JP2003081979A - New method for preparing organometallic compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for preparing an organometallic compound such as an organogallium or an organoaluminum compound under mild conditions such as at room temperature by activating a metal such as gallium or aluminum with the addition of a catalytic amount of a different metal from gallium and aluminum. SOLUTION: The method for preparing the organometallic compound comprising reacting an organohalogen compound with a metal having a stronger reducing power than indium in the presence of a catalytic amount of indium or an indium compound and a reaction reagent for forming a carbon-carbon bond are provided. The preparing method in which the reaction is carried out in the coexistence of a raw material for the carbon-carbon bond forming reaction and a method for forming carbon-carbon bond through a Barbier reaction are provided.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an organogallium reagent, an organoaluminum reagent, etc. used for a carbon-carbon bond forming reaction such as a nucleophilic addition reaction to a carbonyl compound and an addition reaction to an alkyne. To a novel method for preparing the organometallic compound.

[0002]

2. Description of the Related Art Many metals are used in organic synthesis reactions, and Grignard reaction using magnesium and Refomatsky reaction using zinc are well known. The reaction using a metal is one of the most effective means in organic synthesis, but since the metal surface is covered with an oxide film,
In many cases, the reaction does not proceed even if the metal is used as it is, and normally, there is a problem that the metal must be activated before it can be used in the reaction. For example, since metal manganese shows almost no reducing power as it is, one method is to use Rieke's activation method to reduce manganese (2) salt with lithium naphthalenide to reduce benzyl bromide. You are getting manganese. Further, the inventors of the present invention have previously found activation of manganese metal by causing catalytic amounts of lead chloride (2) and Me ₃ SiCl to act on the manganese metal.
In this example, the addition of a very small amount of a different metal is effective in activating the metal. As an example of using gallium metal, for example, a method of adding lead chloride (2) (J. Chem. So
c., Perkin Trans.1,1995,189-191) and the method of adding potassium iodide (Tetrahedron Letters, Vol.35, No.50,943).
3-9434,1994) etc., some methods are known,
In either case, the reaction hardly progresses at room temperature and all require heating conditions, but at high temperatures, it is difficult to manufacture because of side reactions and the like, and the efficiency is poor.

[0003]

DISCLOSURE OF THE INVENTION The present invention provides, for example, gallium, aluminum, etc. by adding a catalytic amount of a metal different from gallium, aluminum, etc. to an organometallic compound such as an organic gallium reactant, an organic aluminum reactant, etc. The purpose of the present invention is to provide a method for activating the metal of the above and preparing it under mild conditions such as room temperature.

[0004]

The present invention is a method for producing an organometallic compound, which comprises reacting an organohalogen compound with a metal having a reducing power higher than that of indium in the presence of a catalytic amount of indium or an indium compound. Regarding

The present invention also relates to a reaction reagent used in the carbon-carbon bond forming reaction obtained by the above-mentioned production method.

Further, the present invention relates to the above-mentioned production method in which the production reaction is carried out in the presence of a raw material compound used in the carbon-carbon bond formation reaction.

Furthermore, the present invention relates to a method for producing a carbon-carbon bond by a Barbie type reaction, characterized in that the above-mentioned production method is carried out in the coexistence of a raw material compound used for a carbon-carbon bond producing reaction.

