JP2014162732A - Trifluoromethylation agent powder, production method thereof, and production method of trifluoromethyl group-containing compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a trifluoromethylation agent powder stable at room temperature and useful as a reaction reagent and a production method thereof, and a production method of trifluoromethyl group-containing compound.SOLUTION: A zinc powder is reacted with a trifluoromethyl iodide in a N,N-dimethylformamide solvent, and it is filtrated and concentrated to obtain a trifluoromethylation agent powder represented by general formula (1) that is (CF)ZnI (DMPU)(1), where DMPU represents N,N-dimethyl propylene urea and n represents an integer of 1 to 4, then it is reacted with substituted aromatic iodide in a presence of copper (I) catalyst to obtain a trifluoromethyl group-containing compound.

Description

  The present invention relates to an easily handled trifluoromethylating agent powder prepared from trifluoromethyl iodide, zinc and N, N-dimethylpropyleneurea (hereinafter abbreviated as DMPU), a method for producing the same, and a trimethylation product using the same. The present invention relates to a method for producing a fluoromethyl group-containing compound. A trifluoromethyl group-containing compound is a useful compound as a synthetic intermediate for medical and agricultural chemicals and electronic materials.

As a conventional technique, as a trifluoromethylating agent for a solid powder, (CF ₃ ) ZnBr · (DMF) ₂ prepared from trifluoromethyl bromide, zinc and N, N-dimethylformamide (hereinafter abbreviated as DMF) is available. It is known (Non-Patent Document 1).

M.M.Kremlev, et.al., Journal of Fluorine Chemistry, 131, 212-216 (2010).

(CF ₃ ) ZnBr · (DMF) ₂ described in Non-Patent Document 1 can be handled as a stable powder at room temperature, but when used as a trifluoromethylating agent in the presence of a copper (I) catalyst The introduction reaction of a pentafluoroethyl group accompanying the generation of difluorocarbene occurs as a side reaction, and the product becomes a mixture of a trifluoromethylated product and a pentafluoroethylated product.

  Further, trifluoromethyl bromide used in Non-Patent Document 1 is a production / import prohibited substance and is a compound that is difficult to obtain industrially.

As a result of intensive studies on a method for solving the above problems, the present inventors have found that (CF ₃ ) ZnI · (DMPU) _n prepared from industrially available trifluoromethyl iodide, zinc and DMPU is room temperature. It is stable and applicable to various trifluoromethylation reactions. Further, when the powder is used to react with an aromatic iodide, a compound having a pentafluoroethyl group introduced is produced, and by-products are produced. It has been found that there is almost nothing, and the present invention has been completed.

That is, the present invention
[1] The following general formula (1)
(CF ₃ ) ZnI. (DMPU) _n (1)
(In the formula, DMPU represents N, N-dimethylpropylene urea, and n represents an integer of 1 to 4).
A trifluoromethylating agent powder represented by:
[2] A trifluoromethylating agent powder represented by the general formula (1) of Item 1, wherein n is a mixture of 1 to 4.
[3] A trifluoromethylating agent powder represented by the general formula (1) of item 1, wherein n is 2.
[4] Any one of Items 1 to 3, wherein N, N-dimethylpropylene urea, zinc powder and trifluoromethyl iodide are reacted in an N, N-dimethylformamide solvent, followed by filtration and concentration. A method for producing a powder of a trifluoromethylating agent represented by the general formula (1) according to claim 1.
[5] The trifluoromethylating agent powder represented by the general formula (1) according to any one of items 1 to 3, and the following general formula (2)

(In the formula, A represents a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, a linear, branched or cyclic alkyl group having 3 to 6 carbon atoms, a methoxy group, an ethoxy group, or a C3 to 6 carbon atoms. A linear, branched or cyclic alkoxy group, a methoxycarbonyl group or an ethoxycarbonyl group, and B represents a carbon atom or a nitrogen atom)
The substituted phenyl iodide represented by the following general formula (3) is reacted in the presence of a copper (I) catalyst:

(Wherein A and B are the same as above)
The manufacturing method of the trifluoromethyl group containing compound represented by these is provided.

  According to the present invention, an industrially usable trifluoromethylating agent powder is provided.

  Hereinafter, embodiments of the present invention will be described.

