JP4786876B2 - Method for producing alkynes - Google Patents

Description

  The present invention relates to a catalyst system useful for a coupling reaction (such as Sonogashira coupling reaction) between an alkyne having a methine group (CH≡) and an organic compound having a leaving group, and a cup using this catalyst system. The present invention relates to a method for producing a ring compound (alkynes having a triple bond at a non-terminal position). In particular, the present invention relates to a method for easily producing alkynes without using any of a copper compound, an amine, or an ammonium compound.

  So far, in the field of organic synthesis, the use of conjugated alkynes such as arylacetylenes as raw materials for the production of functional materials or intermediates thereof has been studied. However, there have been few reported methods for producing conjugated alkynes so far, and only a Sonogashira coupling reaction using a transition metal catalyst has been known. In the Sonogashira coupling reaction, a copper compound is usually used as a cocatalyst in addition to a palladium catalyst, and a base such as an amine is often used as a neutralizing agent for neutralizing the acid produced. Although copper compounds and amines are necessary for the reaction to proceed efficiently, side reactions are likely to occur when copper compounds are used, and when amines are used for neutralization, the substrate is limited and the amount of solvent Of amine is required.

For reactions that do not use amines, see Chem. Lett. , 2002, 31, 756-757 (Non-patent Document 1) include a Pd (OAc) ₂ (PPh ₃ ) catalyst, 2 mol% copper iodide, and 2 equivalents of aqueous ammonia in the presence of an aryl halide and a terminal group. A method of reacting an alkyne with tetrahydrofuran (THF) at room temperature is disclosed.

Regarding the reaction not using a copper compound, Org. Lett. , 2003, 5, 4191-4194 (Non-patent Document 2) include arylacetylene and alkylacetylene in the presence of a palladium complex obtained from (allyl PdCl) ₂ and P (t-butyl), and aryl bromide. Sonogashira coupling reaction is disclosed. In Non-Patent Document 2, the coupling reaction is performed in the presence of a base such as a primary to tertiary amine (butylamine, piperidine, DABCO, etc.) or cesium carbonate.

  Tetrahedron Letters, 43 (2002), 9365-9368 (Non-patent Document 3) discloses a Sonogashira coupling reaction between phenylacetylene and 4-chlorophenyl bromide in an N-methylpyrrolidinone solvent in the presence of an oxime complex of palladium. It is disclosed that the process proceeds. In the coupling reaction, a base such as sodium acetate or ammonium acetate, or a tetrabutylammonium salt (such as tetrabutylammonium acetate) as an additive is used.

  JP-A-2003-260365 (Patent Document 1) is composed of a transition metal compound and a ligand having a coordinating group and an organic group having a negative charge or an organic group capable of generating a negative charge. In addition, a method for producing a coupling compound by coupling a reaction between an organic compound having a leaving group and a reactive agent (an unsaturated compound such as an alkene or alkyne) in the presence of a coupling reaction catalyst is disclosed. Patent Document 1 discloses a base (an organic base such as an amine; an alkali metal or alkaline earth metal hydroxide and carbonate, an alkali metal organic carboxylate, etc.) for removing a deoxidizing component from the reaction system. Is disclosed.

However, when copper compounds, amines, ammonium compounds, etc. are used as in the conventional method, these compounds are mixed in the waste liquid, and the burden on the environment is great. In addition, when removing copper salts and amines from the waste liquid, Further, the post-processing process becomes complicated and the cost burden is large. Against this background, development of an environmentally friendly, simple and economically advantageous production method is expected as a method for producing alkynes (such as conjugated alkynes) in the field of organic synthesis.
Chem. Lett. , 2002, 31, 756-757 Org. Lett. , 2003, 5, 4191-4194 Tetrahedron Letters, 43 (2002), 9365-9368 JP 2003-260365 A (Claims 1 and 9, paragraph number [0031])

  Accordingly, an object of the present invention is to provide a coupling reaction catalyst system and a production method that can easily and efficiently produce alkynes (alkynes having a triple bond at a non-terminal position) and are economically advantageous. .

  As a result of intensive studies to achieve the above-mentioned problems, the present inventors have found that substrate alkynes having a methine group (CH≡) at the terminal (hereinafter sometimes simply referred to as terminal alkynes) and an organic compound having a leaving group, When the coupling reaction (Soto coupling reaction) is carried out in the presence of a catalyst system containing at least a transition metal element and an inorganic salt, the copper compound, the amine, or the ammonium compound is not particularly used in combination. The inventors found that alkynes (alkynes having a triple bond at a non-terminal position) can be produced, and completed the present invention.

  That is, the coupling reaction catalyst system of the present invention is a catalyst system for use in a coupling reaction between an alkyne having a methine group (CH≡) and an organic compound having a leaving group, and at least a transition metal. Contains elements and inorganic salts.

  The first coupling reaction catalyst system of the present invention contains at least a transition metal element and an inorganic salt (except for an ammonium salt and cesium carbonate). The catalyst system may further contain a ligand (such as a phosphine ligand). For example, the ratio of the ligand may be about 0.01 to 20 moles with respect to 1 mole of the transition metal element, and the ratio of the inorganic salt may be about 10 to 2000 moles, for example. The transition metal element may be at least one selected from Group 3A to Group 7A and Group 8 metal elements (such as at least one platinum group metal element selected from nickel, palladium, and platinum). The catalyst system is composed of a periodic table Group 8 metal compound, a phosphine-based ligand, and a metal inorganic acid salt, and the metal element constituting the metal inorganic acid salt is composed of lithium, sodium, and potassium. It may be at least one selected alkali metal. The first coupling reaction catalyst system contains at least a transition metal element and an inorganic salt (except for an ammonium salt, an alkali or alkaline earth metal carbonate, and an alkali metal salt of an organic carboxylic acid). It may be a reaction catalyst system.

  The second coupling reaction catalyst system of the present invention contains a transition metal element, at least one ligand selected from triarylphosphine and iminophosphine compounds, and an inorganic salt.

