JP4311241B2 - Process for producing 1-alkylcarbonyloxy-3-substituted phenyl-propene compound - Google Patents

Description

The present invention relates to a method for producing a 1-alkylcarbonyloxy-3-substituted phenyl-propene compound that is useful as an intermediate for fragrances, medicines and agricultural chemicals, and organic synthetic drugs. In particular, in the following formula (4), OR ¹ is a methoxy group, R ⁴ is a methyl group, R ³ is a hydrogen atom, m is 0, and n is 1, 1-methylcarbonyloxy-3- (3-methoxyphenyl)- 2-Methyl-propene can be derived into 3- (3-methoxyphenyl) -2-methyl-propionaldehyde useful as a fragrance by hydrolysis (Non-patent Document 1).

(Wherein, OR ¹ and OR ² each represent an independently alkoxy group having 1 to 4 carbon atoms, and when these substituents are adjacent to each other, they are bonded to each other to form a methylenedioxy group or an ethylenedioxy group. M represents an integer of 0 to 4, n represents an integer of 1 to 5, R ⁵ represents an alkyl group having 1 to 10 carbon atoms, and R ³ and R ⁴ are independent of each other. It represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms and may be bonded to each other to form a ring, and this compound includes stereoisomers.)

  As a method for synthesizing the 1-alkylcarbonyloxy-3-substituted phenyl-propene compound represented by the above formula (4), for example, Non-Patent Document 1 includes 1,3-dimethoxybenzene and metalylidene diacetate in three fluorines. Described is a method of synthesizing 1-methylcarbonyloxy-3- (3,4-dimethoxyphenyl) -2-methyl-propene by reacting in the presence of titanium tetrachloride activated with a boron bromide diethyl ether complex. Although the yield was 62%, it was insufficient. As a result of the inventor's further trial of the synthesis method, the yield was further lowered to 12%, and the reaction solution turned brown due to the generation of many by-products (see Comparative Example 1).

Patent Document 2 describes a method for synthesizing a 1-alkylcarbonyloxy-3-substituted phenyl-propene compound in which an alkoxy-substituted benzene and an α, β-unsaturated aldehyde are reacted. However, 1-methylcarbonyloxy-3- (3-methoxyphenyl) -2-methyl in which anisole, methacrolein and acetyl chloride described in the examples are reacted in the presence of a stoichiometric amount of titanium tetrachloride. -The synthesis of propene was inadequate with a yield of 57.2%.
Further, in this example, 1-methylcarbonyloxy-3- (t-butylphenyl) -2 is prepared by reacting t-butylbenzene with methacrolein and acetic anhydride in the presence of a stoichiometric amount of titanium tetrachloride. Although the synthesis of -methyl-propene is also described, the yield was also inadequate at 24.8%.

  The synthesis of the above 1-methylcarbonyloxy-3- (3-methoxyphenyl) -2-methyl-propene described in the same document was conducted by the inventor using acetic anhydride instead of acetyl chloride. The yield of 1-methylcarbonyloxy-3- (3-methoxyphenyl) -2-methyl-propene was 54.9%, and the yield was not improved (see Comparative Example 2).

In Patent Document 3, methacrolein and acetic anhydride were reacted in the presence of zinc chloride to synthesize metallylidene diacetate, and then the reaction solution was anisole and then 1.2 equivalents of tetrachloride with respect to methacrolein. The synthesis of 1-methylcarbonyloxy-3- (3-methoxyphenyl) -2-methyl-propene, which is reacted by adding titanium, is described, and the yield is 80.3%. However, in the same synthesis method as in Non-patent Document 1, it is necessary to use a titanium tetrachloride that is so unstable that it is easily decomposed even by moisture in the air, and the handling thereof is complicated. In addition, there are problems such as by-production of a lot of titanium waste.
Japanese Patent Publication No.42-9135 JP 55-141437 A JP 61-161241 A Bull. Soc. Chim. Fr. , 1961, p. 1194

  An object of the present invention is to obtain a 1-alkylcarbonyloxy-3-substituted phenyl-propene compound, which is useful as an intermediate for fragrances, medicines and agrochemicals, and organic synthetic drugs, from an alkoxy-substituted benzene in a simple and high yield. The present invention provides a method for producing a 1-alkylcarbonyloxy-3-substituted phenyl-propene compound suitable for use in the preparation of

As a result of investigations to solve the above-mentioned problems, the present inventors have found a simple and good production method of a 1-alkylcarbonyloxy-3-substituted phenyl-propene compound and completed the present invention.
That is, the present invention is as follows.

