JP4102879B2 - Method for producing organophosphorus compound - Google Patents

Description

  The present invention relates to a method for producing an alkenylphosphonic acid ester, an alkenylphosphinic acid ester, and an alkenylphosphine oxide compound (hereinafter, these compounds are collectively referred to as an alkenylphosphorus compound).

It is known that an alkenyl phosphorus compound has its basic skeleton found in nature and exhibits physiological activity by acting with an enzyme or the like. This compound is also an extremely useful compound that can be easily converted into a tertiary phosphine widely used as an auxiliary ligand for various catalytic reactions. Furthermore, these compounds are a group of compounds that are highly useful in the synthesis of fine chemicals, such as easily reacting with nucleophiles and radical species and can be used in Horner-Wittig reactions.

Among these compounds, anti-Markovnikov-type adducts (those with a phosphorus atom bonded to the carbon at the end of the carbon-carbon triple bond of mono-substituted acetylene) are particularly useful as synthetic intermediates for the commercially available antibiotic fosfomycin. It is.

  As a method for synthesizing such an alkenyl phosphorus compound with the formation of a carbon-phosphorus bond, generally, the corresponding alkenyl halide compound is composed of a hydrogenated phosphonic acid ester, a hydrogenated phosphinic acid ester and a hydrogenated phosphine oxide (hereinafter referred to as “hydrogen phosphine oxide”). , Generally referred to as P—H compounds).

However, in this method, it is necessary to add a base for capturing the hydrogen halide generated simultaneously with the reaction, thereby producing a large amount of a hydrogen halide salt. Moreover, the alkenyl halide compound which is the starting material is not always easily available industrially and generally has toxicity. For this reason, this method is not an industrially advantageous method.

On the other hand, recently, a method for producing an alkenyl phosphorus compound by adding a P—H compound to acetylene using a catalyst has also been reported (Patent Documents 1 to 4), and these methods are both expensive palladium or rhodium catalysts. Is used.
In addition, a method for producing an alkenyl phosphorus compound by adding a P—H compound to acetylene in a polyether solvent using a nickel catalyst (Patent Documents 5 to 6) has also been reported, but the resulting product is Markovnikov. Type adducts (phosphorus atom bonded to carbon inside carbon-carbon triple bond of mono-substituted acetylene), or Markovnikov-type and anti-Markovnikov-type adducts (carbon at the end of carbon-carbon triple bond of mono-substituted acetylene) It was difficult to obtain an anti-Markovnikov type adduct selectively.

Patent No. 2775426 Patent No. 2777985 Specification Japanese Patent No. 2849712 Patent No. 3007984 US Pat. No. 3,673,285 European Patent No. 1203773

  An object of the present invention is to provide a production method in which an alkenyl phosphorus compound of an anti-Markovnikov type adduct can be obtained simply, safely and highly selectively using a P—H compound as a starting material. And

  In the course of studying the mechanism of addition of P—H compounds to acetylene compounds by nickel catalysts, the present inventors succeeded for the first time in isolating nickel hydride, which was an intermediate, and further investigated the reactivity of the intermediate. Surprisingly, it forms a hydrogen bond with the solvent OH in a protic solvent such as alcohol, increases the rate of addition reaction with acetylene, and forms an anti-Markovnikov adduct with high selectivity. It has been found that it has the effect of The present invention has been made based on these findings.

