JP2009136856A - Aqueous catalyst for carbon-carbon bonding reaction - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an aqueous catalyst for promoting a carbon-carbon bonding reaction of a nucleophilic agent and an electrophilic agent in a water-soluble medium, especially in water to produce an object substance. <P>SOLUTION: The aqueous catalyst for carbon-carbon bonding reaction contains a (dialkylamino)pyridine which promotes the carbon-carbon bonding reaction of the nucleophilic agent, an alkene compound having conjugated electron withdrawing groups and the electrophilic agent reactive to it, or the carbon-carbon bonding reaction of the electrophilic agent, an alkene compound having conjugated electron withdrawing groups and the nucleophilic agent reactive to it in the water-soluble medium. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to an aqueous catalyst for promoting a carbon-carbon bond forming reaction in an aqueous medium, and a carbon-carbon bond forming method using the same.

  Organic reactions, such as reacting an organic nucleophile with an organic electrophile to form a carbon-carbon bond, dissolve them and actively move the molecules, so that the molecules can easily approach each other, especially organic solvents, Often performed in a water-insoluble organic solvent. Non-water-soluble organic solvents are dangerous because they are volatile and flammable, and are expensive to use in large quantities for industrial organic reactions, and the inhalation of volatile vapors impairs the health of workers. And the need for troublesome post-processing so as not to pollute the environment, it is gradually being shunned.

  On the other hand, an aqueous medium such as a water-soluble organic solvent or water, especially water, is different from an organic solvent in that it is nonflammable, inexpensive, and harmless to the human body and the environment. Therefore, in recent years, development of environmentally friendly chemical processes using water as a medium has been actively conducted.

  For example, in Non-Patent Document 1, an asymmetric aldol reaction is carried out in water with cycloaccanone such as cyclohexanone and cyclopentanone and benzaldehyde in the presence of optically active 2- (didecylaminomethyl) pyrrolidine and trifluoroacetic acid. A method is described which is carried out to obtain a β-hydroxyketone diastereoselectively and enantioselectively.

  A water-based catalyst that can be used for various carbon-carbon bond forming reactions including an aldol reaction in an aqueous medium and is versatile has been desired.

N. Mase et al., Journal of the American Chemical Society, 2006, 128, 734-735.

  The present invention has been made to solve the above-mentioned problems, and is an aqueous system that promotes a carbon-carbon bond forming reaction by a nucleophilic reagent and an electrophile in an aqueous medium, particularly water, and induces it to a target product. It is an object of the present invention to provide a catalyst and a method for forming a carbon-carbon bond that can be used in a simple and safe manner with a short reaction time and a high yield of the target product.

  The aqueous catalyst for carbon-carbon bond forming reaction according to claim 1, which has been made to achieve the above object, is a method for obtaining an alkene compound or an alkyne compound in which an electron withdrawing group is bonded and conjugated. Carbon-carbon bond formation reaction between a nuclear reagent and an electrophile that reacts with it, or carbon-carbon bond formation between an electrophile of an alkene compound that is conjugated with an electron-withdrawing group and a nucleophile that reacts with it It is characterized in that it contains (dialkylamino) pyridine which promotes the reaction in an aqueous medium.

  The aqueous catalyst according to claim 2 is the one according to claim 1, wherein the (dialkylamino) pyridine is 4- (dialkylamino) pyridine.

  The aqueous catalyst according to claim 3 is the one according to claim 2, wherein the number of carbon atoms of both of the dialkylamino groups in the 4- (dialkylamino) pyridine is 1 to 18. And

  The aqueous catalyst according to claim 4 is the one according to claim 3, wherein the carbon number of at least one alkyl of the dialkylamino group in the 4- (dialkylamino) pyridine is at least 5. Features.

  The water-based catalyst according to claim 5 is the water-based catalyst according to claim 3, wherein the number of carbon atoms of both alkyl groups in the dialkylamino group in the 4- (dialkylamino) pyridine is 5 to 18. And

（式中、alkylは炭素数５〜１８のアルキル基）で表されることを特徴とする。 The (dialkylamino) pyridine according to claim 6 has the following chemical formula:

(Wherein alkyl is an alkyl group having 5 to 18 carbon atoms).

  The (dialkylamino) pyridine according to claim 7 is 4- (dialkylamino) pyridine.

  The method for forming a carbon-carbon bond according to claim 8, wherein the nucleophilic reagent of the alkene compound to which the electron-withdrawing group is bonded and conjugated is combined with the electrophilic reagent that reacts with the nucleophilic reagent, Characterized in that an alkene compound or an alkyne compound electrophile and a nucleophile that reacts with the alkene compound or alkyne compound are reacted in a water-soluble medium in the presence of a (dialkylamino) pyridine-containing aqueous catalyst. To do.

