JP4286694B2 - Novel Grignard reagent and method for producing aliphatic alkynyl Grignard compound using the same - Google Patents

Description

  The present invention relates to a method for producing an aliphatic alkynyl Grignard compound (acetylene derivative) useful as a fragrance, insect pheromone, various agricultural chemicals, pharmaceutical intermediates, and the like, and a Grignard reagent used therefor.

  Aliphatic alkynyl compounds as acetylene derivatives are not only useful as final products themselves, but also extremely useful as synthetic intermediates for most olefin compounds. For example, if a stereoselective reaction is utilized using an acetylene derivative, it is possible to make a Z body and an E body separately. In some cases, the synthesis of such an olefin compound is often superior to the synthesis of an olefin compound utilizing a Wittig reaction. In particular, most of fragrances and insect pheromones have double bonds, and depending on the Z / E ratio, the biological activity often varies depending on the species. For this reason, the aliphatic alkynyl compound as an intermediate capable of synthesizing both the Z-form and the E-form is a chemical product with high utility value.

However, in insect pheromones, E, Z-10,12-hexadecadienol, Z-11-tetradecenyl acetate, Z-13-octadecenal, Z, Z-11,13-hexadecadienal In many cases, the carbon chain from the functional group to the double bond is remarkably long. In order to introduce a desired double bond at a predetermined position, it has a bifunctional group having a long methylene carbon chain, such as Br (CH ₂ ) _m Br (where m is a positive integer). It is necessary to prepare the compound or to extend the carbon chain in a plurality of steps sequentially using the functional group of the compound having an unsaturated bond as a clue.

However, in the former case, difunctional compounds having a methylene carbon chain that can be used industrially include 1,3-dibromopropane, 1-bromo-3-chloropropane, 1,6-hexanediol, and the like-(CH ₂ ) m _- is an m is 3 to 6, m is 7 or more compounds can hardly available industrially. Also, if present, it is expensive at the reagent level. In particular, those with an odd number of m are often not naturally present as raw materials, so their purity is often extremely low, and are not suitable for the production of compounds that exhibit specific action on compounds such as insect pheromones. is there.

In addition, even if a — (CH ₂ ) _m — m having a long m of 7 or more is artificially synthesized, both the diol form and the dihalogen form have extremely high boiling points, making isolation and purification difficult.

  Furthermore, when extending a carbon chain by using a functional group of a compound having an unsaturated bond as a clue, it may be difficult to activate the functional group so that a carbon-carbon bond can be formed. For example, in the case of a Grignard reaction in which halogen is reacted with Mg to form an active species, the Grignard reagent itself cannot often be prepared when the unsaturated bond is a triple bond. On the other hand, the Grignard reagent can be prepared if the triple bond is preliminarily made of an olefin. In this case, isomerization of the geometric structure of the double bond occurs, or in the case of a conjugated diene compound, polymerization occurs during the preparation of the Grignard reagent. May cause a significant decrease in yield.

  Thus, since it seems that it is difficult to obtain inexpensive bifunctional long-chain methylene compounds in the future, simple and effective compounds with long methylene carbon chains from functional groups to unsaturated bonds There was a need for a simple manufacturing method.

  The present invention has been made in view of the above circumstances, and an object thereof is to provide a Grignard reagent of a compound having a triple bond and a method for producing a long-chain aliphatic alkynyl compound using the same.

  As a result of intensive studies to achieve the above object, the present inventor has found a Grignard reagent having a triple bond, which has heretofore been generally difficult, and further uses it to obtain a high yield of aliphatic alkynyl Grignard compounds. It has been found that it can be synthesized at high rate and high purity, and has led to the present invention.

Specifically, according to the present invention, a Grignard reagent represented by the following formula (1) and an aliphatic alkynyl Grignard compound represented by the following formula (2) are provided.
X ¹ MgC≡C (CH ₂ ) ₆ MgX ² (1)
X ¹ MgC≡C (CH ₂ ) _{n + 6} X ³ (2)
(Wherein X ¹ and X ² independently represent a halogen atom, X ³ represents a hydrogen atom, Br or Cl, and n represents an integer of 3 to 10 carbon atoms.)

