JP3015200B2 - Method for producing propene derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a propene derivative using a palladium catalyst. The propene derivative obtained according to the present invention is useful as a synthetic intermediate for natural products and bioactive substances.

[0002]

2. Description of the Related Art Conventionally, many natural products having a structure having a double bond at a terminal, such as nutkatone and eremophilon, which have excellent aroma, are known [The Total Synthesis of Natural Products (The Total Synthe).
sis of Natural Products) Volume 5 (1983), Joh
n See issue of Wiley & Sons]. Also, many compounds having a structure having a double bond at the terminal are known as synthetic intermediates of natural products and physiologically active substances such as 20-methylenepregnene derivatives in the synthesis of steroids.

[0003]

Many proposals have been made on methods for synthesizing compounds having a structure having a double bond at the terminal as described above. However, these methods are based on the double bond transfer or elimination reaction. May cause side reactions such as generation of a diene, and the selectivity of the target compound may be reduced. For example, a method is known in which a terminal allyl carbonate or terminal allyl acetate is hydrogenolyzed using a palladium catalyst in the presence of formic acid and triethylamine to obtain a 1-alkene in high yield and high selectivity. [J. Tuji et al., Synthesis
s), p. 623 (1986)]. However, when the reaction described in the above document is applied to an allyl compound having a large steric hindrance or a complex allyl compound having a substituent, a side reaction of generating a diene by an elimination reaction occurs, and the compound is a target compound. The selectivity of a compound having a double bond at the terminal is reduced. Therefore, as a method for synthesizing a compound having a double bond at a terminal, a method that does not involve side reactions such as transfer of a double bond and generation of a diene by an elimination reaction and that can be applied to synthesis of a wide range of compounds is required. That is the current situation. Accordingly, an object of the present invention is to provide a method for synthesizing a compound having a double bond at a terminal with high yield and high selectivity.

[0004]

According to the present invention, the above object is achieved by the following general formula (I)

[0005]

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Wherein R ↑ 1 and R ↑ 2 represent an organic group and R 、 3 represents a hydrogen atom or a lower alkyl group (hereinafter referred to as formate (I)
Or the following general formula (II)

Embedded image (Wherein R ↑ 1, R ↑ 2 and R ↑ 3 are as defined above) (hereinafter referred to as formate (II)) with a palladium catalyst, Of the general formula (III)

[0007]

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Wherein R ↑ 1, R ↑ 2 and R ↑ 3 are as defined above, wherein the palladium catalyst comprises a palladium salt and a trialkylphosphine, A general formula (II) characterized by using a catalyst wherein the ratio of the palladium salt to the trialkylphosphine is 1: 1 to 1: 2.
A method for producing a propene derivative represented by I), and the following general formula (IV)

[0009]

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(Wherein R ↑ 1, R ↑ 2 and R ↑ 3 are as defined above, and R ↑ 4 represents a lower alkyl group or an aralkyl group). (IV)) or the following general formula (V)

[0011]

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Where R ↑ 1, R ↑ 2, R ↑ 3 and R ↑
↑ 4 is as defined above) (hereinafter abbreviated as carbonate (V)) with a palladium catalyst in the presence of formic acid and a base to give the following general formula (III)

[0013]

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Wherein R ↑ 1, R ↑ 2 and R ↑ 3 are as defined above, wherein the palladium catalyst comprises a palladium salt and a trialkylphosphine, The catalyst of the general formula (I) is characterized by using a catalyst wherein the ratio of the palladium salt to the trialkylphosphine is 1: 1 to 1: 2.
This is achieved by providing a method for producing the propene derivative represented by II).

In the above general formulas (I) to (V), R ↑
The organic group represented by 1 and R ↑ 2 may be any group as long as it does not have a functional group serving as a substrate for a palladium catalyzed reaction, such as an allyl ester.
R ↑ 1 and R ↑ 2 may combine with each other to form a ring. The lower alkyl group represented by R ↑ 3 is preferably a linear or branched alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, a butyl group, and a hexyl group. Examples of the lower alkyl group represented by R ↑ 4 include a linear or branched alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, a butyl group, and a hexyl group. Benzyl group, p-chlorobenzyl group and the like, and a linear or branched alkyl group having 1 to 6 carbon atoms is preferable.