  The present invention provides a method for subjecting an alkyne having a methine group (CH≡) to a terminal and an organic compound having a leaving group to a coupling reaction, the first coupling reaction catalyst system or the first A method for producing alkynes in which the coupling reaction is carried out in the presence of the coupling reaction catalyst 2 is also included. The coupling reaction may be performed in the presence of an aprotic polar solvent.

  The leaving group may be at least one selected from a halogen atom, a sulfonyloxy group or a sulfonyl halide group, a diazonium group, and a carbonyl halide group. The ratio (molar ratio) between the alkynes having a methine group at the end and the organic compound may be about the former / the latter = 1/2 to 2/1 mol, and 0.5% relative to 1 mol of the organic compound. Inorganic salts may be used at a ratio of ˜2 mol.

  In the present invention, since the coupling reaction (Sonogashira coupling reaction) is performed in the presence of a specific coupling reaction catalyst system, the coupling reaction product can be used without particularly using a copper compound, an amine, or an ammonium compound. (Alkynes having a triple bond at the non-terminal position) can be easily and efficiently produced. Moreover, since it is not necessary to use a copper compound or amines, the post-treatment process can be simplified even at an industrial level, which is economically advantageous.

[Coupling reaction catalyst system]
The coupling reaction catalyst system of the present invention is a catalyst system for use in a coupling reaction between an alkyne having a methine group (CH≡) and an organic compound having a leaving group, and at least a transition metal element and Contains inorganic salts. The coupling reaction catalyst may contain a ligand as necessary. The transition metal element usually constitutes a transition metal catalyst.

(A) Transition metal catalyst Examples of the transition metal element constituting the transition metal catalyst include, for example, Group 3A elements of the periodic table (Sc, Y and rare earth elements), Group 4A elements of the periodic table (Ti, Zr, Hf), and period Table Group 5A elements (V, Nb, Ta), Periodic Table Group 6A elements (Cr, Mo, W), Periodic Table Group 7A elements (Mn, Tc, Re), Periodic Table Group 8 elements (Fe, (Ru, Os, Co, Rh, Ir, Ni, Pd, Pt) and periodic table Group 1B elements (Cu, Ag, Au).

  Among these transition metal elements, at least one selected from Group 3A elements of the periodic table to Group 7A elements of the periodic table and Group 8 elements of the periodic table, in particular, Group 8 elements of the periodic table (iron, ruthenium, osmium, cobalt, rhodium) And at least one element selected from iridium, nickel, palladium, platinum). Further preferable transition metal elements are classified as group 10 elements in the periodic table of platinum group metal elements [nickel, palladium and platinum (IUPAC Inorganic Chemical Nomenclature Revision (1989)] among Group 8 elements of the Periodic Table. Element)], in particular palladium.

  The oxidation number of the transition metal element is not particularly limited, and may be, for example, 0, +1, +2, +3, +4, etc., depending on the type of element.

  The transition metal compound may be a single metal, but is usually a compound containing a transition metal element. Transition metal element compounds include, for example, inorganic acid salts (for example, nitrates, sulfates, phosphoric acids, perhalogenates, hydrohalides such as hydrochloric acid, hydrobromic acid, etc.), organic acid salts ( For example, sulfonic acid salts such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, carboxylic acid salts such as phosphonate, formic acid, acetic acid, propionic acid, and the like (eg, chloride) , Bromide, iodide, etc.), complexes (or complex salts) and the like. Further, the transition metal compound (or transition metal catalyst) may be a solid catalyst in which these metal compounds are fixed to a carrier (a carrier such as activated carbon, silica, alumina, titania). Furthermore, metal oxides such as iron oxide, cobalt oxide, and nickel oxide may be used.

Ligands constituting the complexes are, for example, OH (hydroxo), C _1-4 alkoxy, C _l-4 acyl, C _1-4 alkoxy - carbonyl group, acetylacetonato, cycloalkadiene (cyclopenta Dienyl group, cyclooctadienyl group, cyclooctadiene, etc.), benzylidene group, benzylideneacetone, benzylideneacetylacetonato, benzylideneacetophenone, halogen atom, CO, CN, oxygen atom, H ₂ O (aco), phosphine (for example, , Triphenylphosphine such as triphenylphosphine), phosphite (eg triarylphosphite such as triphenylphosphite), NH ₃ (ammine), NO, NO ₂ (nitro), NO ₃ (nitrato), nitrogen-containing Compound (ethylenediamine, diethylenetriamine, pyridine Phenanthroline, bipyridyl, etc.) and the like. In the complex or complex salt, one or two or more of the same or different ligands may be coordinated.

  Transition metal compounds are often used as inorganic acid salts, organic acid salts, halides, and complexes which may be complex salts. More specifically, examples of the complex or complex salt include palladium complexes or complex salts such as palladium acetate (II), palladium (II) acetylacetonate, tris (dibenzylideneacetone) dipalladium (0), and the like. Among the Group 8 metal sources in the periodic table, compounds of Group 8 metal elements, particularly complexes or complex salts, can be exemplified.

  A transition metal compound can be used individually or in combination of 2 or more types.

(B) Ligand The ligand (B) constituting the coupling reaction catalyst system usually has a coordinating group (or a coordinable site) for the transition metal catalyst (transition metal compound, etc.). ing. Such a ligand can be used individually or in combination of 2 or more types. In addition, the ligand may exist in the reaction system in a free form with respect to the transition metal catalyst, or may exist in the reaction system as a complex coordinated with the transition metal catalyst. Further, the ligand may be a chelate ligand.

