JPH06271536A - Production of 3-alkylpyrrole - Google Patents

Abstract

PURPOSE:To selectively produce a 3-alkylpyrrole in high yield from a 1,3- disubstituted intermediate in a few steps. CONSTITUTION:A 3-alkanoyl-1-arylsulfonylpyrrole expressed by formula I (R<1> is 1-20C alkyl or alkenyl; X is aryl which may have substituent group) is reduced with a metallic halide (sodium bismethoxyethoxyaluminum hydride is especially preferred) in an organic solvent to afford the objective 3-alkylpyrrole expressed by formula II (R is 1-20C alkyl). Ethers or alkylbenzenes can be used as the organic solvent and toluene is especially preferred. The concentration of the reducing agent based on the reactional solution is preferably 0.01-0.50mol/l, especially preferably 0.1-0.2mol/l. The compound expressed by formula I is synthesized by acylation, especially the Friedel-Crafts acylation of a 1- arylsulfonylpyrrole.

Description

Detailed Description of the Invention

BACKGROUND OF THE INVENTION

FIELD OF THE INVENTION The present invention has the general formula (II)

[0002]

[Chemical 3] (In the formula, R represents an alkyl group having 1 to 20 carbon atoms) and a method for producing a 3-alkylpyrrole.

More specifically, the present invention relates to the general formula (I)

[0004]

[Chemical 4] (In the formula, R ′ represents an alkyl or alkenyl group having 1 to 20 carbon atoms, X represents an aryl group which may have a substituent), and 3-alkanoyl-1-arylsulfonylpyrrole The present invention relates to a method for producing a 3-alkylpyrrole in good yield by chemical reduction with metal hydride in an organic solvent.

The 3-alkylpyrrole advantageously produced according to the present invention can be industrially used as an intermediate in the synthesis of pyrrole derivatives, especially as an intermediate substance for pharmaceuticals, agricultural chemicals and synthetic dyes. Further, 3-alkylpyrrole can be used as a monomer for producing such a polymer since a π-conjugated polymer can be obtained by polymerizing the 3-alkylpyrrole.

[0006]

2. Description of the Related Art Conventionally, many attempts have been made to introduce a substituent at the 3-position of pyrrole, which has been studied for a long time. In recent years, several review articles summarizing them have been reported,
One of them is a review by Anderson et al. In the synthesis of 3-alkylpyrroles (Synthesis, 353 (1985)).

[0007] Among them, a method of directly introducing an alkyl group into a pyrrole ring has been reported, but such direct alkylation has a very low synthetic yield from pyrrole, and has a regioselectivity in the synthesis. It was extremely low, and separation and purification were complicated. This is because the reactivity at the 2-position of the pyrrole ring is higher than that at the 3-position, and a 2-position-substituted derivative is produced as a by-product.

As a method excellent in position selectivity,
A method in which an electron-withdrawing group is introduced at the 2-position in advance and a substituent is selectively introduced at the 3-position, or 1-group of the pyrrole ring is introduced.
A method in which a bulky substituent is introduced at the N-position to prevent the reactions at the 2- and 5-positions from sterically hindering, and a substituent is selectively introduced at the 3-position (Kakushima et al. J. Org. Chem., 48, 3214
(1983) is proposed.

However, in the former method of utilizing the regioselectivity for the 3-position by the electron-withdrawing group introduced at the 2-position, the yield of introducing the substituent at the 2-position and then at the 3-position is not high. Therefore, it is difficult to obtain the desired 3-position-substituted pyrrole from the starting material pyrrole in high yield, and the number of steps in the synthetic route is large, so that it was not practical from an industrial viewpoint.

On the other hand, in the latter method utilizing the regioselectivity for the 3-position due to the steric hindrance of the substituent introduced at the 1-position, the number of steps in the synthesis is about the same as the former method. However, the synthetic yield at each step related to the introduction of a substituent to the 1-position and then to the 3-position was high, and 3
The position selectivity to the position is very high, and therefore 3-
It was considered to be a preferable method for synthesizing alkylpyrrole.

Whichever method is used, the first compound to be synthesized is an intermediate, that is, a compound having a 2- or 1-position substituent unnecessary for the final compound, 3-alkylpyrrole. , A step of removing unnecessary substituents from such an intermediate, and that it is common that the substituent introduced at the 3-position is not the desired alkyl group but its precursor (ie Friedel, for example). When a substituent is introduced at the 3-position by the Krafts reaction, acylation is generally easier than alkylation),
It is necessary to carry out the step of converting this precursor group into the desired alkyl group, and carrying out these two additional steps gives the desired 3-alkylpyrrole.

