JP2000186084A - Production of dihydrobenzopyran derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To synthesize the subject compound having phenyl group at the 2-position and useful as an intermediate for physiologically active substances such as medicines or agrochemicals by condensing two molecules of a phenol in the presence of a Grignard reagent according to the Diels-Alder reaction. SOLUTION: Two molecules of a phenol represented by formula I (R1, R3 and R5 are each H or a 1-9C alkyl; R2 and R4 are each H, a 1-9C alkyl or a protecting group of hydroxyl group) are condensed in the presence of a Grignard reagent according to the Diels-Alder reaction to thereby produce the objective compound represented by formula II or III. The above reaction is carried out in an aromatic solvent such as benzene, toluene or xylene at 60-80 deg.C by using the Grignard reagent (e.g. ethylmagnesium bromide) in an equivalent amount of preferably 0.5-2.0 based on a substrate. The compound represented by formula I is prepared by reducing the carbonyl of a compound obtained by condensing, e.g. a compound represented by formula IV with a carboxylic acid in the presence of a Lewis acid.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a dihydrobenzopyran derivative.

[0002]

2. Description of the Related Art Dihydrobenzopyran derivatives are important as intermediates of physiologically active substances such as medicines and agricultural chemicals.

[0003] Sideroxilonals having various physiological activities such as growth inhibitory activity of HeLa S-3 cells, antibacterial activity against gram-positive bacteria, aldose reductase inhibitory activity and anti-adhesion activity to aquatic organisms, especially shellfish, etc. It can be used as an intermediate for synthesizing Sideroxylonal A and Sideroxylonal B).

[0004] Tetrahedron Letters, 31 (19), 2789-2792
(1990) describes that a dihydrobenzopyran derivative having a phenyl group (phloroglucinol) at the 2-position can be synthesized by dissolving a polymer consisting of phloroglucinol and acetaldehyde in methanol. However, several types of compounds were generated at the same time, and the yield of the dihydrobenzopyran derivative alone was as low as less than 1%.

Bull.Chem.Soc.Jpn., 56, 2533-2534 (1983)
By heating orthovinylphenol,
It is described that a dihydrobenzopyran derivative having a phenyl group at the 2-position was synthesized in a high yield by dimerization by Diels-Alder reaction. However, only specific substrates are mentioned.

[0006] J. Org. Chem., 48, 3783-3787 (1983)
It is described that orthoquinone methide is formed via magnesium phenolate and reacted with ethyl vinyl ether to give a Diels-Alder adduct, a dihydrobenzopyran derivative. However, when ethyl vinyl ether or the like was not added as a diene-philic agent, Diels-Alder adduct (dihydrobenzopyran derivative) which is a dimer was not produced, but only a complex mixture was obtained.

[0007]

Means for Solving the Problems The present inventors have conducted intensive studies on a method for producing a dihydrobenzopyran derivative having a phenyl group at the 2-position, and as a result, obtained two molecules of phenol represented by the formula (1). Diels-Alder in the presence of reagents
The present inventors have found a method for producing a desired dihydrobenzopyran derivative having a phenyl group at the 2-position by condensing through a reaction, and have completed the present invention.

That is, the present invention provides the following formula (1)

[0009]

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[Wherein, R ¹ and R ³ each independently represent a hydrogen atom or a C _1-9 alkyl group, and R ² and R ⁴ each independently represent a hydrogen atom, a C _1-9 alkyl group or R ⁵ represents a hydrogen atom or a C _1-9 alkyl group. Wherein two molecules of the phenol represented by the formula (2) or (3) are condensed by a Diels-Alder reaction in the presence of a Grignard reagent.

[0011]

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Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are
Represents the same meaning as above. And a method for producing a dihydrobenzopyran derivative represented by the formula:

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail.

In the present specification, "Et" represents ethyl and "n" represents
-"Is normal," i- "is iso," s- "is secondary," t- "is tertiary," c- "is cyclo,
"O-" means ortho and "p-" means para.

First, the terms in each substituent of R ¹ , R ² , R ³ , R ⁴ and R ⁵ will be described.