That is, according to the present invention, the following inventions are provided.
[1] In the presence of a catalyst containing nickel, the following general formula (1)
R ¹ OH (1)
(R ¹ represents an alkyl group, a cycloalkyl group, an aryl group, or an acyl group.)
In a protic solvent represented by
The following general formula (2)
R ² (C≡CR ³ ) _n (2)
(Wherein, n is 1 or 2, R ^2, when n is 1, an alkyl group, a cycloalkyl group, an aryl group, an aralkyl group, a heteroaryl group, an alkenyl group, an alkoxy group, an aryloxy group, or silyl group, when n is 2, an alkylene group, cycloalkylene group, arylene group, aralkylene group, a heteroarylene group, an alkenylene group, alkylenedioxy group, .R ³ showing arylenedioxy group, or a silicon dioxy group Represents a hydrogen atom), and an acetylene compound represented by
The following general formula (3)
HP (O) (OR ⁴ ) (OR ⁵ ) (3)
(Wherein R ⁴ and R ⁵ each independently represents an alkyl group, a cycloalkyl group, an aralkyl group or an aryl group. In addition, R ^{4 to} R ⁵ each represents one hydrogen atom from each group. It may be bonded to each other at a residue formed to form a cyclic structure.) A hydrogenated phosphonate represented by the following general formula (4) is reacted:
R ² {CH = CR ³ [P (O) (OR ⁴ ) (OR ⁵ ) ]} n (4)
(R ² , R ³ , R ⁴ and R ⁵ are the same as above)
The manufacturing method of the alkenylphosphonic acid ester compound represented by these.
[2] In the presence of a catalyst containing nickel, the above general formula (1)
R ¹ OH (1)
(R ¹ is the same as [1] above)
In a protic solvent represented by
General formula (2)
R ² (C≡CR ³ ) _n (2)
An acetylene compound represented by the formula (wherein n, R ² and R ³ are the same as the above [1]),
The following general formula (5)
HP (O) (OR ⁴ ) R ⁵ (5)
(Wherein R ⁴ and R ⁵ are the same as those in the above [1]), the hydrogenated phosphinic acid ester represented by the following general formula (6)
R ² {CH = CR ³ [P (O) (OR ⁴ ) R ⁵ ]} n (6)
(N, R ² , R ³ , R ⁴ and R ⁵ are the same as in the above [1]).
[3] In the presence of a catalyst containing nickel, the above general formula (1)
R ¹ OH (1)
(R ¹ is the same as [1] above.)
In a protic solvent represented by
General formula (2)
R ² (C≡CR ³ ) _n (2)
An acetylene compound represented by (wherein n, R ² and R ³ are the same as in claim 1);
The following general formula (7)
HP (O) R ⁴ R ⁵ (7)
(Wherein, R ⁴ and R ⁵ are the same as those in the above [1]), which is reacted with a hydrogenated phosphine oxide represented by the following general formula (8)
R ² {CH = CR ³ [P (O) R ⁴ R ⁵ ]} n (8)
(N, R ² , R ³ , R ⁴ and R ⁵ are the same as in the above [1]).

According to the method of the present invention, an anti-Markovnikov-type adduct alkenyl phosphorus useful as a synthetic intermediate for the above-mentioned physiologically active substances such as pharmaceuticals and agricultural chemicals and ligands for catalyst preparation, etc., starting from a P—H compound. By using an inexpensive catalyst, the compound can be synthesized simply, safely and highly selectively. Further, the product can be easily separated and purified. Therefore, the present invention is industrially useful.

In the method of the present invention, it is necessary to use a catalyst containing nickel and to use a protic solvent represented by the general formula (1) as a solvent.
In the general formula (1), R ¹ represents an alkyl group, a cycloalkyl group, an aryl group, or an acyl group.
When R ¹ in the general formula (1) is an alkyl group, the alkyl group has 1 to 18 carbon atoms, preferably 1 to 10 carbon atoms. Specific examples thereof include a methyl group, an ethyl group, a propyl group, a hexyl group, and a decyl group. In the case of a cycloalkyl group, the carbon number is 5-18, preferably 5-12. Specific examples thereof include a cyclohexyl group, a cyclooctyl group, and a cyclododecyl group. In the case of an aryl group, the number of carbon atoms is 6 to 14, preferably 6 to 10. Specific examples thereof include a phenyl group and a naphthyl group, and further include substitutions thereof (tolyl group, xylyl group, benzylphenyl group, etc.). In the case of an acyl group, the carbon number is 1 to 10, preferably 1 to 6. Specific examples thereof include formyl, acetyl group, and benzoyl group.

  These protic solvents are used alone or as a mixture of two or more.

  This protic solvent promotes the addition reaction between the P—H compound and acetylene and forms a hydrogen bond via OH with nickel hydride generated in the reaction system, thereby forming a nickel hydride intermediate rich in reactivity. It has a function to generate an anti-Markovnikov type adduct with high selectivity. When an aprotic solvent such as THF, toluene, and polyethers is used as a solvent instead of a protic solvent, only a mixture of Markovnikov type and anti-Markovnikov type adducts can be obtained as shown in Comparative Examples below. Therefore, anti-Markovnikov type adducts cannot be obtained with high selectivity.

The acetylene compound used as a raw material for the reaction of the present invention is represented by the general formula (2).
In the general formula (2), R ² represents an alkyl group, a cycloalkyl group, an aryl group, an aralkyl group, a heteroaryl group, an alkenyl group, an alkoxy group, an aryloxy group or a silyl group when n is 1. Is 2, it represents an alkylene group, a cycloalkylene group, an arylene group, an aralkylene group, a heteroarylene group, an alkenylene group, an alkylenedioxy group, an aryleneoxy group, or a silylenedioxy group. R ³ represents a hydrogen atom.