  A carbon-carbon bond forming method according to a ninth aspect is the method according to the eighth aspect, wherein the (dialkylamino) pyridine is 4- (dialkylamino) pyridine.

  The carbon-carbon bond forming method according to claim 10 is the method according to claim 8, wherein the water-soluble medium is tetrahydrofuran, acetonitrile, dioxane, methanol, ethanol, propanol, and / or water. Features.

  A carbon-carbon bond forming method according to an eleventh aspect is the one according to the eighth aspect, wherein the water-soluble medium is composed of water only.

  The carbon-carbon bond forming method according to claim 12 is the method according to claim 8, wherein the nucleophilic reagent of the alkene compound is an acrylate ester, a cinnamic acid ester, an acrylate amide, β-nitrostyrene, Acrylonitrile, acrolein, cinnamic aldehyde, maleate ester, fumarate ester, and / or vinyl chloride, and the electrophile that reacts with it is aldehyde and / or imine thereof, and contains (dialkylamino) pyridine The carbon number of both alkyls of the water-based catalyst alkyl is 5-18.

  The carbon-carbon bond forming method according to claim 13 is the method according to claim 8, wherein the electrophilic reagent of the alkene compound or alkyne compound is (meth) acrylic acid ester, cinnamic acid ester, (meth). Acrylic acid amide, β-nitrostyrene, (meth) acrylonitrile, (meth) acrolein, cinnamic aldehyde, maleic acid ester, fumaric acid ester, benzylidene malonic acid ester, propiolic acid ester, phenylpropiolic acid ester, and / or vinyl chloride And the nucleophile that reacts therewith is an aliphatic monoaldehyde, aliphatic monoketone, aliphatic monoester, aliphatic β-diketone, aliphatic β-diester, aliphatic β-ketoester, aliphatic β-ketonitrile, fatty Group β-nitroketone and / or aliphatic β-nitroester The number of carbon atoms in the alkyl both alkyl (dialkylamino) pyridine-containing aqueous catalyst is characterized in that 1 to 18.

  According to the water-based catalyst for carbon-carbon bond formation reaction of the present invention, the carbon-carbon bond formation reaction by a nucleophile and an electrophile is promoted in an aqueous medium, particularly in a water-soluble organic solvent or water. , Can be directed to the object.

  According to the carbon-carbon bond forming method using this water-soluble catalyst, the target product can be obtained in a selective manner and in a high yield in a short reaction time without contaminating the environment simply and safely.

  In addition, when this aqueous catalyst is used, a common alkene compound can be subjected to a nucleophilic reaction or an electrophilic reaction, which is excellent in versatility.

Preferred form for carrying out the invention

  Hereinafter, although the preferable form for implementing this invention is demonstrated in detail, the scope of the present invention is not limited to these forms.

  A preferred embodiment of the water-based catalyst for carbon-carbon bond forming reaction contains 4- (dialkylamino) pyridine. For example, 4- (didecylamino) pyridine is synthesized as shown in the following chemical reaction formula (I).

4-Aminopyridine (1) is reacted with decanoic acid chloride (2) to give decanoic acid amide (3). It is reduced to a decylamine body (4) by reducing with a reducing agent such as LiAlH ₄ , and then the decanoic acid chloride (2) is reacted again to form an N-decyl-decanoic acid amide body (5). It is reduced with a reducing agent such as BH ₃ to give 4- (didecylamino) pyridine (5).

  Although 4- (dialkylaminopyridine) is shown as an example in which two alkyls in the dialkylamino group are both decyl, the same applies to other alkyls having different carbon numbers such as pentyl and octyl. Can be synthesized. The two alkyls may be the same as or different from each other as long as they have 1 to 18 carbon atoms, and may be saturated or unsaturated, and may be linear, branched or cyclic. Alkyl is preferably linear. The dialkylamino group may be substituted at the position of another pyridine ring, but is preferably substituted at the 4-position.

  This aqueous catalyst is preferably used in a water-soluble medium which is a water-soluble organic solvent, water, or a mixture thereof.

  The water-based catalyst is used for a carbon-carbon bond forming reaction by a nucleophile that is an alkene compound in which an electron withdrawing group is bonded to an unsaturated group and conjugated, and an electrophilic reagent that reacts with the nucleophile.

  In such alkene compounds that serve as nucleophiles, electron-withdrawing groups such as ester groups, acid amide groups, nitro groups, cyano groups, carbonyl groups, and halogen groups are bonded to unsaturated groups such as ethylenically unsaturated groups. Thus, it is an electron-deficient active alkene compound conjugated to an α, β-unsaturated compound. Since the α-position of the alkene compound has an electron density higher than that of the β-position due to the electron-withdrawing group, nucleophilic attack is performed on electrophilic reagents such as aldehydes and their imines. As a result, a new carbon-carbon bond is formed. Examples of such a carbon-carbon bond forming reaction include a Baylis-Hillman reaction.