The coordinating group is not particularly limited as long as it can coordinate to the transition metal catalyst. For example, an atom or an organic group corresponding to the ligand of the complex or complex salt, such as a hydroxyl group, C _{1 -4} alkoxy, C _l-4 acyl, C _1-4 alkoxy - carbonyl group, acetylacetonato groups, benzylidene acetylacetonato group, cycloalkadienyl group (a cyclopentadienyl group, cyclooctadienyl group such as ), Benzylidene group, halogen atom, cyano group, nitro group, amino group or substituted amino group (C _1-6 alkylamino group such as dimethylamino, diethylamino, dibutylamino group), nitrogen-containing heterocyclic group (at least one nitrogen) 5- or 6-membered heterocyclic group containing an atom as a hetero atom, for example, 5-membered ring group such as pyrrolyl group and imidazolyl group, pyridyl group, bipyridyl Group, 6-membered ring group such as pyrazinyl group and pyrimidinyl group, condensed heterocyclic group such as phenanthrolinyl group, etc.), phosphino group (for example, methylphosphino, dimethylphosphino, diethylphosphino, dibutylphosphino group, etc.) C _1-6 alkyl phosphino group; mono C _1-6 alkyl-mono C _6-12 aryl phosphino group such as methylphenyl phosphino, butylphenyl phosphino group; phenyl phosphino, diphenyl phosphino, ditolyl phosphino group A C _6-12 arylphosphino group such as a fino group; an aralkylphosphino group such as a benzylphosphino group or a dibenzylphosphino group (such as a C _6-10 aryl-C _1-4 alkylphosphino group); Mono C _1-6 alkyl-mono (C _6-10 aryl-C _1-4 alkyl) corresponding to _1-6 alkyl-mono C _6-12 arylphosphino group ) Phosphino groups and mono (C _6-10 aryl-C _1-4 alkyl) -mono C _6-12 aryl phosphino groups, etc.), arsino groups, stibino groups corresponding to these phosphino groups, Examples thereof include a bismuthino group.

  The preferred coordinating group is usually at least one element selected from Group 5B elements of the periodic table, for example, nitrogen atom, phosphorus atom, arsenic, antimony, bismuth, particularly nitrogen atom and phosphorus atom. It is composed of elements. Examples of such a coordinating group include the cyano group, nitro group, phosphino group, arsino group, stibino group, bismuthino group and the like corresponding to these phosphino groups.

  The ligand may be a non-aromatic compound (such as an aliphatic compound or an alicyclic compound) or an aromatic compound. The aromatic compound may be a hydrocarbon cyclic aromatic compound, which is a heterocyclic aromatic compound having at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom as a constituent atom of the ring. There may be. The ligand is usually a non-aromatic compound or aromatic compound having the coordinating group.

The aromatic ring constituting the aromatic compound includes at least one heteroatom selected from a C _6-12 arene ring such as a benzene ring and a naphthalene ring, a nitrogen atom, an oxygen atom and a sulfur atom. Examples thereof include a 5- or 6-membered heterocyclic ring as an atom, a condensed heterocyclic ring of an aromatic or non-aromatic 5- or 6-membered heterocyclic ring and a hydrocarbon ring (such as a benzene ring). Examples of the heterocyclic ring constituting the aromatic compound include a sulfur-containing heterocyclic ring such as thiophene, an oxygen-containing heterocyclic ring such as furan and benzofuran, pyrrole, imidazole, pyridine, pyrazine, pyrimidine, indole, quinoline, carbazole, and acridine. And nitrogen-containing heterocycles such as phenazine and phenanthroline. Examples of the aliphatic compound include aliphatic hydrocarbons such as alkanes (linear or branched C _1-10 alkanes such as methane, ethane, propane, butane, and isobutane). Examples of the alicyclic compounds, (such as C _5-8 cycloalkane such as cyclohexane) cycloalkanes, such as alicyclic hydrocarbons such as cycloalkenes (such as C _5-8 cycloalkene such as cyclohexene) can be exemplified.

The ligand may have a substituent other than the coordinating group. Such substituents include alkyl groups (such as C _1-4 alkyl groups such as methyl groups), hydroxyl groups, alcoholates (oxides) corresponding to hydroxyl groups, mercapto groups, and thiolates (sulfides) corresponding to these mercapto groups. Nitro group, amino group or N-substituted amino group (N-monosubstituted or N, N-disubstituted amino group, for example, alkylamino group such as methylamino and dimethylamino group, arylamino group such as phenylamino group, etc. ), Imino group or substituted imino group [alkylimino group such as methylimino group; cycloalkylimino group; arylimino group such as phenylimino group; aralkylimino group such as benzylimino or phenethylimino group], the imino group or the substituent An iminoalkyl group or a substituted iminoalkyl group corresponding to the imino group, A cyano group, an organic group (such as an acylamide group) capable of generating a negative charge (anion), an alkyl group (such as a linear or branched C _1-4 alkyl group such as a methyl or ethyl group), a halogen atom (F, Cl, Br, I atom, etc.). The ligand may have these substituents alone or in combination of two or more. In addition, the ligand usually has the substituent on the aromatic ring or heterocyclic ring. Of the above substituents, a nitro group, an imino group or a substituted imino group, an iminoalkyl group, a substituted iminoalkyl group, a cyano group, an alkyl group, a halogen atom and the like are preferable.

The ligand (B) will be described by taking a phosphino group as an example of a coordinating group. For example, triarylphosphines ( _triC6-10 aryl such as triphenylphosphine, tolylphosphine, hydroxyphenyldiphenylphosphine, etc.) phosphine, etc.), diaryl alkyl phosphines (diphenylmethyl phosphine, such as di-C _6-10 aryl C _1-10 alkyl phosphines, such as diphenyl ethyl phosphine), C _6-10 aryldi C, such as aryl dialkylphosphinic (phenyldi t- butylphosphine _1-10 and alkyl phosphine), tri C _1-10 alkyl phosphines such as trialkylphosphine (tri t- butylphosphine), imino phosphine compound [Place the imino group or a substituted imino group or iminoalkyl group or a substituted iminoalkyl group Phosphines having the group (alkyl phosphine, cycloalkyl phosphine, aryl phosphine, an aralkyl phosphine) and the like.

