JP6551922B2 - Process for producing alcohol by hydrogenation of carboxylic acid compound, and ruthenium complex used in the process - Google Patents

Description

  The present invention relates to a method for producing an alcohol by hydrogenation of a carboxylic acid compound, and a ruthenium complex used in the production method.

  Hydrogen transfer reactions, such as hydrogenation reactions, are widely used in the synthesis of small molecule and high molecular weight organic compounds.

  For example, Non-Patent Document 1 shows that a specific ruthenium complex is useful for synthesizing an alcohol by hydrogenating an ester or carbon dioxide. Other examples of hydrogenating amides are also known.

  However, there are few examples of hydrogenation of carboxylic acid compounds using molecular catalysts. This is because the carboxylic acid compound has a carboxyl group that is stable with respect to the hydrogenation reaction, so that the hydrogenation reaction is generally difficult. In addition, in the conventional hydrogenation method of carboxylic acid compounds, when homogeneous catalysts are used, the dependence on the substrate is high, so the central metal or ligand of the catalyst, the reaction conditions, etc. are selected each time depending on the type of substrate. I needed to change it a lot.

  For this reason, not only amides and esters but also carboxylic acid compounds can be applied to the synthesis of low-molecular and high-molecular organic compounds as long as the alcohol can be synthesized by a hydrogenation reaction. It is more useful because it can be synthesized.

  For example, when hetero binuclear metal cluster catalysts or heterogeneous catalysts are used, reported examples exist (non-patent documents 2 to 3). However, in Non-Patent Document 2, when a homogeneous catalyst consisting of a single metal is used, hydrogenation of a carboxylic acid compound is difficult, high pressure is required, and ring reduction proceeds. Moreover, in nonpatent literature 3, since it is accompanied by decarboxylation depending on a substrate, substrate generality and selectivity are scarce. Therefore, the methods described in Non-Patent Documents 2 and 3 can not be said to be excellent in substrate generality that can be advanced under mild conditions.

  On the other hand, in Non-Patent Document 4, when a specific carboxylic acid substrate is used by combining a specific complex, a specific ligand, and a specific additive, a cyclic ester, a cyclic ether, an alcohol, etc. are desired. It has been shown that it is possible to obtain compounds of However, it is not shown in Non-patent Document 4 whether or not the reaction proceeds in the same manner even if a general carboxylic acid compound is used, and it is described only when a special carboxylic acid substrate is used.

  As described above, it is difficult to directly reduce the carboxylic acid compound to obtain the alcohol depending on the substrate, and therefore, the reduction reaction is usually performed after intramolecular esterification of the carboxylic acid compound.

  On the other hand, Patent Document 1 also describes hydrogenation of propionic acid, butyric acid, etc. and is said to be excellent in substrate generality, but requires high temperature (190 ° C. or higher), and the reaction is performed under mild conditions. Can not advance. In Patent Document 1, a tridentate ligand such as Triphos (1,1,1-tris (diphenylphosphinomethyl) ethane) is particularly useful as a ligand used in the ruthenium complex. There is.

  For this reason, a method of hydrogenating various carboxylic acid substrates under mild conditions using a homogeneous catalyst to obtain an alcohol has not yet been achieved, and such a method is required.

US Patent Application Publication No. 2005/0234269

Angew. Chem. Int. Ed. 2012, 51, 7499-7502 Tetrahedron Lett. 1995, 36, 1059-1062 Chem. Commun. 2010, 46, 6279-6281 Angew. Chem. Int. Ed. 2010, 49, 5510-5514

  The hydrogenation reaction of a substrate having an inert carbonyl group such as the above-mentioned ester, amide or the like is generally effective in many cases when carried out under basic conditions. However, in the case of using a carboxylic acid compound as a substrate, the reaction system has acidic conditions, and the conditions for hydrogenating an ester or amide can not be applied as it is.

  Under such circumstances, an object of the present invention is to provide a method for efficiently hydrogenating various carboxylic acid compounds using a homogeneous catalyst under mild conditions to obtain an alcohol.

  Another object of the present invention is to provide a novel ruthenium complex that can be used in the method.

  The present inventors have intensively studied to solve the above problems.

  As a result, it has been found that by using a specific ruthenium complex, an alcohol can be obtained efficiently by hydrogenating a carboxylic acid compound under mild conditions. Among the ruthenium complexes used at this time, some are novel compounds not described in any literature.

  Based on such findings, the present inventors have further studied and completed the present invention.

That is, the present invention includes the following alcohol production method and ruthenium complex.
Item 1. A method for producing an alcohol by hydrogenating a carboxylic acid compound,
Hydrogenating the carboxylic acid compound in the presence of a ruthenium complex under a hydrogen atmosphere,
The ruthenium complex is represented by the general formula (1):
RuX _n Y _p Z _q
[Wherein X is

(Wherein R ¹ is a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted aryl group, and A ¹ and A ² are the same or different and O, NR ⁴ (where, R ⁴ is a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted aryl group), or S, and m is an integer greater than or equal to 1. A bond represented by a solid line and a broken line Is a single bond or a double bond)), Y is a phosphine ligand having an alkyl group which may be substituted or an aryl group which may be substituted, Z is It is a ligand other than X and Y, n is 1 or 2, p is an integer of 1 to 4, and q is an integer of 0 to 2. ]
It is a compound shown by these, The manufacturing method.
Item 2. In the general formula (1), X is

(R ¹ is a hydrogen atom, an alkyl group which may be substituted, or an aryl group which may be substituted, and the bond shown by the solid line and the broken line is a single bond or a double bond)
2. The method according to item 1 above, which is a group represented by
Item 3. 3. The method according to item 1 or 2, wherein in the general formula (1), Y is a monodentate or bidentate ligand.
Item 4. In the general formula (1), Z is hydride, oxygen atom, water molecule, carbon monoxide, nitric oxide, cyanide ion, thiocyanate, amine, aromatic hydrocarbon, unsaturated hydrocarbon, heterocyclic compound, The above item, which is a carbonyl compound, a lower alkoxy group, β-diketonate, dimethyl sulfoxide, phosphine oxide, nitrile, nitrogen molecule, hydrogen molecule, oxygen molecule, carbon dioxide, N-heterocyclic carbene, triflate, tosylate, or trifurylimide. The manufacturing method in any one of 1-3.
Item 5. The ruthenium complex is represented by the general formula (1A):
RuX _n Y _p
[Wherein X is