  Alkoxy represented by the following formula (1) in the presence of a catalyst comprising at least one compound selected from the group consisting of triflate compounds of group 11 to group 13 elements, tin and lanthanoid elements, and halogen compounds of these elements With substituted benzene

(Wherein, OR ¹ , OR ² , m and n are as defined above.)

Α, β-unsaturated aldehyde represented by the following formula (2)

(Wherein R ³ and R ⁴ have the same meanings as described above. In addition, the present compound includes stereoisomers.)

It is characterized by reacting a carboxylic acid anhydride represented by the following formula (3)

(In the formula, R ⁵ has the same meaning as described above.)

The present invention relates to a method for producing a 1-alkylcarbonyloxy-3-substituted phenyl-propene compound represented by the following formula (4).

(In the formula, OR ¹ , OR ² , R ³ , R ⁴ , m and n are as defined above. In addition, this compound includes stereoisomers.)

  According to the present invention, a 1-alkylcarbonyloxy-3-substituted phenyl-propene compound that is useful as an intermediate for fragrances, medicines and agricultural chemicals, and organic synthetic drugs can be obtained simply and in good yield from alkoxy-substituted benzene. Therefore, the method for producing a 1-alkylcarbonyloxy-3-substituted phenyl-propene compound of the present invention is industrially suitable and has high industrial applicability.

Hereinafter, the present invention will be described in detail.
The production of the 1-alkylcarbonyloxy-3-substituted phenyl-propene compound represented by the formula (4) is selected from the group consisting of triflate compounds of element periodic table 11-13 elements, tin and lanthanoid elements, and halogen compounds. The reaction can be carried out by reacting the alkoxy-substituted benzene derivative represented by the formula (1) with the α, β-unsaturated aldehyde represented by the formula (2) in the presence of a catalyst containing at least one compound. .
In the present invention, other compounds can be added as long as the reaction is not hindered, but titanium tetrachloride is not used.

The alkoxy-substituted benzene derivative used in the present invention is represented by the above formula (1).
In the formula (1), OR ¹ and OR ² each independently represent an alkoxy group having 1 to 4 carbon atoms, and when these substituents are adjacent to each other, they are bonded to each other to form a methylenedioxy group or an ethylenedioxy group. May be formed. m represents an integer of 0 to 4, and n represents an integer of 1 to 5.

  Here, examples of the alkoxy group having 1 to 4 carbon atoms include a methoxy group, an ethoxy group, a propoxy group, and a butoxy group. These substituents include isomers.

  Specific examples of the alkoxy-substituted benzene derivative include anisole, veratrol, hydroquinone dimethyl ether, 1,4-benzodioxane, pyrogallol trimethyl ether, hydroxyhydroquinone trimethyl ether, and 1,2-methylenedioxybenzene. In addition, these can use a commercially available thing.

  The amount of the alkoxy-substituted benzene derivative used in the present invention is preferably 1 to 50 mol, more preferably 1 to 20 mol, relative to 1 mol of the α, β-unsaturated aldehyde.

  As the α, β-unsaturated aldehyde represented by the formula (2) used in the present invention, a commercially available product can be used. In addition, this compound contains a stereoisomer.

In the formula (2), R ³ and R ⁴ represent a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, and may be bonded to each other to form a ring.

Here, examples of the alkyl group having 1 to 10 carbon atoms include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, and a decyl group. A methyl group is preferred. These groups include various isomers. Examples of the ring formed by combining R ³ and R ⁴ with each other include a cyclopentane ring and a cyclohexane ring, with a cyclohexane ring being preferred.

  Examples of the α, β-unsaturated aldehyde include acrolein, methacrolein, crotonaldehyde, α, β-dimethylacrolein, α-ethylacrolein, β-ethylacrolein, β-propylacrolein, α-cyclohexylacrolein and the like. Acrolein, methacrolein and crotonaldehyde are preferred, and methacrolein is more preferred.

As the catalyst used in the present invention, at least one selected from the group consisting of triflate compounds of element periodic table 11-13 elements, tin and lanthanoid elements, and halogen compounds is used.
The element group names here are based on the Group 18 element periodic table, IUPAC inorganic compound nomenclature, 1990.

