JP6485878B2 - Deuteration method and catalyst - Google Patents

Description

  The present invention relates to a transition metal catalyst and a method of deuterating an organic compound using the same, and more particularly to a precursor of an N-heterocyclic carbene (NHC) type ligand and a deuteration catalyst containing the ligand .

  It is known that deuterated compounds are useful for elucidating chemical reaction mechanism and analyzing in vivo kinetics, and are also effective in controlling the bioactivity and drug interaction of pharmaceuticals. In particular, there is a need for a compound in which deuterium is introduced at a high deuteration ratio, and the need for an efficient deuterium introduction method has rapidly increased in recent years.

  In particular, the aromatic ring is an important structure ubiquitous in physiologically active substances, and various methods for deuteration to the aromatic ring have been studied. Although hydrogen / deuterium (H / D) exchange reaction has been actively studied as a method for catalytic deuteration of aromatic rings, it is necessary to use a large amount of deuterium compounds such as expensive heavy solvents in this method. In addition to the above, it is difficult to control reaction points, and it is difficult to obtain a deuterated product at a high deuteration ratio (see Non-Patent Document 1).

  On the other hand, as a deuteration method in which the control of the reaction point is easy, a method of deuterating an aromatic compound having a leaving group such as a halogenated aromatic compound is known. However, what is a problem in this method is the side reaction of hydrogenation, which is due to the competition between hydrogen and deuterium due to the contamination of hydrogen contained in the solvent etc. into the reaction system, the progress of the hydrogenation reaction of an unexpected mechanism, etc. The deuteration ratio easily decreases.

  On the other hand, in order to increase the deuteration ratio, a method using a large amount of a deuterium compound such as an expensive heavy solvent (see Non-patent documents 2 to 5), and an expensive transition metal per mole of the substrate Although the method (refer nonpatent literature 6 and 7) of using more than equivalent is known, all have a problem in terms of cost.

  In addition, in many of these methods, there is also a problem that selectivity is poor, such as unsaturated sites other than the aromatic ring (for example, alkene site) are simultaneously deuterated (see Non-Patent Documents 4, 5 and 7).

  Thus, there is no known selective deuterium introduction method to an aromatic ring which is excellent in both cost and deuteration ratio.

  On the other hand, various N-heterocyclic carbene (NHC) type ligands used for transition metal catalysts are known. For example, Patent Document 1 discloses ligand precursors of catalysts useful for cross coupling and the like. Is disclosed. However, the example which used the transition metal catalyst which consists of a carbene ligand like patent document 1 for deuteration reaction is not known.

Japanese Patent Application No. 2012-214390

Angew. Chem. Int. Ed. 2007, 46, 7744. Hetelocycles 1986, 24, 669. J. Labeled. Compd. Radiopharm. 1987, 24, 1445. Chem. Eur. J. 2008, 14, 3371. Org. Lett. 2004, 6, 3521. Tetrahedron Lett. 1973, 14, 4699. Tetrahedron Lett. 2002, 43, 5117.

  An object of the present invention is to provide a method of deuteration which is excellent in both cost and deuteration ratio, and further, to selectively deuterate a leaving group (for example, a halogen atom etc.) of an aromatic compound. , And deuterated catalysts for use therein.

As a result of intensive studies to solve the above problems, the present inventors conducted a deuteration reaction using a transition metal catalyst containing a ligand derived from the following compound (I) to obtain an excessive amount of transition metal or It has been found that a high deuteration ratio can be realized without using a deuterium reagent or a heavy solvent, and furthermore, deuterium substitution of a leaving group (for example, a halogen atom etc.) of an aromatic compound can be selectively performed. It came to complete.
That is, the present invention is as follows.

[1] Formula (I):

[In the formula,
Ring A and ring B each independently represent an aromatic ring which may be further substituted;
Ring C represents a cationic dinitrogen-containing ring which may be further substituted;
X ⁻ represents an anion;
Y ¹ and Y ² each independently represent a bond or methylene. ]
Deuteration catalyst containing a carbene ligand derived from a compound represented by and a transition metal.

[2] Formula (I):

[In the formula,
Ring A and ring B each independently represent an aromatic ring which may be further substituted;
Ring C represents a cationic dinitrogen-containing ring which may be further substituted;
X ⁻ represents an anion;
Y ¹ and Y ² each independently represent a bond or methylene. ]
And a deuterated catalyst prepared from the compound represented by and a transition metal compound.

[3] The deuteration catalyst according to [1] or [2], wherein the transition metal is palladium.
[4] The deuteration catalyst according to any one of [1] to [3], wherein X ⁻ is a chloride ion.

[5] The deuteration catalyst according to any one of [1] to [4] for catalyzing a substitution reaction of a leaving group bonded to an aromatic carbon atom to a deuterium atom.
[6] The deuteration catalyst according to [5], wherein the leaving group is a halogen atom.

[7] Formula (I):

[In the formula,
Ring A and ring B each independently represent an aromatic ring which may be further substituted;
Ring C represents a cationic dinitrogen-containing ring which may be further substituted;
X ⁻ represents an anion;
Y ¹ and Y ² each independently represent a bond or methylene. ]
A ligand precursor for a deuteration catalyst, represented by

[8] Formula (II):

[In the formula,
R ^1a and R ^1b each independently represent a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted amino group;
Each R ^1c independently represents a substituent;
R ^2a and R ^2b each independently represent a hydrogen atom or an optionally substituted hydrocarbon group;
Each R ^2c independently represents a substituent;
R ³ and R ⁴ each independently represent a hydrogen atom or an optionally substituted hydrocarbon group, or may be substituted together with the carbon atom to which R ³ and R ⁴ are bonded May form a ring;
X ⁻ represents an anion;
Y represents a bond or methylene;
n1 and n2 each independently represent an integer of 0 to 3. ]
Or a compound represented by the following formula (wherein, 3- (2-ethylphenyl) -4,5-dimethyl-1- (2,4,6-trimethylbenzyl) imidazolium chloride, 1- (2,4,6-trimethylbenzyl) ) 3- (4-Methoxyphenyl) -4,5-dimethylimidazolium chloride and 1- (2,4,6-trimethylbenzyl) -4,5-dimethyl-3-phenylimidazolium chloride excepted).

[9] The compound according to [8], wherein R ^1a and R ^1b are each independently a hydrogen atom, an alkyl group which may be substituted, or an amino group which may be substituted.
[10] The compound according to [8] or [9], wherein at least one of R ^1a and R ^1b is not a hydrogen atom.

[11] The compound according to any one of [8] to [10], wherein R ^2a and R ^2b are each independently a hydrogen atom or an alkyl group which may be substituted.
[12] The compound according to any one of [8] to [11], wherein Y is a bond.

[13] The compound according to any one of [8] to [12], wherein R ³ and R ⁴ are methyl.
[14] The compound according to any one of [8] to [13], wherein X ⁻ is a chloride ion.

[15] A complex comprising a carbene ligand derived from the compound according to any one of [8] to [14] and a transition metal.
[16] A complex prepared from the compound according to any one of [8] to [14] and a transition metal compound.

[17] An aromatic compound having a leaving group is reacted in an organic solvent in the presence of the deuteration catalyst according to any one of [1] to [6], a deuteration agent and a base. A method of substituting a deuterium atom for the leaving group bonded to a carbon atom of

[18] The deuterating agent is a compound of formula (III):

[Wherein, R ⁵ and R ⁶ each independently represent a substituent; D represents a deuterium atom. ]
The method according to [17], which is a compound represented by

[19] The method according to [17] or [18], wherein the amount of deuteration agent used is 1 molar equivalent to 3 molar equivalents with respect to the leaving group.
[20] The method according to any one of [17] to [19], wherein the organic solvent is not a heavy solvent.

  The deuteration method of the present invention is excellent in both cost and deuteration ratio. Furthermore, leaving groups (for example, a halogen atom etc.) of the aromatic compound can be selectively deuterated.

Hereinafter, the terms used in the present specification will be described in detail.
In the present specification, the "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

  In the present specification, as the “hydrocarbon group”, for example, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkadienyl group, an aryl group, an aralkyl group and the like can be mentioned.

In the present specification, “alkyl (group)” indicates a linear or branched saturated hydrocarbon group, and examples thereof include C _1-10 alkyl (group), C _1-6 alkyl (group) and the like. Specific examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2, 2- dimethyl butyl, 3, 3- dimethyl butyl, 2-ethyl butyl etc. are mentioned.

In the present specification, “C _1-2 alkyl group” refers to methyl and ethyl.
In the present specification, examples of the “branched C _3-6 alkyl group” include isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, 1-ethylpropyl, isohexyl, 1,1-dimethylbutyl , 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like. Among them, preferred is a secondary _C3-6 alkyl group.

In the present specification, the "secondary _C3-6 alkyl group" is a methyl group substituted with two alkyl groups, and has 3 to 6 carbon atoms, for example, isopropyl , Sec-butyl, 1-ethylpropyl and the like.

In the present specification, “alkenyl (group)” refers to a linear or branched unsaturated hydrocarbon group containing one or more double bonds, for example, C _2-10 alkenyl (group), C _2-6 alkenyl (group) and the like, and specific examples thereof include vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-butenyl Examples include methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl and the like.

In the present specification, “alkynyl (group)” represents a linear or branched unsaturated hydrocarbon group containing one or more triple bonds, for example, C _2-10 alkynyl (group), C _{2 -6-} alkynyl (group) and the like, and specific examples thereof include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl 4-pentynyl, 1,1-dimethylprop-2-yn-1-yl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like.

In the present specification, “alkoxy (group)” indicates an alkyl-oxy group, and examples thereof include C _1-10 alkoxy (group), C _1-6 alkoxy (group) and the like, and specific examples thereof include And methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy and the like.

In the present specification, “cycloalkyl (group)” represents a cyclic saturated hydrocarbon group, and examples thereof include C _3-8 cycloalkyl (group), and specific examples thereof include cyclopropyl, cyclobutyl, Examples include cyclopentyl, cyclohexyl and the like.

In the present specification, "cycloalkenyl (group)" represents a cyclic unsaturated hydrocarbon group containing one double bond, and examples thereof include C _3-8 cycloalkenyl (group), and the specific examples thereof Examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like.

In the present specification, “cycloalkadienyl (group)” refers to a cyclic unsaturated hydrocarbon group containing two double bonds, and examples thereof include C _4-8 cycloalkadienyl (group). Specific examples thereof include 1,3-cyclobutadiene-1-yl, 1,3-cyclopentadien-1-yl, 1,4-cyclopentadien-1-yl, and 2,4-cyclopentadiene-1-one. , 1,3-cyclohexadiene-1-yl, 1,4-cyclohexadiene-1-yl, 1,5-cyclohexadiene-1-yl, 2,4-cyclohexadiene-1-yl, 2,5- Cyclohexadiene-1-yl and the like can be mentioned.

In the present specification, the "aromatic ring group" refers to an aryl group and an aromatic heterocyclic group.
In the present specification, “aryl (group)” represents a cyclic aromatic hydrocarbon group, and examples thereof include C _6-14 aryl (group), and specific examples thereof include phenyl, 1-naphthyl, 2-naphthyl etc. are mentioned.

In the present specification, “aralkyl (group)” indicates an alkyl group substituted with an aryl group, and examples thereof include C _7-13 aralkyl (group), and specific examples thereof include benzyl, phenethyl and the like. It can be mentioned.

In the present specification, the "heterocycle (group)" refers to an aromatic heterocyclic group and a non-aromatic heterocyclic group.
In the present specification, the "aromatic heterocyclic group" refers to a monocyclic aromatic heterocyclic group and a fused aromatic heterocyclic group.

  In the present specification, the "monocyclic aromatic heterocyclic group" refers to a monocyclic aromatic ring group containing a hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring constituting atom For example, 5- to 7-membered monocyclic aromatic heterocyclic group having 1 to 4 hetero atoms, 5- or 6-membered monocyclic aromatic heterocyclic group, etc. may be mentioned, and specific examples thereof include Furyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like.

  In the present specification, the "fused aromatic heterocyclic group" is derived from a fused ring of one or more rings selected from a monocyclic aromatic heterocycle and an arene ring and a monocyclic aromatic heterocycle. Groups, for example, 8- to 12-membered fused aromatic heterocyclic groups, and specific examples thereof include quinolyl, isoquinolyl, quinazolyl, quinoxalyl, benzofuranyl, benzothienyl, benzoxazolyl, benzoisoxazolyl And benzothiazolyl, benzoimidazolyl, benzotriazolyl, indolyl, indazolyl, pyrrolopyrazinyl, imidazopyridyl, thienopyridyl, imidazopyrazinyl, pyrazolopyridyl, pyrazolothienyl, pyrazolotriazinyl and the like.

In the present specification, the "non-aromatic heterocyclic group" refers to a monocyclic non-aromatic heterocyclic group, a fused non-aromatic heterocyclic group and a spiro heterocyclic group.
In the present specification, the "monocyclic non-aromatic heterocyclic group" means a monocyclic non-aromatic ring group containing a hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring constituting atom And a 3- to 8-membered monocyclic non-aromatic heterocyclic group containing 1 to 4 hetero atoms, a 5- or 6-membered monocyclic non-aromatic heterocyclic group, etc. Specific examples include azetidinyl, pyrrolidinyl, piperidyl, morpholinyl, thiomorpholinyl, piperazinyl, oxazolidinyl, thiazolidinyl, dihydrothiopyranyl, imidazolidinyl, oxazolinyl, thiazolinyl, imidazolinyl, dioxolyl, dioxolanyl, dihydrooxadiazolyl, pyranyl, tetrahydropyranyl, thiopyranyl , Tetrahydrothiopyranyl, tetrahydrofuryl, Kisetaniru, pyrazolidinyl, pyrazolinyl, tetrahydropyrimidinyl, dihydro triazolyl, tetrahydropyran triazolyl, azepanyl, dihydropyridyl, tetrahydropyridyl and the like.

  In the present specification, the “fused non-aromatic heterocyclic group” means an arene ring, a monocyclic non-aromatic heterocyclic ring, a monocyclic aromatic heterocyclic ring, a cycloalkane ring, a cycloalkene ring or a cycloalkadiene ring. Indicates a group derived from a fused ring of one or more selected rings and a monocyclic non-aromatic heterocycle, and examples thereof include 8- to 12-membered fused non-aromatic heterocyclic groups, etc. Specific examples thereof As dihydroindolyl, dihydroisoindolyl, dihydrobenzofuranyl, tetrahydrobenzofuranyl, dihydrobenzodioxinyl, dihydrobenzodioxenyl, chromenyl, dihydrochromenyl, dihydroquinolyl, tetrahydroquinolyl, dihydro Isoquinolyl, tetrahydroisoquinolyl, dihydrophthalazinyl and the like can be mentioned.

  In the present specification, “spiro-type heterocyclic group” means a monocyclic non-aromatic heterocyclic group or a fused non-aromatic heterocyclic group having a monocyclic non-aromatic heterocyclic ring, a cycloalkane ring, a cycloalkene ring And a heterocyclic group spiro-fused via one carbon atom with a ring selected from a cycloalkadiene ring, and examples thereof include an 8- to 12-membered spiro-type heterocyclic group, and specific examples thereof include And rings such as oxaspirodecanedienyl.

In the present specification, “cycloalkane ring” refers to a saturated hydrocarbon ring, and examples thereof include a C _3-8 cycloalkane ring, and specific examples thereof include cyclopropane, cyclobutane, cyclopentane, cyclohexane and cyclo Heptane and cyclooctane rings may be mentioned.

In the present specification, “cycloalkene ring” refers to an unsaturated hydrocarbon ring containing one double bond, and examples thereof include a C _3-8 cycloalkene ring, and specific examples thereof include cyclopropene And rings such as cyclobutene, cyclopentene, cyclohexene and cycloheptene.

In the present specification, "cycloalkadiene ring" refers to an unsaturated hydrocarbon ring containing two double bonds, and includes, for example, a C _4-8 cycloalkadiene ring, and specific examples thereof include Rings such as cyclobutadiene, cyclopentadiene, cyclohexadiene and the like can be mentioned.

  In the present specification, the "aromatic ring" refers to an arene ring and an aromatic heterocyclic ring.

In the present specification, the "arene ring" indicates an aromatic hydrocarbon ring, and examples thereof include a C _6-14 arene ring and the like, and specific examples thereof include rings such as benzene and naphthalene.

As used herein, "heterocycle" refers to aromatic heterocycles and non-aromatic heterocycles.
In the present specification, the "aromatic heterocycle" refers to a monocyclic aromatic heterocycle and a fused aromatic heterocycle.

  In the present specification, “monocyclic aromatic heterocyclic ring” refers to a monocyclic aromatic ring containing a hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring constituting atom, And 5- to 7-membered monocyclic aromatic heterocycles containing 1 to 4 heteroatoms, 5- or 6-membered monocyclic aromatic heterocycles, and the like. Specific examples thereof include furan and thiophene And rings such as pyridine, pyrimidine, pyridazine, pyrazine, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, oxadiazole, thiadiazole, triazole, tetrazole, triazine and the like.

  In the present specification, the “fused aromatic heterocycle” refers to a fused ring of one or more rings selected from a monocyclic aromatic heterocycle and an arene ring and a monocyclic aromatic heterocycle, for example, Examples thereof include 8- to 12-membered fused aromatic heterocycles, and specific examples thereof include quinoline, isoquinoline, quinazoline, quinoxaline, benzofuran, benzothiophene, benzooxazole, benzoisoxazole, benzothiazole, benzoimidazole, benzotriazole, and the like. Rings of indole, indazole, pyrrolopyrazine, imidazopyridine, thienopyridine, imidazopyrazine, pyrazolopyridine, pyrazolothiophene, pyrazolotriazine and the like can be mentioned.

  In the present specification, the "non-aromatic heterocycle" refers to a monocyclic non-aromatic heterocycle, a fused non-aromatic heterocycle, or a spiro heterocycle.

  In the present specification, the "monocyclic non-aromatic heterocycle" refers to a monocyclic non-aromatic ring containing a hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring constituent atom For example, 3- to 8-membered monocyclic non-aromatic heterocyclic ring containing 1 to 4 hetero atoms, 5- or 6-membered monocyclic non-aromatic heterocyclic ring, etc. may be mentioned. , Azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxazolidine, thiazolidine, dihydrothiopyran, imidazolidine, oxazoline, thiazoline, imidazoline, dioxole, dioxolane, dihydrooxadiazole, pyran, dihydropyran, tetrahydropyran, thiopyran, Dihydrothiopyran, tetrahydrothiopyran, tetrahydrofuran, oxe Emissions, pyrazolidine, pyrazoline, tetrahydropyrimidine, dihydro-triazole, tetrahydro triazole, azepane, dihydropyridine, include rings such as tetrahydropyridine.