As a method for synthesizing 3-alkylpyrrole,
Although it was around the time when the method using 1,3-di-substituted pyrrole as an intermediate was advantageous, the additional two steps are specifically performed, for example, as follows. . That is, 3-alkanoyl-1-arylsulfonylpyrrole is dearylsulfonylated by heating in dioxane in the presence of an alkali, and a reducing agent metal hydride such as lithium aluminum hydride is allowed to act in ether. To reduce the ketone group (see Comparative Example 1). However, this additional two step is not only complicated in that it is two steps, but also the total yield of the desired 3-alkylpyrrole is low and it is expensive in the production. It is difficult to say that the above method requiring various steps is industrially preferable.

[0013]

[Problems to be Solved by the Invention]

SUMMARY OF THE INVENTION The present invention aims to provide an improvement in the process from an intermediate to a final compound when synthesizing a desired 3-alkylpyrrole from a 1,3-disubstituted intermediate. It is intended to achieve this object by applying a specific reducing means to.

[0014]

[Means for Solving the Problems]

<Summary> That is, the method for producing a 3-alkylpyrrole according to the present invention is a method of reducing a 3-alkanoyl-1-arylsulfonylpyrrole represented by the following general formula (I) with a metal hydride in an organic solvent, To obtain a 3-alkylpyrrole represented by the formula (II).

[0015]

[Chemical 5] (In the formula, R ′ represents an alkyl or alkenyl group having 1 to 20 carbon atoms, and X represents an aryl group which may have a substituent)

[0016]

[Chemical 6] (In the formula, R represents an alkyl group having 1 to 20 carbon atoms) <Effect> According to the present invention, the additional two steps necessary for the 1,3-di-substituted intermediate are converted into one step. It can be shortened. That is, the target 3-alkylpyrrole can be produced in one step by simultaneously performing a dearylsulfonylation reaction and a ketone group reduction reaction in an organic solvent using a metal hydride that is a reducing agent.

Therefore, the method for producing a 3-alkylpyrrole according to the present invention preserves the innate advantage for producing the 1,3-di-substituted intermediate as described above, and therefore, according to the present invention, the yield in the synthesis is improved. The rate is very high, and it becomes possible to selectively obtain the target substance. [Detailed Description of the Invention] <1,3-Di-Substituted Intermediate> The 1,3-di-substituted intermediate to be subjected to specific chemical reduction according to the present invention is a compound represented by the general formula (I).

[0018]

[Chemical 7] (In the formula, R'represents an alkyl or alkenyl group having 1 to 20 carbon atoms and X represents an aryl group which may have a substituent.) In the 1-position substituent which realizes the 3-position substitution selectivity in the next step. X
Is an aryl group or a substituted aryl group.

In addition to the basic phenyl and α- to β-naphthyl radicals, aryl radicals are intended to include their hydrocarbon-substituted derivatives. The hydrocarbon substituent in that case is typically an alkyl group having about 1 to 4 carbon atoms and is introduced at any position (preferably p-position) of o-, m- and p-. It may be. Further, the substituent consisting of this hydrocarbon is a group which forms a condensed ring with the phenyl group or naphthyl group to which it is bound, for example, in the case of a phenyl group, a condensed 6-membered ring which forms a tetralinyl group. It may be.

X may be a substituted aryl group, in which case the substituent is a halogen atom such as fluorine,
Bases and bromine, alkoxy groups, especially lower alkoxy groups such as methoxy groups, unsubstituted or mono- or di-substituted amino groups (substituents are lower alkyl groups or lower alkanoyl groups), mono-, di- or trihaloalkyl groups (eg chloro). Methyl group or trifluoromethyl group), and others.

Since X in the substituent at the 1-position is for imparting regioselectivity to the acylation at the 3-position, its bulkiness and bulkiness as well as the orientation to 3-acylation, and thus its electron The type (including the type of substituent) is determined from the viewpoint of the degree of donation. Of course, it is necessary to make a judgment from the viewpoint of the difficulty of desorption by chemical reduction.

From such a viewpoint, X in the 1-position substituent is particularly preferably a phenyl group, a lower alkyl-substituted phenyl group, particularly a p-lower alkyl-substituted phenyl group, especially a p-tolyl group.