According to the present invention, in another aspect, an aliphatic alkynyl Grignard compound represented by the formula (2) and an ortho ester (R ¹ C (OR ² ) ₃ ) in an organic solvent in the presence of a copper catalyst. A method for producing a halogen group-containing alkenyl acetal compound represented by the following formula (6), wherein hydrogen is added to the halogen group-containing alkenyl acetal compound obtained by the reaction, followed by hydrolysis in the presence of an acid catalyst A process for producing a halogen group-containing alkenyl aldehyde compound represented by the following formula (7) is provided.
R ¹ C (OR ² ) ₂ C≡C (CH ₂ ) _{n + 6} X ³ (6)
HCOCH = CH (CH ₂ ) _{n + 6} X ³ (7)
(Wherein R ¹ represents a hydrogen atom, R ² independently represents a methyl group or an ethyl group, and n represents an integer of 3 to 10 carbon atoms.)

According to another aspect of the present invention, there is provided a method for producing an aliphatic alkynyl compound represented by the following formula (8), wherein the aliphatic alkynyl Grignard compound represented by the formula (2) is hydrolyzed. Is done.
HC≡C (CH ₂ ) _{n + 6} X ³ (8)

  As will be described in detail below, according to the present invention, a Grignard reagent having a triple bond, which has heretofore been generally difficult, can be obtained, and further, a long-chain aliphatic alkynyl compound can be obtained in a high yield with a high yield. Can be produced in purity.

The Grignard reagent according to the present invention is represented by the following formula (1).
X ¹ MgC≡C (CH ₂ ) ₆ MgX ² (1)
(In the formula, X ¹ and X ² independently represent a halogen atom. The halogen atom of X ¹ is Cl, Br, or I, preferably Cl or Br. The halogen atom of X ² is Cl, Br, I, preferably Cl or Br.)

This Grignard reagent is preferably obtained by reacting 8-halo-1-octyne represented by the following formula (3) with a Grignard reagent represented by the following formula (4) and further reacting with magnesium metal in an organic solvent. Can be prepared.
HC≡C (CH ₂ ) ₆ X ² (3)
RMgX ¹ (4)
(In the formula, R represents an alkyl group.)

  Examples of the 8-halo-1-octyne include 8-chloro-1-octyne, 8-bromo-1-octyne and the like, and commercially available inexpensive 1,6-dibromohexane and 1-bromo-6-chlorohexane. Etc. can be easily prepared by reacting them with acetylene in liquid ammonia.

  In general, this 8-halo-1-octyne cannot be directly converted into a Grignard reagent even if its halogen is used. The reason is that the acetylene proton reacts with the Grignard reagent. Thus, the acetylene proton requires some protection that is inert to the Grignard reagent.

Therefore, for example, we decided to obtain a compound represented by the formula (9) in which the acetylene proton was protected by the Grignard reagent by reacting the Grignard reagent represented by the formula (4) with the acetylene proton.
X ¹ MgC≡C (CH ₂ ) ₆ X ² (9)

  If protected with a Grignard group in this way, a carbon chain can be constructed using this as a clue. On the other hand, a simple protecting group requires a deprotection step after the reaction.

The reaction for protecting this acetylene proton with a Grignard reagent is expressed as follows.
RMgX ¹ + HC≡C (CH ₂ ) ₆ X ²
→ X ¹ MgC≡C (CH ₂ ) ₆ X ² + RH

In the Grignard reagent used for protecting the acetylene proton, R is preferably an alkyl group having 1 or 2 carbon atoms, and examples thereof include methylmagnesium chloride and ethylmagnesium bromide. The amount of the Grignard reagent added is preferably 1.0 to 1.2 mol, and particularly preferably 1 mol, per 1 mol of 8-halo-1-octyne. Further, the reaction temperature at this time is not particularly limited, but 40 to 60 ° C. is particularly preferable. The reaction solvent is preferably an ether organic solvent such as tetrahydrofuran (THF) or diethyl ether. The amount of the solvent is preferably 200 to 400 g with respect to 1 mol of 8-halo-1-octyne. This reaction is usually performed under nitrogen or an inert gas atmosphere.
By the reaction, when R is a methyl group, methane is generated as a gas, and when R is an ethyl group, ethane is generated as a gas, and the acetylene group is converted into a Grignard.

