JP2021070684A - Method of producing halogen compound - Google Patents

Abstract

To provide a method of efficiently producing an aromatic compound including a halogen group of interest.SOLUTION: A method of producing a halogen compound represented by the specified general formula (1) comprises reacting a compound represented by the specified general formula (2) with a compound represented by the specified general formula (3) in the presence of a transition metal compound, a phosphine compound being 1,1'-bis(diphenylphosphino)ferrocene or 4,5'-bis(diphenylphosphino)-9,9'-dimethylxanthene, and a base. (In the formula, Ar1 and Ar2 represent organic groups; X represents a halogen group; Z represents a halogen group different than X; m represents an integer greater than or equal to 0; p represents an integer greater than or equal to 1; and each R represents a hydrogen atom, alkyl group or phenyl group, where the two R's may be linked together to form a ring.)SELECTED DRAWING: None

Description

The present invention relates to a method for efficiently producing a halogen compound.

A compound in which an aromatic compound is linked exhibits various functions by devising a substituent and a substitution mode. Due to its usefulness, it is used in a wide range of applications such as pharmaceuticals, pesticides, and electronic materials, and much research and development has been carried out on synthetic methods for linking aromatic compounds. In particular, the cross-coupling technique using a transition metal catalyst is widely used in the field of industrial production because it can produce a target compound with good selectivity, and its application is being developed (Patent Documents 1 and 2).

Japanese Unexamined Patent Publication No. 2012-171903 Japanese Unexamined Patent Publication No. 2017-052721 Generally, a halogen compound is used as a raw material in a cross-coupling reaction using a transition metal catalyst. Among them, halogen compounds having a plurality of different types of halogen groups are indispensable for the synthesis of complex substituted aromatic compounds. The reason for this is that when a compound having a plurality of the same halogen groups is used as a raw material, it is difficult to stop the reaction at the stage where only one halogen group is reacted, and the above-mentioned complex aromatic compounds This is because it is not suitable for synthesis.

In a conventionally known production method, a multi-coupling reaction product is preferentially produced by a cross-coupling reaction using a halogen compound having two or more of the same halogen groups as a raw material, and a mono-coupling reaction product is highly selected. It was difficult to obtain the target.

According to the present invention, a monocoupling reaction product having an unreacted halogen group by reacting only one halogen group by performing a cross-coupling reaction using a halogen compound having two or more of the same halogen groups as a raw material. Regarding the technology for manufacturing with good selectivity.

As a result of diligent studies to solve the above problems, the inventors of the present application efficiently produce a target halogen compound (corresponding to the above-mentioned monocoupling reaction product) by the production method of the present invention shown below. We found what we could do and completed the invention of the present application. That is, the present invention is a method for producing a halogen compound represented by the following general formula (1), wherein the transition metal compound and the phosphine compound are 1,1'-bis (diphenylphosphino) ferrocene or 4,5'-bis. (Diphenylphosphino) In the presence of -9,9'-dimethylxanthene and a base, the compound represented by the following general formula (2) is reacted with the compound represented by the following general formula (3). The present invention relates to a method for producing a halogen compound represented by the general formula (1).

(In the formula, Ar ¹ and Ar ² each independently represent an organic group having 1 to 40 carbon atoms. X represents the same halogen group. Z represents a halogen group different from X, and Z When there are a plurality of halogen groups, they are the same or different halogen groups. M represents an integer of 0 or more. P represents an integer of 1 or more. R is an independent hydrogen atom and 1 to 1 carbon atoms. Representing an alkyl group or a phenyl group of 4, two Rs may be linked to form a ring containing an oxygen atom and a boron atom.)

The production method of the present invention is based on the prior art in that, in a coupling reaction of a compound having two or more halogen groups, the reactivity of the first halogen group is high and the reactivity of the second and subsequent halogen groups is low. It has the effect of showing no reaction selectivity.

The production method of the present invention provides an industrially very advantageous method for efficiently producing a target halogen compound as compared with a conventionally known production method.

Hereinafter, the invention of the present application will be specifically described.

In the above general formulas (1), (2) and (3), Ar ¹ and Ar ² each independently represent an organic group having 1 to 40 carbon atoms. Incidentally, Ar ¹ of Ar ¹ of the general formula (1) (2) represent the same group, Ar ² of Ar ² of the general formula (1) (3) represent the same group. In addition, Ar ¹ will be exemplified below as the name of a monovalent organic group regardless of the values of m and p.

The organic group having 1 to 40 carbon atoms is not particularly limited, but for example, an aryl group having a total carbon number of 6 to 40, a heteroaryl group having a total carbon number of 3 to 40, and an alkyl having a total carbon number of 1 to 40. Examples include groups and alkoxy groups having a total carbon number of 1 to 40 (these groups may be substituted with any organic group within the range of the total carbon number described above).

Of these, aryl groups having a total carbon number of 6 to 40 or heteroaryl groups having a total carbon number of 3 to 40 (these groups are independent of each other within the above-mentioned range of the total carbon number) in terms of excellent production efficiency. From any alkyl group, any alkoxy group, any aryl group, any aryloxy group, any heteroaryl group, any diarylamino group, any alkoxycarbonyl group, hydroxy group, nitro group, and halogen atom. It is preferable that it has one or more substituents selected from the above group), and an aryl group having a total carbon number of 6 to 30 or a heteroaryl group having a total carbon number of 3 to 30 (these groups are Within the above total carbon number, each independently, any alkyl group, any alkoxy group, any aryl group, any aryloxy group, any heteroaryl group, any diarylamino group, any. It may have one or more substituents selected from the group consisting of an alkoxycarbonyl group, a hydroxy group, a nitro group, and a halogen atom), and an aryl group having a total carbon number of 6 to 20 or a total number of carbon atoms. Heteroaryl groups having 3 to 20 carbon atoms (these groups are independently any alkyl group, any alkoxy group, any aryl group, any aryloxy group within the above-mentioned total carbon number range. , Any heteroaryl group, any diarylamino group, any alkoxycarbonyl group, hydroxy group, nitro group, and one or more substituents selected from the group consisting of halogen atoms). Is more preferable.

