Reduction method

Abstract

The present invention addresses the problem of providing: (i) a reduction method for reducing a substrate, which is composed of one or more compounds each having an unsaturated bond, by means of a mechanochemical treatment using at least a proton source and a metal including one or more elements selected from among alkali metals and alkaline earth metals; and (ii) a reduction method which enables the achievement of a reaction product that is similar to the reaction product by Birch reduction, with which the reaction can be carried out under mild temperature conditions in the ambient atmosphere without using liquid ammonia and high activity in the reduction reaction can be exhibited without using any solvent or substantially without using an organic solvent, and which enables the achievement of a reaction product with a high yield within a short time by a simple operation and is applicable to a wide range of substrates. The present invention provides, as a means for solving the problem, a reduction method for reducing a substrate (A) by a mechanochemical treatment using at least a metal (B) and a proton source (C), wherein: the substrate (A) is composed of one or more compounds each having an unsaturated bond; and the metal (B) includes one or more elements that are selected from among alkali metals and alkaline earth metals.

Description

[Technical Field]

[0001] The present invention relates to a reduction method comprising reducing (A) a substrate by mechanochemical treatment using at least (B) a metal and (C) a proton source, wherein the (A) substrate comprises one or more compounds containing unsaturated bonds, and the (B) metal comprises one or more selected from alkali metals or alkaline earth metals. [Background technology]

[0002] In the synthesis of functional materials such as pharmaceuticals, liquid crystal compounds, organic electroluminescent compounds, battery materials, polymer compounds, oligomers, coloring materials, energy ray absorbing materials, information recording materials, wavelength conversion materials, indicator materials, sensor materials, organic light-emitting diodes (OLEDs), and organic semiconductor materials, reduction reactions of compounds containing unsaturated bonds such as benzene rings may be used. Non-patent document 1 discloses the Birch reduction, which converts a benzene ring to a 1,4-cyclohexadiene ring. The Birch reduction is a special reaction that selectively converts a stable benzene ring to a 1,4-cyclohexadiene ring through partial reduction, and further reduces α,β-unsaturated carbonyl compounds, conjugated dienes, and alkynes. The Birch reduction is one of the most fundamental reactions among the many organic chemical reactions and has been widely used for over 50 years. On the other hand, because the Birch reduction uses liquid ammonia and alkali metals, it requires harsh reaction conditions of extremely low temperatures and an inert atmosphere, and studies have been conducted to relax these reaction conditions. Non-patent document 2 discloses a method of performing Birch reduction in a solution system using lithium and alkylamine. Non-patent document 3 discloses a method of performing Birch reduction in a solution system using lithium and ethylenediamine. Non-patent document 4 discloses that Birch reduction is carried out in a solution system using n-propylamine, ethylenediamine, and tert-butanol as proton sources. Non-patent document 5 discloses that Birch reduction can be carried out in a solution system using ether solvents such as lithium, ethylenediamine, and tetrahydrofuran. Non-patent document 6 discloses a method for treating Lithium bis(trimethylsilyl)amide (LiHMDS) and a substrate mechanochemically, and then reducing the substrate by Birch reduction. Patent Document 1 discloses a method for reducing a compound containing an unsaturated bond, which involves reacting a reducing agent, which is a mixture of a dispersion of sodium in a dispersion solvent and 1,3-dimethyl-2-imidazolidinone, with the reducing agent containing solvated electrons formed when sodium dissolves in the 1,3-dimethyl-2-imidazolidinone, to reduce the unsaturated bond of the compound containing the unsaturated bond. Patent Document 2 discloses a solid-phase organic reaction method in which, in the presence of a solid dispersant, at least a portion of nano-sized metal particles are brought into contact with the raw materials, and the metal particles are used as a reaction initiator to carry out an organic reaction without a solvent. [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] Japanese Patent Publication No. 2019-194206 [Patent Document 2] Japanese Patent Publication No. 2012-20977 [Non-patent literature]

[0004] [Non-Patent Document 1] Journal of the Chemical Society, 1944, p.430-436 [Non-Patent Document 2] Journal of the American Chemical Society, 1955, Vol.77, No.12, p.3230-3233 [Non-Patent Document 3] The Journal of Organic Chemistry, 1957, Vol.22, No.8, p.891-894 [Non-Patent Document 4] The Journal of Organic Chemistry, 2000, Vol.65, No.21, p.7098-7104 [Non-Patent Document 5] Science, 2021, Vol.374, Issue.6568, p.741-746 [Non-Patent Document 6] Chem, 2023, Vol.3, Issue.3, p.576-591 [Overview of the project] [Problems that the invention aims to solve]

[0005] The reduction method (Birch reduction) disclosed in Non-Patent Document 1 uses liquid ammonia, requiring strict temperature control below -33°C and an inert gas atmosphere, and necessitating complicated experimental procedures. The reduction methods disclosed in Non-Patent Documents 2-5 and Patent Document 1 do not use liquid ammonia, but they require strict temperature control and an inert gas atmosphere, and complicated experimental procedures. Furthermore, since the reaction takes place in a solution system, a certain amount of organic solvent is required, which may cause problems in terms of the working environment and safety of workers, protection of the global environment, and the environmental burden during the disposal of organic solvent after use.

[0006] Organic synthesis reaction methods that involve direct contact between reactants and do not use organic solvents have a low environmental impact, present fewer problems in terms of the work environment and safety, and are of interest both academically and industrially. Mechanochemical methods are attracting attention as such organic synthesis reaction methods. Mechanochemical methods allow reactions to be carried out under conditions that are solvent-free or substantially free of organic solvents by applying mechanical energy to solid raw materials through means such as grinding, shearing, impact, and compression. However, until now, no method has been known that uses mechanochemical methods to reduce a substrate, which is one or more compounds containing unsaturated bonds, using a metal containing one or more alkali metals or alkaline earth metals, without using liquid ammonia.

[0007] One of the problems that the present invention aims to solve is to provide a reduction method that reduces a substrate, which is one or more compounds containing unsaturated bonds, by mechanochemical treatment using a metal and proton source containing at least one or more selected from alkali metals or alkaline earth metals. One of the problems that the present invention aims to solve is to provide a reduction method that can obtain reaction products similar to those obtained by Birch reduction, can carry out the reaction under mild temperature conditions in an atmospheric atmosphere without using liquid ammonia, exhibits high activity in the reduction reaction without using solvents or substantially organic solvents, can obtain reaction products in high yield in a short time with simple operation, and is applicable to a wide range of substrates. [Means for solving the problem]

[0008] As a result of diligent research, the inventors discovered that the above-mentioned problems can be solved by a reduction method having specific means, and thus completed the present invention. In other words, the present invention is as follows: [Section 1] (A) A reduction method comprising reducing a substrate by mechanochemical treatment using at least (B) a metal and (C) a proton source, The substrate (A) is one or more compounds containing an unsaturated bond, A reduction method wherein the (B) metal comprises one or more selected from alkali metals or alkaline earth metals. [Section 2] The reduction method according to item 1, wherein the substrate (A) comprises one or more selected from the group consisting of aromatic hydrocarbon compounds, aromatic heterocyclic compounds, internal alkyne-containing compounds, and conjugated alkene compounds. [Section 3] The reduction method according to item 1 or 2, wherein the (B) metal comprises one or more selected from the group consisting of lithium, sodium, and calcium. [Section 4] The reduction method according to any one of items 1 to 3, wherein the (C) proton source includes a sugar compound. [Section 5] A reduction method according to any one of items 1 to 4, wherein the amount of organic solvent with a melting point of less than 30°C used during reduction by mechanochemical treatment is 1.0 mL or less per 1 mmol of substrate. [Section 6] A reduction method according to any one of items 1 to 5, wherein the conditions for reduction by mechanochemical treatment are a temperature of 20°C or higher and / or a non-inert atmosphere. [Effects of the Invention]

[0009] The present invention provides a reduction method for reducing a substrate, which is one or more compounds containing unsaturated bonds, by mechanochemical treatment using a metal and proton source containing at least one or more metals selected from alkali metals or alkaline earth metals. The present invention provides a reduction method that can obtain reaction products similar to those obtained by Birch reduction, can carry out the reaction under mild temperature conditions in an atmospheric atmosphere without using liquid ammonia, exhibits high activity in the reduction reaction without the use of solvents or substantially organic solvents, can obtain reaction products in high yield in a short time by simple means, and is applicable to a wide range of substrates. [Modes for carrying out the invention]

[0010] The present invention relates to a reduction method comprising reducing (A) a substrate by mechanochemical treatment using at least (B) a metal and (C) a proton source, wherein the (A) substrate is one or more compounds containing unsaturated bonds, and the (B) metal is one or more selected from alkali metals or alkaline earth metals. The present invention will be described in detail below.

[0011] [(A) Substrate] The substrate (A) used in the reduction method of the present invention is one or more compounds containing an unsaturated bond. The reduction method of the present invention is a method that can carry out a reduction reaction that is substantially the same as the widely known "Birch reduction". (A) As the compound containing an unsaturated bond as the substrate, for example, one or more can be selected from the group consisting of aromatic hydrocarbon compounds, aromatic heterocyclic compounds, internal alkyne-containing compounds, conjugated alkene compounds and α,β-unsaturated carbonyl compounds.