That is, the inventors of the present invention cooled the suspension obtained by adding a catalytic amount of indium metal to gallium metal or aluminum metal to 10 ° C. and agitated the mixture, and then added dropwise allyl bromide and agitated the mixture. By doing so, gallium or aluminum metal disappears, and allyl gallium bromide,
Alternatively, it was found that allylaluminum bromide was produced (confirmed by NMR), and this Grignard-type gallium and aluminum reagent (reactant) are stable at room temperature for a long period of time, and are addition reactions to carbonyl compounds and acetylene. Was confirmed to be possible with high yield, and further,
By adopting this method, it was found that not only the Grignard type reagent but also the Barbier type reaction in which the addition reaction of the next step is performed simultaneously with the reagent preparation can be effectively performed, and the present invention has been completed. It was By using the organogallium reagent, the organoaluminum reagent, etc. according to the present invention, various useful organic compounds, which have been difficult to synthesize with conventional metal-based reagents, can be newly or more easily and highly selective. Will be obtained.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION Examples of the organic halogen compound used in the present invention include the following general formula [1] R—X [1] (wherein R is a hydrocarbon group which may have a substituent). And X represents a halogen atom). In the general formula [1], examples of the hydrocarbon group represented by R, which may have a substituent, include an alkyl group, an alkenyl group, an alkynyl group, an aralkyl group, and an aryl group. To be
Examples of the alkyl group include a linear, branched or cyclic alkyl group having 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and more specifically,
For example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, secondary butyl group, tertiary butyl group, pentyl group, hexyl group, cyclopropyl group, cyclopentyl group, cyclohexyl group, cyclooctyl group. Groups and the like. Examples of the alkenyl group include those having an unsaturated group such as one or more double bonds in the above-mentioned alkyl group having 2 or more carbon atoms, and more specifically, a vinyl group, an allyl group, 1- Examples thereof include a propenyl group, an isopropenyl group, a 2-butenyl group, a 1,3-butadienyl group, a 2-pentenyl group, a 2-hexenyl group, a cyclopropenyl group, a cyclopentenyl group and a cyclohexenyl group. Examples of the alkynyl group include those having an unsaturated group such as a triple bond in the above-mentioned alkyl group having 2 or more carbon atoms, and more specifically, an ethynyl group, a 1-propynyl group, a 2 A propynyl group and the like. The aralkyl group has, for example, 7 to 30 carbon atoms, preferably 7 to 20 carbon atoms, and more preferably 7 to 20 carbon atoms.
Examples thereof include 15 monocyclic, polycyclic or condensed ring aralkyl groups, and more specific examples thereof include a benzyl group, a phenethyl group, a naphthylmethyl group and a naphthylethyl group. Examples of the aryl group include monocyclic, polycyclic or condensed ring aromatic hydrocarbon groups having 6 to 30 carbon atoms, preferably 6 to 20 carbon atoms, more preferably 6 to 14 carbon atoms, and more specifically. Examples thereof include phenyl group, tolyl group, xylyl group, naphthyl group, methylnaphthyl group, anthryl group, phenanthryl group and biphenyl group. As the substituents of these alkyl group, alkenyl group, alkynyl group, aralkyl group, aryl group and the like, any group may be used as long as it does not interfere with the reaction, for example, methoxycarbonyl group, ethoxycarbonyl group. And alkoxy groups such as methoxy group and ethoxy group.

In the general formula [1], examples of the halogen atom represented by X include chlorine, bromine and iodine, with bromine being particularly preferable. Specific examples of the organic halogen compound represented by the general formula [1] include, for example, allyl bromide (allyl bromide), bromoacetic acid ester,
Benzyl bromide and the like can be mentioned as preferable ones, but of course, it is not limited thereto.

The reaction according to the present invention proceeds most effectively in the presence of indium metal, but the reaction also proceeds effectively in the presence of an indium compound such as indium chloride. A so-called catalytic amount is sufficient as the amount of the metal indium or indium compound used.

Examples of the metal having a stronger reducing power than indium used in the present invention include gallium and aluminum.

In the present invention, as an organometallic compound obtained when gallium is used as a metal having a stronger reducing power than indium, for example, the following general formula [2]

[Chemical 3] (In the formula, R ¹ , R ² , and R ³ each independently represent a hydrocarbon group which may have a substituent.), And an organic gallium reagent (organic gallium reagent).
Further, as an organometallic compound obtained when aluminum is used as a metal having a stronger reducing power than indium, for example, the following general formula [3]

[Chemical 4] (In the formula, R ¹ , R ² , and R ³ are the same as above.), And an organoaluminum reactant (organoaluminum reagent). In the general formulas [2] and [3], R
The definition and specific examples of the optionally substituted hydrocarbon group represented by ¹ , R ² and R ³ are the same as those of R in the above general formula [1].