(Wherein R ¹ is a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted aryl group, and A ¹ and A ² are the same or different and O, NR ⁴ (where, R ⁴ is a hydrogen atom, an alkyl group which may be substituted, or an aryl group which may be substituted, or S, m is an integer of 1 or more, and a bond represented by a solid line and a broken line Is a single bond or a double bond), Y is a phosphine ligand having an optionally substituted alkyl group or an optionally substituted aryl group, and n is It is 1 or 2, p is an integer of 1-4. ]
The manufacturing method in any one of said claim | item 1-4 which is a compound shown by these.
Item 6. The ruthenium complex has the general formula (1A-1):

[Wherein, R ¹ represents a hydrogen atom, an alkyl group which may be substituted or an aryl group which may be substituted, and R ² and R ³ may be the same or different and each may be an alkyl which may be substituted] A group or an aryl group which may be substituted, and one R ² and one R ³ may be bonded to each other to form a ring together with adjacent —P—Ru—P—. A bond indicated by a solid line and a broken line is a single bond or a double bond. ]
6. The method according to item 5, which is a compound represented by
Item 7. General formula (1A-1 '):

[Wherein, R ¹ is a hydrogen atom, an optionally substituted alkyl group or an optionally substituted aryl group, and R ² and R ³ are the same or different, and each may be an optionally substituted alkyl. Or an aryl group which may be substituted (provided that R ² and R ³ are not bonded to each other and form a ring together with the adjacent —P—Ru—P—). A bond indicated by a solid line and a broken line is a single bond or a double bond. ]
Ruthenium complex shown by.

  According to the present invention, the hydrogenation does not require high temperature and high pressure with respect to the carboxylic acid compound, that is, hydrogenation proceeds efficiently even under mild conditions such as a hydrogen pressure of about 8 MPa or less and a reaction temperature of about 160 ° C. or less. Since the alcohol can be obtained, it is highly practical and convenient.

  It is also possible to obtain alcohols with very high yields by choosing the substrate and the complex. In this case, since the selectivity of alcohol is high, there is a high possibility that it leads to the energy saving method. In particular, the present invention is useful in that alcohol can be obtained in high yield even when using an amino acid derivative as a substrate. Furthermore, when the amino acid derivative has a chirality, the resulting alcohol has a certain degree of chirality.

  Furthermore, in the production method of the present invention, a catalyst that is easy to handle even at room temperature and in the air and can be synthesized easily can be used economically, and is highly practical and convenient.

1. First aspect (manufacturing method)
The method for producing an alcohol in the first aspect of the present invention includes a step of hydrogenating a carboxylic acid compound in a hydrogen atmosphere in the presence of a ruthenium complex.

(1) Ruthenium Complex The ruthenium complex used in the present invention in the first aspect is a compound represented by the general formula (1):
RuX _n Y _p Z _q
[Wherein X is

(Wherein R ¹ is a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted aryl group, and A ¹ and A ² are the same or different and O, NR ⁴ (where, R ⁴ is a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted aryl group), or S, and m is an integer greater than or equal to 1. A bond represented by a solid line and a broken line Is a single bond or a double bond.), Y is a phosphine ligand having an optionally substituted alkyl group or an optionally substituted aryl group, and Z is It is a ligand other than X and Y, n is 1 or 2, p is an integer of 1 to 4, and q is an integer of 0 to 2. ]
It is a compound shown by these.

  The valence of ruthenium in the ruthenium complex used in the present invention in the first aspect may be any number, but is preferably divalent or trivalent, and more preferably divalent. In addition, the case where the valence of ruthenium is unknown in the reaction system is included.

  In the general formula (1), X is

(Wherein, R ¹ is a hydrogen atom, an alkyl group which may be substituted, or an aryl group which may be substituted, and A ¹ and A ² are the same or different and O, NR ⁴ (wherein R ⁴ is a hydrogen atom, an alkyl group which may be substituted, or an aryl group which may be substituted, or S, m is an integer of 1 or more, and a bond represented by a solid line and a broken line Is a single bond or a double bond.)

As R ¹ , for example, a hydrogen atom, an alkyl group which may be substituted, an aryl group which may be substituted, etc. may be mentioned.

As the alkyl group represented by R ^1, for example, preferably a linear or branched alkyl group having 1 to 20 carbon atoms. 1-12 are preferable, as for carbon number of an alkyl group, 1-6 are more preferable, and 1-4 are especially preferable. Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group.

The substituent in the case where the alkyl group represented by R ¹ is substituted is not particularly limited. Examples of such substituents include halogen atoms such as fluorine atom, chlorine atom and bromine atom; alkyl groups such as methyl group and ethyl group; alkoxy groups such as methoxy group and ethoxy group; nitro group; amino group; A cyano group; a silyl group such as a trimethylsilyl group; and a thiol group. The number of substituents when substituted by a substituent can be, for example, about 1 to 3.

Examples of the aryl group represented by R ¹ include phenyl group, naphthyl group, pyrenyl group, toluyl group, xylyl group, mesityl group, pyridyl group, furyl group, thiophenyl group, pyrrolyl group and the like.

The substituent in the case where the aryl group represented by R ¹ is substituted is not particularly limited. Examples of such substituents include halogen atoms such as fluorine atom, chlorine atom and bromine atom; alkyl groups such as methyl group and ethyl group; alkoxy groups such as methoxy group and ethoxy group; nitro group; amino group; A cyano group; a silyl group such as a trimethylsilyl group; and a thiol group. The number of substituents when substituted by a substituent can be, for example, about 1 to 3.

Among these, R ¹ is preferably an unsubstituted alkyl group or an unsubstituted aryl group. As the unsubstituted alkyl group, a methyl group, an ethyl group, an n-propyl group and the like are more preferable, and as the unsubstituted aryl group, a phenyl group is more preferable.