In Ar ¹ and Ar ² , the aryl group having a total carbon number of 6 to 40 which may be substituted with an arbitrary organic group is not particularly limited, and is, for example, a phenyl group, a 4-methylphenyl group, 3 -Methylphenyl group, 2-methylphenyl group, 4-ethylphenyl group, 3-ethylphenyl group, 2-ethylphenyl group, 4-n-propylphenyl group, 4-n-butylphenyl group, 4-isobutylphenyl group , 4-tert-Butylphenyl group, 4-cyclopentylphenyl group, 4-cyclohexylphenyl group, 2,4-dimethylphenyl group, 3,5-dimethylphenyl group, 3,4-dimethylphenyl group, 4-methoxyphenyl group , 3-methoxyphenyl group, 2-methoxyphenyl group, 4-hydroxyphenyl group, 3-hydroxyphenyl group, 2-hydroxyphenyl group, 4-alkoxycarbonylphenyl group, 3-alkoxycarbonylphenyl group, 2-alkoxycarbonylphenyl Group, biphenylryl group, terphenylyl group, 9-phenanthryl group, 9,9-dialkyl-fluoren-2-yl group, biphenylenyl group, naphthyl group, benzofluorenyl group, dibenzofluorenyl group, fluoranthenyl group, Examples thereof include a pyrenyl group, a chrysenyl group, a perylenel group and a pisenyl group. Further, although not particularly limited, more specifically, a phenyl group, a 4-methylphenyl group, a 3-methylphenyl group, a 2-methylphenyl group, a 4-ethylphenyl group, a 3-ethylphenyl group, 2 -Ethylphenyl group, 4-n-propylphenyl group, 4-isopropylphenyl group, 2-isopropylphenyl group, 4-n-butylphenyl group, 4-isobutylphenyl group, 4-sec-butylphenyl group, 2-sec -Butylphenyl group, 4-tert-butylphenyl group, 3-tert-butylphenyl group, 2-tert-butylphenyl group, 4-n-pentylphenyl group, 4-isopentylphenyl group, 4-neopentylphenyl group , 2-Neopentylphenyl group, 4-tert-Pentylphenyl group, 4-n-hexylphenyl group, 4- (2'-ethylbutyl) phenyl group, 4-n-heptylphenyl group, 4-n-octylphenyl group , 4- (2'-Ethylhexyl) phenyl group, 4-tert-octylphenyl group, 4-n-decylphenyl group, 3-cyclohexylphenyl group, 2-cyclohexylphenyl group, 4-n-dodecylphenyl group, 4- n-Tetradecylphenyl group, 4-cyclopentylphenyl group, 4-cyclohexylphenyl group, 4- (4'-tert-butylcyclohexyl) phenyl group, 4-tritylphenyl group, 3-tritylphenyl group, 4- (4' -Methylphenyl) phenyl group, 4- (3'-methylphenyl) phenyl group, 4- (4'-methoxyphenyl) phenyl group, 4- (4'-n-butoxyphenyl) phenyl group, 2- (2') -Methenylphenyl) Phenyl group, 3-methyl-4-phenylphenyl group, 3-methoxy-4-phenylphenyl group, 3,5-diphenylphenyl group, 4-triphenylsilylphenyl group, 3-triphenylsilylphenyl group , 2,4-Dimethylphenyl group, 2,5-dimethylphenyl group, 3,4-dimethylphenyl group, 3,5-dimethylphenyl group, 2,6-dimethylphenyl group, 2,4-diethylphenyl group, 2 , 6-diethylphenyl group, 2,5-diisopropylphenyl group, 2,6-diisobutylphenyl group, 2,4-di-tert-butyl-2-methylphenyl group, 2,5-di-tert-butylphenyl group , 5-tert-Butyl-2-methylphenyl group, 2,3,5-trimethylphenyl group, 2,3,6-trimethylphenyl group, 3,4,5-to Limethylphenyl group, 4,6-di-tert-butyl-2-methylphenyl group, 4-tert-butyl-2,6-dimethylphenyl group, 4-methoxyphenyl group, 3-methoxyphenyl group, 2-methoxy Phenyl group, 4-ethoxyphenyl group, 3-ethoxyphenyl group, 2-ethoxyphenyl group, 4-n-propoxyphenyl group, 3-n-propoxyphenyl group, 4-isopropoxyphenyl group, 2-isopropoxyphenyl group , 4-n-Butoxyphenyl group, 4-Isobutoxyphenyl group, 2-sec-Butoxyphenyl group, 4-n-Pentyloxyphenyl group, 4-Isopentyloxyphenyl group, 2-Isopentyloxyphenyl group, 4 -Neopentyloxyphenyl group, 2-neopentyloxyphenyl group, 4-n-hexyloxyphenyl group, 2- (2-ethylbutyl) oxyphenyl group, 4-n-octyloxyphenyl group, 4-n-decyloxy Phenyl group, 4-n-dodecyloxyphenyl group, 4-n-tetradecyloxyphenyl group, 4-cyclohexyloxyphenyl group, 2-cyclohexyloxyphenyl group, 4-phenoxyphenyl group, 2-methyl-4-methoxyphenyl Group, 2-methyl-5-methoxyphenyl group, 3-methyl-4-methoxyphenyl group, 3-methyl-5-methoxyphenyl group, 3-ethyl-5-methoxyphenyl group, 2-methoxy-4-methylphenyl Group, 3-methoxy-4-methylphenyl group, 2,4-dimethoxyphenyl group, 2,5-dimethoxyphenyl group, 2,6-dimethoxyphenyl group, 3,4-dimethoxyphenyl group, 3,5-dimethoxyphenyl Group, 3,5-diethoxyphenyl group, 3,5-di-n-butoxyphenyl group, 2-methoxy-4-ethoxyphenyl group, 2-methoxy-6-ethoxyphenyl group, 3,4,5-tri Methoxyphenyl group, 4-methoxycarbonylphenyl group, 3-methoxycarbonylphenyl group, 2-methoxycarbonylphenyl group, 4-ethoxycarbonylphenyl group, 3-ethoxycarbonylphenyl group, 2-ethoxycarbonylphenyl group, 4- (9) -Carbazolyl) phenyl group, 3- (9-carbazolyl) phenyl group, 4-fluorophenyl group, 3-fluorophenyl group, 2-fluorophenyl group, 2,3-difluorophenyl group, 2,4-difluorophenyl group, 2,5-Difluorophenyl group, 2,6-difluorophenyl Group, 3,4-difluorophenyl group, 3,5-difluorophenyl group, 4- (2-pyridyl) phenyl group, 4- (3-pyridyl) phenyl group, 4- (4-pyridyl) phenyl group, 4- (1-naphthyl) phenyl group, 4- (2-naphthyl) phenyl group, 3- (1-naphthyl) phenyl group, 3- (2-naphthyl) phenyl group, 1-naphthyl group, 2-naphthyl group, 4- Methyl-1-naphthyl group, 6-methyl-2-naphthyl group, 6-n-butyl-2-naphthyl group, 4-phenyl-1-naphthyl group, 6-phenyl-2-naphthyl group, 2-methoxy-1 -Nuftyl group, 4-methoxy-1-naphthyl group, 5-ethoxy-1-naphthyl group, 6-ethoxy-2-naphthyl group, 7-methoxy-2-naphthyl group, 6-n-butoxy-2-naphthyl group , 6-n-hexyloxy-2-naphthyl group, 4-n-butoxy-1-naphthyl group, 7-n-butoxy-2-naphthyl group, 2-anthryl group, 9-anthryl group, 10-phenyl-9 -Anthryl group, 10- (3,5-diphenylphenyl) -9-anthril group, 2-fluorenyl group, 9-methyl-2-fluorenyl group, 9-ethyl-2-fluorenyl group, 9-n-hexyl-2 -Fluolenyl group, 9-Phenyl-2-fluorenyl group, 9,9-dimethyl-2-fluorenyl group, 9,9-diethyl-2-fluorenyl group, 9,9-di-n-propyl-2-fluorenyl group, 9,9-Di-n-octyl-2-fluorenyl group, 9,9-diphenyl-2-fluorenyl group, 9,9'-spirobifluolenyl group, 9-phenanthryl group, 2-phenanthryl group, benzofur Olenyl group, dibenzofluorenyl group, fluoranthenyl group, pyrenyl group, chrysenyl group, perylenyl group, pisenyl group, 4-biphenylyl group, 3-biphenylyl group, 2-biphenylyl group, p-terphenyl group, m- Examples thereof include a terphenyl group and an o-terphenyl group. Of these, in terms of increasing the reaction yield of the halogen compound of the present invention, phenyl group, methylphenyl group, hydroxyphenyl group, methoxyphenyl group, methoxycarbonylphenyl group, biphenylryl group, pyridylphenyl group, anthryl group, phenylan A trill group, a phenanthryl group, a 9,9-dimethylfluorenyl group, or a naphthyl group is preferable, and a phenyl group, a methylphenyl group, a hydroxyphenyl group, a methoxyphenyl group, a methoxycarbonylphenyl group, a biphenylryl group, 4- (2). -Phenyl) phenyl group, 4- (3-pyridyl) phenyl group, 4- (4-pyridyl) phenyl group, 9-anthryl group, 10-phenyl-9-anthryl group, 9-phenanthryl group, 9,9-dimethyl -2-Fluorenyl group or naphthyl group is more preferable, phenyl group, 4-methylphenyl group, 3-methylphenyl group, 2-methylphenyl group, 4-hydroxyphenyl group, 3-hydroxyphenyl group, 2-hydroxyphenyl. Group, 4-methoxyphenyl group, 3-methoxyphenyl group, 2-methoxyphenyl group, 4-methoxycarbonylphenyl group, 3-methoxycarbonylphenyl group, 2-methoxycarbonylphenyl group, biphenylryl group, 9-phenanthryl group, A 9,9-dimethyl-fluoren-2-yl group or a naphthyl group is more preferred.