In the reaction according to the present invention, the reaction sufficiently proceeds at a relatively low temperature of around 10 ° C., and the corresponding organometallic compound can be obtained in a high yield. Examples of the solvent used in the reaction include diethyl ether, tetrahydrofuran (THF)
Ether solvents such as dimethylformamide (DM
F), for example, aromatic hydrocarbon solvents such as benzene and toluene, but not limited to these. The reaction time is usually several tens of minutes to several hours. The ratio of the one or more organic halogen compound used in the reaction and the metal having a reducing power higher than that of indium is, for example, when gallium or aluminum is used as the metal, the organic halogen is used with respect to 2 equivalents of the metal. The total amount of the compound used is 3 equivalents to 1 to 1.2 times the amount.

The organometallic compound according to the present invention, that is, an organogallium reactant, an organoaluminum reactant, etc., is
It can be effectively used for various organic synthetic reactions for forming a carbon-carbon bond, for example, nucleophilic addition reaction of the reaction agent to a carbonyl compound and addition reaction of the reaction agent to an alkyne. That is, more specifically, for example, an allyl gallium reagent, an allyl aluminum reagent, etc. are added to a carbonyl compound such as an aldehyde or a ketone to give homoallyl alcohol. Further, these reactants are rapidly added to acetylene by addition of amine at room temperature to give 1,4-
Give the diene. The amine used here is preferably a bulky amine such as triethylamine or diisopropylethylamine.

The organometallic compound according to the present invention may be produced and isolated by the production method of the present invention and then used as a reaction agent (reaction reagent) in a carbon-carbon bond forming reaction (so-called Grignard type). Reaction), the so-called Barbier (Ba
It is also possible to do this by a rbier) type reaction. In such a case, the organometallic compound production reaction may be carried out in the coexistence of the raw material compound used for the carbon-carbon bond formation reaction. That is, for example, in the case of producing a homoallyl alcohol by a nucleophilic addition reaction of an organometallic compound according to the present invention with a carbonyl compound such as an aldehyde or a ketone, in the coexistence of the aldehyde or the ketone, The organometallic compound-producing reaction may be carried out, and, for example, when the organometallic compound according to the present invention is added to an alkyne to obtain 1,4-dienes, the alkynes may coexist. Then, the reaction for producing the organometallic compound may be performed. In the latter case, it is desirable to add an amine such as triethylamine or diisopropylethylamine to the reaction system.

[0017]

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

Experimental Example 1 Activation of gallium metal was examined by adding various metal salts and using the barbie type allylation of cyclododecanone as a probe. As a result, they have found that the addition of indium metal is effective in activating the gallium metal. Therefore, the equivalents of indium and allyl bromide to gallium were examined. Gallium 0.75 equivalent, indium metal 0.15 equivalent, allyl bromide 1.5 equivalent,
When the reaction was carried out at 25 ° C. in a THF solvent, the yield of the allylated product was 95%. Even if the reaction is carried out only with indium metal, the yield is 38%, which is lower than that obtained by using both. The results of these experiments using gallium metal are shown in Table 1, and the reaction scheme is shown below.

[Chemical 5]

[0019]

[Table 1]

Experimental Example 2 In the Barbie type reaction using allyl bromide, the progress of the reaction and the temperature were examined, and interesting results were observed. In the reaction, 1.5 equivalents of allyl bromide was used with respect to cyclododecanone, and the reaction was carried out in a THF solvent for 2 hours. When only gallium metal was used, the reaction started to proceed when the temperature was raised, but the yield was only 28% even at 70 ° C. Although the yield of gallium and indium of 5: 1 also increased at high temperature, the yield exceeded 90% at 55 ° C. When the reaction temperature was lowered, the yield gradually decreased, but 1
On the contrary, at 0 ° C., the yield rapidly increased to 82%. The reaction scheme is shown below.

[Chemical 6] The results of these experiments are shown in FIG. In addition, in FIG.
-X- shows the result in the system of only gallium metal, and-●-shows the result in the system of gallium / indium = 5/1.