The palladium catalyst used in the present invention comprises a palladium salt and a trialkylphosphine.
Examples of the palladium salt include palladium salts such as palladium acetylacetonate, palladium acetate, palladium chloride, palladium nitrate, bis (acetonitrile) palladium chloride, and tris (dibenzylideneacetone) dipalladium / chloroform. Or palladium acetylacetonate is particularly preferred. Examples of the trialkyl phosphine include tributyl phosphine, trihexyl phosphine, trioctyl phosphine, tricyclohexyl phosphine, and the like, with tributyl phosphine being particularly preferred.

It is necessary that the ratio of the palladium salt, which is a component of the palladium catalyst, to trialkylphosphine is in the range of 1: 1 to 1: 2. By using a palladium catalyst having such a composition, the desired propene derivative can be obtained with high yield and high selectivity.

In the present invention, when carbonate (IV) or carbonate (V) is used as a raw material, it is necessary to carry out the reaction in the presence of formic acid and a base in addition to the above-mentioned palladium catalyst. . The amounts of formic acid and base used are preferably in the range of 1 to 10 molar equivalents relative to the carbonate (IV) or carbonate (V). As the base, triethylamine, diisopropylethylamine and the like can be used. on the other hand,
In the present invention, when formic acid ester (I) or formic acid ester (II) is used as a raw material, it is not necessary to make formic acid coexist in addition to the above-mentioned palladium catalyst, but the reaction is carried out in the presence of the above base. Is preferably performed.

The palladium catalyst is prepared from the raw materials formate (I), formate (II), carbonate (I)
0.0001 to V) or carbonate (V)
It is preferable to use in the range of 1 equivalent, and 0.01 to 0.1.
More preferably, it is used in the range of 2 equivalents.

The reaction can be carried out at a low temperature by using the above-mentioned palladium catalyst. The reaction is usually
It is preferably carried out at a temperature in the range of 10 ° C to 40 ° C,
It is more preferable to carry out at a temperature in the range from to room temperature.

The reaction can be carried out in the presence or absence of an organic solvent. Examples of the organic solvent include hexane, hydrocarbons such as benzene, diethyl ether, tetrahydrofuran, dioxane, ethers such as dimethoxyethane, acetonitrile, dimethylformamide,
Although dimethyl sulfoxide, chloroform and the like can be used, it is preferable to use tetrahydrofuran, dioxane and benzene.

The raw materials formate (I) and carbonate (IV) can be synthesized by esterifying the corresponding allyl alcohol. This esterification can be performed by a general esterification reaction. For example,
By reacting formic acid / acetic acid mixed anhydride or chlorocarbonate on allyl alcohol in the presence of pyridine, formate (I) and carbonate (IV) can be obtained respectively [Helvetica Kimica Actor (Helv. Chim. Acta), Vol. 37, p. 45 (1954)]. The allyl alcohol can be easily synthesized by reacting the corresponding carbonyl compound with an alkenyl metal such as vinylmagnesium chloride and isopropenyllithium.

Further, the formate (II) and the carbonate (V) as the raw materials can be synthesized by esterifying the corresponding allyl alcohol in the same manner as described above. The allyl alcohol can be synthesized by converting the corresponding carbonyl compound into an unsaturated ester by a Wittig-Horner reaction, and then reducing the unsaturated ester by a conventional method.

The thus obtained general formula (III)
The isolation and purification of the propene derivative from the reaction mixture represented by is generally performed by the same method as that used for isolating and purifying an organic compound from the reaction mixture. For example, the reaction mixture is poured into ice water, and diethyl ether is added.
Extracted with an organic solvent such as ethyl acetate, ethyl acetate, and the like, and the extract is washed with cold diluted hydrochloric acid, aqueous sodium bicarbonate, brine, and the like, dried, and concentrated to obtain a crude product. Purified by recrystallization, chromatography, etc.,
The propene derivative represented by II) can be obtained.