When R ² in the general formula (2) is an alkyl group, the alkyl group has 1 to 18 carbon atoms, preferably 1 to 10 carbon atoms. Specific examples thereof include a methyl group, an ethyl group, a propyl group, a hexyl group, and a decyl group.

In the case of a cycloalkyl group, the carbon number is 5-18, preferably 5-12. Specific examples thereof include a cyclohexyl group, a cyclooctyl group, and a cyclododecyl group.

In the case of an aryl group, the number of carbon atoms is 6 to 14, preferably 6 to 10. Specific examples thereof include a phenyl group and a naphthyl group, and further include substitutions thereof (tolyl group, xylyl group, benzylphenyl group, etc.).

The heteroaryl group in the case of a heteroaryl group is various heteroaromatic ring groups containing hetero atoms, such as oxygen, nitrogen, and sulfur, The carbon number contained in it is 4-12, Preferably it is 4-8. Specific examples thereof include a thienyl group, a furyl group, a pyridyl group, and a pyrrolyl group.

In the case of an aralkyl group, the carbon number is 7 to 13, preferably 7 to 9. Specific examples thereof include a benzyl group, a phenethyl group, a phenylbenzyl group, and a naphthylmethyl group. In the case of an alkenyl group, the number of carbon atoms is 2 to 18, preferably 2 to 10. Specific examples thereof include a vinyl group, a 3-butenyl group, and a cyclohexenyl group.

The number of carbon atoms in the case of an alkoxy group is 1-8, preferably 1-4. Specific examples thereof include a methoxy group, an ethoxy group, and a butoxy group. In the case of an aryloxy group, the carbon number is 6 to 14, preferably 6 to 10. Specific examples thereof include a phenoxy group and a naphthoxy group.

In the case of a silyl group, those substituted with an alkyl group, an aryl group, an aralkyl group, or an alkoxy group are included. Specific examples thereof include a trimethylsilyl group, a triethylsilyl group, a triphenylsilyl group, a phenyldimethylsilyl group, a trimethoxysilyl group, and a t-butyldimethylsilyl group.

When n is 2, the alkylene group, cycloalkylene group, arylene group, aralkylene group, heteroarylene group, alkenylene group, alkylenedioxy group, aryleneoxy group, or silylenedioxy group represented by R ² is the n Is selected from divalent residues obtained by removing one hydrogen atom from R ² when R is 1, and specific examples thereof include methylene group, pentamethylene group, cyclohexylene group, phenylene group, naphthylene group, frangiyl Group, 2-butenediyl group, tetramethylenedioxy group, phenylenedioxy group, dimethylsilylene group and the like.

Regardless of n, R ² in the general formula (1) is a functional group inert to the reaction, such as methoxy group, methoxycarbonyl group, cyano group, dimethylamino group, fluoro group, chloro group, hydroxy group. It may be substituted with.

  Examples of acetylene compounds preferably used in the reaction of the present invention include unsubstituted acetylene, methylacetylene, butyne, octyne, phenylacetylene, trimethylsilylacetylene, ethynylthiophene, hexinonitrile, cyclohexenylacetylene, 1,4-pentadiyne, 1,8- Nonadyne, diethynylbenzene and the like can be mentioned, but are not limited thereto.

The phosphorus compound used as the other raw material in the reaction of the present invention is a P—H compound represented by the general formula (3), general formula (5) and general formula (7).
In these general formulas, R ⁴ and R ⁵ each independently represents an alkyl group, a cycloalkyl group, an aralkyl group or an aryl group. Further, they may be bonded to each other by a residue formed by removing one hydrogen atom from each group of R ^{3 to} R ⁴ to form a cyclic structure. )

When R ⁴ and R ⁵ are each independently an alkyl group, the alkyl group has 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. Specific examples thereof include a methyl group, an ethyl group, a propyl group, and a hexyl group.

In the case of a cycloalkyl group, the carbon number is 3 to 12, preferably 5 to 12. Specific examples thereof include a cyclohexyl group, a cyclooctyl group, and a cyclododecyl group.

In the case of an aralkyl group, the carbon number is 7 to 13, preferably 7 to 11. Specific examples thereof include a benzyl group, a phenethyl group, a phenylbenzyl group, and a naphthylmethyl group.