Experimental Example 3 From the above results, it was considered that indium metal may be used in a catalytic amount, and the number of equivalents was reduced. The reaction was a Barbie type reaction using 1.5 equivalents of allyl bromide to cyclododecanone, and the reaction was carried out at 10 ° C. for 5 hours. Even if indium metal was reduced to 10 mol%, 5 mol%, and 1 mol% with respect to gallium metal, the reaction proceeded at a yield of 90% or more. In addition, the reaction did not proceed at all as expected without adding indium metal. The yield of indium metal alone is 64.
%, Which was lower than that of the gallium-indium system. The results of these experiments are shown in Table 2 and the reaction scheme is shown below.

[Chemical 7]

[0022]

[Table 2]

Experimental Example 4 An allylgallium compound was prepared first, and it was examined whether a Grignard type reaction could be carried out. Under argon atmosphere, gallium (0.90 mmol) and catalytic amount of indium (0.04
5 mmol) was stirred in THF solvent at 10 ° C. Allyl bromide
(1.5 mmol) was added, and the mixture was stirred for 2 hours. The metal powders of gallium and indium disappeared completely, and a colorless transparent solution was obtained. When cyclododecanone (1.0 mmol) was added thereto, the addition reaction proceeded almost quantitatively. From this, it was found that the reaction can be carried out not only with the Barbier type but also with the Grignard type. With benzaldehyde, the adduct was obtained in high yield regardless of the reaction. With cyclohexanecarbaldehyde, a by-product was produced when the reaction was carried out in the Barbier type, so the yield was reduced to 58%, but by using the Grignard type, the by-product could be suppressed.
Even with such a methyl ketone, an adduct was obtained in high yield for both Grignard type and Barbie type. This reaction is TH
Performed in solvent F at 10 ° C. without heat. The results of these experiments are shown in Tables 3 and 4, and the reaction schemes are shown below.

[Chemical 8]

[Chemical 9]

[0024]

[Table 3]

[0025]

[Table 4]

In the above experiment, when allyl bromide was added by adding a catalytic amount of indium metal, the gallium metal was completely dissolved and the reaction could be performed in Grignard type, so that allyl gallium species are generated. It is suggested. The mechanism of this reaction is considered as follows.

[Chemical 10] That is, when a catalytic amount of indium is added to gallium, the surface of the indium powder has a metallic luster. This suggests that active indium metal was produced. In the reaction, allyl bromide is reduced by this indium, and allyl indium species are first produced. Next, allyl gallium species are generated by transmetallization (metal exchange) with trivalent gallium, and trivalent indium is regenerated. Three
It is considered that the valent indium is reduced by the gallium metal and the original indium metal is regenerated.

Experimental Example 5 Allylgallium species was prepared in deuterated THF and ¹ HNMR was measured. The results are shown in Figure 2. Methylene at the allylic position
It was considered that such an allyl gallium species could be prepared because it was observed as a doublet of about 1: 2 at 2.0 ppm and 1.7 ppm.

Experimental Example 6 Stability of Allyl Gallium The stability of the prepared allyl gallium species was investigated. 0.67 equivalents of gallium metal and 0.033 equivalents of indium metal were added to allyl bromide, and the mixture was stirred in a THF solvent at 10 ° C. for 2 hours to completely eliminate the metal and prepare an allyl gallium species. It was stored at room temperature under an argon atmosphere.
One equivalent of nonanal was added to the prepared allyl gallium species for reaction, and the yields were compared. The yields of the allyl gallium immediately after it was prepared and those stored at room temperature for 1 month did not change at all (former: 75%, latter: 77%). I found that it was stable and could not be crushed.

Example 1 Preparation of Allyl Gallium In an argon atmosphere, gallium metal (0.13 g, 1.8 m) was prepared.
mol), TH of indium metal (10 mg, 0.090 mmol)
The F (7 mL) suspension was cooled to 10 ° C. and stirred for 10 minutes.
Allyl bromide (0.26 mL, 3.0 mmol) was added dropwise thereto,
After stirring for 2 hours, the gallium metal disappeared and became invisible.