  In the present specification, “fused non-aromatic heterocycle” is selected from arene ring, monocyclic non-aromatic heterocycle, monocyclic aromatic heterocycle, cycloalkane ring, cycloalkene ring, cycloalkadiene ring And a fused ring of one or more rings and a monocyclic non-aromatic heterocycle, and examples thereof include 8- to 12-membered fused non-aromatic heterocycles. Specific examples thereof include dihydroindole and dihydroiso. Rings of indole, dihydrobenzofuran, tetrahydrobenzofuran, dihydrobenzodioxine, dihydrobenzodioxepin, chromene, dihydrochromene, dihydroquinoline, tetrahydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, dihydrophthalazine, benzothiazine and the like can be mentioned.

  In the present specification, “spiro-type heterocycle” means a monocyclic non-aromatic heterocycle or a fused non-aromatic heterocycle, a monocyclic non-aromatic heterocycle, a cycloalkane ring, a cycloalkene ring, a cycloalkene ring A ring selected from a diene ring and a heterocyclic ring spiro-fused via one carbon atom, such as an 8- to 12-membered spiro heterocyclic ring, and specific examples thereof include oxaspirodecanediene And the like.

  In the present specification, the "cationic dinitrogen-containing ring" refers to a cationic monocyclic dinitrogen-containing ring and a cationic fused dinitrogen-containing ring.

In the present specification, the "cationic monocyclic dinitrogen-containing ring" has a ring structure "N ⁺ = CH-N", and an oxygen atom, a sulfur atom and a nitrogen other than a carbon atom as a ring constituting atom Indicates a cationic heterocyclic ring which may further contain a hetero atom selected from atoms, for example, a 5- to 7-membered cationic monocyclic dinitrogen-containing ring, a 5-membered cationic monocyclic dinitrogen-containing ring And the like, and specific examples thereof include imidazolium (1H-imidazole-3-ium), dihydroimidazolium (4,5-dihydro-1H-imidazole-3-ium), dihydropyrimidinium (eg, 1,6-dihydropyrimidin-3-ium etc.), tetrahydropyrimidinium (1,4,5,6-tetrahydropyrimidin-3-ium), diazepinium (1H-1,3-diazepi) -3-ium), dihydrodiazepinium (eg, 6,7-dihydro-1H-1,3-diazepin-3-ium, etc.), tetrahydrodiazepinium (4,5,6,7-tetrahydro-1H- And rings such as 1,3-diazepine-3-ium).

  In the present specification, the “cationic fused dinitrogen-containing ring” means one or more rings selected from a heterocycle, an arene ring, a cycloalkane ring, a cycloalkene ring and a cycloalkadiene ring, and a cationic monocyclic dicycle A fused ring with a nitrogen-containing ring is shown, and examples thereof include a 8- to 16-membered cationic fused di-nitrogen containing ring, and a 8- to 12-membered cationic fused di-nitrogen containing ring, and specific examples thereof include benzimidazo. And rings such as lithium, dihydrobenzimidazolium, tetrahydrobenzimidazolium, tetrahydrocyclopentaimidazolium and dihydroquinazolinium.

  In the present specification, as the “substituent”, for example, a cyano group, a nitro group, an acyl group, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, amino which may be substituted Groups, carbamoyl groups which may be substituted, hydroxy groups which may be substituted, etc. may be mentioned.

In the present specification, “optionally substituted” indicates that the group may be substituted with any substituent, and in certain embodiments, unless otherwise specified, for example,
In the case of "optionally substituted amino group" or "optionally substituted carbamoyl group", the amino group or carbamoyl group is an acyl group, an optionally substituted hydrocarbon group, or even substituted Indicates that it may be mono- or di-substituted with a substituent selected from a favorable heterocyclic group etc .;
In the case of "optionally substituted hydroxy group" or "optionally substituted sulfanyl group", the hydroxy group is an acyl group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic ring Indicates that it may be substituted by a substituent selected from the group etc .;
In other cases, it indicates that the target group may be substituted with 1 to 3 substituents selected from the following substituent groups (1) to (8) and the like.

Substituent group (1): alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, cycloalkadienyl group, aryl group, aralkyl group, heterocyclic group;
Substituent group (2): formyl group, alkyl-carbonyl group, alkenyl-carbonyl group, alkynyl-carbonyl group, cycloalkyl-carbonyl group, cycloalkenyl-carbonyl group, cycloalkadienyl-carbonyl group, aryl-carbonyl group, Aralkyl-carbonyl group, heterocyclic-carbonyl group;
Substituent group (3): carboxy group, alkoxy-carbonyl group, alkenyl-oxycarbonyl group, alkynyl-oxycarbonyl group, cycloalkyl-oxycarbonyl group, cycloalkenyl-oxycarbonyl group, cycloalkadienyl-oxycarbonyl group, Aryl-oxycarbonyl group, aralkyl-oxycarbonyl group, heterocycle-oxycarbonyl group;
Substituent group (4): carbamoyl group, mono or di-alkyl-carbamoyl group, mono or di-alkenyl-carbamoyl group, mono or di-alkynyl carbamoyl group, mono or di-cycloalkyl-carbamoyl group, mono or di -Cycloalkenyl-carbamoyl group, mono- or di-cycloalkadienyl-carbamoyl group, mono- or di-aryl-carbamoyl group, mono- or di-aralkyl-carbamoyl group, mono- or di-heterocycle-carbamoyl group;
Substituent group (5): hydroxy group, alkoxy group, alkenyl-oxy group, alkynyl-oxy group, cycloalkyl-oxy group, cycloalkenyl-oxy group, cycloalkadienyl-oxy group, aryl-oxy group, aralkyl- Oxy group, heterocyclic ring-oxy group;
Substituent group (6): alkyl-carbonyloxy group, alkenyl-carbonyloxy group, alkynyl-carbonyloxy group, cycloalkyl-carbonyloxy group, cycloalkenyl-carbonyloxy group, cycloalkadienyl-carbonyloxy group, aryl- Carbonyloxy group, Aralkyl-Carbonyloxy group, Heterocycle-Carbonyloxy group;
Substituent group (7): amino group, mono- or di-alkyl-amino group, mono- or di-alkenyl-amino group, mono- or di-alkynyl-amino group, mono- or di-cycloalkyl-amino group, mono- or di- -Cycloalkenyl-amino group, mono- or di-cycloalkadienyl-amino group, mono- or di-aryl-amino group, mono- or di-aralkyl-amino group, mono- or di-heterocycle-amino group;
Substituent group (8): halogen atom, cyano group, nitro group.

  In the present specification, the term "acyl group" refers to the formula "-C (= O) -Z-G" (wherein G is a hydrogen atom, an optionally substituted hydrocarbon group or substituted Z is a bond or O is a group represented by ()).

  In the present specification, "anion" refers to organic or inorganic 1 to 5 monovalent anions, for example, halide ions (eg, chloride ion, bromide ion, iodide ion etc.), borate ion (Eg, tetrafluoroborate ion, tetraphenylborate ion, butyltriphenylborate ion, etc.), phosphate ions (eg, hexafluorophosphate ion, etc.), antimonate ions (eg, hexafluoroantimony ion, etc.) Acid ions etc., arsenate ions (eg, hexafluoroarsenate ion etc.), carboxylate ions (eg, formate ion, acetate ion, trifluoroacetate ion, lactate ion, propionate ion, benzoate ion, oxalate ion Acid ion, succinic acid ion, stearic acid ion etc), sulfonic acid ions (eg, methane sulfonic acid ion, benzene sulfone Acid ion, trifluoromethane sulfonic acid ion, toluene sulfonic acid ion, naphthalene sulfonic acid ion, nitrobenzene sulfonic acid ion, dodecylbenzene sulfonic acid ion, ethane sulfonic acid ion, etc., sulfonic acid imide ions (eg, bis (trifluoromethane sulfonic acid) And imide ions, etc., perhalogenate ions (eg, perchlorate ion, periodate ion, etc.), thiocyanate ion, nitrate ion and the like.

  In the present specification, "transition metal" refers to an element belonging to Groups 3 to 11 of the periodic table.

  In the present specification, examples of the "basic salts" include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium acetate, ammonium acetate and the like.

  In the present specification, examples of the "metal hydrides" include sodium hydride, potassium hydride and the like.

  In the present specification, examples of the "alkali metal hydroxides" include sodium hydroxide, potassium hydroxide, cesium hydroxide and the like.

  In the present specification, examples of the "alkali metal carbonate" include sodium carbonate, potassium carbonate, cesium carbonate and the like.

  In the present specification, examples of the "alkali metal fluorides" include sodium fluoride, potassium fluoride, cesium fluoride and the like.

  In the present specification, examples of the "alkali metal phosphates" include sodium phosphate, potassium phosphate and the like.

  In the present specification, examples of the "aromatic amines" include pyridine, lutidine and the like.

  In the present specification, examples of the "tertiary amines" include triethylamine, tripropylamine, tributylamine, diisopropylethylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, and N-methylpiperidine. , N-methyl pyrrolidine, N-methyl morpholine, 1,8-diazabicyclo [5,4,0] undec-7-ene and the like.

  In the present specification, examples of the "metal amides" include sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide and the like.

In the present specification, as the "alkyl metals", for example, butyllithium, sec-butyllithium, tert-butyllithium and the like can be mentioned.
In the present specification, as the "aryl metals", for example, phenyllithium and the like can be mentioned.

  In the present specification, examples of the "metal alkoxides" include sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and the like.

  In the present specification, examples of the “hydrocarbons” include aliphatic hydrocarbons such as hexane, alicyclic hydrocarbons such as cyclohexane, and aromatic hydrocarbons such as benzene and toluene.

  In the present specification, examples of the "halogenated hydrocarbons" include chloroform, dichloromethane and the like.

  In the present specification, examples of the "alcohols" include methanol, ethanol, isopropanol and the like.

In the present specification, examples of the "ethers" include linear ethers such as dimethyl ether, diisopropyl ether and dibutyl ether, cyclic ethers such as 1,4-dioxane and tetrahydrofuran, and the like.
In the present specification, examples of the "esters" include ethyl acetate and the like.

In the present specification, examples of the "ketones" include acetone, methyl ethyl ketone, methyl isobutyl ketone and the like.
In the present specification, examples of the "amides" include N, N-dimethylformamide, N, N-dimethylacetamide and the like.
In the present specification, examples of the "nitriles" include acetonitrile and the like.

  In the present specification, examples of the "sulfoxides" include dimethyl sulfoxide and the like.

  In the present specification, the term "heavy solvent" refers to a solvent in which part or all of hydrogen atoms contained in solvent molecules are replaced with deuterium atoms.

  As used herein, "deuteration ratio" refers to the ratio of deuteration at a particular reaction site where deuteration or hydrogenation has been performed.

In the present specification, the term "leaving group" refers to a group generally known as one which is easily eliminated by nucleophilic substitution, and examples thereof include a chlorine atom, a bromine atom, an iodine atom, and an ethylsulfonyloxy Group, propylsulfonyloxy group, isopropylsulfonyloxy group, tert-butylsulfonyloxy group, trifluoromethylsulfonyloxy group, benzenesulfonyloxy group, 2,4,6-trimethylbenzenesulfonyloxy group, 2-nitrobenzenesulfonyloxy group, 4-nitrobenzenesulfonyl group, dimethylsulfamoyl group, diethylsulfamoyl group, morpholino sulfonyloxy group and the like, preferably a chlorine atom, a bromine atom, an iodine atom and dimethylsulfamoyl group , More preferably, chlorine source It is.

  The present invention provides a deuteration catalyst comprising a carbene ligand derived from compound (I) and a transition metal. The present invention also provides a deuteration catalyst prepared from compound (I) and a transition metal compound. The present invention also provides a ligand precursor for the deuteration catalyst represented by formula (I). In the deuteration catalyst and ligand precursor of the present invention, compound (I) is preferably compound (II). Deuteration with compound (II) can give a deuterated product in higher yield.

Hereinafter, each symbol of Formula (I) and Formula (II) is demonstrated.
Ring A represents an aromatic ring which may be further substituted. Ring A is preferably an arene ring which may be further substituted; more preferably a benzene ring which may be further substituted; still more preferably a compound of the formula (A):

And particularly preferably a ring represented by the formula (A1):

Or a ring represented by or formula (A2):

It is a ring represented by

As shown in ring A, "optionally further substituted aromatic ring", "optionally further substituted arene ring", "optionally further substituted C _6-14 arene ring" or "optionally further substituted As the substituent of the “optionally substituted benzene ring”, for example, a cyano group, a nitro group, an acyl group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted The amino group, the carbamoyl group which may be substituted, the hydroxy group which may be substituted, etc. are mentioned. The substituent is preferably a hydrocarbon group which may be substituted, an amino group which may be substituted, or a hydroxy group which may be substituted, more preferably a hydrocarbon which may be substituted. It is a group or an amino group which may be substituted. The number of substituents is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is two or more, each substituent may be the same or different.

In one embodiment, R ^1a and R ^1b each independently represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted amino group or an optionally substituted hydroxy group.

Preferably, R ^1a and R ^1b are each independently (1) a hydrogen atom, (2) an alkyl group which may be substituted, (3) an aryl group which may be substituted, (4) It is an amino group which may be mono- or di-substituted with an alkyl group which may be substituted, or a hydroxy group which may be substituted with an alkyl group which may be substituted (5).

More preferably, R ^1a and R ^1b are each independently substituted with (1) a hydrogen atom, (2) 1 to 3 (preferably 1 or 2) C _6-14 aryl groups C _1-6 alkyl group (eg, methyl, ethyl, isopropyl, diphenylmethyl etc.), (3) C _6-14 aryl group (eg, phenyl etc.), (4) C _1-6 alkyl group mono or It is an amino group which may be disubstituted (eg, dimethylamino etc.), or a hydroxy group which may be substituted by (5) C _1-6 alkyl group (eg, methoxy etc.).

In another embodiment, R ^1a and R ^1b represent a hydrogen atom, a hydrocarbon group which may be substituted, or an amino group which may be substituted.

In one preferred embodiment, R ^1a and R ^1b are each independently a hydrogen atom, an alkyl group which may be substituted, an aryl group which may be substituted or an amino group which may be substituted. In a more preferred embodiment, at least one of R ^1a and R ^1b is not a hydrogen atom.

Preferably, R ^1a and R ^1b are each independently (1) a hydrogen atom, (2) an alkyl group which may be substituted, (3) an aryl group which may be substituted, or (4) a substituent It is an amino group which may be mono- or di-substituted with an alkyl group which may be substituted.

More preferably, R ^1a and R ^1b are each independently substituted with (1) a hydrogen atom, (2) 1 to 3 (preferably 1 or 2) C _6-14 aryl groups C _1-6 alkyl group (eg, methyl, ethyl, tert butyl, isopropyl, diphenylmethyl etc.), (3) C _6-14 aryl group (eg, phenyl etc.), or (4) C _1-6 alkyl An amino group (eg, dimethylamino etc.) optionally mono- or di-substituted with a group.

More preferably, R ^1a and R ^1b are each independently substituted with (1) a hydrogen atom or (2) 1 to 3 (preferably 1 or 2) C _6-14 aryl groups. A C _1-6 alkyl group (eg, methyl, ethyl, tert butyl, isopropyl, diphenylmethyl etc.) or (3) an amino group which may be mono- or di-substituted by a C _1-6 alkyl group (eg, Dimethylamino and the like).

Particularly preferably, R ^1a and R ^1b are each independently (1) a hydrogen atom, (2) a branched C _3-6 alkyl group (in particular, a secondary C _3-6 alkyl group) (eg, R ^1a is a C _1-2 alkyl group (eg, diphenylmethyl etc.) substituted with isopropyl or the like, or (3) 1 to 3 (preferably 1 or 2) C _6-14 aryl groups; And at least one of R ^1b is not a hydrogen atom.

In another preferred embodiment, R ^1a and R ^1b are each independently a hydrogen atom, an alkyl group which may be substituted, or an amino group which may be substituted. In a more preferred embodiment, at least one of R ^1a and R ^1b is not a hydrogen atom.

Preferably,
R ^1a is (1) 1-3 (preferably, 1 or 2) _{C 6-14} aryl optionally substituted _{C 1-6} alkyl group a group (example, methyl, isopropyl, diphenylmethyl, etc. Or (2) an amino group (eg, dimethylamino etc.) optionally mono- or di-substituted with a C _1-6 alkyl group; and R ^1b is (1) a hydrogen atom, or (2) 1 A C _1-6 alkyl group (eg, methyl, isopropyl, diphenylmethyl and the like) which may be substituted with one to three (preferably, one or two) C _6-14 aryl groups;

More preferably, each of R ^1a and R ^1b is independently a C _1-6 alkyl group _optionally substituted with 1 to 3 (preferably 1 or 2) C _6-14 aryl groups ( Examples are methyl, isopropyl, diphenylmethyl and the like).

More preferably, R ^1a and R ^1b are each independently (1) a branched C _3-6 alkyl group (in particular, a secondary C _3-6 alkyl group) (eg, isopropyl etc.), or 2) a C _1-2 alkyl group (eg, diphenylmethyl etc.) substituted with 1 to 3 (preferably 1 or 2) C _6-14 aryl groups;

R ^1c each independently represents a substituent; preferably each independently is a hydrocarbon group which may be substituted; more preferably each independently is an alkyl which may be substituted. Particularly preferably each independently a C _1-6 alkyl group (eg, methyl etc.).

  n1 represents an integer of 0 to 3; preferably 0 or 1.

  Ring B represents an aromatic ring which may be further substituted. Ring B is preferably an arene ring which may be further substituted; more preferably a benzene ring which may be further substituted; still more preferably a compound of formula (B):

And even more preferably, a ring of the formula (B1):

Or a ring represented by or formula (B2):

And particularly preferably a ring represented by the formula (B1):

It is a ring represented by

“An optionally further substituted aromatic ring”, an “optionally further substituted arene ring”, a “optionally further substituted C _6-14 arene ring”, or a “optionally further substituted aromatic ring” represented by ring B As the substituent of the “optionally substituted benzene ring”, for example, a cyano group, a nitro group, an acyl group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted The amino group, the carbamoyl group which may be substituted, the hydroxy group which may be substituted, etc. are mentioned. The number of substituents is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is two or more, each substituent may be the same or different.

^R2a and ^R2b each independently represent a hydrogen atom or an optionally substituted hydrocarbon group.

Preferably, R ^2a and R ^2b are each independently a hydrogen atom or an alkyl group which may be substituted. More preferably, each of R ^2a and R ^2b is independently C _{1- optionally} substituted with a hydrogen atom, or 1 to 3 (preferably 1 or 2) C _6-14 aryl groups. ₆ alkyl group (eg, methyl, isopropyl, diphenylmethyl). More preferably, R ^2a and R ^2b are each independently a C _1-6 alkyl group _optionally substituted with 1 to 3 (preferably 1 or 2) C _6-14 aryl groups ( Examples are methyl, isopropyl, diphenylmethyl and the like). Particularly preferably, R ^2a and R ^2b are each independently a C _1-6 alkyl group (eg, methyl, isopropyl etc.).