In the case of an aryl group, the number of carbon atoms is 6 to 14, preferably 6 to 10. Specific examples thereof include a phenyl group and a naphthyl group, and further include substitutions thereof (tolyl group, xylyl group, benzylphenyl group, etc.).

R ⁴ and R ⁵ may be substituted with a functional group inert to the reaction, such as a methoxy group, a methoxycarbonyl group, a cyano group, a dimethylamino group, a fluoro group, a chloro group, or a hydroxy group.

Further, they may be bonded to each other at a residue obtained by removing one hydrogen atom from each group of R ^{4 to} R ⁵ to form a cyclic structure. Specific examples thereof include, but are not limited to, an ethylene group, a tetramethylethylene group, and a tetramethylene group.

  Specific examples of suitable PH compounds include dimethylphosphonate, diethylphosphonate, dibutylphosphonate, diphenylphosphonate, 4,4,5,5-tetramethyl-1,3,2- Examples include, but are not limited to, dioxaphosphorane 2-oxide, ethyl phenylphosphinate, cyclohexyl phenylphosphinate, and diphenylphosphine oxide.

  The molar ratio of the acetylene compound and the P—H compound used is generally preferably 1: 1, but it does not inhibit the occurrence of the reaction, even if it is larger or smaller than this.

  In order to cause the reaction of the present invention to occur efficiently, it is essential to use a nickel catalyst having a low valence. Although the thing of various structures can be used as the form, The thing which has tertiary phosphine as a ligand is especially preferable. It is also a preferred embodiment to use a precursor that is easily converted to a low valence in the reaction system. Furthermore, a method in which a complex containing no tertiary phosphine as a ligand and a tertiary phosphine are mixed in the reaction system to generate a complex having the tertiary phosphine as a ligand in the reaction system is also a preferred embodiment. Examples of the ligand that exhibits advantageous performance by any of these methods include various tertiary phosphines.

  Examples of ligands that can be preferably used in the present invention include triphenylphosphine, diphenylmethylphosphine, phenyldimethylphosphine, 1,4-bis (diphenylphosphino) butane, 1,3-bis (diphenylphosphino). ), Propane, 1,2-bis (diphenylphosphino) ethane, 1,1′-bis (diphenylphosphino) ferrocene, triethylphosphine, trimethylphosphine, and the like, but are not limited thereto.

  Examples of the complex not containing tertiary phosphine as a coordination used in combination or alone include bis (1,5-cyclooctadiene) nickel, but are not limited thereto.

  Specific examples of phosphine complexes that can be suitably used include tetrakis (triphenylphosphine) nickel, tetrakis (diphenylmethylphosphine) nickel, tetrakis (dimethylphenylphosphine) nickel, tetrakis (triethylphosphine) nickel, and the like.

  Furthermore, a highly active nickel catalyst can be easily generated by reaction with an organometallic reagent such as Grignard or organolithium in a reaction system using a precursor that is easily converted to a low valence. Specific examples of the precursor include dichlorobis (triphenylphosphine) nickel, dichlorobis (diphenylmethylphosphine) nickel, dichlorobis (dimethylphenylphosphine) nickel and the like, but are not limited thereto.

  The amount of these catalysts used may be a so-called catalytic amount, and generally 20 mol% or less is sufficient with respect to the acetylene compound.

  The reaction temperature is selected from the range of 20 ° C. to 150 ° C. below zero, preferably from room temperature to 100 ° C., because the reaction does not proceed at an advantageous rate at too low temperatures and the catalyst decomposes at too high temperatures. Implemented in a range.

  The catalyst used in this reaction is sensitive to oxygen, and the reaction is preferably carried out in an inert gas atmosphere such as nitrogen, argon or methane. Separation of the product from the reaction mixture is readily accomplished by chromatography, distillation or recrystallization.

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

Comparative Example 1
1 milliliter of THF was reacted with 1 mmol of HP (O) (OMe) _2, 1 mmol of 1-octyne, and Ni (PPh ₂ Me) ₄ (5 mol%) as a catalyst at room temperature for 5 hours under a nitrogen atmosphere. However, a mixture of CH ₂ = C (nC ₆ H ₁₃ ) [P (O) (OMe) ₂ ] and (E) -CH (nC ₆ H ₁₃ ) = CH [P (O) (OMe) ₂ ] (ratio = 46:54) was obtained in a yield of 87%.
The former CH ₂ = C (nC ₆ H ₁₃ ) [P (O) (OMe) ₂ ] is a Markovnikov type adduct, and the latter (E) −CH (nC ₆ H ₁₃ ) = CH [P (O ) (OMe) ₂ ] is an anti-Markovnikov type adduct.

