JPH0136830B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula 1 [In the formula, R is a (CH ₃ ) ₃ Si- group,

[Formula] Group (in the group, R ¹ and R ² represent hydrogen or an alkyl group having 1 to 7 carbon atoms, and R ³ represents an alkyl group having 1 to 7 carbon atoms) or

It relates to a compound represented by [Formula] represents a group]. Furthermore, in producing the compound of general formula 1, the present invention provides the compound of formula 2 4-ethylenedioxy-2,6,6-trimethyl-2-cyclohexen-1-one of general formula 3 (wherein M represents an alkali metal or a magnesium halide group, and R has the same meaning as R in General Formula 1). The acetylene derivative represented by the above general formula 1 is 4-hydroxy-4-[(E)-
3-hydroxy-1-butenyl)-3,5,5-
It is useful as an intermediate for producing trimethyl-2-cyclohexen-1-one (commonly known as Blumenol A). Conventionally, 4-ethylenedioxy-2,6, of formula 2
To the ketone of 6-trimethyl-2-cyclohexen-1-one, using the nucleophilic reaction of acetylene, 3
The following method has been proposed as a method for introducing the structural unit of -butyn-2-ol. (1) Helv.Chim.Acta, 57, 2087 (1974) However, since the reaction is carried out with the hydroxyl group of 3-butyn-2-ol in a free state, this method consumes base not only in the acetylene part but also in the hydroxyl part, and is therefore less economical. In addition, the relatively low molecular weight 3
Since the two sites of -butyn-2-ol have a metal salt structure, the solubility in organic solvents is low, resulting in poor reaction operability such as salt precipitation. In addition, the present inventors, J.Chem.Soc.(C), 404
(1971).
Using the corresponding magnesium halide salt derived from 2-ol and ethylmagnesium bromide, in addition to the 1,2-adduct 4, the 1,4
- adduct, The disadvantage of the formation of so-called Michael adduct 5 was confirmed. Particularly when a hydrocarbon solvent such as benzene is used, the 1,4-adduct 5 becomes the main product. The present inventors conducted research to overcome the above drawbacks or disadvantages, and as a result, they arrived at the present invention. The method of the present invention is characterized in that an organometallic compound of general formula 3 with a protected hydroxyl group is used as a component for extending four carbon atoms to the compound of formula 2. By using the compound of general formula 3, the amount of base used can be reduced. Furthermore, since the solubility of the reaction reagent is improved, the operability of the reaction is improved. Furthermore, by using the compound of general formula 3, the formation of 1,4-adducts can be almost suppressed, and in some cases, they are not detected at all. The method of the invention consists of reacting a compound of formula 2 with an organometallic compound of general formula 3. M in organometallic compound 3 is an alkali metal, preferably
Li, Na, Ka or halogenated magnesium groups,
Preferred are magnesium chloride, magnesium bromide, and magnesium iodide groups. Generally, halogenated magnesium groups are preferred. As the reaction solvent, an ether solvent, preferably diethyl ether, dipropyl ether, tetrahydrofuran, 1,2-dimethoxyethane, diethylene glycol dimethyl ether or a hydrocarbon solvent,
Preferably, benzene, toluene, xylene or liquid ammonia is used. The reaction temperature is -
The temperature is 40 to 100°C, preferably -40 to 60°C. As R of the organometallic compound of general formula 3,
(CH ₃ ) ₃ Si−,