In Ar ¹ and Ar ² , the heteroaryl group having a total carbon number of 3 to 40 which may be substituted with an arbitrary organic group is not particularly limited, but for example, a quinolyl group, a pyridyl group, a frill group, and the like. Examples thereof include a thienyl group, an oxazolyl group, a thiazolyl group, a benzothiophenyl group, a dibenzofuranyl group, a benzothiazolyl group, a benzimidazolyl group, a dibenzothiophenyl group and an N-carbazolyl group. Although not particularly limited, more specifically, for example, 4-quinolyl group, 4-pyridyl group, 4- (2-methyl) pyridyl group, 4- (2-ethyl) pyridyl group, 4-phenylpyridyl. Group, 3-phenylpyridyl group, 2-phenylpyridyl group, 3-pyridyl group, 2-pyridyl group, 2,2'-bipyridyl group, 2,3'-bipyridyl group, 2,4'-bipyridyl group, 3- Frill group, 2-furyl group, 3-thienyl group, 2-thienyl group, 2-oxazolyl group, 2-thiazolyl group, 2-benzoxazolyl group, 2-benzothiazolyl group, 2-benzoimidazolyl group, 2-dibenzothio Examples thereof include a phenyl group, a 4-dibenzothiophenyl group, a 2-dibenzofuranyl group, a 4-dibenzofuranyl group, a 2-thiantrenyl group, a 4-phenoxatienyl group and the like. Of these, quinolyl group, pyridyl group, methylpyridyl group, ethylpyridyl group, phenylpyridyl group, bipyridyl group, thienyl group, carbazolyl group and 9-phenylcarba in terms of increasing the reaction yield of the aromatic compound containing a halogen group. Zolyl group, 9- (4-biphenylyl) carbazolyl group, dibenzofuranyl group, or dibenzothienyl group is preferable, 4-quinolyl group, 4-pyridyl group, 4- (2-methyl) pyridyl group, 4- (2). -Ethyl) pyridyl group, 4-phenylpyridyl group, 3-phenylpyridyl group, 2-phenylpyridyl group, 3-pyridyl group, 2-pyridyl group, 2,2'-bipyridyl group, 2,3'-bipyridyl group, More preferably, a 2,4'-bipyridyl group, a 3-thienyl group, a carbazolyl group, a 9-phenylcarbazolyl group, a 9- (4-biphenylyl) carbazolyl group, a dibenzofuranyl group, or a dibenzothienyl group.