The group R'of the 3-position substituent -COR 'is an alkyl or alkenyl group having 1 to 20 carbon atoms, preferably 5 to 17 carbon atoms, particularly an alkyl group. The alkyl or alkenyl group may be linear or branched and includes a cycloalkyl group and a cycloalkenyl group.

Intermediate compounds of general formula (I) are usually synthesized by acylation of 1-arylsulfonylpyrroles, especially Friedel-Crafts acylation. The acylating agent in that case is an acid halide R'-CO-
Y (Y is halogen) or acid anhydride R'-CO-O-C
It is usually O—R ″ (where R ″ is the same or different from R ′ and is the same group as R ′) and the Friedel-Crafts catalyst used is also conventional, eg aluminum trichloride, tetrachloride. It is usually tin chloride, zinc chloride, etc. The 1,3-disubstituted pyrrole of the general formula (I) is a known compound. Therefore, it will be acceptable to refer to the aforementioned publications and others for further details about this compound. <Chemical Reduction> In the present invention, 1 of 1,3-di-substituted pyrrole is used.
The reductive removal of the position substituent and the reduction of the acyl group of the position 3 substituent are carried out by chemical reduction with metal hydride.

Chemical reduction with metal hydride is well known as a unit operation or unit reaction in organic synthesis. Therefore, if the chemical reduction in the present invention is also necessary for matters other than the points described below, refer to the textbooks for organic synthesis, review articles and the like.

The reducing agent used in the method of the present invention is metal hydride. In that case, the "metal" may be a single metal or a plurality of metals. Also,
This metal hydride only needs to have at least one metal-hydrogen bond, and the valence of the metal may be satisfied by another group. Preferred metal hydrides for use in the present invention include, for example, sodium bismethoxyethoxyaluminum hydride (hereinafter referred to as SAH), lithium aluminum hydride (hereinafter referred to as LAH) or a trialkoxy derivative thereof (LiAIH (OR ″) ₃ (Where R ″ represents a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or tert-butyl group)), sodium aluminum hydride, particularly preferably SAH. This is because some other reducing agents are insoluble in the reaction solvent, and the reaction may be a heterogeneous reaction. Since the above-mentioned ones, especially SAH, are dissolved in a general organic solvent, the reaction is uniform and the reaction efficiency is high.
In particular, since 70% SAH toluene solution is commercially available as a reagent for SAH, use of this toluene solution facilitates handling in the reaction. It should be noted that the present invention does not exclude the heterogeneous reaction, and if necessary, consideration should be given to making the metal hydride insoluble or hardly soluble in the reaction solvent into fine particles to increase the surface area, vigorous stirring, etc. Good.

As the solvent used in the reaction, ethers such as diethyl ether and tetrahydrofuran which are general organic solvents, or alkylbenzenes such as benzene, toluene and xylene can be used. In particular, the latter alkylbenzenes are suitable when SAH is used as the reducing agent, and toluene is particularly preferable. The organic solvent used for the chemical reduction is preferably one having a dissolving ability such that the reactant and / or the product are at least partially dissolved.

The concentration of the reducing agent in the reaction solution is relatively low, for example, 0.01 to 0.50 mol per liter is preferable, and 0.1 to 0.2 mol is more preferable.
Particularly, in the reduction reaction in toluene using SAH, if the concentration is too high, the viscosity in the solution becomes high, and the hydrogen bubbles generated during the reaction disperse in the solution, and the liquid level in the reaction vessel This makes it difficult to control.

The amount of reducing agent required to reduce 1 mole of 3-alkanoyl-1-arylsulfonylpyrrole is
When the metal hydride that is a reducing agent is represented by the chemical formula MHn, the amount thereof is 2 nmol. This is because the phenylsulfonyl group eliminated by the reaction is also reduced by the reducing agent at the same time to be converted into a thiol, so that the reducing agent is additionally consumed. Further, in this reaction, the target 3-alkylpyrrole can be obtained in good yield when the amount of the reducing agent used is larger than the required amount (see Example 2). Therefore, the amount required for the actual reaction is most preferably in the range of 2n to (2n + 2) mol, particularly preferably 2n to (2n + 1) mol.

