JP2008239544A - Method for producing aryl ether compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an industrially suitable method for producing an aryl ether compound capable of producing an aryl ether compound under mild conditions and without requiring a complicated operation. is there.
An object of the present invention is to react an aryl halide, a hydroxy compound and a phosphazene compound in the absence of a silylating agent and under mild conditions without requiring a complicated operation, thereby to produce an aryl ether. It is solved by producing the compound.
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Description

The present invention relates to a method for producing an aryl ether compound by reacting an aryl halide with an alcohol or a hydroxy compound such as hydroxyaryl and a phosphazene compound.
Aryl ether compounds are compounds used in many fields, such as physiologically active substances such as pharmaceuticals and agricultural chemicals, and other synthetic raw materials (see, for example, Non-Patent Document 1).

Nicolaou.K.C., Boddy.C.N.C .; J.Am.Chem.Soc. 2002,124,10451.

  Conventionally, as a method for obtaining an aryl ether compound, it has been common to use phenols and irritating alkyl halides or highly toxic alkyl sulfates. However, these have not been fully satisfactory as a safe and industrial production method (see, for example, Non-Patent Document 2).

On the other hand, as a method for obtaining an aryl ether compound by reacting an aryl halide with a hydroxy compound, a reaction in which a hydroxy compound is once converted to a metal salt with an alkali metal such as sodium and copper halide (for example, For example, the reaction performed using metal catalysts, such as palladium, is known (for example, refer nonpatent literature 4).
More recently, as a method for obtaining an aryl ether compound, a reaction of a phosphazene compound in the presence of a silylating agent, for example, 1-fluoro-2-nitrobenzene and trimethylsilyloxyphenol in 1 N-N-dimethylformamide in 1-tert. - butyl-4,4,4-tris (dimethylamino) -2,2'-bis [tris (dimethylamino) phosphoranylidene two isopropylidene amino] -2Λ ^5, 4Λ ⁵ - Katenaji (phosphazene) (hereinafter, t- butyl - A method for producing 1- (4-methoxyphenoxy) -2-nitrobenzene by reacting in the presence of P4 phosphazene) has been reported (for example, see Non-Patent Document 5). However, in this method, in order to obtain the desired product in good yield, aryl fluoride or an aryl halide having an electron withdrawing group at the 2-position or 4-position is used as a starting material. In order to carry out the reaction after silylation, a silylating agent must be added, which is disadvantageous industrially as a method for producing an aryl ether compound.

R.C.Larock, Comprehensive Organic Transformations.Second edition, 1999, John Wiley & Sons, Inc. J. Am. Chem. Soc., 2005, 127, 8146 Tefrahedron, Vol. 48, No. 17, pp. 3633 (1992) Eur.J.Org.Chem., 2005,1965

  An object of the present invention is to solve the above-mentioned problems, and in the absence of a silylating agent and under mild conditions, without requiring complicated operation, an aryl halide, a hydroxy compound, and a phosphazene compound It is an object to provide an industrially suitable method for producing an aryl ether compound, in which an aryl ether compound can be produced.

  In the absence of a silylating agent, general formula (1)

(In the formula, Ar represents an aryl group, and X represents a halogen atom.)
An aryl halide represented by the general formula (2)

（式中、Ｒは置換基を有していてもよい、炭化水素基又は複素環基を示す。）

(In the formula, R represents a hydrocarbon group or a heterocyclic group which may have a substituent.)

Characterized by reacting a hydroxy compound represented by the above and a phosphazene compound,
General formula (3)

(In the formula, Ar and R are as defined above.)

It is solved by the manufacturing method of the aryl ether compound shown by these.

  According to the present invention, an aryl ether compound is produced by reacting an aryl halide, a hydroxy compound, and a phosphazene compound in the absence of a silylating agent, under mild conditions and without requiring complicated operation. An industrially suitable production method can be provided.

  The aryl halide used in the reaction of the present invention is represented by the general formula (1). In the general formula (1), Ar represents an aryl group which may have a substituent, for example, an aromatic hydrocarbon group such as phenyl group, naphthyl group, anthryl group, phenanthryl group; quinolyl group, pyridyl A heterocyclic aromatic group such as a group is shown. X is a halogen atom, and represents, for example, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

  The aryl group may have a substituent. Examples of the substituent include a substituent formed through a carbon atom, a substituent formed through an oxygen atom, a substituent formed through a nitrogen atom, and a substituent formed through a sulfur atom.