As the C _1-9 alkyl group, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-
Butyl, t-butyl, n-pentyl, 1-methyl-n-butyl, 2
-Methyl-n-butyl, 3-methyl-n-butyl, 1,1-dimethyl-
n-propyl, 1,2-dimethyl-n-propyl, 2,2-dimethyl-
n-propyl, 1-ethyl-n-propyl, n-hexyl, 1-methyl-n-pentyl, 2-methyl-n-pentyl, 3-methyl-n-
Pentyl, 4-methyl-n-pentyl, 1,1-dimethyl-n-butyl, 1,2-dimethyl-n-butyl, 1,3-dimethyl-n-butyl,
2,2-dimethyl-n-butyl, 2,3-dimethyl-n-butyl, 3,3-
Dimethyl-n-butyl, 1-ethyl-n-butyl, 2-ethyl-n-
Butyl, 1,1,2-trimethyl-n-propyl, 1,2,2-trimethyl-n-propyl, 1-ethyl-1-methyl-n-propyl, 1-
Ethyl-2-methyl-n-propyl, 2-ethyl-2-methyl-n-propyl, n-heptyl, n-octyl, n-nonyl, c-propyl, c-butyl, 1-methyl-c-propyl, 2-methyl-c-propyl, c-pentyl, 1-methyl-c-butyl, 2-methyl-c-butyl, 3-methyl-c-butyl, 1,2-dimethyl-c-propyl,
2,3-dimethyl-c-propyl, 1-ethyl-c-propyl, 2-ethyl-c-propyl, c-hexyl, 1-methyl-c-pentyl,
2-methyl-c-pentyl, 3-methyl-c-pentyl, 1-ethyl
-c-butyl, 2-ethyl-c-butyl, 3-ethyl-c-butyl,
1,2-dimethyl-c-butyl, 1,3-dimethyl-c-butyl, 2,2-
Dimethyl-c-butyl, 2,3-dimethyl-c-butyl, 2,4-dimethyl-c-butyl, 3,3-dimethyl-c-butyl, 1-n-propyl
-c-propyl, 2-n-propyl-c-propyl, 1-i-propyl
-c-propyl, 2-i-propyl-c-propyl, 1,2,2-trimethyl-c-propyl, 1,2,3-trimethyl-c-propyl, 2,2,
3-trimethyl-c-propyl, 1-ethyl-2-methyl-c-propyl, 2-ethyl-1-methyl-c-propyl, 2-ethyl-2-methyl-c-propyl, 2-ethyl-3- Methyl-c-propyl, c-
Heptyl, c-octyl, c-nonyl and the like.

Examples of the hydroxyl-protecting group include methoxymethyl, benzyloxymethyl, methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, methylthiomethyl, phenylthiomethyl, 2,2-dichloro-1, 1-difluoroethyl group, tetrahydropyranyl group, phenacyl group, p-bromophenacyl group, cyclopropylmethyl group, allyl group, benzyl group, 2,6-
Dimethylbenzyl group, 4-methoxybenzyl group, o-nitrobenzyl group, 2,6-dichlorobenzyl group, 4-
(Dimethylaminocarbonyl) benzyl group, 9-anthrylmethyl group, 4-picolyl group, heptafluoro-p-
Examples include a tolyl group, a tetrafluoro-4-pyridyl group, a t-butyldimethylsilyl group, and a trimethylsilyl group.

Next, a specific method for producing the dihydrobenzopyran derivative will be described.

The Grignard reagent used in the present invention is not particularly limited as long as it can generate a phenolate ion from phenol. For example, methylgnesium bromide, ethylgnesium bromide, n-propylgnesium bromide, i-propylgnesium bromide N-butylgnesium bromide, i-butylgnesium bromide, phenylgnesium bromide, benzylgnesium bromide, methyl magnesium iodide, ethyl magnesium iodide, n-propyl magnesium iodide, i-propyl magnesium iodide, n-butyl magnesium iodide Dyde, i-butyl magnesium iodide, phenyl magnesium iodide, benzyl magnesium iodide, methyl magnesium chloride, ethyl Magnesium chloride,
n-propyl magnesium chloride, i-propyl magnesium chloride, n-butyl magnesium chloride,
Examples thereof include i-butylmagnesium chloride, phenylmagnesium chloride and benzylmagnesium chloride, and preferably include ethylmagnesium bromide.

The amount of the Grignard reagent to be used is 0.5 to 2.0 equivalents, preferably 1.0 to 1.2 equivalents, based on the substrate.
Equivalent range.

As the solvent to be used, aromatic solvents such as benzene, toluene and xylene are preferable, and benzene is particularly preferable.

The reaction temperature is 60 to 80 ° C., preferably
70-80 ° C.

Next, the stereoisomers of the resulting dihydrobenzopyran derivative will be described.

At the beginning of the reaction, the dihydrobenzopyran derivative represented by the formula (3) is produced exclusively, but as the reaction time becomes longer, the dihydrobenzopyran derivative represented by the formula (2) is gradually produced. , Isomerizing.

Therefore, the dihydrobenzopyran derivative represented by the formula (2) or (3) can be selectively synthesized by adjusting the reaction time and the reaction temperature.

The reaction temperature of the dihydrobenzopyran derivative represented by the formula (2) or (3) is 60 to 60.
80 ° C, preferably 70 to 80 ° C.

The dihydrobenzopyran derivative represented by the formula (3) is preferably prepared, for example, at a temperature of 80 ° C.
It is selectively manufactured in 0.5 to 1 hour, more preferably 0.5 hour.