R ^2c each independently represents a substituent; preferably each independently is a hydrocarbon group which may be substituted; more preferably each independently is an alkyl which may be substituted. More preferably each independently a C _1-6 alkyl group (eg, methyl, isopropyl etc.).

  n2 represents an integer of 0 to 3; preferably 0 or 1; more preferably 1.

  Ring C represents a cationic dinitrogen-containing ring which may be further substituted. Ring C is preferably a 5-membered cationic monocyclic dinitrogen-containing ring which may be further substituted; more preferably a compound of the formula (C1):

And further preferably a ring represented by the formula (C2):

It is a ring represented by

  As a substituent for the “optionally further substituted cationic dinitrogen-containing ring” or the “optionally further substituted 5-membered monocyclic monocyclic dinitrogen-containing ring” for ring C, , A halogen atom, a cyano group, a nitro group, an acyl group, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, an amino group which may be substituted, a carbamoyl group which may be substituted And hydroxy group which may be substituted. The substituent is preferably a hydrocarbon group which may be substituted. The number of substituents is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is two or more, each substituent may be the same or different.

R ³ and R ⁴ each independently represent a hydrogen atom or an optionally substituted hydrocarbon group, or may be substituted together with the carbon atom to which R ³ and R ⁴ are bonded It may form a ring.

Examples of the “ring” of the “optionally substituted ring” formed by R ³ and R ⁴ include a heterocycle, an arene ring, a cycloalkane ring, a cycloalkene ring and a cycloalkadiene ring.

R ³ and R ⁴ are preferably each independently a hydrogen atom or a hydrocarbon group which may be substituted; more preferably each of which is a hydrogen atom or an alkyl group which may be substituted. More preferably each independently a hydrogen atom or a C _1-6 alkyl group (eg, methyl etc.); still more preferably each independently a C _1-6 alkyl group (eg methyl) Etc.); particularly preferably methyl.

  In formula (C1), the formula:

The moiety represented by represents a single bond or a double bond.

X < ^- > shows an anion. X ⁻ is preferably a halide ion (eg, chloride ion, bromide ion, iodide ion, etc.), a borate ion (eg, tetrafluoroborate ion, tetraphenylborate ion, butyltriphenylboron ion). Acid ions), phosphate ions (eg, hexafluorophosphate ion), antimonate ions (eg, hexafluoroantimonate ion), etc .; more preferably halide ions (eg, chloride) Organic ions, bromide ions, iodide ions etc.); more preferably chloride ions.

In formula (I), Y ¹ and Y ² each independently represent a bond or methylene. Preferably, Y ¹ is a bond and Y ² is a bond or methylene, more preferably, Y ¹ is a bond and Y ² is methylene.

  In formula (II), Y represents a bond or methylene. Preferably, Y is a bond.

The preferred compound (I) is shown below.
[Compound IA]
Ring A and Ring B are each independently a C _6-14 arene ring which may be further substituted; and Ring C is a cationic monocyclic dinitrogen containing ring which may be further substituted ; X ^- is an anion; ^{Y 1} is a bond, ^{Y 2} is a bond or methylene, the compound (I).

[Compound IB]
Ring A and ring B are each independently a benzene ring which may be further substituted; ring C is a 5-membered cationic monocyclic dinitrogen containing ring which may be further substituted; Compounds (I) in which X ⁻ is an anion; Y ¹ is a bond, and Y ² is a bond or methylene.

The preferred compound (II) is shown below.
[Compound IIA]
R ^1a and R ^1b are each independently (1) a hydrogen atom, (2) an alkyl group which may be substituted, (3) an aryl group which may be substituted, or (4) which is substituted R ^1c is each independently an alkyl group which may be substituted; and R ^2a and R ^2b are each independently. R ^2c each independently represents an alkyl group which may be substituted; R ³ and R ⁴ each independently represent a hydrogen atom or a hydrogen atom or an alkyl group which may be substituted; optionally substituted be an alkyl group; X ^- is an anion; Y is a bond hand; n1 and n2 are each independently an integer of 0 to 3, the compound (II).
[Compound IIB]
R ^1a and ^{R 1b} are each independently (1) hydrogen atom, (2) 1-3 (preferably, 1 or 2) _{C 6-14} optionally _{C 1} optionally substituted with an aryl group ₆ alkyl group (eg, methyl, ethyl, tert butyl, isopropyl, diphenylmethyl etc.), (3) C _6-14 aryl group (eg, phenyl etc.), or (4) C _1-6 alkyl group mono or R ^1c is each independently a C _1-6 alkyl group (eg, methyl etc.); R ^2a and R ^2b are each independently di-substituted amino group (eg, dimethylamino etc.); Each independently, a hydrogen atom or a C _1-6 alkyl group _optionally substituted by 1 to 3 (preferably 1 or 2) C _6-14 aryl groups (eg, methyl, isopropyl, diphenyl) Methyl and the like); R ^2c is independently _{To, C 1-6} alkyl group (e.g., methyl, isopropyl, etc.) be; ^{R 3} and ^{R 4} are each independently a hydrogen atom or a _{C 1-6} alkyl group (e.g., methyl, etc.); Compounds (II) in which X ⁻ is an anion; Y is a bond; and n 1 and n 2 are each independently 0 or 1.
[Compound IIC]
R ^1a is (1) 1-3 (preferably, 1 or 2) _{C 6-14} aryl optionally substituted _{C 1-6} alkyl group a group (example, methyl, isopropyl, diphenylmethyl, etc. Or (2) an amino group (eg, dimethylamino etc.) optionally mono- or di-substituted with a C _1-6 alkyl group; and R ^1b is (1) a hydrogen atom, or (2) 1 to 3 (preferably, 1 or 2) C _1-6 alkyl groups which may be substituted with C _6-14 aryl groups (eg, methyl, isopropyl, diphenylmethyl etc.); R ^1c is each _{independently} be a _{C 1-6} alkyl group (e.g., methyl, ^{etc.); R 2a} and ^{R 2b} are each independently, _{C 6-14} aryl 1-3 (preferably, 1 or 2) C _1-6 alkyl group which may be substituted by a group (eg, methyl, R ^2c is each independently a C _1-6 alkyl group (eg, methyl, isopropyl etc.); R ³ and R ⁴ are each independently a hydrogen atom or A compound wherein a C _1-6 alkyl group (eg, methyl etc.); X ^- is an anion; Y is a bond; n 1 and n 2 are each independently 0 or 1; ).

  The compound (I) also includes a compound represented by the following formula (I ′ ′) which is a tautomer.

  Compound (I) may be produced by a known method or a method analogous thereto, or may be a commercially available product.

Below, the manufacturing method of compound (I) is demonstrated.
The starting compound for each step may be a commercially available product, or can be produced by a known method or a method according thereto, a method described below, or the like.

  In each of the following reactions, when the starting compound or the intermediate has an amino group, a carboxy group, a hydroxy group or the like as a substituent, these groups may be protected by a known protecting group. In this case, after the reaction, the target compound can be obtained by removing the protecting group as necessary. The introduction or removal of these protective groups may be carried out according to a method known per se.

  In addition, the compound obtained in each step can be used as the reaction solution or as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method. Crystallization, filtration, concentration, solvent It can be easily purified by separation means such as extraction, recrystallization, chromatography and the like.

Furthermore, it is also possible to carry out the reaction of each step under microwave irradiation using a microwave reactor, if necessary.
Compound (I) can be produced, for example, using the method of step 1 (and step 2) of the following reaction scheme 1.

(Wherein, X ′ represents a halogen atom, and the other symbols are as defined above).
As a halogen atom shown by X ', a fluorine atom, a chlorine atom, a bromine atom, an iodine atom is mentioned, for example, Preferably, it is a chlorine atom or a bromine atom.

(Step 1)
The compound (I ′) can be obtained by reacting the compound (a) with the compound (b) in an inert solvent, as shown in the above Reaction scheme 1.
The amount of compound (a) to be used is generally 0.5 to 5 mol, preferably 0.7 to 2.5 mol, more preferably 0.8 to 1 mol, per 1 mol of compound (b). 2 moles.
Examples of the inert solvent include hydrocarbons, alcohols, ethers, esters, ketones, amides, nitriles, sulfoxides and the like, and these solvents can be used alone or as a mixed solvent.
The reaction temperature is 30 to 120 ° C, preferably 50 to 100 ° C, and more preferably 60 to 80 ° C.
The reaction time is usually 1 to 48 hours, preferably 10 to 30 hours, and more preferably 12 to 18 hours.

(Step 2)
X in the compound (I) ^- compounds other than halides ions is by conventional ion exchange method, can be obtained by replacing the halogen anion in the other anions.

  Among the compounds (a), the compound (a ′) having an imidazole ring can be produced, for example, using the method of the following reaction formula 2.

(Wherein each symbol is as defined above)
Compound (a ′) can be obtained by reacting compound (c) with compound (d), ammonia or ammonium salts, and formaldehydes in an inert solvent, as shown in the above-mentioned reaction formula 2 . The compound (a ′) can also be obtained by reacting the compound (c) with the compound (d) in an inert solvent, and further reacting with ammonia or an ammonium salt and formaldehyde.
The amount of compound (d) to be used is generally 0.5 to 5 mol, preferably 0.8 to 2.5 mol, more preferably 1 to 1.5 mol, per 1 mol of compound (c). It is.
Examples of ammonium salts include ammonium acetate, ammonium chloride and the like.
Formaldehydes include formaldehyde aqueous solution, paraformaldehyde and the like.
The amount of formaldehydes and ammonia (ammonium salt) to be used is, for example, 0.5 to 5 moles, preferably 0.8 to 2.5 moles, more preferably 1 to 1 mole of the compound (c), respectively. ~ 1.5 moles.
The reaction may, if necessary, further include an acid (for example, an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or heteropoly acid, or an organic acid such as p-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid or acetic acid In the presence of
Examples of inert solvents include hydrocarbons, halogenated hydrocarbons, alcohols, ethers, esters, ketones, amides, nitriles, sulfoxides and the like, and these solvents may be used alone or in combination. It can be used as
The reaction temperature is generally 20 to 100 ° C, preferably 50 to 70 ° C.
The reaction time is usually 1 to 96 hours, preferably 2 to 50 hours.

  The compound (a) can also be produced, for example, using the method of the following reaction formula 3.

(Wherein, LG represents a leaving group, and the other symbols are as defined above).
Examples of the leaving group represented by LG include a halogen atom, an optionally substituted C _1-6 alkyl-sulfonyloxy group, an optionally substituted C _6-10 aryl-sulfonyloxy group and the like. .
The compound (a) can be obtained by reacting the compound (e) with the compound (f) in an inert solvent under basic conditions as shown in the above-mentioned reaction formula 3.
The amount of compound (f) to be used is generally about 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of compound (e).
As the base, for example, basic salts, metal hydrides, aromatic amines, tertiary amines, metal amides, alkyl metals, aryl metals, metal alkoxides and the like can be mentioned. The amount of the base to be used is generally about 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of compound (e).
Inert solvents include ethers, hydrocarbons, amides, halogenated hydrocarbons, sulfoxides, and these solvents can be used alone or as a mixed solvent.
The reaction temperature is generally 10 to 200 ° C, preferably 10 to 150 ° C.
The reaction time is generally 0.5 to 48 hours, preferably 1 to 20 hours.

The deuteration catalyst of the present invention is formed, for example, by coordinating a carbene ligand derived by treating compound (I) (ligand precursor) with a base or the like to a transition metal. It is a complex. The ligand thus derived corresponds to, for example, a compound obtained by removing H ⁺ and the anion X ⁻ from the compound (I) (ligand precursor).

In such a ligand, for example, as an N-heterocyclic carbene (NHC), the carbon atom of the ring structure “N ⁺ CHCH—N” of ring C of compound (I) is coordinated to a transition metal. Furthermore, when a substituent of ring A or ring B of compound (I) contains a hetero atom such as an oxygen atom, a sulfur atom, or a nitrogen atom, these hetero atoms are also coordinated to the transition metal and the polydentate arrangement It may function as an ligand (eg, a bidentate ligand, a tridentate ligand).

  The transition metal in the deuteration catalyst of the present invention is preferably a group 8 element (iron, ruthenium, osmium), a group 9 element (cobalt, rhodium, iridium), a group 10 element (nickel, palladium) of the periodic table. Platinum, a group 11 element (copper, silver, gold), more preferably a group 10 element, still more preferably nickel or palladium, particularly preferably palladium. The transition metal is, for example, 0 to 6, preferably 0 to 4 and particularly preferably 0 to 2 (e.g. 0 or 2).

Below, the preparation method of the complex containing the carbene ligand and transition metal derived from compound (I) is demonstrated.
The complex can be obtained, for example, by mixing compound (I) with a transition metal compound in the presence of a base in an inert solvent.
The amount of the ligand precursor to be used is generally 1 to 100 moles, preferably 1 to 50 moles (eg, 1.2 to 25 moles), and more preferably 1 to 1 mole of the transition metal compound. 0.5 to 10 moles (e.g. 1.5 to 5 moles), more preferably 1.5 to 2.5 moles.
Examples of the base include alkali metal hydroxides, alkali metal carbonates, alkali metal fluorides, alkali metal phosphates, metal alkoxides, aromatic amines, tertiary amines, metal amides and the like. .
The amount of the base used may be usually 1 to 1000 mol, more preferably 1 to 500 mol, and still more preferably 1 to 200 mol, per 1 mol of the transition metal compound.
As a transition metal compound, for example, in the case of a palladium compound, a halide (eg, palladium (II) chloride, lithium palladium (II) lithium tetrachloride, palladium (II) bromide etc.), inorganic acid salts (eg, palladium nitrate (eg, palladium nitrate) II), palladium (II) and the like, organic acid salts (eg palladium (II) acetate, palladium (II) propionate), allyl complexes (eg allyl palladium (II) chloride dimer etc.), dibenzylidene Acetone complexes (eg, bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0), etc.), phosphine complexes (eg, palladium (0) tetrakis (triphenylphosphine), palladium (0) Bis (tri-o-tolyl phosphine), palladium (I ) Bis (triphenylphosphine) dichloride, bis (tricyclohexylphosphine) palladium (0), tris (triethylphosphine) palladium (0), etc.), acetylacetone complexes (eg, acetylacetone palladium (II) etc.), nitrile complexes (eg, And palladium (II) bis (acetonitrile), palladium (II) bis (benzonitrile) and the like. In the case of nickel compounds, halides (for example, nickel (II) chloride, nickel (II) bromide, nickel (II) iodide), inorganic acid salts (nickel (II) nitrate, nickel (II) sulfate, nickel carbonate ( II), nickel (II) acetate, nickel (II) benzoate, organic acid salt (nickel (II) trifluoromethanesulfonate), alkene complex (for example, bis (1,5-cyclooctadiene) nickel (0) And phosphine complexes (eg, chloro (1-naphthyl) bis (triphenylphosphine) nickel (II), tetrakis (triphenylphosphine) nickel (0)) and the like.
As the inert solvent, alcohols, ethers, ketones, hydrocarbons, esters, amides, nitriles, sulfoxides can be mentioned, and these solvents can be used alone or as a mixed solvent.
The preparation time is usually 1 minute to 24 hours, preferably 5 minutes to 3 hours. The preparation temperature is usually 10 to 150 ° C, preferably 70 to 100 ° C.

Hereinafter, the deuteration method using the deuteration catalyst of this invention is demonstrated.
The deuteration catalyst of the present invention can catalyze the substitution reaction of a leaving group bonded to an aromatic carbon atom to a deuterium atom, for example, a halogen bonded to an aromatic carbon atom in a halogenated aromatic compound The substitution reaction of atoms to deuterium atoms can be catalyzed. The deuteration method of the present invention is excellent in both the cost aspect and the deuteration ratio, and in particular, it is possible to selectively deuterate a leaving group (for example, a halogen atom etc.) of an aromatic compound. it can.

The deuteration reaction may be carried out, for example, by using an aromatic compound (eg, a halogenated aromatic compound) having a leaving group which is a reaction substrate in an organic solvent, the deuteration catalyst of the present invention, a deuteration agent and a base The reaction may be carried out in the presence.
The deuteration reaction may be carried out using a previously prepared catalyst, may be carried out in one pot after the preparation of the catalyst, or may be carried out simultaneously with the preparation of the catalyst, but using the previously prepared catalyst or the catalyst It is preferable to carry out in one pot after preparation of and more preferable to carry out in one pot after preparation of the catalyst.

The amount of the deuterating agent used is usually 1 to 50 molar equivalents, preferably 1 to 15 molar equivalents, more preferably 1 to 5 molar equivalents, still more preferably 1 to 3 relative to the leaving group of the aromatic compound. It is a molar equivalent, still more preferably 1 to 2 molar equivalents, particularly preferably 1 to 1.5 molar equivalents.
The amount of the deuteration catalyst used is usually 1 × 10 ⁻⁵ to 1 molar equivalent, preferably 1 × 10 ⁻⁴ to 2 × 10 ⁻¹ relative to the leaving group of the aromatic compound as a transition metal equivalent. The molar equivalent is more preferably 1 × 10 ^{−3 to} 5 × 10 ⁻² molar equivalent.
As the base, the same base as in preparing the catalyst may be used, and alkali metal hydroxides, alkali metal carbonates, alkali metal fluorides, alkali metal phosphates, metal alkoxides, aromatic amines, Tertiary amines, metal amides, etc. may be mentioned.
The amount of the base used may be the same as in preparing the catalyst, and is preferably 1 to 10 molar equivalents, more preferably 1 to 3 molar equivalents, with respect to the leaving group of the aromatic compound. Good.
As the organic solvent, the same solvent as in preparing the catalyst may be used, and examples thereof include alcohols, ethers, ketones, hydrocarbons, esters, amides, nitriles, sulfoxides, etc. The solvents can be used alone or as a mixed solvent. It is not necessary to use a heavy solvent as the organic solvent.
The reaction time is generally 1 to 48 hours, preferably 12 to 24 hours.
The reaction temperature is generally 20 to 200 ° C, preferably 70 to 130 ° C.

  According to the deuteration method of the present invention, it is possible to realize a high deuteration ratio without using a heavy solvent and suppressing the amount of use of a deuterium compound such as a deuteration agent. Specifically, the deuterated product can be obtained at a deuteration ratio of 95% or more, 97% or more, 98% or more, particularly 99% or more.