  Examples of the substituent formed through the carbon atom include alkyl groups such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group; a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cyclo group. Cycloalkyl groups such as heptyl group; Alkenyl groups such as vinyl group, allyl group, propenyl group, cyclopropenyl group, cyclobutenyl group, cyclopentenyl group; quinolyl group, pyridyl group, pyrrolidyl group, pyrrolyl group, furyl group, thienyl group, etc. A heterocyclic group of: aryl group such as phenyl group, tolyl group, fluorophenyl group, xylyl group, biphenyl group, naphthyl group, anthranyl group, phenanthryl group; acetyl group, propionyl group, acryloyl group, pivaloyl group, cyclohexylcarbonyl group, Benzoyl group, naphthoyl Group, (may be acetalized) acyl groups such as toluoyl group; a methoxycarbonyl group, an alkoxycarbonyl group such as methoxycarbonyl group and ethoxycarbonyl group; a cyano group; an aryloxycarbonyl group such as phenoxycarbonyl group. These groups include various isomers.

  Examples of the substituent formed through the oxygen atom include a hydroxyl group; an alkoxyl group such as a methoxyl group, an ethoxyl group, a propoxyl group, a butoxyl group, a pentyloxyl group, a hexyloxyl group, a heptyloxyl group, and a benzyloxyl group; Aryloxyl groups such as phenoxyl group, toluyloxyl group, naphthyloxyl group and the like can be mentioned. These groups include various isomers.

  Examples of the substituent formed through the nitrogen atom include a primary amino group such as a methylamino group, an ethylamino group, a propylamino group, a butylamino group, a cyclohexylamino group, a phenylamino group, and a naphthylamino group; Secondary amino group such as amino group, diethylamino group, dipropylamino group, dibutylamino group, methylethylamino group, methylpropylamino group, methylbutylamino group, diphenylamino group, N-methyl-N-methanesulfonylamino group A morpholino group, a piperidino group, a piperazinyl group, a pyrazolidinyl group, a pyrrolidino group, an indolyl group or the like; an imino group; These groups include various isomers.

  Examples of the substituent formed through the sulfur atom include a mercapto group; a thioalkoxyl group such as a thiomethoxyl group, a thioethoxyl group, and a thiopropoxyl group; a thiophenoxyl group, a thiotoluyloxyl group, and a thionaphthyloxyl group. Thioaryloxyl group and the like. These groups include various isomers.

  The hydroxy compound used in the reaction of the present invention is represented by the general formula (2). In the general formula (2), R represents a hydrocarbon group or a heterocyclic group which may have a substituent. Examples of the hydrocarbon group include a linear alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group; a branched alkyl group such as a 2-propyl group and a 2-butyl group; a cyclopentyl group. And cycloalkyl groups such as cyclohexyl group; aralkyl groups such as benzyl group, phenethyl group, and phenylpropyl group; aryl groups such as phenyl group, tolyl group, biphenylyl group, and naphthyl group. Examples of the heterocyclic group include tetrahydropyrani group. An alicyclic heterocyclic group such as a thio group and a tetrahydrothiopyranyl group; and an aromatic heterocyclic group such as a pyridyl group, a furyl group and a thienyl group. These groups include various isomers.

  The hydroxy compound may have a substituent. Examples of the substituent include a substituent formed through a carbon atom, a substituent formed through an oxygen atom, a substituent formed through a nitrogen atom, and a substituent formed through a sulfur atom. These substituents are synonymous with those represented by the aryl group which may have the substituent.

The amount of the hydroxy compound to be used is preferably 1 mol to 100 mol, more preferably 1 mol to 10 mol, per 1 mol of the aryl halide.

  The phosphazene compound is a compound having a phosphorus-nitrogen bond, and examples thereof include a commercially available phosphazene compound synthesized by Schwesinger et al. And a proazaphosphatran compound synthesized by Verkade et al. The phosphazene compound used in the reaction of the present invention is preferably a tetrameric phosphazene compound of Schwesinger et al., More preferably t-butyl-P4 phosphazene. (For example, refer nonpatent literature 7).

Sigma Aldrich Reagent Catalog Strong and Hindered Bases in Organic Synthesis, Chemfiles, Vol3, No.1.

  In addition, you may use these phosphazene compounds individually or in mixture of 2 or more types. Moreover, you may use it as it is, or you may use what is melt | dissolved in water or an organic solvent.

  The phosphazene compound is preferably 0.01 to 10 mol, more preferably 1 to 5 mol, per 1 mol of the aryl halide.

  The reaction of the present invention is carried out in the presence or absence of a solvent. The organic solvent to be used is not particularly limited as long as it does not participate in the reaction. For example, aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as toluene and xylene; ethyl acetate and butyl acetate Esters such as tetrahydrofuran; tetrahydropyran, ethers such as 1,4-dioxane; sulfoxides such as dimethyl sulfoxide; sulfones such as sulfolane; N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl Amides such as pyrrolidone; and ureas such as 1,3-dimethyl-2-imidazolidinone. In addition, you may use these organic solvents individually or in mixture of 2 or more types.