  The iminophosphine compound can be represented by the following formula, for example.

R ^a −N = R ^b −Y
(In the formula, R ^a represents a hydrogen atom or a hydrocarbon group, and the group Y—R ^b = represents a phosphinoalkylidene group or a phosphinoarylalkylidene group)
Examples of the hydrocarbon group represented by ^Ra include a saturated or unsaturated hydrocarbon group, for example, an aliphatic hydrocarbon group (a linear or branched alkyl group such as a methyl or ethyl group (C _1-6 alkyl group etc.); Linear or branched alkenyl groups such as propenyl groups (such as C _2-6 alkenyl groups), alicyclic hydrocarbon groups (C _5-8 cycloalkyl groups such as cyclohexyl groups; C _5-8 such as cyclohexenyl groups) Cycloalkenyl groups, etc.), aromatic hydrocarbon groups (C _6-10 aryl groups such as phenyl groups; aralkyl groups such as benzyl and phenethyl groups (C _6-10 aryl-C _1-4 alkyl groups, etc.)), etc. Can be mentioned.

These hydrocarbon groups include substituents such as hydroxyl groups, alkoxy groups (such as methoxy groups), alkyl groups (such as C _1-4 alkyl groups such as methyl groups), halogen atoms (F, Cl, Br, I atoms). Etc.). The number of substituents is not particularly limited, and may be one or plural.

In the above formula, the phosphino group (—Y) constituting the phosphinoalkylidene group or phosphinoarylalkylidene group Y—R ^b ═ corresponds to the phosphino group exemplified above. Examples of the phosphinoalkylidene group include C _1-6 alkylidene groups such as an ethylidene group having the phosphino group exemplified above, and examples of the phosphinoarylalkylidene group include an arylalkylidene group having a phosphino group exemplified above (benzylidene group). Group, C _6-10 aryl-C _1-4 alkylidene group such as phenylethylidene group) and the like.

As a specific example of the iminophosphine compound, the case where the group Y—R ^b ═ is an arylalkylidene group will be described as an example. For example, N- [2- (diphenylphosphino) benzylidene] -2-phenylethylamine N- (di-C _6-10 aryl phosphino -C _6-10 aryl C _1-4 alkylidene) -C _6-10 aryl -C _1-4 alkyl amine; N- [2- (diphenylphosphino) benzylidene] - such as aniline N- (di C _6-10 aryl phosphino -C _6-10 aryl C _1-4 alkylidene) -C _6-10 aryl amine; N- [2- (diphenylphosphino) benzylidene]-tert-butylamine such as N- (di C _6-10 aryl phosphino -C _6-10 aryl C _1-4 alkylidene) - straight or branched C _1-6 aryl phosphino group such as an alkyl amine (the illustration of a Alkylphosphino group-containing compounds corresponding to these compounds, aralkyl phosphino group-containing compounds, monoalkylmonoarylphosphino group-containing compounds, monoalkylmonoaralkyl group-containing compounds, and And monoaralkyl monoarylphosphino group-containing compounds.

  The ligand may be a compound having the other coordinating group (for example, a coordinating group having a nitrogen atom such as a cyano group or a nitro group) instead of the phosphino group. Among the ligands, a phosphine-based ligand, for example, a ligand having a phosphino group as a coordinating group such as the triarylphosphine, diarylphosphine, and iminophosphine compound is preferable.

  The amount of the ligand (B) used is not particularly limited, and can be selected from a wide range of about 0 to 50 mol per 1 mol of the transition metal catalyst (A) (particularly a transition metal element), preferably It is about 0.01 to 20 mol, more preferably about 0.1 to 10 mol, and usually about 0.5 to 5 mol (for example, 1 to 5 mol) in many cases.

(C) Inorganic salt The inorganic salt constituting the coupling reaction catalyst system may be an ammonium salt or an organic carboxylic acid metal salt (such as an organic carboxylic acid alkali metal salt such as sodium acetate). Inorganic acids can be used. Inorganic acids constituting the metal inorganic acid salt include nitric acid, nitrous acid, sulfuric acid, sulfurous acid, phosphoric acid (such as orthophosphoric acid, metaphosphoric acid, polyphosphoric acid), halogen acids (halogen acids such as chloric acid and bromic acid; perchlorine Perhalogen acids such as acids), carbonic acid and the like.

  The metal constituting the metal inorganic acid salt may be the transition metal exemplified above, but usually alkali metal (Li, Na, K etc.), alkaline earth metal (Mg, Ca etc.), etc. Can be mentioned. The inorganic salt may contain the metal alone or a double salt containing two or more metals. Of these metals, at least one alkali metal selected from lithium, sodium and potassium is preferred.

  Preferred inorganic salts include alkali metal or alkaline earth metal salts of phosphoric acid (alkali metal salts such as potassium phosphate, alkaline earth metal salts such as calcium phosphate), alkali metal carbonates or alkaline earth metal salts (carbonic acid carbonates). Alkali metal salts such as potassium, alkaline earth metal salts such as calcium carbonate, etc.), in particular, alkali metal phosphates or carbonates are preferred.

  The ratio of the inorganic salt with respect to the transition metal catalyst is not particularly limited, and is, for example, 10 to 2000 mol, preferably 15 to 1500 mol, and more preferably 20 to 1000 mol (for example, 20 to 1000 mol) with respect to 1 mol of the transition metal element. It may be about 500 mol).

  The coupling reaction catalyst system of the present invention includes the following first and second coupling reaction catalyst systems.

(1) First coupling reaction catalyst system The first coupling reaction catalyst system (hereinafter sometimes referred to simply as the first catalyst system) includes at least a transition metal element and an inorganic salt (however, an ammonium salt, And cesium carbonate). Such a first catalyst system is a catalyst system containing at least a transition metal element and an inorganic salt (excluding alkali or alkaline earth metal carbonates and alkali metal salts of organic carboxylic acids). Also good. The first catalyst system may further contain a ligand (a ligand exemplified in the section of the ligand (B), for example, a phosphine-based ligand) if necessary.