Comparative Examples 2-3
Under the conditions of Comparative Example 1, various HP compounds and acetylenes were reacted. The results are summarized in Table 1.

Example 1
1 ml of ethanol, 1 mmol of HP (O) (OMe) _2, 1 mmol of 1-octyne, Ni (cod) ₂ as catalyst
(cod = 1,5-cyclooctadiene) (5 mol%) and PPh ₂ Me (5 mol%) were reacted in a nitrogen atmosphere at room temperature for 7 hours. (E) -CH (nC ₆ H ₁₃ ) = CH [P (O) (OMe) ₂ ] was selectively obtained in 89% yield.

Example 2
1 milliliter of methanol was used with 1 mmol of HP (O) (OMe) _2, 1 mmol of 1-octyne, and Ni (PPh ₂ Me) ₄ (5 mol%) as a catalyst. However, (E) —CH (nC ₆ H ₁₃ ) ═CH [P (O) (OMe) ₂ ] was selectively obtained in a yield of 97%.

Example 3
When ethanol was used instead of methanol and the reaction was carried out under the same conditions as in Example 1, (E) -CH (nC ₆ H ₁₃ ) = CH [P (O) (OMe) ₂ ] was 91%. Obtained selectively in yield.

Examples 4-8
Under the conditions of Example 2, various HP compounds and acetylenes were reacted. The results are summarized in Table 2.

Claims (3)

In the presence of a catalyst containing nickel, the following general formula (1)
R ¹ OH (1)
(R ¹ represents an alkyl group, a cycloalkyl group, an aryl group, or an acyl group.)
In a protic solvent represented by
The following general formula (2)
R ² (C≡CR ³ ) _n (2)
(Wherein, n is 1 or 2, R ^2, when n is 1, an alkyl group, a cycloalkyl group, an aryl group, an aralkyl group, a heteroaryl group, an alkenyl group, an alkoxy group, an aryloxy group, or silyl group, when n is 2, an alkylene group, cycloalkylene group, arylene group, aralkylene group, a heteroarylene group, an alkenylene group, alkylenedioxy group, .R ³ showing arylenedioxy group, or a silicon dioxy group Represents a hydrogen atom), and an acetylene compound represented by
The following general formula (3)
HP (O) (OR ⁴ ) (OR ⁵ ) (3)
(Wherein R ⁴ and R ⁵ each independently represents an alkyl group, a cycloalkyl group, an aralkyl group or an aryl group. In addition, R ^{4 to} R ⁵ each represents one hydrogen atom from each group. It may be bonded to each other at a residue formed to form a cyclic structure.) A hydrogenated phosphonate represented by the following general formula (4) is reacted:
R ² {CH = CR ³ [P (O) (OR ⁴ ) (OR ⁵ ) ]} n (4)
(R ² , R ³ , R ⁴ and R ⁵ are the same as above)
The manufacturing method of the alkenylphosphonic acid ester compound represented by these. In the presence of a catalyst containing nickel, the general formula (1)
R ¹ OH (1)
(R ¹ is the same as claim 1)
In a protic solvent represented by
General formula (2)
R ² (C≡CR ³ ) _n (2)
An acetylene compound represented by (wherein n, R ² and R ³ are the same as in claim 1);
The following general formula (5)
HP (O) (OR ⁴ ) R ⁵ (5)
(Wherein R ⁴ and R ⁵ are the same as those in claim 1), and a hydrogenated phosphinic acid ester represented by the following general formula (6)
R ² {CH = CR ³ [P (O) (OR ⁴ ) R ⁵ ]} n (6)
(N, R ² , R ³ , R ⁴ and R ⁵ are the same as in claim 1). In the presence of a catalyst containing nickel, the general formula (1)
R ¹ OH (1)
(R ¹ is the same as in claim 1)
In a protic solvent represented by
General formula (2)
R ² (C≡CR ³ ) _n (2)
An acetylene compound represented by (wherein n, R ² and R ³ are the same as in claim 1);
The following general formula (7)
HP (O) R ⁴ R ⁵ (7)
(Wherein, R ⁴ and R ⁵ are the same as those in claim 1), and the following general formula (8)
R ² {CH = CR ³ [P (O) R ⁴ R ⁵ ]} n (8)
(N, R ² , R ³ , R ⁴ and R ⁵ are the same as in claim 1).