JP3951024B2 - Method for producing organic sulfur compound - Google Patents

Description

The present invention relates to a method for producing an organic sulfur compound . More specifically, the present invention easily reacts with various nucleophiles and radical species and is widely used for the synthesis of pharmaceuticals and natural compounds, and is useful in the synthesis of fine chemicals. The present invention relates to a method for producing a highly alkenylsulfur compound.

  Various methods have been developed so far for synthesizing alkenylsulfur compounds. For example, a method using radical addition of a corresponding thiol to acetylene (Non-patent Document 1), palladium or rhodium catalyst. A method using an addition reaction of thiols with acetylene to acetylene (Non-patent Document 2) is known.

However, the former method generally requires heating for a long time, resulting in poor product selectivity and reaction efficiency. In the latter reaction, an expensive palladium or rhodium catalyst is used, which is not an industrially advantageous method.
On the other hand, although addition of PhSH acetylene has been attempted using a divalent nickel complex catalyst Ni (PPh ₃ ) ₂ Cl ₂ (Non-patent Document 3), this method can be heated at 80 ° C. for 16 hours. The yield of the target alkenyl sulfide was only about 22%.

The Chemistry of the Thiol Group; Patai, S., Ed .; Wiley: London, 1974; Vol. 2 J. Am. Chem. Soc. 1999, 121, 5108 J. Am. Chem. Soc. 1992, 114, 5902

  An object of the present invention is to provide a method capable of producing a target alkenylsulfur compound at a high yield and low cost by an addition reaction of thiols to acetylene.

  In the present invention, as a result of intensive studies on the reaction between a readily available thiol compound and an acetylene compound, the addition reaction proceeds efficiently in the presence of an inexpensive zero-valent nickel catalyst at room temperature to give the corresponding alkenyl sulfide. The present invention has been completed based on these facts.

That is, according to this application , the following invention is provided.
[1] Using zero-valent nickel having a phosphorus-containing ligand as a catalyst, the general formula (1)
R ¹ C≡CR ² (1)
(Wherein R ¹ and R ² represent a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, an aralkyl group, a heteroaryl group, a ferrocenyl group, an alkenyl group, an alkoxy group, an aryloxy group or a silyl group) An acetylene compound represented by the general formula (2)
HSR ³ (2)
(Wherein R ³ represents an alkyl group, a cycloalkyl group, an aralkyl group or an aryl group), and is reacted with a thiol represented by the general formula (3)
R ¹ CH = CR ² (SR ³ ) (3)
And / or general formula (4)
R ¹ CH = CR ² (R ¹ C = CR ² SR ³ ) (4)
(R ¹ , R ² and R ³ are the same as above)
The manufacturing method of the alkenyl sulfur compound represented by these.
[2] Reaction is represented by general formula (5)
HO−P (O) (R ⁴ ) ₂ (Five)
(Wherein R ⁴ represents an alkyl group, a cycloalkyl group, or an aryl group). The method for producing an organosulfur compound according to the above [1], which is carried out in the presence of a phosphinic acid represented by .

  In the synthesis method of the present invention, an alkenyl sulfide useful as a synthetic intermediate for a physiologically active substance such as a pharmaceutical or agrochemical or a ligand for catalyst preparation is obtained by simply reacting acetylenes with a thiol compound under mild conditions. It can be synthesized simply, safely and efficiently.

The acetylene compound used as a raw material for the reaction of the present invention is represented by the general formula (1). In the general formula (1), R ¹ and R ² represent a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, an aralkyl group, a heteroaryl group, a ferrocenyl group, an alkenyl group, an alkoxy group, an aryloxy group, or a silyl group. Show.

When R ¹ and / or R ² 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.). 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 carbon number is 2-18, preferably 2-10. 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 trimethylsilyl group, triethylsilyl group, triphenylsilyl group, phenyldimethylsilyl group, trimethoxysilyl group, t-butyldimethylsilyl group and the like.

  Examples of the acetylene compound 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 thiol compound used as the other raw material in the reaction of the present invention is represented by the general formula (2). R ³ represents an alkyl group, a cycloalkyl group, an aralkyl group or an aryl group.

When R ³ is 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 ³ 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.

  Specific examples of suitable thiol compounds include, but are not limited to, thiophenol, butyl mercaptan, t-butyl mercaptan, cyclohexyl mercaptan, and the like.