Furthermore, as in the following formula, another organic reactor is similarly charged with an ether-based organic solvent and metallic magnesium, and the above X ¹ MgC≡C (CH ₂ ) ₆ X ² is added dropwise to obtain the formula (9). The compounds shown can be easily led to the new Grignard reagents of formula (1). Preferably, iodine or the like may be used as a reaction initiator.
X ¹ MgC≡C (CH ₂ ) ₆ X ² + Mg
→ X ¹ MgC≡C (CH ₂ ) ₆ MgX ²

  In addition, it is preferable to perform the production | generation reaction of this Grignard reagent on the following conditions. That is, the solvent used in this reaction is preferably an ether solvent such as tetrahydrofuran or diethyl ether. The amount of the solvent is preferably 250 to 500 g per mol of magnesium. The amount of magnesium is preferably 1.05 to 1.15 mol per mol of 8-halo-1-octyne. Further, the reaction temperature of this reaction is preferably 60 to 80 ° C., particularly preferably 68 to 80 ° C. under conditions where THF is refluxed in the case of tetrahydrofuran, and 35 to 40 ° C. is preferable in the case of diethyl ether. . This reaction is usually performed under nitrogen or an inert gas atmosphere.

Whether or not the Grignard reagent represented by the above formula (1) is prepared according to its structural formula is determined by, for example, reacting this Grignard reagent with 1-bromo-3-chloropropane in THF in the presence of a copper catalyst. It can be confirmed by decomposition that HC≡C (CH ₂ ) ₉ Cl is generated.

Subsequently, the aliphatic alkynyl Grignard shown by Formula (2) is made to react with the Grignard reagent shown by Formula (1) in the presence of a copper catalyst in an organic solvent. Compounds can be synthesized.
Br (CH ₂ ) _n X ³ (5)
X ¹ MgC≡C (CH ₂ ) _{n + 6} X ³ (2)
(In the formula, X ³ represents a hydrogen atom, Br or Cl, and n represents an integer of 3 to 10 carbon atoms.)

  That is, by adding the Grignard reagent (1) dropwise to a bromine compound represented by the formula (5) in the presence of a copper catalyst in a solvent, a cis-coupling reaction proceeds in a form in which a methylene chain extends, and the formula ( The aliphatic alkynyl Grignard compound represented by 2) is produced.

This reaction is preferably carried out under the following conditions. That is, the solvent is preferably an ether organic solvent such as THF or ether. The amount of the solvent is preferably 100 to 400 g per mole of the Grignard reagent represented by the formula (1). The amount of the bromine compound represented by the formula (5) is preferably 1.1 to 1.3 moles per mole of the Grignard reagent represented by the formula (1). As a copper catalyst for the Grignard cross-coupling reaction in this reaction, anhydrous cuprous halides such as CuCl, CuBr and CuI, anhydrous cupric halides such as CuCl ₂ and CuBr ₂ , and copper such as Li ₂ CuCl ₄ -It is preferable to use a lithium compound. The amount of the copper catalyst is preferably 0.2 to 10.0 g, more preferably 0.5 to 5 g, per mole of the Grignard reagent represented by the formula (1). The reaction temperature is preferably 0 to 40 ° C, particularly preferably 0 to 20 ° C. This reaction is usually performed under nitrogen or an inert gas atmosphere.

  The Grignard reagent represented by the above formula (1) has two reactive groups as Grignard reagents in one molecule, but under the above reaction conditions, the coupling reaction rate between the acetylene carbon side Grignard reagent and the bromine compound Is extremely slow and virtually unresponsive. Therefore, as a result, the coupling reaction by the Grignard reaction proceeds only in the direction in which the methylene chain extends.

If the hydrolysis is carried out as it is after the reaction, a long-chain alkynyl compound having an ethynyl group (acetylene group) at the end can be obtained. That is, the aliphatic alkynyl compound represented by the following formula (8) can be synthesized by hydrolyzing the aliphatic alkynyl Grignard compound represented by the formula (2).
HC≡C (CH ₂ ) _{n + 6} X ³ (8)
(In the formula, X ³ represents a hydrogen atom, Br or Cl, and n represents an integer of 3 to 10 carbon atoms.)

