JP2564141B2 - Method for producing alkylbenzothiazoles - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial field of application] The present invention provides compounds of formula (I) (In the formula, R is a hydroxyl group, an amino group, an aldehyde group, an acyl group, a carboxyl group, an alkoxyl group having 1 to 3 carbon atoms, a lower alkyl group, a lower halogenated alkyl group, a halogen atom or a hydrogen atom, and R ¹ is an alkyl group. A group or a substituted alkyl group) is shown. This compound is industrially useful as a raw material for medicines, agricultural chemicals, dyes, antioxidants, resin stabilizers, and the like.

[Prior Art] Conventionally, alkylbenzothiazoles are usually synthesized by a condensation reaction between 2-aminothiophenol and a carboxylic acid or a derivative thereof.

On the other hand, as a separate method for producing alkylbenzothiazoles, 1-amino-2-
A method of direct synthesis by reaction of halobenzenes and thioamide can be considered.

However, when performing the latter separate method,
There are some problems. That is, conventionally, a method of reacting an alkyl halide with thioamide to synthesize isothioamide has been known. As is well known, the reactivity of the alkyl halides is good, but the reactivity of the sp ² C-halogen bond is low. Therefore, the use of 1-amino-2-halobenzenes in organic synthesis is considerably limited. Has been done.

Therefore, instead of the alkyl halide described above, 1
A method for synthesizing alkylbenzothiazoles by directly reacting amino-2-halobenzenes with thioamide has been tried, but the nucleophilic substitution reaction does not occur because the halogen bonded to the aromatic ring is inactive. Because of this, the situation is not yet completed.

[Problems to be Solved by the Invention] As a result of conducting research in view of such conventional techniques, the present inventor has found that a palladium complex is used as a catalyst in a reaction between 1-amino-2-halobenzenes and thioamides. It was found that the use of the compound facilitates the reaction to proceed under mild conditions, and the alkylbenzothiazoles can be obtained in a high yield via the isothioamide intermediate, resulting in the completion of the present invention. .

[Means for Solving the Problems] That is, the present invention provides the formula (II) (In the formula, X is a halogen atom, R is a hydroxyl group, an amino group, an aldehyde group, an acyl group, a carboxyl group, and 1 carbon atom.
~ 3 alkoxyl group, lower alkyl group, lower halogenated alkyl group, halogen atom or hydrogen atom), and 1-amino-2-halobenzenes represented by the formula (III) Wherein thioamides represented by the formula (wherein R ¹ represents an alkyl or substituted alkyl group) are reacted in the presence of a palladium complex. (Wherein R and R ¹ have the above-mentioned meanings).

 Hereinafter, the present invention will be described in detail.

The method for producing alkylbenzothiazoles according to the present invention is represented by the following reaction formula.

First, the present invention provides 1-amino-2-halobenzenes represented by the formula (II), which are inactive and do not undergo a nucleophilic substitution reaction, which bond to an aromatic ring, by the reaction represented by the above reaction formula (A), The palladium complex is used as a catalyst for activation, and the isothioamide intermediate represented by the formula (IV) is synthesized by a substitution reaction with a thioamide nucleophile.

Then, according to the following reaction formula (B), The alkylbenzothiazoles represented by the formula (I) can be obtained by generating a benzothiazole ring at once through a cyclocondensation reaction initiated by nucleophilic addition of an ortho-position amino group to an imino bond.

As is clear from the above reaction formulas (A) and (B), in the present invention, it is desirable to carry out the reaction by specifying the amounts of 1-amino-2-halobenzenes and thioamides of the raw material system in a fixed ratio. The molar ratio of thioamides to 1-amino-2-halobenzenes
It is desirable to use 1.0 to 3.0 mol, preferably 1.0 to 1.5 mol, and the alkylbenzothiazoles can be selectively produced by reacting the raw material system at this specific ratio.

The 1-amino-2-halobenzenes used as the raw material of the present invention have the formula (II) In the formula, X represents a halogen atom, and iodine or bromine is particularly preferable.