[0012] <Aromatic hydrocarbon compounds> In the reduction method of the present invention, (A) the aromatic hydrocarbon compound used as a substrate is not particularly limited as long as it has one or more aromatic rings in its molecule. In the aromatic hydrocarbon compound, the number of carbon atoms forming the aromatic ring in the molecule is 6 or more and 30 or less, preferably 6 or more and 14 or less. The aromatic ring may constitute a fused ring or a spiro ring. Examples of aromatic rings include one or more selected from the group consisting of benzene, naphthalene, pentalene, indene, azulene, biphenylene, indacene, acenaphthylene, fluorene, phenalene, phenanthrene, anthracene, fluoranthrene, aceanthrylene, triphenylene, pyrene, tetracene, perylene, tetraphenylene, pentacene, coronene, heptacene, etc. In the reduction method of the present invention, one or more aromatic hydrocarbon compounds can be used.

[0013] In aromatic hydrocarbon compounds, the aromatic ring within the molecule may have one or more substituents at arbitrary positions. If there are multiple substituents, they may be identical or distinct from one another. Examples of substituents include alkyl groups, aromatic groups, hydroxyl groups, alkoxy groups, carboxyl groups, carboxylic acid ester groups, acyl groups, and amino groups.

[0014] The reduction method of the present invention typically reduces a benzene ring in an aromatic hydrocarbon compound to a cyclohexadiene ring as described below. In the reduction method of the present invention, compounds in which the cyclohexadiene ring is further reduced are not preferentially formed, thus enabling reactions that cannot be achieved by reduction by hydrogenation. [ka]

[0015] When a substituent is attached to an aromatic ring, the regioselectivity of reduction depends on the properties of the substituent. In the reduction method of the present invention, when the substituent is an electron-donating group (EDG) such as a hydroxyl group, alkoxy group, primary amino group, secondary amino group, or alkyl group, the reaction proceeds as follows, resulting in a compound with hydrogen added at the 2,5 positions (2,5-dihydro type). The position of the electron-donating group relative to the 1,4-cyclohexadiene ring is the carbon portion that constitutes the unsaturated bond. Furthermore, when the substituent is an electron-donating group, the reduction rate is generally slower compared to the unsubstituted product. [ka]

[0016] In the reduction method of the present invention, when the substituent is an electron-withdrawing group (EWG) such as a carboxyl group, phenyl group, acyl group, or carboxylic acid ester group, the reaction proceeds as follows, resulting in a compound with hydrogen added at the 1,4 position (1,4-dihydro type). The position of the electron-withdrawing group relative to the 1,4-cyclohexadiene ring is the carbon portion that does not constitute an unsaturated bond. [ka]

[0017] In the reduction method of the present invention, when naphthalene was used as the substrate (A), 1,2,3,4,5,8-hexahydronaphthalene was preferentially produced by the method described in Example A23 below, and 1,4,5,8-tetrahydronaphthalene was preferentially produced by the method described in Example B25 below. In the reduction method of the present invention, when anthracene was used as the substrate (A), 9,10-dihydroanthracene was preferentially produced, as shown in Examples A20 and B26 described below. In the reduction method of the present invention, when acenaphthylene was used as the substrate (A), acenaphthene was preferentially produced, as shown in Example A24 described below. In the reduction method of the present invention, when m-anisic acid (3-methoxybenzoic acid) was used as the substrate (A), 5-oxo-2-cyclohexene-1-carboxylic acid was preferentially produced, as shown in Example B42 described below. In the reduction method of the present invention, when 1-indanol was used as the substrate (A), 2,3,4,7-tetrahydro-1H-indene was preferentially produced, as shown in Example B45 described below. In the reduction method of the present invention, 4,7-dihydro-1-indanol, a reaction product in which the phenyl ring of 1-indanol is reduced, was not preferentially produced. In the reduction method of the present invention, when N-(2-phenylethyl)acetamide was used as the substrate (A), 1-(2-aminoethyl)-1,4-cyclohexadiene was preferentially produced, as shown in Example B46 below. In the reduction method of the present invention, N-[2-(1,4-cyclohexadienyl)ethyl]acetamide, which is a reaction product obtained by reducing the phenyl ring of N-(2-phenylethyl)acetamide, was not preferentially produced.

[0018] In the reduction method of the present invention, when tetraphenylethylene (a compound in which an internal alkene group is bonded to an aromatic ring) was used as the substrate (A), 1,1,2,2-tetraphenylethane, in which only the internal alkene group is reduced, was preferentially produced, as shown in Examples A25 and B47 described below.

[0019] In the reduction method of the present invention, when (A) benzoic acid was used as the substrate and water was used as the quenching agent, 2,5-cyclohexadiene-1-carboxylic acid was preferentially produced, as shown in Example B1 below. When methyl iodide was used as the quenching agent and further mechanochemical treatment was performed, 1-methyl-2,5-cyclohexadiene-1-carboxylic acid was preferentially produced, as shown in Example B51 below.

[0020] <Aromatic heterocyclic compounds> In the reduction method of the present invention, (A) the aromatic heterocyclic compound used as a substrate is not particularly limited as long as it has one or more aromatic heterocyclic rings in its molecule, each having one or more heteroatoms as ring constituent atoms. In the aromatic heterocyclic compound, the number of atoms forming the aromatic heterocyclic ring is 4 to 30, preferably 6 to 14. There are no restrictions on the number and position of the heteroatoms constituting the aromatic heterocyclic ring. The heteroatoms are oxygen atoms, nitrogen atoms, and sulfur atoms. Examples of aromatic heterocyclic rings include aromatic heterocyclic compounds having 1 to 29 carbon atoms and 1 to 29 heteroatoms. If multiple heteroatoms are present, the heteroatoms may be the same atom or different atoms. The aromatic heterocyclic ring may constitute a fused ring or a spiro ring.

[0021] Examples of aromatic heterocycles include pyrroline, pyrazole, pyridine, imidazole, pyrazine, pyrimidine, pyridazine, indolidinyl, isoindole, indole, indazole, purine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, carboline, phena hmmOne or more compounds selected from the group consisting of nitrogen-containing aromatic heterocycles such as toridine, acridine, perimidine, phenanthroline, and phenazine; oxygen-containing aromatic heterocycles such as furan, benzofuran, isobenzofuran, and benzopyran; sulfur-containing aromatic heterocycles such as thiophene, benzothiophene, and thianthlene; nitrogen-containing oxygen-containing aromatic heterocycles such as oxazoline, isoxazoline, furazan, benzoxazole, and benzoisoxazole; nitrogen-containing sulfur-containing aromatic heterocycles such as thiazole, isothiazole, benzothiazole, benzoisothiazole, and phenothiazine; and oxygen-containing sulfur-containing aromatic heterocycles such as phenoxathiine.

[0022] In the reduction method of the present invention, when acridine is used as the substrate (A), 9,10-dihydroacridine can be produced as shown in Example B48 described below. In the reduction method of the present invention, when N-methylindole is used as the substrate (A), 1-methyl-2,3-dihydroindole can be produced as shown in Example B49 described later. In the reduction method of the present invention, when indole is used as the substrate (A), 4,7-dihydro-1H-indole can be produced as shown in Example B50 described below.

[0023] <Internal alkyne-containing compounds> In the reduction method of the present invention, (A) the internal alkyne compound used as the substrate has the structure shown in (1) below; [ka] (In the formula, R 1 and R 2 (These are monovalent organic groups that may be identical or different from each other.) The compounds are not particularly limited as long as they are represented by [the formula / symbol].

[0024] In the reduction method of the present invention, the internal alkyne compound reacts as follows. [ka] (In formula (1), R 1 and R 2 may be the same or different from each other and are monovalent organic groups) The reduction method of the present invention can selectively produce an E-olefin compound (trans-alkene compound) from an internal alkyne compound.

[0025] <Conjugated alkene compound> In the reduction method of the present invention, the conjugated alkene compound used as the substrate (A) has, for example, the following structures (2) to (4) in the molecule; [Chemical formula] R 6 -N=C(R 7 )-CH=CR 8 R 9 (3) R 10 R 11 C=C(C 12 )-CR 13 =CR 14 R 15 (4) (In formulas (2) to (4), R 3 to R 15 may be the same or different from each other and are monovalent organic groups.) There is no particular limitation as long as it is a compound having the structure represented by .

[0026] Among these, examples of the conjugated alkene compound having the structure represented by formula (2) in the molecule include α,β-unsaturated carboxylic acids such as acrylic acid, methacrylic acid, and itaconic acid; (Meth)acrylic acid ester compounds such as methyl acrylate, methyl methacrylate, ethylene glycol dimethacrylate, and ethylene glycol dimethacrylate; (Meth)acrylamide compounds such as acrylamide and methacrylamide; Examples thereof include one or more α,β-unsaturated carbonyl compounds selected from the group consisting of the above. Examples of conjugated alkene compounds having a structure represented by formula (3) or formula (4) include one or more selected from the group consisting of N-cinnamyrideniline, 1,3-butadiene, isoprene, 1,3-pentadiene, 2,3-dimethylbutadiene, 2,4-hexadiene, 1,4-diphenylbutadiene, 1,3-heptadiene, 2,5-dimethyl-2,4-hexadiene, chloroprene, 2,4-heptadiene, 2,4-octadiene, and the like.

[0027] In the reduction method of the present invention, the reduction of α,β-unsaturated carbonyl compounds among conjugated alkene compounds is, for example, as shown below. [ka] (In the formula, R 3 ~R 5 These are monovalent organic groups, which may be identical or different.