Example 2 Addition Reaction of Allylgallium to Carbonyl Compound To allylgallium obtained in the same manner as in Example 1, cyclododecanone (0.37 g, 2.0 mmol) in THF (3 mL) was added.
The solution was added and stirred at 10 ° C. After 5 hours, the reaction mixture was poured into ice water and worked up. The aqueous layer is ether (5 mL x
After extraction in 3), the organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure (1 Torr). The crude product was subjected to silica gel column chromatography (hexane /
Purified with ethyl acetate = 100/1), 0.44 g (1.98 mmol, yield 99) of 1-allylcyclododecanol
%).

Example 3 Addition Reaction of Allyl Gallium to Terminal Acetylene (Grignard Type Reaction) Allyl gallium obtained in the same manner as in Example 1 was
Phenyl-1-butyne (0.13 g, 1.0 mmol) TH
F (2mL) solution and diisopropylethylamine (0.17m
L, 1.0 mmol) was added, and the mixture was stirred at 25 ° C. Two hours later,
The reaction mixture was poured into dilute hydrochloric acid (6M) and worked up. The aqueous layer was extracted with hexane (5 mL × 3), washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure (1 Torr), and the crude product was purified by silica gel column chromatography (hexane) to give 2- (2-phenylethyl).
0.17 g (0.97 mmol, yield 97%) of -1,4-pentadiene was obtained.

Example 4 Preparation of Allylaluminum Aluminum metal (aluminum foil was cut into 2-3 mm square pieces and used in an argon atmosphere. 49 mg, 1.8 mm
ol), indium metal (10 mg, 0.090 mmol) TH
The F (7 mL) suspension was cooled to 10 ° C. and stirred for 10 minutes.
Allyl bromide (0.26 mL, 3.0 mmol) was added dropwise thereto,
After stirring for 30 minutes, aluminum metal disappeared and became invisible.

Example 5 Addition Reaction of Allylaluminum to Carbonyl Compound (Grignard Type Reaction) Allylaluminum obtained in the same manner as in Example 4 was
Cyclododecanone (0.37g, 2.0mmol) in THF
(3 mL) solution was added and stirred at 10 ° C. After 30 minutes, the reaction mixture was poured into ice water and worked up. The aqueous layer is ether (5m
The organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure (1 Torr). The crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 100/1) to obtain 0.44 g (1.97 mmol, yield 98%) of 1-allylcyclododecanol.

Example 6 Addition Reaction of Allylaluminum to Carbonyl Compound (Barbier Type Addition Reaction) Aluminum metal (49 mg, 1.8 m) under an argon atmosphere.
mol) and indium metal (10 mg, 0.090 mmol) T
The HF (7 mL) suspension was cooled to 10 ° C. and stirred for 10 minutes. There, cyclododecanone (0.37g, 2.0mmo
A solution of 1) in THF (3 mL) was added, and the mixture was stirred for 15 minutes. Then, allyl bromide (0.26 mL, 3.0 mmol) was added dropwise, and the mixture was stirred as it was for 5 hours. After confirming that the metal had completely disappeared, the reaction mixture was poured into ice water and worked up.
The aqueous layer was extracted with ether (5 mL × 3), the organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure (1 Torr). The crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 100/1) to give 0.45 g of 1-allylcyclododecanol.
(1.98 mmol, yield 99%) was obtained.

[0035]

INDUSTRIAL APPLICABILITY According to the present invention, for example, an organometallic compound such as an organogallium reactant or an organoaluminum reactant is activated by adding indium in a catalytic amount to activate the metal under mild conditions such as room temperature. The organometallic compound according to the present invention thus obtained, for example, an organogallium reactant, an organoaluminum reactant, etc., provides a method for preparing, and various organic synthetic reactions for forming a carbon-carbon bond. For example, it can be effectively used for a nucleophilic addition reaction of the reactant to a carbonyl compound, an addition reaction of the reactant to an alkyne, and the like. By using the organogallium reagent, the organoaluminum reagent, etc. according to the present invention, various useful organic compounds, which have been difficult to synthesize with conventional metal-based reagents, can be newly or more easily and highly selective. Will be obtained. The organometallic compound according to the present invention,
After being produced and isolated by the production method of the present invention, it may be subjected to a carbon-carbon bond forming reaction as a reactant (reaction reagent) (so-called Grignard type reaction), but the carbon-carbon bond forming reaction of the next step. It is also possible to do this by means of the so-called Barbier type reaction, which is carried out simultaneously with the preparation of the reagents.