  In the Biris-Hillman reaction, nitrogen in the water-based catalyst is added to the β-position of the alkene compound, the electron density at the α-position is increased, the nucleophilic attack is performed on the electrophilic reagent, and then the water-based catalyst is desorbed. Progresses.

  More specifically, alkene compounds that are nucleophiles are acrylic acid esters, cinnamic acid esters, acrylic acid amides, β-nitrostyrene, acrylonitrile, acrolein, cinnamic aldehydes, maleic acid esters, fumaric acid esters, chlorides. Vinyl is mentioned. Examples of these esters include methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, t-butyl ester, and menthyl ester.

  The electrophilic reagent that reacts with the alkene compound, which is a nucleophilic reagent, may or may not be substituted with an aldehyde such as an electron withdrawing group such as a nitro group, a cyano group, or a halogen group, or an alkyl group. Examples thereof include aromatic aldehydes and aliphatic aldehydes exemplified by benzaldehyde, and imines obtained by iminization of the aldehydes.

  Such a bilith-Hillman reaction lacks specificity and is difficult to proceed unless each substrate, catalyst, and medium, which are alkene compounds and electrophiles that react with the alkene compound, are appropriate. When this aqueous catalyst is used, the Bilith-Hillman reaction proceeds efficiently in an aqueous medium, particularly in water.

  When 4- (dialkylamino) pyridine, which is an aqueous catalyst, is used for the bilith-Hillman reaction, if the medium is only a water-soluble organic solvent, for example, tetrahydrofuran, the dialkylamino group has a long-chain alkyl dipentylamino group or A compound having a dimethylamino group having a smaller number of carbon atoms than a dioctylamino group or a didecylamino group is preferred. On the other hand, if the medium is only water, at least one of the alkyl groups has a carbon number such that the dialkylamino group is a dipentylamino group, a dioctylamino group or a didecylamino group having a long-chain alkyl having more carbon atoms than the dimethylamino group. A compound having 5 or more is preferred. Although the details of the reason are not necessarily clear, 4- (dialkylamino) pyridine exhibits excellent lipid solubility in water due to its long-chain alkyl and hydrophilicity due to two nitrogen atoms. It is speculated that it is cloudy and forms an emulsion, and the Birith-Hillman reaction proceeds rapidly at this emulsion site.

  This aqueous catalyst is also used for a carbon-carbon bond forming reaction between an electrophile that is an alkene compound to which an electron withdrawing group is bonded and conjugated, and a nucleophile that reacts with the electrophilic reagent.

  The alkene compound or alkyne compound, which is an electrophile, is also an electron-deficient alkene compound or alkyne compound in which an electron withdrawing group is bonded to an unsaturated group and conjugated to an α, β-unsaturated compound. (Meth) acrylic acid esters such as acid esters and methacrylic acid esters, cinnamic acid esters, (meth) acrylic acid amides, β-nitrostyrene, (meth) acrylonitrile, (meth) acrolein, cinnamic aldehydes, maleic acid esters , Fumaric acid ester, benzylidene malonic acid ester, propiolic acid ester, phenylpropiolic acid ester, and vinyl chloride. Examples of these esters include the same esters as the above nucleophiles. Since the β-position of the alkene compound has a lower electron density than the α-position because of the electron withdrawing group, nucleophiles such as active hydrogen compounds, more specifically aliphatic monoaldehydes, aliphatic monoketones , Aliphatic monoesters, aliphatic β-diketones, aliphatic β-diesters, aliphatic β-ketoesters, aliphatic β-ketonitriles, aliphatic β-nitroketones, aliphatic β-nitroesters The α-position-active hydrogen-containing carbon resulting from nucleophilic attack. As a result, a new carbon-carbon bond is formed. Such a carbon-carbon bond forming reaction includes, for example, a Michael reaction.

Nucleophiles that react with alkene compounds that are electrophiles are preferred specific examples,
^{R 1 - (CO) -CHR 2} - (CO) R 3 ( where, R 1 ^- (CO) ^- and - (CO) ^{R 3} represents an aldehyde group, a ketone group, an ester group, an amide group, ^{R 2} -Represents a hydrogen atom, an alkyl group, or an aromatic group, or R ^1- (CO) -CHR ² -represents a ring-forming group such as cycloalkanone, lactone, or lactam,-(CO) R ³ represents an aldehyde group, a ketone group, an ester group, or an amide group.