Specifically, (CF ₃ ) ZnI · (DMPU) _n represented by the general formula (1) of the present invention is, for example, trifluoromethyl zinc iodide, N, N-dimethylpropylene urea complex, trifluoromethyl zinc iodide.・ (N, N-dimethylpropylene urea) ₂ complex, trifluoromethyl zinc iodide. (N, N-dimethylpropylene urea) ₃ complex, trifluoromethyl zinc iodide. (N, N-dimethylpropylene urea) ₄ complex are shown. Also shown are mixtures of each of these.

(CF ₃ ) ZnI · (DMPU) _n represented by the general formula (1) of the present invention supplies trifluoromethyl iodide to a DMF solvent in which DMPU and zinc powder are added and suspended, and reacts for a predetermined time. Then, the residue is filtered off, the resulting solution is concentrated and dried, and if necessary, it is washed with a solvent inert to the trifluoromethylating agent and dried.

In the production of (CF ₃ ) ZnI · (DMPU) _n represented by the general formula (1) of the present invention, the trifluoromethyl iodide is preferably in an amount of 1.1 to 5.0 moles relative to the zinc powder. Is used in an amount of 1.5 to 4.0 moles.

In the production of (CF ₃ ) ZnI · (DMPU) _n represented by the general formula (1) of the present invention, DMPU to be used is 1.1 to 5.0 mol, preferably 1 with respect to zinc powder. Used in an amount of 5 to 4.0 moles.

In the production of (CF ₃ ) ZnI · (DMPU) _n represented by the general formula (1) of the present invention, the N, N-dimethylformamide used is 5 to 200 times by weight, preferably 10 Use up to 100 times by weight.

In the production of (CF ₃ ) ZnI · (DMPU) _n represented by the general formula (1) of the present invention, the reaction temperature and time are in the temperature range of −40 to 40 ° C., and the reaction time is 1 to 100 hours. . When the reaction is performed at a reaction temperature of −20 ° C. or higher, the reaction may be performed in a pressurized system because the boiling point of the trifluoromethyl iodide used is −22.5 ° C.

As a post-treatment of the production of (CF ₃ ) ZnI · (DMPU) _n represented by the general formula (1) of the present invention, for example, the residue is separated by filtration in a nitrogen or argon stream and reduced in pressure at 50 ° C. or lower. Concentrated and dried, washed with 1 to 20 times by weight of ether or hexane, and dried to give (CF ₃ ) ZnI · (DMPU) _n represented by the general formula (1) as a white to slightly yellow powder obtain.

  Specific examples of the substituted phenyl iodide represented by the general formula (2) of the present invention include 2-fluorophenyl iodide, 3-fluorophenyl iodide, 4-fluorophenyl iodide, 2-chlorophenyl iodide. 3-chlorophenyl iodide, 4-chlorophenyl iodide, 2-bromophenyl iodide, 3-bromophenyl iodide, 4-bromophenyl iodide, 2-methylphenyl iodide, 3-methylphenyl iodide, 4 -Methylphenyl iodide, 2-ethylphenyl iodide, 3-ethylphenyl iodide, 4-ethylphenyl iodide, 4-n-propylphenyl iodide, 4-iso-propylphenyl iodide, 4-cyclopropylphenyl Iodide, 4-n-butylphenyl iodide, 4-iso-butylphenol Luiozide, 4-tert-butylphenyl iodide, 4-n-pentylphenyl iodide, 4-cyclopentylphenyl iodide, 4-n-hexylphenyl iodide, 4-cyclohexylphenyl iodide, 2-methoxyphenyl iodide, 3-methoxyphenyl iodide, 4-methoxyphenyl iodide, 2-ethoxyphenyl iodide, 3-ethoxyphenyl iodide, 4-ethoxyphenyl iodide, 4-n-propoxyphenyl iodide, 4-iso-propoxyphenyl Iodide, 4-cyclopropoxyphenyl iodide, 4-n-butoxyphenyl iodide, 4-iso-butoxyphenyl iodide, 4-tert-butoxyphenyl iodide, 4-n-bentoxyphenyl iodide, 4- Cyclopentoxyphenyliod 4-n-hexyloxyphenyl iodide, 4-cyclohexyloxyphenyl iodide, methyl 2-iodobenzoate, methyl 3-iodobenzoate, methyl 4-iodobenzoate, ethyl 2-iodobenzoate, 3- Examples include ethyl iodobenzoate, ethyl 4-iodobenzoate, 2-iodopyridine, and 5-bromo-2-iodopyridine.