In Ar ¹ and Ar ² , the alkyl group having a total carbon number of 1 to 40 which may be substituted with an arbitrary organic group is not limited to the following, but specifically, a methyl group and a chloromethyl group. Group, trifluoromethyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, tert-butyl group, pentyl group, propine group, hexyl group, heptyl group, octyl group, stearyl group, trichloromethyl group , Trifluoromethyl group, cyclopropyl group, cyclohexyl group, 1,3-cyclohexadienyl group, 2-cyclopenten-1-yl group and the like can be exemplified.

In Ar ¹ and Ar ² , the alkoxy group having a total carbon number of 1 to 40 which may be substituted with an arbitrary organic group is not limited to the following, but specifically, a methoxy group and a chloromethoxy group. Group, trifluoromethoxy group, ethoxy group, propyloxy group, isopropyloxy group, butyloxy group, sec-butyloxy group, tert-butyloxy group, pentyloxy group, propinoxy group, hexyloxy group, heptyloxy group, octyloxy group. Examples of a group, a stearyloxy group, a trichloromethyloxy group, a trifluoromethyloxy group, a cyclopropyloxy group, a cyclohexyloxy group, a 1,3-cyclohexadienyloxy group, a 2-cyclopenten-1-yloxy group and the like can be exemplified. it can.

The above-mentioned arbitrary organic group is not particularly limited, but for example, any alkyl group, any alkoxy group, any aryl group, any aryloxy group, any heteroaryl group, any diarylamino. A group, any alkoxycarbonyl group, a hydroxy group, a nitro group, or a halogen atom can be exemplified.

In Ar ¹ and Ar ² , the arbitrary alkyl group is not limited to the following, but specifically, a methyl group, an ethyl group, or a linear, branched, or cyclic group having 3 to 18 carbon atoms. Alkyl groups can be exemplified, and more specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, tert-butyl group, pentyl group, propine group, hexyl group and heptyl group. Examples thereof include a group, an octyl group, a stearyl group, a trichloromethyl group, a trifluoromethyl group, a cyclopropyl group, a cyclohexyl group, a 1,3-cyclohexadienyl group, a 2-cyclopenten-1-yl group and the like.

In Ar ¹ and Ar ² , the optional alkoxy group is not limited to the following, but specifically, a methoxy group, an ethoxy group, or a linear, branched, or cyclic group having 3 to 18 carbon atoms. Alkoxy groups can be exemplified, and more specifically, methoxy group, ethoxy group, propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, hexyloxy group. , Stearyloxy group, trifluoromethoxy group and the like can be exemplified.

In Ar ¹ and Ar ² , the arbitrary aryl group is not limited to the following, but specifically, a phenyl group, a 4-methylphenyl group, a 3-methylphenyl group, a 2-methylphenyl group, and the like. 4-Ethylphenyl group, 3-Ethylphenyl group, 2-Ethylphenyl group, 4-n-propylphenyl group, 4-n-butylphenyl group, 4-isobutylphenyl group, 4-tert-butylphenyl group, 4- Cyclopentylphenyl group, 4-cyclohexylphenyl group, 2,4-dimethylphenyl group, 3,5-dimethylphenyl group, 3,4-dimethylphenyl group, biphenylryl group, terphenylyl group, 9-phenanthryl group, 9,9- Examples thereof include dialkyl-fluoren-2-yl group, biphenylenyl group, naphthyl group, benzofluorenyl group, dibenzofluorenyl group, fluoranthenyl group, pyrenyl group, chrysenyl group, peryleneyl group, pisenyl group and the like. ..

In Ar ¹ and Ar ² , the arbitrary aryloxy group is not limited to the following, but specifically, a phenoxy group, an o-triloxy group, an m-triloxy group, a p-triloxy group, 4-. Examples thereof include a biphenyloxy group, a 3-biphenyloxy group, a 1-naphthyloxy group, a 2-naphthyloxy group, a p-tert-butylphenoxy group, a 3-fluorophenoxy group, a 4-fluorophenoxy group and the like.

In Ar ¹ and Ar ² , the arbitrary heteroaryl group is not limited to the following, and specifically, a quinolyl group, a pyridyl group, a furyl group, a thienyl group, an oxazolyl group, a thiazolyl group, and a benzothiol group. Examples thereof include a phenyl group, a dibenzofuranyl group, a benzothiazolyl group, a benzimidazolyl group, a dibenzothiophenyl group, an N-carbazolyl group and the like.

In Ar ¹ and Ar ² , the arbitrary diarylamino group is not limited to the following, but specifically, a diphenylamino group, a di (p-tolyl) amino group, and a bis (4-biphenylyl) amino. Examples thereof include a group, a di (1-naphthyl) amino group, a phenyl (p-tolyl) amino group, a phenyl (4-biphenylyl) amino group, and a phenyl (1-naphthyl) amino group.

In Ar ¹ and Ar ² , the arbitrary alkoxycarbonyl group is not limited to the following, but specifically, a methoxycarbonyl group, an ethoxycarbonyl group, a 1-propoxycarbonyl group, a 2-propoxycarbonyl group, and the like. Examples thereof include 1-butoxycarbonyl group, 2-butoxycarbonyl group, phenoxycarbonyl group and the like.

In Ar ¹ and Ar ² , the halogen atom is not particularly limited, and specific examples thereof include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

In the general formulas (1) and (2), X represents the same halogen group. Z represents a halogen group different from X, and when there are a plurality of Z, they are the same or different halogen groups. The halogen group described above is not particularly limited, and examples thereof include a chlorine group, a bromine group, and an iodine group.

Regarding X and Z, from the viewpoint of high usefulness of subsequent molecular skeleton formation and improvement of reaction selectivity, (i) X is all bromine group and Z is all chlorine group. Alternatively, (ii) X is preferably an iodine group and Z is an independent chlorine group or a bromine group, and (i) X is an all bromine group and Z is an all chlorine group. It is more preferable that (iii) X is all iodine groups and Z is all chlorine groups, or (iv) X is all iodine groups and Z is all bromine groups.

In the general formulas (1) and (2), m represents an integer of 0 or more. From the viewpoint of improving the reaction selectivity, m is preferably an integer of 0, 1, or 2. The m of the general formula (1) and the m of the general formula (2) are the same.

In the general formulas (1) and (2), p represents an integer of 1 or more. From the viewpoint of improving the reaction selectivity, p is preferably 1 or 2. The p of the general formula (1) and the p of the general formula (2) are the same.