  When 4- (dialkylamino) pyridine, which is an aqueous catalyst, is used for the Michael reaction, the medium may be only a water-soluble organic solvent, for example, tetrahydrofuran, acetonitrile, dioxane, methanol, ethanol, propanol, or only water. Even with these mixtures, the yield of the Michael reaction is high. In that case, both alkyls of the dialkylamino group of 4- (dialkylamino) pyridine may be the same or different with 1 to 18 carbon atoms.

  Such a Michael reaction lacks specificity and is difficult to proceed or easily cause side reactions unless the alkene compound and each substrate, catalyst, and medium that are nucleophiles that react with the alkene compound are appropriate. . When this aqueous catalyst is used, the Michael reaction proceeds efficiently and cleanly in an aqueous medium, particularly water.

  In particular, in the case of the Michael addition reaction of methyl acrylate to the α-unsubstituted β-ketoester, 4- (di-short chain alkylamino) pyridine, for example 4-dimethylaminopyridine, gives 1 Michael addition reaction to the α-position. In contrast, when 4- (di-long-chain alkylamino) pyridine such as 4-dioctylaminopyridine is used, the Michael addition reaction to the α-position is repeated twice rapidly. Thus, by simply changing the aqueous catalyst, synthesis of products having different structures from the same substrate can be controlled. In addition, in the case of Michael addition reaction of methyl acrylate or acrylonitrile to α-monosubstituted or cyclic β-ketoester, 4- (di-long-chain alkylamino) pyridine such as 4-dioctylaminopyridine is more preferable. -Short chain alkylamino) pyridine, for example, faster reaction rate than using 4-dimethylaminopyridine.

Furthermore, when the propiolic acid ester analog that is an electrophile undergoes a Michael addition reaction to the nucleophile R ^1- (CO) -CHR ^2- (CO) R ³ , an extremely short time of about 10 to 10 minutes. The reaction is complete.

  The carbon-carbon bond forming reaction may be performed at 0 ° C. to room temperature, or may be performed under heating.

  Below, the specific example which formed the carbon-carbon bond using the aqueous catalyst of this invention is shown.

  First, 4- (dialkylamino) pyridine serving as an aqueous catalyst was synthesized according to the chemical reaction formula (I).

(Synthesis Example 1 Synthesis of 4- (didecylamino) pyridine)
(Step 1-1 Addition of decanoic acid chloride to 4-aminopyridine)
A solution of decanoic acid chloride (4.77 mL, 23 mmol) in methylene chloride (5 mL) was added methylene chloride (15 mL) with 4-aminopyridine (2.00 g, 21 mmol) and diisopropylethylamine (10.993 mL, 63 mmol) at 0 ° C. ) Added to the solution with stirring and then stirred overnight. The reaction mixture was then heated to 80 ° C. and refluxed for 2 hours before being allowed to cool to room temperature. Methylene chloride was added thereto, and then transferred to a separatory funnel and washed with water. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain pale yellow crystals of N- (4-pyridyl) decanoic acid amide in a yield of 75%.

(Step 1-2 Reduction of N- (4-pyridyl) decanoic acid amide)
Under a nitrogen gas atmosphere, a 12 mL suspension of LiAlH ₄ (0.594 g, 14.4 mmol) in anhydrous tetrahydrofuran (THF) was mixed with anhydrous N- (4-pyridyl) decanoic acid amide (2.98 g, 9.26 mmol). A solution of THF (12 mL) was added over 1.5 hours at a gentle reflux rate. The reaction mixture was refluxed in a 60 ° C. water bath overnight, then water was added to decompose excess LiAlH ₄ while releasing a nitrogen gas atmosphere and cooling to 0 ° C. The solution was poured into a 1M aqueous sulfuric acid solution, and then THF was distilled off under reduced pressure. The aqueous solution was transferred to a separatory funnel and washed with ether. The aqueous phase was made alkaline by the addition of NaOH tablets. Extraction from this alkaline aqueous solution with ether was repeated, the ether extracts were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 4- (decylamino) pyridine in a yield of 64%. .

(Step 1-3 Addition of decanoic acid chloride to 4- (decylamino) pyridine)
A solution of decanoic acid chloride (1.66 mL, 8 mmol) in methylene chloride (3.5 mL) was added methylene chloride (3.66 mL) of 4- (decylamino) pyridine (1.64 g, 7 mmol) and diisopropylethylamine at 0 ° C. The solution was added with stirring and then stirred overnight. The reaction mixture was then heated to 80 ° C. and refluxed for 2 hours before being allowed to cool to room temperature. Methylene chloride was added thereto, and then transferred to a separatory funnel and washed with water. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain N-decyl-N-pyridin-4-yldecanoic acid amide in a yield of 68%.