The reaction temperature is preferably in the range from room temperature to the boiling point of the solvent used in the reaction. Although the reaction can proceed gently at a temperature close to room temperature, it takes a very long time to complete the reaction. Therefore, it is preferable to carry out the reaction at a temperature as high as possible, and it is particularly preferable to carry out the reaction under reflux. The desired 3-alkylpyrrole may be recovered from the reaction solution by a conventional method.

[0031]

【Example】

Example 1 A three-necked flask was equipped with a Dimroth and a dropping funnel, 500 ml of anhydrous toluene was placed in a reaction vessel kept at 20 ° C. under a nitrogen stream, and then 70 wt% sodium bis (2-methoxyethoxy) aluminum hydride was added. 100 g (0.350 mol) of the toluene solution of was added gradually and stirred. Furthermore, at the same temperature, 3-dodecanoyl-
33.2 g (82.2) of 1-toluenesulfonylpyrrole
Solution of 150 millimoles) in 150 ml of toluene
It dripped over time. After stirring for 1 hour, 11
The mixture was heated to 0 ° C. and stirred for 4 hours for reaction. After completion of the reaction, the reaction solution was returned to room temperature, ion-exchanged water was gradually added with stirring, and the mixture was stirred until the generation of hydrogen was stopped, and then left for a while.

The reaction mixture was separated into an organic layer, an aqueous layer and a solid, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The aqueous layer and solids were suction filtered and washed with toluene. The filtrate was extracted, and the obtained organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The two dried organic layers were concentrated to give 21.5 g of a brown viscous solution as crude product. This crude product was separated and purified by flash chromatography (manufactured by Tokyo Rika Kikai Co., Ltd., developing layer: silica gel 60 manufactured by Merck, developing solvent: hexane: ethyl acetate = 10: 1) to give 3-dodecylpyrrole 17. 0 g (yield 88%) was obtained.

The structure of the purified compound was confirmed by IR, ¹ H-NMR and ¹³ C-NMR. (1) IR (cm ^-1 ) 3408, 3097, 2962, 2
932, 2859, 1065 (2) ¹ H-NMR (δ: CDCl ₃ ) 0.87 (3H,
t) J = 5 Hz, 1.2 to 2.0 (20 H, m), 2.
46 (2H, t) J = 7Hz, 6.0-6.2 (1H,
m), 6.4 to 6.8 (2H, m) (3) ¹³ C-NMR (δ: CDCl ₃ ) 124.6, 11
7.5, 114.7, 108.5, 31.9, 31.
3, 29.7, 29.6, 29.4, 27.0, 22.
7, 14.1 [Examples 2 to 12] Only the alkyl group in the alkanoyl group of 3-alkanoyl (ie, dodecanoyl) -1-toluenesulfonylpyrrole of Example 1 was replaced with the alkyl group shown in Table 1, and Experiments were performed under the same conditions as in Example 1 (Examples 2, 3, 4, 6, 7). In addition, Example 1
SAH which is a reducing agent of LAH is shown in Table 1 (Example 5).
Instead of the above, the experiment was performed under the same conditions as in Example 1 except for the above.
Furthermore, under the same conditions as in Example 1, except that only the aryl group (X) of the 3-dodecanoyl-1-arylsulfonyl (ie, toluenesulfonyl) pyrrole of Example 1 was replaced with the aryl group shown in Table 2. Experiments were conducted (Examples 8-12). The results of those Examples were as shown in Tables 1-2.

As is clear from Tables 1 and 2, according to the present invention, 3-alkylpyrrole was obtained in high yield. Table 1 _{Examples Alkyl group} * Metal Hyde Produced 3- Alkylpyrrole Yield ^{Boiling point (bp) or melting point (mp) (%) of ride} 2 Hexyl SAH bp 75 ° C./2Pa 90 3 octyl SAH bp 95 ° C./2Pa 89 4 decyl SAH bp 115 ° C / 2Pa 89 5 dodecyl LAH mp 20 ° C 69 6 pentadecyl SAH mp 38 ° C 87 7 stearyl SAH mp 53 ° C 85 * Indicated as a substituent at the 3-position (ie, -CH ₂ R) after reduction.