In the present invention, the compound represented by the general formula (2) is 1,2-dibromobenzene, 1,3 from the viewpoint of high usefulness for later molecular skeleton formation and improvement of reaction selectivity. -Dibromobenzene, 1,4-dibromobenzene, 1,3-dibromo-5-chlorobenzene, 1,2-dibromo-4-chlorobenzene, 1,3-dibromo-4-chlorobenzene, 1-chloro-3,5-di Iodobenzene, 1-chloro-3,4-diiodobenzene, 1-chloro-2,5-diiodobenzene, 2,3-dibromotoluene, 2,4-dibromotoluene, 2,5-dibromotoluene, 3, 5-dibromotoluene, 3,6-dibromo-9-phenylcarbazole, 3,5-dibromopyridine, 2,8-dibromodibenzofuran, 1,3-dibromo-5-nitrobenzene, 1,2-diiodobenzene, 1, 3-Diiodobenzene, 1,4-diiodobenzene, 3,5-dibromophenol, 3,5-dibromoanisole, methyl 3,5-dibromobenzoate, 3,5-dibromobiphenyl, 1,8-dibromonaphthalene , Or 3,4-dibromothiophene, preferably 1,3-dibromobenzene, 1,3-dibromo-5-chlorobenzene, 3,5-dibromotoluene, 3,5-dibromophenol, 3,5-dibromoanisole, 3 , 5-Dibromomethylbenzoate, 3,5-dibromobiphenyl, 1,8-dibromonaphthalene, 3,5-dibromopyridine, or 3,4-dibromothiophene is more preferred.

In the general formula (3), R independently represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or a phenyl group, and the two Rs are linked to form a ring containing an oxygen atom and a boron atom. You may be doing it.

The above-mentioned alkyl group having 1 to 4 carbon atoms is not particularly limited, but for example, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, a 1-propen-3-yl group, an n- Butyl group, iso-butyl group, tert-butyl group and the like can be exemplified.

Examples of the ring in which two Rs are connected and contain an oxygen atom and a boron atom can be exemplified by the rings shown in (B-1) to (B-6) below.

In the present invention, with respect to the compound represented by the general formula (3), Ar ² is a phenyl group, 2-methyl, from the viewpoint of high usefulness for later molecular skeleton formation and improvement of reaction selectivity. Phenyl group, 3-methylphenyl group, 4-methylphenyl group, 4-biphenyl group, 3-biphenyl group, 2-biphenyl group, 2-naphthyl group, 1-naphthyl group, 4-pyridyl group, 3-pyridyl group or A compound represented by a combination of 2-pyridyl group and the _{group represented by −B (OR) 2} being dihydroxyboron, pinacholate boron or neopentylglycolate boron is preferable.

The present invention relates to a transition metal compound, 1,1'-bis (diphenylphosphino) ferrocene or 4,5'-bis (diphenylphosphino) -9,9'-dimethylxanthene as a phosphine compound, and in the presence of a base. A method for producing a halogen compound represented by the general formula (1), which comprises reacting a compound represented by the general formula (2) with a compound represented by the general formula (3). ..

The production method of the present invention is not particularly limited, but usually, the compound represented by the general formula (3) is 0.5 to 3 with respect to 1 mol of the compound represented by the general formula (2). It is preferable to carry out a 0-fold molar reaction. In order to highly selectively synthesize the desired aromatic compound containing a halogen group, the compound represented by the general formula (3) is preferably in the amount of 0.5 to 2.0 times the molar amount, and is 0.7. It is more preferable to use ~ 1.5 times the molar amount.

The transition metal compound is not particularly limited, and examples thereof include a palladium compound and a nickel compound. The palladium compound is not particularly limited, but for example, palladium (II) chloride, palladium (II) bromide, palladium (II) acetate, palladium acetylacetonate (II), and dichlorobis (benzonitrile) palladium (II). ), Dichlorobis (acetritale) palladium (II), dichlorobis (triphenylphosphine) palladium (II), dichlorotetraammine palladium (II), dichloro (cycloocta-1,5-diene) palladium (II), palladium trifluoroacetate (II). ), Tris (dibenzilidenacetone) dipalladium (0), Tris (dibenzilidenacetone) dipalladium chloroform complex (0), Tetrakis (triphenylphosphine) palladium (0), and the like.

The nickel compound is not particularly limited, but is, for example, nickel halide such as nickel fluoride (II), nickel chloride (II), nickel bromide (II), nickel iodide (II), and nickel (0). ) Powder, inorganic salts such as nickel sulfate (II), nickel nitrate (II), nickel perchlorate (II), nickel formate (II), nickel oxalate (II), nickel acetate (II), nickel benzoate ( II), nickel acetylacetonate (II) and the like can be mentioned.

In addition, those in which these transition metal compounds are supported on carriers such as carbon, silica gel, and fibers can also be used in the production method of the present invention. For example, activated carbon, polystyrene fiber and the like can be exemplified.

As the phosphine compound, 1,1'-bis (diphenylphosphino) ferrocene or 4,5'-bis (diphenylphosphino) -9,9'-dimethylxanthene is used. By using these phosphine compounds, an aromatic compound containing a halogen group, which is a feature of the present invention, can be produced with high selectivity. As the phosphine compound, a compound prepared by mixing with a transition metal compound in advance to prepare a complex may be used in the reaction, or a compound which is put into the reaction system by a different route from the transition metal compound and coexisted in the reaction may be used in the reaction. You may use it.

In the present invention, the amount of the transition metal compound used is defined by a mathematical formula represented by {(the number of moles of the transition metal in the transition metal compound) ÷ (the number of moles of the compound represented by the general formula (2))}. , Usually in the range of 0.001-20. When the amount of the transition metal compound used is within the above range, the halogen compound represented by the general formula (1) can be produced with high selectivity. From the viewpoint of more selectively producing the aromatic compound containing the desired halogen group, (the number of moles of the transition metal in the transition metal compound) ÷ (the number of moles of the compound represented by the general formula (2))} , 0.01 to 20, more preferably 0.1 to 10.