  Specific examples of the trifluoromethyl group-containing compound represented by the general formula (3) of the present invention include 2-fluorobenzotrifluoride, 3-fluorobenzotrifluoride, 4-fluorobenzotrifluoride, 2-fluorobenzotrifluoride, Chlorobenzotrifluoride, 3-chlorobenzotrifluoride, 4-chlorobenzotrifluoride, 2-bromobenzotrifluoride, 3-bromobenzotrifluoride, 4-bromobenzotrifluoride, 2-methylbenzotrifluoride, 3-methyl Benzotrifluoride, 4-methylbenzotrifluoride, 2-ethylbenzotrifluoride, 3-ethylbenzotrifluoride, 4-ethylbenzotrifluoride, 4-n-propylbenzotrifluoride, 4-iso-propyl base Zotrifluoride, 4-cyclopropylbenzotrifluoride, 4-n-butylbenzotrifluoride, 4-iso-butylbenzotrifluoride, 4-tert-butylbenzotrifluoride, 4-n-pentylbenzotrifluoride, 4- Cyclopentylbenzotrifluoride, 4-n-hexylbenzotrifluoride, 4-cyclohexylbenzotrifluoride, 2-methoxybenzotrifluoride, 3-methoxybenzotrifluoride, 4-methoxybenzotrifluoride, 2-ethoxybenzotrifluoride, 3-ethoxybenzotrifluoride, 4-ethoxybenzotrifluoride, 4-n-propoxybenzotrifluoride, 4-iso-propoxybenzotrifluoride, 4-cyclop Poxybenzotrifluoride, 4-n-butoxybenzotrifluoride, 4-iso-butoxybenzotrifluoride, 4-tert-butoxybenzotrifluoride, 4-n-bentoxybenzotrifluoride, 4-cyclopentoxybenzotrifluoride 4-n-hexyloxybenzotrifluoride, 4-cyclohexyloxybenzotrifluoride, methyl 2-trifluoromethylbenzoate, methyl 3-trifluoromethylbenzoate, methyl 4-trifluoromethylbenzoate, 2-trifluoro Examples include methyl methylbenzoate, ethyl 3-trifluoromethylbenzoate, ethyl 4-trifluoromethylbenzoate, 2-trifluoromethylpyridine, 5-bromo-2-trifluoromethylpyridine, and the like.

  The method for producing a trifluoromethyl group-containing compound represented by the general formula (3) of the present invention includes a trifluoromethylating agent powder represented by the general formula (1) in a solvent inert to the reaction, the general formula The substituted phenyl iodide represented by (2) and copper (I) chloride are charged, and the reaction is carried out for a predetermined temperature, time.

  In the production of the trifluoromethyl group-containing compound represented by the general formula (3) of the present invention, the amount of the trifluoromethylating agent powder represented by the general formula (1) is used as the general formula (2) to be used. Is used in an amount of 1.0 to 3.0 moles relative to the substituted phenyl iodide.

  The solvent that can be used in the production of the trifluoromethyl group-containing compound represented by the general formula (3) of the present invention is not particularly limited as long as it is inert to the reaction, but N, N-dimethylformamide, dimethyl Aprotic polar solvents such as sulfoxide, N-methylpyrrolidone, and N, N′-dimethylpropyleneurea are preferable, and 1 to 50 weight based on the substituted phenyl iodide represented by the general formula (2) used in the reaction. Use double the amount.

  As the copper (I) catalyst used in the production of the trifluoromethyl group-containing compound represented by the general formula (3) of the present invention, specifically, for example, copper (I) chloride, copper (I) bromide, Examples thereof include copper iodide (I) and trifluoromethanesulfonyl copper (I), and are used in an amount of 0.1 to 30 mol% based on the substituted phenyl iodide represented by the general formula (2) used in the reaction.

  The reaction temperature and time for producing the trifluoromethyl group-containing compound represented by the general formula (3) of the present invention are usually within a temperature range of 30 to 80 ° C. and a reaction time of 12 to 48 hours.

  The post-treatment after the production of the trifluoromethyl group-containing compound represented by the general formula (3) of the present invention can be carried out by a method known in the art. For example, 5% hydrochloric acid is added, extracted with ether, and sodium sulfate. A crude trifluoromethylbenzene derivative represented by the general formula (3) is obtained by drying, filtration and concentration, and further, if necessary, purification by distillation, purification by silica gel column chromatography, etc. may be performed. .