The propene derivative represented by the general formula (III) is useful as a synthetic intermediate for natural products and physiologically active substances. For example, 20-methylene-3- (t-butyldimethylsilyloxy) pregna-5-ene is described in the literature [J. Am. Chem. Soc., Vol. 105, 3725. ~ 3727
(1983)], a hydroxyl group is introduced into the side chain by hydroboration to obtain a vitamin D derivative synthetic intermediate (3) described in JP-A-53-50512. -T-butyldimethylsilyloxy) pregn-5-en-20-yl) methanol.

[0026]

The present invention will be described below in detail with reference to examples. Note that the present invention is not limited by these examples.

Example 1 A yellow solution of a palladium catalyst was prepared by mixing 0.1 mmol of palladium acetylacetonate and 0.1 mmol of tributylphosphine in 3 mL of benzene under an argon atmosphere. Next, a solution obtained by dissolving 5 mmol of formic acid and 5 mmol of triethylamine in 5 mL of benzene was added, and 1-isopropenyl-4-t-butyl-1-cyclohexylmethyl carbonate 1 mm was further added.
and stirred at room temperature for 3 hours. 40 m of water in the reaction solution
L was added and extracted with pentane. The extract was dried and concentrated, and the obtained residue was purified by silica gel column chromatography to give 1-isopropenyl-4-.
148 mg of t-butylcyclohexane was obtained (yield: 82).
%).

Example 2 A yellow solution of a palladium catalyst was prepared by mixing 0.1 mmol of palladium acetylacetonate and 0.1 mmol of tributylphosphine in 3 mL of benzene under an argon atmosphere. Then, 2-m- (4-t-butylcyclohexylidene) propyl formate 1m
The solution was added with 3 ml of a benzene solution and stirred at room temperature for 1 hour. The reaction solution was diluted with hexane, filtered and concentrated, and the obtained residue was purified by silica gel column chromatography to give 1-isopropenyl-4-t-.
166 mg of butylcyclohexane was obtained (yield 88
%).

Example 3 In Example 2, 0.1 mmol of tributylphosphine was used.
Reaction and separation and purification were carried out in the same manner as in Example 2 except that l was changed to 0.2 mmol of tributylphosphine, whereby 161 mg of 1-isopropenyl-4-t-butylcyclohexane was obtained (yield: 85%). ).

Comparative Example 1 Under an argon atmosphere, 0.1 mmol of tris (dibenzylidene) dipalladium / chloroform complex and 0.8 mmol of tributylphosphine were mixed in 5 mL of tetrahydrofuran.
A palladium catalyst was prepared by mixing in water. Then, 1 mmol of 2- (4-t-butylcyclohexylidene) propyl formate in tetrahydrofuran 5
Then, the mixture was stirred at room temperature for 14 hours. The reaction solution was diluted with hexane, filtered and concentrated, and the obtained residue was purified by silica gel column chromatography to give 1-isopropenyl-4-t-butylcyclohexane (94 mg, yield 50%) and 1-isopropenyl. Propenyl-
89 mg of 4-t-butyl-1-cyclohexene (40
%).

Examples 4 to 7 In Example 1, 1 mmol of 1-isopropenyl-4-tert-butyl-1-cyclohexylmethyl carbonate was added.
1 is replaced by 1-isopropenyl-2-pentyl-1-
Cyclopentyl methyl carbonate, 20-methylene-3- (t-butyldimethylsilyloxy) pregna
5-en-17β-yl methyl carbonate, 1-ethenyl-4-t-butyl-1-cyclohexyl methyl carbonate, 3- (t-butyldimethylsilyloxy) pregna-5,20-dien-17β-yl methyl carbonate The reaction and separation and purification were carried out in the same manner as in Example 1 except that each 1 mmol was used and the reaction time was changed to the time shown in Table 1 to obtain the corresponding 1-.
Isopropenyl-2-pentylcyclopentane, 20-
Methylene-3- (t-butyldimethylsilyloxy) pregna-5-ene, 1-ethenyl-4-t-butylcyclohexane, 3- (t-butyldimethylsilyloxy)
Pregna-5,20-diene was obtained. The results are shown in Table 1.