[0028] [(B) Metal] The metal (B) used in the reduction method of the present invention includes alkali metals and / or alkaline earth metals. Examples of alkali metals include one or more selected from the group consisting of lithium, sodium, potassium, rubidium, and cesium. Of these, one or more selected from the group consisting of lithium, sodium, and potassium are preferred, lithium and / or sodium are more preferred, and sodium is even more preferred. Examples of alkaline earth metals include one or more selected from the group consisting of magnesium, calcium, strontium, and barium. Of these, one or more selected from the group consisting of magnesium, calcium, and strontium are preferred, and magnesium and / or calcium are more preferred.

[0029] (B) The shape of the metal is not particularly limited. A person skilled in the art can appropriately select and determine it according to the reaction conditions such as the scale and container. For example, metal pieces (metal blocks) of metal in the form of a block or wire with dimensions within the range of length (0.1 mm to 10 mm) x width (0.1 mm to 10 mm) x thickness (0.1 mm to 10 mm) can be used.

[0030] In the reduction method of the present invention, the amount of metal (B) used is not particularly limited. It is, for example, 1.0 equiv (1.0 equivalent) or more relative to the substrate, preferably 1.5 equiv or more, more preferably 2.0 equiv or more, and for example, 10.0 equiv or less, preferably 8.0 equiv or less.

[0031] [(C) Proton Source] The (C) proton source used in the reduction method of the present invention is not particularly limited as long as it is a compound capable of releasing hydrogen atoms as protons. Examples of proton sources include compounds having one or more groups capable of releasing a hydrogen atom as a proton. Examples of groups capable of releasing a hydrogen atom as a proton include hydroxyl groups, amino groups, and carboxyl groups. Examples of proton sources include one or more selected from the group consisting of alcohol compounds, amine compounds, amino alcohol compounds, carboxylic acid compounds, amino carboxylic acid compounds, ammonium salts, and the like.

[0032] Alcohol compounds are compounds having one or more hydroxyl groups, for example, Monofunctional alcohols such as methanol, ethanol, n-propanol, i-propanol, n-butanol, tert-butanol, 2-methyl-2-propanol, 1-adamantanol, 2-adamantanol, and cyclohexanol; Ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, 1,2-pentanediol, 1,3-pentanediol, 1,5-pentanediol, 1,6-hexanediol, 1,7-heptanediol, 1,8-octanediol, 1,9-nonanediol, 1,10-decanediol, 1,12-dodecanediol, 2-methyl-1,3-propanediol Neopentyl glycol, 3-methyl-1,5-pentanediol, 2-methyl-1,3-pentanediol, 1,3-cyclohexanediol, 1,4-cyclohexanediol, 1,4-cyclohexanedimethanol, 1,2-cyclopentanediol, 1,3-cyclopentanediol, 1,1-cyclohexanedimethanol, 1,2-cyclohexanedimethanol, 1,3-cyclohexanedimethanol, 1,4-cyclohexanedimethanol L, 1,2-cyclooctanediol, 1,5-cyclooctanediol, 5-norbornene-2,2-dimethanol, 5-norbornene-2,3-dimethanol, norbornane-2,3-dimethanol, norbornane-2,5-dimethanol, 2,6-decahydronaphthalenedimethanol, 1,3-adamantanediol, 1,4-adamantanediol, 2,4-adamantanediol, tricyclodecanedimethanol, glycerin, trimethylol One or more selected from the group consisting of ropane, trimethylolethane, hexanetriol, pentaerythritol, dipentaerythritol, 1,3,5-cyclohexanetriol, sorbitol, mannitol, sorbitan, diglycerin, triglycerin, tetraglycerin, polypentaglycerin, sucrose, glucose, mannose, fructose, cellulose, methyl glucoside, and other polyfunctional alcohols or sugar compounds; etc.

[0033] Amine compounds are compounds having one or more amino groups, for example, Aliphatic amines such as methylamine, ethylamine, n-propylamine, isopropylamine, diisopropylamine, triisopropylamine, n-butylamine, tert-butylamine, sec-butylamine, 2-ethylhexylamine, n-octylamine, N-methylethylamine, dimethylamine, diethylamine, triethylamine, ethylenediamine, and propylenediamine; Aromatic amines such as aniline, o-triidine, 2,4,6-trimethylaniline, anisidine, 3-(trifluoromethyl)aniline, and phenylenediamine; Heterocyclic amines such as piperazine, pyridine, triazine, and melamine; One or more species selected from the group consisting of the following can be mentioned.

[0034] Amino alcohol compounds are compounds having one or more amino groups and one or more hydroxyl groups, and examples include one or more selected from the group consisting of ethanolamine, propanolamine, butanolamine, dimethanolamine, trimethanolamine, diethanolamine, triethanolamine, N-methyldiethanolamine, dipropanolamine, trippropanolamine, diisopropanolamine, triisopropanolamine, trishydroxymethylaminomethane, 2-amino-2-methyl-1,3-propanediol, etc.

[0035] Carboxylic acid compounds are aliphatic compounds having one or more carboxyl groups, and examples include one or more selected from the group consisting of formic acid, acetic acid, propionic acid, pivalic acid, trifluoroacetic acid, cyclohexanecarboxylic acid, etc.

[0036] Aminocarboxylic acid compounds are compounds having one or more amino groups and one or more carboxyl groups, and examples include one or more selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, serine, threonine, aspartic acid, glutamic acid, asparagine, glutamine, cysteine, cystine, methionine, lysine, hydroxylysine, histidine, arginine, etc.

[0037] In the reduction method of the present invention, it is preferable to use a proton source with a melting point of 30°C or higher, preferably 50°C or higher, as (C) the proton source. As a result, when the reduction reaction is carried out at room temperature (25°C), the proton source exists in the reaction system as a solid, and in addition to its function as a proton source, it can also function as a grinding accelerator for (A) the substrate and / or (B) the metal. In the reduction method of the present invention, (C) it is preferable to use an alcohol compound or an amine compound as the proton source. (B) When sodium is used as the metal, it is particularly preferable to use an alcohol compound, especially a sugar compound. (B) When lithium is used as the metal, it is preferable to use an amine compound and / or an alcohol compound.

[0038] In the reduction method of the present invention, the amount of (C) proton source used is not particularly limited. It is, for example, 1.0 equiv (1.0 equivalent) or more relative to the substrate, preferably 1.5 equiv or more, more preferably 2.0 equiv or more, and for example, 20.0 equiv or less, preferably 15.0 equiv or less, more preferably 12.0 equiv or less.

[0039] [(D) Other ingredients] In the reduction method of the present invention, "(D) other components" other than (A) substrate, (B) metal, and (C) proton source can be used. As (D) other components, for example, one or more components selected from the group consisting of ion trapping agents, reaction stopping agents (quenching agents), and grinding accelerators can be used.

[0040] The ion trapping agent is not particularly limited as long as it can trap and stabilize the metal ions generated when (B) metals, especially alkali metals, calcium, strontium, and barium, are used in the reduction reaction. For example, one or more solvents with a melting point of less than 30°C, preferably 20°C or lower, can be used. Examples of metal stabilizers include organic solvents used in Birch reduction in solution. These include, for example, diethyl ether, diisopropyl ether, dibutyl ether, t-butyl methyl ether, tetrahydrofuran, tetrahydropyran, cyclopentyl methyl ether, dimethoxyethane, 1,4-dioxane, anisole, acetoxy-2-ethoxyethane, propylene glycol monomethyl ether acetate, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, 1-methoxy-1,1,2,2-tetrafluoroethane, 1-ethoxy-1,1,2,2-tetrafluoroethane, acetone, methyl ethyl ketone, ethyl acetate, butyl acetate, 15-crown 5-ether, and other oxygen-containing organic solvents; benzene, toluene, xylene, and mesitylene. 、 One or more solvents selected from the group consisting of aromatic solvents such as durene and decalin; aliphatic organic solvents such as hexane, pentane, and heptane; halogenated hydrocarbon organic solvents such as dichloromethane, chloroform, carbon tetrachloride, chlorobenzene, and 1,2-dichlorobenzene; nitrogen-containing organic solvents such as 1,3-dimethyl-2-imidazolidinone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, and pyridine; sulfur-containing organic solvents such as dimethyl sulfoxide; and phosphorus-containing organic solvents such as hexamethylphosphoric triamide.

[0041] The reaction stopper (quenching agent) is not particularly limited as long as it can stop the reduction reaction. For example, it may contain one or more selected from the group consisting of water, methyl iodide, methylene chloride, acetone, methyl ethyl ketone, ethyl acetate, butyl acetate, etc. In the present invention, it is preferable to use a reaction stopper (quenching agent) that contains water.

[0042] The grinding accelerator (grinding aid) is not particularly limited as long as it can accelerate grinding or the reaction by mechanochemical treatment for at least one of the following: (A) substrate, (B) metal, and (C) proton source. As a grinding accelerator, (C) it may be used as a proton source and / or a metal stabilizer.

[0043] As a grinding accelerator, one or more compounds with a melting point of 30°C or higher, preferably 50°C or higher (compounds that are solid at room temperature (25°C)) can be used. For example, one or more compounds selected from the group consisting of inorganic particles such as silica, alumina, zirconia, calcium carbonate, ceramics, glass beads, and sea sand, and organic particles such as sucrose, glucose, mannose, fructose, and cellulose. The average particle size of these grinding accelerators is usually 1 μm or more, preferably 10 μm or more, and for example, 1 mm or less. When a compound that is solid at room temperature (25°C) is used as a grinding accelerator, the reaction can be carried out efficiently even when a compound that is liquid at room temperature is used as (A) the substrate and / or (C) the proton source.