  In the first catalyst system, the transition metal element constitutes a transition metal catalyst and may be a copper element, and the metal elements exemplified in the section of the transition metal element can be used. Among these transition metal elements, at least one selected from non-copper transition metal elements, particularly Group 3A-7A and Group 8 metal elements of the periodic table (particularly, Group 8 metal elements such as platinum group metal elements). These transition metal elements are preferred.

  Examples of the inorganic salt include inorganic salts other than ammonium salts (or ammonium salts and organic carboxylic acid alkali metal salts), such as metal inorganic acid salts (for example, potassium sulfate, calcium sulfate) among the above-mentioned metal inorganic acid salts. And alkali or alkaline earth metal sulfates such as nitrates, phosphates and carbonates (excluding cesium carbonate) corresponding to the sulfates. Of these metal inorganic acid salts, alkali metal or alkaline earth metal salts of phosphoric acid and alkali metal or alkaline earth metal salts of carbonic acid, particularly phosphates are preferred.

  In addition, the metal inorganic acid salt may be a metal inorganic acid salt (for example, phosphate) excluding alkali metal or alkaline earth metal carbonate.

(2) Second coupling reaction catalyst system The second coupling reaction catalyst system (hereinafter sometimes simply referred to as the second catalyst system) is selected from transition metal elements, triarylphosphine and iminophosphine compounds. Containing at least one ligand and an inorganic salt.

  In the second catalyst system, the transition metal element constitutes a transition metal catalyst and may be a copper element, and the metal elements exemplified in the section of the transition metal element can be used. Among these transition metal elements, similarly to the first catalyst system, non-copper-based transition metal elements, particularly Group 3A-7A and Group 8 metal elements of the periodic table (in particular, 8th group such as platinum group metal elements). At least one transition metal element selected from group metal elements) is preferred.

Examples of the triarylphosphine and iminophosphine compound include the triarylphosphine (such as _{triC 6-10} arylphosphine) and the iminophosphine compound exemplified in the section of the ligand (B) [for example, N- (diC _6-10 aryl phosphino -C _6-10 aryl C _1-4 alkylidene) -C _6-10 aryl -C _1-4 alkyl amine, N- (di-C _6-10 aryl phosphino -C _6-10 aryl C _1-4 alkylidene) -C _6-10 arylamine, N- (di-C _6-10 arylphosphino-C _6-10 aryl C _1-4 alkylidene) -straight or branched C _1-6 alkylamine etc.] Can be mentioned. The triarylphosphine and iminophosphine compounds may have the substituents exemplified in the section of the ligand (B) (for example, on the aryl group). The aryl group constituting the triarylphosphine may be unsubstituted.

  In the second catalyst system, the inorganic salt is not particularly limited and may be an ammonium salt (tetraalkylammonium halide such as tetrabutylammonium fluoride; a hydroxide or acetate corresponding to the halide) or an organic carboxylic acid metal salt. (Organic carbonates of organic carboxylic acids exemplified above), in particular, metal inorganic acid salts (in addition to the metal inorganic acid salts exemplified in the section of the first catalyst system, sodium carbonate, calcium carbonate, etc. Alkali metal or alkaline earth metal carbonate, etc.) can be used. Of these inorganic salts, metal inorganic acid salts, particularly phosphates and carbonates are preferred.

[Method for producing coupling compound]
In the present invention, alkynes (alkynes as substrates) having a methine group (CH≡) in the presence of the coupling reaction catalyst system (first or second catalyst system) R ¹ —C≡CH ( Terminal alkynes) and an organic compound R ² -L having a leaving group are subjected to a coupling reaction, and alkynes (that is, alkynes having a triple bond at a non-terminal position R ¹ —C≡C—R ² ) Manufacturing.

(Alkynes as substrates)
The substrate alkyne is not particularly limited as long as it has a methine group (CH≡) at the end of the molecule, and can be represented by the formula R ¹ —C≡CH (wherein R ¹ represents an organic group).

In the above formula, examples of the organic group represented by R ¹ include an aliphatic, alicyclic or aromatic hydrocarbon group. These hydrocarbon groups may have an unsaturated bond such as a double bond or a triple bond in the molecule, and a hetero atom (such as O, N, S, P, Sn, B and / or Si atom). You may have. The hydrocarbon group may have a substituent.

  Examples of the hydrocarbon group include an aliphatic hydrocarbon group (alkyl group, alkenyl group, etc.), an alicyclic hydrocarbon group (cycloalkyl group, cycloalkenyl group, cycloalkadienyl group, cycloalkylalkyl group, cycloalkenyl group). Alkyl group, cycloalkadienyl alkyl group, etc.), aryl group, aralkyl group and the like.

Examples of the aliphatic hydrocarbon group include alkyl groups (such as C _1-20 alkyl groups such as methyl, ethyl, propyl, butyl, and t-butyl groups), alkenyl groups (such as vinyl, propenyl, allyl, and butenyl groups). C _2-20 alkenyl group and the like.

Examples of the alicyclic hydrocarbon group include cycloalkyl groups (such as C _5-10 cycloalkyl groups such as cyclohexyl and cyclooctyl groups), cycloalkenyl groups (such as C _5-10 cycloalkenyl groups such as cyclohexenyl groups), Cycloalkadienyl groups (such as C _6-10 cycloalkadienyl groups such as cyclohexedienyl group), cycloalkylalkyl groups (such as C _5-10 cycloalkyl C _1-4 alkyl groups such as cyclohexylmethyl group), cyclo Alkenylalkyl groups (C _5-10 cycloalkenyl C _1-4 alkyl groups such as cyclohexenylmethyl group), cycloalkadienyl alkyl groups (C _6-10 cycloalkadienyl C _1- such as cyclohexadienylmethyl group) ₄ alkyl group).

