, 6H), 3.00(s, 2H), 6.60 ~ 7.55(m, 3H), 10.05(s, IH).

EXAMPLE 4 - 13

The compounds of formular (I) in Table 1 and Table 2 were prepared substantially in accordance with the procedure detailed from Example 1 to i s Example 3, using essentially pure stereoisomers. These compounds are identified in Heterocycles, 1993, Vol.36, pp. 497 ~ 505

20

25 Table 1.

(III-l)

Table 2.

(HI-2) ( I )

Claims

WHAT IS CLAIMED IS

A process for preparing the compounds of the formula (I), which is characterized by the Claisen rearrangement of (β -alkylallyl)oxybenzene derivatives of the formula(II) to stereoisomers of the formula(III-l) and (III-2); and then cyclization in the presence a catalytic amount of iodine in an inert organic solvent at room temperature,

wherein,

X is selected from the group consisting of hydrogen, halogen, hydroxy group, aldehyde group and C,~C₆ alkyl group ; R is selected from the group consisting of C_j~Q alkyl group. 2. The process according to claim 1, wherein said stereoisomers are used as mixed with 2-{β -alkylallyl)phenol derivatives having the formula (III-l) and 2-(alkylpropenyl)phenol derivatives having the formula (III- 2), or are used alone as essentially pure stereoisomers.