A ¹ and A ² are the same or different and are O, NR ⁴ , or S.

Here, R ⁴ of NR ⁴ is a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted aryl group. As the optionally substituted alkyl group represented by R ^4, include the same alkyl group which may be substituted as above R ^1, a methyl group, an ethyl group, n- propyl group, n- butyl Groups and the like are preferred. Further, as the optionally substituted aryl group represented by R ^4, optionally substituted as above R ¹ include the same also aryl group, a phenyl group, toluyl group, xylyl group and the like. Specific examples of NR ⁴ include NH, NCH ₃ , NC ₆ H _{5 and the} like, with NH being preferred.

Examples of combinations of A ¹ and A ² include O and O, NR ⁴ and NR ⁴ , S and S, O and NR ⁴ , O and S, and the like, and a combination in which both A ¹ and A ² are O is preferable.

  In General formula (1), m is an integer greater than or equal to 1, From the viewpoint of the yield of the alcohol by hydrogenation (reduction) of a carboxylic acid compound, the integer of 1-3 is preferable and 1 or 3 is more preferable.

  As X, for example,

(R ¹ is a hydrogen atom, an alkyl group which may be substituted, or an aryl group which may be substituted, and the bond shown by the solid line and the broken line is a single bond or a double bond)
Etc. are preferred, and among these,

(R ¹ is a hydrogen atom, an alkyl group which may be substituted, or an aryl group which may be substituted, and the bond shown by the solid line and the broken line is a single bond or a double bond)
Etc. are more preferable. As X, in the above formula, R ¹ is preferably a methyl group, an ethyl group, or an n-propyl group, and —OC (CH ₃ ) O— (acetato) is particularly preferable.

  In the general formula (1), Y is a phosphine ligand having an alkyl group which may be substituted or an aryl group which may be substituted. As such a ligand, any of a monodentate ligand, a bidentate ligand, a tridentate ligand and a tetradentate ligand can be used, but a monodentate ligand or a bidentate ligand is preferred.

Examples of the alkyl group which may be substituted include the same ones as the alkyl group which may be substituted as R ¹ described above, and a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group , Isobutyl group, sec-butyl group, tert-butyl group and the like are preferable.

Examples of the aryl group which may be substituted include the same as the aryl group which may be substituted as R ¹ described above, and include phenyl group, naphthyl group, pyrenyl group, toluyl group, xylyl group, mesityl group, Pyridyl group, furyl group, thiophenyl group, pyrrolyl group and the like are preferable.

  As the phosphine ligand Y having an optionally substituted alkyl group or an optionally substituted aryl group that can be used in the present invention, specifically, as a monodentate ligand, for example, trimethylphosphine and the like can be used. Trialkyl phosphines; triphenyl phosphine, tri (4-fluorophenyl) phosphine, tri (2-tolyl) phosphine, tri (3-tolyl) phosphine, tri (4-tolyl) phosphine, tris [4- (trifluoromethyl) Phenyl] phosphine, tri (4-anisyl) phosphine, tri (2,4-xylyl) phosphine, tri (3,5-xylyl) phosphine, tri (2,4,6-trimethoxyphenyl) phosphine, tris (3 5-di-t-butylphenyl) phosphine, tris (3,5-di-isopropylphenyl) Sphin, triaryl phosphines such as tris (3,5-di-methoxyphenyl) phosphine, etc., and the like, and examples of bidentate ligands include bisdiphenylphosphinomethane (dppm), 1,2-bis (diphenylphosphino) ) Ethane (dpppe), 1,3-bis (diphenylphosphino) propane (dppp), 1,4-bis (diphenylphosphino) butane (dppb), 1,5-bis (diphenylphosphino) pentane (dpppn) 1,6-bis (diphenylphosphino) hexane (dpphe), 1,2-bis (diphenylphosphino) benzene, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene, 2,2 ′ -Bis (diphenylphosphino) -1,1'-binaphthyl (BINAP), 2,2'-bis (bis (3 5-dimethylphenyl) phosphino) -1,1′-binaphthyl, 1,1′-bis (diphenylphosphino) ferrocene, 1,4-bis (bis (3,5-dimethylphenyl) phosphino) butane, 1,4 -Bis (bis (3,5-di-t-butylphenyl) phosphino) butane, 1,4-bis (bis (3,5-di-methoxybutylphenyl) phosphino) butane, 1,4-bis (bis ( 3,5-di-isopropylphenyl) phosphino) butane and the like, and tridentate ligands include bis (2-diphenylphosphinoethyl) phenyl phosphine, 1,1,1-tris (diphenylphosphinomethyl) Examples include ethane, 1,1,1-tris (bis (3,5-dimethylphenyl) phosphinomethyl) ethane, and the tetradentate ligand includes tris (2-di-). Phenylphosphinoethyl) phosphine and the like. Of these, monodentate or bidentate ligands are preferable. Specifically, triphenylphosphine, tri (3,5-xylyl) phosphine, tris (3,5-di-t-butylphenyl) phosphine, tris (3 , 5-di-isopropylphenyl) phosphine, tris (3,5-di-methoxyphenyl) phosphine, bisdiphenylphosphinomethane (dppm), 1,3-bis (diphenylphosphino) propane (dppp), 1,4 -Bis (diphenylphosphino) butane (dppb), 1,5-bis (diphenylphosphino) pentane (dpppn), 1,1'-bis (diphenylphosphino) ferrocene, 2,2'-bis (diphenylphosphino) ) -1,1′-binaphthyl (BINAP), 2,2′-bis (bis (3,5-dimethylphenyl) phosphine F) -1,1'-binaphthyl, bis (diphenylphosphinoethyl) phenylphosphine, 1,1,1-tris (diphenylphosphinomethyl) ethane, 1,4-bis (bis (3,5-dimethylphenyl) Phosphino) butane, 1,4-bis (bis (3,5-di-t-butylphenyl) phosphino) butane, 1,4-bis (bis (3,5-di-methoxybutylphenyl) phosphino) butane, 1 , 4-bis (bis (3,5-di-isopropylphenyl) phosphino) butane is preferred.