  The amount of the organic solvent to be used is preferably 0 to 100 ml, more preferably 0 to 50 ml, with respect to 1 g of aryl halide.

  The reaction of the present invention is performed by, for example, a method of mixing an aryl halide compound, a hydroxy compound, and a phosphazene compound in an organic solvent and reacting them with stirring. The reaction temperature at that time is preferably -20 to 300 ° C, more preferably 0 to 150 ° C, and the reaction pressure is not particularly limited.

  The aryl ether compound can be obtained by the reaction of the present invention, which can be obtained by a general production method such as neutralization, extraction, filtration, concentration, distillation, recrystallization, crystallization, column chromatography after completion of the reaction. Separated and purified.

  Next, the present invention will be specifically described with reference to examples, but the scope of the present invention is not limited thereto.

Example 1 (Synthesis of anisole)
In a glass container having an internal volume of 20 ml equipped with a stirrer and a condenser tube, 0.80 ml (7.6 mmol) of bromobenzene, 0.026 ml (0.64 mmol) of methanol and 1-mol / L t-butyl-P4 phosphazene n- A hexane solution (manufactured by Fluka) (1.3 ml, 1.3 mmol) was added, and the mixture was reacted at 80 ° C. for 5 hours with stirring. After completion of the reaction, methanol and 6 mol / L hydrochloric acid were added to the reaction solution and then analyzed by high performance liquid chromatography (absolute calibration method). As a result, 59 mg of anisole was produced (reaction yield; 85%).

Example 2 (Synthesis of diphenyl ether)
In a glass container having an internal volume of 20 ml equipped with a stirrer, a thermometer and a condenser, 0.134 ml (1.27 mmol) of bromobenzene, 0.128 g (1.36 mmol) of phenol, 1 mol / L t-butyl- An n-hexane solution of P4 phosphazene (manufactured by Fluka) 2.55 ml (2.55 mmol) and 0.8 ml of xylene were mixed and reacted at 100 ° C. for 5 hours with stirring. After completion of the reaction, 50 ml of ethyl acetate was added to the reaction solution, washed 3 times with 20 ml of water and once with 20 ml of saturated brine, and then the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (developing solvent: hexane) to obtain 0.160 g of diphenyl ether as a colorless liquid (isolation yield: 70%).
CI-MS (m / z); 171 (M + 1)
¹ H-NMR (CDCl ₃ , δ (ppm)); 6.98 to 7.03 (4H, m), 7.06 to 7.12 (2H, m), 7.29 to 7.36 (4H, m)

Example 3 (Synthesis of benzyl phenyl ether)
In a 20 ml glass container equipped with a stirrer, thermometer and condenser, chlorobenzene 0.450 ml (4.44 mmol), benzyl alcohol 0.460 ml (4.45 mmol), 1 mol / L t-butyl-P4 phosphazene N-hexane solution (manufactured by Fluka) 8.88 ml (8.88 mmol) and 2 ml of toluene were mixed and reacted at 100 ° C. for 5 hours with stirring. After completion of the reaction, 50 ml of toluene was added to the reaction solution, washed 3 times with 30 ml of water and once with 30 ml of saturated saline, and then the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (developing solvent; hexane / toluene = 70/30) to obtain 0.260 g of benzyl phenyl ether as a colorless liquid (isolation yield: 32%).
CI-MS (m / z); 185 (M + 1)
¹ H-NMR (CDCl ₃ , δ (ppm)); 5.07 (2H, s), 6.93 to 7.01 (3H, m), 7.25 to 7.46 (7H, m)

  The present invention relates to a method for producing an aryl ether compound by reacting an aryl halide, a hydroxy compound and a phosphazene compound. Aryl ether compounds are useful compounds as raw materials for pharmaceuticals and agricultural chemicals and synthetic intermediates, for example.

Claims (3)

In the absence of a silylating agent, general formula (1)

(In the formula, Ar represents an aryl group which may have a substituent, and X represents a halogen atom.)
An aryl halide represented by the general formula (2)

(In the formula, R represents a hydrocarbon group or a heterocyclic group which may have a substituent.)
Characterized by reacting a hydroxy compound represented by the above and a phosphazene compound,
General formula (3)

(In the formula, Ar and R are as defined above.)
The manufacturing method of the aryl ether compound shown by these.   The method for producing an aryl ether compound according to claim 1, wherein the phosphazene compound is a tetrameric phosphazene compound. The tetrameric phosphazene compound is represented by 1-tert-butyl-4,4,4-tris (dimethylamino) -2,2′-bis [tris (dimethylamino) phosphoranylideneamino] -2Λ ⁵ , 4Λ ⁵ -catenadi ( The method for producing an aryl ether compound according to claim 1 or 2, which is phosphazene).