[0044] As a grinding accelerator (grinding aid), for example, one or more solvents with a melting point of less than 30°C, preferably 20°C or lower, can be used as a liquid-assisted grinding aid (LAG). Examples of LAGs include one or more selected from the group consisting of the solvents listed above that can be used as metal stabilizers.

[0045] In the present invention, when the reaction system contains an organic solvent with a melting point of less than 30°C as (C) a proton source and / or (D) other components, the amount of organic solvent used is preferably 1.0 mL or less, more preferably 0.8 mL or less, based on 1 mmol of the total substrate. The lower limit of the amount of organic solvent used may be 0 mL (no organic solvent used). The amount of organic solvent used in mechanochemical treatment represents one of the following: no organic solvent is used at all, no solvent is actively used, or an organic solvent is used but only in such a small amount that no solvent effect is exhibited. This allows (A) the substrate, (B) the metal, ( C The proton source and (D) other components usually exist in a solid state, at least partially, and in some cases entirely, at the time of mechanochemical treatment (reaction initiation), and react in that state. Generally, when carrying out a reaction in a solution system, an amount of organic solvent greater than 1 mL, preferably 10 mL or more, is used per 1 mmol of total substrate. In the present invention, the amount of organic solvent used is 1.0 mL or less per 1 mmol of total substrate.

[0046] [Mechanochemical treatment] In the reduction method of the present invention, the mechanochemical treatment is a process for reducing a substrate by directly adding mechanical energy, generated mechanically by means such as grinding, shearing, impact, or compression, to at least (A) the substrate, (B) the metal, and (C) the proton source. The mechanochemical treatment can be carried out under solvent-free or substantially solvent-free conditions, contributing to waste reduction and having a low environmental impact, and eliminating the need for complicated reaction condition setting and preparation. Furthermore, the reduction reaction can be carried out simply and in a very short time, making it possible to achieve both reduced energy consumption and high productivity. The following can be adopted for the reaction equipment and various conditions used in mechanochemical treatment.

[0047] <Reaction apparatus> The reaction apparatus used in mechanochemical processing is not particularly limited, as long as it can apply mechanical energy to at least (A) a substrate, (B) a metal, and (C) a proton source, thereby enabling the reduction reaction of (A) the substrate. Such a device would be, for example, Grinding machines such as ball mills, rod mills, jet mills, and SAG mills; Grinding machines such as rotary millstones and mortars; (Horizontal axis rotation) container-rotating mixing apparatus such as horizontal cylindrical, V-shaped, double cone-shaped, square cube-shaped, S-shaped, and continuous V-shaped; Rotating container mixing apparatus (with baffle blades) such as horizontal cylindrical, V-shaped, double cone, and ball mill type; Rotary (rotational vibration) container mixing apparatus such as rocking type and cross-rotary type; Ribbon type, paddle type, single-axis rotor type, and bag mill type (horizontal axis rotation) fixed container type mixing apparatus; Ribbon type, screw type, planetary type, turbine type, high-speed fluid type, rotating disc type, and Mahler type (vertical axis rotation) fixed vessel type mixing apparatus; Vibrating mill type and (vibrating) fixed container type mixing apparatus such as sieves; Fluid-moving mixing devices such as heterogeneous fluidized beds, swirling fluidized beds, riser-type and jet-pump type devices; Gravity-type and static mixers, and other (gravity) fluid dynamic mixing devices; Mixing machines such as twin-shaft mixers, single-shaft mixers, mixers, and roll mills; One or more species selected from the group consisting of the following can be mentioned.

[0048] In mechanochemical processing, one or more devices selected from the group consisting of pulverizers, grinders, mixers, kneaders, etc. are preferably used, and a mixer is particularly preferred. As for the mixer, for example, one can refer to the powder mixing devices described in Table 5 and Figure 9 of Sakashita, "Powder Mixing Process Technology," Colorants, 77(2), 75-85(2004). Specifically, ball mills, twin-screw kneaders, planetary ball mills, SPEX mixer mills, twin-screw ball mills, etc. can be used.

[0049] The apparatus used in mechanochemical processing may include one or more means selected from the group consisting of metering means, vacuum or pressurizing means, atmosphere adjustment means (gas introduction or discharge means), means for introducing various components, means for discharging various components and reaction products, purification means, analytical means, reaction monitoring means, etc.

[0050] <Reaction vessel> The reaction vessel used in mechanochemical processing is not particularly limited. An appropriate reaction vessel is selected and used considering the physical properties, reactivity, and abundance of (A) the substrate, (B) the metal, (C) the proton source, and other components present in the reaction system, as well as the reaction conditions in the mechanochemical processing. For example, when using a device that performs mechanical mixing (e.g., a ball mill), a ball mill jar can be used as the reaction vessel. The internal volume of a reaction vessel such as a ball mill jar is not particularly limited. For example, the internal volume can be 1 mL or more, or it can be 10 mL. The reaction vessel used in mechanochemical processing may be equipped with stirring means for stirring (A) the substrate, (B) the metal, (C) the proton source, and other components present in the reaction system. The stirring means that the reaction vessel may be equipped with are not particularly limited to any of the various stirring means that can be provided in the reaction apparatus. The means of mechanical mixing using the apparatus described above (reaction apparatus) can be used. As the apparatus for mechanical mixing, for example, a ball mill is preferably used.

[0051] <Conditions for Mechanochemical Treatment> The conditions for mechanochemical treatment are not particularly limited, and appropriate conditions are adopted considering the physical properties, reactivity, and abundance of (A) the substrate, (B) the metal, (C) the proton source, and other components present in the reaction system, as well as the reaction conditions in the mechanochemical treatment. By mechanochemically treating at least (A) the substrate, (B) the metal, and (C) the proton source under appropriate conditions, (A) the substrate, (B) the metal, and (C) the proton source are activated by the mechanical action of the mechanochemical treatment, and the reduction reaction of (A) the substrate takes place.

[0052] (Added mechanical energy) In mechanochemical processing, the amount of mechanical energy added is not particularly limited, as long as it is sufficient to react (A) the substrate, (B) the metal, and (C) the proton source to carry out the reduction reaction of (A) the substrate. For example, when a mixing device is used in a mechanochemical treatment, the mixing speed is not particularly limited. It can be appropriately determined considering the physical properties, reactivity, and abundance of (A) the substrate, (B) the metal, (C) the proton source, and other components present in the reaction system, as well as the reaction conditions in the mechanochemical treatment. For example, when a ball mill is used, the vibration frequency of shaking and stirring can be, for example, 5 Hz or higher, preferably 10 Hz or higher, more preferably 20 Hz or higher, and for example, 100 Hz or lower, preferably 80 Hz or lower.

[0053] (temperature) In mechanochemical processing, the temperature inside the reaction vessel (temperature of the reaction system) is not particularly limited, as long as it is a temperature at which the reduction reaction of (A) the substrate can be carried out. It can be appropriately determined considering the physical properties, reactivity, abundance of (A) the substrate, (B) the metal, (C) the proton source, and other components present in the reaction system, as well as the reaction conditions in the mechanochemical processing. For example, it is 0°C or higher, preferably 10°C or higher, and for example, 500°C or lower, preferably 300°C or lower, and more preferably 250°C or lower. In the present invention, it can be carried out at room temperature (25°C). The method of controlling the temperature is not particularly limited. Various temperature control methods used when carrying out chemical reactions can be used. For example, methods include controlling the temperature inside the reaction vessel (reaction system) by heating or cooling the reaction vessel itself using heating or cooling means, controlling the temperature inside the reaction vessel by covering the reaction vessel with a heat transfer medium at a predetermined temperature, and controlling the temperature inside the reaction vessel by providing a heating element or cooling element. When carrying out a reaction under heating conditions, a method of controlling the temperature inside the reaction vessel by applying hot air generated by a heat gun to the reaction vessel can be used, from the viewpoint of safety and ease of temperature control operation.

[0054] (pressure) In mechanochemical processing, the pressure inside the reaction vessel (pressure of the reaction system) is not particularly limited, as long as it is a pressure that allows at least (A) the reduction reaction of the substrate to take place. It can be appropriately determined considering the physical properties, reactivity, abundance of (A) the substrate, (B) the metal, (C) the proton source, and other components present in the reaction system, as well as the reaction conditions in the mechanochemical processing. For example, it can be a substantially vacuum, reduced pressure, pressurized, or atmospheric pressure state. If it is possible to perform the mechanochemical processing at atmospheric pressure without pressurizing or depressurizing, it is preferable to use atmospheric pressure from the viewpoints of operability, reaction equipment, cost, safety, etc. The method of controlling the pressure is not particularly limited. When pressurizing or depressurizing a reaction vessel (reaction system), various pressure control methods used in chemical reactions can be used. For example, the pressure inside the reaction vessel (pressure of the reaction system) can be increased or decreased using pressurizing or depressurizing means.

[0055] (atmosphere) In mechanochemical processing, the atmosphere inside the reaction vessel (the atmosphere of the reaction system) is not particularly limited, as long as it is an atmosphere capable of carrying out the reduction reaction of at least (A) the substrate. It can be appropriately determined considering the physical properties, reactivity, abundance of (A) the substrate, (B) the metal, (C) the proton source, and other components present in the reaction system, as well as the reaction conditions in the mechanochemical processing. For example, it can be carried out in an air atmosphere, which is a non-inert atmosphere, without any special atmosphere adjustment. Alternatively, it can be carried out in an inert gas atmosphere such as nitrogen, helium, neon, or argon, if necessary. In the present invention, it is usually carried out in an air atmosphere, which is a non-inert atmosphere.