The base in the present invention is not particularly limited, and examples thereof include an inorganic base, an organic base, or a mixture of an inorganic base and an organic base. The base is not particularly limited, but for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium phosphate, sodium phosphate, etc., sodium-methoxyd, sodium-ethoxydo, potassium-methoxyd, potassium-ethoxydo, etc. , Alkali metal alkoxides such as lithium-tert-butoxide, sodium-tert-butoxide, potassium-tert-butoxide and the like, triethylamine, tributylamine, pyridine, preferably sodium hydroxide, potassium hydroxide, sodium carbonate, etc. Examples thereof include potassium carbonate, potassium phosphate, sodium hydroxide and the like. The base may be used as an aqueous solution in the production method of the present invention.

The amount of the base used in the production method of the present invention is not particularly limited, but is usually in the range of 0.5 to 50 times mol with respect to 1 mol of the aromatic compound represented by the general formula (2). Is. Within the above range, an aromatic compound containing a target halogen group can be efficiently produced. In order to highly selectively synthesize the desired aromatic compound containing a halogen group, the amount of the base used is preferably in the range of 1 to 5 times the molar amount.

This reaction is usually carried out in the presence of an inert solvent. The inert solvent may be any solvent as long as it does not significantly inhibit the reaction carried out by the production method of the present invention, and is not particularly limited. For example, aromatic organic solvents such as benzene, toluene, xylene and mesitylene can be used. , Diethyl ether, tetrahydrofuran, dimethoxyethane, dioxane and other ether-based organic solvents, methanol, ethanol, isopropanol and other alcohol-based solvents, acetonitrile, dimethylformamide, dimethylsulfoxide, hexamethylphosphotriamide and the like. Of these, aromatic organic solvents such as benzene, toluene, xylene, and mesitylene are preferable in terms of highly selective synthesis of the target aromatic compound containing a halogen group.

The reaction carried out by the production method of the present invention is not particularly limited, but is usually carried out under an atmosphere of an inert gas such as nitrogen or argon, and is carried out under normal pressure or pressure. The reaction is usually carried out in the range of 0 to 250 ° C, but preferably in the range of 20 to 150 ° C.

The reaction time required for the reaction carried out by the production method of the present invention is 1,1'-bis as a compound represented by the general formula (2), a compound represented by the general formula (3), a transition metal compound, and a phosphine compound. The amount of (diphenylphosphino) ferrocene or 4,5'-bis (diphenylphosphino) -9,9'-dimethylxanthene, and the amount of base, and the reaction temperature are not constant, but usually range from several minutes to 72 hours. You can choose from.

Hereinafter, the invention of the present application will be specifically described with reference to Examples. However, these do not limit the invention of the present application.
[Purity measurement after reaction (gas chromatography analysis)]
Measuring device: GC-2014 manufactured by Shimadzu Corporation
Measurement conditions: Column = InertCap5 (30 m x 0.32 mm x 0.40 μm)
Vaporization chamber temperature = 280 ° C
Detector temperature = 300 ° C
Column temperature = 120 ° C-300 ° C
Heating rate = 10 ° C / min
Example 1

1,3-Dibromobenzene (Compound 1) 236 mg (1 mmol), phenylboronic acid 122 mg (1 mmol), toluene 5 mL, palladium acetate 4.5 mg (Pd atom 0.02 mmol, 0.02 relative to the amount of Compound 1 used Double molar Pd atom present), 4,5'-bis (diphenylphosphino) -9,9'-dimethylxanthene (Xantphos) 23 mg (0.04 mmol), and 2 prescribed tripotassium phosphate aqueous solution 925 mg (phosphorus) Tripotassium phosphate (2 mmol) was added to a 20 mL Schlenck tube and heated at 100 ° C. for 12 hours under a nitrogen atmosphere. After completion of the reaction, the reaction solution was cooled to room temperature, and the reaction solution was analyzed by GC (gas chromatograph) (internal standard = dibenzyl). The GC yield of the produced 3-bromobiphenyl (product 1) was 81%. From the reaction kinetics analysis, the reaction rate ratio (K1 / Kn) comparing the reaction rate of the first halogen group (K1) and the reaction rate of the second and subsequent halogen groups (Kn, n ≧ 2). Was as high as 7.

Example 2
In Example 1, 5 mL of 1,2-dimethoxyethane was used instead of 5 mL of toluene, and the same operation as in Example 1 was carried out except that the reaction temperature was set to 80 ° C., and product analysis was performed. The produced 3-bromobiphenyl (product 1) had a GC yield of 70%. K1 / Kn was as high as 7.

Example 3
In Example 1, the same operation as in Example 1 was carried out except that 5 mL of dimethylformamide was used instead of 5 mL of toluene, and product analysis was performed. The produced 3-bromobiphenyl (product 1) had a GC yield of 65%. K1 / Kn was as high as 6.

Example 4
In Example 1, the same operation as in Example 1 was carried out except that 5 mL of 1,4-dioxane was used instead of 5 mL of toluene, and product analysis was performed. The produced 3-bromobiphenyl (product 1) had a GC yield of 66%. K1 / Kn was as high as 6.

Example 5
In Example 1, the same operation as in Example 1 was carried out except that 5 mL of o-xylene was used instead of 5 mL of toluene, and product analysis was performed. The produced 3-bromobiphenyl (product 1) had a GC yield of 75%. K1 / Kn was as high as 7.

Example 6
In Example 1, instead of 4.5 mg (0.02 mmol) of palladium acetate, 9.2 mg (0.01 mmol, 0.02 mmol of Pd atom, compound 1) of tris (dibenzylideneacetone) dipalladium (0) was used. The same operation as in Example 1 was carried out except that 0.02 times the molar amount of Pd atom was used), and the product analysis was performed. The produced 3-bromobiphenyl (product 1) had a GC yield of 79%. K1 / Kn was as high as 7.

Example 7
In Example 1, the same operation as in Example 1 except that the amount of 4,5'-bis (diphenylphosphino) -9,9'-dimethylxanthene (Xantphos) used was reduced to 12 mg (0.02 mmol). Was performed, and product analysis was performed. The produced 3-bromobiphenyl (product 1) had a GC yield of 66%. K1 / Kn was as high as 6.