(Step 1-4 Reduction of N-decyl-N-pyridin-4-yldecanoic acid amide)
N-decyl-N-pyridin-4-yldecanoic acid amide (500 mg, 1.3 mmol) was stirred in a BH ₃ -THF solution (1M, 6.5 mL, 6.5 mmol) at room temperature under an argon gas atmosphere. A solution of anhydrous THF (2 mL) was added. The reaction mixture was refluxed in a 70 ° C. water bath overnight. After allowing to cool, water was added. Thereafter, the solution was poured into a 1M aqueous sulfuric acid solution, THF was distilled off under reduced pressure, the aqueous solution was transferred to a separatory funnel, and washed with chloroform. The aqueous phase was made alkaline by the addition of NaOH tablets. Extraction was repeated twice from this alkaline aqueous solution with chloroform, and the obtained organic layers were combined and dried over anhydrous potassium carbonate, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography using chloroform: methanol (15: 1 by volume) as an elution solvent, and then recrystallized from methylene chloride / ethyl acetate to give 4- (didecylamino) as white crystals. ) 282.6 mg of pyridine were obtained with a yield of 58%.

The physicochemical analysis data of this 4- (didecylamino) pyridine is as follows.
Melting point 142.0-150.0 ℃ (Recrystallized from methylene chloride / ethyl acetate)
IR (KBr) ν 2952, 2922, 2850, 1602, 1537, 1517, 1489 cm ⁻¹ .
¹ H-NMR (CDCl ₃ , 400MHz) d 0.88 (6H, t, J = 6.7Hz), 1.27-1.31 (28H, m), 1.56 (4H, m), 3.25 (4H, t, J = 7.7Hz) , 6.41 (2H, dd, J = 5.1, 1.5Hz), 8.16 (2H, dd, J = 5.1, 1.5Hz).
¹³ C-NMR (CDCl ₃ , 100 MHz) d 14.09 (x2), 22.64 (x2), 26.92 (x2), 26.99 (x2), 29.27 (x2), 29.42 (x2), 29.51 (x2), 29.59 (x2) , 31.85 (x2), 50.14 (x2), 106.27 (x2), 149.83 (x2), 152.34.
Elemental analysis Theoretical value (C ₂₅ H ₄₆ N ₂ · 2H ₂ O): C, 73.12; H, 12.27; N, 6.82. Actual measurement: C, 73.26; H, 12.16; N, 6.66.

  This physicochemical analysis data supports 4- (didecylamino) pyridine.

(Synthesis Examples 2-3 Synthesis of 4- (dioctylamino) pyridine and 4- (dipentylamino) pyridine)
4- (Dioctylamino) pyridine and 4- (Dioctylamino) pyridine and 4- (Dioctylamino) pyridine were synthesized in the same manner as in Synthesis Example 1 except that octanoic acid chloride and pentanoic acid chloride were used in place of the decanoic acid chloride of Synthesis Example 1. (Dipentylamino) pyridine was obtained.

  As described above, when physicochemical analysis was performed, the analysis data supported these structures.

  A commercially available 4- (dimethylamino) pyridine (DMAP) and the obtained 4- (dialkylamino) pyridine were used as an aqueous catalyst to form a carbon-carbon bond.

  As a reaction for reacting an alkene compound, which is a nucleophile, with an electrophile to form a carbon-carbon bond, the Billis-Hillman reaction was performed.

  Examples 1 to 14 show examples in which the Biris-Hillman reaction was performed in various water-soluble media using DMAP or 4- (didecylamino) pyridine as an aqueous catalyst.

(Example 1)
4-Nitrobenzaldehyde (151.12 mg, 1 mmol) as an electrophile and DMAP (12.217 mg, 0.1 mmol) as an aqueous catalyst were added to 2 mL of water as a medium and stirred to obtain a nucleophile. The alkene compound methyl acrylate (0.27 mL, 3 mmol) was added at room temperature and allowed to react for 66 hours. After the reaction, extracted and the solvent was distilled off under reduced pressure, was determined by ¹ H- nuclear magnetic resonance spectrum ^{(1 H-NMR)} method of the non-purified product. Separately Bairisu isolated - by calculating the ratio of the integral value of peaks of the ^{1 H} integrated value of the peaks of the ^{1 H} of the benzyl position Hillman reaction product with 4-nitrobenzaldehyde aldehyde, seeking conversion yield It was. The results are shown in Table 1.

(Examples 2 to 12, Comparative Examples 1 to 4)
The conversion yield was determined in the same manner as in Example 1 except that the aqueous catalyst, medium, reaction time, and reaction temperature in Example 1 were changed to the conditions shown in Table 1. The results are summarized in Table 1.