Table 2 _{Examples Aryl group} Metal Hyde _{formation 3-Alkyl yield} Ride / _* Pyrrole boiling point ^{(X) Alkyl group (bp) or melting point (mp) (%)} 8 Phenyl SAH / Dodecyl mp 20 ° C. 88% 9 Phenyl LAH / dodecyl mp 20 ° C 67% 10 β-naphthyl SAH / octyl bp 95 ° C / 2Pa 84% 11 Methoxyphenyl SAH / decyl bp 115 ° C / 2Pa 87% 12 2,4,6-trimethyl SAH / dodecyl mp 20 ° C 81 ° C % ^Phenyl * See footnote in Table 1 [Comparative Example 1] A three-necked flask was equipped with a Dimroth and a dropping funnel, kept at 20 ° C. under a nitrogen stream, and charged with 300 ml of purified dioxane, 3-dodecanoyl-1-toluenesulfonylpyrrole 93 g ( 0.230 mol) was dissolved. Next, 5N sodium hydroxide aqueous solution 4
00 ml was added, and the mixture was heated at 20 ° C. for 1 hour, further heated to 100 ° C. and stirred for 6 hours. After completion of the reaction, the stirring was stopped and the mixture was separated into two layers. After decanting the organic layer,
The aqueous layer was extracted with diethyl ether. The organic layer was washed with water, then dried over anhydrous sodium sulfate, concentrated,
58 g of crude product was obtained. Further, recrystallization was performed in hexane containing 2% toluene to obtain 45 g of 3-dodecanoylpyrrole white crystals (yield 78%).

Next, a Dim funnel and a dropping funnel were attached to a separately prepared three-necked flask, the temperature was kept at 0 ° C. under an argon stream, 500 ml of purified diethyl ether was added, and 9.50 g of lithium aluminum hydride was further added.
(0.250 mol) was added slowly. 45 g (0.1 g of the white crystalline 3-dodecanoylpyrrole) under the same air flow
(80 mol) was dissolved in purified diethyl ether, placed in a dropping funnel, and added dropwise over 1 hour while stirring the inside of the flask.

The mixture was reacted under reflux with stirring for 3 hours. After the reaction vessel was allowed to cool, it was further cooled to 0 to 5 ° C., saturated saline was slowly added from a dropping funnel, and the produced white precipitate was suction filtered and washed with ether.

The filtrate obtained by suction filtration was extracted and the organic layer was separated, dried over anhydrous sodium sulfate and concentrated to obtain a liquid product. The liquid crude product was separated by flash chromatography to obtain 33.1 g of 3-dodecylpyrrole (yield 78%).

[0039]

INDUSTRIAL APPLICABILITY It becomes possible to produce 3-alkylpyrrole from 3-alkanoyl-1-arylsulfonylpyrrole in one step, and the yield in synthesis is very high, and the desired product can be selectively obtained. What has become possible has been described above in the section of [Summary of the Invention].

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[Procedure amendment]

[Submission date] May 20, 1993

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] 0029

[Correction method] Change

[Correction content]

The amount of reducing agent required to reduce 1 mole of 3-alkanoyl-1-arylsulfonylpyrrole is
When the metal hydride that is a reducing agent is represented by the chemical formula MHn, the amount thereof is 8 / n. This is because the phenylsulfonyl group eliminated by the reaction is also reduced by the reducing agent at the same time to be converted into a thiol, so that the reducing agent is additionally consumed. Further, in this reaction, the target 3-alkylpyrrole can be obtained in good yield when the amount of reducing agent used is larger than necessary (see Example 2). Therefore,
The amount required for the actual reaction is 8 / n to ((8 / n) +2)
Most preferably, the range is from 8 / n to ((8 / n) +1) mol.

Claims (3)

[Claims] 1. A 3-alkanoyl-1-arylsulfonylpyrrole represented by the following general formula (I) is reduced with a metal hydride in an organic solvent to obtain a 3-alkylpyrrole represented by the following general formula (II). Characterized by 3
-Process for making alkylpyrroles. [Chemical 1] (In the formula, R'represents an alkyl or alkenyl group having 1 to 20 carbon atoms, and X represents an aryl group which may have a substituent.) (In the formula, R represents an alkyl group having 1 to 20 carbon atoms) 2. The production of 3-alkylpyrrole according to claim 1, wherein the metal hydride that is a reducing agent is sodium bismethoxyethoxyaluminum hydride, sodium aluminum hydride, or lithium aluminum hydride or a trialkoxy derivative thereof. Law. 3. The method for producing a 3-alkylpyrrole according to claim 1, wherein R'is an alkyl group having 1 to 20 carbon atoms and X is a phenyl group or a tolyl group.