R in the formula is a hydroxyl group, an amino group, an aldehyde group,
An acyl group, a carboxyl group, an alkoxyl group having 1 to 3 carbon atoms, a lower alkyl group, a lower halogenated alkyl group, a substituent such as a halogen atom or a hydrogen atom is shown, and further a substituted carbonyl group, an ester group, a phenyl group, Substituted carboxy group, cyano group, substituted amino group, substituted amide group, hydroxymethyl group, heteroaromatic group (furyl group,
Thienyl group, pyridiyl group, morpholyl group, imidazolyl group, thiazolyl group), methyl trifluoride group, vinyl group,
It may be substituted with a substituent such as a substituted ethynyl group. The position of the substituent of R is 1-amino-depending on the substituent.
It can be provided at any position of the 3,4,5 and 6-positions of the 2-halobenzenes. Moreover, you may provide in multiple positions.

Specific examples of the substituents are shown below. Examples of the alkoxyl group having 1 to 3 carbon atoms include:
Methoxy, ethoxy, propoxy, isopropoxy, lower alkyl groups include methyl, ethyl, propyl, butyl, amyl and their isomers, and substituted amino groups include methylamino, dimethylamino, ethylamino, diethylamino, propylamino. , Butylamino,
Phenylamino, N-methylamide, N-ethylamide, N-phenylamide, NN-dimethylamide, N-methyl-N-phenylamide as the substituted amide group, acetyl, propionyl, butyryl, benzoyl as the acyl group,
Examples of the substituted ethynyl group include allyl, isopropenyl, and 1-propenyl, and examples of the substituted carboxy group include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and phenoxycarbonyl, but the above are specific examples. It is not limited to the substituents.

Next, the thioamides used as the other raw material of the present invention are not only used as a donor of a sulfur atom, but also various substituents substituted by the 2-amino group of 1-amino-2-halobenzenes. Can also be a donor of the formula (III) In the formula, R ¹ represents a substituent of an alkyl group or a substituted alkyl group.

As the alkyl group, a lower alkyl group and a carbon number 6
-10 alkyl groups are preferred, eg methyl, ethyl,
Examples include propyl, butyl, amyl, hexyl, octyl, cyclohexyl groups and their isomers.

The substituted alkyl group is a substituent of R at any position of α, β, ... ω of the alkyl group, that is, a hydroxyl group, an amino group, an aldehyde group, an acyl group, a carboxyl group, and the number of carbon atoms. 1 to 3 shows an alkoxyl group, a lower alkyl group, a lower halogenated alkyl group, a halogen atom or a substituent such as a hydrogen atom. Further, a substituted carbonyl group, an ester group, a cyano group, a phenyl group,
Substituted carboxy group, substituted amino group, substituted amide group, hydroxymethyl group, heteroaromatic group (furyl group, thienyl group, pyridiyl group, morpholyl group, imidazolyl group, thiazolyl group), methyl trifluoride group, vinyl group, substituted Examples thereof include those containing a substituent such as an ethynyl group, but are not limited thereto. Moreover, you may provide a substituent in multiple positions.

Specific examples of the substituents are shown below. Examples of the alkoxyl group having 1 to 3 carbon atoms include:
Methoxy, ethoxy, propoxy, isopropoxy, lower alkyl groups include methyl, ethyl, propyl, butyl, amyl and their isomers, and substituted amino groups include methylamino, dimethylamino, ethylamino, diethylamino, propylamino. , Butylamino,
Phenylamino, N-methylamide, N-ethylamide, N-phenylamide, NN-dimethylamide, N-methyl-N-phenylamide as a substituted amide group, acetyl, propionyl, butyryl, benzoyl as an acyl group,
Examples of the substituted ethynyl group include allyl, isopropenyl, and 1-propenyl, and examples of the substituted carboxy group include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and phenoxycarbonyl, but the above are specific examples. It is not limited to the substituents.

Next, as the catalyst in the present invention, a palladium complex prepared by the following (a) or (b) is used.

(A) The following A, B, and C are combined and prepared in the reaction solution, or a complex is separately synthesized between A and B, and this one and C are combined. Prepare in the reaction solution.

A. (Palladium species) PdX ₂ (X represents a halogen atom, a conjugate base of an organic acid, or acetylacetonate) and the hydrate thereof per mole of B. (ligand) PR ⁵ ₃ (R ⁵ represents each group of methyl, ethyl, butyl, cyclohexyl, phenyl, o-tolyl or p-dimethylaminophenyl) and 0 to 6 molar equivalents.