  As is clear from Table 1, when reacted with DMAP in water at room temperature to 40 ° C. as in Examples 1 to 4, the reaction proceeded with a conversion yield of several percent. When the reaction was carried out using 4- (didecylamino) pyridine, the reaction proceeded with a dramatically high conversion efficiency of about 60 to 70%. The difference in the results was that when DMAP was used, the reaction did not proceed because the substrate was in a solid state and was not sufficiently dispersed, whereas 4- (didecylamino) pyridine was used. The substrate and the water-based catalyst are not completely dissolved in water, but are presumably due to the rapid dispersion by stirring.

  When reacted with DMAP in acetonitrile at room temperature as in Examples 5-6, the reaction proceeded with a relatively high conversion yield, but when 4- (didecylamino) pyridine was used, The reaction proceeded at a dramatically high conversion efficiency of about 70%, equivalent to the case.

  Even when the medium is a water / 1,4-dioxane mixed solvent, tetrahydrofuran, a water / methanol mixed solvent, or a water / 2-propanol mixed solvent as in Examples 7 to 12, it is not as much as in the case of water or acetonitrile. However, the reaction proceeded relatively quickly.

  These DMAP and 4- (didecylamino) pyridine function as a catalyst that promotes the Biris-Hillman reaction, which is usually difficult to react, in water or in a water-soluble medium, especially in water. Such water and water-soluble solvents are suitable for industrial mass production because they are easier to dispose of than water-insoluble organic solvents.

  On the other hand, as in Comparative Examples 1 to 4, the reaction proceeds to some extent even in a medium such as methylene chloride, which is a flame retardant organic solvent, or water / toluene separated in two layers. Is not suitable for industrial mass production.

  Next, in Examples 13 to 19, 0.1 to 5 each of DMAP, 4- (dipentylamino) pyridine, 4- (dioctylamino) pyridine and 4- (didecylamino) pyridine having different alkyl chain lengths as the aqueous catalyst. The example which performed Billis-Hillman reaction in water using 0.2 equivalent is shown.

(Examples 13 to 19)
The conversion yield was determined in the same manner as in Example 1 except that the aqueous catalyst and reaction time in Example 1 were changed to the conditions shown in Table 2. The results are summarized in Table 2.

  As is apparent from Table 2, 4- (dialkylamino) pyridine has a different catalytic effect depending on the chain length of the alkyl. When the Biris-Hillman reaction is carried out with these substrates, the alkyl is methyl having a chain length of 1 or In the case of pentyl having a chain length of 5 or decyl having a chain length of 10 as compared with the case of octyl having a chain length of 8, the higher the concentration thereof, the reaction proceeds more rapidly, and a high conversion yield is exhibited. It was. The difference in the results is that when DMAP or 4- (dioctylamino) pyridine is used, this substrate or this aqueous catalyst does not dissolve and floats as a solid or adheres to the reaction vessel wall and is sufficiently dispersed. However, when 4- (dipentylamino) pyridine or 4- (didecylamino) pyridine is used, the substrate and water-based catalyst are not completely dissolved in water, but they are rapidly dissolved by stirring. It is inferred that this is due to the dispersal. Since the conversion yield is not proportional to the alkyl chain length of 4- (dialkylamino) pyridine, the type and concentration of the substrate and the type and concentration of the aqueous catalyst are important for emulsion formation and the high conversion efficiency resulting therefrom. It was suggested that it was a factor.

  Next, Examples 20 to 22 show examples in which the Billis-Hillman reaction was performed in water in the presence of 4- (didecylamino) pyridine using various alkene compounds as substrates.

(Examples 20 to 22)
The Bilith-Hillman reaction was carried out in the same manner as in Example 1 except that the water-based catalyst, alkene compound, reaction time, and reaction temperature in Example 1 were changed to the conditions shown in Table 3 and the post-treatment was performed. It was. In the post-treatment, the reaction mixture was extracted repeatedly with chloroform, and the organic layers were combined, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting crude product was purified with chloroform: methanol ( This was purified by silica gel column chromatography using 50: 1) by volume as the effluent solvent. The results of obtaining the isolation yield are summarized in Table 3.

  As is clear from Table 3, when the alkene compound is an acrylate ester, the lower the lipophilicity of the ester group, the higher the yield.

  Next, Examples 23 to 26 show examples in which the Billis-Hillman reaction was performed in water in the presence of 4- (didecylamino) pyridine using various benzaldehydes as substrates.

(Examples 23 to 26)
Bilith in the same manner as in Example 1 except that the amount of the aqueous catalyst, benzaldehyde, alkene compound, reaction time, and reaction temperature in Example 1 were changed to the conditions shown in Table 4 and the post-treatment was performed. -A Hillman reaction was performed. In the post-treatment, the reaction mixture was extracted repeatedly with chloroform, and the organic layers were combined, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting crude product was purified with chloroform: methanol ( This was purified by silica gel column chromatography using 50: 1) by volume as the effluent solvent. The results of obtaining the isolation yield are summarized in Table 4.