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited only to these examples.
Example 1 Preparation of Trifluoromethylzinc Iodide / (Dimethylpropylene Urea) _n Complex A 20 ml round bottom two-necked flask equipped with a stirrer was charged with zinc powder (an unactivated product made by Aldrich, 654 mg, 10 mmol) under an argon stream. ), DMPU (2.4 ml, 20 mmol) and DMF (7 ml) were charged to −20 ° C. Next, trifluoromethyl iodide (about 8.0 g) was bubbled into this, then returned to room temperature, and reacted at the same temperature for 24 hours. After completion of the reaction, unreacted zinc powder was filtered off under an argon stream and then concentrated under reduced pressure to obtain a crude product as a pale yellow solid. The obtained crude product was washed three times with toluene under an argon stream to obtain a white solid trifluoromethyl zinc iodide · (DMPU) ₂ complex [(CF ₃ ) ZnI · (DMPU) ₂ ].
¹⁹ F-NMR (282 MHz, DMF-d ₇ ) δ-42.9 (s), -44.6 (s) (benzotrifluoride internal standard: -63.24). In addition, (CF ₃ ) ZnI · (DMPU) ₂ became the following equilibrium state in the DMF-d ₇ solvent, and was detected as two peaks.

In addition, in microTOF (MS-ESI) measurement, a peak of 517.2888 (M ⁺ , m / e) attributed to (CF ₃ ) ZnI · (DMPU) ₂ was obtained (calculated value 517.6490).

In the DSC measurement, an exothermic peak was observed at 100 to 155 ° C. (Top: 137 ° C.), and the thermal stability was stable at 100 ° C. or less.

Example 2 Production of ethyl 2-trifluoromethylbenzoate Trifluoromethylzinc iodide (DMPU) ₂ complex (160 mg, 0.2 mmol) and iodine prepared in Example 1 in a test tube equipped with a stir bar and a septum cap Copper (I) chloride (1.9 mg, 0.01 mmol) was charged, and argon substitution was performed three times. Next, a solution of ethyl 2-iodobenzoate (16.6 μl, 0.1 mmol) in DMPU (0.2 ml) was added, the septum cap was replaced with a screw cap, and the mixture was sealed, followed by reaction at 50 ° C. for 24 hours. After completion of the reaction, the reaction solution was quantified by ¹⁹ F-NMR (benzotrifluoride internal standard). As a result, ethyl 2-trifluoromethylbenzoate was produced in a yield of 80%.

Example 3 Production of 4-bromo-2-trifluoromethylpyridine Except for replacing 2-iodobenzoic acid in Example 2 with 4-bromo-2-iodopyridine (28.4 mg, 0.1 mmol), The same operation as in Example 2 was performed to obtain 4-bromo-2-trifluoromethylpyridine in a yield of 75%.

  According to the present invention, a trifluoromethylating agent powder that is stable at room temperature and easy to handle can be proposed, and various trifluoromethyl group-containing compounds can be produced industrially using the powder.

Claims (5)

The following general formula (1)
(CF ₃ ) ZnI. (DMPU) _n (1)
(In the formula, DMPU represents N, N-dimethylpropylene urea, and n represents an integer of 1 to 4).
A trifluoromethylating agent powder represented by: A trifluoromethylating agent powder represented by the general formula (1) of claim 1, wherein n is a mixture of 1 to 4. A trifluoromethylating agent powder represented by the general formula (1) of claim 1, wherein n is 2. 4. The N, N-dimethylformamide solvent is reacted with N, N-dimethylpropylene urea, zinc powder and trifluoromethyl iodide, and then filtered and concentrated. A method for producing a trifluoromethylating agent powder represented by the general formula (1) according to item 1. The trifluoromethylating agent powder represented by the general formula (1) according to any one of claims 1 to 3, and the following general formula (2)

(In the formula, A represents a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, a linear, branched or cyclic alkyl group having 3 to 6 carbon atoms, a methoxy group, an ethoxy group, or a C3 to 6 carbon atoms. A linear, branched or cyclic alkoxy group, a methoxycarbonyl group or an ethoxycarbonyl group, and B represents a carbon atom or a nitrogen atom)
The substituted phenyl iodide represented by the following general formula (3) is reacted in the presence of a copper (I) catalyst:

(Wherein A and B are the same as above)
The manufacturing method of the trifluoromethyl group containing compound represented by these.