Examples of the aromatic hydrocarbon group include aryl groups (C _6-10 aryl groups such as phenyl and naphthyl groups) and aralkyl groups (C _6-10 aryl C _1-4 alkyl groups such as benzyl and phenethyl groups). included.

Examples of the hydrocarbon group substituent which may have a halogen atom (fluorine, chlorine, bromine, iodine), alkyl group (methyl, ethyl, propyl, above exemplified C _1-20 alkyl, such as butyl Groups, preferably C _1-10 alkyl groups, in particular C _1-6 alkyl groups), haloalkyl groups corresponding to these alkyl groups (eg trichloromethyl group, trifluoromethyl group, perfluoroethyl group, perfluoropropyl group) Halo C _1-6 alkyl group and the like), cycloalkyl group (C _5-10 cycloalkyl group exemplified above, particularly C _5-8 cycloalkyl group), alkenyl group (C _2-10 alkenyl group exemplified above, in particular C _2-6 alkenyl group), C _6-10 aryl groups the aryl group (the illustration), C _6-10 aryl -C _1-4 alkyl group aralkyl group (the illustration), a hydroxyl group, alkoxycarbonyl Shea group (methoxy, ethoxy, C _1-6 alkoxy group such as butoxy group), (such as phenoxy group) an aryloxy group, an oxo group (or a group), an acyl group (acetyl, aliphatic, such as propionyl group C _{1- 6} Aromatic acyl groups such as acyl groups and benzoyl groups), carboxyl groups, alkoxycarbonyl groups (C _1-6 alkoxy-carbonyl groups such as methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl groups), aryloxycarbonyl groups (phenoxycarbonyl) Groups), amino groups, N-substituted amino groups (N-mono C _1-4 alkylamino groups such as methylamino and butylamino groups, N, N-diC _1- such as dimethylamino, diethylamino and dibutylamino groups) ₄ alkylamino group, etc. acylamino group such as acetylamino group), a nitro group, shea Etc. groups can be exemplified. The substituent of the hydrocarbon group is usually a group different from the hydrocarbon group. For example, when the hydrocarbon group is an aromatic hydrocarbon group, the aromatic ring contains a halogen atom. , An alkyl group, a haloalkyl group, an alkenyl group, a hydroxyl group, an alkoxy group, a carboxyl group, an alkoxycarbonyl group, an amino group and the like may be substituted.

Examples of the acetylene compounds (acetylenes) include α-C _2-20 acetylenes (acetylene, methylacetylene, 1-butyne, 3-methyl-1-butyne, 3,3-dimethyl-1-butyne, 1- C _2-16 acetylene which may have a substituent such as an alkyl group such as pentyne, 1-hexyne, 1-heptin and 1-octyne, particularly C _2-12 acetylene), C ₅ having a plurality of triple bonds _-20 alkazines (such as C _5-16 alkazines such as 1,4-decadiyne), cycloalkyl acetylene (such as C _5-8 cycloalkyl acetylene), aryl acetylene (phenyl acetylene, 4-hydroxyphenyl acetylene, 4-chlorophenyl acetylene) Substituents on aryl groups such as 4-methoxyphenylacetylene and 4-trifluoromethylphenylacetylene C _6-10 arylacetylene etc. which may have

  Further, the acetylene compounds include acetylene compounds having the above-described substituents, for example, compounds having an oxygen-containing substituent [for example, compounds having a hydroxyl group (propargyl alcohol, etc.), compounds having a carbonyl group (3-butyne- 2-one, etc.), a compound having a carboxyl group or a derivative thereof (acetylene carboxylic acid, acetylenedicarboxylic acid diester, etc.), a compound having an alkoxy group (such as ethoxyacetylene), etc.], a halogen-containing compound [propargyl chloride, 3, 3, 3-trifluoro-1-propyne etc.], etc., and compounds containing hetero atoms such as phosphorus, tin, boron, silicon [phosphonium salts such as propargyltriphenylphosphonium bromide, tin compounds such as alkynyl tin, alkynyl Bora Boron compounds such as silicon, silicon compounds such as (trimethylsilyl) acetylene, and the like].

(Organic compound R ² -L having a leaving group)
An organic compound having a leaving group can be represented by the formula R ² -L (wherein L represents a leaving group, and R ² represents a group in which the leaving group L is removed from the organic compound).

  The leaving group L of the organic compound is not particularly limited as long as it can be eliminated by a coupling reaction. For example, a halogen atom (fluorine, chlorine, bromine, iodine atom), a sulfonyloxy group (benzenesulfonyloxy group, p -Tosyl group such as toluenesulfonyloxy group arenesulfonyloxy group such as OTs, methanesulfonyloxy group OMs, trifluoromethanesulfonyloxy group (triflate group) OTf, alkanesulfonyloxy group such as trichloromethanesulfonyloxy group, ethanesulfonyloxy group Etc.) or sulfonyl halide groups (such as sulfonyl chloride and sulfonyl bromide groups), diazonium groups, carbonyl halide groups (such as carbonyl chloride groups), and the like. The organic compound may have these leaving groups alone or a plurality of the same or different leaving groups. Of these leaving groups, halogen atoms (especially bromine atoms or iodine atoms), arenesulfonyloxy groups (OTs, etc.), alkanesulfonyloxy groups (OMs, OTf, etc.) are usually used.