  These ligands Y may be contained in the ruthenium complex to be charged, or may be formed into a ruthenium complex in the system.

In the general formula (1), the ligand represented by Z is a ligand other than X and Y, and is not particularly limited as long as it can coordinate to Ru. Specifically, hydrogen atom (hydride; H ⁻ ), oxygen atom (oxo group; O ²⁻ ), water molecule (H ₂ O), carbon monoxide (CO), aromatic hydrocarbon (benzene, naphthalene, pyrene) , Cyclopentadiene, p-cymene etc., lower alkoxy group (C 1-4 alkoxy group such as methoxy group etc.), β-diketonate (acetylacetone etc.), dimethyl sulfoxide, nitrogen monoxide (NO), unsaturated hydrocarbon (cyclo) octadiene, acetylene, 2-methylallyl, etc.), cyanide ion ^(- CN), thiocyanate (NCS ^-), amines (ammonia, triethylamine, etc.), heterocyclic compounds (pyridine, thiophene, THF), carbonyl compounds (formaldehyde, Acetone, ethyl acetate, DMF, etc.), phosphine oxide, nitrile (acetonitrile) Etc.), molecular nitrogen (N _2), hydrogen molecules _(H 2), oxygen molecules _(O 2), carbon dioxide _(CO 2), N-heterocyclic carbenes, triflate _(CF 3 SO ₃ ^-), tosylate (p- CH ₃ C ₆ H ₄ SO ₃ ⁻ ), triflylimide ((CF ₃ SO ₂ ) ₂ N ⁻ ) and the like, water molecule (H ₂ O), carbon monoxide (CO), aromatic hydrocarbon ( Cyclopentadiene, p-cymene and the like), 1,3-diketone (acetylacetone and the like), dimethyl sulfoxide, cyclooctadiene and the like are preferable.

  In the general formula (1), n is 1 or 2, and 2 is preferable from the viewpoint of the yield of alcohol by hydrogenation (reduction) of a carboxylic acid compound.

  In the general formula (1), p is an integer of 1 to 4 and is preferably 1 or 2 from the viewpoint of the alcohol yield by hydrogenation (reduction) of the carboxylic acid compound.

  In General formula (1), q is an integer of 0-2, and 0 or 1 is preferable from the viewpoint of the yield of alcohol by hydrogenation (reduction) of the carboxylic acid compound, and 0 is more preferable.

  In addition, 2 to 4 times of a ruthenium atom are preferable, and, as for the number of the phosphorus atoms coordinated to a ruthenium atom, 2 to 3 times are more preferable.

Preferred examples of the ruthenium complex used in the present invention include, for example, general formula (1A):
RuX _n Y _p
[Wherein X is

(Wherein R ¹ is a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted aryl group, and A ¹ and A ² are the same or different and O, NR ⁴ (where, R ⁴ is a hydrogen atom, an alkyl group which may be substituted, or an aryl group which may be substituted, or S, m is an integer of 1 or more, and a bond represented by a solid line and a broken line Is a single bond or a double bond), Y is a phosphine ligand having an optionally substituted alkyl group or an optionally substituted aryl group, and n is It is 1 or 2, p is an integer of 1-4. ]
And the compounds shown below (hereinafter sometimes referred to as ruthenium complex (1A)).

  In the general formula (1A), X, Y, n, and p are the same as described above.

  As a preferable example of such a ruthenium complex (1A), for example, general formula (1A-1):

[Wherein, R ¹ represents a hydrogen atom, an alkyl group which may be substituted or an aryl group which may be substituted, and R ² and R ³ may be the same or different and each may be an alkyl which may be substituted] A group or an aryl group which may be substituted, and one R ² and one R ³ may be bonded to each other to form a ring together with adjacent —P—Ru—P—. A bond indicated by a solid line and a broken line is a single bond or a double bond. ]
And a compound represented by the formula (hereinafter sometimes referred to as a ruthenium complex (1A-1)).

In General Formula (1A-1), R ¹ represents a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted aryl group. Examples of the alkyl group which may be substituted include methyl group, ethyl group, n-propyl group and n-butyl group. Examples of the aryl group which may be substituted include phenyl group, naphthyl group, pyrenyl group, toluyl group, xylyl group, mesityl group, pyridyl group, furyl group, thiophenyl group, pyrrolyl group and the like. Preferred as R ¹ is a hydrogen atom, a methyl group, a phenyl group, a xylyl group or the like.

In General Formula (1A-1), R ² and R ³ are an optionally substituted alkyl group or an optionally substituted aryl group. Examples of the alkyl group which may be substituted include methyl group, ethyl group, n-propyl group and n-butyl group. Examples of the aryl group which may be substituted include phenyl group, naphthyl group, pyrenyl group, toluyl group, xylyl group, mesityl group, pyridyl group, furyl group, thiophenyl group, pyrrolyl group and the like. Preferred as R ² and R ³ are methyl group, phenyl group, xylyl group and the like.

However, one R ² and one R ³ may be bonded to each other to form a ring together with adjacent —P—Ru—P—. When forming a ring, the ring that can be formed is not particularly limited, but specifically,

[R ² and R ³ are the same or different and are the same as above. ]
Etc.

Also when forming a ring in this way, R ² and R ³ are an optionally substituted alkyl group or an optionally substituted aryl group. Examples of the alkyl group which may be substituted include methyl group, ethyl group, n-propyl group, n-butyl group and the like, and as an aryl group which may be substituted, phenyl group, naphthyl group, pyrenyl group And toluyl group, xylyl group, mesityl group, pyridyl group, furyl group, thiophenyl group, pyrrolyl group and the like. R ² and R ³ are preferably a methyl group, a xylyl group, a phenyl group, or the like.

  As the ruthenium complex (1A-1) described above, for example,

[Ar represents a 3,5-xylyl group, Ph represents a phenyl group; the same shall apply hereinafter.]
Ruthenium complex (1A-1a), ruthenium complex (1A-1b), etc. are preferable from the viewpoint of the yield of alcohol by hydrogenation (reduction) of a carboxylic acid compound.