  The aromatic compound having a leaving group means a compound in which at least one leaving group is covalently bonded to a carbon atom (that is, an aromatic carbon atom) which is a ring member atom of an aromatic ring, and is known It may be a compound or a derivative thereof or an unknown compound. As a specific example, formula (IV):

[Wherein, Ar represents an aromatic ring; LG each independently represents a leaving group (eg, a halogen atom or the like); R ⁷ each independently represents a substituent; na is 1 or more Nb is an integer of 0 or more; when nb is 2 or more, two or more R ^{7 taken} together are one or more rings which may be further substituted (eg, non-aromatic) Heterocycle, cycloalkene ring, cycloalkadiene ring, etc.) may be formed. ]
Examples of the compound represented by the formula are, but not limited to:

The substituent (R ⁷ ) other than the leaving group in the aromatic ring of the aromatic compound having a leaving group is not particularly limited, and, for example, a nitro group, an acyl group, and carbonization which may be substituted A hydrogen group, a heterocyclic group which may be substituted, a hydroxy group which may be substituted, a sulfanyl group which may be substituted (the sulfur atom of the sulfanyl group may be oxidized), which is substituted And amino groups and the like. Furthermore, these substituents may be substituted by the substituent chosen from the said substituent group (1)-(8) grade | etc.,.

As a further substituent of “one or more rings which may be further substituted” formed by two or more R ⁷ together, for example, a nitro group, an acyl group, an optionally substituted hydrocarbon Group, heterocyclic group which may be substituted, amino group which may be substituted, carbamoyl group which may be substituted, hydroxy group which may be substituted, sulfanyl group which may be substituted The sulfur atom of the group may be oxidized), oxo group and the like.

  The deuteration method of the present invention can be applied to various aromatic compounds because of its high substrate generality.

For example, a plurality of aromatic rings may exist in the aromatic compound having a leaving group. Moreover, substituents (R ⁷ ) may be bonded to each other to form a dimer or a polymer independently. Furthermore, the aromatic compound having a leaving group may form a salt.

  When the aromatic compound having a leaving group has a basic group, for example, an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, The salt may be formed with an organic acid such as citric acid, tartaric acid, maleic acid, fumaric acid, malic acid, lactic acid and the like. When having an acidic group or groups, it may be, for example, a sodium salt, a potassium salt, a calcium salt, a magnesium salt and the like.

  As the deuterating agent, for example, a secondary alcohol in which the 1-position is substituted by a deuterium atom may be used, for example, a compound of the formula (III):

[Wherein, R ⁵ and R ⁶ each independently represent a substituent; D represents a deuterium atom. ]
Examples of the compound represented by the formula are, but not limited to:

In formula (III), R ⁵ and R ⁶ are preferably each independently a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; more preferably, it is substituted An alkyl group which may be substituted, a cycloalkyl group which may be substituted, an aryl group which may be substituted, or a 5- to 12-membered aromatic heterocyclic group which may be substituted; Optionally substituted phenyl.

  The deuteration agent may be produced by a known method or a method analogous thereto, or may be a commercially available product.

  Compound (III) can be produced, for example, using the method of the following reaction formula 4.

(Wherein each symbol is as defined above)
Compound (III) can be obtained by reacting compound (g) with a deuterated reducing reagent in an inert solvent, as shown in the above Reaction scheme 4.
As a deuterated reduction reagent, for example, lithium aluminum deuteride, sodium borohydride, lithium borohydride, sodium cyanoborohydride, lithium triethylborohydride, sodium triacetoxyborohydride, etc. Can be mentioned.
As the deuteration reducing reagent, it is preferable to use one having as high deuteration ratio as possible, preferably 98% or more, and more preferably 99% or more.
The amount of the deuterated reducing reagent to be used is generally 0.1 to 10 mol, preferably 0.3 to 3 mol, per 1 mol of compound (g).
As the inert solvent, hydrocarbons, halogenated hydrocarbons, ethers and the like can be mentioned, and these solvents can be used alone or as a mixed solvent.
The reaction temperature is generally -78 to 100 ° C, preferably -20 ° C to room temperature.
The reaction time is usually 0.1 to 50 hours, preferably 0.1 to 5 hours.

  The present invention is further described in detail by the following synthesis examples and examples, which are not intended to limit the present invention and may be changed without departing from the scope of the present invention.

"Room temperature" in the following examples usually indicates about 10 ° C to about 30 ° C.
¹ H NMR and ¹³ C NMR were measured at 400 MHz (or 500 MHz) and 100 MHz, respectively, by Fourier transform NMR. Chemical shift values are expressed in ppm relative to TMS (tetramethylsilane). High resolution mass spectra (HRMS) were measured using electron ionization (EI) mass spectrometry or fast atom bombardment (FAB) mass spectrometry.

The abbreviations used in the text have the following meanings.
s: singlet
d: doublet
t: Triplet
q: Quartet
m: Multiplet
br: Broad
Me: methyl
Et: Ethyl
iPr: isopropyl
Bu: Butyl
tBu: tert-butyl
Hex: hexyl
Ph: phenyl
Bn: benzyl

Synthesis Example 1-1
Synthesis of 3-mesityl-4,5-dimethyl-1- (2,4,6-trimethylbenzyl) imidazolium chloride (compound 1)

(1) 1-mesityl-4,5-dimethyl-1H-imidazole
In a solution of 2,4,6-trimethylaniline (12 mmol) in chloroform (20 mL), diacetyl (10 mmol), acetic acid (50 mmol), ammonium acetate (12 mmol), paraformaldehyde (10 mmol) and water (0.5) mL) was added and refluxed for 48 hours. After evaporation of the solvent, the dark residue obtained was dissolved in diethyl ether and adjusted to pH 14 with 40% aqueous potassium hydroxide solution in an ice bath. The resulting mixture was extracted with diethyl ether. The combined organic layer is washed with water, dried over sodium sulfate, concentrated and purified by silica gel chromatography (hexane / ethyl acetate = 3/1) to give the title compound (1.46 g, 6.8 mmol, a pale brown solid) Rate of 68%).
mp 130-131 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.84 (s, 3H), 1.93 (s, 6H), 2.24 (s, 3H), 2.34 (s, 3H), 6.97 (s) , 2H), 7.25 (s, 1H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 8.1 (CH ₃ ), 12.9 (CH ₃ ), 17.3 (CH ₃ ), 20.9 (CH ₃ ), 122.5 (12 MHz) C), 128.8 (CH), 132.4 (C), 133.7 (C), 134.3 (CH), 135.9 (C), 138.5 (C). IR (ATR): 770, 1490 cm ^-1 . HRMS (EI) m ^{/ z: (M +) Calcd} for C 14 H 18 N 2: 214.1470; Found: 214.1461.

(2) 3-mesityl-4,5-dimethyl-1- (2,4,6-trimethylbenzyl) imidazolium chloride
Anhydrous tetrahydrofuran (2.0 mmol) of 1-mesityl-4,5-dimethyl-1H-imidazole (2.0 mmol) obtained in step (1) of Synthesis Example 1-1 was obtained by using 2,4,6-trimethylbenzyl chloride (2.0 mmol). 2 mL) was added to the solution. The reaction mixture was refluxed for 15 hours and then concentrated. The obtained solid was filtered and washed with tetrahydrofuran to give the title compound (535 mg, 1.40 mmol, 70% yield) as a white solid.
mp 285-286 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.92 (s, 3H), 1.99 (s, 6H), 2.12 (s, 3H), 2.27 (s, 3H), 2.336 (s) , 6H), 2.342 (s, 3H), 5.95 (s, 2H), 6.88 (s, 2H), 7.01 (s, 2H), 9.90 (s, 1H). ¹³ C-NMR (100 MHz, CDCl ₃ ) : δ 7.9 (CH ₃ ), 8.9 (CH ₃ ), 17.1 (CH ₃ ), 19.7 (CH ₃ ), 20.5 (CH ₃ ), 20.7 (CH ₃ ), 47.2 (CH ₂ ), 125.3 (C), 127.5 (C), 128.0 (C), 128.5 (C), 129.5 (CH), 124.3 (CH), 134.3 (C), 135.1 (CH), 137.2 (C), 138.8 (C), 140.9 (C). IR. (ATR): 850, 1550 cm ^-1 . HRMS (FAB) m / z: [M-Cl] ⁺ Calcd for C ₂₄ H ₃₁ N ₂ : 347.2487; Found: 347.2488.

Synthesis Example 1-2
Synthesis of 3- (2,6-diisopropylphenyl) -4,5-dimethyl-1- (2,4,6-trimethylbenzyl) imidazolium chloride (compound 2)

(1) 1- (2,6-diisopropylphenyl) -4,5-dimethyl-1H-imidazole
The title compound (1.59 g, 6.2 mmol) as a brown oil was prepared in the same manner as in step (1) of Synthesis Example 1-1 except that 2,6-diisopropylaniline was used instead of 2,4,6-trimethylaniline. , Yield 62%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.09 (d, J = 6.8 Hz, 6 H), 1.14 (d, J = 6.8 Hz, 6 H), 1.86 (s, 3 H), 2.26 (s, 3 H) , 2.33-2.40 (m, 2H), 7.24 (s, 1H), 7.28 (d, J = 7.6 Hz, 2 H), 7.43 (t, J = 7.6 Hz, 1 H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 8.1 (CH ₃ ), 12.7 (CH ₃ ), 22.9 (CH ₃ ), 24.9 (CH ₃ ), 27.6 (CH), 123.3 (C), 123.5 (CH), 129.4 (CH), 131.5 ( C), 133.3 (C), 135.3 (CH), 146.6 (C). IR (ATR): 770, 1490 cm ^-1 . HRMS (EI) m / z: (M ⁺ ) Calcd for C ₁₇ H ₂₄ N ₂ Found: 256.1933.

(2) 3- (2,6-diisopropylphenyl) -4,5-dimethyl-1- (2,4,6-trimethylbenzyl) imidazolium chloride
In place of 1-mesityl-4,5-dimethyl-1H-imidazole, 1- (2,6-diisopropylphenyl) -4,5-dimethyl-1H- obtained in step (1) of Synthesis Example 1-2 The title compound (403 mg, 0.95 mmol, yield 48%) was obtained as a white solid in the same manner as in step (2) of Synthesis Example 1-1 except that imidazole was used.
mp 267-268 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.16 (d, J = 6.8 Hz, 6 H), 1. 19 (d, J = 6.8 Hz, 6 H), 1. 93 (s, 3 H), 2.19-2.23 (m, 2H), 2.27 (s, 6H), 2.34 (s, 6H), 6.03 (s, 2H), 6.89 (s, 2H), 7.31 (d, J = 7.8 Hz, 2H), 7.53 (t, J = 7.8 Hz, 1 H), 9.65 (s, 1 H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 8.3 (CH ₃ ), 9.2 (CH ₃ ), 19.7 (CH ₃ ), 20.7 (CH ₃ ), 22.7 (CH ₃ ), 24.9 (CH ₃ ), 28.4 (CH), 47.4 (CH ₂ ), 124.6 (CH), 125.2 (C), 128.0 (C), 128.5 (C), 128.6 ( C), 129.8 (CH), 131.7 (CH), 134.7 (CH), 137.6 (C), 139.3 (C), 145.4 (C). IR (ATR): 810, 1460 cm ^-1 . HRMS (FAB) m / z: [M-Cl] + Calcd for C 22 H 27 N 2 O: 389.2957; Found: 389.2955.

Synthesis Example 1-3
Synthesis of 3- (2,6-diisopropylphenyl) -4,5-dimethyl-1- (2,4,6-triisopropylbenzyl) imidazolium chloride (compound 3)

In place of 1-mesityl-4,5-dimethyl-1H-imidazole, 1- (2,6-diisopropylphenyl) -4,5-dimethyl-1H- obtained in step (1) of Synthesis Example 1-2 The same as step (2) of Synthesis Example 1-1 except that imidazole (2.0 mmol) was used and 2,4,6-triisopropylbenzyl chloride was used instead of 2,4,6-trimethylbenzyl chloride The title compound (515 mg, 1.01 mmol, 51% yield) was obtained as a white solid.
mp 208-209 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.07 (d, J = 6.8 Hz, 6 H), 1.18 (d, J = 6.8 Hz, 6 H), 1.23 (d, J = 6.8) Hz, 6H), 1.24 (d, J = 6.8 Hz, 6H), 2.03 (s, 3H), 2.19-2.26 (m, 2H), 2.70 (s, 3H), 2.86-2.92 (m, 1H), 3.10 -3.17 (m, 2H), 5.76 (s, 2H), 7.08 (s, 2H), 7.50 (d, J = 8.0 Hz, 2 H), 7.52 (t, J = 8.0 Hz, 1 H), 7.95 (s, 1 H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 8.6 (CH ₃ ), 9.9 (CH ₃ ), 23.1 (CH ₃ ), 23.5 (CH ₃ ), 24.2 (CH ₃ ), 24.8 (CH ₃ ) ), 28.3 (CH), 29.7 (CH), 34.0 (CH), 45.0 (CH 2), 121.4 (C), 122.0 (CH), 124.8 (CH), 127.8 (C), 129.3 (C), 129.6 ( C), 131.9 (CH), 132.0 (CH), 145.5 (C), 148.6 (C), 151.3 (C). IR (ATR): 760, 1540 cm ^-1 . HRMS (FAB) m / z: [M _{^{-Cl] + Calcd for C 33 H}} 49 N 2: 473.3896; Found: 473.3901.

Synthesis Example 1-4
Synthesis of 3- (2,6-Dibenzhydryl-4-methylphenyl) -4,5-dimethyl-1- (2,4,6-trimethylbenzyl) imidazolium chloride (compound 4)

(1) 1- (2,6-Dibenzhydryl-4-methylphenyl) -4,5-dimethyl-1H-imidazole Diacetyl is 2.5 mmol, and 2,6-dibenzhydryl instead of 2,4,6-trimethylaniline The title compound (585 mg, 1.13 mmol, yield 45%) was obtained as a pale yellow solid in the same manner as in step (1) of Synthesis Example 1-1 except that -4-methylaniline was used.
mp 87-88 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.30 (s, 3H), 2.15 (s, 3H), 2.26 (s, 3H), 4.99 (s, 2H), 6.61 (s) , 1H), 6.87-6.91 (m, 6H), 6.94-6.97 (m, 4H), 7.15-7.26 (m, 12H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 7.7 (CH ₃ ), 12.9 (CH ₃ ), 21.7 (CH ₃ ), 51.3 (CH), 123.3 (C), 126.5 (CH), 128.2 (CH), 128.3 (CH), 129.1 (CH), 129.5 (CH), 129.6 (CH) ), 132.2 (C), 133.8 (C), 135.5 (CH), 138.7 (C), 142.3 (C), 142.7 (C), 142.8 (C). IR (ATR): 700, 1490 cm ^-1 . HRMS. (EI) m / z: (M ⁺ ) Calcd for C ₃₈ H ₃₄ N ₂ : 518.2722; Found: 518.2719.

(2) 3- (2,6-Dibenzhydryl-4-methylphenyl) -4,5-dimethyl-1- (2,4,6-trimethylbenzyl) imidazolium chloride
Instead of 1-mesityl-4,5-dimethyl-1H-imidazole, 1- (2,6-dibenzhydryl-4-methylphenyl) -4,5- obtained in step (1) of Synthesis Example 1-4 The title compound (941 mg, 1.37 mmol, yield 69%) was obtained as a white solid in the same manner as in step (2) of Synthesis Example 1-1 except that dimethyl-1H-imidazole was used.
mp 214-215 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.28 (s, 3H), 2.14 (s, 6H), 2.23 (s, 3H), 2.24 (s, 3H), 2.28 (s) , 3H), 4.97 (s, 2H), 5.63 (s, 2H), 6.80 (s, 2H), 6.83 (s, 2H), 6.93 (t, J = 6.8 Hz, 8H), 7.21-7.27 (m, 12 H), 8.54 (s, 1 H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 7.7 (CH ₃ ), 9.2 (CH ₃ ), 19.8 (CH ₃ ), 20.8 (CH ₃ ), 21.6 (CH ₃ ) ₃ ), 47.0 (CH ₂ ), 51.4 (CH), 126.9 (CH), 127.0 (CH), 128.1 (CH), 128.5 (CH), 128.6 (CH), 128.7 (CH), 129.1 (CH), 129.7 (CH), 134.7 (CH), 137.3 (CH), 139.1 (C), 140.6 (C), 141.1 (C), 141.3 (C). IR (ATR): 700 ^{, 1490 cm -1 HRMS (FAB)} m / z: [M-Cl] + Calcd for C 48 H 47 N 2:... 651.3739; Found: 651.3743 Anal Calcd for C 48 H 47 N 2 Cl: C, 83.87 H, 6.89; N, 4.08. Found: C, 83.77; H, 7.04; N, 4.01.

Synthesis Example 1-5
Synthesis of 4,5-dimethyl-3- [2- (dimethylamino) phenyl] -1- (2,4,6-trimethylbenzyl) imidazolium chloride (compound 5)

(1) 4,5-Dimethyl-1- [2- (dimethylamino) phenyl] -1H-imidazole
To a solution of 2- (dimethylamino) aniline (36.9 mmol) in chloroform (61.4 mL), diacetyl (30.7 mmol), acetic acid (153.5 mmol), ammonium acetate (30.7 mmol), paraformaldehyde (30.7 mmol) and water (1.54 mL) ) Was added and the mixture was refluxed for 4 hours. After evaporation of the solvent, the dark residue was dissolved in diethyl ether and adjusted to pH 14 with 40% aqueous potassium hydroxide solution in an ice bath. The resulting mixture was extracted with diethyl ether. The combined organic layer is washed with water, dried over sodium sulfate, concentrated and purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give the title compound (3.46 g, 16.1 mmol, brown oil) 52% yield was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.01 (s, 3 H), 2.23 (s, 3 H), 2. 49 (s, 6 H), 6. 97 (t, J = 7.6 Hz, 1 H), 7.03 (d, J = 7.6 Hz, 1 H), 7.08 (dd, J = 1.5, 7.6 Hz, 1 H), 7.30-7.35 (m, 1 H), 7.46 (s, 1 H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 8.5 (CH ₃ ), 12.7 (CH ₃ ), 41.8 (CH ₃ ), 118.3 (CH), 120.7 (CH), 123.4 (C), 128.1 (C), 128.9 (CH), 129.1 (CH), 133.4 (C), 135.4 (CH), 149.0 (C). IR (ATR): 750, 1500 cm ^-1 . HRMS (EI) m / z: (M ⁺ ) Calcd for C ₁₃ H ₁₇ N ₃ : 215.1422; Found 215.1411.