  As is apparent from Table 4, the Biris-Hillman reaction proceeds with any benzaldehyde, and the yield is particularly high in the case of 3- or 4-nitrobenzaldehyde.

  Moreover, Michael reaction was performed as reaction which makes the alkene compound which is an electrophilic reagent react with the substrate of a nucleophilic reagent, and forms a carbon-carbon bond.

  Various β-ketoesters were used as nucleophiles. First, Example 27 shows an example using methyl 2-oxocyclopentanecarboxylate, which is a cyclic β-ketocarboxylic acid ester.

(Example 27)
A nucleophilic methyl 2-oxocyclopentanecarboxylate (0.127 mL, 1 mmol) and 4- (didecylamino) pyridine (37.427 mg, 0.1 mmol) are added to 2 mL of water as a medium and stirred. Then, methyl acrylate (0.18 mL, 2 mmol), which is an alkene compound, was added as an electrophilic reagent at room temperature and stirred for 1.5 hours. The reaction mixture was extracted repeatedly with ethyl acetate, and the organic layers were combined and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting crude product was treated with hexane: ethyl acetate (volume ratio). And purified by silica gel column chromatography using 4: 1 to 2: 1) as an effluent solvent. The product Michael reaction adduct was obtained in> 99% isolated yield as shown in Table 5.

  The Michael reaction proceeds regardless of whether the water-based catalyst is 4-decylaminopyridine or DMAP. Particularly, when 4-decylaminopyridine is used, the desired product is obtained in a high yield. When 4- (didecylamino) pyridine is used as the aqueous catalyst, the reaction is carried out in water rather than in a water-soluble organic solvent such as tetrahydrofuran, acetonitrile, or methanol, or in a water-insoluble organic solvent such as methylene chloride. The reaction proceeded much more quickly and neatly, and there was no side reaction. When methyl 2-oxocyclohexanecarboxylate is used as the nucleophile, the yield is much less than that obtained when the methyl 2-oxocyclopentanecarboxylate is used almost quantitatively. It was.

  Next, a methyl reaction with acrylonitrile, another electrophile, was performed using methyl 2-oxocyclopentanecarboxylate as the nucleophile. Examples thereof are shown in Examples 28 to 29.

(Examples 28 to 29)
A Michael reaction was performed in the same manner as in Example 27 except that acrylonitrile was used instead of methyl acrylate in Example 27, and the aqueous catalyst and reaction time were changed to the conditions shown in Table 6. The product was isolated and the yield was determined. The results are summarized in Table 6.

  As is apparent from Table 6, the addition rate of quaternary carbon having a high reaction rate, complexity and steric hindrance is higher when 4-di-n-decylaminopyridine is used than when DMAP is used. The product was obtained in high yield in a short time.

  Next, an example is shown in which ethyl acetoacetate, which is a linear and non-substituted α-ketocarboxylate ester, is used as the nucleophile, and methyl acrylate is used as the electrophile.

(Examples 30 to 33)
In place of methyl 2-oxocyclohexanecarboxylate in Example 27, ethyl acetoacetate was used, 4 equivalents of methyl acrylate were used, and the aqueous catalyst and reaction time were changed to the conditions shown in Table 7. Except for this, a Michael reaction was carried out in the same manner as in Example 27, the product was isolated, and the yield was determined. The results are summarized in Table 7.

  As is apparent from Table 7, in the case of Michael addition reaction of methyl acrylate to α-unsubstituted β-ketoester, when DMAP is used, Michael addition reaction by one molecule of methyl acrylate mainly occurs and product A is obtained. On the other hand, when 4-di-n-decylaminopyridine is used, Michael addition reaction by two molecules of methyl acrylate repeatedly occurs rapidly, and as a result, product B having a complex and sterically hindered quaternary carbon is obtained in a short time. In high yield. Therefore, even if the same substrate is used, the product can be controlled only by changing the catalyst.

  Next, an example is shown in which ethyl 3-keto-2-methylbutyrate, which is a chain and α-substituted β-ketocarboxylic acid ester, is used as the nucleophile, and methyl acrylate is used as the electrophile.

(Examples 34 to 35)
Except that ethyl 3-keto-2-methylbutyrate was used in place of methyl 2-oxocyclohexanecarboxylate in Example 27 and that the aqueous catalyst and reaction time were changed to the conditions shown in Table 8, The Michael reaction was carried out in the same manner as in Example 27, the product was isolated, and the yield was determined. The results are summarized in Table 8.

  As is clear from Table 8, in the case of Michael addition reaction of methyl acrylate to α-monosubstituted β-ketoester, when 4-di-n-decylaminopyridine is used rather than when DMAP is used. However, an addition product having a quaternary carbon having a high reaction rate and a large steric hindrance could be obtained in a high yield in a short time.