This reaction is preferably carried out under the following conditions. That is, the reaction proceeds by dropping 20 to 60 g of ammonium chloride and 250 to 500 g of pure water per mole of the Grignard reagent represented by the formula (1) so as not to exceed 50 ° C.
Further, the aliphatic alkynyl compound represented by the formula (8) obtained by the above reaction can be purified by a known method, for example, extraction by an organic phase and distillation under reduced pressure. According to the said method, the aliphatic alkynyl compound shown by Formula (8) is compoundable with a yield of about 70%, for example.

  Further, after the coupling reaction, it is possible to proceed to the next reaction by using the remaining acetylene-side Grignard reagent as a clue without hydrolysis. For example, by using the present invention, a methylene carbon chain having 6 or more methylene chains and a long methylene chain from a functional group can be obtained even if an α, ω-2 functional raw material having a bifunctional group does not exist at low cost. It is possible to synthesize insect pheromones having

That is, by containing an aliphatic alkynyl Grignard compound represented by the formula (2) and an ortho ester (R ¹ C (OR ² ) ₃ ) in an organic solvent, the halogen group containing the following formula (6) is contained. Alkenyl acetal compounds can be synthesized.
R ¹ C (OR ² ) ₂ C≡C (CH ₂ ) _{n + 6} X ³ (6)
(In the formula, R ¹ represents a hydrogen atom, and R ² independently represents a methyl group or an ethyl group.)

  This reaction is preferably carried out under the following conditions. That is, the solvent is preferably an aromatic hydrocarbon such as toluene or xylene, or an ether organic solvent such as THF or ether. The amount of the solvent is preferably 300 to 700 g per mole of the aliphatic alkynyl Grignard compound represented by the formula (2). Specific examples of the orthoester are methyl orthoformate and ethyl orthoformate. The amount of the organic acid orthoester is preferably 1.0 to 1.3 mol per mol of the aliphatic alkynyl Grignard compound represented by the formula (2). This reaction is usually performed under nitrogen or an inert gas atmosphere.

  The halogen group-containing alkenyl acetal compound represented by the formula (6) obtained by the above reaction can be purified by a known method, for example, extraction by an organic phase and distillation under reduced pressure. According to the above method, the halogen group-containing alkenyl acetal compound represented by the formula (6) can be synthesized, for example, in a yield of about 60%.

Further, in the halogen group-containing alkenyl acetal compound represented by the formula (6), when R ¹ is a hydrogen atom, a hydrogenation reaction is performed, and further, hydrolysis is performed in the presence of an acid catalyst, whereby the following formula (7) The halogen group-containing alkenyl aldehyde compounds shown can be synthesized.
HCOCH = CH (CH ₂ ) _{n + 6} X ³ (7)

This hydrogenation reaction is preferably carried out under the following conditions. That is, the solvent is preferably an alcohol solvent such as ethanol. The amount of the solvent is preferably 200 to 500 g per mole of the halogen group-containing alkenyl acetal compound represented by the formula (6). As the catalyst, a nickel acetate catalyst, a Pd—C catalyst, or the like is preferably used. The amount of the catalyst is preferably 5 to 50 g per mole of the halogen group-containing alkenyl acetal compound represented by the formula (6). The amount of hydrogen to be fed is preferably 1.0 to 5.0 kg / cm ² .
Further, an acid catalyst such as hydrochloric acid, organic acid such as formic acid or oxalic acid is added to the reaction solution to carry out a hydrolysis reaction. The amount of the acid catalyst is preferably 0.01 to 1.5 mol per mol of the halogen group-containing alkenyl acetal compound represented by the formula (6).

  The halogen group-containing alkenyl aldehyde compound represented by the formula (7) obtained by the above reaction can be extracted by a known method, for example, an organic phase, and purified by column chromatography. According to the said method, the halogen group containing alkenyl aldehyde compound shown by Formula (7) is compoundable with a yield of about 80%, for example.

The above synthetic scheme is summarized below.