(2) 4,5-Dimethyl-3- [2- (dimethylamino) phenyl] -1- (2,4,6-trimethylbenzyl) imidazolium chloride
The 4,5-dimethyl-1- [2- (dimethylamino) phenyl] -1H-imidazole obtained in the step (1) of Synthesis Example 1-5, 2,4,6-trimethylbenzyl chloride (6.94 mmol) It was added to a solution of (6.94 mmol) in anhydrous tetrahydrofuran (30 mL). The reaction mixture was refluxed for 15 hours. The obtained solid was filtered and washed with tetrahydrofuran to give the title compound (1.39 g, 3.61 mmol, yield 52%) as a white solid.
mp 238-239 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): 2.06 (s, 3 H), δ 2. 25 (s, 3 H), 2. 27 (s, 3 H), 2. 36 (s, 6 H), 2.52 (s , 6H), 5.84 (s, 2H), 6.89 (s, 2H), 7.13-7.19 (m, 2H), 7.40-7.49 (m, 2H), 9.46 (s, 1H). ¹³ C-NMR (100 MHz) , CDCl ₃ ): δ 8.6 (CH ₃ ), 9.1 (CH ₃ ), 19.9 (CH ₃ ), 20.9 (CH ₃ ), 43.1 (CH ₃ ), 47.1 (CH ₂ ), 120.5 (CH), 123.4 (CH ₃ ) ), 125.5 (C), 126.2 (C), 127.6 (C), 128.2 (C), 128.7 (CH), 129.9 (CH), 131.8 (CH), 135.4 (CH), 137.8 (C), 139.3 (C) , 149.0 (C). IR (ATR): 770, 1450 cm ^-1 . HRMS (FAB) m / z: [M-Cl] ⁺ Calcd for C ₂₃ H ₃₀ N ₂ : 348.2440; Found: 348.2458.

Synthesis Example 1-6
Synthesis of 3- (2-methoxyphenyl) -4,5-dimethyl-1- (2,4,6-trimethylbenzyl) imidazolium chloride (compound 6)

(1) 1- (2-Methoxyphenyl) -4,5-dimethyl-1H-imidazole Synthesis Example 1- except that 10 mmol of diacetyl was used and o-anisidine was used instead of 2- (dimethylamino) aniline. The title compound (1.09 g, 5.4 mmol, 54% yield) as a yellow solid was obtained in the same manner as step 5 (1).
mp 79-80 ° C. ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.97 (3H, s), 2.23 (3H, s), 3.80 (3H, s), 7.01-7.05 (2H, m), 7.17 (7H) 1 H, d, J = 7.1 Hz), 7.39 (1 H, s), 7. 39-7. 42 (1 H, m). ¹³ C NMR (100 MHz, CDCl ₃ ): 8.3 (CH ₃ ), 12.7 (CH ₃ ), 55.4 _{(CH 3), 111.8 (CH} ), 120.5 (CH), 123.8 (C), 125.4 (C), 128.3 (CH), 129.7 (CH), 133.0 (C), 135.5 (CH), 154.4 (C). IR (ATR): 760, 1220, 1500 cm ^-1 . HRMS (EI) m / z: (M ⁺ ) Calcd for C ₁₂ H ₁₄ N ₂ O: 202.1106; Found: 202.1104.

(2) 3- (2-methoxyphenyl) -4,5-dimethyl-1- (2,4,6-trimethylbenzyl) imidazolium chloride
1- (2-methoxyphenyl) -4 obtained in the step (1) of Synthesis Example 1-6 instead of 4,5-dimethyl-1- [2- (dimethylamino) phenyl] -1H-imidazole The title compound (408 mg, 1.1 mmol, yield 79) was a white solid in the same manner as in the step (2) of Synthesis Example 1-5 except that 5-dimethyl-1H-imidazole (281 mg, 1.39 mmol) was used. %) Got.
mp 213 ° -214 ° C. ¹ H NMR (400 MHz, CDCl ₃ ): δ 2.01 (3H, s), 2.17 (3H, s), 2.27 (3H, s), 2.34 (6H, s), 3.82 (3H, s) s), 5.84 (2H, s), 6.88 (2H, s), 7.07 (1 H, d, J = 8.0 Hz), 7.11 (1 H, t, J = 8.0 Hz), 7.46-7.48 (1 H, m), 7.50-7.55 (1 H, m), 9.51 (1 H, s). ¹³ C NMR (100 MHz, CDCl ₃ ): 8.4 (CH ₃ ), 8.8 (CH ₃ ), 19.8 (CH ₃ ), 20.8 (CH ₃ ) , 46.9 (CH ₂ ), 55.8 (CH ₃ ), 112.3 (CH), 121.4 (C), 125.4 (C), 127.0 (C), 128.1 (CH), 128.6 (C), 129.8 (C) CH), 132.5 (CH), 135.5 (CH), 137.7 (C), 139.1 (C), 153.6 (C). IR (ATR): 770, 1260, 1500 cm ^-1 . FABMS m / z: 335 [M ^{.. -Cl] + Anal Calcd for} C 22 H 27 ClN 2 O:. C, 71.24; H, 7.34; N, 7.55 Found: C, 71.52; H, 7.55; N, 7.52.

Synthesis Example 1-7
Synthesis of 3- (2-methylphenyl) -4,5-dimethyl-1- (2,4,6-trimethylbenzyl) imidazolium chloride (compound 7)

(1) 4,5-Dimethyl-1- (2-methylphenyl) -1H-imidazole
The title compound of a brown oil was obtained in the same manner as in step (1) of Synthesis Example 1-1 except that 2-methylaniline was used instead of 2,4,6-trimethylaniline and dichloromethane was used as the extraction solvent. 1.11 g, 6.0 mmol, yield 60%) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.92 (s, 3H), 2.05 (s, 3H), 2.24 (s, 3H), 7.15 (d, J = 7.8 Hz, 1H), 7.27-7.39 ( m, 4H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 8.3 (CH ₃ ), 12.7 (CH ₃ ), 17.1 (CH ₃ ), 123.2 (C), 126.6 (CH), 127.8 (CH) , 128.9 (CH), 130.8 (CH), 133.5 (C), 134.8 (CH), 135.6 (C), 135.7 (C). IR (ATR): 770, 1500 cm ^-1 . HRMS (EI) m / z ^{: (M +) Calcd for C} 12 H 14 N 2: 186.1157; Found: 186.1157.

(2) 3- (2-Methylphenyl) -4,5-dimethyl-1- (2,4,6-trimethylbenzyl) imidazolium chloride
Instead of 1-mesityl-4,5-dimethyl-1H-imidazole, the 4,5-dimethyl-1- (2-methylphenyl) -1H-imidazole obtained in step (1) of Synthesis Example 1-7 is used. The reaction mixture was concentrated and purified by silica gel chromatography (dichloromethane / methanol = 10/1) and then washed with tetrahydrofuran in the same manner as in step (2) of Synthesis Example 1-1, except that it was white. The solid title compound (476 mg, 1.34 mmol, yield 67%) was obtained.
mp 243-244 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.99 (s, 3H), 2.11 (s, 3H), 2.18 (s, 3H), 2.27 (s, 3H), 2.35 (s) , 6H), 5.72 (d, J = 15.2 Hz, 1H), 6.04 (d, J = 15.2 Hz, 1H), 6.89 (s, 2H), 7.35-7.40 (m, 3H), 7.45-7.50 (m, 1 H), 9.66 (s, 1 H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 8.3 (CH ₃ ), 8.8 (CH ₃ ), 17.0 (CH ₃ ), 19.8 (CH ₃ ), 20.6 (CH ₃ ) ₃ ), 46.9 (CH ₂ ), 125.2 (C), 127.2 (CH), 127.7 (CH), 127.7 (C), 127.8 (C), 129.7 (CH), 131.0 (CH), 131.4 (CH), 131.8 (C), 134.2 (C), 134.8 (CH), 137.4 (C), 139.0 (C). IR (ATR): 770, 1560 cm ^-1 . HRMS (FAB) m / z: [M-Cl] ⁺ Calcd for C ₂₂ H ₂₇ N ₂ : 319.2174; Found: 319.2173.

Synthesis Example 1-8
Synthesis of 3- (2-ethylphenyl) -4,5-dimethyl-1- (2,4,6-trimethylbenzyl) imidazolium chloride (compound 8)

(1) 1- (2-ethylphenyl) -4,5-dimethyl-1H-imidazole Synthesis Example 1 except that 10 mmol of diacetyl was used and 2-ethylaniline was used instead of 2- (dimethylamino) aniline. In the same manner as in step (1) of -5, the title compound (1.36 g, 6.8 mmol, yield 68%) as a brown oil was obtained.
¹ H NMR (400 MHz, CDCl ₃ ): 1.09 (3 H, t, J = 7.6 Hz), 1.91 (3 H, s), 2.24 (3 H, s), 2.28-2.44 (2 H, m), 7.13 (1 H, d, J = 7.6 Hz), 7. 27-7. 31 (1 H, m), 7. 37 (1 H, s), 7. 38-7. 44 (2 H, m). ¹³ C NMR (100 MHz, CDCl ₃ ): 8.4 (CH ₃ ), 12.6 (CH ₃ ), 14.7 (CH ₃ ), 23.5 (CH ₂ ), 123.4 (C), 126.5 (CH), 128.0 (CH), 129.2 (CH), 129.3 (CH), 133.2 (C), 135.0 ( C), 135.2 (CH), 141.5 (C). IR (ATR): 770, 1490 cm ^-1 . HRMS (EI) m / z: (M ⁺ ) calcd for C ₁₃ H ₁₆ N ₂ : 200.1313. Found: 200.1293.

(2) 3- (2-ethylphenyl) -4,5-dimethyl-1- (2,4,6-trimethylbenzyl) imidazolium chloride
1- (2-ethylphenyl) -4 obtained in the step (1) of Synthesis Example 1-8 instead of 4,5-dimethyl-1- [2- (dimethylamino) phenyl] -1H-imidazole The title compound (442 mg, 1.20 mmol, yield 60) was a white solid in the same manner as in Synthesis Example 1-5, step (2) except that 5-dimethyl-1H-imidazole (400 mg, 2.0 mmol) was used. %) Got.
mp 242-243 ° C. ¹ H NMR (400 MHz, CDCl ₃ ): 1.13 (3H, t, J = 7.6 Hz), 1.99 (3H, s), 2.21 (3H, s), 2.27 (3H, s), 2.29-2.42 (2H, m), 2.35 (6H, s), 5.68 (1H, d, J = 15.4 Hz), 6.06 (1 H, d, J = 15.4 Hz), 6.89 (2H, s), 7.37-7. (3H, m), 7.50-7.54 (1 H, m), 9.54 (1 H, s). ¹³ C NMR (100 MHz, CDCl ₃ ): 8.5 (CH ₃ ), 8.9 (CH ₃ ), 14.4 (CH ₃ ) , 19.9 (CH ₃ ), 20.7 (CH ₃ ), 23.5 (CH ₂ ), 47.1 (CH ₂ ), 125.4 (C), 127.5 (CH), 127.6 (CH), 127.8 (C), 128.1 (C), 129.85 (CH), 129.88 (CH), 131.3 (C), 131.4 (CH), 135.2 (CH), 137.6 (C), 139.1 (C), 140.1 (C). IR (ATR): 1560 cm ^-1 . HRMS (FAB) m / z: [M-Cl] + calcd for C 23 H 29 N 2:. 333.2331 Found: 333.2326.

Synthesis Example 1-9
Synthesis of 3- (2-isopropylphenyl) -4,5-dimethyl-1- (2,4,6-trimethylbenzyl) imidazolium chloride (compound 9)

(1) 1- (2-isopropylphenyl) -4,5-dimethyl-1H-imidazole
The title compound of a brown oil was obtained in the same manner as in step (1) of Synthesis Example 1-1 except that 2-isopropylaniline was used instead of 2,4,6-trimethylaniline and dichloromethane was used as the extraction solvent. 1.41 g, 6.6 mmol, 66% yield were obtained.
¹ H-NMR (400 MHz, CDCl ₃ ): 1.12 (d, J = 7.2 Hz, 3 H), 1.15 (d, J = 7.2 Hz, 3 H), 1.91 (s, 3 H), 2.24 (s, 3 H), 2.58 (septet, J = 7.2 Hz , 1H), 7.11 (d, J = 7.6 Hz, 1H), 7.25-7.29 (m, 1H), 7.36 (s, 1H), 7.43-7.47 (m, 1H). 13 C-NMR (100 MHz, CDCl ₃ ): δ 8.5 (CH ₃ ), 12.8 (CH ₃ ), 23.0 (CH ₃ ), 24.7 (CH ₃ ), 27.4 (CH), 123.7 (C), 126.3 (CH) 126.6 (CH), 128.1 (CH), 129.5 (CH), 133.4 (C), 134.2 (C), 135.4 (CH), 146.4 (C). IR (ATR): 770, 1500 cm ^-1 . HRMS ( EI) m / z: (M ⁺ ) Calcd for C ₁₄ H ₁₈ N ₂ : 214.1470; Found: 214.1461.

(2) 3- (2-isopropylphenyl) -4,5-dimethyl-1- (2,4,6-trimethylbenzyl) imidazolium chloride
Instead of 1-mesityl-4,5-dimethyl-1H-imidazole, 1- (2-isopropylphenyl) -4,5-dimethyl-1H-imidazole obtained in step (1) of Synthesis Example 1-9 is used. The reaction mixture thus concentrated is purified by silica gel chromatography (dichloromethane / methanol = 9.5 / 1), and then washed with tetrahydrofuran, and then white in the same manner as in step (2) of Synthesis Example 1-1. The solid title compound (421 mg, 1.10 mmol, 55% yield) was obtained.
mp 250-251 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.14 (d, J = 6.8 Hz, 3 H), 1.22 (d, J = 6.8 Hz, 3 H), 1.98 (s, 3 H), 2.24 (s, 3 H), 2. 27 (s, 3 H), 2. 32-2. 43 (m, 1 H), 2. 35 (s, 6 H), 5. 65 (d, J = 15.2 Hz, 1 H), 6.08 (d, J = 15.2 Hz , 1H), 6.89 (s, 2H), 7.34-7.41 (m, 2H), 7.46-7.48 (m, 1H), 7.53-7.57 (m, 1H), 9.49 (s, 1H). ¹³ C-NMR ( 100 MHz, CDCl ₃ ): δ 8.4 (CH ₃ ), 8.9 (CH ₃ ), 19.7 (CH ₃ ), 20.6 (CH ₃ ), 22.4 (CH ₃ ), 24.5 (CH ₃ ), 27.8 (CH), 46.9 (CH ₂ ), 125.2 (C), 127.0 (CH), 127.7 (CH), 128.2 (C), 129.7 (CH), 130.2 (C), 131.5 (CH), 134.8 (CH), 137.4 (C), 139.0 (C), 144.8 (C). IR (ATR): 770, 1560 cm ^-1 . HRMS (FAB) m / z: [M-Cl] ⁺ Calcd for C ₂₄ H ₃₁ N ₂ : 347.2487; Found: 347.2492.

Synthesis Example 1-10
Synthesis of 1- (2-methylbenzyl) -4,5-dimethyl-3- (2,4,6-trimethylphenyl) imidazolium chloride (compound 10)

The reaction mixture was concentrated using 2-methylbenzyl chloride instead of 2,4,6-trimethylbenzyl chloride and purified by silica gel chromatography (dichloromethane / methanol = 9.5 / 1), except for the synthesis example 1- In the same manner as in step (2) of 1, the title compound (392 mg, 1.10 mmol, 55% yield) as a white solid was obtained.
mp 244-245 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.95 (s, 3H), 2.06 (s, 6H), 2.14 (s, 3H), 2.36 (s, 3H), 2.44 (s) , 3H), 5.99 (s, 2H), 6.87 (d, J = 7.6 Hz, 1H), 7.03 (s, 2H), 7.16-7.25 (m, 3H), 10.49 (s, 1H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 7.8 (CH ₃ ), 8.6 (CH ₃ ), 17.0 (CH ₃ ), 18.9 (CH ₃ ), 20.5 (CH ₃ ), 48.9 (CH ₂ ), 126.1 (CH), 126.5 (CH), 127.0 (C), 128.1 (C), 128.4 (CH), 129.3 (CH), 130.5 (CH), 131.1 (C), 134.2 (C), 135.6 (C), 136.5 (CH), 140.6 (C). IR (ATR): 750, 1540 cm ^-1 . HRMS (FAB) m / z: [M-Cl] ⁺ Calcd for C ₂₂ H ₂₇ N ₂ : 319.2174; Found: 319.2169 .

Synthesis Example 1-11
Synthesis of 3- (4-methylphenyl) -4,5-dimethyl-1- (2,4,6-trimethylbenzyl) imidazolium chloride (compound 11)

(1) 4,5-Dimethyl-1- (4-methylphenyl) -1H-imidazole
The title compound of a brown oil was obtained in the same manner as in step (1) of Synthesis Example 1-1 except that 4-methylaniline was used instead of 2,4,6-trimethylaniline and dichloromethane was used as the extraction solvent. 763 mg, 4.1 mmol, 41% yield were obtained.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.08 (s, 3 H), 2.23 (s, 3 H), 2.42 (s, 3 H), 7. 15 (d, J = 8.1 Hz, 2 H), 7.27 (d, J = 8.1 Hz, 2 H), 7.46 (s, 1 H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 8.9 (CH ₃ ), 12.6 (CH ₃ ), 20.9 (CH ₃ ), 122.7 (C) , 125.2 (CH), 129.8 (CH), 134.0 (C), 134.3 (C), 135.0 (CH), 137.8 (C). IR (ATR): 820, 1520 cm ^-1 . HRMS (EI) m / z ^{: (M +) Calcd for C} 12 H 14 N 2: 186.1157; Found: 186.1153.

(2) 3- (4-Methylphenyl) -4,5-dimethyl-1- (2,4,6-trimethylbenzyl) imidazolium chloride
Instead of 1-mesityl-4,5-dimethyl-1H-imidazole, the 4,5-dimethyl-1- (4-methylphenyl) -1H-imidazole obtained in step (1) of Synthesis Example 1-11 is used. The reaction mixture was concentrated and purified by silica gel chromatography (dichloromethane / methanol = 10/1) and then washed with tetrahydrofuran in the same manner as in step (2) of Synthesis Example 1-1, except that it was white. The solid title compound (440 mg, 1.24 mmol, yield 62%) was obtained.
mp 214-215 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.13 (s, 3H), 2.20 (s, 3H), 2.27 (s, 3H), 2.35 (s, 6H), 2.42 (s) , 3H), 5.75 (s, 2H), 6.89 (s, 2H), 7.32-7.38 (m, 4H), 9.48 (s, 1H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 8.9 (CH ₃ ), 9.0 (CH ₃ ), 20.0 (CH ₃ ), 20.7 (CH ₃ ), 21.0 (CH ₃ ), 46.9 (CH ₂ ), 125.4 (C), 125.5 (CH), 127.6 (C), 127.7 (C) C), 129.8 (CH), 130.4 (C), 130.6 (CH), 134.7 (CH), 137.7 (C), 139.1 (C), 141.0 (C). IR (ATR): 810, 1550 cm ^-1 . HRMS (FAB) m / z: [M-Cl] + Calcd for C 22 H 27 N 2: 319.2174; Found: 319.2165.

