JP3115410B2 - Method for producing allyl-type carboxylic acid - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing an allylic carboxylic acid having high regioselectivity and stereoselectivity.

[0002]

2. Description of the Related Art
Many magnesium and zinc reagents have been applied in the field of synthetic organic chemistry. For example, organomagnesium halides known as Grignard reagents are widely used as reagents useful for various chemical reactions. For example, JP-A-3-271236 discloses that an allyl magnesium reactant
It is disclosed that an allylation reagent prepared by adding copper cyanide and lithium chloride causes a head-to-tail type coupling reaction with an allylic halide compound to obtain a terpene derivative having high regioselectivity.

However, the conventionally known reaction between an allyl metal reactant and a carbonyl compound, for example, the reaction between an allyl-type magnesium halide and a carbonyl compound mainly produces a γ-substituted compound, and the starting of the allyl-type magnesium reactant. The tertiary structure of the substance may also change, and the problem of position and steric control resulting from the reaction with the electrophile has not been solved yet.

[0004] The present inventors have conducted a reaction with a carbonyl compound using an allyl-type barium reactant, and have conducted intensive studies on the position and stereoselectivity. As a result, in the reaction with various aldehydes and ketones, a high yield was obtained. It has been found that an α-adduct can be obtained with high selectivity and that the stereochemistry of the double bond is retained, and a patent application has already been filed (Japanese Patent Application No. Hei.
No. 317297). Furthermore, the present inventors have maintained the steric structure of the starting material by reaction with carbon dioxide using an allyl-type barium reactant prepared from various allyl halide-type compounds, and selectively added the α-position. The inventors have found that an allyl-type unsaturated carboxylic acid can be obtained, and have completed the present invention.

[0005]

That is, the present invention provides a compound represented by the general formula (I):

[0006]

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(Wherein, R ¹ represents a hydrogen atom, an alkyl group or an alkenyl group, R ² represents a hydrogen atom, an alkyl group or an alkenyl group, R ³ represents a hydrogen atom, an alkyl group or an alkenyl group, and R ¹ and R ³ May together form a ring, X
Represents a halogen atom. ) Is reacted with CO ₂ to give a compound of the general formula (II)

[0008]

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Wherein R ¹ , R ² , and R ³ have the same meanings as described above, wherein an active metal barium is used in the reaction for obtaining the allylic carboxylic acid.
It is intended to provide a method for producing an allyl-type carboxylic acid represented by the general formula (II).

The production method of the present invention will be described in more detail.
An allylic halide compound represented by the general formula (I)
The allyl-type carboxylic acid represented by the general formula (II) can be obtained by reacting with an active metal barium in an inert organic solvent and subsequently reacting with a CO ₂ gas. The active metal barium used herein can be prepared reductively by an anionic radical species of a barium halide and an aryl compound of lithium, sodium or potassium. The specific preparation method is shown below.

That is, 2 equivalents of an aryl compound of lithium, sodium or potassium such as biphenyllithium is added to 1 equivalent of barium halide such as barium iodide, and reacted at room temperature in an inert organic solvent such as dry THF. Can be obtained. As the inert organic solvent used here, besides THF, for example, an ether-based solvent such as diethyl ether can be used. The amount of barium halide for forming the active metal barium required in the present invention is not particularly limited, but is usually 1 to 3 equivalents, preferably 2 to 1 equivalent of the allyl halide compound represented by the general formula (I). Is equivalent. The thus-obtained solvent in which the active metal barium is suspended is cooled to −78 ° C. to 0 ° C., and the allyl halide type compound represented by the general formula (I) is added. A reddish suspension of the allyl barium reactant of the general formula (III) is thus obtained immediately.

[0012]

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(Wherein R ¹ , R ² , R ³ , and X have the same meaning as described above.) While maintaining the suspension at −78 to 0 ° C.,
When reacted with CO ₂ gas, an allyl-type carboxylic acid represented by the general formula (II) is obtained.

Specific examples of the allyl halide type compound represented by the general formula (I) as a raw material of the present invention include (E) -n-
C ₇ H ₁₅ CH = CHCH ₂ Cl, (Z) -n C ₇ H ₁₅ CH = CHCH ₂ Cl, (Z) -CH ₃ CH
＝ CHCH ₂ Cl,

[0015]

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[0016]

According to the method of the present invention, an α-adduct represented by the general formula (II) can be obtained with high selectivity, and the double bond at the β-position is represented by the general formula (I) ) Completely retains the stereochemistry of the allyl halide compound represented by
High stereoselectivity was obtained.

[0017]

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

Embodiment 1

[0019]