  Next, an example in which methyl propiolate having a triple bond is used as the electrophile and methyl 2-oxocyclopentanecarboxylate is used as the nucleophile is shown.

(Example 36)
In place of methyl acrylate in Example 27, methyl propiolate was used, 4- (di-n-decylamino) pyridine was used as the aqueous catalyst, and the reaction time was changed to the conditions shown in Table 8. Except that, the Michael reaction was carried out in the same manner as in Example 27, the product was isolated, and the yield was determined. The results are shown in Table 9.

  As is apparent from Table 9, the reaction was completed almost instantaneously, and an acrylic acid derivative to which methyl propiolate was added was obtained in a high yield as an E / Z mixture.

  The aqueous catalyst of the present invention is useful as a catalyst for a reaction in which an alkene compound and a nucleophile or an electrophile are reacted to form a carbon-carbon bond in an aqueous medium, particularly in an aqueous organic solvent or water. It is.

  This carbon-carbon bond forming method using an aqueous catalyst is useful for selectively producing a compound useful as an intermediate for chemical products and pharmaceuticals with high purity.

Claims (13)

  Carbon-carbon bond-forming reaction between a nucleophilic reagent of an alkene compound to which an electron-withdrawing group is bonded and conjugated, and an electrophile to react with the alkene compound, or an alkene or alkyne compound to which an electron-withdrawing group is bonded and conjugated A carbon-carbon bond-forming reaction characterized in that it contains (dialkylamino) pyridine, which promotes a carbon-carbon bond-forming reaction between an electrophile and a nucleophile reacting therewith in an aqueous medium. An aqueous catalyst.   The aqueous catalyst according to claim 1, wherein the (dialkylamino) pyridine is 4- (dialkylamino) pyridine.   The water-based catalyst according to claim 2, wherein the number of carbon atoms of both dialkylamino groups in the 4- (dialkylamino) pyridine is 1-18.   The aqueous catalyst according to claim 3, wherein the carbon number of at least one alkyl of the dialkylamino group in the 4- (dialkylamino) pyridine is at least 5.   The water-based catalyst according to claim 3, wherein the number of carbon atoms of both dialkylamino groups in the 4- (dialkylamino) pyridine is 5 to 18. The following chemical formula

(Wherein alkyl is an alkyl group having 5 to 18 carbon atoms) (dialkylamino) pyridine.   The (dialkylamino) pyridine according to claim 6, which is 4- (dialkylamino) pyridine.   An alkene compound nucleophile conjugated with an electron withdrawing group and an electrophilic reagent reacting therewith, or an alkene compound or alkyne compound electrophile with an electron withdrawing group conjugated and A method for forming a carbon-carbon bond, which comprises reacting a nucleophile to be reacted in a water-soluble medium in the presence of a (dialkylamino) pyridine-containing aqueous catalyst.   The method for forming a carbon-carbon bond according to claim 8, wherein the (dialkylamino) pyridine is 4- (dialkylamino) pyridine.   The method for forming a carbon-carbon bond according to claim 8, wherein the water-soluble medium is tetrahydrofuran, acetonitrile, dioxane, methanol, ethanol, propanol, and / or water.   The carbon-carbon bond forming method according to claim 8, wherein the water-soluble medium is composed of only water.   The alkene compound nucleophile is acrylic acid ester, cinnamic acid ester, acrylic acid amide, β-nitrostyrene, acrylonitrile, acrolein, cinnamic aldehyde, maleic acid ester, fumaric acid ester, and / or vinyl chloride, The electrophile that reacts therewith is an aldehyde and / or an imine thereof, wherein both alkyls in the alkyl of the (dialkylamino) pyridine-containing aqueous catalyst have 5 to 18 carbon atoms. 8. The carbon-carbon bond forming method according to 8.   The alkene compound or alkyne compound electrophile is (meth) acrylic acid ester, cinnamic acid ester, (meth) acrylic acid amide, β-nitrostyrene, (meth) acrylonitrile, (meth) acrolein, cinnamic aldehyde, malein Acid ester, fumaric acid ester, benzylidene malonic acid ester, propiolic acid ester, phenylpropiolic acid ester, and / or vinyl chloride, and the nucleophile that reacts with them is aliphatic monoaldehyde, aliphatic monoketone, aliphatic monoester , Aliphatic β-diketone, aliphatic β-diester, aliphatic β-ketoester, aliphatic β-ketonitrile, aliphatic β-nitroketone, and / or aliphatic β-nitroester, containing (dialkylamino) pyridine Water based catalyst alkyl both alkyl charcoal 9. The carbon-carbon bond forming method according to claim 8, wherein the prime number is 1-18.