For example, the present invention is applied to 12-chloro-2-dodecinal diethyl acetal, which is an intermediate for the synthesis of E, Z-10,12-hexadecadien-1-ol (Bombicol), a silkworm sex pheromone. Then, in the synthesis scheme, X ¹ , X ² and X ³ are Cl, R is CH ₃ , n is 3, and ethyl orthoformate (R ¹ is H, R ² is C ₂ H ₅ ) as an orthoester. Use.
At this time, the synthesis of 12-chloro-2-dodecinal diethyl acetal represented by the formula (7), which is the final product, from the 8-halo-1-octyne represented by the formula (3) is performed at each synthesis step. The product may be isolated, but if the synthesis is performed without separating these products, no separation operation is required, and 12-chloro-2-dodecinal diethyl acetal can be obtained in a very simple process. Can be synthesized.

  EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to the following examples.

[Example 1]
[Synthesis of 8-chloro-1-octyn-1-ylmagnesium chloride]
To a reactor in a nitrogen atmosphere, 8-chloro-1-octyne (144.5 g: 1 mol) and anhydrous THF (200 g) were added, and a methylmagnesium chloride-THF solution (equivalent to 330 g: 1 mol) was added at 30 ° C. It was dripped so that it might not exceed 50 degreeC. After dropping, the mixture was stirred at 60 ° C. for 1 hour, and then extracted into a 1 L flask.
Next, anhydrous THF (100 g), metallic magnesium (25 g: 1.029 mol), and iodine 0.1 g were added to another reactor, and 30 g of the extracted liquid was added dropwise, and the reaction was performed at an internal temperature of 68 ° C. Started. Thereafter, the flask solution was added dropwise so that the internal temperature did not drop below 70 ° C., and the reaction was allowed to proceed. After completion of the addition, the mixture was aged for 2 hours to prepare a Grignard reagent, 8-chloro-1-octyn-1-ylmagnesium chloride. .

[Example 2]
[Synthesis of 8-Bromo-1-octyn-1-ylmagnesium chloride]
The same operation as in Example 1 was carried out except that 8-bromo-1-octyne (169 g: 1 mol) was used instead of 8-chloro-1-octyne, and 8-bromo-1-octyn-1-ylmagnesium chloride was used. Of THF was prepared.

[Example 3]
[Synthesis of 11-chloro-1-undecyne]
Anhydrous THF (100 g), CuI (1 g), 1-bromo-3-chloropropane (157.5 g: 1 mol) were added to a reactor in a nitrogen atmosphere, and the mixture was cooled with water at 10 to 30 ° C. at 1 to 30 ° C. 8-dichloromagnesium-1-octyne was added dropwise.
After completion of the dropwise addition, the mixture was stirred at 20 ° C. for 1 hour, and then hydrolyzed by adding dropwise 400 g of a saturated ammonium chloride aqueous solution and 200 g of 5 wt% aqueous hydrochloric acid. After separating the organic phase with a separatory funnel, the concentrated liquid from which THF was removed was distilled under reduced pressure with a rotary evaporator. As a result, 11-chloro-1-undecyne (127 g pure; yield 68%, bp = 120 to 125 ° C./400 Pa) was obtained.

[Example 4]
[12-chloro-2-dodecinal diethyl acetal]
In the same manner as in Example 1, 8-chloro-1-octin-1-ylmagnesium chloride was prepared.
Subsequently, anhydrous THF (100 g), CuI (1 g), 1-bromo-3-chloropropane (157.5 g; 1 mol) were added to the reactor in a nitrogen atmosphere, and the mixture was cooled with water at 10 to 30 ° C. at 8 ° C. in Example 1. -Chloro-1-octin-1-ylmagnesium chloride was added dropwise.
After completion of dropping, the mixture was stirred at 20 ° C. for 1 hour, then 250 g of toluene was added, and the internal temperature was raised to 90 to 95 ° C. Thereto, ethyl orthoformate (HC (OC ₂ H ₅ ) ₃ )) (151 g: 1 mol) was added dropwise at a high speed and stirred at 93 to 96 ° C. for 7 hours.
After the reaction, the reaction solution was cooled and poured into a saturated aqueous ammonium chloride solution so as not to exceed 30 ° C., and the organic phase was taken out. When THF-toluene in the organic phase was removed under reduced pressure with a rotary evaporator and the concentrate was distilled, 178 g (yield 61.7%) of 12-chloro-2-dodecinal diethyl acetal was obtained.