  As a ruthenium complex used in the present invention, a ruthenium complex (1A-1) is preferable, and among them, a ruthenium complex (1A-1a) and a ruthenium complex (1A-1b) are particularly preferable.

  Such ruthenium complexes may be known or commercially available, or may be synthesized.

(2) Hydrogenation Reaction In the production method of the present invention, specifically, hydrogen is added to a substrate (carboxylic acid compound) in the presence of a ruthenium complex to cause a hydrogenation reaction to obtain an alcohol.

  The substrate to be used for the reaction is not particularly limited as long as it is a carboxylic acid compound, and a wide variety of carboxylic acid compounds can be used. In this respect, the present invention is useful in comparison with the prior art in which hydrogenation reaction can only occur on a special substrate and the complex needs to be changed depending on the substrate.

  In the present invention, not only a carboxylic acid having only one carboxyl group but also a carboxylic acid compound having a plurality of these groups can cause a hydrogenation reaction to obtain an alcohol. That is, alcohols can be obtained by hydrogenating a wide variety of carboxylic acid compounds, including carboxylic acids that cannot be intramolecularly esterified.

  In addition, when a substrate has a functional group (a ketone group, an ether group, an ester group, an amide bond, a double bond, etc.) other than a carboxyl group, it can also be hydrogenated like a carboxyl group, The functional group can be protected and only the carboxyl group can be hydrogenated (reduced). The protection of functional groups can be carried out in a conventional manner. The same applies to the case where the substrate has a plurality of carboxyl groups. In particular, according to the present invention, an alcohol can be obtained by hydrogenating an amino acid derivative that has been difficult to hydrogenate by a conventional method. Furthermore, when the amino acid derivative has a chirality, the resulting alcohol has a certain degree of chirality.

  However, from the viewpoint of the yield of alcohol by hydrogenation (reduction) of the carboxylic acid compound, it is preferable not to have a functional group other than a carboxyl group, to have only one carboxyl group, and to have other functional groups. More preferred are carboxylic acid compounds.

  A wide variety of carboxylic acid compounds can be used as such a substrate. For example, acetic acid, propionic acid, butyric acid, valeric acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, benzoic acid, 4-tert -Butylbenzoic acid, 4-trifluoromethylbenzoic acid, 3-phenylpropionic acid, cinnamic acid, 1-adamantanecarboxylic acid, phenoxyacetic acid, monomethyl suberate, 3- (4-methoxycarbonyl) phenyl) acrylic acid, 5 -(Benzoyl) valeric acid, 4- (2- thienyl) butanoic acid, 3-cyclohexyl propionic acid, 3- (4- chlorophenyl) acrylic acid, formic acid, lauric acid, myristic acid, pentadecyl acid, palmitic acid, palmitoleic acid, Margaric acid, stearic acid, oleic acid, vacenic acid, linoleic acid, linolenic acid 3-hydroxypropionic acid, lactic acid, malonic acid, malic acid, fumaric acid, succinic acid, sebacic acid, xylonic acid, glutaric acid, glutaric acid, itaconic acid, levulinic acid, akonitic acid, citric acid, gluconic acid, glucaric acid, lysine, glutamic acid 2,5-furandicarboxylic acid, aspartic acid, serine, threonine, 2- (1-pyrrolyl) propanoic acid, 2- (1-pyrrolyl) -3-phenylpropanoic acid, 2- (1-pyrrolyl) -4- 4 Methylpentanoic acid or the like can be used.

  The amount of ruthenium complex used can be appropriately selected according to the type of substrate (carboxylic acid compound), and from the viewpoint of the yield of alcohol by hydrogenation (reduction) of the carboxylic acid compound, for example, substrate (carboxylic acid compound) Or less), usually about 0.0001 to about 1 mole, preferably about 0.001 to about 0.1 mole, and more preferably about 0.003 to about 0.07 mole, per 1 mole.

  The hydrogenation of the present invention is preferably carried out in a solvent.

  Examples of the solvent include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), dioxane (1,4-dioxane and the like), t-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, diglyme and triglyme. Aromatic hydrocarbons such as benzene, trifluoromethylbenzene, toluene, xylene and mesitylene; aliphatic hydrocarbons such as pentane, hexane, heptane, cyclopentane, cyclohexane, octane, nonane, decane and petroleum ether; isopropanol, n- Examples thereof include branched C3 to C6 alcohols such as butyl alcohol, tert-butyl alcohol and sec-butyl alcohol. These solvents may be used alone or in combination of two or more. Among these, ethers, aromatic hydrocarbons or C3 to C6 alcohols are preferable, dioxane, trifluoromethylbenzene, toluene, mesitylene, tert-butyl alcohol and the like are more preferable, and dioxane and toluene are particularly preferable.

  In the hydrogenation step of the present invention, hydrogen is added to the substrate (carboxylic acid compound), and hydrogen gas can be used as the hydrogen. The hydrogen partial pressure during hydrogenation (hydrogen pressure) is usually about 0.1 to 8 MPa, preferably about 0.5 to 6 MPa, from the viewpoint of the yield of alcohol by hydrogenation (reduction) of the carboxylic acid compound. More preferably, it can be about 1 to 4 MPa.

  The reaction temperature and reaction time may vary depending on the type of substrate (carboxylic acid compound), but from the viewpoint of the alcohol yield by hydrogenation (reduction) of the carboxylic acid compound, the reaction temperature is usually about 0 to 190 ° C. The temperature may be about 10 to 170 ° C., more preferably about 20 to 160 ° C. The reaction time can be generally about 10 minutes to 100 hours, preferably about 1 to 50 hours, from the viewpoint of the alcohol yield in hydrogenation (reduction). In this reaction, usually an autoclave or the like can be used.