[0056] (process) In mechanochemical treatment, the treatment time is not particularly limited, as long as it is sufficient to allow the reduction reaction of (A) the substrate to take place. It can be appropriately determined considering the physical properties, reactivity, and abundance of (A) the substrate, (B) the metal, (C) the proton source, and other components present in the reaction system, as well as the reaction conditions in the mechanochemical treatment. For example, it can be 15 seconds or more, usually 30 seconds or more, preferably 1 minute or more, more preferably 3 minutes or more, and even more preferably 5 minutes or more. The upper limit of the reaction time is not particularly limited, but for example, it can be 24 hours or less, preferably 12 hours or less, more preferably 6 hours or less, even more preferably 1 hour or less, and even more preferably 30 minutes or less.

[0057] (Order of adding the substances / substrates to be treated during processing, post-reaction treatment, etc.) In mechanochemical processing, the order in which (A) the substrate, (B) the metal, (C) the proton source, and other components present in the reaction system are added to the reaction vessel is not particularly limited. Nor is the method of addition particularly limited. For example, all components may be added to the reaction vessel at once, or some components may be added to the reaction vessel and reacted first, and then the remaining components may be added to the reaction vessel. After performing mechanochemical treatment and the reduction reaction of the substrate (A), the reaction product obtained can be purified if necessary. The purification method is not particularly limited, and for example, methods such as filtration, distillation, recrystallization, column chromatography, washing with a solvent, etc. are used.

Examples

[0058] Hereinafter, the present invention will be described in detail with specific examples. These specific examples are merely one aspect of the present invention. The present invention is not limited by these examples in any way. "equiv" represents "equivalent".

[0059] In the examples and comparative examples, when performing the reaction using a ball mill, each reagent was placed in a stainless steel ball mill jar, and a ball mill MM400 type manufactured by Verder Scientific Co., Ltd. (formerly Retsch) was used.

[0060] {Mechanochemical reduction using an alkali metal} <<Mechanochemical reduction using metallic sodium>> The compounds Aa1 - Aa11 containing unsaturated bonds and the reaction products Ab1 - Ab11 used in Examples A1 - A28 and Reference Examples A1 - A4 are as follows. In the structural formula, "Me" represents a methyl group, "iPr" represents an isopropyl group, and "tBu" represents a tertiary butyl group, respectively.

[0061] <Aromatic hydrocarbon compound>

Chemical formula

[0062] <Reaction product>

Chemical formula

[0063] <Mechanochemical reduction of Decylbenzene> (Example A1) In a 10 mL stainless steel ball mill jar containing two 10 mm diameter stainless steel balls, 1.0 mmol of Decylbenzene (Aa1) was added as the substrate under air conditions. A 6.0 equiv of a metallic sodium block approximately 3-5 mm long, 3-5 mm wide, and 3 mm thick was added relative to the substrate. A 6.0 equiv of 1,3-Dimethyl-2-imidazolidinone was added relative to the substrate. A 3.0 equiv of D-(+)-glucose was added as a proton source. The lid of the ball mill jar was then closed. The ball mill jar was then mounted in a ball mill, and the reaction was carried out by shaking and stirring at a vibration frequency of 30 Hz for 15 minutes at room temperature (internal temperature 25°C). Next, the lid of the ball mill jar was opened, water was added to terminate the reaction, and 1-Decyl-1,4-cyclohexadiene (Ab1) was obtained as the reaction product. The isolation yield of the reaction product was 99%.

[0064] (Example A2) The reaction was carried out in the same manner as in Example A1, except that a 4.0 equiv of metallic sodium mass and a 4.0 equiv of 1,3-Dimethyl-2-imidazolidinone were added relative to the substrate, and the reaction product was obtained. 1 The yield of the 1H NMR spectrum was 86%.

[0065] (Example A3) The reaction was carried out in the same manner as in Example A1, except that tert-butanol was added as a proton source in an amount equal to 3.0 equiv relative to the substrate, instead of D-(+)-glucose, to obtain the reaction product. 1 The yield of 1H NMR was 6%.

[0066] (Example A4) The reaction was carried out in the same manner as in Example A1, except that tert-butanol was added in an amount equal to 3.0 equiv relative to the substrate, instead of D-(+)-glucose as the proton source, and 100 mg of sea sand (particle size 425 μm to 850 μm) was added, and the reaction time was 30 minutes after shaking and stirring, to obtain the reaction product. 1 The yield of 1H NMR was 18%.

[0067] (Example A5) The reaction was carried out in the same manner as in Example A1, except that 2-propanol was added as a proton source in an amount equal to 3.0 equiv relative to the substrate, instead of D-(+)-glucose, to obtain the reaction product. 1 The yield of 1H NMR was 13%.

[0068] (Example A6) The reaction was carried out in the same manner as in Example A1, except that 1-adamantanol was added as a proton source in an amount equal to 3.0 equiv relative to the substrate, instead of D-(+)-glucose, to obtain the reaction product. 1 The yield of 1H NMR was 18%.

[0069] (Example A7) The reaction was carried out in the same manner as in Example A1, except that cellulose was added as a proton source in an amount equal to 3.0 equiv relative to the substrate, instead of D-(+)-glucose, to obtain the reaction product. 1 The yield of 1H NMR was 13%.

[0070] (Example A8) The reaction was carried out in the same manner as in Example A1, except that hexamethylphosphoric triamide was added in an amount equal to 6.0 equiv relative to the substrate instead of 1,3-Dimethyl-2-imidazolidinone, and the reaction product was obtained. 1 The yield of 1H NMR was 19%.

[0071] (Example A9) The reaction was carried out in the same manner as in Example A1, except that 15-Crown5-Ether was added in an amount equal to 6.0 equiv relative to the substrate instead of 1,3-Dimethyl-2-imidazolidinone, and the reaction product was obtained. 1 The yield of the 1H NMR spectrum was 23%.

[0072] (Example A10) The reaction was carried out in the same manner as in Example A1, except that one stainless steel ball with a diameter of 10 mm was used, and the reaction product was obtained. 1 The yield of the 1H NMR was 85%.

[0073] (Example A11) The reaction was carried out in the same manner as in Example A1, except that the reaction was performed by shaking and stirring at an vibration frequency of 25 Hz, and the reaction product was obtained. 1 The yield of the 1H NMR spectrum was 72%.

[0074] (Example A12) The reaction was carried out in the same manner as in Example A1, except that the reaction time was set to 5 minutes by shaking and stirring, and the reaction product was obtained. 1 The yield of 1H NMR was 61%.

[0075] (Reference example A1) In a reaction vessel, under air, 1.0 mmol of Decylbenzene (Aa1) was added as the substrate, along with 6.0 equiv of metallic sodium relative to the substrate, 6.0 equiv of 1,3-Dimethyl-2-imidazolidinone relative to the substrate, 3.0 equiv of D-(+)-glucose relative to the substrate as a proton source, and Tetrahydrofuran (THF) was added to a concentration of 0.28 M (0.28 mol / L) of Decylbenzene (Aa1). The mixture was stirred at room temperature (25°C) for 15 minutes to carry out the reaction, and water was added to the reaction vessel to terminate the reaction. The reaction product, 1-Decyl-1,4-cyclohexadiene (Ab1), was then prepared. 1 The yield of 1H NMR was less than 5%.

[0076] (Reference example A2) The reaction was carried out in the same manner as in Example A1, except that a dispersion of metallic sodium (dispersion solvent: mineral oil) was added in an amount such that the metallic Na was 6.0 equiv relative to the substrate, instead of metallic sodium. The reaction product, 1-Decyl-1,4-cyclohexadiene (Ab1), 1 The yield of 1H NMR was less than 5%.

[0077] (Reference example A3) In a reaction vessel, under air, 1.0 mmol of Decylbenzene (Aa1) was added as the substrate, along with 4.0 equiv of metallic sodium relative to the substrate, 2.6 mL of 1,3-Dimethyl-2-imidazolidinone, 4.0 equiv of tert-Butanol relative to the substrate as a proton source, and 1.0 mL of Tetrahydrofuran (THF). The mixture was stirred at room temperature (25°C) for 15 minutes to allow the reaction to proceed, and water was added to the reaction vessel to terminate the reaction. The reaction product, 1-Decyl-1,4-cyclohexadiene (Ab1), was then prepared. 1 The yield of 1H NMR was less than 5%.

[0078] (Reference example A4) In a reaction vessel, under air, 1.0 mmol of Decylbenzene (Aa1) was added as the substrate, along with 9.0 equiv of metallic sodium relative to the substrate, 9.0 equiv of 15-Crown 5-Ether relative to the substrate, 9.0 equiv of 2-Propanol relative to the substrate as a proton source, and 6.0 mL of Tetrahydrofuran (THF). The reaction was carried out by stirring at room temperature (25°C) for 35 minutes, and then water was added to the reaction vessel to terminate the reaction. The reaction product, 1-Decyl-1,4-cyclohexadiene (Ab1), was... 1 The yield of 1H NMR was less than 5%.