[Brief description of drawings]

FIG. 1 is a result of examining the relationship between the progress of the reaction and the temperature in the Barbie type reaction using allyl bromide in the system containing only gallium metal and the system containing gallium / indium = 5/1. Indicates.

FIG. 2 shows the results of ¹ H NMR measurement of allyl gallium species prepared in deuterated THF by the method of the present invention.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) C07C 33/30 C07C 33/30 35/205 35/205 C07F 5/06 C07F 5/06 C // C07B 61 / 00 300 C07B 61/00 300 F term (reference) 4G069 AA02 BB02A BB02B BB08A BC18A BC18B BD12A CB25 CB68 4H006 AA01 AB84 FC22 FC74 FE12 4H039 CA93 CD20 4H048 AA02 AA03 AB81 AC22 BA09 VA80VA

Claims (18)

[Claims] 1. A method for producing an organometallic compound, which comprises reacting an organohalogen compound with a metal having a stronger reducing power than indium in the presence of a catalytic amount of indium or an indium compound. 2. An organic halogen compound is represented by the following general formula [1] R—X [1] (wherein, R represents a hydrocarbon group which may have a substituent, and X represents a halogen atom). The manufacturing method of Claim 1 which is one or more types of compounds shown by these. 3. The method according to claim 1, wherein the metal having a stronger reducing power than indium is gallium, and the organometallic compound is an organogallium reactant. 4. An organic gallium reactant is represented by the following general formula [2]: The production method according to claim 3, wherein the compound is a compound represented by the formula (wherein R ¹ , R ² and R ³ each independently represent a hydrocarbon group which may have a substituent). 5. The method according to claim 1, wherein the metal having a stronger reducing power than indium is aluminum, and the organometallic compound is an organoaluminum reactant. 6. The organoaluminum reactant is represented by the following general formula [3]: The production method according to claim 5, which is a compound represented by the formula (wherein R ¹ , R ² and R ³ each independently represent a hydrocarbon group which may have a substituent). 7. The method according to claim 1, wherein the organic halogen compound represented by the general formula [1] is allyl bromide. 8. A reaction reagent used in the carbon-carbon bond forming reaction obtained by the production method according to claim 1. 9. The reaction reagent according to claim 8, wherein the carbon-carbon bond formation reaction is a nucleophilic addition reaction of the reaction reagent to a carbonyl compound. 10. The reaction reagent according to claim 8, wherein the carbon-carbon bond formation reaction is an addition reaction of the reaction reagent to an alkyne. 11. The production method according to claim 1, wherein the production reaction is carried out in the presence of a raw material compound used in the carbon-carbon bond formation reaction. 12. The production method according to claim 11, wherein the starting compound used in the carbon-carbon bond formation reaction is a carbonyl compound. 13. The production method according to claim 11, wherein the raw material compound used in the carbon-carbon bond formation reaction is an alkyne. 14. The production method according to claim 13, wherein the reaction is carried out in the presence of an amine. 15. A carbon-carbon bond by a Barbier type reaction, characterized in that the production method according to any one of claims 1 to 7 is carried out in the coexistence of a raw material compound used for a carbon-carbon bond formation reaction. Generation method. 16. A method for nucleophilic addition of an organometallic compound to a carbonyl compound by a Barbie type reaction, which comprises carrying out the production method according to claim 1 in the presence of a carbonyl compound. . 17. A method for adding an organometallic compound to an alkyne by a Barbier type reaction, which comprises carrying out the production method according to claim 1 in the presence of an alkyne. 18. The addition method according to claim 17, wherein the reaction is carried out in the presence of an amine.