  In the hydrogenation of the present invention, the ruthenium complex is reacted in the presence or absence of hydrogen, and then the substrate (carboxylic acid compound) can be reacted in the presence of hydrogen. Since a catalytically active species having a high hydrogenation reduction ability is once prepared by the reaction of a ruthenium complex, a hydrogenation reaction product can be efficiently obtained by reacting this with a substrate (carboxylic acid compound). In this case, in any reaction, the conditions can be the same as described above.

  After completion of the reaction, the hydrogenation reaction product (alcohol) can be obtained through the usual isolation and purification steps.

2. Second aspect (new ruthenium complex)
Among the ruthenium complexes used in the manufacturing method of the present invention described above, the general formula (1A-1 ′):

[Wherein, R ¹ is a hydrogen atom, an optionally substituted alkyl group or an optionally substituted aryl group, and R ² and R ³ are the same or different, and each may be an optionally substituted alkyl. Group or an aryl group which may be substituted (however, R ² and R ³ are bonded to each other and do not form a ring with the adjacent —P—Ru—P—). A bond indicated by a solid line and a broken line is a single bond or a double bond. ]
Is a novel compound not described in any literature. As a ruthenium complex (1A-1 '), for example,

Etc.

  This group of compounds can be used as a catalyst for producing an alcohol by hydrogenating a carboxylic acid compound. In particular, it can be used in the production method of the present invention.

  Hereinafter, the novel ruthenium complex of the present invention has, for example, the following reaction formula:

[Wherein, X ^{1 to} X ⁴ are the same or different and are each a halogen atom, and R ^{1 ′ to} R ^{4 ′} are the same or different, and each may be an alkyl group which may be substituted or substituted X ⁵ is the same or different and each is a halogen atom and is the same as any of X ^{1 to} X ⁴ ; R ^{6 ′} is the same or different and each is an alkyl group which may be substituted or substituted And an aryl group which may be substituted, and is the same as R ² and R ^{3 in} the general formula (1A-1 ′). ]
The first step of synthesizing a complex (precursor) having two ruthenium atoms synthesized according to the above, and the second step of reacting the obtained precursor with R ¹ —CO ₂ M (M: alkali metal) be able to.

(1) First Step In the first step, a complex (precursor) having two ruthenium atoms is produced.

The compound represented by RuX ⁵ ₃ used as a raw material is a ruthenium halide. In the formula, each X ⁵ is a halogen atom, and specific examples thereof include those described above. Moreover, X ⁵ is the same as any ^one of X ^{1 to} X ⁴ in the obtained precursor.

As such a ruthenium halide, specifically, RuCl ₃ , RuBr ₃ , RuF ₃ , RuI _{3 and the} like can be used. These may be used as they are, or may be used as hydrates or solvates.

In addition, PR ^{6 '} ₃ used as a ligand is the same as the phosphine ligand Y having the optionally substituted alkyl group or the optionally substituted aryl group described above. R ^{6 ′} is an optionally substituted alkyl group or an optionally substituted aryl group, and is the same as R ² and R ³ in the finally obtained new ruthenium complex (1A-1 ′). It is.

The amount of the ligand PR ^{6 ′} ₃ used is preferably an excess amount relative to the ruthenium halide. Specifically, from the viewpoint of the yield of alcohol by hydrogenation (reduction) of the carboxylic acid compound, ruthenium The amount can be generally 2 to 100 mol, preferably 3 to 50 mol, more preferably 4 to 20 mol, per 1 mol of the halide.

  This reaction can usually be carried out in a solvent. Examples of the solvent include ethers such as diethyl ether, tetrahydrofuran (THF), dioxane, t-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, diglyme and the like; aromatic carbonization such as benzene, toluene, xylene, mesitylene and the like Hydrogen: aliphatic hydrocarbons such as pentane, hexane, heptane, cyclopentane, cyclohexane, octane, nonane, decane, petroleum ether; methanol, ethanol, isopropanol, n-butyl alcohol, tert-butyl alcohol, sec-butyl alcohol, etc. C1-C6 alcohol etc. are mentioned. These solvents may be used alone or in combination of two or more. Among these, aromatic hydrocarbons or C1 to C6 alcohols are preferable, linear C1 to C6 alcohols are more preferable, and methanol, ethanol and the like are particularly preferable.

  The reaction atmosphere is not particularly limited, but is preferably an inert gas atmosphere. Specifically, a nitrogen gas atmosphere, an argon gas atmosphere, or the like may be used.

  The reaction temperature and reaction time may vary depending on the type of ruthenium halide, but from the viewpoint of yield, the reaction temperature is usually about 0 to 190 ° C., preferably about 10 to 170 ° C., more preferably 20 to 160 It can be about ° C. The reaction time is generally about 10 minutes to 50 hours, preferably about 20 minutes to 30 hours, from the viewpoint of yield. An oil bath etc. can usually be used in this reaction.

  After completion of the reaction, the precursor can be obtained through normal isolation. If necessary, a normal purification step may be performed after isolation.

(2) Second Step In the second step, a new ruthenium complex is produced from the precursor obtained in the first step.

R ^{1 -CO} 2 _M: R 1 of (M alkali metal) is a hydrogen atom, an optionally substituted alkyl or optionally substituted aryl group, and specific examples thereof include those described above . Also, R ¹ is the same as R ¹ in the novel ruthenium complex finally obtained. M is an alkali metal, and examples thereof include sodium and potassium.

As R ¹ -CO ₂ M, specifically, sodium formate, potassium formate, sodium acetate, potassium acetate, sodium propanoate, potassium propanoate, sodium butanoate, potassium butanoate, sodium benzoate, sodium benzoate, 3 -Sodium phenylpropionate, potassium 3-phenylpropionate, sodium 4-trifluoromethylbenzoate, potassium 4-trifluoromethylbenzoate, sodium 4-tert-butylbenzoate, potassium 4-tert-butylbenzoate, etc. It can be mentioned.

The amount of R ¹ —CO ₂ M used is preferably excessive with respect to the precursor obtained in the first step. Specifically, the yield of alcohol by hydrogenation (reduction) of the carboxylic acid compound From this viewpoint, it is usually about 2 to 100 mol, preferably about 3 to 50 mol, and more preferably about 10 to 30 mol with respect to 1 mol of the precursor.