Example 8
In Example 1, 1,1'-bis (diphenylphosphino) ferrocene (dppf) was replaced with 23 mg (0.04 mmol) of 4,5'-bis (diphenylphosphino) -9,9'-dimethylxanthene (Xantphos). ) The same operation as in Example 1 was carried out except that 22 mg (0.04 mmol) was used, and product analysis was performed. The produced 3-bromobiphenyl (product 1) had a GC yield of 69%. K1 / Kn was as high as 6.

Example 9

In Example 1, the same as in Example 1 except that 3,5-dibromo-1-chlorobenzene (Compound 2) 270 mg (1 mmol) was used instead of 236 mg (1 mmol) of 1,3-dibromobenzene (Compound 1). Manipulation was performed and product analysis was performed. The produced 3-bromo-5-chlorobiphenyl (product 2) had a GC yield of 77%. K1 / Kn was as high as 7.

Example 10
Same as Example 9 except that 3.0 mg (0.02 mmol) of bis (2,4-pentanedionato) palladium (II) is used instead of 4.5 mg (0.02 mmol) of palladium acetate. Was performed to analyze the product. The produced 3-bromo-5-chlorobiphenyl (product 2) had a GC yield of 68%. K1 / Kn was as high as 6.

Example 11
In Example 9, instead of 4.5 mg (0.02 mmol) of palladium acetate, 9.2 mg (0.01 mmol, 0.02 mmol of Pd atom, compound 2) of tris (dibenzylideneacetone) dipalladium (0) was used. The same operation as in Example 9 was carried out except that 0.02 times the molar amount of Pd atom was used), and the product analysis was performed. The produced 3-bromo-5-chlorobiphenyl (product 2) had a GC yield of 72%. K1 / Kn was as high as 6.

Example 12
In Example 9, 1,1'-bis (diphenylphosphino) ferrocene (dppf) was replaced with 23 mg (0.04 mmol) of 4,5'-bis (diphenylphosphino) -9,9'-dimethylxanthene (Xantphos). ) The same operation as in Example 9 was carried out except that 22 mg (0.04 mmol) was used, and product analysis was performed. The produced 3-bromo-5-chlorobiphenyl (product 2) had a GC yield of 67%. K1 / Kn was as high as 5.
Example 13
In Example 9, 5 mL of tetrahydrofuran was used instead of 5 mL of toluene, and the same operation as in Example 9 was carried out except that the reaction temperature was set to 65 ° C., and product analysis was performed. The produced 3-bromo-5-chlorobiphenyl (product 2) had a GC yield of 71%. K1 / Kn was as high as 7.

Example 14

Product analysis was performed in the same manner as in Example 1 except that 3,5-dibromotoluene 250 mg (1 mmol) was used instead of 236 mg (1 mmol) of 1,3-dibromobenzene (compound 1). Was done. The produced 3-bromo-5-phenyltoluene had a GC yield of 74%. K1 / Kn was as high as 5.

Example 15

Product analysis was performed in the same manner as in Example 1 except that 252 mg (1 mmol) of 3,5-dibromophenol was used instead of 236 mg (1 mmol) of 1,3-dibromobenzene (Compound 1). Was done. The produced 3-bromo-5-phenylphenol had a GC yield of 63%. K1 / Kn was as high as 7.

Example 16

Product analysis was performed in the same manner as in Example 1 except that 3,5-dibromoanisole 266 mg (1 mmol) was used instead of 236 mg (1 mmol) of 1,3-dibromobenzene (Compound 1). Was done. The produced 3-bromo-5-phenylanisole had a GC yield of 70%. K1 / Kn was as high as 4.

Example 17

In Example 1, the same procedure as in Example 1 was carried out except that 294 mg (1 mmol) of methyl 3,5-dibromobenzoate was used instead of 236 mg (1 mmol) of 1,3-dibromobenzene (Compound 1). Object analysis was performed. The produced methyl 3-bromo-5-phenylbenzoate had a GC yield of 72%. K1 / Kn was as high as 4.

Example 18

Product analysis was performed in the same manner as in Example 1 except that 3,5-dibromobiphenyl 312 mg (1 mmol) was used instead of 236 mg (1 mmol) of 1,3-dibromobenzene (compound 1). Was done. The produced 1-bromo-3,5-diphenylbenzene had a GC yield of 75%. K1 / Kn was as high as 4.

Example 19

In Example 1, the same procedure as in Example 1 was carried out except that 1,8-dibromonaphthalene (362 mg (1 mmol) was used instead of 236 mg (1 mmol) of 1,3-dibromobenzene (Compound 1), and product analysis was performed. Was done. The produced 1-bromo-8-phenylnaphthalene had a GC yield of 80%. K1 / Kn was as high as 5.

Example 20

Product analysis was performed in the same manner as in Example 1 except that 3,5-dibromopyridine (237 mg (1 mmol)) was used instead of 236 mg (1 mmol) of 1,3-dibromobenzene (Compound 1). Was done. The produced 3-bromo-5-phenylpyridine had a GC yield of 66%. K1 / Kn was as high as 3.

Example 21

Product analysis was performed in the same manner as in Example 1 except that 3,4-dibromothiophene 242 mg (1 mmol) was used instead of 236 mg (1 mmol) of 1,3-dibromobenzene (Compound 1). Was done. The produced 3-bromo-4-phenylthiophene had a GC yield of 47%. K1 / Kn was as high as 2.

Example 22

In Example 9, the same procedure as in Example 9 was carried out except that 198 mg (1 mmol) of 2-biphenylboronic acid was used instead of 122 mg (1 mmol) of phenylboronic acid, and product analysis was performed. The produced 2- (3-bromo-5-chlorophenyl) biphenyl had a GC yield of 83%. K1 / Kn was as high as 8.

Example 23

In Example 9, the same procedure as in Example 9 was carried out except that 172 mg (1 mmol) of 2-naphthylboronic acid was used instead of 122 mg (1 mmol) of phenylboronic acid, and product analysis was performed. The produced 1-bromo-3-chloro-5- (2-naphthyl) benzene had a GC yield of 80%. K1 / Kn was as high as 6.

Example 24

In Example 9, the same procedure as in Example 9 was carried out except that 123 mg (1 mmol) of 4-pyridineboronic acid was used instead of 122 mg (1 mmol) of phenylboronic acid, and product analysis was performed. The produced 1-bromo-3-chloro-5- (4-pyridyl) benzene had a GC yield of 76%. K1 / Kn was as high as 5.