Examples of the triflate compound and halogen compound of the Group 11 element of the periodic table include copper, silver and gold triflate compounds and halogen compounds. Copper, silver and gold triflate compounds are preferable, and copper triflate compounds are more preferable.
Here, “triflate” means trifluoromethanesulfonate.

  As the triflate compounds and halogen compounds of Group 12 elements of the periodic table, zinc halides (zinc fluoride, zinc chloride, zinc bromide, zinc iodide), cadmium halides (cadmium fluoride, cadmium chloride, cadmium bromide) , Cadmium iodide), mercury halides (mercury fluoride, mercury chloride, mercury bromide, mercury iodide), and the like. Of these, zinc halides are preferred, and zinc chloride is more preferred.

Examples of triflate compounds and halogen compounds of Group 13 elements of the periodic table include boron triflate compounds and halogen compounds, with boron halogen compounds being preferred.
Examples of boron halides include boron fluoride, boron trifluoride diethyl ether complex, boron trifluoride tetrahydrofuran complex, boron trifluoride acetic acid complex salt, boron trifluoride dihydrate, boron trifluoride n-butyl ether complex. Among them, boron trifluoride diethyl ether complex and boron trifluoride acetic acid complex salt are preferable. Commercially available compounds can be used.

Examples of triflate compounds and halogen compounds of tin and lanthanoid elements include tin triflate, tin halides (tin fluoride, tin chloride, tin bromide, tin iodide), cerium halides (cerium fluoride, cerium chloride, odor) Cerium iodide, cerium iodide), cerium triflate, dysprosium halide (dysprosium fluoride, dysprosium chloride, dysprosium bromide, dysprosium iodide), dysprosium triflate, holmium halides (holmium fluoride, holmium chloride, holmium bromide) , Holmium iodide), holmium triflate, erbium halide (erbium fluoride, erbium chloride, erbium bromide, erbium iodide), erbium triflate, thulium halide (thulium fluoride, Thulium iodide, thulium bromide, thulium iodide), thulium triflate, ytterbium halide (ytterbium fluoride, ytterbium chloride, ytterbium bromide, ytterbium iodide), ytterbium triflate, lutetium halide (lutetium fluoride, lutetium chloride) , Lutetium bromide, lutetium iodide), lutetium triflate and the like. Alternatively, these compounds include hydrates thereof.
Among these compounds, tin chloride, tin triflate, cerium triflate, erbium triflate, or ytterbium triflate is preferable.

The usage-amount of the said catalyst is 1 mol or less with respect to 1 mol of ( alpha), (beta) -unsaturated aldehyde , Preferably it is 0.005-0.5 mol. If the amount used is less than this range, the reaction is not completed in 24 hours. If the amount is too large, complicated operations such as decomposition and disposal of an excessive amount of catalyst are required, and this is not suitable for an industrial scale.

  The synthesis reaction of the 1-alkylcarbonyloxy-3-substituted phenyl-propene compound of the present invention may be performed using a solvent, but is preferably solventless.

While the reaction temperature varies depending on the type of raw material substance involved in the reaction, it is −10 to 80 ° C., preferably 0 to 50 ° C.
The reaction time varies depending on the concentration and temperature, but is 0.5 to 24 hours.

  This reaction is usually performed in an inert gas atmosphere such as argon or nitrogen, or in a gas stream of these gases. The reaction pressure used is usually atmospheric pressure.

  The synthesized 1-alkylcarbonyloxy-3-substituted phenyl-propene compound is subjected to usual post-treatments such as extraction, concentration, and filtration after completion of the reaction, and may be subjected to distillation, recrystallization, various chromatography, etc. as necessary. It can be appropriately purified by known means.

  The following are typical examples of the present invention.

Example 1
Content: 88.5 wt% methacrolein (0.39 g, 5.0 mmol), anisole (5.41 g, 50.0 mmol), acetic anhydride (0.72 g, 7.1 mmol) was added. Boron trifluoride diethyl ether complex (0.07 g, 0.5 mmol) was added to the mixture at an internal temperature of 24 ° C., and the mixture was stirred at an internal temperature of 24 to 25 ° C. for 1 hour. After completion of the reaction, water (30 ml) and acetonitrile (50 ml) were added to the reaction solution, and quantitative analysis was performed using high performance liquid chromatography. As a result, the target 1-acetoxy-2-methyl-3- (4- The yield of methoxyphenyl) propene was 91.9% (yield 1.01 g).