The organic compound R ² -L having such a leaving group L is not particularly limited, and examples thereof include halides (haloalkanes, haloalkenes, halocycloalkanes, haloarenes, halogenated arylalkanes, haloheterocycles. Compounds), sulfonic acids or derivatives thereof (C _2-10 alkenyl triflates such as vinyl triflate and allyl triflate; C _4-10 alkenyl triflates such as cyclohexenyl triflate), aromatic diazonium salts (benzenediazonium chloride, naphthalene diazonium chloride) , P-aminoazobenzene, azoxybenzene, hydrazobenzene, etc.), organic acid halides (acetyl chloride, propionyl chloride, butyryl chloride, valeryl chloride, lactoyl chloride, maloyl chloride, etc.) Alkylcarbonyl halides that may be used; alkenylcarbonyl halides such as acryloyl chloride, methacryloyl chloride, crotonoyl chloride; benzoyl chloride, chlorobenzoyl chloride, toluoyl chloride, salicyloyl chloride, anisoyl chloride, vanilloyl chloride, naphthoyl Arylcarbonyl halides such as chloride and phthaloyl chloride; aralkylcarbonyl halides such as cinnamoyl chloride; heterocyclic carbonyl halides such as furoyl chloride, thenoyl chloride, nicotinoyl chloride, and isonicotinoyl chloride).

Preferred organic compounds are halides. Examples of the haloalkanes include brominated alkanes such as bromomethane, bromoethane, methylene bromide, and ethylene dibromide, and corresponding alkanes. Examples of haloalkenes include C _2-10 alkenes such as vinyl bromide, vinylidene bromide, tetrabromoethylene, allyl bromide, propenyl bromide, crotyl bromide, α-bromostyrene, bromophenylethylene, etc. Examples thereof include aromatic vinyl bromides and iodides corresponding to these. Examples of halocycloalkanes include bromo C _3-10 cycloalkanes such as bromocyclohexane and bromocyclooctane, bridged bromocycloalkanes such as bromoisobornyl, bromonorbornane, bromonorbornene, and bromoadamantane. Corresponding iodocycloalkanes and bridged cyclic iodocycloalkanes can be exemplified.

  Examples of haloarenes include bromobenzene, bromonaphthalene, bromotoluene, bromotrichloromethylbenzene, bromotrifluoromethylbenzene, bromoxylene, bromoethylbenzene, bromophenol, bromoanisole, bromonitrobenzene, bromoaniline, mono- or di- Examples thereof include bromine arenes which may have a substituent such as alkylaminobromobenzene, bromobenzoic acid, bromobenzenesulfonic acid, bromobenzaldehyde, acetylbromobenzene, and corresponding iodinated arenes. Examples of halogenated arylalkanes include benzyl bromide and phenethyl bromide. Examples of haloheterocyclic compounds include bromothiophene, bromofuran, bromobenzofuran, bromopyrrole, bromoimidazole, bromopyridine, bromopyrimidine, bromoindole, bromoquinoline, bromoisoquinoline, bromophthalazine, bromocarbazole, bromoacridine, bromophenanthroline and the like 5 or Examples thereof include brominated compounds of 6-membered heterocyclic rings (and condensed heterocyclic rings with hydrocarbon rings such as benzene rings), iodides corresponding to these brominated substances, and the like.

  Of these organic compounds having a leaving group, aromatic halides (for example, haloarenes) are usually used in many cases.

  The proportion of the terminal alkyne is, for example, 0.0001 to 1000 mol, preferably 0.001 to 100 mol, more preferably 0.005 to 10 mol, relative to 1 mol of the organic compound (particularly 1 mol of the leaving group). It is about 0.2-5 mol (for example, 0.5-3 mol, especially 0.8-2 mol) in many cases. The ratio (molar ratio) between the terminal alkynes and the organic compound is usually the former / the latter = 1/2 to 2/1 (for example, 0.8 / 1 to 2/1), preferably 1/1 to 2/1. More preferably, it may be about 1/1 to 1.5 / 1.

  The ratio of the transition metal compound (or transition metal catalyst) may be at least a catalytic amount, for example, 0.000001 to 1 mol, preferably 0.0001 to 0.5 mol, more preferably 1 mol to 1 mol of the organic compound. Preferably it is about 0.0005-0.2 mol, and may be about 0.001-0.1 mol.

  The ratio of the inorganic salt constituting the catalyst system is 0.5 to 2 mol, preferably 0.8 to 1.8 mol, more preferably about 0.9 to 1.5 mol, relative to 1 mol of the organic compound. It may be.

  The coupling reaction may be performed in the absence of a solvent, but is usually performed in the presence of a solvent in many cases. In a solution reaction system using a solvent, it is easy to control the reaction temperature. The solvent in the reaction system may be an aqueous solution (a homogeneous or heterogeneous aqueous solution) or a mixed solvent of a plurality of solvents. Further, the reaction system solvent may be a two-phase solvent of an aqueous phase and an organic phase.

  The solvent is not particularly limited as long as it is inert to the reaction. For example, ethers (diethyl ether, dibutyl ether, tetrahydrofuran (THF), dioxane, dimethoxyethane, etc.), ketones (aliphatic ketones such as acetone, etc.) ), Aliphatic hydrocarbons (normal hexane, heptane, octane, cyclohexane, cyclopentane, etc.), aromatic hydrocarbons (benzene, toluene, xylene, etc.), halogenated hydrocarbons (dichloroethane, dichloromethane, chloroform, tetrachloride) Chlorine-containing hydrocarbons such as carbon; fluorine-containing hydrocarbons such as trifluoromethylbenzene, hexafluorobenzene, perfluorooctane and perfluorocyclohexane), nitro group-containing hydrocarbons (nitroalkanes such as nitromethane; Nitroarenes such as Zen), sulfur-containing solvents (dimethylsulfoxide (DMSO), sulfolane, etc.), amides (N, N-dimethylformamide (DMF), N, N-dimethylacetamide, N-methylpyrrolidone (NMP) ), Hexamethylphosphoramide (HMPA), etc.), nitriles (acetonitrile, propionitrile, benzonitrile, etc.) and the like. In addition, a component that is liquid in the reaction system (for example, a liquid component in a supercritical state, such as a supercritical fluid such as carbon dioxide, ethane, or fluorocarbon) can be used even if it is not liquid at normal temperature and pressure.