Comparative Example 1
In Example 9, the same operation as in Example 9 was carried out except that 23 mg (0.04 mmol) of 4,5'-bis (diphenylphosphino) -9,9'-dimethylxanthene (Xantphos) was not added. An object analysis was performed. The produced 3-bromo-5-chlorobiphenyl (product 2) had a GC yield of 6%. K1 / Kn was less than 1, and the selectivity of the monocoupling reaction product was low.

Comparative Example 2
In Example 9, 2-dicyclohexylphosphino-2', 4', 6'instead of 23 mg (0.04 mmol) of 4,5'-bis (diphenylphosphino) -9,9'-dimethylxanthene (Xantphos). -The same procedure as in Example 9 was carried out except that 19 mg (0.04 mmol) of triisopropylbiphenyl (XPhos) was used, and product analysis was performed. The produced 3-bromo-5-chlorobiphenyl (product 2) had a GC yield of 45%. K1 / Kn was less than 1, and the selectivity of the monocoupling reaction product was low.

Comparative Example 3
In Example 9, instead of 4.5 mg (0.02 mmol) of palladium acetate, 9.2 mg (0.01 mmol, 0.02 mmol of Pd atom, compound 2) of tris (dibenzylideneacetone) dipalladium (0) was used. 4,5'-bis (diphenylphosphino) -9,9'-dimethylxanthene (Xantphos) 23 mg (0.04 mmol) instead of 4,4'-di-tert-butyl The same procedure as in Example 9 was carried out except that 11 mg (0.04 mmol) of −2,2′-bipyridyl (dtbpy) was used, and product analysis was performed. The produced 3-bromo-5-chlorobiphenyl (product 2) had a GC yield of 40%. K1 / Kn was less than 1, and the selectivity of the monocoupling reaction product was low.

Comparative Example 4
In Example 9, triphenylphosphine (PPh3) 11 mg (0.04 mmol) is used in place of 23 mg (0.04 mmol) of 4,5'-bis (diphenylphosphino) -9,9'-dimethylxanthene (Xantphos). Except for the above, the same operation as in Example 9 was carried out to analyze the product. The produced 3-bromo-5-chlorobiphenyl (product 2) had a GC yield of 41%. K1 / Kn was less than 1, and the selectivity of the monocoupling reaction product was low.

Comparative Example 5
In Example 9, tri-tert-butylphosphonium tetrafluoroborate 12 mg (0.04 mmol) instead of 4,5'-bis (diphenylphosphino) -9,9'-dimethylxanthene (Xantphos) 23 mg (0.04 mmol). ) Was used, and the same operation as in Example 9 was performed to analyze the product. The produced 3-bromo-5-chlorobiphenyl (product 2) had a GC yield of 9%. K1 / Kn was less than 1, and the selectivity of the monocoupling reaction product was low.

Comparative Example 6
In Example 9, 2- (dicyclohexylphosphino) -3,6-dimethoxy-2 instead of 23 mg (0.04 mmol) of 4,5'-bis (diphenylphosphino) -9,9'-dimethylxanthene (Xantphos) Product analysis was performed in the same manner as in Example 9 except that 22 mg (0.04 mmol) of', 4', 6'-triisopropyl-1.1'biphenyl (BretPhos) was used. The produced 3-bromo-5-chlorobiphenyl (product 2) had a GC yield of 3%. K1 / Kn was less than 1, and the selectivity of the monocoupling reaction product was low.

According to the present invention, it is possible to efficiently synthesize an aromatic compound containing a target halogen group by performing a monocoupling reaction with good selectivity using an inexpensive industrial raw material. The obtained aromatic compound containing a halogen group can be further reacted with the remaining halogen group to obtain an organic compound that can be used in a wide range of applications such as pharmaceuticals, agricultural chemicals, and electronic materials.

Claims (6)

A method for producing a halogen compound represented by the following general formula (1), wherein the transition metal compound and the phosphine compound are 1,1'-bis (diphenylphosphino) ferrocene or 4,5'-bis (diphenylphosphino). In the presence of -9,9'-dimethylxanthene and a base, the compound represented by the following general formula (2) is reacted with the compound represented by the following general formula (3). The method for producing a halogen compound represented by (1).

(In the formula, Ar ¹ and Ar ² each independently represent an organic group having 1 to 40 carbon atoms. X represents the same halogen group. Z represents a halogen group different from X, and Z When there are a plurality of halogen groups, they are the same or different halogen groups. M represents an integer of 0 or more. P represents an integer of 1 or more. R is an independent hydrogen atom and 1 to 1 carbon atoms. Representing an alkyl group or a phenyl group of 4, the two Rs may be linked to form a ring containing an oxygen atom and a boron atom.) Ar ¹ is a phenyl group, a methylphenyl group, a hydroxyphenyl group, a methoxyphenyl group, a methoxycarbonylphenyl group, a biphenylyl group, a pyridylphenyl group, an anthryl group, a phenylanthryl group, a phenanthryl group, 9,9-dimethylfluore. Nyl group, naphthyl group, quinolyl group, pyridyl group, methylpyridyl group, ethylpyridyl group, phenylpyridyl group, bipyridyl group, thienyl group, carbazolyl group, 9-phenylcarbazolyl group, 9- (4-biphenylyl) carbazolyl group , The production method according to claim 1, which is a dibenzofuranyl group or dibenzothienyl. Ar ² is phenyl group, methylphenyl group, biphenylryl group, pyridylphenyl group, anthryl group, phenylanthryl group, phenanthryl group, 9,9-dimethylfluorenyl group, naphthyl group, quinolyl group, pyridyl group, methyl. Claims to be a pyridyl group, an ethylpyridyl group, a phenylpyridyl group, a bipyridyl group, a thienyl group, a carbazolyl group, a 9-phenylcarbazolyl group, a 9- (4-biphenylyl) carbazolyl group, a dibenzofuranyl group, or a dibenzothienyl group. The manufacturing method according to 1. The manufacturing method according to claim 1, wherein p is 1 or 2. The manufacturing method according to claim 1, wherein m is 0, 1 or 2. (I) X is all bromine groups and Z is all chlorine groups, or (ii) X is all iodine groups and Z is each independently chlorine group or bromine group. The manufacturing method described.