Example 2
Content: 88.5 wt% methacrolein (0.40 g, 5.0 mmol), 1,2-methylenedioxybenzene (3.06 g, 25.0 mmol) in a 20 ml two-necked flask under argon atmosphere Acetic anhydride (0.72 g, 7.1 mmol) was added. Boron trifluoride diethyl ether complex (0.07 g, 0.5 mmol) was added to the mixture at an internal temperature of 23 ° C., and the mixture was stirred at an internal temperature of 23 ° C. for 1 hour. After completion of the reaction, the reaction solution was washed twice with water (5 ml). The obtained organic layer was separated and distilled by distillation under reduced pressure (8 to 10 mmHg, 80 to 84 ° C.), and then the residue was purified by silica gel chromatography (elution solvent: hexane / ethyl acetate = 15/1) and colorless. The target 1-acetoxy-2-methyl-3- (3,4-methylenedioxyphenyl) propene (yield 80.5%, yield 0.94 g) was obtained as a liquid.
The physical property values of 1-acetoxy-2-methyl-3- (3,4-methylenedioxyphenyl) propene are shown below.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.59 (3H, d, J = 1.5 Hz), 2.15 (3H, s), 3.17 (2H, s), 5.92 (2H , S), 6.63 (1H, dd, J = 7.8 Hz, J = 1.5 Hz), 6.67 (1H, d, J = 1.5 Hz), 6.72 (1H, d, J = 7.8 Hz), 7.02 (1H, q, J = 1.5 Hz)

¹³ C-NMR (75.5 MHz, CDCl ₃ ) δ = 13.43, 20.78, 40.05, 100.86, 108.10, 109.10, 121.31, 121.70, 131.24. 132.79, 146.08, 147.69, 168.26

Elemental analysis:
C (%) H (%)
Expected value for C ₁₃ H ₁₄ O ₄ 66.66 6.02
Measurement 66.71 6.16

Examples 3 and 4
The same reaction as in Example 1 was carried out except that the alkoxybenzene (50.0 mmol) shown in Table 1 below was used in place of the anisole of Example 1. The results are shown in Table 1 below.

Example 5
The same reaction as in Example 2 was carried out except that propionic anhydride (0.92 g, 7.1 mmol) shown in Table 1 was used instead of acetic anhydride in Example 2.
As a result, 1-ethylcarbonyloxy-2-methyl-3- (3,4-methylenedioxyphenyl) propene (yield: 78.6% (yield 0.97 g)) was obtained.
The physical properties of 1-ethylcarbonyloxy-2-methyl-3- (3,4-methylenedioxyphenyl) propene are shown below.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.19 (3H, t, J = 7.5 Hz), 1.59 (3H, d, J = 1.5 Hz), 2.43 (2H, q, J = 7.5 Hz), 3.18 (2H, s), 5.92 (2H, s), 6.62-6.74 (3H, m), 7.03 (1H, q, J = 1. 5Hz)

MS (FAB) m / z 248 (M +)

Example 6
The same reaction as in Example 2 was performed except that isobutyric anhydride (1.10 g, 7.1 mmol) shown in Table 1 was used instead of acetic anhydride in Example 2. As a result, 1-isopropylcarbonyloxy-2-methyl-3- (3,4-methylenedioxyphenyl) propene (yield 78.6%, yield 0.97 g) was obtained.
The physical properties of 1-isopropylcarbonyloxy-2-methyl-3- (3,4-methylenedioxyphenyl) propene are shown below.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.22 (3H, d, J = 6.8 Hz), 1.59 (3H, d, J = 1.5 Hz), 2.64 (1H, qq, J = 6.8 Hz), 3.18 (2H, s), 5.29 (2H, s), 6.62-6.74 (3H, m), 7.01 (1H, q, J = 1. 5Hz)

MS (FAB) m / z 262 (M +)

Examples 7-18
A reaction similar to that of Example 2 was performed except that the catalyst shown in Table 2 was used instead of the boron trifluoride diethyl ether complex of Example 2. The results are shown in Table 2.