[0079] <Mechanochemical reduction of various substrates> (Examples A13-A21) Into a 10 mL stainless steel ball mill jar containing two 10 mm diameter stainless steel balls, 1.0 mmol of substrate Aan, a piece of metallic sodium in an amount of X A equiv with respect to the substrate, 1,3 - Dimethyl - 2 - imidazolidinone in an amount of Y A equiv with respect to the substrate, and D-(+)-glucose as a proton source in an amount of Z A equiv with respect to the substrate were placed, and the lid of the ball mill jar was closed. Then, the ball mill jar was attached to a ball mill and shaken / stirred at a vibration frequency of 30 Hz at room temperature (internal temperature 25 °C) for T A minutes to carry out the reaction. Next, the lid of the ball mill jar was opened, water was added to terminate the reaction, and the reaction product Abn was obtained. The types of Aan, X A , Y A , Z A , T A and Abn, and the yield of the reaction product (isolated yield or 1 1H NMR yield) are shown in Table 1.

[0080]

Table 1

[0081] <Mechanochemical Reduction Using Na of Naphthalene> (Example A22) A 10 mL stainless steel ball mill jar containing two 10 mm diameter stainless steel balls was charged under air with 1.0 mmol of substrate Aa11 (Naphthalene), an amount of metallic sodium chunks equivalent to 6.0 equiv relative to the substrate, 6.0 equiv of 1,3-Dimethyl-2-imidazolidinone relative to the substrate, and an amount of D-(+)-glucose as a proton source equivalent to 3.0 equiv relative to the substrate. The lid of the ball mill jar was then closed. Subsequently, the ball mill jar was mounted on a ball mill and shaken / stirred at a vibration frequency of 30 Hz for 30 minutes at room temperature (internal temperature 25 °C) to effect the reaction. Next, the lid of the ball mill jar was opened and water was added to terminate the reaction, yielding reaction product Ab11 (1,2,3,4,5,8-Hexahydronaphthalene). The isolated yield of the reaction product was 57%.

[0082] <Mechanochemical Reduction of Acenaphthylene Using Na> (Example A23) A 10 mL stainless steel ball mill jar containing two 10 mm diameter stainless steel balls was charged under air with 1.0 mmol of substrate Aa12 (Acenaphthylene), an amount of metallic sodium chunks equivalent to 2.2 equiv relative to the substrate, 6.0 equiv of 1,3-Dimethyl-2-imidazolidinone relative to the substrate, and an amount of D-(+)-glucose as a proton source equivalent to 3.0 equiv relative to the substrate. The lid of the ball mill jar was then closed. Subsequently, the ball mill jar was mounted on a ball mill and shaken / stirred at a vibration frequency of 30 Hz for 15 minutes at room temperature (internal temperature 25 °C) to effect the reaction. Next, the lid of the ball mill jar was opened and water was added to terminate the reaction, yielding reaction product Ab12 (Acenaphthene). The isolated yield of the reaction product was 81%.

[0083] <Mechanochemical Reduction of Tetraphenylethylene Using Na> (Example A24) In a 10 mL stainless steel ball mill jar containing two 10 mm diameter stainless steel balls, 1.0 mmol of substrate Aa13 (Tetraphenylethylene), 3.0 equiv of metallic sodium, 6.0 equiv of 1,3-Dimethyl-2-imidazolidinone, and 3.0 equiv of D-(+)-glucose as a proton source were added under air conditions, and the lid of the ball mill jar was closed. The ball mill jar was then mounted on a ball mill, and the reaction was carried out by shaking and stirring at a vibration frequency of 30 Hz for 15 minutes at room temperature (internal temperature 25°C). Next, the lid of the ball mill jar was opened, water was added to terminate the reaction, and the reaction product Ab13 (1,1,2,2-Tetraphenylethane) was obtained. The isolation yield of the reaction product was 78%.

[0084] <Mechanochemical reduction using inorganic particles> (Example A25) In a 5 mL stainless steel ball mill jar containing two 10 mm diameter stainless steel balls, 1.0 mmol of Decylbenzene (Aa1) was added as the substrate, along with a 6.0 equiv of metallic sodium granules relative to the substrate, a 6.0 equiv of 1-Adamantanol as the proton source, a 6.0 equiv of 1,3-Dimethyl-2-imidazolidinone relative to the substrate, and 100 mg of sea sand (particle size 425 μm to 850 μm) under air conditions. The lid of the ball mill jar was then closed. The ball mill jar was then mounted in a ball mill, and the reaction was carried out by shaking and stirring at a vibration frequency of 30 Hz for 30 minutes at room temperature (internal temperature 25 °C). Next, the lid of the ball mill jar was opened, water was added to terminate the reaction, and 1-Decyl-1,4-cyclohexadiene (Ab1) was obtained as the reaction product. The isolation yield of the reaction product was 93%.

[0085] (Examples A26-A28) Reaction products Ab2, Ab5, and Ab7 were obtained in the same manner as in Example A25, except that Aa2, Aa5, or Aa7 was used as the substrate instead of Aa1. The yields (isolation yield and / or 1 1H NMR yield) of the reaction products are shown in Table 2.

[0086]

Table 2

[0087] <<Mechanochemical Reduction Using Lithium Metal>> The aromatic hydrocarbon compounds Ba1 to Ba38 and the reaction products Bb1 to Bb38, Bb1', and Bb32' used in Examples B1 to B53 are as follows. In the structural formulas, "Me" represents a methyl group, "iPr" represents an isopropyl group, "tBu" represents a tertiary butyl group, "TBS" represents a tertiary butyldimethylsilyl group, and "Boc" represents a tertiary butoxycarbonyl group, respectively. The lithium wire used as the lithium metal source was approximately 3 mm in length and approximately 43.2 mm in diameter. The adhering oil was wiped off, and it was used after being scratched slightly.

[0088] <Aromatic Hydrocarbon Compound>

Chemical Formula

[0089] <Reaction Product>

Chemical Formula

[0090] <Mechanochemical Reduction of Benzoic Acid> (Example B1) In a 1.5 mL stainless steel ball mill jar containing one 5 mm diameter stainless steel ball, 0.25 mmol of benzoic acid (Ba1), 3.0 equiv of lithium wire relative to the substrate, 6.0 equiv of ethylenediamine relative to the substrate, and 6.0 equiv of tetrahydrofuran (THF) relative to the substrate were added under air conditions, and the lid of the ball mill jar was closed. Then, the ball mill jar was mounted on a ball mill, and the reaction was carried out by shaking and stirring at a vibration frequency of 30 Hz for 30 minutes at room temperature (internal temperature 25°C). Next, the lid of the ball mill jar was opened, water was added to terminate the reaction, and Cyclohexa-2,5-diene-1-carboxylic acid (Bb1) was obtained as the reaction product. 1 The yield of the 1H NMR spectrum was 38%.

[0091] (Examples B2-B8) In a 5 mL stainless steel ball mill jar containing one 10 mm diameter stainless steel ball, the substrate Ba1 was added under air conditions. B mmol, lithium wire against the substrate X B The amount of ethylenediamine that is equivable, relative to the substrate Y B The amount that is equivable and the amount of Tetrahydrofuran (THF) relative to the substrate Z B The equivalent amount was added, and the lid of the ball mill jar was closed. Then, the ball mill jar was attached to the ball mill, and the reaction was carried out by shaking and stirring at room temperature (internal temperature 25°C) for TB minutes at an oscillation frequency of 30 Hz. Next, the lid of the ball mill jar was opened, water was added to terminate the reaction, and Cyclohexa-2,5-diene-1-carboxylic acid (Bb1) was obtained as the reaction product. B , X B , Y B , Z B and T B value And the reaction product 1 The 1H NMR yields are shown in Table 3.

[0092]

Table 3

[0093] (Reference Example B1) 1.0 mmol of substrate Ba1, an amount of lithium wire equivalent to 2.5 equiv with respect to the substrate, and an amount of Ethylenediamine equivalent to 5.0 equiv with respect to the substrate were placed in a test tube, and the reaction was carried out at room temperature (internal temperature 25 °C) for 120 minutes under a nitrogen atmosphere. Then, water was added to terminate the reaction, and Cyclohexa-2,5-diene-1-carboxylic acid (Bb1) was obtained as the reaction product. The 1 1H NMR yield of the reaction product was 44%.

[0094] <Mechanochemical Reduction of n-Butoxybenzene> (Example B9) 1.0 mmol of n-Butoxybenzene (Ba2) as a substrate, an amount of lithium wire equivalent to 2.5 equiv with respect to the substrate, an amount of Ethylenediamine equivalent to 5.0 equiv with respect to the substrate, and an amount of tert-Butanol equivalent to 1.5 equiv with respect to the substrate were placed in a 5 mL stainless steel ball mill jar containing one 10 mm diameter stainless steel ball under air, and the lid of the ball mill jar was closed. Then, the ball mill jar was attached to the ball mill, and the reaction was carried out by shaking and stirring at room temperature (internal temperature 25 °C) for 1 minute at a vibration frequency of 30 Hz. Next, the lid of the ball mill jar was opened and water was added to terminate the reaction, and 1-n-Butoxy-1,4-cyclohexadiene (Bb2), 1-n-Butoxy-1-cyclohexene (Bb2’), Phenol (Bb2’’), and 1-n-Butoxy-1,3-cyclohexadiene (Bb2’’’) were obtained as the reaction products. The conversion of n-Butoxybenzene (Ba2) was 85%, and the 1 1H NMR yield of the reaction product Bb2 was 23%, the 1H NMR yield of the reaction product Bb2’ was 6%, the 1 1H NMR yield of the reaction product Bb2’’ was 7%, the1 The yield of 1H NMR was 32%.