Synthesis Example 1-12
Synthesis of 1- (2,4,6-trimethylbenzyl) -3- (2,4,6-trimethylphenyl) imidazolium chloride (compound 12)

The title compound as a white solid was obtained in the same manner as in step (2) of Synthesis Example 1-1 except that 1-mesityl-1H-imidazole was used instead of 1-mesityl-4,5-dimethyl-1H-imidazole. (414 mg, 1.17 mmol, 59% yield) was obtained.
mp 286-287 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.08 (s, 6 H), 2.30 (s, 3 H), 2. 35 (s, 9 H), 6.04 (s, 2 H), 6. 94 (s) , 2H), 7.00 (s, 2H), 7.07 (t, J = 1.6 Hz, 1 H), 7.13 (t, J = 1.6 Hz, 1 H), 10.97 (s, 1 H). ¹³ C-NMR (100 MHz, 100 MHz, CDCl ₃ ): δ 17.3 (CH ₃ ), 19.6 (CH ₃ ), 20.8 (CH ₃ ), 20.8 (CH ₃ ), 48.1 (CH ₂ ), 121.1 (CH), 123.5 (CH), 125.7 (C), 129.6 (CH), 129.7 (CH), 130.5 (C), 133.8 (C), 137.8 (C), 138.0 (CH), 139.5 (C), 140.9 (C). IR (ATR): 760, 1190, 1540 ^{. cm -1 HRMS (FAB) m} / z: [M-Cl] + Calcd for C 22 H 27 N 2: 319.2174; Found: 319.2157.

Synthesis Example 1-13
Synthesis of 4,5-dimethyl-1,3-bis (2,4,6-trimethylbenzyl) imidazolium chloride (compound 13)

(1) 4,5-Dimethyl-1- (2,4,6-trimethylbenzyl) -1H-imidazole
2,4,6-Trimethylbenzyl chloride (337 mg, 2.0 mmol) was added to a solution of 4,5-dimethyl-1H-imidazole (769 mg, 8.0 mmol) in dry N, N-dimethylformamide (2 mL) . Potassium carbonate (1382 mg, 10 mmol) was added to the reaction mixture and stirred at 120 ° C. for 2 hours. Then water was added at room temperature and the resulting mixture was extracted with AcOEt. The combined organic layers were dried over sodium sulfate. The residue was concentrated and purified by silica gel column chromatography (hexane / AcOEt = 10/1) to give the title compound (348 mg, 1.52 mmol, yield 76%) as a pale yellow solid.
mp 91-92 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.17 (s, 3H), 2.21 (s, 3H), 2.22 (s, 6H), 2.30 (s, 3H), 4.84 (s) , 2H), 6.75 (s, 1H), 6.92 (s, 2H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 8.6 (CH ₃ ), 12.8 (CH ₃ ), 19.3 (CH ₃ ), 20.9 (CH ₃ ), 43.2 (CH ₂ ), 122.2 (C), 127.8 (C), 129.4 (CH), 133.75 (CH), 133. 78 (C), 137.6 (C), 138.3 (C). IR (ATR) ^{: 730, 1500 cm -1 HRMS (} EI) m / z: (M +) Calcd for C 15 H 20 N 2:. 228.1626; Found: 228.1625.

(2) 4,5-Dimethyl-1,3-bis (2,4,6-trimethylbenzyl) imidazolium chloride
2,4,6-trimethylbenzyl chloride (253 mg, 1.5 mmol) was added to 4,5-dimethyl-1- (2,4,6-trimethylbenzyl) obtained in step (1) of Synthesis Example 1-13. It was added to a solution of 1H-imidazole (343 mg, 1.5 mmol) in dry tetrahydrofuran (6.5 mL). The reaction mixture was refluxed for 14 hours. The resulting solid was filtered and washed with tetrahydrofuran to give the title compound (417 mg, 1.05 mmol, 70% yield) as a white solid.
mp 243-244 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): 2.16 (s, 6 H), δ 2.2 1 (s, 12 H), 2. 26 (s, 6 H), 5. 39 (s, 4 H), 6. 86 (s) , 4H), 8.67 (s, 1H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 8.7 (CH ₃ ), 19.5 (CH ₃ ), 20.7 (CH ₃ ), 46.3 (CH ₂ ), 124.8 ( C), 127.8 (C), 129.6 (CH), 133.6 (CH), 137.3 (C), 139.3 (C). IR (ATR): 1160, 1570 cm ^-1 . HRMS (FAB) m / z: [M -Cl] ⁺ Calcd for C ₂₅ H ₃₃ N ₂ : 361.2644; Found: 361 .2662.

Synthesis Example 1-14
Synthesis of 3- (2-tert-butylphenyl) -4,5-dimethyl-1- (2,4,6-trimethylbenzyl) imidazolium chloride (compound 14)

(1) 1- (2-tert-butylphenyl) -4,5-dimethyl-1H-imidazole
The title of a brown oil was obtained in the same manner as in step (1) of Synthesis Example 1-1 except that 2-tert-butylaniline was used instead of 2,4,6-trimethylaniline and dichloromethane was used as the extraction solvent. The compound (3.87 g, 16.9 mmol, yield 85%) was obtained.
mp 83-84 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.19 (s, 9H), 1.91 (s, 3H), 2.23 (s, 3H), 6.94 (dd, J = 1.4, 7.8) Hz, 1 H), 7. 26 (dt, J = 1.4, 7.8 Hz, 1 H), 7.41 (dt, J = 1.4, 7.8 Hz, 1 H), 7.43 (s, 1 H), 7. 60 (dd, J = 1.4, 7.8 Hz , 1H).

(2) 3- (2-tert-butylphenyl) -4,5-dimethyl-1- (2,4,6-trimethylbenzyl) imidazolium chloride
In place of 1-mesityl-4,5-dimethyl-1H-imidazole, 1- (2-tert-butylphenyl) -4,5-dimethyl-1H- obtained in step (1) of Synthesis Example 1-14 The title compound (white solid) was obtained in the same manner as in step (2) of Synthesis Example 1-1 except that the concentrated reaction solution was purified using silica gel chromatography (dichloromethane / methanol = 9/1) using imidazole. 181 mg, 0.46 mmol, 10% yield was obtained.
mp 235-236 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.14 (s, 9H), 2.03 (s, 3H), 2.27 (s, 3H), 2.37 (s, 3H), 2.38 (s) , 6H), 5.54 (d, J = 15.2 Hz, 1H), 5.90 (d, J = 15.2 Hz, 1H), 6.90 (s, 2H), 7.34-7.42 (m, 2H), 7.49 (dt, J = 1.5, 8.2 Hz, 1 H), 7. 59 (dd, J = 1.0, 8.2 Hz, 1 H), 8.82 (s, 1 H).

Synthesis Example 1-15
Synthesis of 1- (2,4,6-triisopropylbenzyl) -4,5-dimethyl-3- (2,4,6-trimethylphenyl) imidazolium chloride (compound 15)

The title compound as a white solid was obtained in the same manner as in step (2) of Synthesis Example 1-1 except that 2,4,6-triisopropylbenzyl chloride was used instead of 2,4,6-trimethylbenzyl chloride. 514 mg, 1.1 mmol, 32% yield was obtained.
mp 195-196 ° C. δ 1.21 (d, J = 6.4 Hz, 12 H), 1.25 (d, J = 6.4 Hz, 6 H), 1.95 (s, 6 H), 2.01 (s, 3 H), 2.33 (s, 3 H) ), 2.58 (s, 3 H), 2. 89 (septet, J = 6, 8 Hz, 1 H), 3. 15 (septet, J = 6.8 Hz, 2 H), 5. 76 (s, 2 H), 7.00 (s, 2 H), 7.09 (s, 2H), 8.21 (s, 1H).

Synthesis Example 2-1
Synthesis of α-deuterio benzhydrol

(Method 1)
Under argon atmosphere, a solution of benzophenone (12 mmol) in tetrahydrofuran (20 mL) was added at 0 ° C. to a suspension of lithium aluminum deuteride (14.4 mmol, manufactured by Sigma-Aldrich Co.) in tetrahydrofuran (40 mL). The mixture was stirred at 0 ° C. for 30 minutes and water was added. The resulting mixture was extracted with dichloromethane and the combined organic layers were dried over sodium sulfate. The organic layer is concentrated and then purified by silica gel chromatography (hexane / ethyl acetate = 5/1) to give the title compound (2.07 g, 11.2 mmol, 93% yield, 99% or more of deuteration ratio) as a white solid The

(Method 2)
The title compound as a white solid (531 mg, 2.87 mmol, 96% yield, 99% or more deuteration ratio) in the same manner as in Method 1 except that 3 mmol of benzophenone and 1.5 mmol of lithium aluminum deuteride were used. I got
mp 64-65 ° C. ¹ H-NMR (500 MHz, CDCl ₃ ): δ 2.20 (s, 1 H), 7.25-7.28 (m, 2 H), 7.32-7.35 (m, 4 H), 7.37-7.40 (m, 4H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 75.6 (t, J = 22.2 Hz, C), 126.5 (CH), 127.4 (CH), 128.4 (CH), 143.7 (C). IR ( ATR): 730, 1040, 1190, 1490, 1600, 3260 cm ^-1 . HRMS (EI) m / z: (M ⁺ ) Calcd for C ₁₃ H ₁₁ DO: 185.0951; Found: 185.0958.

Synthesis Example 2-2
Synthesis of α-deuterio-α-phenylethanol

In the same manner as in Synthesis Example 2-1, except that acetophenone (4 mmol) was used instead of benzophenone (12 mmol) and lithium aluminum deuteride was changed to 2 mmol, the title compound (468 of a colorless oil) mg, 3.80 mmol, yield 95%, deuteration ratio of 99% or more).
¹ H-NMR (500 MHz, CDCl ₃ ): δ 1.50 (s, 3 H), 1. 76 (s, 1 H), 7.26-7.29 (m, 1 H), 7.34-7. 39 (m, 4 H). ¹³ C-NMR ( 100 MHz, CDCl ₃ ): δ 24.8 (CH ₃ ), 69.6 (t, J = 22.3 Hz, C), 125.3 (CH), 127.2 (CH), 128.3 (CH), 145.7 (C). IR (ATR) HRMS (EI) m / z: (M ⁺ ) Calcd for C ₈ H ₉ DO: 123.0794; Found: 123.0796 .: 700, 750, 1130, 1450, 2970, 3330 cm ^-1 .

Synthesis Example 2-3
Synthesis of α-deuterio-α-cyclohexylbenzenemethanol

A colorless oil in the same manner as in Synthesis Example 2-1, except that cyclohexyl (phenyl) methanone (8 mmol) was used instead of benzophenone (12 mmol) and lithium aluminum deuteride was changed to 4 mmol. The title compound (1.52 g, 7.94 mmol, yield 99%, deuteration ratio of 99% or more) was obtained.
¹ H-NMR (500 MHz, CDCl ₃ ): δ 0.89-0.97 (m, 1 H), 1.01-1.27 (m, 4 H), 1.36-1.40 (m, 1 H), 1.59-1.68 (m, 3 H), 1.75 -1.79 (m, 2H), 1.97-2.01 (m, 1H), 7.25-7.36 (m, 5H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 25.9 (CH ₂ ), 26.0 (CH ₂ ) , 26.3 (CH ₂ ), 28.7 (CH ₂ ), 29.1 (CH ₂ ), 44.6. (CH), 78.6 (t, J = 21.4 Hz, C), 126.5 (CH), 127.1 (CH), 127.9 (CH) ), 143.5 (C). IR (ATR): 700, 760, 1450, 2850, 2920, 3370 cm ^-1 . HRMS (EI) m / z: (M ⁺ ) Calcd for C ₁₃ H ₁₇ DO: 191.1420; Found 191.1420.

Synthesis Example 2-4
5-Juterio-5-nonanol

A colorless oil was obtained in the same manner as in Synthesis Example 2-1, except that nonan-5-one (8 mmol) was used instead of benzophenone (12 mmol), and lithium aluminum deuteride was changed to 4 mmol. The title compound (1.15 g, 7.92 mmol, yield 99%, deuteration ratio of 99% or more) was obtained.
¹ H-NMR (500 MHz, CDCl ₃ ): δ 0.91 (t, J = 7.1 Hz, 6 H), 1.25 (s, 1 H), 1.27-1. 50 (m, 12 H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 13.8 (CH ₃ ), 22.6 (CH ₂ ), 27.7 (CH ₂ ), 36.8 (CH ₂ ), 71.0 (t, J = 21.4 Hz, C). IR (ATR): 2860, 2870, 2930 , 2960, 2970, 3340 cm ^-1 . HRMS (EI) m / z: (M ⁺ ) Calcd for C ₉ H ₁₉ DO: 145.1577; Found: 145.1571.

[Example 1: Investigation of ligand]
Example 1-1
Compound 1 (ligand precursor) (7.7 mg, 0.02 mmol), allylpalladium (II) chloride dimer (1.83 mg, 0.005 mmol) and cesium carbonate (326 mg, 1.0 mmol) in a flask under an argon atmosphere Toluene (2.0 mL) was added to the mixture of. The mixture was stirred at 80 ° C. for 15 minutes and allowed to cool to room temperature. 1-Chloro-3,5-dimethoxybenzene (1.0 mmol) and α-deuterio benzhydrol (222 mg, 1.2 mmol) were added. The reaction mixture was stirred at 90 ° C. for 16 hours and allowed to cool to room temperature. Water was added and the resulting mixture was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain 1-deuterio-3,5-dimethoxybenzene (yield 65%; deuteration ratio of 99% or more).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.79 (s, 6 H), 6.47 (t, J = 2.4 Hz, 1 H), 6.51 (d, J = 1.0 Hz, 2 H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 55.2 (CH ₃ ), 100.4 (CH), 106.0 (CH), 129.6 (t, J = 24.0 Hz, C), 160.8 (C). IR (ATR): 1200, 1430, 1600 ^{. cm -1 HRMS (EI) m} / z: (M +) Calcd for C 8 H 9 DO 2: 139.0744; Found: 139.0756.

Example 1-2
In the same manner as in Example 1-1 except that Compound 2 was used as a ligand precursor, 1-deuterio-3,5-dimethoxybenzene (yield: 72%; deuteration ratio of 99% or more) was obtained .

Example 1-3
In the same manner as in Example 1-1 except that compound 3 was used as a ligand precursor, 1-deuterio-3,5-dimethoxybenzene (yield: 62%; deuteration ratio: 99% or more) was obtained .

Example 1-4
In the same manner as in Example 1-1 except that the compound 4 was used as a ligand precursor, 1-deuterio-3,5-dimethoxybenzene (yield: 92%; deuteration ratio of 99% or more) was obtained .

Example 1-5
In the same manner as in Example 1-1 except that the compound 5 was used as a ligand precursor, 1-deuterio-3,5-dimethoxybenzene (yield: 57%; deuteration ratio of 99% or more) was obtained .

Example 1-6
In the same manner as in Example 1-1 except that compound 6 was used as a ligand precursor, 1-deuterio-3,5-dimethoxybenzene (yield 50%; deuteration ratio of 99% or more) was obtained .

Example 1-7
Example 1 1-deuterio-3,5-dimethoxybenzene (collection) in the same manner as in Example 1-1 except that commercially available 1,3-dimesityl imidazolium chloride (IMes · HCl) was used as a ligand precursor. Rate of 53%; deuteration rate of 99% or more).

Example 1-8
1-deuterio-3,5-dimethoxybenzene (in the same manner as Example 1-1 except that commercially available 1,3-dimesityl imidazolidinium chloride (SIMes.HCl) was used as a ligand precursor A yield of 36% (deuteration ratio of 99% or more) was obtained.

Example 1-9
1-deuterio-3 in the same manner as in Example 1-1 except that commercially available 1,3-bis (2,6-diisopropylphenyl) imidazolidinium chloride (SIPr · HCl) was used as a ligand precursor. , 5-Dimethoxybenzene (yield 15%; deuteration ratio of 99% or more) was obtained.

Example 1-10
Compound 1 (ligand precursor) (0.06 mmol), chloro (1-naphthyl) bis (triphenylphosphine) nickel (II) in an argon atmosphere in a reaction tube (0.03 mmol) and potassium phosphate (2.0 mmol) were added, toluene (2.0 mL) was further added thereto, and the mixture was stirred at 80 ° C. for 15 minutes. Then, 3,5-dimethoxyphenyl N, N-dimethylsulfamate (1.0 mmol) and α-deuterio benzhydrol (1.2 mmol) were added at room temperature. The reaction mixture was stirred at 110 ° C. for 15 hours and allowed to cool to room temperature. Water was added and the resulting mixture was extracted with CH ₂ Cl ₂ . The combined organic layer was dried over magnesium sulfate, concentrated, and purified by silica gel column chromatography to obtain 1-deuterio-3,5-dimethoxybenzene (yield 75%; deuteration ratio of 99% or more).

Example 1-11
In the same manner as in Example 1-10 except that Compound 7 was used as a ligand precursor, 1-deuterio-3,5-dimethoxybenzene (yield 84%; deuteration ratio of 99% or more) was obtained .

Example 1-12
In the same manner as in Example 1-10 except that Compound 8 was used as a ligand precursor, 1-deuterio-3,5-dimethoxybenzene (yield: 80%; deuteration ratio of 99% or more) was obtained .

Example 1-13
In the same manner as in Example 1-10 except that Compound 9 was used as a ligand precursor, 1-deuterio-3,5-dimethoxybenzene (yield: 86%; deuteration ratio of 99% or more) was obtained .

Example 1-14
In the same manner as in Example 1-10 except that the compound 10 was used as a ligand precursor, 1-deuterio-3,5-dimethoxybenzene (yield 77%; deuteration ratio 99%) was obtained.

Example 1-15
A 1-deuterio-3,5-dimethoxybenzene (yield 77%; deuteration ratio 99%) was obtained in the same manner as in Example 1-10 except that Compound 11 was used as a ligand precursor.

Example 1-16
In the same manner as in Example 1-10 except that Compound 12 was used as a ligand precursor, 1-deuterio-3,5-dimethoxybenzene (yield 77%; deuteration ratio of 99% or more) was obtained. .

Example 1-17
In the same manner as in Example 1-10 except that Compound 13 was used as a ligand precursor, 1-deuterio-3,5-dimethoxybenzene (yield 77%; deuteration ratio of 99% or more) was obtained. .

Example 1-18
In the same manner as in Example 1-10 except that Compound 5 was used as a ligand precursor, 1-deuterio-3,5-dimethoxybenzene (yield 71%; deuteration ratio of 99% or more) was obtained. .

Example 1-19
In the same manner as in Example 1-10 except that compound 6 was used as a ligand precursor, 1-deuterio-3,5-dimethoxybenzene (yield 69%; deuteration ratio of 99% or more) was obtained .

Example 1-20
In the same manner as in Example 1-10 except that Compound 14 was used as a ligand precursor, 1-deuterio-3,5-dimethoxybenzene (yield: 63%; deuteration ratio of 99% or more) was obtained .

Example 1-21
A 1-deuterio-3,5-dimethoxybenzene (yield 63%; deuteration ratio 98%) was obtained in the same manner as in Example 1-10 except that compound 15 was used as a ligand precursor.