When the temperature of the dihydrobenzopyran derivative represented by the formula (2) is, for example, 80.degree.
It is selectively produced by reacting for 5 hours or more.

By reacting for 60 hours or more, the dihydrobenzopyran derivative represented by the formula (2) can be produced exclusively.

Next, a method for producing a phenol represented by the formula (1), which is a substrate for this reaction, will be described. Equation 1

[0031]

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The compound represented by the formula (4) is condensed with a carboxylic acid in the presence of a Lewis acid to give a compound represented by the formula (5). The phenols represented can be produced.

[0033]

The present invention will be described in more detail with reference to the following examples.
The present invention is not limited to these.

Reference Example 1 Synthesis of compound (6)

[0035]

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Under an argon atmosphere, 3.71 ml (34.17 mmol) of isovaleric acid was added to 5.01 g (32.54 mmol) of 3,5-dimethoxyphenol, and then BF ₃ .OEt _2.
16.5 ml (130.2 mmol) was added, and the mixture was stirred at 80 ° C for 5 hours. The reaction solution was 10% aqueous potassium acetate solution 4
The solution was poured into 0 ml, extracted with ethyl acetate (50 ml × 3), and washed with a saturated aqueous solution of sodium hydrogen carbonate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (BW-820MH 400 g, eluent n-hexane: ethyl acetate = 8: 1) to give compound (6) 6.
51 g (27.28 mmole, 84% yield) were obtained as white crystals.

¹ H NMR (CDCl ₃ 500 MHz) δ: 0.97 (6H, d, J =
6.7Hz), 2.20 (1H, tq, J = 6.7Hz, 6.7Hz), 2.85 (2H, d, J = 6.7H
z), 3.81 (3H, s), 3.85 (3H, s), 5.91 (1H, d, J = 2.4Hz), 6.06 (1
(H, d, J = 2.4Hz), 14.15 (1H, s)

Reference Example 2 Synthesis of compound (7)

[0039]

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Compound (6) 20.2 in an argon atmosphere
2 g (84.85 mmol) of anhydrous diethyl ether 4
Dissolved in 00 ml. Cool to 0 ° C. and add LiAlH ₄ 2.26
g (59.55 mmol) in small portions over 10 minutes,
Stir for 30 minutes. Sodium sulfate decahydrate 19.1
4 g (59.40 mmol) was added in small portions, and 1
Stirred for hours. The precipitate was removed by filtration through Celite, and the residue was washed with ethyl acetate. The organic layers were combined and the solvent was distilled off under reduced pressure. The residue is subjected to silica gel column chromatography (BW
-820MH 600 g, eluent n-hexane: ethyl acetate = 7: 1) to give 17.31 g of compound (7)
2.03 mmol, 85% yield) as a pale orange oil.

¹ H NMR (CDCl ₃ 90 MHz) δ: 0.75 (3H, s), 0.8
0 (3H, s), 1.00-2.50 (4H, m), 3.65 (6H, s), 6.85 (1H, s), 6.95
(1H, s)

Example 1 Synthesis of Compound 8

[0043]

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Compound (7) 25.9 under an argon atmosphere
4 g (107.9 mmol) was dissolved in 400 ml of anhydrous tetrahydrofuran. 95.2 ml (97.15 mmol) of 1.02 M EtMgBr-tetrahydrofuran solution at room temperature
Was added and stirred at room temperature for 8 hours. After evaporating the solvent under reduced pressure, 400 ml of anhydrous benzene was added, and the mixture was stirred at 80 ° C for 30 minutes. After returning to room temperature, diethyl ether 400
ml and stirred at room temperature until a precipitate formed. After the formed precipitate was removed by filtration through Celite, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (BW-82).
The mixture was subjected to 1100 g of 0MH and an eluent of n-hexane: ethyl acetate = 7: 1) to obtain 18.71 g (42.
08 mmol, yield 78.0%) as a white solid.

¹ H NMR (CDCl ₃ 500 MHz) δ: 0.78 (3H, d, J =
6.7Hz), 0.82 (3H, d, J = 6.4Hz), 0.92 (3H, d, J = 7.0Hz), 0.93
(3H, d, J = 6.4Hz), 1.30-1.45 (3H, m), 1.61 (1H, m), 2.22 (1H,
ddd, J = 11.0Hz, 2.5Hz, 2.5Hz), 3.17 (1H, ddd, J = 8.3Hz, 2.5H
z, 2.5Hz), 3.69 (3H, s), 3.74 (3H, s), 3.79 (3H, s), 3.80 (3H,
s), 5.01 (1H, d, J = 11.0Hz), 6.05 (1H, d, J = 2.5Hz), 6.19 (3H,
m), 7.42 (1H, s)

Example 2 Synthesis of compound (9)