  This reaction can usually be carried out in a solvent. Examples of the solvent include ethers such as diethyl ether, tetrahydrofuran (THF), dioxane, t-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, diglyme and the like; aromatic carbonization such as benzene, toluene, xylene, mesitylene and the like Hydrogen: aliphatic hydrocarbons such as pentane, hexane, heptane, cyclopentane, cyclohexane, octane, nonane, decane, petroleum ether; methanol, ethanol, isopropanol, n-butyl alcohol, isobutyl alcohol, tert-butyl alcohol, sec-butyl C1-C6 alcohol, such as alcohol, etc. are mentioned. These solvents may be used alone or in combination of two or more. Among these, C1 to C6 alcohols are preferable, branched alcohols are more preferable, and tert-butyl alcohol and the like are particularly preferable.

  The reaction atmosphere is not particularly limited, but is preferably an inert gas atmosphere. Specifically, a nitrogen gas atmosphere, an argon gas atmosphere, or the like may be used.

  The reaction temperature and reaction time may vary depending on the type of precursor, but from the viewpoint of yield, the reaction temperature is usually about 0 to 150 ° C, preferably about 10 to 130 ° C, more preferably 20 to 90 ° C. The degree can be. From the viewpoint of yield, the reaction time is usually about 10 minutes to 10 hours, preferably about 20 minutes to 2 hours. In this reaction, usually an oil bath or the like can be used.

  After completion of the reaction, the novel ruthenium complex can be obtained through the usual isolation and purification steps.

  Next, the present invention will be described with reference to examples, but the present invention is not limited to the following examples.

Synthesis Example 1: Synthesis of Ruthenium Complex b
(1) Synthesis of ruthenium complex ([P (3,5-xylyl) ₃ ] ₂ ClRu (μ-H ₂ O) (μ-Cl) ₂ RuCl [P (3,5-xylyl) ₃ ] ₂ )

Ruthenium chloride hydrate (RuCl ₃ · nH ₂ O: Ru content 41.91 wt%, 241.7 mg, 1.0 mmol), degassed and purged with argon in a 75 mL Young Stopcock vessel under argon gas atmosphere Of ethanol (20 mL) and a magnetic stir bar. The mixture was stirred at 90 ° C. for 15 minutes and cooled to room temperature. To this reaction mixture was added tri (3,5-xylyl) phosphine (2.08 g, 6.0 mmol) and degassed ethanol (3 mL), and the mixture was heated at 90 ° C. for 19 hours without stirring. Crystals were obtained. The crystals are collected by filtration under argon atmosphere before the mother liquor temperature is cooled to room temperature, washed with degassed chloroform (3 × 20 mL) and degassed diethyl ether (3 × 10 mL), and vacuum By drying with the above, the above ruthenium complex (721.8 mg, 0.41 mmol, yield 83%) was obtained. In addition, ethanol is contained in crystal structure.

The spectrum data of the obtained ruthenium complex were as follows. When ¹ H NMR and ¹³ C NMR of the ruthenium complex were measured at 25 ° C., one set of complex wide peaks was obtained, and thus measurement was performed at 75 ° C. instead.
¹ H NMR (600 MHz, C ₆ D ₆ , 75 ° C) δ 1.93 (bs, 36H, 12CH ₃ ), 2.01 (bs, 36H, 12CH ₃ ), 3.53 (bs, 2H, H ₂ O), 6.66-6.80 (m, 12H, 12Me ₂ C ₆ H ₂ H), 7.38 (bs, 12H, 12Me ₂ C ₆ H ₂ H), 7.58 (bs, 12H, 12Me ₂ C ₆ H ₂ H);
¹³ C NMR (151 MHz, C ₆ D ₆ , 75 ° C.) δ 21.3 (12 C), 21.4 (12 C), 130.0-131.8 (m, 12 C), 132.3-134.8 (m, 24 C), 135.2-137.5 (m, 36C);
³¹ P { ¹ H} NMR (243 MHz, C ₆ D ₆ ) δ 52.2 (d, ² J _PP = 39.5 Hz), 61.2 (d, ² J _PP = 39.5 Hz);
IR (KBr): 3417 (m), 3021 (m), 2993 (m), 2948 (m), 2916 (s), 2859 (m), 1955 (w), 1598 (m), 1582 (m), 1455 (m), 1415 (m), 1375 (w), 1271 (w), 1169 (w), 1131 (s), 1038 (w), 994 (w), 849 (m), 694 (s);
HRMS (ESI, {Ru [P (3,5-xylyl) ₃ ] ₂ Cl} ⁺ ) calcd for C ₄₈ H ₅₄ ClP ₂ Ru ⁺ : 829.2427. Found m / z = 829.2434;
elemental analysis calcd (%) for C ₉₆ H ₁₁₀ Cl ₄ OP ₄ Ru ₂・ C ₂ H ₆ O: C 65.62, H 6.52; found: C 65.69, H 6.45.

(2) Under an argon gas atmosphere ruthenium complex _{b (Ru (OC (CH 3} ) O) 2 [P (3,5-xylyl) 3] 2), in a vessel equipped with Young stopcock 75 mL, the ( The ruthenium complex obtained in 1) (as finely ground as possible, 174.4 mg, 0.10 mmol), sodium acetate (163.3 mg, 2.0 mmol), and degassed, argon-purged tert-butyl alcohol (25 mL), and A magnetic stirrer was housed. The mixture was stirred at 90 ° C. for 2 hours and cooled to room temperature. The mixture was filtered through a Celite® pad to remove white residue and washed with a small amount of tert-butyl alcohol under an argon gas atmosphere. The solution was concentrated under reduced pressure until an orange precipitate formed. The slurry was stirred and heated at 90 ° C. using an oil bath until the orange precipitate was dissolved again, and then heating of the oil was stopped to obtain orange crystals. After 14 hours, orange crystals were collected by filtration, washed with water and tert-butyl alcohol, and dried under vacuum to obtain the above ruthenium complex b (90.1 mg, 0.099 mmol, yield 49%).