Example 1-22
1-deuterio-3,5-dimethoxybenzene (in the same manner as in Example 1-10 except that commercially available 1,3-dimesityl imidazolidinium chloride (SIMes.HCl) was used as a ligand precursor A yield of 11%; deuteration ratio of 99% or more) was obtained.

Comparative Example 1-23
1-deuterio-3,5-dimethoxybenzene (yield 4%; heavy) in the same manner as in Example 1-10 except that commercially available tri-tert-butylphosphonium tetrafluoroborate was used as a ligand precursor The hydrogenation rate was 87% or more).

Comparative Example 1-24
The intended product of the attempt to synthesize 1-deuterio-3,5-dimethoxybenzene was obtained in the same manner as in Example 1-10 except that commercially available tricyclohexylphosphonium tetrafluoroborate was used as a ligand precursor. It was not.

  Examples 1-1 to 1-22 and comparative examples 1-23 and 1-24 are summarized in Tables 1 to 3 below.

[Example 2: Examination of reaction conditions]
Example 2-1
1-deuterio-3,5-dimethoxybenzene (yield 72%) in the same manner as in Example 1-4 except that 0.01 mmol of palladium (II) acetate was used instead of allylpalladium (II) chloride dimer. A deuteration ratio of 99% or more) was obtained.

Example 2-2
1-Deuterio-3,5-dimethoxybenzene in the same manner as in Example 1-4 except that 0.01 mmol of bis (dibenzylideneacetone) palladium (0) was used instead of allylpalladium (II) chloride dimer. (Yield 54%; deuteration ratio 99% or more) was obtained.

Example 2-3
In the same manner as in Example 1-4 except that tris (dibenzylideneacetone) dipalladium (0) was used in place of allylpalladium (II) chloride dimer, 0.005 mmol (Pd equivalent 0.01 mmol) was used. Deuterio-3,5-dimethoxybenzene (yield 75%; deuteration ratio of 99% or more) was obtained.

Example 2-4
1-deuterio-3,5-dimethoxybenzene (yield 79%; deuteration ratio of 99% or more) in the same manner as in Example 1-4 except that potassium tert-butoxide was used instead of cesium carbonate Obtained.

Example 2-5
In the same manner as in Example 1-4 except that cesium fluoride was used instead of cesium carbonate, 1-deuterio-3,5-dimethoxybenzene (yield: 32%; deuteration ratio of 99% or more) was obtained. The

Example 2-6
1-deuterio-3,5-dimethoxybenzene (yield 74%; deuteration ratio 99% or more) in the same manner as in Example 1-4 except that 1,4-dioxane was used instead of toluene Obtained.

Example 2-7
1-deuterio-3,5-dimethoxybenzene (yield 69%; deuteration ratio 99% or more) in the same manner as in Example 1-4 except that N, N-dimethylacetamide was used instead of toluene. I got

Example 2-8
In the same manner as in Example 1-4 except that the amount of cesium carbonate used was changed to 1.5 mmol, 1-deuterio-3,5-dimethoxybenzene (yield: 99%; deuteration ratio of 99% or more) was obtained .

Example 2-9
The procedure of Example 1-4 is repeated except that the amount of compound 4 (ligand precursor) is 0.002 mmol and the amount of allylpalladium (II) chloride dimer used is changed to 0.0005 mmol (Pd equivalent 0.001 mmol). , 1-deuterio-3,5-dimethoxybenzene (yield 35%; deuteration ratio of 99% or more) were obtained.

Example 2-10
1-deuterio-3,5-dimethoxybenzene (yield 78%; deuteration ratio) in the same manner as in Example 1-13 except that the amount of compound 9 (ligand precursor) used was changed to 0.03 mmol 99% or more).

Example 2-11
1-deuterio-3,5-dimethoxybenzene (yield 85%; deuteration ratio) in the same manner as in Example 1-13 except that the amount of compound 9 (ligand precursor) used was changed to 0.09 mmol 99% or more).

Comparative Example 2-12
An attempt was made to obtain 1-deuterio-3,5-dimethoxybenzene in the same manner as in Example 1-13 except that Compound 9 (ligand precursor) was not used, but the desired product was not obtained.

  Examples 1-4, Examples 1-13, Examples 2-1 to 2-11, and Comparative Examples 2-12 are summarized in Tables 4 and 5 below.

Example 3 Application to Various Reactive Substrates
Example 3-1
1-benzyloxy-4-deuteriobenzene (yield) in the same manner as in Example 2-8 except that 1-benzyloxy-4-chlorobenzene was used instead of 1-chloro-3,5-dimethoxybenzene 99%; deuteration ratio of 99% or more) was obtained.
mp 38-39 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 5.07 (s, 2 H), 6.98 (d, J = 8.4 Hz, 2 H), 7.28-7.34 (m, 3H), 7.39 ( t, J = 7.2 Hz, 2 H), 7.44 (d, J = 7.2 Hz, 2 H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 69.8 (CH ₂ ), 114.8 (CH), 120.6 (t, . J = 24.3 Hz, C) , 127.4 (CH), 127.9 (CH), 128.5 (CH), 129.3 (CH), 137.1 (C), 158.8 (C) IR (ATR): 1010, 1240, 1590 cm - ^1. HRMS (EI) m / z: (M ⁺ ) Calcd for C ₁₃ H ₁₁ DO: 185.0951; Found: 185.0938.

Example 3-2
1-benzyloxy-4-deuterio in the same manner as in Example 2-8 except that 1-benzyloxy-4-chloro-3-methylbenzene was used instead of 1-chloro-3,5-dimethoxybenzene -3-Methylbenzene (yield: 99%; deuteration ratio of 99% or more) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.33 (s, 3 H), 5.05 (s, 2 H), 6.79 (dd, J = 2.4, 8.1 Hz, 1 H), 6.82 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 8.1 Hz, 1H), 7.30-7.33 (m, 1H), 7.36-7.40 (m, 2H), 7.43 (d, J = 7.2 Hz, 2H). ¹³ C-NMR ( 100 MHz, CDCl ₃ ): δ 21.4 (CH ₃ ), 69.8 (CH ₂ ), 111.6 (CH), 115.7 (CH), 121.4 (t, J = 23.9 Hz, C), 127.4 (CH), 127.8 (CH) ), 128.5 (CH), 129.1 (CH), 137.1 (C), 139.4 (C), 158.8 (C). IR (ATR): 730, 1030, 1240, 1600 cm ^-1 . HRMS (EI) m / z : (M ⁺ ) Calcd for C ₁₄ H ₁₃ DO: 199.1107; Found: 199.1112.

Example 3-3
1-benzyloxy-4 was prepared in the same manner as in Example 2-8 except that 1-benzyloxy-4-chloro-3,5-dimethylbenzene was used instead of 1-chloro-3,5-dimethoxybenzene Deuterio-3,5-dimethylbenzene (yield: 99%; deuteration ratio of 99% or more) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.29 (s, 6 H), 5.03 (s, 2 H), 6.62 (s, 2 H), 7.32 (t, J = 7.2 Hz, 1 H), 7.38 (t, J = 7.2 Hz, 2 H), 7.43 (d, J = 7.2 Hz, 2 H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 21.3 (CH ₃ ), 69.7 (CH ₂ ), 112.5 (CH), 122.4 (t, J = 23.5 Hz, C), 127.4 (CH), 127.8 (CH), 128.5 (CH), 137.3 (C), 139.1 (C), 158.9 (C). IR (ATR): 850, 1060 ^{, 1590 cm -1 HRMS (EI)} m / z: (M +) Calcd for C 15 H 15 DO:. 213.1264; Found: 213.1262.

Example 3-4
2-[(4-deuteriophenoxy) in the same manner as in Example 2-8 except that 2-[(4-chlorophenoxy) methyl] oxirane was used instead of 1-chloro-3,5-dimethoxybenzene ) Methyl] oxirane (yield 93%; deuteration ratio of 99% or more) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.77 (dd, J = 2.8, 5.2 Hz, 1 H), 2.91 (t, J = 5.2 Hz, 1 H), 3.34-3.38 (m, 1 H), 3.97 (3 dd, J = 5.6, 11.0 Hz, 1 H), 4.22 (dd, J = 3.2, 11.0 Hz, 1 H), 6.91-6.94 (m, 2 H), 7. 29 (d, J = 8.2 Hz, 2 H). ¹³ C- NMR (100 MHz, CDCl ₃ ): δ 44.7 (CH ₂ ), 50.1 (CH), 68.6 (CH ₂ ), 114.5 (CH), 120.9 (t, J = 24.7 Hz, C), 129.3 (CH), 158.4 (C). IR (ATR): 1040, 1240, 1590 cm ^-1 . HRMS (EI) m / z: (M ⁺ ) Calcd for C ₉ H ₉ DO ₂ : 151.0744; Found: 151.0730.

Example 3-5
In the same manner as in Example 2-8 except that (E) -4- (4-chlorophenyl) but-3-en-2-one was used instead of 1-chloro-3,5-dimethoxybenzene, E) -4- (4-deuteriophenyl) but-3-en-2-one (yield 98%; deuteration ratio of 99% or more) was obtained.
mp 39-40 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.39 (s, 3 H), 6.72 (d, J = 16.4 Hz, 1 H), 7. 40 (d, J = 8.0 Hz, 2 H), 7.52 (d, J = 16.4 Hz, 1 H), 7.55 (d, J = 8.0 Hz, 2 H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 27.5 (CH ₃ ), 127.1 (CH), 128.2 (12 CH), 128.8 (CH), 130.2 (t, J = 24.3 Hz, C), 134.4 (C), 143.4 (CH), 198.3 (C). IR (ATR): 990, 1190, 1680 cm ^-1 . HRMS (EI) m / z: (M ⁺ ) Calcd for C ₁₀ H ₉ DO: 147.0794; Found: 147.0771.

Example 3-6
1-deuterio-2-nitrobenzene (yield 97%; heavy) in the same manner as in Example 2-8 except that 1-chloro-2-nitrobenzene was used instead of 1-chloro-3,5-dimethoxybenzene The hydrogenation rate was over 99%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.55-7.58 (m, 2 H), 7.71 (t, J = 7.8 Hz, 1 H), 8.24 (d, J = 7.8 Hz, 1 H). ¹³ C NMR (100 MHz, CDCl ₃ ): δ 123.1 (t, J = 24.3 Hz, C), 123.4 (CH), 129.1 (CH), 129.2 (CH), 134.5 (CH), 148.1 (C). IR (ATR) ^{: 1340, 1520 cm -1 HRMS (} EI) m / z: (M +) Calcd for C 6 H 4 DNO 2:. 124.0383; Found: 124.0362.

Example 3-7
In the same manner as in Example 2-8 except that 2-benzyloxy-5-chloropyridine was used instead of 1-chloro-3,5-dimethoxybenzene, 2-benzyloxy-5-deuteriopyridine Rate of 97%; deuteration rate of 99% or more).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 5.38 (s, 2 H), 6.81 (dd, J = 0.7, 8.5 Hz, 1 H), 7.30-7.34 (m, 1 H), 7.37-7.40 (m, 2H) ), 7.46-7.48 (m, 2H), 7.59 (dd, J = 2.0, 8.5 Hz, 1 H), 8.19 (d, J = 1.5 Hz 1 H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 67.5 (CH ₂ ), 111.3 (CH), 116.6 (t, J = 24.7 Hz, C), 127.9 (CH), 128.0 (CH), 128.4 (CH), 137.3 (C), 138.5 (CH), 146.7 (CH) ), 163.6 (C). IR (ATR): 740, 990, 1590 cm ^-1 . HRMS (EI) m / z: (M ⁺ ) Calcd for C ₁₂ H ₁₀ DNO: 186.0903; Found: 186.0899.

Example 3-8
Butyl 4-deuteriobenzoate (yield: 94%; deuteration ratio) in the same manner as in Example 2-8 except that butyl 4-chlorobenzoate was used instead of 1-chloro-3,5-dimethoxybenzene 99% or more).
¹ H-NMR (500 MHz, CDCl ₃ ): δ 0.99 (t, J = 7.5 Hz, 3 H), 1.45-1.52 (m, 2 H), 1.73-1.79 (m, 2 H), 4.33 (t, J = 6.5) Hz, 2 H), 7. 45 (d, J = 8.0 Hz, 2 H), 8.05 (d, J = 8.0 Hz, 2 H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 13.6 (CH ₃ ), 19.2 ( _{CH 2), 30.7 (CH 2} ), 64.7 (CH 2), 128.1 (CH), 129.4 (CH), 130.4 (C), 132.3 (t, J = 24.7 Hz, C), 166.5 (C). IR ( ATR): 1100, 1270, 1720, 2960 cm ^-1 . HRMS (EI) m / z: (M ⁺ ) Calcd for C ₁₁ H ₁₃ DO ₂ : 179.1057; Found: 179.1056.

Example 3-9
Using 3-chlorophenyl (isopropyl) sulfane instead of 1-chloro-3,5-dimethoxybenzene, change the reaction temperature from 90 ° C. to 100 ° C. to make allyl palladium (II) chloride dimer 0.015 mmol, In the same manner as in Example 2-8 except that Compound 4 (ligand precursor) was changed to 0.06 mmol, 3-deuteriophenyl (isopropyl) sulfane (yield 82%; deuteration ratio 99% or more) Obtained.
¹ H-NMR (500 MHz, CD ₃ CN): δ 1.26 (d, J = 6.5 Hz, 6 H), 3.43 (septet, J = 6.5 Hz, 1 H), 7.24 (dt, J = 1.0, 7.5 Hz, 1 H ), 7.30-7.33 (m, 1 H), 7. 38-7. 40 (m, 2 H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 23.1 (CH ₃ ), 38.1 (CH), 126.5 (CH), 128.4 (t, J = 24.0 Hz, C), 128.7 (CH), 131.7 (CH), 131.8 (CH), 135.5 (C). IR (ATR): 660, 1580, 2960 cm ^-1 . HRMS (EI) m / z: (M ⁺ ) Calcd for C ₉ H ₁₁ DS: 153.0722; Found: 153.0726.

Example 3-10
Instead of 1-chloro-3,5-dimethoxybenzene, use 3-chlorobenzoic acid, change the reaction temperature from 90 ° C. to 100 ° C., and make cesium carbonate 3.0 mmol, allylpalladium (II) chloride dimer The crude product of 3-deuteriobenzoic acid was obtained in the same manner as in Example 2-8 except that 0.015 mmol of the compound 4 and 0.06 mmol of the compound 4 (ligand precursor) were used.
The resulting crude product was directly converted to allyl 3-deuteriobenzoate by a known method to determine the chemical structure, the deuteration ratio and the yield. First, water was added to the reaction mixture containing the crude product, the mixture was acidified with 10% hydrochloric acid, and the resulting mixture was extracted with dichloromethane. Summary The organic layer was dried over magnesium sulfate and concentrated to give a crude product. A solution of the crude product in tetrahydrofuran (1 mL) was added to a mixture of tetrabutylammonium hydrogen sulfate (0.05 mmol) and potassium fluoride (5.0 mmol) in tetrahydrofuran (1 mL). Allyl bromide (1.1 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. Water was added and the resulting mixture was extracted with diisopropyl ether. The combined organic layer is dried over sodium sulfate, concentrated and purified by silica gel column chromatography (hexane / benzene = 5/1) to give allyl 3-deuteriobenzoate (131 mg, 0.80 mmol, yield as a colorless oil) 80%, deuteration ratio of 99% or more).
¹ H-NMR (500 MHz, CDCl ₃ ): δ 4.83 (dt, J = 1.0, 5.6 Hz, 2 H), 5. 29 (dd, J = 1.0, 10.5 Hz, 1 H), 5.42 (dd, J = 1.5, 17.3 Hz, 1 H), 6.01-6.09 (m, 1 H), 7.43-7.46 (m, 1 H), 7.56 (d, J = 7.5 Hz, 1 H), 8.06-8.08 (m, 2 H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 65.5 (CH ₂ ), 118.1 (CH ₂ ), 128.0 (t, J = 24.7 Hz, C), 128.3 (CH), 129.5 (CH), 129.6 (CH), 130.1 (C) , 132.2 (CH), 132.8 (CH), 166.2 (C). IR (ATR): 640, 1090, 1110, 1250, 1430, 1720, 3080 cm ^-1 . HRMS (EI) m / z: (M ⁺ ) _{Calcd for C 10 H 9 DO 2} : 163.0744; Found: 163.0747.

Example 3-11
Using 3-chloro-N-methylbenzamide instead of 1-chloro-3,5-dimethoxybenzene, the reaction temperature was changed from 90 ° C. to 100 ° C., and the amount of cesium carbonate used was changed to 2.0 mmol In the same manner as in Example 2-8, 3-deuterio-N-methylbenzamide (yield: 99%; deuteration ratio of 99% or more) was obtained.
mp 74-75 ° C. ¹ H-NMR (500 MHz, CDCl ₃ ): δ 3.03 (d, J = 4.8 Hz, 3 H), 7.43 (dd, J = 7.5, 8.2 Hz, 1 H), 7.49 (d, J ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 26.6 (CH ₃ ), 126.7 (CH), 126.8 (CH), 127.9 (t, J) = 7.5 Hz, 1 H), 7.75-7.77 (m, 2 H). IR (ATR): 690, 1550, 1630, 2930, 3320 cm- ¹ . HRMS (EI) m = 24.7 Hz, C), 128.2 (CH), 131.0 (CH), 134.3 (C), 168.4 (C). / z: (M ⁺ ) Calcd for C ₈ H ₈ DNO: 136.0747; Found: 136.0749.

Example 3-12
Using 1-benzyloxy-2,4-dichlorobenzene instead of 1-chloro-3,5-dimethoxybenzene, change the reaction temperature from 90 ° C. to 100 ° C., and change the amount of cesium carbonate used to 3.0 mmol Conducted, except that the amount of α-deuterio benzhydrol used was doubled, and the amounts of allylpalladium (II) chloride dimer and compound 4 (ligand precursor) were changed threefold. In the same manner as in Example 2-8, 1-benzyloxy-2,4-dideuteriobenzene (yield: 95%; deuteration ratio of 99% or more) was obtained.
mp 33-34 ° C. ¹ H-NMR (500 MHz, CDCl ₃ ): δ 5.07 (s, 2 H), 6.98 (d, J = 8.5 Hz, 1 H), 7.29-7.34 (m, 3H), 7.37-7.40 (m, 2H), 7.43-7.45 (m, 2H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 69.8 (CH ₂ ), 114.5 (t, J = 24.7 Hz, C), 114.8 (CH) , 120.6 (t, J = 24.7 Hz, C), 127.4 (CH), 127.9 (CH), 128.5 (CH), 129.2 (CH), 129.3 (CH), 137.0 (C), 158.8 (C). ATR): 1010, 1050, 1230, 1580 cm ^-1 . HRMS (EI) m / z: (M ⁺ ) Calcd for C ₁₃ H ₁₀ D ₂ O: 186.1014; Found: 186.1016.