R ⁶ ₂ P (CH ₂ ) _n PR ⁶ ₂ (R ⁶ , n is phenyl, 1 to 3; methyl, 1
~ 3; ethyl, representing 1-3) 0-3 molar equivalents.

1,1'-bis (diphenylphosphino) ferrocene, 1,
10-phenanthroline, 1,10-phenanthroline-5,6-
Dione, cis-1,2-bis (diphenylphosphino) ethylene, or 1,2-bis (diphenylphosphino)
0-3 molar equivalents of benzene.

0-6 molar equivalents of P (Oph) ₃ . (However, ph represents a phenyl group) NR ⁷ ₃ (R ⁷ is ethyl, shows each group of butyl or cyclohexyl) 0-6 molar equivalents of.

 0-6 molar equivalents of dibenzylideneacetone.

C. (Reducing agent) NaBH ₄ , NaBH ₃ CN, AlEt ₂ (OEt), Al (i-Bu) ₂ H, AlEt ₃ , Z
0 to 6 molar equivalents of n, Na (Hg), Mn (Fe) and hydrazine hydrate (however, Et represents an ethyl group and Bu represents a butyl group) (b) The following D alone or 1 mol of D B of (a) above
Are prepared in the reaction solution by combining one of the above.

D. Pd (dibenzylideneacetone) ₂ , Pd ₂ (dibenzylideneacetone) ₃ · CHCl ₃ , Pd (Pdh ₃ ) ₄ , and the method for preparing the catalyst is either (a) or (b) above. The palladium complex can be easily obtained by preparing each compound selected by the combination in a solvent under an inert gas stream.

Examples of the solvent used for preparing the catalyst include dimethylformamide (DMF), acetonitrile, acetone, 1,4-dioxane, tetrahydrofuran, hexamethylphosphoric triamide (HMPA), dimethyl sulfoxide, N-methyl-
2-pyrrolidone (NMP), tetramethylurea, 1,2-diethoxyethane, benzene, chloroform, toluene,
Methanol, ethanol, n-butanol and the like are preferable.

The amount of the catalyst used in the present invention is 1-amino-2 as a raw material.
0.0001 to 0.5 mol, preferably 0.002 to 0.05 mol per 1.0 mol of halobenzenes is desirable, and if less than 0.0001 mol, the reaction activity is low, and it is not advisable to use a large amount exceeding 0.5 mol.

Further, the reaction of the present invention is preferably carried out in the presence of a base, and as the base, calcium oxide, potassium carbonate, sodium carbonate, NR ₃ (R is a carbon atom number of 1 to 4)
(Which represents an alkyl group of) is desirable. It should be noted that the reaction can be carried out without any problem even in the absence of a base.

Next, as the reaction conditions of the present invention, the reaction temperature varies depending on the raw materials used, but is usually 20 to 100 ° C, preferably 40 to 8
It is better to carry out at 0 ° C. The pressure is usually atmospheric pressure, but it may be applied under pressure.

The reaction time varies depending on the type of raw material and the reaction temperature, but is usually 0.5 to 100 hours, preferably 0.5 to 60 hours, but depending on the type of raw material, the reaction may be carried out for a long time.

The above reaction is preferably carried out in a solvent, and as the solvent, dimethylformamide, N-methylpyrrolidone, acetonitrile, acetone, 1,4-dioxane, tetrahydrofuran, hexamethylphosphoric triamide, dimethyl sulfoxide, tetramethylurea, 1, It is preferable to use 2-dimethoxyethane, benzene, toluene, chloroform, methanol, ethanol, n-butanol and the like.

Further, the reaction is preferably carried out under an inert gas stream,
As the inert gas, nitrogen, helium, argon or the like can be used.

In the reaction of the present invention, 1-amino- is added to a solvent in which the prepared palladium complex of the catalyst is dissolved or dispersed.
After adding the 2-halobenzenes and the thioamides, it is carried out in the presence or absence of a base under an inert gas stream at a predetermined temperature for a predetermined time. After completion of the reaction, the reaction product is isolated by cooling crystallization as it is, or by recovering the objective alkylbenzothiazoles by treatment such as solvent concentration.