[0032]

[Table 1]

Examples 8 to 13 In Example 2, (Z) -4-tetrahydropyranyloxy-2,3-dimethyl-2-yl was replaced with 1 mmol of 2- (4-t-butylcyclohexylidene) propyl formate. Buten-1-yl formate, 2-
(4-t-butylcyclohexylidene) propyl formate, 2- (2- (3- (t-butyldimethylsilyloxy) propyl) cyclohexylidene) ethyl formate, 2- (2- (t-butyldimethylsilyloxy) ) Cyclohexylidene) ethyl formate,
(Z) -4-tetrahydropyranyloxy-3-methyl-2-buten-1-yl formate, 2- (2-
1 mmol each of (t-butyldimethylsilyloxy) -3-methylcyclopentylidene) ethyl formate
The reaction and separation and purification were carried out in the same manner as in Example 2 except that the reaction mixture was used and the reaction time was changed to the time shown in Table 1, thereby obtaining the corresponding 2,3-dimethyl-3-butene-
1-yl tetrahydropyranyl ether, 1-isopropenyl-4- (t-butyl) cyclohexane, 1-ethenyl-2- (3- (t-butyldimethylsilyloxy) propyl) cyclohexane, 1-ethenyl-2-
(T-butyldimethylsilyloxy) cyclohexane,
2-methyl-3-buten-1-yl tetrahydropyranyl ether and 1-ethenyl-2- (t-butyldimethylsilyloxy) -3-methylcyclopentane were obtained.
The results are shown in Table 2.

[0034]

[Table 2]

[0035]

According to the present invention, there is provided a method for synthesizing a propene derivative useful as a synthetic intermediate of a natural product and a physiologically active substance with high yield and high selectivity.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI C07C 13/20 C07C 13/20 69/145 69/145 C07J 7/00 C07J 7/00 // C07B 61/00 300 C07B 61 / 00 300 (58) Field surveyed (Int. Cl. ⁷ , DB name) C07C 1/213 C07B 31/00 C07C 1/207

Claims (2)

(57) [Claims] 1. A compound of the general formula (I) (Wherein R お よ び 1 and R を 2 represent an organic group, and R ↑ 3 represents a hydrogen atom or a lower alkyl group) or a formula (II): (Wherein R ↑ 1, R ↑ 2 and R ↑ 3 are as defined above) with a palladium catalyst to give a general formula (III) Wherein R ↑ 1, R ↑ 2 and R ↑ 3 are as defined above, wherein the palladium catalyst comprises a palladium salt and a trialkylphosphine, A method for producing a propene derivative represented by the above general formula (III), wherein a catalyst having a ratio of salt to trialkylphosphine of 1: 1 to 1: 2 is used. 2. A compound of the general formula (IV) Wherein R ↑ 1 and R ↑ 2 represent an organic group, R ↑ 3 represents a hydrogen atom or a lower alkyl group, and R ↑ 4 represents a lower alkyl group or an aralkyl group. Formula (V) (Wherein R ↑ 1, R ↑ 2, R ↑ 3 and R ↑ 4 are as defined above) with a palladium catalyst in the presence of formic acid and a base to give a general formula ( III) Wherein R ↑ 1, R ↑ 2 and R ↑ 3 are as defined above, wherein the palladium catalyst comprises a palladium salt and a trialkylphosphine, A method for producing a propene derivative represented by the above general formula (III), wherein a catalyst having a ratio of salt to trialkylphosphine of 1: 1 to 1: 2 is used.