[0095] (Example B10) In Example B9, the reaction product was obtained in the same manner as in Example B9, except that an additional 5.0 equiv of Tetrahydrofuran (THF) was added. The conversion of n-Butoxybenzene (Ba2) was 82%, and the reaction product Bb2 1 The ¹H NMR yield was 57%, the ¹H NMR yield of the reaction product Bb2' was 7%, and the yield of the reaction product Bb2'' was 7%. 1 The yield of the 1H NMR was 5%, and the reaction product Bb2''' 1 The yield of 1H NMR was 9%.

[0096] (Example B11) In Example B9, the reaction product was obtained in the same manner as in Example B9, except that lithium wire was added in an amount equal to 3.0 equiv relative to the substrate, ethylenediamine in an amount equal to 6.0 equiv relative to the substrate, tert-butanol in an amount equal to 2.5 equiv relative to the substrate, and tetrahydrofuran (THF) in an amount equal to 5.0 equiv. The conversion of n-butoxybenzene (Ba2) was 100%, and the reaction product Bb2 1 The 1H NMR yield was 89%, and the reaction product Bb2' 1 The 1H NMR yield was 11%, and the reaction product Bb2'' 1 1H NMR yield was 0%, reaction product Bb2''' 1 The 1H NMR yield was 0%.

[0097] <Mechanochemical reduction of various substrates> (Examples B12-B32) In a 5mL stainless steel ball mill jar containing one 10mm diameter stainless steel ball, add the substrate Ban under air. B mmol, lithium wire X B mmol, Ethylenediamine Y B mmol and tert-butanol are used in V BI added mmol and closed the lid of the ball mill jar. Then I attached the ball mill jar to the ball mill and left it at room temperature (internal temperature 25°C) until it was fully heated. B The reaction was carried out by shaking and stirring at an oscillation frequency of 30 Hz for several minutes. Then, the lid of the ball mill jar was opened and water was added to terminate the reaction, yielding the reaction product Bbn. The aforementioned Ban, W B , X B , Y B , V B , T B and the type of Bbn and the yield of the reaction product (isolation yield and / or 1 The yields of the 1H NMR spectrum are shown in Table 4.

[0098] [Table 4]

[0099] <Mechanochemical reduction of various substrates using Tetrahydrofuran (THF)> (Examples B33-B41) In a 5mL stainless steel ball mill jar containing one 10mm diameter stainless steel ball, add the substrate Ban under air. B mmol, lithium wire against the substrate X B mmol and Ethylenediamine are used as substrates. B mmol and tert-butanol are used as substrates. B mmol and Tetrahydrofuran (THF) were used with respect to the substrate Z B I added mmol and closed the lid of the ball mill jar. Then I attached the ball mill jar to the ball mill and left it at room temperature (internal temperature 25°C) until it was fully heated. B The reaction was carried out by shaking and stirring at an oscillation frequency of 30 Hz for several minutes. Then, the lid of the ball mill jar was opened and water was added to terminate the reaction, yielding the reaction product Bbn. The aforementioned Ban, W B , X B , Y B , V B , Z B , T Band the types of Bbn and the yields of the reaction products (isolated yield and / or 1 H NMR yield) are shown in Table 5.

[0100]

Table 5

[0101] <Production of cyclic γ-keto acid by mechanochemical reduction of m-Anisic acid> (Example B42) Into a 5 mL stainless steel ball mill jar containing one 10 mm diameter stainless steel ball, 1.00 mmol of the substrate Ba31 (m-Anisic acid), 3.06 mmol of lithium wire and 6.00 mmol of ethylenediamine were added under air, and the lid of the ball mill jar was closed. Then, the ball mill jar was attached to the ball mill and shaken and stirred at a vibration frequency of 30 Hz for 1 minute at room temperature (internal temperature 25 °C) to carry out the reaction. Next, the lid of the ball mill jar was opened and water was added to terminate the reaction, and the reaction product Bb31 (5-Oxo-2-cyclohexene- carboxylic acid) was obtained. The isolated yield of the reaction product Bb31 was 73%, 1 and the H NMR yield was 80%.

[0102] <Mechanochemical reduction of 1-Naphthoic acid> (Example B43) In a 5 mL stainless steel ball mill jar containing one 10 mm diameter stainless steel ball, 1.00 mmol of the substrate Ba32 (1-Naphthoic acid), 2.97 mmol of lithium wire, and 6.00 mmol of ethylenediamine relative to the substrate were added under air conditions, and the lid of the ball mill jar was closed. The ball mill jar was then mounted in a ball mill, and the reaction was carried out by shaking and stirring at a vibration frequency of 30 Hz for 1 minute at room temperature (internal temperature 25°C). Next, the lid of the ball mill jar was opened, water was added to terminate the reaction, and the reaction product Bb32 (1,4-dihydronaphthalene-1-carboxylic acid) was obtained. The isolation yield of the reaction product Bb32 was 83%. 1 The yield of 1H NMR was 96%.

[0103] (Example B44) In a 5 mL stainless steel ball mill jar containing one 10 mm diameter stainless steel ball, 0.5 mmol of Ba32 (1-Naphthoic acid), 3.06 mmol of lithium wire, 6.00 mmol of ethylenediamine, and 1.50 mmol of tert-butanol were added as substrates under air conditions, and the lid of the ball mill jar was closed. Then, the ball mill jar was mounted on a ball mill, and the reaction was carried out by shaking and stirring at a vibration frequency of 30 Hz for 1 minute at room temperature (internal temperature 25°C). Next, the lid of the ball mill jar was opened, water was added to terminate the reaction, and a crude reaction mixture was obtained. Analysis of the crude reaction mixture revealed that the reaction product Bb32'(1,4,5,8-Tetrahydro-1-naphthoic Acid) 1 The 1H NMR yield was 49%. Additionally, the reaction product Bb32 (1,4-dihydronaphthalene-1-carboxylic acid) was present as a by-product at 18%. 1 (H NMR yield) and 1,2,3,4,5,8-hexahydronaphthalene-1-carboxylic acid at 15% ( 1 It was found that 1H NMR yield was being produced.

[0104] <Mechano-Chemical Reduction under Optimal Conditions of 1-Indanol> (Example B45) Into a 5 mL stainless steel ball mill jar containing one 10 mm diameter stainless steel ball, 0.75 mmol of substrate Ba33 (1-Indanol), 3.36 mmol of lithium wire, 6.75 mmol of ethylenediamine and 2.25 mmol of tert-butanol were added under air, and the lid of the ball mill jar was closed. Then, the ball mill jar was attached to the ball mill, and the reaction was carried out by shaking and stirring at a vibration frequency of 30 Hz for 1 minute at room temperature (internal temperature 25 °C). Next, the lid of the ball mill jar was opened, water was added to terminate the reaction, and the reaction product Bb33 (2,3,4,7-Tetrahydro-1H-indene) was obtained. The isolated yield of the reaction product Bb33 was 51%, 1 The 1H NMR yield was 54%. In addition, the reaction product Bb33’ (4,7-Dihydro-1-indanol) in which the phenyl ring of the substrate Ba33 (1-Indanol) was reduced was not detected.

[0105] <Mechano-Chemical Reduction under Optimal Conditions of N-(2-Phenylethyl)acetamide> (Example B46) Into a 5 mL stainless steel ball mill jar containing one 10 mm diameter stainless steel ball, 0.50 mmol of substrate Ba34 (N-(2-Phenylethyl)acetamide), 2.57 mmol of lithium wire, 5.00 mmol of ethylenediamine and 1.50 mmol of tert-butanol were added under air, and the lid of the ball mill jar was closed. Then, the ball mill jar was attached to the ball mill, and the reaction was carried out by shaking and stirring at a vibration frequency of 30 Hz for 1 minute at room temperature (internal temperature 25 °C). Next, the lid of the ball mill jar was opened, water was added to terminate the reaction, and the reaction product Bb34 (1-(2-Aminoethyl)-1,4-cyclohexadiene) was obtained. The 1H NMR yield of the reaction product Bb 34 of 1 was 60%. In addition, as the main inseparable by-product, Bb34’ (N-(2-(cyclohexa-1,4-dien-1-yl)ethyl)acetamide) was formed in a 1H NMR yield of 12%.

[0106] <Mechanochemical Reduction of Tetraphenylethylene Using Li> (Example B47) Into a 5 mL stainless steel ball mill jar containing one 10 mm diameter stainless steel ball, 0.50 mmol of the substrate Ba35 (Tetraphenylethylene; the same as substrate Aa13), 3.01 mmol of lithium wire and 6.00 mmol of Ethylenediamine were added under air, and the lid of the ball mill jar was closed. Then, the ball mill jar was attached to the ball mill, and the reaction was carried out by shaking and stirring at a vibration frequency of 30 Hz for 1 minute at room temperature (internal temperature 25 °C). Next, the lid of the ball mill jar was opened and water was added to terminate the reaction, and the reaction product Bb35 (1,1,2,2-Tetraphenylethane; the same as reaction product Ab13) was obtained. The isolated yield of the reaction product Bb35 was 82%, 1 and the 1H NMR yield was 91%.