Example 3-13
In the same manner as in Example 2-8 except that 2-benzyloxy-6-chloropyridine was used instead of 1-chloro-3,5-dimethoxybenzene, Rate of 99%; deuteration rate of 99% or more).
¹ H-NMR (500 MHz, CDCl ₃ ): δ 5.38 (s, 2 H), 6.81 (dd, J = 1.0, 8.0 Hz, 1 H), 6.88 (d, J = 7.0 Hz, 1 H), 7.30-7.33 ( m, 1H), 7.36-7.39 (m, 2H), 7.46-7.48 (m, 2H), 7.58 (dd, J = 7.1, 8.3 Hz 1 H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 67.4 (CH ₂ ), 111.2 (CH), 116.6 (CH), 127.8 (CH), 128.3 (CH), 137.3 (C), 138.5 (CH), 146.4 (t, J = 27.2 Hz, C ), 163.5 (C). IR (ATR): 1250, 1590 cm ^-1 . HRMS (EI) m / z: (M ⁺ ) Calcd for C ₁₂ H ₁₀ DNO: 186.0903; Found: 186.0907.

Example 3-14
In the same manner as in Example 2-8 except that 2- (dibenzylamino) -5-chloropyridine was used instead of 1-chloro-3,5-dimethoxybenzene, 2- (dibenzylamino) -5 was used. Deuteriopyridine (yield 92%; deuteration ratio of 99% or more) was obtained.
¹ H-NMR (500 MHz, CDCl ₃ ): δ 4.80 (s, 4 H), 6.46 (dd, J = 0.8, 8.5 Hz, 1 H), 7.23-7.26 (m, 6 H), 7.29-7.32 (m, 4 H) ), 7.38 (dd, J = 2.0, 8.5 Hz, 1 H), 8. 20-8. 21 (m, 1 H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 50.7 (CH ₂ ), 105.7 (CH), 111.9 (t, J = 25.6 Hz, C), 126.8 (CH), 127.0 (CH), 128.5 (CH), 137.2 (CH), 138.3 (C), 147.9 (CH), 158.5 (C). IR (ATR) ^{: 1240, 1490, 1580 cm -1} HRMS (EI) m / z: (M +) Calcd for C 19 H 17 DN 2:. 275.1533; Found: 275.1530.

Example 3-15
4-Deuterio-2- (trifluoro) in the same manner as in Example 2-8 except that 4-chloro-2- (trifluoromethyl) quinoline was used instead of 1-chloro-3,5-dimethoxybenzene Methyl) quinoline (yield 97%; deuteration ratio of 99% or more) was obtained.
mp 53-54 ° C. ¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.67-7.70 (m, 1 H), 7.75 (s, 1 H), 7.82-7.85 (m, 1 H), 7. 92 (dd, J = 1.0, 8.5 Hz, 1 H), 8.24 (d, J = 8.5 Hz, 1 H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 116.5 (CH), 121.6 (q, J = 274.8 Hz, C), 127.6 (CH), 128.5 (CH), 128.7 (C), 130.0 (CH), 130.8 (CH), 137.7 (t, J = 24.8 Hz, C), 147.1 (C), 147.9 (q, J = 34.8 Hz) , C). IR (ATR): 770, 1120, 1200 cm ^-1 . HRMS (EI) m / z: (M ⁺ ) Calcd for C ₁₀ H ₅ DF ₃ N: 198.0515; Found: 198.0505.

Example 3-16
In the same manner as in Example 2-8 except that 2-chloro-1-methyl-1H-indole was used instead of 1-chloro-3,5-dimethoxybenzene, 2-deuterio-1-methyl-1H- An indole (yield 97%; deuteration ratio of 99% or more) was obtained.
¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 3.78 (s, 3 H), 6.40 (d, J = 0.7 Hz, 1 H), 7.00-7.03 (m, 1 H), 7.12-7.15 (m, 1 H) 7.42 (dd, J = 0.7, 8.0 Hz, 1 H), 7.53 (d, J = 8.0 Hz, 1 H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 32.5 (CH ₃ ), 100.6 (CH) ), 109.1 (CH), 119.1. (CH), 121.3 (CH), 128.4 (C), 128.5 (t, J = 27.2 Hz, C), 136.5 (C). IR (ATR): 730, 1230 cm ^-1 . HRMS (EI) m / z: (M ⁺ ) Calcd for C ₉ H ₈ DN: 132.0798; Found: 132.0801.

Example 3-17
5-butyl-2-deuteriobenzofuran (yield 94%) in the same manner as in Example 2-8 except that 5-butyl-2-chlorobenzofuran was used instead of 1-chloro-3,5-dimethoxybenzene. %; Deuteration ratio of 99% or more).
¹ H-NMR (500 MHz, CDCl ₃ ): δ 0.93 (t, J = 7.5 Hz, 3 H), 1.33-1. 41 (m, 2 H), 1.60-1. 66 (m, 2 H), 2. 70 (t, J = 7.5) Hz, 2H), 6.70 (d, J = 0.8 Hz, 1 H), 7.11 (dd, J = 1.5, 8.3 Hz, 1 H), 7.39 (s, 1 H), 7.40 (d, J = 8.3 Hz, 1 H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 13.9 (CH ₃ ), 22.3 (CH ₂ ), 34.3 (CH ₂ ), 35.5 (CH ₂ ), 106.1 (CH), 110.8 (CH), 120.3 (CH) , 124.9 (CH), 127.4 (C), 137.2 (C), 144.6 (t, J = 30.5 Hz, C), 153.4 (C). IR (ATR): 810, 1030, 1450 cm ^-1 . HRMS ( EI) m / z: (M ⁺ ) Calcd for C ₁₂ H ₁₃ DO: 175.1107; Found: 175.1107.

Example 3-18
In the same manner as in Example 2-8 except that 2-chloro-3-hexylthiophene was used instead of 1-chloro-3,5-dimethoxybenzene, 2-deuterio-3-hexylthiophene (yield 96%) A deuteration ratio of 99% or more) was obtained.
¹ H-NMR (500 MHz, CDCl ₃ ): δ 0.88 (t, J = 6.5 Hz, 3 H), 1.30-1. 35 (m, 6 H), 1.62 (quintet, J = 7.5 Hz, 2 H), 2.62 (t, J = 7.5 Hz, 2 H), 6.93 (d, J = 4.8 Hz, 1 H), 7.23 (d, J = 4.8 Hz, 1 H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 14.0 (CH ₃ ) , 22.6 (CH ₂ ), 29.0 (CH ₂ ), 30.2 (CH ₂ ), 30.5 (CH ₂ ), 31.7 (CH ₂ ), 119.5 (t, J = 27.3 Hz, C), 124.9 (CH), 128.2 ( CH), 143.1 (C). IR (ATR): 720, 830, 1460 cm ^-1 . HRMS (EI) m / z: (M ⁺ ) Calcd for C ₁₀ H ₁₅ DS: 169.1035; Found: 169.1039.

Example 3-19
3-deuteriobenzothiophene (yield 93%; deuteration ratio) in the same manner as in Example 2-8 except that 3-chlorobenzothiophene was used instead of 1-chloro-3,5-dimethoxybenzene I got 99%).
¹ H-NMR (500 MHz, benzene-d ₆ ): 6.91 (s, 1 H), 7.04-7.07 (m, 1 H), 7.12-7.15 (m, 1 H), 7.56 (d, J = 8.0 Hz, 1 H) ¹³ C-NMR (100 MHz, CDCl ₃ ): 122.4 (CH), 123.58 (CH), 123.62 (t, J = 25.6 Hz, C), 124.1 (CH), 7.58 (d, J = 8.0 Hz, 1 H). ), 124.2 (CH), 126.2 (CH), 139.5 (C), 139.7 (C). HRMS (EI) m / z: (M ⁺ ) Calcd for C ₈ H ₅ DS: 135.0253; Found: 135.0252.

Example 3-20
Using 5-chloro-2-methyl-1,3-benzothiazole instead of 1-chloro-3,5-dimethoxybenzene, change the reaction temperature from 90 ° C. to 100 ° C., change the cesium carbonate to 2.0 mmmol And 5-deuterio-2-methyl- in the same manner as in Example 2-8 except that the amounts of allylpalladium (II) chloride dimer and compound 4 (ligand precursor) were changed to 3 times. 1,3-benzothiazole (yield 91%; deuteration ratio of 99% or more) was obtained.
¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 2.80 (s, 3 H), 7. 39 (d, J = 8.0 Hz, 1 H), 7. 91 (s, 1 H), 8.03 (dd, J = 0.5, 8.0 Hz, 1 H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 19.8 (CH ₃ ), 121.1 (CH), 122.0 (CH), 124.3. (CH), 125.4 (t, J = 24.8 Hz, C ), 135.4 (C), 153.1 (C), 166.6 (C). IR (ATR): 1170, 1520 cm ^-1 . HRMS (EI) m / z: (M ⁺ ) Calcd for C ₈ H ₆ DNS: 150.0362 Found: 150. 0365.

Example 3-21
Instead of 1-chloro-3,5-dimethoxybenzene, 6-chloro-2-phenyl-4H-chromen-4-one was used to make allyl palladium (II) chloride dimer 0.015 mmol, compound 4 6-deuterio-2-phenyl-4H-chromen-4-one (collection) in the same manner as in Example 2-8 except that the precursor (precursor precursor) was 0.06 mmol and the reaction temperature was changed from 90 ° C. to 100 ° C. Rate of 92%; deuteration rate of 99% or more).
mp 96 ° C. ¹ H-NMR (500 MHz, CDCl ₃ ): 6.86 (s, 1 H), 7.53-7. 57 (m, 3 H), 7. 60 (dd, J = 0.37, 8.5 Hz, 1 H), 7.73 (dd, J = 1.6, 8.4 Hz, 1 H), 7.94-7.98 (m, 2 H), 8. 26 (d, J = 1.4 Hz, 1 H). ¹³ C-NMR (100 MHz, CDCl ₃ ): 107.5 (CH), 118.0 ( CH), 123.9 (C), 124.9 (t, J = 24.7, C), 125.5 (CH), 126.2 (CH), 129.0 (CH), 131.5 (CH), 131.7 (C), 133.6 (CH), 156.2 IR (ATR): 770, 1130, 1640 cm ^-1 . HRMS (EI) m / z: (M ⁺ ) Calcd for C ₁₅ H ₉ DO ₂ : 223.0744 (C), 163.3 (C), 178.3 (C). Found: 223.0743.

Example 3-22
The reaction temperature was changed from 90 ° C. to 100 ° C., using isopropyl 2- [4- (4-chlorobenzoyl) phenoxy] -2-methylpropanoate instead of 1-chloro-3,5-dimethoxybenzene In the same manner as in Example 2-8, isopropyl 2- [4- (4-deuteriobenzoyl) phenoxy] -2-methylpropanoate (yield 95%; deuteration ratio of 99% or more) was obtained. .
mp 83 ° C. ¹ H-NMR (500 MHz, CDCl ₃ ): 1.20 (d, J = 6.2 Hz, 6 H), 1.67 (s, 6 H), 5.09 (sep, J = 6.3 Hz, 1 H), 6.86 (dt , J = 2.7, 9.0 Hz, 2 H), 7.47 (d, J = 8.2 Hz, 2 H), 7.74-7. 78 (m, 4 H). ¹³ C-NMR (100 MHz, CDCl ₃ ): 21.3 (CH ₃ ), 25.3 (CH ₃ ), 69.3 (CH), 79.3 (C), 117.1 (CH), 128.1 (CH), 129.7 (CH), 130.6 (C), 131.6 (t, J = 24.0 Hz, C), 132.0 ( CH), 138.1 (C), 159.5 (C), 173.1 (C), 195.5 (C). IR (ATR): 850, 1660, 1720 cm ^-1 . HRMS (EI) m / z: (M ⁺ ) Calcd for C ₂₀ H ₂₁ DO ₄ : 327.1581; Found: 357.1582.

Example 3-23
Amount of cesium carbonate used using 3- (2-chloro-10H-phenothiazin-10-yl) -N, N-dimethylpropan-1-amine hydrochloride instead of 1-chloro-3,5-dimethoxybenzene 3- (2-deuterio-10H-phenothiazine-10-yl) -N, N-dimethylpropan-1-amine (yield 90%) in the same manner as in Example 2-8 except that the concentration was changed to 2.5 mmol. Deuteration ratio of 99% or more) was obtained.
¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 1.79 (quintet, J = 6.9 Hz, 2 H), 2.08 (s, 6 H), 2.30 (t, J = 6.9 Hz, 2 H), 3.90 (t, J = 6.9 Hz, 2 H), 6.92-6.95 (m, 2 H), 7.02-7.03 (m, 2 H), 7.14 (d, J = 7.6 Hz, 2 H), 7.18-7.22 (m, 1 H). ¹³ C- NMR (100 MHz, CDCl ₃ ): δ 25.1 (CH ₂ ), 45.2 (CH ₂ ), 45.5 (CH ₃ ), 57.0 (CH ₂ ), 115.3 (CH), 115.4 (CH), 122.2 (CH), 122.3 . (CH), 125.0 (C ), 126.8 (t, J = 24.7 Hz, C), 127.1 (CH), 127.3 (CH), 145.2 (C) IR (ATR): 740, 1220, 1240, 1450 cm - ¹ HRMS (EI) m / z: (M ⁺ ) Calcd for C ₁₇ H ₁₉ DN ₂ S: 285.1410; Found: 285.1417.

Example 3-24
Instead of 1-chloro-3,5-dimethoxybenzene, (2S, 6'R) -7-chloro-2 ', 4,6-trimethoxy-6'-methyl-3H-spiro [1-benzofuran-2, Using 1′-cyclohexane] -2′-ene-3,4′-dione (griseofulvin) and changing the amount of α-deuterio benzhydrol to 1.5 mmol, with allylpalladium (II) chloride dimer (2S, 6'R) -7-deuterio-2 ', 4,6-trimethoxy in the same manner as in Example 2-8 except that the amount of compound 4 (ligand precursor) used is changed 3-fold There was obtained -6'-methyl-3H-spiro [1-benzofuran-2,1'-cyclohexane] -2'-ene-3,4'-dione (yield 95%; deuteration ratio 97%).
mp 180-181 ° C. [α] ¹⁷ _D + 358.2 (c 1.00, acetone). ¹ H-NMR (500 MHz, CDCl ₃ ): δ 0.98 (d, J = 6.7 Hz, 3 H), 2.42 (dd, J = 4.8, 16.8 Hz, 1H), 2.73-2.80 (m, 1H), 3.08 (dd, J = 13.5, 16.8 Hz, 1H), 3.64 (s, 3H), 3.91 (s, 3H), 3.92 (s, 3) 3H), 5.55 (s, 1H), 6.06 (s, 1H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 13.9 (CH ₃ ), 36.2 (CH), 39.7 (CH ₂ ), 55.79 (CH) ₃ ), 55.83 (CH ₃ ), 56.3 (CH ₃ ), 88.1 (t, J = 24.0 Hz, C), 89.5 (C), 93.0 (CH), 103.9 (C), 104.3 (CH), 158.7 (C) ), 170.1 (C), 171.1 (C), 175.7 (C), 192.1 (C), 196.9 (C). IR (ATR): 810, 1210, 1610 cm ^-1 . HRMS (EI) m / z ^{: (M +) Calcd for C} 17 H 17 DO 6: 319.1166; Found: 319.1161.

Example 3-25
1-benzyloxy in the same manner as in Example 1-13 except that 4-benzyloxyphenyl N, N-dimethylsulfamate was used instead of 3,5-dimethoxyphenyl N, N-dimethylsulfamate -4- deuteriobenzene (yield 88%; deuteration ratio of 99% or more) was obtained.

Example 3-26
A butyl 4-deuteriobenzoate was prepared in the same manner as in Example 1-13 except that butyl 4- (dimethylsulfamoyloxy) benzoate was used instead of 3,5-dimethoxyphenyl N, N-dimethylsulfamate. (Yield 93%; deuteration ratio 99% or more) was obtained.

  Examples 1-13, 2-8 and Examples 3-1 to 3-26 are summarized in Tables 6-8 below.

Example 4 Examination of Deuteration Agent
Example 4-1
1-deuterio-3,5-dimethoxybenzene (yield 87%) in the same manner as in Example 1-4 except that α-deuterio-α-phenylethanol was used instead of α-deuteriobenzhydrol. A deuteration ratio of 99% was obtained.

Example 4-2
1-deuterio-3,5-dimethoxybenzene (yield 83%) in the same manner as in Example 1-4 except that α-deuterio-α-cyclohexylbenzenemethanol was used instead of α-deuteriobenzhydrol A deuteration ratio of 99% was obtained.

Example 4-3
1-deuterio-3,5-dimethoxybenzene (yield: 78%; heavy) in the same manner as in Example 1-4 except that 5-deuterio-5-nonanol was used instead of α-deuteriobenzhydrol. The hydrogenation rate was over 99%).

  Examples 1-4 and Examples 4-1 to 4-3 are summarized in Table 9 below.

  The deuteration method of the present invention is excellent in both the cost aspect and the deuteration ratio, and furthermore, since the leaving group of the aromatic compound can be selectively deuterated, elucidation of the chemical reaction mechanism, It is useful for pharmacokinetic analysis, development and manufacture of medicines including deuterated compounds.

  This application is based on Japanese Patent Application No. 2014-035554 filed Feb. 26, 2014 in Japan, the contents of which are incorporated in full herein.

Claims (8)

Formula (I):


[In the formula,
Ring A and ring B each independently represent an aromatic ring which may be further substituted;
Ring C represents a cationic dinitrogen-containing ring which may be further substituted;
X ⁻ represents an anion;
Y ¹ and Y ² each independently represent a bond or methylene. ]
And a carbene ligand derived from a compound represented by and palladium or nickel. The deuteration catalyst according to claim 1, wherein X ^- is a chloride ion. The deuteration catalyst according to claim 1 or 2 , for catalyzing a substitution reaction of a leaving group bonded to an aromatic carbon atom to a deuterium atom. The deuteration catalyst according to claim 3 , wherein the leaving group is a halogen atom, a dimethylsulfamoyloxy group or a diethylsulfamoyloxy group. An aromatic carbon atom by reacting an aromatic compound having a leaving group in the presence of the deuteration catalyst according to any one of claims 1 to 4 , a deuteration agent and a base in an organic solvent. A method of substituting the above-mentioned leaving group bonded to a deuterium atom. The deuterated agent is of formula (III):


[Wherein, R ⁵ and R ⁶ each independently represent a substituent; D represents a deuterium atom. ]
The method according to claim 5 , which is a compound represented by The method according to claim 5 or 6 , wherein the amount of deuteration agent used is 1 molar equivalent to 3 molar equivalents with respect to the leaving group. The method according to any one of claims 5 to 7 , wherein the organic solvent is not a heavy solvent.