[Formula] CH ₃ OCH ₂ −, CH ₃ CH ₂ OCH ₂ −,

[Formula] etc. are preferably used. The organometallic compound of general formula 3 is usually produced by reacting a compound of general formula 3 in which M is hydrogen with a base. As a base,
NaH, LiNH ₂ , NaNH ₂ , Grignard reagent, etc. are used. Grignard reagents include methyl,
Ethyl, propyl, butyl, vinyl, allyl Grignard reagents, etc. are preferably used. Organometallic induction of general formula 3 is 4-ethylenedioxy-
2,6,6-trimethyl-2-cyclohexene-
Usually 1 to 4 times the mole of 1-one is used. Preferably it is 1 to 2 times the mole. All of the above compounds of general formula 1 produced in this way are new compounds. The compound of general formula 1 is then converted into MAlHn(OR ⁴ ) _4-o
(In the formula, M represents an alkali metal, and R ⁴ has 1 carbon number.
~7 alkyl groups or oxygen-substituted alkyl groups; oxygen substitution means that the continuity of the carbon skeleton is interrupted by the presence of an oxygen atom. n
represents an integer from 1 to 3), and then acid hydrolysis to produce 4-hydroxy-4-[(E)-3-hydroxy-1-butenyl]-3, 5,5-trimethyl-
It can be derived into 2-cyclohexen-1-one. The solvent for the reduction reaction is not particularly limited as long as it does not deactivate the active hydrogen of the reducing agent.
For example, benzene, toluene, xylene, diethyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, dioxane, and any mixtures thereof are used. M in the reducing agent MAln(OR ⁴ ) _4-o is an alkali metal, preferably Li, Na, or K.
R ⁴ is methyl, ethyl, propyl, butyl,
Pentyl, 2-methoxyethyl, 2-ethoxyethyl groups, etc. are preferred. n is an integer from 1 to 3, preferably n=2. Specific examples of preferable reducing agents include NaAlH ₂ (OCH ₂ CH ₂ OCH ₃ ) ₂ ,
NaAlH ₂ (OCH ₃ ) ₂ , NaAlH ₂ (OC ₂ H ₅ ) ₂ ,
NaAlH ₂ (O-n-Pr) ₂ , NaAlH ₂ (O-i-
Pr) ₂ , NaAlH ₂ (O-n-Bu) ₂ , NaAlH ₂ (O-i
-Bu) ₂ , NaAlH ₂ (O-t-Bu) ₂ and the like. The reducing agent is used in an amount of 1 to 10 times, preferably 1 to 4 times, per mol of the compound of formula 1. Reduction temperature is -30~50℃, preferably -10℃
~20℃. Acid hydrolysis is carried out using inorganic or organic acids. Preferred acids include sulfuric acid, hydrochloric acid, phosphoric acid, perchloric acid, formic acid, acetic acid, propionic acid, and oxalic acid. The solvent used for hydrolysis is not particularly limited as long as it dissolves the reduction product and the above acid and does not reduce the activity of the acid.
Methanol, ethanol, propanol, acetone, methyl ethyl ketone, diethyl ether, dipropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, methyl acetate,
Ethyl acetate, water or a mixed solvent thereof is preferably used. Hydrolysis temperature is -30~100℃,
Preferably it is -10 to 40°C. Next, the present invention will be specifically explained using examples. Example 1 (1) Production of acetylene derivative 1 [R=-Si(CH ₃ ) ₃ ] Metallic magnesium (820 mg, 33.7 mmol) was added to tetrahydrofuran (25 ml), and ethylene bromide (3.23 g, 29.6 mmol) was added under ice cooling. mmol) in tetrahydrofuran (7 ml) was added dropwise over 35 minutes. After completion of the dropwise addition, stir for 1 hour. 2-trimethylsilyloxy-3-butyne (4.43 g, 30.9 mmol) is added dropwise to this solution of ethyl Grignard reagent. here 4-ethylenedioxy-2,
6,6-trimethyl-2-cyclohexene-1
-one 2 (3.92 g, 20.0 mmol) was added all at once;
Stir at 40°C for 1 hour. The reaction mixture is poured into water and extracted with ethyl acetate. After washing the organic layer with water, the power medium was distilled off and compound 1 [R=-Si
(CH ₃ ) ₃ ] (6.79 g, 96%) was obtained. No 1,4-adduct was detected. The spectral data of this product is as follows. IR (liquid film) 3470, 1670, ^{1245, 1090} , 840, 750cm -1 ¹ H-NMR (CDCl ₃ ) δ 0.15 (s, 9H), 1.08 (s, 3H), 1.13 (s,
3H), 1.41 (d, J=6Hz, 3H), 1.8-2.1
(m, 5H), 3.92 (A ₂ B ₂ , 4H), 4.54 (q, J
=6Hz, 2H), 5.35 (br.s, 1H) (2) 4-hydroxy-4-[(E)-3-hydroxy-1-butenyl]-3,5,5-trimethyl-
Production of 2-cyclohexen-1-one The above compound 1 [R=-Si(OH ₃ ) ₃ ] (6.79 g,
Dissolve 19.3 mmol) in tetrahydrofuran (62 ml) and add NaAlH ₂ while stirring under ice-cooling.
(OCH ₂ CH ₂ OCH ₃ ) 70% toluene solution of ₂ (21.8
ml) dropwise. After completing the dropwise addition, the mixture was returned to room temperature and stirred for 1 hour. The reaction mixture is poured into ice water and extracted with ethyl acetate. The organic layer is washed with water and the solvent is distilled off. Add acetone (70 ml) and 1N hydrochloric acid (14 ml) to the residue and stir for 1 hour. The reaction mixture was added to an aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer is washed with water and the solvent is distilled off. The residue was separated by silica gel column chromatography (ethyl acetate) and 4-hydroxy-
4-[(E)-3-hydroxy-1-butenyl]-
3,5,5-trimethyl-2-cyclohexen-1-one (3.244 g, 72% yield from 2) was obtained. The ¹ H-NMR, IR, and mass spectra of this product completely matched those of the standard product. Example 2 (1) Acetylene derivative 1