  The molar ratio of the acetylene compound and thiol 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 efficiently cause the reaction of the present invention, it is essential to use a zero-valent nickel catalyst having a phosphorus-containing ligand.
In the present invention, by using such a zero-valent nickel catalyst, it is possible to react only with a thiol compound to acetylenes under mild conditions. Alkenyl sulfides useful as synthetic intermediates can be synthesized simply, safely and efficiently at room temperature, as shown in the Examples below. In the addition reaction of acetylenes of PhSH at room temperature using multivalent, for example, divalent nickel complex catalyst Ni (PPh ₃ ) ₂ Cl ₂ as a catalyst, the yield of alkenyl sulfide is extremely high. Even if it was made to react for 20 hours, the adduct was hardly obtained. Even when heated at 80 ° C. for 16 hours, the yield of the desired alkenyl sulfide is only about 22%.
Although the reason why the yield of alkenyl sulfides varies greatly depending on the valence of nickel is not clear at present, zero-valent nickel has the ability to activate the SH bond of PhSH, and oxidation of SH bond to nickel It is considered that an active species such as PhS-Ni-H is generated by the chemical addition. Reaction with this active species of acetylene gives the adduct. On the other hand, such an active species (or activation of SH bond) does not easily proceed using divalent nickel including multivalent nickel. Therefore, multivalent nickel does not show catalytic activity or has low activity.

As the form of the zero-valent nickel used in the present invention, those having various structures can be used, but those containing phosphorus-containing ligands such as tertiary phosphine and phosphite in advance are used. The phosphorus-containing ligand is preferably a tertiary phosphine or phosphite.
Examples of ligands that can be suitably 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, triphenylphosphite, etc. is not.

Specific examples of nickel complexes containing phosphorus-containing ligands such as phosphine and phosphite among zero-valent nickel catalysts preferably used in the present invention include tetrakis (triphenylphosphine) nickel and tetrakis (diphenylmethyl). Phosphine) nickel, tetrakis (dimethylphenylphosphine) nickel, tetrakis (triethylphosphine) nickel, tetrakis (triphenylphosphite) nickel and the like.

  The zero-valent nickel used in the present invention is a mixture that forms a complex having tertiary phosphine or phosphite as a ligand in the reaction system, for example, tertiary phosphine or phosphite as a ligand. A mixture of a complex not containing it and a ligand such as tertiary phosphine or phosphite can also be used.

In the present invention, a precursor that is easily converted to zero valence in the reaction system can also be used. A precursor that easily gives a highly active zero-valent nickel catalyst by reaction with an organometallic reagent such as Grignard or organolithium in the reaction system can also be used. Specific examples of such a precursor include dichlorobis (triphenylphosphine) nickel, dichlorobis (diphenylmethylphosphine) nickel, dichlorobis (dimethylphenylphosphine) nickel and the like, but are not limited thereto. These precursors interact with organometallic reagents such as Grignard and organolithium to reduce polyvalent nickel and generate zero-valent nickel. Similarly, a zero-valent nickel catalyst can be prepared by allowing a reducing agent such as LiAlH ₄ to act on a mixture of a divalent nickel compound such as nickel acetylacetonate and a phosphine or phosphite.

  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 represented by the general formula (1).

The zero-valent nickel catalyst used in the present invention is active alone, but can also be used with a phosphinic acid additive. By using this phosphinic acid additive, the selectivity of the product can be improved. These phosphinic acids are represented by the general formula (5), and R ⁴ represents an alkyl group, a cycloalkyl group or an aryl group.

When R ⁴ is an alkyl group, the alkyl group has 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Specific examples thereof include methyl, ethyl, propyl, hexyl and the like. In the case of the said cycloalkyl group, carbon number is 3-12, Preferably it is 5-6. Specific examples thereof include a cyclohexyl group, a cyclooctyl group, and a cyclododecyl group. The number of carbon atoms in the case of the aryl group 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 alkyl group, cycloalkyl group or aryl group represented by R ⁴ is a functional group inert to the reaction, for example, a methoxy group, a methoxycarbonyl group, a cyano group, a dimethylamino group, a fluoro group, a chloro group, a hydroxy group, etc. May be substituted.

  Specific examples of the phosphinic acid used in the present invention include diphenylphosphinic acid and dimethylphosphinic acid. The usage-amount is the same mol or less with respect to the thiol compound represented by the said General formula (2), Preferably, it is 0.1-10 mol%.

  The reaction is not particularly required to use a solvent, but can be carried out in a solvent if necessary. Various solvents such as hydrocarbons, halogen hydrocarbons, ethers, ketones, nitriles, and esters can be used as the solvent. Moreover, these are used individually or in mixture of 2 or more types.

  The reaction temperature is selected from the range of 20 ° C. to 300 ° C. below zero, preferably from room temperature to 150 ° C., because the reaction does not proceed at an advantageous rate at too low temperature and the catalyst decomposes at too high temperature. 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.