[0047]

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Compound (7) 9.43 under an argon atmosphere
g (39.24 mmol) in anhydrous diethyl ether 1
Dissolved in 00 ml. At room temperature, 43.2 ml (43.16 mmole) of a 1.0 M EtMgBr-tetrahydrofuran solution was added, and the mixture was stirred at room temperature for 14.5 hours. After evaporating the solvent under reduced pressure, 100 ml of anhydrous benzene was added, and the mixture was stirred at 80 ° C for 29 hours. After returning to room temperature, 43.2 ml of 1N hydrochloric acid
(43.2 mmol) and extracted with ethyl acetate.
(100 ml × 3) After the organic layer was washed with 50 ml of saturated saline, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (450 g of BW-820MH, eluent n-hexane: ethyl acetate = 10: 1). ) To give 6.45 g (29.03 mmol, yield 7) of compound (9).
4.0%) as a white solid.

¹ H NMR (CDCl ₃ 500 MHz) δ: 0.66 (3H, d, J =
7.1Hz), 0.83 (3H, d, J = 7.1Hz), 0.97 (3H, d, J = 6.7Hz), 1.07
(3H, d, J = 6.4Hz), 1.49-1.59 (2H, m), 1.73 (1H, m), 1.84 (1H,
dd, J = 2.4Hz, 2.4Hz), 1.94 (1H, m), 2.86 (1H, dd, J = 9.2Hz, 3.
7Hz), 3.75 (6H, s), 3.79 (3H, s), 3.81 (3H, s), 5.72 (1H, d, J =
2.4Hz), 6.05 (1H, d, J = 2.5Hz), 6.06 (1H, d, J = 2.5Hz), 6.12
(1H, d, J = 2.0Hz), 6.13 (1H, d, J = 2.0Hz), 8.39 (1H, s)

Example 3 2342 mg (9.84 mmol) of the compound (7) was dissolved in 45 ml of anhydrous diethyl ether under a stream of argon. At room temperature, 0.94 M ethylmagnesium bromide-tetrahydrofuran solution (10.4 ml, 9.84 mmol)
e) was added and stirred at room temperature for 2.5 hours. After evaporating the solvent under reduced pressure, 45 ml of anhydrous benzene was added, and the mixture was added
Stir for 6 hours. The precipitate formed was filtered off through Celite, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (BW-820MH, eluent n-hexane: ethyl acetate = 6: 1) to give compound (9). ) 897mg
21% and 7% of compound (8) were obtained.

Comparative Example 1 Reaction in the Absence of Ethyl Magnesium Bromide Compound (7) was dissolved in n-hexane, sealed, and
The reaction was carried out at 80 ° C., but the desired compound (8) or compound (9) was not obtained.

Comparative Example 2 Reaction using ZnCl ₂ instead of ethylmagnesium bromide Compound (7) was dissolved in methylene chloride, ZnCl ₂ was added, and the reaction was carried out at room temperature. ) Or compound (9) was not obtained.

Comparative Example 3 Reaction Using BF ₃ .OEt ₂ Instead of Ethyl Magnesium Bromide Compound (7) was dissolved in methylene chloride to obtain BF ₃ .OEt _2.
Was added and the reaction was carried out at room temperature, but the desired compound (8) or compound (9) could not be obtained.

[0054]

According to the method of the present invention, a dihydrobenzopyran derivative which is important as an intermediate of a physiologically active substance such as a medical or agricultural chemical can be produced.

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Claims (5)

[Claims] (1) Formula (1) Wherein R ¹ and R ³ are each independently a hydrogen atom or C
_1-9 refers to an alkyl group, R ² and R ⁴ each independently represents a hydrogen atom, C _1-9 alkyl group or a hydroxyl-protecting group, R ⁵ is a hydrogen atom or a C _1-9 alkyl group Means Wherein the two molecules of phenol represented by the formula (2) or (3) are condensed by a Diels-Alder reaction in the presence of a Grignard reagent. [Wherein, R ¹ , R ² , R ³ , R ⁴ and R ⁵ represent the same meaning as described above. The method for producing a dihydrobenzopyran derivative represented by the formula: 2. The method for producing a dihydrobenzopyran derivative according to claim 1, wherein the dihydrobenzopyran derivative represented by the formula (2) is produced. 3. The method for producing a dihydrobenzopyran derivative according to claim 1, wherein the dihydrobenzopyran derivative represented by the formula (3) is produced. 4. The method for producing a dihydrobenzopyran derivative according to claim 1, wherein ethyl magnesium bromide is used as the Grignard reagent. 5. The method for producing a dihydrobenzopyran derivative according to claim ⁴ , wherein R ¹ and R ³ are hydrogen atoms, R ² and R ⁴ are methyl groups, and R ⁵ is an isopropyl group.