Production of [Formula] In the same manner as in Example 1, using the same reaction conditions and the same amounts of reagents, 2-(2-oxa-1-methylbutyloxy) was used instead of 2-trimethylsilyloxy-3-butyne. The reaction was carried out using -3-butyne (4.39g, 30.9mmol) to give 7.99g of crude product. As a result of gas chromatography analysis of this product, compound 1

It was found to contain 6.29g (93%) of [Formula]. No formation of 1,4-adduct was observed. Compound 1

A pure product of the formula can be obtained by separation using silica gel column chromatography (hexane-ethyl acetate-triethylamine 66:33:1). The spectral data of this product is as follows. IR (liquid film) 3450, 1670, 1205, 1090, 1025, 950, 795cm
^{-1 1} H−NMR (CDCl ₃ ) δ 1.10, 1.12, (6H,

[Formula] ) 1.14, 1.20, 1.28, 1.30, 1.36, 1.40, 1.47
(9H,

【formula】

[expression] and

[Formula]), 1.90 (3H,

[Formula]), 3.93 (4H,

[Formula]), 4.2−4.6 (1H,

[Formula]), 4.7−5.1 (1H,

[Formula]), 5.36 (1H,

[Formula]) (2) 4-hydroxy-4-[(E)-3-hydroxy-1-butenyl]-3,5,5-trimethyl-
Production of 2-cyclohexen-1-one 7.99 g of the above crude product was reduced and acid-hydrolyzed in the same manner as in Example 1, resulting in compound 2.
4-hydroxy-4-[(E)-
3-hydroxy-1-butenyl]-3,5,5
-trimethyl-2-cyclohexen-1-one was obtained. Example 3 (1) Acetylene derivative 1

Production of [Formula] In the same manner as in Example 1, using the same reaction conditions and the same amounts of reagents, 2-(2-oxacyclohexyloxy)-3-butyne was used instead of 2-trimethylsilyloxy-3-butyne. (4.76g,
30.9 mmol) was used to carry out the reaction, and 8.55 g
A crude product was obtained. As a result of gas chromatography analysis of this product, compound 1

It was found to contain 6.37g (91%) of [Formula]. Compound 1

A pure product of the formula can be obtained by separation using silica gel column chromatography (hexane-ethyl acetate-triethylamine 66:33:1). The spectral data of this product is as follows. IR (liquid film) 3460, 1350, 1205, 1095, 1020, 980, 955,
815cm ^{-1 1} H−NMR (CDCl ₃ ) δ 1.10, 1.13, 1.14 (6H,

[Formula]), 1.39, 1.42, 1.46, 1.49 (3H,

[Formula]), 1.89 (3H,

[Formula]), 3.93 (4H,

[Formula]), 4.3−4.7 (1H,

[Formula]), 4.7−5.0 (1H,

[Formula]), 5.36 (1H,

[Formula]) (2) 4-hydroxy-4-[(E)-3-hydroxy-1-butenyl-3,5,5-trimethyl-2
-Production of cyclohexen-1-one 8.55 g of the above crude product was subjected to reduction and acid hydrolysis in the same manner as in Example 1, resulting in compound 2.
4-hydroxy-4-[(E)-
3-hydroxy-1-butenyl]-3,5,5
-trimethyl-2-cyclohexen-1-one was obtained. Examples 4 to 6 In the same manner as in Example 1, methyl chloride was used instead of ethyl bromide, and as R of organometallic derivative 3, (CH ₃ ) ₃ Si- group,

【formula】

Compound 1 was prepared by carrying out a reaction on a combinatorial system using the formula. The results are shown in the table below.