Example 1
When 1 milliliter of 1,4-tetrahydrofuran was reacted with 1 mmol of HSPh, 1 mmol of 1-octyne, Ni (PPh ₂ Me) ₄ (5 mol%) as a catalyst, and reacted for 1 hour at room temperature in a nitrogen atmosphere. The sulfur compound was obtained in a yield of 95% (ratio of nC ₆ H ₁₃ C (SPh) = CH ₂ : (E) -nC ₆ H ₁₃ CH═CHSPh = 74: 26).

Example 2
When the reaction was carried out for 20 hours using an ethanol solvent under the same conditions as in Example 1, an alkenylsulfur compound was obtained in a yield of 91% (nC ₆ H ₁₃ C (SPh) = CH ₂ : (E ) -nC ₆ H ₁₃ CH = CHSPh ratio = 83: 17).

Example 3
When the reaction was carried out for 20 hours using an acetonitrile solvent under the same conditions as in Example 1, an alkenylsulfur compound was obtained in a yield of 93% (nC ₆ H ₁₃ C (SPh) = CH ₂ : (E )-nC ₆ H ₁₃ CH = CHSPh ratio = 80: 20).

Example 4
When the reaction was carried out for 20 hours using a toluene solvent under the same conditions as in Example 1, an alkenylsulfur compound was obtained in a yield of 98% (nC ₆ H ₁₃ C (SPh) = CH ₂ : (E ) -nC ₆ H ₁₃ CH = CHSPh ratio = 70: 30).

Example 5
When the reaction was carried out for 2 hours in the presence of 5 mol% Ph ₂ P (O) OH under the same conditions as in Example 1, an alkenylsulfur compound was obtained in a yield of 97% (nC ₆ H ₁₃ C ( SPh) = CH ₂ : (E) -nC ₆ H ₁₃ CH = CHSPh ratio = 95: 5).

Example 6
When the reaction was carried out under the conditions of Example 1 using acetylene gas (one atmosphere), CH ₂ = CHSPh was obtained in a yield of 92%.

Example 7
When 5 ml of 1,4-tetrahydrofuran was used and the reaction was conducted under the conditions of Example 6, CH ₂ = CHSPh was obtained in a yield of 41% and CH ₂ = CHCH = CHSPh in a yield of 53%.

Comparative Example In Example 1, the catalyst was a divalent nickel complex catalyst Ni (PPh ₃ ) ₂ Cl ₂
The reaction was carried out in the same manner as in Example 1 except that. As a result, almost no adduct was obtained.

Example 8
The reaction was carried out under the conditions of Example 1 using phenylacetylene instead of 1-octyne. )Met. An alkenylsulfur compound was obtained in 89% yield (Ph (SPh) C = CH ₂ : (E) -PhCH = CHSPh ratio = 41: 59).

Example 9
When the reaction was carried out in the presence of Ph ₂ P (O) OH (10 mol%) under the conditions of Example 8, an alkenylsulfur compound was quantitatively obtained (Ph (SPh) C═CH ₂ :( E) -PhCH = CHSPh ratio = 74: 26).

Example 10
When Example 9 was carried out at zero temperature for 20 hours, an alkenylsulfur compound was obtained in a yield of 93% (Ph (SPh) C = CH ₂ : (E) -PhCH = CHSPh ratio = 81: 19). .

Example 11
When ethanol was used as a solvent and the reaction was carried out under the conditions of Example 9, an alkenylsulfur compound was obtained in a yield of 96% (Ph (SPh) C = CH ₂ : (E) -PhCH = CHSPh Ratio = 89: 11).

Example 12
When the reaction was carried out under the conditions of Example 11 using isopropanol as a solvent, an alkenylsulfur compound was obtained in a yield of 91% (Ph (SPh) C = CH ₂ : (E) -PhCH = CHSPh Ratio = 91: 9).

Claims (2)

  Using zero-valent nickel having a phosphorus-containing ligand as a catalyst, the general formula (1)
      R ¹ C≡CR ² (1)
(R ¹ And R ² Represents a hydrogen atom, alkyl group, cycloalkyl group, aryl group, aralkyl group, heteroaryl group, ferrocenyl group, alkenyl group, alkoxy group, aryloxy group or silyl group. The acetylene compound represented by the general formula (2)
      HSR ³   (2)
(Wherein R ³ Represents an alkyl group, a cycloalkyl group, an aralkyl group or an aryl group. Thiol represented by the general formula (3)
      R ¹ CH = CR ² (SR ³ (3)
And / or general formula (4)
      R ¹ CH = CR ² (R ¹ C = CR ² SR ³ ) (Four)
(R ¹ , R ² , R ³ Is the same as the above). The reaction is represented by the general formula (5)
HO−P (O) (R ⁴ ) ₂ (Five)
The method for producing an organosulfur compound according to claim 1, wherein the method is carried out in the presence of phosphinic acid represented by the formula (wherein R ⁴ represents an alkyl group, a cycloalkyl group or an aryl group).