  Preferred solvents are aprotic polar solvents such as ketones (acetone, etc.), nitro group-containing hydrocarbons (nitromethane, etc.), sulfoxides (DMSO, etc.), amides (DMF, dimethylacetamide, NMP, HMPA, etc.) ), Nitriles (acetonitrile, benzonitrile, etc.). The said solvent can be used individually or in combination of 2 or more types.

  The amount of the solvent used is not particularly limited as long as the reaction operation is not impaired. For example, 0 to 10,000 parts by weight, preferably 0.01 to 100 parts by weight, and more preferably 0.1 to 100 parts by weight with respect to 1 part by weight of the organic compound. About 50 parts by weight.

  In the reaction system, if necessary, an inorganic base such as a metal hydroxide (an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide, an alkaline earth such as calcium hydroxide or magnesium hydroxide) is used. Metal hydroxides, etc.), salts of weak acids (organic acids) and strong alkalis (for example, alkali metal salts of organic carboxylic acids such as sodium acetate and potassium acetate) may be used in combination.

  The reaction temperature is, for example, room temperature (about 25 to 35 ° C.) to 200 ° C., preferably room temperature to 150 ° C., more preferably about 40 to 100 ° C., and usually about 50 to 100 ° C. The reaction time can be appropriately selected in consideration of, for example, economy.

  The reaction may be performed in air, but is usually performed in an inert gas (rare gas such as argon or helium or nitrogen gas) in many cases. The reaction pressure can be selected depending on the type of reaction components, and the total pressure in the reactor at the reaction temperature is, for example, 0.0001 to 100 MPa, preferably 0.001 to 10 MPa, and more preferably 0.00. 01 to 1 MPa.

  The present invention can efficiently produce alkynes (alkynes having a triple bond at a non-terminal position) with a high selectivity by a coupling reaction. Therefore, it can be used for the production of alkynes by the reaction of alkynes having a methine group at the terminal and various reagents (for example, aromatic halides), for example, Sonogashira coupling reaction.

  Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.

Examples 1-13
In a 20 mL glass reaction vessel, dimethyl sulfoxide (DMSO) (1.6 mL), potassium phosphate (K ₃ PO ₄ 204 mg, 0.96 mmol), palladium acetate (1.8 mg, 0.008 mmol), Phenylphosphine (b1) (8.4 mg, 0.032 mmol) was added. To this mixture, the terminal alkyne (R ¹ ≡CH, 1.2 mmol) and the organic compound (R ² -L, 0.8 mmol) shown in Table 1 and Table 2 were added and reacted at 80 ° C. for 24 hours with stirring. It was. In Examples 6 and 9 to 13, the amounts of palladium acetate and triphenylphosphine used were three times the above, that is, palladium acetate (5.4 mg, 0.024 mmol) and triphenylphosphine (25.2 mg, 0.2 mg). 096 mmol).

From the obtained reaction mixture, the product was separated using preparative high performance liquid chromatography (manufactured by Nippon Analytical Industries, Ltd., LC-908, developing solvent: chloroform), and further gel permeation chromatography (GPC) ( The target coupling reaction product R ¹ —C≡C—R ² was obtained by purification using GPC column: JAIGEL-1H or 2H).

Examples 14-18
Instead of triphenylphosphine (0.032 mmol), N- [2- (diphenylphosphino) benzylidene] -2-phenylethylamine (b2) or N- [2- (diphenylphosphino) benzylidene] -tert-butylamine ( 0.013 mmol of b3) was used, and the reaction and separation / purification were performed in the same manner as in Example 1 except that the compounds shown in Table 2 were used as the terminal alkyne to obtain a product.

Example 19
The product diphenylacetylene (yield 84%) was obtained in the same manner as in Example 1 except that potassium carbonate (0.96 mmol) was used in place of potassium phosphate.

Comparative Example 1
The reaction was performed in the same manner as in Example 1 except that potassium phosphate was not used. The reaction did not proceed and the desired product was not obtained (yield 0%).

  The results of Examples 1 to 18 are shown in Tables 1 and 2.

Claims (4)

A coupling reaction catalyst system for producing alkynes having a triple bond at a non-terminal position by Sonogashira coupling reaction between an alkyne having a methine group (CH≡) and an organic compound having a leaving group. And at least one transition metal element selected from nickel, palladium and platinum, or a compound thereof, and a triarylphosphine, N- [2- (diC _6-10 arylphosphino) -C _6-10 aryl C _{1 -4} alkylidene] -C _6-10 aryl-C _1-4 alkylamine, and N- [2- (diC _6-10 arylphosphino) -C _6-10 aryl C _1-4 alkylidene] -linear or At least one ligand selected from branched C _1-6 alkylamines and at least one ligand selected from lithium, sodium and potassium. A coupling reaction catalyst system consisting only of an inorganic salt, which is a metal inorganic acid salt composed of lukari metal .   The catalyst system according to claim 1, wherein the inorganic salt is a phosphate. And alkynes each having a methine group (CH≡) at the end, a an organic compound having a leaving group subjected to Sonogashira coupling reaction, a method of manufacturing a alkynes having a triple bond to a non-terminal position, a nickel , At least one transition metal element selected from palladium and platinum or a compound thereof , and triarylphosphine, N- [2- (diC _6-10 arylphosphino) -C _6-10 aryl C _1-4 alkylidene] -C _6-10 aryl-C _1-4 alkylamine, and N- [2- (diC _6-10 arylphosphino) -C _6-10 aryl C _1-4 alkylidene] -linear or branched C _1- Consists of at least one ligand selected from ₆ alkylamines and at least one alkali metal selected from lithium, sodium and potassium A coupling reaction catalyst system consisting only of an inorganic salt which is a metal inorganic acid salt , and a method for producing alkynes wherein the coupling reaction is carried out in the presence of an aprotic polar solvent . The production method according to claim 3 , wherein the leaving group is at least one selected from a halogen atom, a sulfonyloxy group or a sulfonyl halide group, a diazonium group, and a carbonyl halide group.