注）ＭＡＬ ：メタクロレイン
ＭＤＢ ：１，２−メチレンジオキシベンゼン
ＡＭＤＢ：１−アセトキシ−２−メチル−３−(３，４−メチレンジオキシフェニル)
プロペン
ＯＴｆ ：トリフルオロメタンスルホネート

Note) MAL: methacrolein MDB: 1,2-methylenedioxybenzene AMDB: 1-acetoxy-2-methyl-3- (3,4-methylenedioxyphenyl)
Propene OTf: trifluoromethanesulfonate

Comparative Example 1
Under an argon atmosphere, titanium tetrachloride (1.18 g, 6.2 mmol) was added to a 25 ml three-necked flask, and boron trifluoride diethyl ether complex (0.016 g, 0.11 mmol) was added. 1,2-Dimethoxybenzene (3.40 g, 24.6 mmol) was added dropwise over 30 minutes at an internal temperature of 8 to 12 ° C. Subsequently, a mixture of 2-methyl-3,3-diacetoxypropene (0.75 g, 6.1 mmol) and 1,2-dimethoxybenzene (0.77 g, 5.6 mmol) having a content of 100% by weight was taken over 5 minutes. And dripped. The mixture was stirred at an internal temperature of 8 to 10 ° C. for 60 minutes, 6N hydrochloric acid (10 ml) and dichloromethane (10 ml) were added, and the mixture was stirred for 30 minutes. After completion of the reaction, the precipitated insoluble matter was filtered off and extracted with dichloromethane. The obtained organic layer was washed with water, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain 4.54 g of a crude product. As a result of quantitative analysis of the crude product using high performance liquid chromatography, the target 1-acetoxy-2-methyl-3- (3,4-dimethoxyphenyl) propene was obtained in a yield of 12.0% (a yield of 0). .18 g).
Moreover, this reaction liquid was brown, and many by-products were confirmed by analysis by high performance liquid chromatography.

Comparative Example 2
Content: 88.5 wt% methacrolein (0.39 g, 5.0 mmol), anisole (5.41 g, 50.0 mmol), acetic anhydride (0.72 g, 7.1 mmol) was added. Titanium tetrachloride (0.95 g, 5.0 mmol) was added to the mixture at an internal temperature of 3 ° C., and the mixture was stirred at an internal temperature of 3 ° C. for 1 hour. After completion of the reaction, acetonitrile (50 mL) was added to the reaction solution, and then quantitative analysis was performed using high performance liquid chromatography. As a result, the target 1-acetoxy-2-methyl-3- (4-methoxyphenyl) propene was analyzed. The yield was 54.9% (yield 0.60 g).

Claims (5)

An alkoxy-substituted benzene represented by the following formula (1 ′)

(Wherein, OR ¹ and OR ² is to adjacency, methylenedioxy bonded to each other, or form a ethylenedioxy group.) Alpha represented by the following formula (2), and β- unsaturated aldehyde

(Wherein R ³ and R ⁴ each represent an independent hydrogen atom or an alkyl group having 1 to 10 carbon atoms, and may be bonded to each other to form a ring. Carboxylic anhydride represented by the following formula (3):

(In the formula, R ⁵ represents an alkyl group having 1 to 10 carbon atoms.)
And a catalyst containing at least one compound selected from the group consisting of triflate compounds of Group 11 to 13 elements of the Periodic Table of Elements, tin and lanthanoid elements, and halogen compounds of these elements are represented by the formula (2) 1-alkylcarbonyloxy-3-substituted phenyl represented by the following formula (4 ′) , wherein 0.005 to 0.5 mol is used per 1 mol of .beta.-unsaturated aldehyde. -Propene compound production method.

^{(Wherein, OR 1, OR 2, R} 3, R 4 及 beauty R ⁵ are as defined above. Further, the compound contains stereoisomers.) Alkoxy-substituted benzene represented by the formula (1 ') is 1, 2-methylene Ru dioxybenzenes der claim 1 1- alkylcarbonyloxy-3-substituted phenyl according - preparation of propene compound. The method for producing a 1-alkylcarbonyloxy-3-substituted phenyl-propene compound according to claim 1 or 2 , wherein the α, β-unsaturated aldehyde represented by the formula (2) is selected from acrolein, methacrolein, and crotonaldehyde. . The production of a 1-alkylcarbonyloxy-3-substituted phenyl-propene compound according to any one of claims 1 to 3 , wherein the carboxylic acid anhydride represented by the formula (3) is selected from acetic anhydride and isobutyric anhydride. Law. The catalyst is composed of zinc fluoride, zinc chloride, zinc bromide, zinc iodide, boron trifluoride diethyl etherate complex, boron trifluoride acetic acid complex salt, tin chloride, tin triflate, cerium triflate, erbium triflate, or ytterbium triflate. The method for producing a 1-alkylcarbonyloxy-3-substituted phenyl-propene compound according to any one of claims 1 to 4 , comprising at least one compound selected from the group.