The spectrum data of the obtained ruthenium complex b were as follows.
¹ H NMR (600 MHz, CDCl ₃ ) δ 1.42 (s, 6 H, 2 CH ₃ COO), 2. 11 (s, 36 H, 6 (CH ₃ ) 2 Ph), 6. 80-6. 89 (m, 18 H, ₆ Me ₂ C ₆ H ₃ );
¹³ C NMR (151 MHz, CDCl ₃ ) δ 21.3 (12C), 23.3 (2C), 130.4 (6C), 132.1 (t, ² J _PC = 4.34 Hz, 12C), 134.9-135.7 (m, 6C), 136.2 (t, ³ J _PC = 4.33 Hz, 12 C), 187.7 (2 C);
³¹ P { ¹ H} NMR (243 MHz, CDCl ₃ ) δ 62.9;
HRMS (ESI, {Ru [P (3,5-xylyl) ₃ ] ₂ (OAc) (CH ₃ CN)} ⁺ ) calcd for C ₅₂ H ₆₀ NO ₂ P ₂ Ru ⁺ : 894.3137. Found m / z = 894.3158 ;
IR (KBr): 3447 (w), 3023 (w), 2992 (w), 2947 (w), 2916 (m), 2858 (w), 1599 (w), 1583 (w), 1517 (m, κ) ² -OCO _asym ), ^6,7 1458 (s, κ ² -OCO _sym ), ^6,7 1414 (m), 1376 (w), 1129 (s), 1038 (w), 943 (w), 848 ( m), 691 (s);
elemental analysis calcd (%) for C ₅₂ H ₆₀ O ₄ P ₂ Ru: C 68.48, H 6.63; found: C 68.15, H 6.61.

Example 1

  Reduction (hydrogenation) of 3-phenylpropionic acid was performed by the following method.

In a glass tube, 3-phenylpropionic acid (150.2 mg, 1.0 mmol), the ruthenium complex b (18.2 mg, 0.020 mmol) obtained in Synthesis Example 1, and a magnetic stirrer were housed. The glass tube was inserted into the autoclave, the autoclave was closed tightly, evaporated under vacuum and filled with argon gas. While argon gas was kept flowing, dehydrated toluene (3.0 mL) was added to the mixture, and the inside of the autoclave was purged several times with hydrogen gas (P _H2 = 1.5 MPa). The autoclave was pressurized with hydrogen gas (P _H2 = 1 MPa) at 25 ° C. and heated at 160 ° C. for 24 hours with stirring (1000 rpm). The autoclave was cooled to 0 ° C. in an ice water bath. The reaction mixture was transferred with chloroform to a 100 mL round bottom flask and concentrated under reduced pressure (about 35 mmHg, 40 ° C.). The residue was diluted with CDCl3 and analyzed by ¹ H NMR. The yields of 3-phenylpropyl alcohol and 1- (3-phenylpropyl) 3-phenylpropionate (35% and 18%, respectively) are based on the integral ratio between the signals of these compounds relative to the internal standard (mesitylene). Calculated.

  The result of Example 1 corresponds to entry 5 in Table 1 described later.

Example 2
In Example 1 above, with respect to the ruthenium complex, additive, solvent, and hydrogenation conditions (hydrogen pressure and reaction time), 3 mol% of the ruthenium complex was added, and the conditions described in Table 1 were adopted otherwise. The reduction (hydrogenation) was carried out in the same manner as in Example 1. In addition, the raw materials other than the ruthenium complex b synthesize | combined by the synthesis example 1 used what was synthesize | combined by the commercial item or the well-known method. The results are shown in Table 1.

Example 3
Example 1 except that the conditions described in Table 2 were employed for the substrate (carboxylic acid), ruthenium complex, additive, solvent, and hydrogenation conditions (hydrogen pressure and reaction time) in Example 1 above. The reduction (hydrogenation) was performed in the same manner as in. The results are shown in Table 2. Note that entry 1 in Table 2 corresponds to entry 13 in Table 1, entry 2 in Table 2 corresponds to entry 4 in Table 1, entry 3 in Table 2 corresponds to entry 1 in Table 1, and Entry 4 corresponds to entry 2 in Table 1.

Claims (5)

A method for producing an alcohol by hydrogenating a carboxylic acid compound,
A step of hydrogenating a carboxylic acid compound in the presence of a ruthenium complex in a hydrogen atmosphere, wherein the ruthenium complex has the general formula (1A-1):

[Wherein, R ¹ represents a hydrogen atom, an alkyl group which may be substituted or an aryl group which may be substituted, and R ² and R ³ may be the same or different and each may be an alkyl which may be substituted] A group or an aryl group which may be substituted, and one R ² and one R ³ may be bonded to each other to form a ring together with adjacent —P—Ru—P—. A bond indicated by a solid line and a broken line is a single bond or a double bond. ]
It is a compound shown by these, The manufacturing method. Said R ² And R ³ The production method according to claim 1, wherein is the same or different and each is an optionally substituted aryl group. General formula (1A-1 '):

[Wherein, R ¹ represents a hydrogen atom, an alkyl group which may be substituted or an aryl group which may be substituted, and R ² and R ³ may be the same or different and each may be an alkyl which may be substituted] Or an aryl group which may be substituted (provided that R ² and R ³ are not bonded to each other and form a ring together with the adjacent —P—Ru—P—). A bond indicated by a solid line and a broken line is a single bond or a double bond. ]
A catalyst for producing an alcohol by hydrogenating a carboxylic acid compound, which contains a ruthenium complex represented by the formula: Said R ² And R ³ The catalyst according to claim 3, wherein is the same or different and each is an optionally substituted aryl group.   General formula (1A-1 '):

[In the formula, R ¹ Is a hydrogen atom, an optionally substituted alkyl group or an optionally substituted aryl group, and R ² And R ³ Are the same or different and are toluyl, xylyl or mesityl, respectively (where R is ² And R ³ And do not form a ring with the adjacent -P-Ru-P-). A bond indicated by a solid line and a broken line is a single bond or a double bond. ]
Ruthenium complex shown by.