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470 mg (1.2 mmol) of barium iodide was weighed into a 50-ml Schlenk tube, and sufficiently dried by heating with a heat gun under reduced pressure (5 mmHg). After cooling, the reaction vessel was filled with argon gas and 5 ml of dry THF was added. Meanwhile, another 30ml
Prepare a Schlenk tube with lithium pieces (16 mg, 2.3 mmol)
And biphenyl (370 mg, 2.4 mmol) were weighed. This was degassed under reduced pressure (5 mmHg), filled with argon gas, added with dry THF (5 ml) and stirred at room temperature (20 ° C.) for 2 hours to obtain dark blue lithium biphenylide TH.
An F solution was obtained. TH of previously prepared barium iodide
A THF solution of lithium biphenylide was dropped into the F suspension at room temperature through a stainless steel tube, and stirred for 30 minutes to obtain a brown active barium suspension. After cooling to −78 ° C., a solution of 190 μl (0.97 mmol) of geranyl chloride represented by the formula (2) in THF (2 ml) was slowly added using a syringe. After stirring at the same temperature for 30 minutes, carbon dioxide gas generated from an excessive amount of dry ice was directly introduced into the reaction solution through a needle for 30 minutes. To this was added cooled 1N hydrochloric acid (8 ml) to terminate the reaction.
After warming the reaction mixture to room temperature, saturated saline (20 ml)
And ethyl acetate (20 ml), and the mixture was shaken well, and then separated into an organic layer and an aqueous layer. The aqueous layer was further adjusted to pH 2 or more with concentrated hydrochloric acid, and then extracted again with chloroform (10 ml × 2) and ethyl acetate. The organic layers were combined, washed with a dilute solution of sodium thiosulfate, and then dried over anhydrous magnesium sulfate. The drying agent was filtered, the filtrate was concentrated under reduced pressure, and the crude product obtained was subjected to silica gel column chromatography (50 g, ethyl acetate). Was obtained as a colorless oil (154 mg, 87% yield). Further, the carboxylic acid was diluted with ether, and an ether solution of diazomethane was added to obtain a methyl ester. GLC analysis of this product (25 mx 0.25 mm id, PEG-HT Bonded, Gas Chromatography, column temperature 130 ° C, injector temperature 1
The ratio of α-form to γ-form is> 99 at 50 ° C. and nitrogen pressure 0.8 kg / cm ² ).
1. It was confirmed that the E / Z ratio of the α-form was 98: 2.・ Retention time: γ-isomer 4.23 minutes, α-E-isomer 7.57 minutes, α-Z
Body 6.89 minutes

[0021]

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TLC: Rf 0.45 (ethyl acetate) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.60 (s, 3H, CH ₃ ) _, 1.65
(s, 3H, CH ₃ ), 1.68 (s, 3H, CH ₃ ), 2.02-2.15 (m, 4H, 2CH ₂ ),
3.10 (d, 2H, J = 7Hz, CH 2), 5.10 (m, 1H, vinyl group), 5.31 (d
t, 1H, J = 1.4,8.4Hz, vinyl group), 10.8 (br, 1H, CO ₂ H)

[0023]

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TLC: Rf 0.70 (1: 2 ethyl acetate / hexane) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.60 (s, 3H, CH ₃ ) _, 1.64
(s, 3H, CH ₃ ), 1.68 (s, 3H, CH ₃ ), 1.85-2.23 (m, 4H, 2CH ₂ ),
3.06 (d, 2H, J = 7.2Hz, CH 2), 3.69 (s, 3H, OCH 3), 5.10 (m, 1
Example 2 (H, vinyl group), 5.33 (t, 1H, J = 8.4 Hz, vinyl group)

[0025]

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In the same manner as in Example 1, allylic carboxylic acids represented by the formulas (3α) and (3γ) and methyl ester thereof were obtained from the compound represented by the formula (4). GLC analysis of this product (25 mx 0.25 mm id, PEG-HT Bonde
d, gas chromatography, column temperature 130 ° C, injector temperature 150 ° C, nitrogen pressure 0.8kg / cm ² )
It was confirmed that the E / Z ratio of 98: 2 and α-form was 99: 1.・ Retention time: γ-isomer 5.97 minutes, α-E-isomer 10.31 minutes, α-Z
Body 9.92 minutes

[0027]

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TLC: Rf 0.54 (ethyl acetate) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 0.88 (t, 3H, CH ₃ ) _, 1.18
_{-1.46 (m, 10H, 5CH 2} ), 2.03 (m, 2H, CH 2), 3.07 (d, 2H, J = 6.7
Hz, CH ₂ ), 5.56 (m, 2H, 2 x vinyl group), 10.1 (br, 1H, CO ₂ H)

[0029]

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TLC: Rf 0.65 (1: 2 ethyl acetate / hexane) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 0.88 (t, 3H, CH ₃ ) _, 1.20
_{-1.48 (m, 10H, 5CH 2} ), 2.02 (m, 2H, CH 2), 3.04 (d, 2H, J = 4.6
Hz, CH ₂ ), 3.69 (s, 3H, OCH ₃ ), 5.53 (m, 2H, 2 × vinyl group) Examples 3 to 6 Instead of geranyl chloride in Example 1, various halogenated compounds shown in Table 1 were used. An allylic carboxylic acid was obtained in the same manner as in Example 1 except that an allylic compound was used. The results are shown in Table 1.

[0031]

[Table 1]

As is clear from the above examples, according to the method of the present invention, an allyl-type carboxylic acid can be obtained with high regioselectivity and high stereoselectivity.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) C07C 51/15 B01J 23/02 C07C 57/03 C07C 57/26 C07B 61/00 300

Claims (2)

(57) [Claims] 1. A compound of the general formula (I) (Wherein R ¹ is a hydrogen atom, an alkyl group or an alkenyl group,
R ² represents a hydrogen atom, an alkyl group or an alkenyl group, R ³ represents a hydrogen atom, an alkyl group or an alkenyl group, and R ¹ and R ³ together represent a group represented by the formula : May form a ring represented by X represents a halogen atom. ) And CO
₂ and reacting with the general formula (II) ^{(Wherein, R 1, R 2, R} 3 is. Having the same meanings as defined above) in the reaction for obtaining the allylic carboxylic acid represented by halo
Barium genoide and lithium, sodium or potassium
Depending on the anion radical species with the aryl compound
A method for producing an allyl-type carboxylic acid represented by the general formula (II), wherein an originally prepared active metal barium is used. 2. A compound of the general formula (I) (Wherein R ¹ , R ² , R ³ and X have the same meanings as described above) in an inert organic solvent in a barium halide, lithium and sodium
Anion radicals with aryl compounds of lithium or potassium
General formula (II) characterized by reacting with an active metal barium prepared reductively and subsequently with CO ₂ gas, depending on the kind of calcium. (Wherein R ¹ , R ² and R ³ have the same meanings as described above).