[Table] Example 7 A reaction was carried out in the same manner as in Example 1, using the same reaction conditions and the same amounts of reagents used. However, at the stage of preparing the ethyl Grignard reagent, after distilling off tetrahydrofuran, toluene (32 ml) was added to perform solvent replacement. As a result, compound 1
[R=-Si(CH3) _{3 ]} was obtained with a yield of 71%. Example 8 Lithium (215 mg,
Add 31.0 mmol) and iron nitrate (20 mg) and stir until the color caused by lithium disappears. Here 2-(2-oxa-1-methylbutyloxy)-3
-Butyne (4.39 g, 30.9 mmol) is dissolved in tetrahydrofuran (30 ml) and added dropwise over 15 minutes. Then stir for 2 hours. 4-ethylenedioxy-2,6,6-trimethyl-2-cyclohexen-1-one 2 (3.92 g, 20.0 mmol) was dissolved in tetrahydrofuran (10 ml) and added dropwise over 30 minutes. After completion of the dropwise addition, stir at -35°C for 15 hours. After distilling off the ammonia, water was added to the residue and extracted with ethyl acetate. The organic layer was washed with water and the solvent was distilled off to obtain 7.82 g of crude product. As a result of analyzing this substance by gas chromatography, compound 1 was found.
It was found to contain 5.61g (83%). Comparative Example 1 Magnesium (10.0 g, 0.411 mol) was added to diethyl ether (150 ml), and ethyl bromide (44.0 g, 0.404 mol) was added dropwise over 1 hour while stirring under ice cooling. After the addition was completed, the mixture was further stirred at room temperature for 2 hours. Then, heat is applied to distill off diethyl ether, and at the same time, benzene (150 ml) is added.
After distilling off the ether, cool to 20°C. 3
-Butyn-2-ol (14.0 g, 0.197 mol) was dissolved in benzene (200 ml) and added dropwise over 1 hour.
After the addition is complete, the reaction mixture is heated under reflux for 1 hour and cooled again to 20°C. 4-ethylenedioxy-2,
6,6-trimethyl-2-cyclohexene-1-
On2 (19.6g, 0.100mol) in benzene (100ml)
Dissolve it in water and add it dropwise in 1 hour. The reaction mixture was heated under reflux for 3 hours and then stirred at 20°C for 16 hours. The reaction mixture is added to an aqueous ammonium chloride solution and the organic layer is separated. The aqueous layer is extracted with ethyl acetate. The extracted organic layers were combined and washed with water, and then the solvent was distilled off. The residue was distilled (bp 151-153°C/0.01 Torr) to obtain 19.3 g of fraction. Analysis of this product by gas chromatography revealed that it contained 1,2-adduct 4 and 1,4-adduct 5 in a ratio of 33:67. Each was separated by silica gel column chromatography (hexane:ethyl acetate 1:1). The IR and ¹ H-NMR spectra of 1,2-adduct 4 completely matched those of the standard product. 1,4-
The spectral data of the adduct is as usual. Trans body: IR (liquid film) 3450, 1720, 1290, 1165, 1095, 1030, 1000,
955cm ^{-1 1} H-NMR (CDCl ₃ ) δ 1.04 (s, 3H), 1.17 (d, J = 6Hz, 3H),
1.29 (s, 3H), 1.45 (d, J=6Hz, 3H),
1.82 (AB, 2H), 2.23 (br.s, 1H), 2.72 (dd, J
=2and13Hz, 1H), 3.03(dq, J=6and13Hz,
1H), 3.90−4.40 (A ₂ B ₂ , 4H), 4.55 (dq, J=
2and6Hz, 1H) Cis body: IR (liquid film) 3450, 1715, 1290, 1165, 1095, 990, 945,
885cm ^{-1 1} H-NMR (CDCl ₃ ) δ 1.07 (s, 3H), 1.10 (d, J = 6Hz, 3H),
1.27 (s, 3H), 1.38 (d, J=6Hz, 3H),
1.72 (dd, J=3and14Hz, 1H), 2.39 (dd, J=
2and14Hz, 1H), 2.7-3.0 (m, 3H), 3.25 (dq,
J = 2and6Hz, 1H), 4.04 (A ₂ B ₂ , 4H), 4.46
(dq, J=2and6Hz).

Claims (1)

[Claims] 1 General formula 1 [In the formula, R is a (CH ₃ ) ₃ Si- group, [Formula] group (In the group, R ¹ and R ² represent hydrogen or an alkyl group having 1 to 7 carbon atoms, and R ³ represents a C 1 to 7 alkyl group. 7 alkyl groups) or [Formula] group]. 2 General formula 1 [In the formula, R is a (CH ₃ ) ₃ Si- group, [Formula] group (In the group, R ¹ and R ² represent hydrogen or an alkyl group having 1 to 7 carbon atoms, and R ³ represents a C 1 to 7 alkyl group. In producing a compound represented by 7 alkyl groups) or [formula] group], formula 2 4-ethylenedioxy-2,6,6-trimethyl-2-cyclohexen-1-one of general formula 3 (wherein M represents an alkali metal or a magnesium halide group, and R has the same meaning as above).