[Application example]
[Intermediate 12-chloro- (E) -2-dodecenal of silkworm pheromone]
To the autoclave was added 178 g of 12-chloro-2-dodecinal diethyl acetal of Example 4 and an ethanol solution of P-2 nickel catalyst obtained by reducing nickel acetate with sodium borohydride (equivalent to 2 g of nickel acetate / 100 g of ethanol), and hydrogen. Was fed at 5 kg / cm ² to carry out a hydrogenation reaction. After confirming the completion of the reaction by GC analysis, the catalyst was removed by filtration, and ethanol was completely concentrated and removed under reduced pressure. Into the concentrate, 200 ml of hexane was added, 200 ml of 20% by weight hydrochloric acid was added, and the mixture was stirred for 30 minutes. The hexane layer was taken out and washed thoroughly with water, and the hexane was removed by a rotary evaporator. (Pure content 112 g; yield 83, 8%) was obtained.

Claims (6)

Grignard reagent represented by the following formula (1).
X ¹ MgC≡C (CH ₂ ) ₆ MgX ² (1)
(In formula, X < ¹ >, X < ² > shows a halogen atom independently.) The organic solvent according to claim 1, which is obtained by reacting 8-halo-1-octyne represented by the following formula (3) with a Grignard reagent represented by the following formula (4) and further reacting with magnesium metal. Grignard reagent.
HC≡C (CH ₂ ) ₆ X ² (3)
RMgX ¹ (4)
(In the formula, R represents an alkyl group, and X ¹ and X ² independently represent a halogen atom.) An aliphatic alkynyl Grignard compound represented by the following formula (2), wherein a bromine compound represented by the following formula (5) is reacted with a Grignard reagent represented by the following formula (1) in an organic solvent in the presence of a copper catalyst. Manufacturing method .
X ¹ MgC≡C (CH ₂ ) ₆ MgX ² (1)
Br (CH ₂ ) _n X ³ (5)
X ¹ MgC≡C (CH ₂ ) _{n + 6} X ³ (2)
(In the formula, X ¹ and X ² independently represent a halogen atom, X ³ represents a hydrogen atom, Br or Cl, and n represents an integer of 3 to 10 carbon atoms.) It is characterized by reacting an aliphatic alkynyl Grignard compound represented by the following formula (2) obtained by the production method according to claim 3 and an orthoester (R ¹ C (OR ² ) ₃ ) in an organic solvent. The manufacturing method of the halogen group containing alkenyl acetal compound shown by following formula (6).
X ¹ MgC≡C (CH ₂ ) _{n + 6} X ³ (2)
R ¹ C (OR ² ) ₂ C≡C (CH ₂ ) _{n + 6} X ³ (6)
(Wherein X ¹ represents a halogen atom, X ³ represents a hydrogen atom, Br or Cl, R ¹ represents a hydrogen atom or an alkyl group, R ² independently represents an alkyl group, and n represents a carbon number of 3 Represents an integer of -10.) A halogen group-containing alkenyl represented by the following formula (7), wherein hydrogen is added to the halogen group-containing alkenyl acetal compound obtained by the production method according to claim 4 and further hydrolyzed in the presence of an acid catalyst. A method for producing an aldehyde compound.
HCOCH = CH (CH ₂ ) _{n + 6} X ³ (7)
(In the formula, X ³ represents a hydrogen atom, Br or Cl, and n represents an integer of 3 to 10 carbon atoms.) A method for producing an aliphatic alkynyl compound represented by the following formula (8), wherein an aliphatic alkynyl Grignard compound represented by the following formula (2) obtained by the production method according to claim 3 is hydrolyzed.
X ¹ MgC≡C (CH ₂ ) _{n + 6} X ³ (2)
HC≡C (CH ₂ ) _{n + 6} X ³ (8)
(In the formula, X ¹ represents a halogen atom, X ³ represents a hydrogen atom, Br or Cl, and n represents an integer of 3 to 10 carbon atoms.)