[Operation] In the present invention, a palladium complex is used as a catalyst in the reaction between 1-amino-2-halobenzenes and thioamides. It improves the reactivity and enables the substitution reaction of 1-amino-2-halobenzenes with thioamide nucleophiles. Furthermore, the reaction proceeds all at once by the spontaneous cyclization reaction by the amino group at the ortho position, and via the isothioamide intermediate. It is presumed that the alkylbenzothiazoles can be obtained in high yield.

[Examples] Next, the present invention will be described more specifically with reference to Examples.

Example 1 Preparation of 2-methylbenzothiazole In a synthetic flask in a nitrogen stream, 200 ml of solvent dimethylformamide was added to tris (dibenzylideneacetone) (chloroform) dipalladium (0) (abbreviated as Pd ^* ).
002 mol and triphenylphosphine (= PPh ₃ )
0.016 mol was added and dissolved with sufficient stirring. 0.22 mol of calcium oxide, 0 with thorough stirring
After adding 0.2 mol of iodoaniline and 0.22 mol of thioacetamide, warm slowly to 60 ° C. in a water bath. After reacting for 3 hours as it was, it was cooled to room temperature and the insoluble matter was removed with a glass filter. Dimethylformamide was recovered from the solution under reduced pressure, and the residue was analyzed by gas chromatography by the internal standard method. The yield was 99%.
Then, 2-methylbenzothiazole was obtained.

Moreover, the structure was confirmed by a gas chromatography mass spectrometer, an infrared absorption spectrum and the like.

Example 2 Preparation of 2-methylbenzothiazole In a synthetic flask in a nitrogen stream, 400 ml of solvent dimethylformamide was added to 0.001 mol of tris (dibenzylideneacetone) (chloroform) dipalladium (0) and 1,1 '.
0.004 mol of -bis (diphenylphosphino) ferrocene (abbreviated as dPPf) was added and dissolved with sufficient stirring.
0.4 mol of calcium oxide, 0.4 mol of 0-iodoaniline and thioacetamide were added thereto while thoroughly stirring.
After adding 0.4 mol, the mixture was slowly heated to 60 ° C in a water bath. After reacting for 1 hour as it was, it was cooled to room temperature and insoluble matter was passed through a glass filter. Next, after recovering dimethylformamide from the liquid under reduced pressure, the degree of vacuum is
After vacuum distillation at 15 mmHg, 2-methylbenzothiazole was distilled at 150 ° C. The yield was 98%.

Examples 3 to 9 2- (Substituted) alkylbenzothiazoles were used in Example 1
By the same operation as above, the raw materials and reaction conditions shown in Table 1 were synthesized. The yield of the obtained 2- (substituted) alkylbenzothiazoles was determined by gas chromatography internal standard method. Table 1 shows the results.

[Effects of the Invention] Next, the effects of the present invention are listed below.

(1) The present invention is a novel method for producing alkylbenzothiazoles, which comprises using a combination raw material of 1-amino-2-halobenzenes and thioamides, which has not been conventionally used, in the presence of a palladium complex pair catalyst. The reaction proceeds easily and the alkylbenzothiazoles can be obtained in high yield.

(2) In the present invention, as compared with the prior art, the reaction can be easily carried out under normal conditions at room temperature and within 100 ° C. under mild conditions to obtain the desired product.

(3) The objective alkylbenzothiazoles are industrially useful compounds, which are used as raw materials for chemical industrial products such as pharmaceuticals, agricultural chemicals, dyes, antioxidants, resin stabilizers, etc. The industrial value of the present invention, which can be obtained in yield, is extremely high.

Claims (1)

(57) [Claims] 1. A formula (In the formula, X is a halogen atom, R is a hydroxyl group, an amino group, an aldehyde group, an acyl group, a carboxyl group, and 1 carbon atom.
1 to 3, an alkoxyl group, a lower alkyl group, a lower halogenated alkyl group, a halogen atom or a hydrogen atom). (Wherein R ¹ represents an alkyl group or a substituted alkyl group), the thioamides are reacted in the presence of a palladium complex. (In the formula, R and R ¹ have the above-mentioned meanings) A method for producing an alkylbenzothiazole.