[0107] <Mechanochemical Reduction of Acridine> (Example B48) Into a 5 mL stainless steel ball mill jar containing one 10 mm diameter stainless steel ball, 1.00 mmol of the substrate Ba36 (Acridine), 3.00 mmol of lithium wire and 6.00 mmol of Ethylenediamine were added under air, and the lid of the ball mill jar was closed. Then, the ball mill jar was attached to the ball mill, and the reaction was carried out by shaking and stirring at a vibration frequency of 30 Hz for 1 minute at room temperature (internal temperature 25 °C). Next, the lid of the ball mill jar was opened and water was added to terminate the reaction, and the reaction product Bb36 (9,10-dihydroacridine) was obtained. The isolated yield of the reaction product Bb36 was 97%.

[0108] <Mechanochemical Reduction of N-Methylindole> (Example B49) Into a 5 mL stainless steel ball mill jar containing one 10 mm diameter stainless steel ball, 1.00 mmol of substrate Ba37 (N-Methylindole), 3.52 mmol of lithium wire, 7.00 mmol of Ethylenediamine and 5.00 mmol of Tetrahydrofuran (THF) were added under air, and the lid of the ball mill jar was closed. Then, the ball mill jar was attached to a ball mill, and shaken and stirred at a vibration frequency of 30 Hz for 1 minute at room temperature (internal temperature 25 °C) to carry out the reaction. Next, the lid of the ball mill jar was opened and water was added to terminate the reaction, and the reaction product Bb37 (1-methyl-2,3-dihydroindole) was obtained. The isolated yield of the reaction product Bb37 was 54%, 1 The H NMR yield was 60%.

[0109] <Mechanochemical reduction of Indole> (Example B50) Into a 5 mL stainless steel ball mill jar containing one 10 mm diameter stainless steel ball, 0.75 mmol of substrate Ba38 (Indole), 2.91 mmol of lithium wire, 6.00 mmol of Ethylenediamine, 3.75 mmol of Tetrahydrofuran (THF) and 1.88 mmol of tert-Butanol were added under air, and the lid of the ball mill jar was closed. Then, the ball mill jar was attached to a ball mill, and shaken and stirred at a vibration frequency of 30 Hz for 1 minute at room temperature (internal temperature 25 °C) to carry out the reaction. Next, the lid of the ball mill jar was opened and water was added to terminate the reaction, and the reaction product Bb38 (4,7-Dihydro-1H-indole) was obtained. The isolated yield of the reaction product Bb38 was 37%, 1 The H NMR yield was 48%.

[0110] <Mechanochemical reduction of Benzoic acid using Methyl iodide> (Example B51) A 5 mL stainless steel ball mill jar containing one 10 mm diameter stainless steel ball was charged with 1.00 mmol of substrate Ba1, 2.50 mmol of lithium wire, and 5.00 mmol of Ethylenediamine under air, and the lid of the ball mill jar was closed. Then, the ball mill jar was attached to a ball mill and shaken / stirred at a vibration frequency of 30 Hz for 1 minute at room temperature (internal temperature 25 °C) to carry out the reaction. Next, the lid of the ball mill jar was opened and Methyliodide was added in an amount equivalent to 3.0 equiv to the substrate, and the reaction was carried out by shaking / stirring at a vibration frequency of 30 Hz for 5 minutes at room temperature (internal temperature 25 °C). Then, the lid of the ball mill jar was opened and water was added to terminate the reaction, and the reaction product Bb1’ (1-Methylcyclohexa-2,5-diene-1-carboxylic acid) was obtained. The 1 1H NMR yield was 51%.

[0111] <<Mechanochemical Reduction on Gram-scale>> The aromatic hydrocarbon compounds Ba5 and Ba36 and the reaction products Bb5 and Bb36 used in Examples C1 to C3 are the same compounds as those used in Example B15 and Example B'48, respectively.

[0112] [[ID=:12]]<Mechanochemical Reduction of 3,5-Dimethylbenzoic Acid on Gram-scale> (Example C1) A 10 mL stainless steel ball mill jar containing two 15 mm diameter stainless steel balls was charged under air with 7.0 mmol (1.05 g) of the substrate Ba5(3,5 - Dimethylbenzoic Acid), cut into small pieces of about 3 mm, 17.5 mmol (122.0 mg) of lithium wire, and 35.0 mmol (2.104 g) of Ethylenediamine. The lid of the ball mill jar was then closed. Subsequently, the ball mill jar was mounted on a ball mill and shaken / stirred at a vibration frequency of 30 Hz for 1 minute at room temperature (internal temperature 25 °C) to effect the reaction. Next, the lid of the ball mill jar was opened and water was added to terminate the reaction. The contents were washed with an organic solvent and then by evaporation to obtain the reaction product Bb5(3,5 - Dimethyl - 2,5 - cyclohexadiene - 1 - carboxylic acid). The isolated yield of the reaction product Bb5 was 98% (6.85 mmol, 1.042 g).

[0113] <Mechanochemical Reduction of Acridine on a Gram - scale> (Example C2) A 10 mL stainless steel ball mill jar containing two 15 mm diameter stainless steel balls was charged under air with 6.0 mmol (1.075 g) of the substrate Ba36(Acridine), cut into small pieces of about 3 mm, 18.0 mmol (125.5 mg) of lithium wire, and 36.0 mmol (2.164 g) of Ethylenediamine. The lid of the ball mill jar was then closed. Subsequently, the ball mill jar was mounted on a ball mill and shaken / stirred at a vibration frequency of 30 Hz for 1 minute at room temperature (internal temperature 25 °C) to effect the reaction. Next, the lid of the ball mill jar was opened and water was added to terminate the reaction, yielding the reaction product Bb36(9,10 - dihydroacridine). The isolated yield of the reaction product Bb36 was 95% (5.72 mmol, 1.037 g).

[0114] (Example C3) A 10 mL stainless steel ball mill jar containing two 10 mm diameter stainless steel balls was charged with 1.073 g (6.0 mmol) of substrate Ba36(Acridine), an amount of metallic sodium chunks corresponding to 2.6 equiv relative to the substrate, an amount of 1,3-Dimethyl-2-imidazolidinone corresponding to 6.0 equiv relative to the substrate, and an amount of D-(+)-glucose as a proton source corresponding to 3.0 equiv relative to the substrate under air. The lid of the ball mill jar was closed. Then, the ball mill jar was mounted on a ball mill and shaken / stirred at a vibration frequency of 30 Hz for 15 minutes at room temperature (internal temperature 25 °C) to conduct the reaction. Next, the lid of the ball mill jar was opened and water was added to terminate the reaction, and the reaction product Bb36(9,10-dihydroacridine) was obtained. The isolated yield of the reaction product Bb36 was 95% (5.72 mmol, 1.030 g).

[0115] {Mechanochemical reduction using alkaline earth metals} <<Mechanochemical reduction using metallic calcium>> The metallic calcium used in Example D1 was metallic calcium chunks with a length of about 3 - 5 mm, a width of about 3 - 5 mm, and a thickness of about 3 mm.

[0116] <Mechanochemical reduction using Ca of Naphthalene> (Example D1) In a 5 mL stainless steel ball mill jar containing two 10 mm diameter stainless steel balls, 1.0 mmol of substrate D1 (Naphthalene; same as substrate Ba15), 2.5 mmol of metallic calcium, 5.0 mmol of ethylenediamine, and 3.0 mmol of tert-butanol were added under air conditions, and the lid of the ball mill jar was closed. The ball mill jar was then mounted on a ball mill, and the reaction was carried out by shaking and stirring at a vibration frequency of 30 Hz for 60 minutes at room temperature (internal temperature 25°C). Next, the lid of the ball mill jar was opened, water was added to terminate the reaction, and the reaction mixture was obtained. Analysis of the reaction mixture showed that the isolation yield of the main reaction product D1 (1,2,3,4-Tetrahydronaphthalene) was 31%, and the isolation yield of the side reaction product D1' (1,4,5,8-Tetrahydronaphthalene) was 3%.

Claims

1. (A) A reduction method comprising reducing a substrate by mechanochemical treatment using at least (B) a metal and (C) a proton source, The substrate (A) is one or more aromatic hydrocarbon compounds which may have one or more substituents bonded to an aromatic ring. A reduction method wherein the (B) metal comprises one or more selected from alkali metals or alkaline earth metals.

2. A reduction method comprising reducing (A) a substrate by mechanochemical treatment using at least (B) a metal and (C) a proton source, The (A) substrate comprises one or more selected from the group consisting of aromatic hydrocarbon compounds, aromatic heterocyclic compounds, internal alkyne-containing compounds, conjugated alkene compounds, and α,β-unsaturated carbonyl compounds. A reduction method wherein the (B) metal comprises one or more selected from the group consisting of lithium, sodium, and calcium.

3. The reduction method according to claim 1, wherein the (B) metal comprises one or more selected from the group consisting of lithium, sodium, potassium, magnesium, calcium, and strontium.

4. The reduction method according to claim 1, wherein the (B) metal comprises one or more selected from the group consisting of lithium, sodium, and calcium.

5. The reduction method according to claim 2, wherein the substrate (A) is one or more aromatic hydrocarbon compounds which may have one or more substituents bonded to an aromatic ring.

6. The reduction method according to claim 1 or 2, wherein the (C) proton source comprises a sugar compound.

7. The reduction method according to claim 1 or 2, wherein the amount of organic solvent with a melting point of less than 30°C used during reduction by mechanochemical treatment is 1.0 mL or less per 1 mmol of substrate.

8. The reduction method according to claim 1 or 2, wherein the conditions for reduction by mechanochemical treatment are a temperature of 20°C or higher and / or a non-inert atmosphere.

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